Asymnletric Induction in the SYllthesis of
Oxygen-Heterocyclic Compounds by Chiral
Auxiliaries(:f: 7 )~*ffl§)] £~= J: ~'2T M* :f~7f-~~ 1~~ 4mO)~)J~ ~=svt ~/F ~a*~)Ryukichi Takagi

January, 1998

Contents

General Introduction
References
Chapter 1.

............
...........

I

17

Asymmetric Induction in Darzens Condensation

Introduction...........

19

Results and Discussion• •0 • • • • • f ' .

22

Experimental Section• •0 • • • • • 41•

38

Supplementary Material••••••••

54

References• •1 • • • • • • • •67

Chapter 2.

Stereoselectivity in the Formation of 2:,5-Disubstituted
Tetrahydropyran by Intramolecular Hetero-Mlichael Addition

Introduction
Results and Discussion..........

.'.........

71
74

Experimental Section....... ".

Supplementary Material..........

125

References..........

146

List of Publications....... .
'

(

94

ISO

General Introductioll1

General Introduction
Chirality is thc property which do not superimpo

it mirror imagc.

he separat dcnantiomers rotate the plane of polarized light and the sign of the sped ric rotation value orthe each enantiomers is opposite but equal amounl<;. Chirality is a prop rty which often
determines the actions and behavior of the molecules. The world around us i also chiraland most of the important building blocks which make up the biological macromoleculesof living systems do so in onc cnantiomeric form only. When, thereforc, a biologically
active chiral compound, from drag to food, interacts with iL<; receptor site that is chiral, it
is no wonder that those two enantiomers interact dil1erently and may lead to different
effect. A good example is the drug thabdomide for which only (-)-enantiomer has thedesired sedative effect but the racemic mixture causes fetal deformities (Fig 1).
Aspartame, artificial sweetener, is also one of the examples. Only one of the four
stereoisomers, (5,5)-form, is sweet and the other three arc all slightly bitter (Fig 1).
There[ore, the need for enantiopure compounds is rapidly increasing and it is necessary
to design synthetic route of targct molecules so as La obtain not only in ch mically pureform but also in enantiomeric pure [arm.

o

~NVO
~O
H

o

(-)-TIlalidomidc

Fig 1.

(S. S)- Aspartanc

Bioactive chiral conlpounds

Almost all asymmetric reactions are based on a kinetic phenor enon. In reactions
which givc risc to two or more products, the product ratio may be co ltrolled either by the
relative rate of fomlation (kinetic control, Fig 2a) or by the equilibrium constant of the
products (thermodynamic control, Fig 2b) or both. The contribution of the two effects

depends on the relative magnitudes of the activation free en rgies for the [ormation andequilibration o[ the products. On kinetic control, the slereoisom r ratio Cl P211[ PI]) of
products is determined by the free energy differences ( ~C;:f:) he tw en the tran ition
states. On thermodynamic control, the stereoisomer ratio ([P2J/[P 1]) or products isdetermined hy the equilihrium constant K, which in turn depends on the ground state freeenergy difference (~G 12) o[ the stereoisomers.

Pl

S

+

P2

(s: starting material)(a) Kinetic control

k,
PI

S

[P 2J / [P d = k2 / k 1 = Ack2
fl ,;/RTP2- L\( if IRT/ Ae= e - .6.6d IRT(b) Thermodyna.mic control
Ks
K=l P2 1/[Pd- RT InK = -RT In[P21 / I Pd = ~~GI2[P 2J / [P 11 = e....6G I 2/RT

Fig 2.

Kinetic aspect of asymmetric reactions

The energy o[ the transition state determines the rate (k 1, k2) of the reactions and therates affect the stereoseleclivity of the reactions. Therefore, information about thestructure of transition state is crucial to understanding reaction mechanism. However,
because transition states have only transitory existence, it has not been possihle to directly
measure information about the structure of transition state. Hamm(lnd's postulate states"if two states, as [or example, a transition state and an unstable intermediate, occur
consecutively during a reaction process and have nearly the same energy content, theirinterconversion will involve only a small reorganization of molecular structure".

2

The tran . ition state can be roughly describ d a v ry arly, ecu-ly, Jate, according to thestrength of the interactions between the uhstrate and the reagent. When the new bondformation is very weak, the tran ition state is very early and th reaction is a highly
exothermic step and a low activation energy (Fig 3a). On the hasis of Hammond's
postulatc, thc very early transition state will structurally resemble the reactant ~ ince they
are close each other in energy and therefore interconverted by a small structural change.
This is depicted in the potential energy diagram by a small displacement toward productalong the reaction coordinate. When the new bond is somewh()\ more formed, thetransition state is still early and the reagents maintain most of their ground state orbital
characteristics (Fig 3b).

Fig 3b describes a step in which the: transition state issufficiently higher in energy than both the reactant and the product. In this case, neither
the reactant nor the product will be a good model of the transillion state. Fig 3c illustrates
an endothermic step which would occur in the formation of an unstable product. In thiscase, the energy of the transition state is similar to that of the product and the transition
state should be similar in structure to the product.
Gibbs free energy
transition slale

(V

JP
s
p

p

(a) very carly lransition slale(b) early transition slate(c) late transition state(S: starling material; P: product.)Fig 3.

Distinction of transition state3

Some factors contribute to asymmetric induction . On (or more) n w honding areformed by orbital mixing and honding interaction may be on factor for asymmetricinduction. The important interactions are between the frontier orbitals. Secondary orbital
interaction may also playa role on asymmetric induction. The interactions hetween thesubstrate and the reagent also affect the position of the transition state along the reaction
coordinate. Cuprates, Grignard reagents doped with CuI, and hydrogen activated by
Pd/C add to dioxanone 1 containing a stereogenic acetal centLr exclusiv Iy from Si face
(Scheme 1).2 The dioxanone 1 is distorted and carbon-4 is pyramidalized toward
carbon-2 over the mean plane. This distortion is enhanced in the transition state [or anucleophilic attack, so such reactions are stereoselective because o[ b'vller overlap control.
SchemelEu

1lEu

R CuLi
1

RMgDr
RSIII ea!.!:I)
1[21 Pd-C or PI

O~()

AA'IC

o
LUMO

H1

Nu

Nu : R RS, If

Nonbonding interactions also may inCluence asymmetric induction. The mostimportant types of non bonding interactions are through space repulsion hetween filled
orbitals (steric effects). Energy of such interactions in a transition state can be estimatedas the sum of several factors:
E = E(r) + E(8) + E(<j» + E(d)where E(r) is the energy increment associated with stretching or cl,mpression of single
honds, E(8) is the strain energy of bond-angle distortion, E(<j» is the torsional strain, andE( d) are the energy increments that result from non bonding interactions between atoms orgroups. In most transition-state models, the reagents attack with Laggered form tovicinal bonds in order Lo minimile gauche interactions.

4

Moreover, the new bond

formation(s) must occur with minimization of torsional interactions. The transition statemodels of aldol reaction are shown in Scheme 23 and the tran ition tate 11 i ba ed on
the minimization of torsional interactions; the exi ting and forming bonds are staggered.
Another example for nonbonding interaction is 1t-stacking interaction (Fig 4). The chiral
Lewis acids bearing a tryptophan residue form complex with a,p-unsaturated aldehyde,
and the reagent approach from only one side of the unsaturated aldehyde by the 1tstacking arrangement between tryptophan residue and a,p-unsaturatcd aldehyde.
Scheme 2

OH 0-

H 20 2

J... Jl
R~ Y
-G*
Me

o

~

syn

0

U BU2BOTf
N'''o -

LJ

Bn"-

OH 0

2

RA?G*
Me
anti

Br

Me

Fig 4. 1t-Stacking transition state5

When the substrate and the reagent have s veral low en rgy conformation ,confomlational effect may he important for asymmetric introduction . When barriers tointerconversion are high by com parison with acti vation fret' energy (k I, k- l « k II,k2'), transition state conformers usually resemble ground state on s (Fig 5a). If theinterconversion barrier between the two conformers S I,

2 i~, low energy to theactivation free energies (kII, k- ll « kl, k2), the Curlin-Hammett principle can heapplied and the selectivity depends only upon free energy difference (G I t - Gil:) between
the transition states. In this case, lwo possibilities can again be considered whether the
more stable conformer S 1 is (Fig 5b) or is nOl (Fig 5c) the more reactive one and it inecessary to evaluate the conformational effects on transition states or transition
structures. For example, the base-induced elimination of hydrogen chloride from 1,2diphenyl-l-chloroethane is considered (Scheme 3). The elimination reaction proceed via
each of two conformations S I, S2 and frans-stilbene was produced in preference lo cisone. The reason why this selectivity that the rates of the intercon version between theconfomlers S I, S2 are faster than that of the [ormation of products and the tran ition statwhich leads to frans-stilbene is lower energy than that leading to cis-sti Ibene by th
repulsion forces between the two phenyl rings in the transition slale.

K = [S d I [SzJdP 2/dt =k2'I S21
PI/P2 = k\'ISll/kz'I S 2] = kl'K/k2' = c- (G,t

(b)

(a)

Fig 5.

Conformational effect

6

(c)

,i)

Schenle 3

Ph

H

()Ph
I I Ph

[ ~Hl

~H
CI

Ph

H

CI

SI

H H
1l ph

~

---..

cis-stilbene

[~((l
Ph
CJ

S2

~

)Ph
Ph

H

f,nn.\' -slilhene

The diastereoselectivity resulting from nucleophilic addition to thl~ carhonyl group canbe explained by the Felkin-Anh model (Scheme 4). In this concept, considering both the
BUrgi-Dunitz trajectory and non bonding interaction of the largest substituent at the chiral
center, the nucleophile attacks the carbonyl group via conformer III in spi t of many stableconformers at the ground state and high diastereoselectivity turns up (Scheme 4a). If
electron-withdrawing group presents at an adjacent chiral center, favorable conformation
at transition state is changed fr0111 the conformer III hy n*-cr* int raction ( cheme 4b).
The LUMO of the carbonyl group (the n* orbital) interacts with the cr*-orhitaJ of the (J.electron-withdrawing group and the energy gap between the LUTv10 or the carbonylgroup and the HOMO of the nucleophile is decreased. Theref, re, the reaction proceeding
via conformer IV is facilitated.

7

Schenle 4)k~/NlI­-----..

L-~

L
~u
~R

9" "1---\

MOIl

OM

III
Nu(a)

11

~-L

L

ij.

~Nu

~""'J\
M
OH

S 0

EWG-~
o s
Nu-

(b)

Nu-

\S R

~-EWG

LJNU
S""" / \

[ 0

W,

IV

..

,.------,

,,
....

,

(J*

o~clcctroll-will1drawillg group

.

:~

"
~

:

n* (LUMO)", ______:'
ofC=O

-+t-

HOMO ofNu-

Fig 6, 1(*-cr* Interaction between the carbonyl group andex-electron-withdrawing group

8

OH

The reaction conditions (temperatur , pres, ure, solvent, the natur of a, ociatedmetals or of counter ions in the case of polar reactions, the pre ence or additives such as
salts, Lewis acid or base, and so on) may also influence th~ substrate-reagent
interactions.

Both the geometrical characteristics of thtran , ition states (attack

directionality or pyramidalization of the reacting sites) and the structure of the reactive
confom1ers can be altered by changing reaction conditions and the relative energy level orthe transition states can be changed. As a result, the stereoselectivity is inlluenced by thereaction conditions.
Chelates may playa role on asymmetric induction, because of substrates and reagent,whether chiral or prochiral, are often multifunctional. Chelated molecules are usuallymore stable than nonchelated species, and their ground-state structure can be maintainedat transition state. Moreover, chelated molecules, although more stable, can al 0 be more
rcacti ve. The stereoselccti vi ty of aldol and related reactions may al 0 be con trolled bychelation of Lewis acid with reagents and/or substrates. N-Acyloxazolidinone 2 arechelated with boron tril1ate to form boron enolate 3 in the ground , tate ( ch 'me 2).3n

the reaction of the complex 3 with aldehyde, the aId hyde coordinat s wi th the horon
atom at transition state. The initial bidentate chelate is broken and th ster os lectivity of
the reaction favors the syl1 aldol (transition state I). In the aldol reactions p r1'orl11 d withthe chelated boron enolate 3 in the presence of another Lewis acid ~;uch as BU2BO l' or
Et2AICI, the (Il1fi aldol is preferentially formed by both the act.ivation of the aldehyde andthe prevention of disruption of the boron enolate (transition state II).
When both the reagent (or catalyst) and the substrate bear a stereocenter, thediastereoselectivity can be increased relaLi ve to that observed when a single stereocenter isinvolved. In this case, a ymmetric induction may arise from the combined inlluence ofchiral center pre ent in the substrate and the reagent and the part ers of the sub trate
and the reagent are said to be matched. On the other hand, i [ the d iastereoscleetivity is
reduced, the partners are mismatched. Diels-Alder reaction in W I ieh both diene and9dienophile 4 contrun a chiral center is concerned as an example. in Scheme 5. 4 Both thesechiral centers in the diene and the dienophile 4 are retained in the product. In cheme 5a,
the diastereoisomer ratio of the product is > 100: 1 (single a, ymmetric induction). H
methoxy group which is (S) configuration is introduced to diene, the dia 'tereoselectivity
is increased and a pair of the diene and the dienophile 4 is matched ( cheme 5b). The
diastereosclectivity of the reaction between the dienophile 4 and the diene having the R
configuration is decreased and the pair is mismatched (Scheme 5c).
Scheme 5

o

~O

o

(a)

~~~

+

0

P h l i 1"H

I

OH
fBu

4
>100

McO~__

o

+

~~:

o

0

Jl

H~ -0

I3F

y

OEt 2

..

Jl

McC\

~~

0

P h l i 1" HI

+ H PhO
::

I

OH

IBu

4

-0

0

.)~II
011
fBu

>130

)c

()

o
McO~ Jl

McO~H ")(R
(c)

Ph~

+ 1-1

+

Jl

"l -0 0
PhO
~ )~H
I

~

OH
lBu

~

35

Effective method [or asymmetric synthesis may be divided into five types. One
classification [or asymmetric synthesis is that a stereogcnic center of target molecule is[armed by directly utilization of enantion1eric pure available substrates (Type 1, Sub trate
controlled method, Scheme 6, S: part or the substrate which reacts, G*: chiral directing
group, R: reagent, P-G*: product, *: chirality). Chiral compounds ~;uch as amino acids,

10

amino alcohols, hydroxy acids, alkaloids, amines. tcrpencs, and carhohydrates arewidely used as chiral starting materials that are cheap and readi Iy available in highenantiomeric purity. In this method, the chiral starting materials con~truct a part of target
molecule and chirality of starting materials is introduced into stereogenic center of thetarget molecule. The total synthesis of (R)-(- )-Frontalin is achieved with a starting
material from the naturally occurring enantiomeric pure compound, (3R)-(- )-Linaloo1. 5
Scheme 6.

Type 1: Substrate controlled nle hod

R

S-G*

P*-G*
TMS

O

1. TMSC1, TMS 2NH

OHC

Me(R)-( +)-Frontali n(3R)-( - )- Linalool

Indirectly utilization of chiral starting materials i also one classification forasymmetric synthesis (Type 2, Auxiliary controlled method, Scheme 7). In this m thod,
the available enantiomeric pure compounds are used as a chiral auxiliary G* andintroduced onto an achiral substrate S. This modified substrate-G* is subsequently

transformed into diastereomer P*-G* through a highly diastereoselective process. After
cleavage of the chiral auxi liary G*, the final product P* bearing a new tereocenter i
obtained. The cleaved auxiliaries can be recovered and repetitively l sed. In this method,
if each pure enantiomer of the chiral auxiliary could be readily available, it is possib le toprepare both enantiomers of the target molecules. Most chiral aux iliaries are therefore
either enantiomeric pure available natural product or compound derived from tho e byclassical high yielding transformations. Most of the new asymmetnc synthesis methods
introduced in the last 20 years are of this classification. 3-Pcntanone is alkylated via its

11

SAMP hydrazo ne on chelation control and converted into an ant alarm ph ro mone 5 witha highly enantiollleric purity.6
Scheme 7. Type 2:

S

+G '"

Auxiliary controlled nle thod

S-G *

R

P'"

~OMC
I

1. MelN~ 2. Hel aq .

5 99.50/0 ee

The usc of a chiral reagent R'" is an another method (Type 3, Reagent controll dmethod, Scheme 8). If chiralligand is introduced on a reagent or a ataly t, the structurof the transition state is converted to diastereoisomeric fonl1 and asymmetry is induced on
the transition state. In most of the cases, the ligands favor rigidified chelates, and there
are only a few considerable low-energy conformers on the trdnsitioTl state. Unnece 'saryof the extra step to attach and/or remove the chiral source onto achiral compound is
attractive feature of this classi rication. Reaction of com pound 6 wi th (- )-(Ipc)2B H
results in not only diastereoselective attack anti to the bcnzyl-oxymethyJ group but also
cnantiosclectivity between the two enantiotopic double bonds. Then oxidative workup of
the boranc gives unsaturated alcohol 7. The asymmetric reaction [>layed a key role inearly prostaglandin synthesis)

12Scheme 8. Type 3:

Reagent controlled nlethod
R*

s

p*

Prostaglandin

Recovery and recycling of the chiral auxiliaries and ligands is another importantconcern in asymmetric synthesis, mainly when they are expensi ve. Therefor, the chiralinductors are used in catalytic amounts either as chiral reagents or as ligands of chiralcatalysts.

The reaction using a chiral catalyst and ligand may afford excellent

consequence (Type 4, Catalyst controlled method, Scheme 9). In this method, chiralsource, chiral catalyst (cat*), can be recovered without change at the end of the reaction
and in many cases even a small quantity is satisfactorily for asymmetric introduction.
The chiral intermediate, (S)-glycidol 8, is prepared from allyl alcohol by the recent
catalytic variant of the Sharpless epoxidation, using (+ )-diisopropyl tartrate as a chiralsource of asymmetry. The compound 8 was reacted in situ with I-naphthoxide anion to
give compound 9 with high stereoselectivity.8

Scheme 9. Type 4: Catalyst controlled method
RS~

OH 2PhC(Me ) p~1I
0.05 TI (OiPr).\
0.06 (+)-DIPT

[

p*

cat*

]c6 rYr

H
~OH

• ~

-

o H"../Ol-bH

8

~~~

9

13

-- (- )-Propranolol

Kinetic rc olution is aL 0 one method for obtaining chiral compound (Type 5, Kinetic
resolution method, Scheme 10). This procedure involves reaction of either a racemicchiral compound or an achiral compound containing equivalent enantiotopic groups witha chiral reagent or an achiral reagentlchiral cataly ,t system. In dther case, the twoenantiomers or enantiotopic groups ((±)-S) react with reagent at different rate and in theideal case one enantiomer (cnantiotopic group) ((- )-S) is converted to product ((- )-P*)
while the other (( +)-S) remains unchanged. Because, when the substrate and the reagent
are matched partner, the chiral centers in both partners are conlri buling to lower thetransition state energy, a'nd therefore the reaction rate was increased. Utilization of
enzymes in asymmetric synthesis may also involve in Type 5. A rac~n1ic secondary allyl
alcohol 10 is epoxidised with the Sharpless reagent. Only one enantiomer reacts andasymmetric resolution of the allyl alcohol 10 is achieved.9
Scheme l().

Type 5:

Kinetic resolution met.hod

R*
(+)-s

(±)-s

+ (- )-P*

or R/cat*

R~R'
OH

R~R' +

fBuOOH.

(+)-DIPT / Ti(O iPr)4

HO

H

o
R~R'
H

OH

10

Type 2 chirali ty introduction is reasonable method. Because, Type 2 method ischaracterized by recyclable and availability of chirality source (chiral auxiliary): Chiralauxiliary can by recycled after a new stereogenic center is inlroduced to achiralcompound. It is also casily prepared from natural enantiomeric pure cOJnpounds. So,
Type 2 method have been vigorously investigated and orten utilized for natural productsynthesis .
Amino acids and terpenes, which arc naturally occurring cnanliomeric purecompounds, are often used as chiral auxiliaries. For cxamplc, 8-phenylmenthol l 0 and

14

camphorsultam 1 L are prepared from terpene and 2-oxazolidinon 12 i prepared fromamino acid (Fig 7). 8-Phenylmenthol is a famou s chiral auxilia··y and variou s typeasymmetric reactions using the 8-phenylmenthol as a chiral auxiliary have been
investigated (Scheme 11). L3 In their reactions, high stcreoselectivity have been carriedout. The high levels of asymmetric introduction achieved by 8 ·phenylmenthol hasuggested the transition state models with 1t stacking of the aromatic moiety of theauxiliary and that of the attached substrates during the course oj" the reaction . 14 2Oxazolidinone was developed as a chiral auxiliary by Evans i:lIld the enolates ofacyloxazolidinones also demonstrates good levels of diastercoselection in various typereactions . The diastcreosclectivity can be explained by facial selective approach of theelectrophile to the oxazolidiny] enolate (Scheme 12). If the metal is not coordinated withthe oxazolidinone carbonyl oxygen, the attack of an elcctrophile occurs from the Re faceof the enolate double bond (Scheme 12a). This is explained :is the result of theoxazolidinyl enolate equilibration to the conformation which place the dipoles oppo ite toeach other. If the metal is coordinated , the attack occurs from thG Si rac to give Ihdiastercomeric product (Scheme t2b) .

Camphorsultam(-)-8-Phenylmenthol

Fig 7.

(S)-4-Benzyl -2-oxazolidinone

Som e chiral a uxili a rits

In this thesis, asyn1metric Darzens reaction using 8-phenylmenthyl group as a chira]auxiliary (chapter]) and a ymmetric introduction in the formation of 2,5-di ubstituted
tetrahydropyran derivative and stereoselective synthesis of Rhopalo lc acid A (chapter 2)
are deseri bed.

15

Scheme 11
Electrophilic reaction 13 b

~~~O

~R
Sn C~, CHj:12

H

'~

()

~<~~

-78 °C~>99 .<)(,k deR

Nucleophilic reaction 13 c¢:~~

1. LDA, -78 °C

2.

MC~

)LPhyC02Me~(r
Me
Urreo <; 0% de

C02Me

Cycloaddition reaction 13d

¢:~~

)

¢:~~
>96 % deScheme 12(a) Non-chela-tion model

o

OM

OAN~

~

J

OM

~E+

;~

[~ME+lo01l~ OrJYO-{~(b) Chelation model
M

o "0
/

o)L~

~

S i attack

16

E+
----

)t)L-/--'. ~ =S i altac '-0W-----1..Re alt u( k0()ANJly~EReferences

1.

Aitkens, R. A.; Kilcnyi, S. N.

Asymmelirc

Syntliesis,

ds, Blackie

Academic&Professional, Glasgow, U.K., 1992, Chapter 4 5, 6, 7. Koskinen, A.
M. P. Asymmetric Syntheosis of Natural Products, John Willy&Sons, New York
1993, Chaper 2. N6gnldi, M. Slereoselective S.vnthe\·is: A Proct;c:ol Approach, 2nd
cd., VCH Publishers , New York , 1994, Chapter 1.

Seyden-Penne, J. Chiral

Auxiliaries and Ligands in Asymmetric Synthesis, John Willy&Sons, New York,

1995, Chapter 1.
2. Seebach, D.: Zimmermman , J.: Gysel, U.; Ziegler, R.; Ha, T. K. 1. Am. Chem.

Soc,1993 , 115, 4024.

3. Reetz, M. T. Ace. Chem. Res., 1993,26,462. Reetz, M. T. Angew. Chem. Inl.
Ed. Engl., 1991,30, 1531. Reearz, M. T.; lung, A. ; Boinl, C. Tetrahedron,
1988,44,- 3889. Reetz, M. T.; Raguse, B.; Marth, C. F.; HUgel , H. M.; Bach, T.;

Fox, D. N. Tetrahedron, 1992,48, 5731.
4. Masamune, S.; Choy, W.: Petersen , J. S.; Sita, L. R. Angew.

helJl. Inl. Ed. Engl.,

1985,24, 1.

5. Magnas, P.: Roy, G. 1. Chem . Soc. Chem. COI71I11UI7., 1978, 2()7.
6. Enders, D. Asymmetric Synthesis, Vol 3., Morrison, J. D. cd., Academic Press,
OrIana, 1984, Chapter 4.
7. Biggadike, K.: Borthwick, A. D.; Evans, D.; Exall, A. M.; Kivk, B. E.; Reberts, S.
M.: Stephenson, L.; Youds, P.; Slawin, A. M. Z.: Williams, D. J. 1. Chell1. Soc.
Chem. COlJ1IJ1Lln., 1987 ,2 51.

8. Sih, C. J.: Heater, J. B.: Sood R.; Price, P.; Permzott, G.: HSll Lee , L. F.' Lee, S.
S.1. Am. Chem. Soc., 1975, 97, 865.

17

9. Martin, V. S.: Woodward, S. S.; Katsuki, K.: Yamada, Y.; Ikeda, M.; Sharpless, K.
B.1. Am. Chem. Soc., 1981, 103,6237.

Carlier, P. R.; Mungall, W. S.;

Schroder, G.: Sharpless, K. B. 1. Am. Chel17. Soc., 1988,1 J(I, 2978.
10. Oswald , O. Org. Synth., 1985, (j5, 203.
11. Oppolzr, W; Moretti, R.; Thomi, S. Tetrahedron Left., 1989,30,5603.

]2. Evans, D. A.; Bartro, J.; Shih, T. L. 1. Am. Chel11. Soc., 1981 , 103 ,2 127 .
13. (a) For a review: Whitesell, J. K. ChelJ1. Rev., 1992,953. (h) Whitesell, J. K.;
Bhattacharya, A.; Buchana, C. M.; Chen, H. H.; Deyo, D. Tetrahedron, 1986,42,2993. (c) Ojima, I.; Halws, I.; Zhao, M.; Georg, G. I.; Jayasinghe, L. R. 1. Org.
Chel17., 1991,56, 1681. (d) Corey, E. J.; Ensley, H. E. J. Am. Chel11. Soc.,
1991, 56, 6908.

]4. Tucker, J. A.; Houk, K. N.; Trost, B. M. 1. Am. Chem. Soc., 1990,112, 5465.
15. Evans, D. A.: Weber, A. E. 1. Am. Che11l. Soc., 1986,108,6757.

18

Chapter 1

Asymmetric Induction in Darzens COJlldensation

Introduction
8-Phenylmenthol was designed to foster attractiv interactions at the tran ition statelevel of a [4+2J cycloaddition reaction to avoid recours to resolution m thods. 1

heauxiliary has found widespread use in organic ynthesis. It ha, proved to be dramaticallysuperior in diastereoface discriminating ability to the commonly u~,ed chiral auxiliarie
such as menthol , borneol, etc. (- )-8-Phenylmenthol as a chlral auxiliary was 'ynth sizedfrom (+ )-pulegone, via alkylation, base induced equilibrium, and reduction in 7201£
overall yield (Scheme 1).2
Scheme 1.

Synthesis of (-)-8-phenyl'mentlhol

1. PhMgBr/CuI_-.>:----

NaliPrOH

2, KOH/EtOH

Ph

~OH

toluene, 6(-)-8-phcnylmcnthol

Various types of asymmetric reaction using 8-phenylmenthol as a chiral auxiliary hav
been investigated (Scheme 2)3 and high stereoselectivity has been carried out in th ir
reactions. The high level of control exhibited by 8-phenylmenthol has inspired numerou
hypotheses as to the origin or the directing effect. Investigators activ,.- in the developmentof the auxiliary have invoked models for absolute control with 1t stacking effect between
the aromatic moiety of the auxiliary and that of the attached substrat.es during the courseof the reaction. 4 Thought many examples as to eleclrophilic,5 cyclo ddition,6 oxidation,
reduction, rearrangement reactions, and so on have been reported, that as to nucleophilic
reactions are few'? In this chapter, Darzens reaction, which is one of the nucleophilic
reactions using (- )-8-phenylmenthol as a chiral auxiliary, is described.
The glycidic esters which are produced by the Darzens reaction can he multi functional
precursors and asymmetric synthesis of the glycidic ester is synth(~tically interesting. 8
The stereocontrolled direct and versatile routs to elcctrophilic epoxides have not been]9

developed so far compared with that of the nucleophilic epoxides such a the Sharplessepoxidation. Y
Scheme 2. Reaction using 8-phenylnlenthyl group as a chiral auxiliaryelectrophilic reaction 5~R0i;) ;'o~-Ph

Sf1C~. CH:zC1 2-78 °C>99.9% deRnucleophilic reaction 7.

I. LDA, -78 °C
2.Mc~

tJ1H~() 90% de

cycloaddition reaction 6

Darzens reaction is generally accepted the condensation of an aldehyde or ketone withan ex-halo ester to produce an ex,~-epoxy ester (glycid ic ester).! 0 The m chanism ofglycidic ester formation probably involves the addition of the enolate of the halo ester tothe carbonyl group of the aldehyde or ketone (aldol type reaction), followed by an
intran101ecular nucleophilic displacement on carbon (Scheme 3). The function of thebasic condensing agent is to convert the halo ester to its enolaLe. The rate of theintramolecular nucleophilic displacement of hydroxyl ion to carbon atom is, at least insome cases, very slow and a rate determining step of the Darzens reaction. The Darzens
reaction of ethyl ex-chlorophenylacetate and benzaldehyde preferentially afforded fransglycidic e ter and it is explained by the overlap control mode1. 1l120Scheme 3.

Reaction mechanism of Darzens reaction
Ph,

CI

HO

Ph

rate dctcnnining , lcp

H~~~--~~COEt-------------~fBUO~
PhCHCIC02Et

0

2

~uOII

H,~. ~
Ph

major

" Ph

f-~"'

+

fmlls

- =

D~~4 (~

PhCHO

EtO

Ph

H---}
HO

C1

~Ph
C02Et

H~\Ph
Ph
0
C02 .. tcis

Several asymmetric Darzens reactions have been reported. The approach involves theusc of the enolate of chiral a-haloester in aldol type condensations with aldehydes andthen converting the resulting halohydrins to epoxides. 12 Although studies have b en
made on one step procedure using a-halo acetate of chiral alcohol, di appointingly low
levels of chiral induction were reported. I3 Only few attempts have so far been made atasymmetric Darzens reaction with ketones.

21

Results and Discussion
a-Haloacetates 1-4 were obtained hy the reaction of the corresponding a -haloac tyl
halide with (- )-menthol and (- )-8-phenylmenthol in the presence of N,N-dimethylaniline(Scheme 4). Treatment of 1-4 with t-BuOK, followed by addition of aldehyde or k tone
at -78 to 0 °C provided, on work up, glycidic ester. The geometric a signments wereconfirmed through the difference NOE analysis of the IH NMR spectra of the glycidic
esters whilst the diastereoseleclivity was determined by means or 1H NMR and HPLC.
Scheme 40x~x

N ,lV-dirnethylal1ilinc
RjOH.. RIO~X

Et20, 0 °C to reflux

R

Me

Me

0

1-4 R

Ho"9
Mc

110,,2Mc(- )-mcntJlOl

Mc

Mc
Ph
(- )-8-phcllylmclltJlol

1: X = CI, R = H RL = Me
2a: X = CI , R = H, RI = (-)-mclllhyl
2b: X = Br, R = H, Rl = (-)-mcntJlyl
3a: X = CI, R = H, Rl = (-)-8-phcnylmenlhyl
3b: X = Br, R = H, Rl = (- )-8-phcnylmcnlhyl
4: X = Br, R = Me, Rl = (- )-8-phcnylmcntJlyl

{BuOK
----~

+

1-4

Darzens Reaction of Benzaldehyde. The Darzens reaction of a-haloacetates 14 with benzaldehyde afforded the corresponding glycidic esters 5-8 as a cis/transmixture, respectively (Table 1). The geometry (cis and tran.s)of the glycidic esters 5-8
was assigned on the basis of the 1H NMR vicinal coupling constanL (cis: J2,3 = 4.4-4.9
Hz, trans: J2,3 = 1.5-2.0 Hz, Table 2) . The chemical shifts of ploton attached at C2
position in the trans isomers 5-7 were observed at higher magnetic fjeld than those of thecis as a result of the magnetic anisotropic effect of the phcnyl rjng. The geometricisomers of some of the glycidic esters were separated as pure samples by preparative

22

TLC on silica gel. The relative stereochemistry of the 'cparatcd cis- and tral1s-glycidic
ester 6 were confirmed hy difference NOE analysL of its I H NMR sp ctrum (Fig I):
when the proton at C3 position was irradiated, NOE (8 .2o/rJ) wa ohscrv d at the proton
at C2 posi tion in the major diastereomer of cis-6. The geometry of (- )-8-phenylmel1thyl
glycidic ester 8 was also confirmed by difference NOE analysis of its IH NMR spectrum(Fig 1): when the proton at C3 position was irradiated , NOE (8.4%,) was ohserved at the

methyl proton of C2 position in the cis-8 but was absent for the trans.
Table 1.

Darzens condensations of benzaldehyde with 1-4

0

RIO~X
1-4

R

0

H

tBuOK

+

Ph)lH

~

CH2C12, -78 to 0 °C

Ph

0

R

)I~ C02Rl
5-8

5 : R = H, Rl = Me
R = H, Rl = (-)-mcntllyl
R = H, R} = (-)-8-phcnylmcntllyl
8 : R = Mc, Rl =: (-)-8-phcnylmclltllyl
9{ de bcis/trans 0-yield6:

7 :entry haloester
1
2
3
4
5
6
7
8
9
10
11
12
13
14

1
2a
2a
2a
2b
2b
2b
3a
3a
3a
3b
3b
3b
4

solvent
CH2C12n-hexane
CH2Cl2Et20
n-hexane
CH2C12Et20
n-hexane
CH2C12Et20
n-hexane
CH2C12
Et20
CH2Cl2

product

(%)a
52
90
97
65
68
81
42
95
90
90
81
75
26
92

5

6
6

6
6
6
6
7
7
7
7
7
7
8

cis: transl.0 : 9.5
2.9 : 1.0
1.8 : 1.0
l.1 : 1.0
6.1 : 1.0
6.1: 1.0
7.0 : 1.0
1.0 : 1.1
2.8 : 1.0
1.0 : 1.3
5.2 : 1.0
6.7 : 1.0
6.7 : 1.0
4.9 : 1.0

CIS

trans

low
low
low
low
low
low
43
38
63
31
43
37
29

low
low
low
low
low
low
low
33
23
50
41
50
33

a Thc yield was not optimized.
b The dia5tcreose lectivity and the geometric ratio were measured by 1H NMR analysis of a mixture oftJ1C crude product.

23

Table 2.

Coupling constant (12 23) 0 f 5 -7

8 2-H (ppm)

gl ycidic ester diastereomer
5

3.85
3.52
3.81
3.82
3.49
3.50
2.67
3.46
2.49
2.72

CIS

trans
cis (minor)cis (major)trans (minor)trans (major)cis (minor)cis (major)trans (minor)trans (major)

6

7

8 3-H (ppm)
4.27
4.10
4.26
4.26
4.06
4.07
3.99
4.16
3.743.93./2,3 (Hz)
4.9
2.0
4.9
3.9
1.5
2.0
4.9
4.4
1.5
2.0

8.2o/n0%r::\

H I" /\.,, 1\

G\.,"H(r:;; 2'H

Ph~C0 MeC0 2Metrans -6 (major diastereomer)2

cis-6 (major diastereomer)
8.4%

(;\
H I, , / \.\I\Me

~CO R

Ph

2

1

Rl = (-)-menthyl

cis-8trans -8

Fig 1.

DIF -NOE Data of 6, 8

Table I shows the results for the Darzens reaction of benzaldehyde with 1-4. The
Darzens reaction of benzaldehyde with methyl cx-chloroacetatc 1 gave preferential1y thetrans-5 (cis/frons = 1.0:9.5), as expected from the overlap control model in which thetrans-epoxide should be predominant. The Darzens reaction of (- )-menthyl and (-)-8-

phenylmenthyl cx-haloacetate (2-4) with benzaldehyde gave predominantly cis glycidic
esters 6-8 respectively as the major isomers, respectively as shown in Table 1. Chart 1
shows 1H NMR spectrum of geometric and diastereomeric mixture of 7 (seesupplementary material).

Chart 2 shows 13C NMR spectrum of geometric anddiastereomeric mixture of 7 (see supplementary material). In the chart j, there were24

ob erved the charactcristic signals assig ncd to th pro ton at :2 andeach diastereomers (Table 1). In the 13

3 po. iti on of the

NMR spectrum (chart 2), th r were ob. erved

the following characteristic signals, 855.1 , 55.7 , 56.8,57 .4, 67.0, and 74.5 for C2 andC3 carbons. The cis/trans ratio of the glycidic ester 6 wa slightly depended on reaction
medium (entries 2-4, 5-7). The Darzens reactions of a -bronl o derivatives 2b and 3b
afforded more preferentially cis glycidic ester than a -chloro dcrivalive 2a and 3a.

orcxample, the Darzens reaction of (- )-menthyl a-bromoacetate 2b gave 6 (cis/trans = 6. 17.0: 1.0, entries 5-7) , while the reaction of the cx-chloroacetate 2it afforded the same

product 6 (cis/frans = 1.1-2.9: 1.0, entries 2-4). The phenomenon was al 0 observed inthe (- )-8-phcnylmenthyl esters 3a,b (entries 8- J 3). Diastereose1ccLivity in the Darzens
reactions o[ benzaldehyde was moderate (23-63% de) with (- )-8-phcnylmenthyl group asa chiral auxiliary (entries 8-13) , and very low selectivity [or a (- -) -menthyl auxiliary(entries 2-7).
Darzens Reaction with Ketones. The Darzens reaction of cx-haloacetates 1-4

with various ketones gave the corresponding glycidic esters 9-20, re, pectiv ly (Table 3).
Some of cis/trans isomers were separated by preparative TLC on ilica gland the r laLiv
stereochemistry was confirmed by DIF-NOE measurement (Fig 2):

or the methyl

glycidate 9, when proton attached at C-2 position was irradiated, the intensity or the
methyl proton signal was enhanced by 2.50/£ for the major diast.ereol11er of cis L omer andthat of the proton o[ the aromatic part was enhanced by 3.2% for the major diastereomero[ trans one. For 12, when proton attached at C-2 position was irradiated , the intensityof the methyl proton signal was enhanced by 3.20/0 in the major dia tereomer of cis
isomer and that o[ the aromatic proton signal was enhanced by 5.5% in the major
diastercomer of trans one. For 13, when the proton attached at C-2 po ition wasirradiated , the intensity of the methylene proton signal of the ethyl group wa enhanced
by 5.7% in the cis isomer. In the 1H NMR spectra of 9- 13" the ~;ignal of the methin
proton at C2 of the trans isomer series appearcd at higher magnetic field than that o[ the25cis series.

Chart 3 shows 1H NMR spectrum or cis-12 (major dia, t reomer) (secsupplementary material).

CharL 4 shows 13C NMR spectrum or cis-12 (major

diastercomer) (see supplementary material). Chart 5 show IH NM

spectrum of trans-

12 (major diastereomer) (see supplementary material) . Chart (, shows 13

pectrum or frol1,s-12 (major diastereomer) (sec supplementary material).

NMR

hart 7 shows

1H NMR spectrum of fral7s-12 (minor diastereomer) (sec supplementary material). The
characteristic signals of cis-12 (major diastereomer) and frol1s - 12 in 1Hand 13C NMR
spectrum are summarized in Table 4.
Table 3.

Darzens condensations of ketones with 1-4 in CH2CI2o

R[O~X +

(BuOK-----~

1-4 R
9

10
1 1

12
13
14
15
I 6
17
1~
19

20

entry

ha]oesterketoneR = H R L= Mc, R2 = Ph, R3 = Me
R = H, R 1 = Mc, R2 = Ph, R3 = El
R = H, Rl = (-)-mcnlhyl, R2 = Ph, R3 = Mc
R = H, R 1 = (-)-8-phcnylmcnlhyl, R2 = PI!. R3 = Mc
R = H. R 1 = (-)-8-phcllylmclllhyl, 1R2 = Ph, R3 = Et
R = H, R1 = (-) -mcnlhyl. R2 = R3 == Mc
R = H, R I = (- )-B-phcllylmcllthyl. lR2 = R, = Mc
R = H. Rl = (- )-B-phcnylmcllthyl. R2 = R \ = El
R = H. R 1 = (-)-8-phcnylmcllthyl, 1R2 = R \ = -( '112)4 R = H. Rj = (- )-8-phcnylmclllbyl. 1R2 = R \ = ((,112)')R = H. R 1 = (-) -B-phcllyllllcllthyi. R2 = R \ = Ph
R = Mc, Rl = (-)-8 -phenylmcnlhyl , R2 = R] = -(CH2)S -product yield a
(~ )

I

2
3
4

5
6
7
8
9

10
11

]2
]3
14

1
1
2a
3a
3b
3a
3b
2a
3a
3a
3a
3a
3a
4

acetophenone
propiophenone
acetophenone
acetophenone
acetophenone
propiophenone
propiophenone
acetoneacetone3-pentanonecyc]opentanonccyc]ohexanone
benzophenone
c~clohexanone

9

In
11
12
12
13
13
14
15
16
17
18
19
20

66
58
83
79
56
47
43

cis/! rw-;;-D
cis: transo/r, de b
CIS

frons

38
93
>95
87
>95

<10

1.0 : 1.3

J.O : 1.4
S.3 : 1.0
7.6 : 1.0
5.6 : LO

4.5 : 1.0
4.2 : 1.0

52
21
78
>95

39

14

64
47
45
45
45

87

18

81

80
96
77
36

a The yields were not optimized.
b The diastereosciectivity and the geometric ratio were detennined by 1H NMR c laJysi of a mixture of
the crude product.

26

Table 4. The characteristic signals of 12 in 1 II and 13C r_~M_R_s_p_e_c_tr_a_ _dia)tereomer
8 2-H (ppm)83-CH38 C28 3c;s (major)
3.31 (s)1.67 (s)60.6
63.2
tral1s (minor)
2.32 (s)1.63 (s)trons (major)
3.31 (s)1.67 (s)61.5
61.R--------

0%

0%

0%

RI = (-)-8-phcnyLmcnthyltrans -12Cmajor diastcrcomcr)

cis-I2(major diastcrcomcr)

5.6%

5.7%

~\
CH)CH 2 A H

Ph

~

3

2

~

/

i01R
...

I

0%
R I = (-)-8-phcnylmcnUlyl

trans -13

cis-I3

Fig 2.

DIF-NOE Data of 9, 12, and 13

The results of the Darzens reaction of a-haloacetates 1-4 with ketone

aresummarized in Table 3. The trans glycidic esters 9 and 10 were the major products inthe Darzcns reaction of acetophenone and propiophel1one with 1 (entrie 1, 2). The
preference of the frans isomer was inferior to that in the reaction of benzaldehyde. The
Darzens reaction of ketones with the a-haloacetate 2a,b and 3a,b pre[erentially
produced the cis isomers of 11-13 as the major isomer (entries 3-7). The geometric27

ratios were independent of th halogeno ubstituent (X = Cl or Br) (entrie ' 4, 5 and 6
7).

The diastereosclcctivity in the reaction o[ acetoph none with 2awa moderate to low(380/0 de for the cis isomer; < 10% de for the trans i 'omer, entry 3). On the other hand,

the high diastercoselectivity (93, >950/0 de [or the cis isonler) was observed in threaction of acetophenone with the (-)-8-phenyltuenlhyl cst rs 3a,b (entries 4, 5).
The Darzens reaction of (- )-mcnthyl a-chloroacetate 2a with acetone afforded theglycidic ester 14 in 390/0 yicld and 140/0 dc (entry 8). Thc reaction of acetone with (-)-8phcnylmenthyl cx-chloroacetate 3a yielded the glycidic ester 15 in 64<7£ yield and 87%) de(entry 9) . The Darzcns reactions of the other symmetric ketones (3-pentanone,
cyclopentanone, and bcnzophenone) with (-)-8-phenylmenthyl a-chloroacetate 3a weresimilar to that of acetone and yielded the glycidic esters 16-19 in highdiastercoselecti vities (77-960/0 dc, entries 10-13), respectively. Howe vcr, the Darzen
reaction of cyclohexanone with 4 gave the glycidic ester 20 with moderate
diastcreoselectivity (360/0 dc, entry 14).

Chart 8 show

IH Nrv1R spcctrum of 18(major diastereomer) (see supplementary material). Chart 9 shows 13

NMR spectrumof 18 (major diastereomer) (sec supplementary material). The proton or 2 posi lion wasobserved at 8 2.96 as a singlet in the I H NMR spectrum. In the 13

NMR pectrum, thecharacteristic signals assigned to C2 and C3 position were observed at 8 59.2 and 64.4,
respectively.
Asymmetric Aza-Darzens Reaction.

The al.a-Darzens reaction of (-)- 8-

phenylmcnthyl a-chloroacetate 3a with N-benzylidencaniUnL gav\~ the aziridine 21 in
40% yield as a stereoisomcric mixture (Scheme 5). The geometry (cis- 'cries or tral1sseries) in each isomer of aziridine 21 was determined by comparisons of the coupling
constants (cis: J = 6.8 Hz, trans: ] = 2.4 Hz) between vicinal protons of the aziridine
ring. I5 One of the diastereomeric isomers of 21 was separated by preparative TLC on
silica gel and thc relative stereochemistry wa confirmcd by difference NOE analysis of28

its IH NMR pectrul1l (Fig 3): when the proton at C2 position in th a/jridinc ring wasirradiated, NOE wa observed at the proton at C3 po ition (10.79'<;) in the cis-21 isomer.
The trans isomer 21 demonstrated only 1.7o/r, enhancement of the signal at C3 position.
The cis/trans ration wa) 3:2 and the diastereoselectivity of the frans aziridine 21 was high(>850/0 de).

~().7%H

II , /

\

.\\\\

H

Ph~C02R 1

Rl = (-)-8-phcnylmenthyl

i 2, ] = 2.4, 2.7 Hz

i 2,3 = 6.4, 6.5 Hztrans -21

cis-21

Fig 3.

Scheme 5.

DIF -NOE Data of 21

Aza-Darzens reaction
Ph
I

HAOzR,
o
II

RIO

~CI

N/

+

R 1=( - )-8-phenylmenthyl Ph
3a

40% yield

cis

trans

3

2

Ph

Ph
tBuOK

II

~

H
(2S.3~

Ph

H

I>----<.

Ph/"./N\ .,..:,C02Rl

Dia5tcrcosclectivityHHcis (% de)trans (%d)(2S,3.'S)

>85

41

cis

21

trans

Absolute Configuration of the Glycidic Esters. The absolute configurationof the glycidic ester cis-12 was established to be 2R,3R by comparison between the signof the specific rotation value o[ the corresponding reduction produ t 27 and that o[ thereported value (Scheme 6).16 Thus the reduced producl27 showed the rotation [cx]25 D-65.8 (c 0.137 \ benzene) whercas the literature value [or (3R)-3-phenylbutane-l 3-diol is29

[a] 25 D +66.7° (c maximum).

Chart 10 shows 1H NMR ,pec trum of 27 (seesupplementaty material). There were observed the following characteristic signals, 8
1. 57 (s, 3 H) for CH 3, 2.00 (d dd, J = 14.7, 5.3, 3.9 Hz, 1 H) an d 2. 10 (d dd, J = 14.7,

R.6, 4.4 HI" 1 H) for CH2CH20H, 2.85 (bs, 1 H) and 3.80 (b"I II) for hydroxy

protons, and 3.60-3.44 (m, 1 H) and 3.80-3 .64 (m, 1 H) for CH20H, together withsignals [or aromatic protons.
Scheme 6.

Determination of the absolute configurationof glycidic ester 12

90% yield

R I =(-)-8-phcnylmentllyl[(J.]25J) -65.8° (c 0.137, benzene)

cis-12(>95% de)

The absolute configuration of the glycidic ester 18 was also determined by conv rsion
into a known compound (Scheme 7). Cleavage of the epoxide ring of 1M in the presenceof molecular sieve (MS 41\.) afforded oxyester 28, whICh upon reduction wi th LiAIl 14
gave 1,3-diol 29. The optical valuc Ia]25 D -27.0° (c 0.196, CH 13) or the present 1,3diol 29 was consistent wi th that reponed for 2R-l ,3-diol 29 ([ a 125 0 -28.1° (c 1.02,
CHC13»).17 Further, the 2R configuration was confirmed by analogy to the reported
optical rotation for R-2 cyclohexyl-l ,2-ethanediol (I aJ25 D -4.17° (c 1.73,
Chart 11 shows 1H NMR spectrum of 29 (see supplemcntary material).

H 13».18

hart 12 shows

13C NMR spectrum of 29 (see supplementary material). The ob. erved signals in 1H
and 13C NMR spectra were assigned as following . 8H 1.54-1.83 (m, 4 H) and 1.942.11 (m, 4 H): methylene proton of cyclohexene moiety, 1.84-1.93 (m, 2 H): hydroxy
protons, 3.53-3.81 (m, 2 H): CH20H, 4.05-4.15 (m, 1 H): CHOH, 8C 22.4,22.5,
24.8, 24.9: methylene proton of cyclohexene moiety, 63.4: CH20H, 76 .2: CHOH,
124.0: CH=C, 136.7: CH=C.

30

Schenle 7.

Determination of the ab olute configurationof gylcidic ester 18

R 1=(- )-8 -pllenylrncnlllyl
1 8 (96% dc)

28

29

52% yicld

13% yicld[a( 5[) _27° (c 0.196, CH ' 1.1)

Table 5 shows the characteristic 1H NMR chemkal shifts as:;igncd to the epoxy
proton at C2 position of the glycidic esters 12-19. While the diff, . . rences (~=O.O I) of
the chemical shifts between the two diastereoisomers of 14 are very small, thedifferences (~=O.57 -0.86) between the two isomers [or 12 and 13 are remarkably large.
With the exception o[ menthyl ester 14, the epoxide ring proton of the major
diastereomers [or 12, 13, and 15-19 was observed at lower 111agnetic field than that o[the corresponding minor diastereomer when (-)-8-phenylmenLhyl group was used as achiral auxiliary. On the basis of the absolute configuration (2 R,3R) of the major
diastereoisomer of 12, it is reasonable that the absolute configuration at

2 and

:3

carbons in the major diastereoisomers of 13 is estimated to be 2R, ~R.
The chemical shifts of the major diastereoisomers of 15-19 deri ved from , ymmetricketones were also observed at lower magnetic field than those of the minor
diastereomers. Since the absolute configuration o[ the major diastereoiso111er o[ 18 was
also determined to be 2R through its conversion into the known compound R-29, theabsolute configuration at C2 carbon of the other major diastereoisorners in 15-17 and 19
is also estimated to be 2R.

31

Table 5. The 1 H NMR chemical shifts (8) of proton attached atin the diastereomers of glycidic esters 12-192oo
R 1/;", .. /~""\\ COOR2

R4~

COOR2

(2R)

2 --""""'tl(2.)')

12 - 19

R2 = (- )-mcnthyl, (-)-8-phcnylmclllhyl
R3 = Ph , R4 = Mc, El or Rj = Me, El. R4 = Ph
R3 = R4 = Me, El, -(CH2)4-, -(CH2)S-, Ph

compound
12
13
14
15
16
17

18
19

R3 R4
Ph Me
Ph Et

chiral auxiliary
phenylmenthyl
phenylmenthyl

Me Me
Me Me
Et Et
-( CH 2)4-(CH2)SPh Ph

menthylphenylmenthyl
phenylmenthyl
phenylmenthyl
phenylmenthyl

chemical shift, 8
for cisfor frans
major
minor
major
minor
3.31 a
2.62
3.07
2.32
3.36
2.50
3.16
2.36
ma.ior
3.32
2.84
3.00
3.01
2.96 h3.65

Qhen~lmenth~l

minor
3.33
2.19

2.14
2.44
2.18
2.80

a The configuration of tJle major product of cis-diastcrcomcr in 12 wa<; (2R,3R)-,.onfiguralion.
b TIle configuration of tJ1C m~ior prodUl18 was 2R.

Substituent Effect on

Stereoselectivity.

Suh. titu nt en cts on thestereoselectivity in the Darzens reaction arc shown in Tahle 6, 7. In the Darzens reactionof 3a with substituted acetophenones, the selectivity between cis and frans glycidic ester
was enhanced from cis/frans = 4.4: 1.0 to 10: 1.0, when the p-suh tituent of acetophenone
was changed [rom the electron-donating group to the electroll-withdrawing one.
According to Hammond's postulate, it is considered that the stereo-determining step of
the Darzens reaction of 3a with acetophenone substituted by the electron-withdrawing
group proceeds via more later transition state as compared with that having the electrondonating substituent.

32

Table 6. Substituent effect in the Darzen reaction of (- )-8phenyl menthyl a-chloroacetate 3a with substituted benzaldehyde----'------substituent
cis (2R)
trans (2R)
cr
product
p-MeO
-O.2R
22
4.3
H

o

7

2.9

The diastcrcoselcctivity of major product was determincd hy 1H NMR.

Table 7. Substituent effect in the Darzens rea('tion of (-)-8phenylmenthyl a-chloroacetate 3a with substituted acetophenones
substituent
p-MeO
p-Me

m-Me
H
111- MeO

cr
-0.28
-0.14

product-0 .06
0
O. 1

23
24
25

12
26

cis (2R)
4.4

4.2
5.4
7.6
10

-------trans (2R)
I
I
1

I
1

The stcreosclcctivity of major product was determincd by 1H NNlR.

Stereochemical Considerations of the Geonletric St~lectivity. The Dar7.ens
reactions of benzaldehyde and the unsymmetric ketones with methyl a-chloroacetate 1
preferenUally afforded the corresponding trans glycidic esters 5,9, and 10 a the major
isomer, respectively. 19 The trol1S selectivity coincides with the ov dap control mod I in
which epoxide C-O hond formation is the rate determining st p.l I Th geometricselectivity in the production of 5 from benzaldehyde was more remarkable compared withthose of 9 and 10 from ketones.

On the other hand, t.he Dan:ens reaction of Cf.,-haloacetates 2a,b and 3a,b containing (-)-menthyl and (- )-8-phenylmenthyl group as achiral auxihary gave predominantly the cis glycidic esters of 6,7, J 1, and 12 etc. a the
major isomer (Table 4). Judging from the facts of the cis selectivity in the Dar7.ens
reaction, it is considered that the stereo-determining step would be the initial aldol typereaction rather than the final C-O bond formation step in the oxirane ring. Furthermore,
the aldol type reaction proceeds via the open-chain or non-chelated anUperiplanartransition tate model, in which the potassium enolate and carbonyl moieties are aligned
in an antiperiplanar fashion as shown in Scheme 8. 20 For both the £- and Z-enolates,
the transi tion state leading to the trans oxirane product is destabilized through the steric33

rcpul ion hctwecn the halogcn and phcnyl group. R ccntly ({I, initio calculations
suggcsted that the opcn chain transition state model i. favored for mctal rr

cnolate.. 21

Scheme 8

IBuOK

R I = (-)-menthylor(-)-8-phcnylmcnt!1yl

X
Ph X X

major

K+O~O
RIO R

2

R

R= H. MeR2 = H. Me. El

minor

According to the open chain transition modcl, it is understandable that <x-bromoacetatc
with benzaldehyde is more effective in the cis selectivity than that of <x-chloroacetate(Table 2 entries 2-5, and 6). Because the repulsion between phenyl and bromo group is
more large than that of chi oro group. The explanation is not inconsistent with the smallerdifference of cis/trans selectivity in the acetophenone series in changing th halogen froma bromo to a chloro group (Table 4, entries 4, 5) . Moreover, it i reasonable that lh
more efficient leaving ability of bromidc ion relativc chloride ion results a smootherepoxide C-O bond formation process for the bromide series compared with the chloride
series.
Stereochemical Consideration of the Diasttreoselectivity.

The Darzens

reaction of (- )-mcnthyl and (-)-8-phcnylmenthyl <x-haJoacetate with carbonyl compounds
afforded glycidic esters 6-8 and 11-20 with 0-95% de. In the Darzens reaction of (-)-8phenylmenthyl <x-haloacetates 3a,b with ketones, high diast\.~reoselectivity wasobserved. Howevcr, the (-)-mcnthyl chiral auxiliary was not so effective in the present
asymmetric induction. Therefore, it is considered that high diastereofacjal allack would
be controlled in the initial aldol type step as a result of the sterk and/or elcctronic effectsof the phenyl group in the chiml auxiliary.4

34

The Darzen reaction of cyclohexanone with (- )-8-phcnylmenth) 1 a -chloroacetate 3aproceeded with high stereoselectivity (96% de) to give the glycidic est r 18. The 2R
absolute configuration of the major product was confirmed. The ster ochemical outcome
can be explained by the open chain transition model as illustrated in Scheme 9. Thus,
cyclohcxanone attacks the Z-enolate of 3a from the front side to giv the 2R-glycidic
ester 2R-18, while the E-enolate gave the 2S-g1ycidic ester 2S-18 hy a similar type ofattack. Indeed, it is suggested that the major diastereoisomer of each geometric isomers
generated from the Darzens reaction is 2R configuration. Therefore, the Darz ns reaction
should proceed via aldol type addition of cyclohexanone from theintermediate la, followed by cyclization and give 2R-18.

i face on the

According to the econsiderations, the Z-enolate in la must be more predominant and/or reactive than the Eenolate in the reaction intermediate lb. II has been widely accepted that the most stable Zi omer is the one obtained under thermodynamic contro1. 22 Recently, it was reported

that the usc of potassium t-butoxide should favor the transition state leading to the ZIsomer

In

the

deprotonationof

8-phenylm nthylN-[bis(methylthio)methylcnclglycidate.2 3 The stereochemical outcome obtained from thDarzens reaction of acetophenone with a-chloroacetate 3a can be also rationalized on thehasis of the above explanation.

35

Schellle 9a: Z-enolateo£::::A,\H
2R- l RR J = (- )-8-phcnylmclltbyl

It seems reasonable that the IT-IT interaction between the phenyl group of the chiralauxiliary and the enolate moiety in the intermediate la tabilises the transition, tate of thstereo determining step)b,4 Within this conformation, the phenyl group of the chiralauxiliary are suitably positioned to the back face of the enolate moiety and ketone
approaches from the front side (Si face) of Ia to give the 2R-glycidic ester 18.
Moreover, the upfield position of the methylene proton of the e: ter moiety of 3a (8 3.35,
3.(1) relative to 2a (8 4.01, 4.(7) is presumably due to magnetic shielding by thearomatic ring and clearly indicates that in the ground state the confornler with the phenyl
ring behind the ester moiety is significantly populated.
The diastereoselcctive level in the Darzens reaction between (- )-8-phenylmenthyl (Xhaloacetates 3a,b and ketones was higher than that in the reaction with benzaldehyde. It
can be deduced in terms of the reactivity-selectivity rule that difference of the selectivity
between the carbonyl compounds was remarkable. It i reasonable that the reaction ofaldehyde proceeds through more reactant like transition state (early tran ition state)36

compared with that or ketones . Th refore, the asymmetric induction in the Daf/:e ns
reaction by means of the chiral auxiliary results in higher degree in the reactions ofketones. With regard to the Darl.ens reaction with ketones, Ilhc r action with keton
substituted by more electron-withdrawing group affordcd more predominantly cis
glycidic ester. It is probably that ketone substitutcd by more electron -withdrawing group
can react via more latcr transition state for formation of cis glycidic est r.
As mentioned above, the absolute configuration of the major diastereom r of Ir(ll1s- 21
is expected to be 2R,3S as illustrated in Scheme 10.
Scheme IO

frans -aziridinc

Conclusion. The Darzens reaction of (- )-8-phcnylmenthyl cx-haloacetate withvarious ketones can produce cis-glycidic esters with high diastercosel ctivity. Thc
stereochemical outcome of such a reaction is understandable in terms of two factors: (I)the open chain or the non-chelated antiperiplanar transition statL model and (2) the facial
elective attack of ketones to the Z-enolate in which the phenyl ring (If the chiral auxiliary
and the enolate part arc in [ace to [ace conformation. It is clearly that the aromatic moietyof (-)-8-phcnylmcnthyl group is critically important for the high levels of asymmetricinduction and presumably is intimatc1y involvcd at thc transition sLatc.

37

Experiolcntal Section
All reactions were calTied out under N2. Dry THf was prepared by distillation afLer
heing relluxed over Nalbenzophel1one. Dry CH2 12 was ohtain d by distillation over
CaH2. Silica gel 60F254 was used for preparative TLC with UV lamp being used todetect spots.
NMR spectra were recorded on J EOL GSX-270 instruments and III and 13

NMR

spectra were ohserved in CDC]3 solution with TMS as internal reference. MS sp ctra
were recorded on SHIMADZU GCMS-QP2000A and JEOL SX-J 02A instruments.
FAB spectra were obtained with glycerol as a matrix and EI data were ohtained at 70 eV.
Optical rotations were recorded on JASCO DIP-360 polarimeter. Melting point wererecorded on YANAGIMOTO melting point apparatus. Recycle HPLC was calTied out
using a J ASCO LC-908 and a JAIGEL-IH and 2H column (CHCI3).
General procedure for preparation of u-haloacetate.

(-)-Mcnthyl u-chloroacetate 2a. To a solution of (-)-mcnthol (39.S> g, 0.28 mol) in Et20 (100 mL),

was added N,N-dimethylaniline (35 mL, 276 mmol) and the solution was cooled at 0 ° .
To the solution, was added chloroacctyl chloride (20 mL, 0.25 mol) at 0 ° and wasstirred. After 3 h, the reaction mixture was warmed and renuxed for 3 h. Aft r thesol vent was removed under reduced pressure, CH2C12 (100 mL) and water (RO 111) was

added to the residue. The organic layer was washed with water (3 >< RO mL), brine (3 x
100 mL), and dried over anhydrous MgS04. Removal of the olvent left a yellow oiland distillation of the crude product at 90-100 °C/2 mmHg afforded 2a as a colorless oil(50.7 g, 87o/cl) [lit. 24: bp: 104-105 °C/4 mmHg\: 1H NMR (270 ~I1Hz, CDC]3) 80.77(d, ] = 6.8 Hz, 3 H), 0.80-1.13 (m, 3 H), 0.90 (d, ] = 6.8 Hz, 3 H), 0.92 (d, ] = 6.4
Hz. 3 H), 1.37-1.52 (m, 2 H), 1.65-1.72 (m, 2 H), 1.81-1.99 (111, 1 H), 2.00-2.06(m I H), 4.00 (d, J = 14.7 Hz, 1 H), 4.07 (d, J
4.6 Hz. I H) .

38

= 14.7 Hz, I H), 4.76 (dt, J = 10.9,

(-)-Menthyl a-bromoacetate 2b. The general proc dure was followed u 'ing ()-menthol (5.3 g, 34 mmol) and N.N-dimcthylaniline (4.5 mL, 36 mmol). Distillation of
the product at 95-100 °C/1.0 mmHg gave 2b 25 (colorless oil, 7.2 g, 770/0): 1H NMR(270 MHz, CDC13) 8 0.77 (d, J = 6.8 Hz, 3 H), 0.81-1.13 (m, 3 H) 0.90 (d, J = 6.8

HZ,3 H), 0.91 (d, J = 6.4 Hz, 3 H), 1.38-1.59 (m, 2 H), 1.66-1.71 (m, 2 H), 1.852.03 (m, 2 H), 3.78 (d, J = 12.2 Hz, 1 H), 3.83 (d, J = 12.2 Hz, 1 H), 4.73 (dt, J =10.7,4.4 Hz, 1 H).

(-)-8-Phenylmenthyla-chloroacetate 3a.

The general procedure wasfollowed using (-)-8-phcnylmenthol (1.1 g, 4.4 mmol) and N.N-dimethylaniline (0.6mL, 4.7 mmol) . Recrystallization of the crude product from hexane: gave a pure sample«().92 g, 67o/c, colorless crystal):

mp 81-82 °C flit. 2 : mp: 82-83 °C]; IH NMR (270MHz, CDCI3) 8 0.86-1.05 (m, 2 H), 0.89 (d, J = 6.3 Hz, 3 H), 1.11-1.26 (m, 1 H),
1.20 (s, 3 H), 1.31 (s, 3 H), 1.42-1.55 (m, 1 H), 1.66-1.75 (m I fI), 1.79-1.93 (m,2 H), 2.08 (ddd, J = 12.1, 10.8, 3.4 Hz, 1 H), 3.01 (d, J = 14.9 H,t:, 1 II), 3.35 (d, J =14.9 Hz, 1 H), 4.90 (dt, J = 10.7,4.4 Hz, 1 H), 7.11-7.19 (m, 1 11),7.26-7.33 (m, 4H); Anal. Calcd for C 18H2502CI: C, 70.00; H, 8.16. Found: C, (19.88; II, 8.14.

(-)-8-Phenylmenthyla-bromoacetate 3b.

The general procedure wasfollowed using (-)-8-phenylmenthol (960 mg, 4.13 mmol) and N.N-dimethylaniline (0.6mL, 4.6 mmol). Recrystallization of the crude product from hexane afforded a puresample of 3b 26 as a colorless crystal (915 mg, 63o/r) : mp 62-63 °C; 1H NMR (270MHz, CDC13) 8 0 .84-1.01 (m, 2 H), 0.89 (d, J = 6 .4 Hz, 3 H), 1.05-1.25 (m, 1 H),
1.20 (s, 3 H), 1.31 (s, 3 H), 1.42-1.52 (m, 1 H), 1.66- 1.73 (m, 1 H), 1.79-1.91 (m,2 H)~ 2.02-2.12 (m, 1 H), 2.96 (d J = 12.7 Hz, 1 H), 3.05 (d, J = 12.7 Hz, 1 H),

39

4.R6 (dt, J = 10.7,4.9 Hz, 1 H), 7.11-7.17 (m, 1 H), 7.26-7.33 (m, 4 H)~ Anal.
Calcd [or C18H2s02Br: C, 61.19~ H, 7.13. Found C, 61.24: H 7. 16.

(-)-8-Phenylmenthyl a-bromopropionate 4.

The general procedure wasfollowed using (- )-8-phenylmenthol (2.3 g, 9.98 m111(1) and N,N-dil11ethylaniline (1.4mL , 11 mmol). The crude product was purified by preparativ
hexane/AcOEt 1311) to give 4 (3.60 g, 980/0, colorless oil):TL(silica gel,II-[ NMR (270 MHz,COC 13) 8 0.78-1.18 (m, 3 H) , 0.88 and n.89 (d, J = 6.8 Hz, 3 H). 1.21 and 1.23 (s, 3H), 1.30 and 1.34 (s, 3 H), 1.38- 1.54 (m, 1 H), 1.55 and 1..56 (d, J = 6.8 Hz, 3 H)
1.55-1.75 (m, 1 H), 1.79-1.93 (m, 2 H), 1.98-2.15 (m, 1 H), 3.22 and 3.77 (q, J =6.8 Hz, 1 H), 4.84 (dt, J= 10.7 , 4.2 Hz, 1 H), 7.12-7.16 (m, 1 H), 7.26-7.30 (m, 4H); HR-EIMS mlz 368.] 159, M+ calcd [or C 19H270281 Br 368 .1] 74.

General procedure for Darzens condensation:

Methyl 3-phenyl-2,3-oxiranecarboxylate 5. To a suspension of potas . i lim f-blltox id(412 111 g, 3.78mmol) in CH2Cl2 (3 mL) at -78°C was added a solution o[ 1 (0.3 mL, 3.4 mmol) inCH2C12 (2 mL). After stirred at -78°C [or 3 h, a soluti n o[ benzaldehyde (0.5 111 ,5mm01) in CH2C12 (2 mL) was added dropwise to the reaction mixture and the mixtur
was slowly warmed fr0l11 -78 to () °C over 8 h. After the reaction mixture wa

tirred at ()°C for 16 h, water (60 mL) and ether (60 mL) was added to the mixture. The aqueoulayer was extracted with Et20 (3 x 60 mL) and the combined organic layers were wa hed
with bline (2 x 60 mL), dried over anhydrous Na2S04, and evaporated. The residue
was treated by preparative TLC (silica gel, hexane/AcOEt 13/1) to give a mixture of cisand frans-5 27 as a colorless oil (375 mg, 52%, ciS/fra!1s 1.0/9.5): 1H NMR (270 MHz,
COC13) 8 3.52 (d, J = 2.0 Hz, frons-2-H), 3.56 (s, cis-O-CH3), 3.83 (s, fra!1s-0-CH3),
3.85 (d, J = 4.9 Hz, cis-2-H), 4.10 (d, J = 2.0 Hz, frol7s-3 -H), 4.27 (d, J = 4.9 Hz, cis3-H). 7.26-7.40 (m. 5 H) .

40

(-)-Menthyl 3-phenyl-2,3-oxiranecarboxylate 6. The general proc dure wa.
followed using t-BuOK (325 mg, 2.90 mmol), 2a (0.65 I11L, 2.8 mmol), andhenzaldehyde (0.3 mL, 3 mmol). The crude product was eparated by pr parative TL(silica gel, hexane/ AcOEt 6/1) into the cis-6 and trons-6 (dia terenl11eric mixture) a a
colorless oil, respectively (829 mg, 97%, cis/trans 1.8/1.0). When 2b (0.5 mL, 2.2mmol) was lIsed under the reaction conditions (t-BuOK:

249 mg, 2.28 11111101;

benzaldehyde: 0.25 mL, 2.5 111mol) , cis- and trans-6 was obtained a a mixture ofdiastereomers, respectively (colorless oil, 67 mg, 81O/c), cis/frllns 6. II l.0): cis-6(diastereomeric mixture): 1H NMR (270 MHz, CDCI3) 8 0.32 (d, J = 6.8 Hz, minorCH(CH3)2), 0 .62 (d, J= 6.8 Hz, minor-CH3), 0.67 (d, J = 6.8 Hz, m1nor-

CH(CH3)2), 0.76 (d, J = 6.8 Hz, major-CH(CH3)2), 0 .78 (d, J = 6.8 Hz, major-CH3),
U.83 (d, J = 6.8 Hz, major-CH(CH3)2), 0.86-0.99 (m, 1 H), 1.14-1.70 (m, 6 H),
3.80-3.83 (m~ 1 H), 3.81 (d, J = 4.9 Hz, minor-2-H), 3.82 (d, J = 3.9 Hz, major-2-H),
4.26 (d, J = 4.9 Hz, minor-3-H), 4.26 (d, J = 3.9 Hz, major-3-II), 4.54 (dl J = 10.7,
4.4 Hz, minor-O-CH), 4.58 (dt, J = 11.0,4.4 Hz, major-O-CH), 7.26-7.42 (m, 5 II) 'trons-6 (diastereomeric mixture): 1H NMR (270 MHz, CDC13) 8 0.77-0.82 (m, 3 Il) ,0.88-0.94 (m, 7 H), 0.97-1.14 (m, 2 H), 1.38-1.67 (m, 2 H), 1.7 J - 1.80 (m, 1 H),
1.83-2.00 (m, 1 H), 2.02-2.08 (m, 1 H), 3.49 (d, J = 1.5 Hz, minor-2-H), 3.49-3.51(m, 1 H) , 3.50 (d, J = 2.0 Hz, major-2-H), 4.06 (d, J = 1.5 Hz, minor-3-H), 4.07 (d, J= 2.0 Hz, n1ajor-3-H), 4.82 (dt, J = 10.7,4.4 Hz, major-O-CH), 4.83 (dt, J = 10.9,4.4
Hz, minor-O-CH), 7.26-7.41 (m, 5 H).

(-)-8-Phenylmenthyl 3-phenyl-2,3-oxiranecarboxylate 7. The generalprocedure was followed using f-BuOK (38 mg, 0.33 mlnol), 3a (99 mg, 0.32 I11mol),and benzaldehyde (0.05 mL, 0.5 ml11ol). Preparative TLC (silica gel, hexane/AcOEt 6/l)of the cnlde product afforded a mixture of ci \'- and frans-7 as a cl)lorless oil (109 mg,

41

90o/c, cis/frans = 2.8/1.0, c;;s: 38% dc, 'rans: :13%· d ). When 3b (lOO mg, 0.29 111111(1)was u cd under the reaction conditions (t-BuOK: 35 mg, 0.31 I11lllol; h nzaldehyd :0.05 mL, 0.5 m111(1), a mixture of cis- and 'rans-7 was ohtainLd as a colorless oil (81mg, 750/(1, cis/'rans 6.7/1.0, cis: 43o/r) dc, 'rans: 41 % de): geometric and diastereoll1ericmixture of 7: 1H NMR (270 MHz, CDC13) 8 0.66-2.14 (111, 17 H), 2.49 (d, J = 1.5
Hz, 'rons-minor-2-H), 2.67 (d, J = 4.9 Hz, cis-minor-2-H), 2.72 (tI, J = 2.0 Hz, 'ransmajor-2-H), 3.46 (d, J = 4.4 Hz, cis-major-2-H), 3.74 (0, J = 1.5 Hz, Irans -minor-3H), 3.93 (d, J = 2.0 Hz, ,rans-major-3-H), 3.99 (0, J = 4.9 Hz, cis-minor-3-H), 4.16

(d, J = 4.4 Hz, cis-major-3-H), 4.58 (dt, J = 10.7,4.4 Hz, frans-major-O-CH), 4.71
(dt, J = 10.7,4.4 Hz, 'rans-minor-O-CH), 4.86 (dt, J = 10.7, 4.4 H :~, cis-1l1ajor-O-CH),
4.96 (dt, J = 10.7,4.4 Hz, cis-minor-O-CH), 7.15-7.67 (m, 10 H); 13

NMR (68

MHz, CDCI3) 8 21.5 (x2), 22.6, 25 .3, 26.0, 26.7, 27.4, 29.5, 30.9, 31.1, 34.2, 34.3,
39 .3, 39.8,41.0, 4J.l, 42.7, 50.2, 50.3, 55.3, 55.7, 56.8, 57.4, 67.0,74.5,76.2,
125 .0, 125 .2, 125.4, 125.5, 126.4, 126.9, 127.8, 128.0, 128.1, 128.3, 132.8, 150.6,
151.7,165.3,165.9; HR-EIMS m/z. 378.2181, M+ caIed for C25H3003 378.2195.

(-)-8 -Phenylmenthyl 2-methyl-3-phenyl-2,3-oxiranecarboxylate 8. The

general procedure was followed using f- BuOK (51 mg, 0.45 mm 01), 4 (83 mg, 0.23
11111101),and benzaldehyde (1.1 n1L, 11 mmol).

Preparati vc TL(silica gel,hexane/AcOEt 13/1) afforded 'r([ns-8 (major diastereomer) and a diastereomeric mixtureof cis-8 together with fl'0I1S-8 (minor diastereomer), respectively (pale yel10w oil, 78 mg,
920/c, cis/frons 4.9/1.0, cis: 290/0 dc, frans: 33o/c de): the mixture or cis-8 (diastereomericmixture) and Irans-8 (minor diastereomcr): 1H NMR (270 MHz, CDC13) 80.59 (d, J =6.5 Hz, cis-minor-CH3), 0.60-1.87 (111, 8 H), 0.75 (d, J = 6.3 Hz, cis-major-C H 3),
0.89 (d, J = 6.4 Hz, fral1s-minor-CH3), 0.95 (s, cis-major-C(CH.3)2), l.OO (s, fran.\'minor-2-C H 3), l.07 (s, cis-ma.ior-C(CH3)2), l.19 ( ~ cis-minor-C(CH3)2), 1.29 (s,,rans-minor-C(C H 3)2), t.31 (s, cis-minor-C(CH3)2), 1.39 (s, frafls-minor-C(C H 3)2),42

1.40 (s, cis-minor-2-CH3), 1.52 (s, cis-major-2-CH3), 3.93 (s, cis-minnr-3-H), 3.95
(s. cis-major-3-H), 4.1R (s, 'ral7s-minor-3-H), 4.52 (dt. J= 10.7,4.4 HI., cis-major-O-

CH), 4.68 (dt, J = 10.7,4.4 Hz, cis-minor-O-CH), 4.91 (dt, J = 16. 1,4.4 Hz, fransminor-O-CH), 7.11-7.23 (m, 2 H), 7.24-7.52 (m, 8 H); IIR-EIM~; m/z 392.2350, M+
calcd for C26H3203 392.235 j; frol7s-8 (pure major diastereomer):

1H NMR (270MHz. CDCI3) 8 0.81-1.70 (m, 6 H), 0.89 (d, J = 6.4 Hz, 3 H, CH3), 0.95 (s, 3 1-1, 2CH3), 1.25 (s, 3 H, C(CH3)2), 1.38 (s, 3 H, C(CH1)2), l.87-1.92 (m, j II), 2.052.15 (m, 1 H), 4.01 (s, 1 H, 3-H), 5.04 (dl, J = 10.6,4.7 Hz, 1 H, -0- H),7 .2 1-7.44(m. I() H): HR-EIMS m/z 392.2342, M+ calcd [or C26H3203 392.23 51.

Methyl

3-methyl-3-phenyl-2,3-oxiranecarboxyllate

9.

The generalprocedure was followed using f-BuOK (412 mg, 3.68 I11mol) , t (0.30 mL, 3.4 mmo]),and acetophenone (0.6 mL, 5 mmol). Preparative TLC (silica gel, hexane/ AcOEt 15/1)of the cnlde product afforded cis- and frans-9 28 as a colorless oil, respectively (435 mg,

66o/c, cis/tral1s 1.01l.3): cis-9: 1H NMR (270 MHz CD ]1) 8 1.75 (s. 3 I 1) ,3 .45 (s, 3H). 3.70 (s, 1 H), 7.26-7.41 (m, 5 H): MS (EI) mlz (relative inlen ity): 192 (M+, 5 Yc) ;'r(117s-9: 1H NMR (27() MHz., CDCI3) 8 l.77 (s, 3 II), 3.47 (s, I II), 3.84 (s, 3 II),
7.26-7.39 (m, 5 H); MS (El) m/z (relalive intensity): 192 (M+, 59?).

Methyl 3-ethyl-3-phenyl-2,3-oxiranecarboxylate 10. The general procedur
was followed using ,-BuOK (415 mg, 3.70 mmol), 1 (0.3 mL, 3.4 mmol), andpropiophenone (0.07 mL, 5 mmol). Preparative TLC (silica gel, hexane/ AcO t] 3/1) oflhe crude product afforded cis-I () and trans-H) as a colorless oi 1, rC'spectivcly (414 mg,

58%, cis/'rons l.()I1.4). The IH NMR dala of t() accorded with the lilcralure 29 : ci '-10:I H NMR (270 MHz. CDC13) 8 0.93 (l, J = 7.3 Hz, 3 H), 1.82 (dq, J = 14.5,7.3 Hz, 1
H), 2.18 (dC), J = 14.5,7.3 Hz, 1 H), 3.43 (s, 3 H), 3.7l (s, 1 H), '7.25-7.38 (m, 5 H);
MS (EI) m/z: 206 (M+): frolls-IO: 1H NMR (270MHz, CDCl3) b 0.94 (l, J = 7.3 Hz,

433 H). 1.88 (dq, ) = 14.3,7.3 HI" 1 II) 2.17 (dq, ) = 14.3,7.3 II!., 1 H), 3.48 (5,H), 3.83 (s, 3 H), 7.40-7.27 (m, 5 H); MS (El) II1/Z: 206 (M+).

(-)-Menthyl 3-nlethyl-3-phenyl-2,3-oxiranecarboxylat

11. The generalprocedure was followed using t-BuOK (325 mg, 2.82 111mol), 2a (0.65 mL, 2.8 11111101),
and acetophenone (0.4 mL 3.4 mmol) . Preparative TLC (silica gel, h xanel AcOEt 151 I)of the crude product afforded cis-l1 and trans - II as a mixture of diastereomers,30
respectively (colorless oil, 737 mg , 83 0/(', cis/trans 8.3/1.0, cis: 3~; ~) dc, trans: < 10%,de): cis -11 (diastcreomeric mixture): 1H NMR (270 MHz, CDC!3) 80.46 (d, J = 6.8
Hz, major-CH(CH3)2) , 0.53 (d, ) = 6.8 Hz, minor-CH(CH3)2), 0.64-1.01 (m, 3 H),
0.74 (d, J = 6.8 Hz, minor-CH(CH3)2), 0.77 (d, J = 6.8 Hz, major-CH(CH3)2), 0.77(d, ) = 6.3 Hz, major-CH3), 0.79 (d, ) = 6.3 Hz, minor-CH3), 1.15-1.60 (m, 6 H),
1.73 (s, minor-3-CH3), 1.76 (s, major-3-CH3), 3.65 (s, major-2-H), 3.68 (s, minor-2H) , 4.47 (dt, J = 10.7, 4.4 Hz, major-O-CH), 4.52 (dt, J = 10.7, 4.4 Hz, minor-OCH), 7.22-7.41 (m,5 H); HR-EIMS m/z 316.2036, M+ C20H2803 316.2039; trans11 (diastereomeric nlixture): 1H NMR (270 MHz, CD 13) 8 0.77-2. 05 (111,21 II) ,3.44 (s, minor-2-H), 3.45 (s, major-2-H), 4.84 (dt, J = 10.7, 4.4 lIz, m inor-O- II),
4.87 (dt, )= 10.7, 4.4 Hz, major-O-CH), 7.24-7.38 (m, 5 1-1);

HR- ~ IM

111/Z.

3-methyl-3- pheny 1-2,3-oxi n'anecarboxyl a te

12,

316.2030, M+ C20H2803 316.2039.

(- )-8- Phenylmenthyl

The genera] procedure was followed using t-BuOK (74 mg, 0.66 m111ol) , 3a (201 mg,
0.65 mI1101), and acetophenone (0.15 mL, 1.3 I11mol ). Preparative TL(silica gel,hexanel AcOEt 8/1) of the crude product gave cis-12 (major diastereomer), trans-12(major diastcreomer) , and trans-12 (minor diastereomer) as the pure samples,
respectively (colorless oil, 20 I mg, 790/0, cis/trans 7.6/1.0, cis: 93~ dc, trans: 520/0 de) .
When 3b (150 mg, 0.43 mmol) was u ed under the reaction conditic)ns (f-BuOK: 49 mg,44

0.44 mmol: acetophenone: O.OS mL, 0.4 m111(1), cis- and Irrms-ll was obtained as a
mixture of diasteromers, respectively (colorless oil, 94 mg, 56(~ , cis/trans 5.6/1.0, cis:>95~) dc, trans: 21 % de): cis-12 (major diastereomer): 1H NMR (270 MHz, CDC]3)

8 0.30 (4, J = 12.2 Hz, 1 H), 0.61-1.21 (m, 4 H), 0.67 (d, J = 6.4 Hz, 3 H), 1.10 (s, 3H), 1.25 (s, 3 H), 1.37-1.47 (m, 2 H), 1.67 (s, 3 H), 1.75-l.83 (m, 1 H), 3.31 (s, 1H), 4.S0 (dt, J = 10.7, 4.4 Hz, 1 H), 7.13-7.40 (m, 10 H);

13 C NMR (68 MIIz,

CDCI3) 8 21.4, 24.6,25.6,26.6,27.4,30.9,34.2,40.4, ';0.1,60.6,63.2, 125.2,
125.5,

126.6~

127.7, 127.8, 127.9, 128.2, 137.1, 150.5, 166.4;

HR-EIMS /I1/z

392.2371, M+ calcd for C26H3203 392.2351; Irans-12 (major diastereomer):

1H

NMR (270 MHz, CDCl3) 80.30 (4, J = 12.2 Hz, 1 H), 0.61-1.21 (m,4 H), 0.67 (d, J= 6.4 Hz, 3 H), 1.10 (s, 3 H), 1.25 (s, 3 H), 1.34-1.47 (m, 2 H), 1.67 (s, 3 H), 1.751.83 (m, 1 H), 3.31 (s, 1 H), 4.50 (dt, J = 10.7,4.4 Hz, 1 H), 7.13-7.40 (m, 10 H);
13 C NMR (68 MHz, CDCI3) 8 17.3,21.7,26.0,26.8,27.3, 3l.3, 34.4,40.0,41.7,
5U.4, 61.5, 61.8,76.3, 125.3, 125.4, 127.9, 128.0, 128.4, 140.3, 150.7, 166.9; HRElMS m/z 392.2335, M+ ca1cd [or C26 H 3 203 392.2351;
diastcrcomer):l/"al1s - 12 (minor

1H NMR (270 MHz, CDC13) 8 0.85-1.88 (In, 7 H), 0.89 (d, J = 6.4

Hz, 3 H), 1.22 (s, 3 H), 1.34 (s, 3 H), 1.63 (s, 3 H), 2.02-2.11 (111, 1 I I), 2.32 ( , 1

H), 4.96 (dt, J = 10.7,4.4 Hz, 1 H), 7.01-7.07 (m, 1 H), 7.18-7.37 (m, 9 H); HR-ElMS mlz 392.2365, M+ calcd for C26H3203 392.2351.

(-)-8-Phenylmenthyl 3-ethyl-3-phenyl-2,3-oxiranecarboxylate 13. The
general procedure was followed llsing t- BuOK (37 mg, 0.33 11111101), 3a (101 mg, 0.33mmol), and propiophenone (0.05 mL, 0.4 mmol).

Preparative TL(silica gel,hexane/ AcOEt 13/1) afforded cis-13 and frans-13 as a n1ixture of diastereomers,
respectively (colorless oil, 63 mg, 470/<, cis/frons 4.5/l.0, cis: 87% de, frans: 78% de).
When 3b (94 mg, 0.26 111mol) was used under the reaction conditions (I-BuOK: 33mg,
O.3{) mmol: propiophenone: 0.05 mL, 0.4 mmol), cis- and frans-13 was obtained a a45mixture of dia tereomers, respectively (colorless oil, 46 mg, 43(/'<J, cis/trails 4.2/1.0, cis:>950/(1 dc, trans: >950/(, de): cis-I3 (diastereomeric mixture):

1H NMR (270 MHz,CDCI3) 8 0.20 (q, 1 = 12.5 Hz 1 H), 0.58-1.45 (m, 6 H), 0.65 (d, 1 = 6.4 Hz, 3 H),
0.88 (t, 1 = 7.3 Hz, 3 H), 1.14 (s, 3 H), 1.28 (s, 3 H), \.65-1.80 (m 2 H) 2.17 (dg, 1= 14.7,7.3 Hz, 1 H), 3.36 (s, 1 H), 4.49 (dt, 1= 10.6,4.4 Hz, 1 H) 7.13-7.37 (m,1() H);

HR-EIMS m/z 406.2537, M+ calcd for C27H3403 406.2S08: tra/1s-13(diastereomeric mixture): 1H NMR (270 MHz, CDC]3) 8 0.77-1.S6 (m, 6 H), n.87 (d,1 = 6.4 Hz, 3 H), 0.95 (l, 1 = 7.3 Hz, 3 H), 1.29 (5, 3 H), 1.39 ( , 3 II), 1.85-2.05(m, 3 H), 2.17 (dq, 1= 14.2,7.3 Hz, 1 H), 3.16 (5,1 H), 4.89 (dt, 1= 14.2,4.1 Hz, I

H), 7.04-7.10 (m, 1 H), 7.20-7.38 (m, 9 H); HR-EIMS mlz 406.2537, M+ calcd for

C27H3403 406.2508.

(-)-Menthyl

3,3-dimethyl-2,3-oxiranecarboxyI3Ite

14.

The generalprocedure was followed using t-BuOK (34 mg, 0.31 n1mol), 2a (0.1 mL, 0.43 mlnol),and acetone (0.05 mL, 0.7 mmol). Preparalive TL(silica gel, l1exan / AcO l 13/1)

afforded 14 as a mixture of diaslereomers (colorless oil, 30 mg, 39~7cJ, 140/<-1 de):or lhemajor diastereomer. The 1H NMR dala of 14 accorded with the lileralure 31 : 1H NMR(270 MHz, CDCI3) 8 0.75 (d, 1 = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3 H), 0.91 (d, J =6.8 Hz, 3 H), 0.97-1.14 (m, 3 H), 1.36 (s, 3 H), 1.43 (s, 3 H), 1.44-1.54 (m, 2 H),
1.64-1.74 (m, 2 H), 1.81-1.94 (m, 1 H), 1.95-2.05 (m, 1 H), 3.32 (s, 1 H), 4.83 (dt,1 = 11.2, 4.4 Hz, 1 H); for the minor diaslercomer: 1H NMR (270 MHz, CD ]3) 8

0.77 (d, 1 = 6.8 Hz, 3 H), 0.91 (d, 1 = 6.8 Hz, 3 H), 0.91 (d, 1 = 6.8 Hz, 3 H), 0.941.14 (m, 3 H), 1.32-1.63 (m, 2 H), 1.38 (s, 3 H), 1.43 (s, 3 H), 1.64-1.73 (m, 2 H),
1.80-l.9] (m, 1 H), 1.92-2.05 (m, 1 H), 3.33 (5, 1 H), 4.80 (dl, J = 1 1.2 , 4.4 Hz, 1
H).

46

(- )-8- Phenyl nlen thyJ

3,3-di methyl-2,3-oxiranecarboxylate

15.

The

general procedure was followed u ing f-BuOK (38 mg, 0.34 11111101), 3a (l01 mg, 0.33
mOlal), and acetone (0.05 mL, 0.7 111mol). Preparative TLC (silica gel, hexan 1AcOEt
13/1) afforded 15 as a mixturc of diastereol11crs (colorless oil, 70 mg, 64 Yo , 870/0 de):[or the major diastereomer: 1H NMR (270 MHz, CDCI3) 8 0.77-· 1.15 (m, 3 H), 0.87
(d , J = 6.4 Hz, 3 H), 1.23 (s, '1 H), 1.31 (s, 3 H), 1.33 (s, 3 H), t .37 (s, 3 H), 1.401.65 (m, 3 H), 1.92-2.00 (m, 1 H), 2.06 (ddd, J = 12.2, 10.8, 3.4 Hz, 1 H), 2.84 (s, 1H), 4.87 (dt, ) = 10.8,4.4 Hz, 1 H), 7.12-7.29 (m, 5 H); HR-ElMS m/z 330.2229,
M+ calcd [or C21 H3003 330.2195.

(-)-8- Pheny Imenth yl 3,3-diethy 1-2,3-oxiranecarboxy la t(! 16. The generalprocedure was followed using f-BuOK (36 mg, 0.32 ml11ol), 3a (99 mg, 0.32 mmol),and 3-pentanone (0.05 mL, 0.5 mI1101). Preparative TLC (silica gel, hexanel AcOEt 13/1)of the crude product afforded 16 as a mixture of diastereomers (colorless oil, 54 mg,

479", 81 o/c de): [or the major diastereomer: 1H NMR (270 MHz L C13) 8 0.73- 1.(1)(m. 3 H), 0.86 (d, J = 6.8 Hz, 3 H), 0.89, (t, J = 7.3 HI" 3 H), 1.00 (t, J = 7 .3 II!., ~H), 1.25 (s, 3 H), 1.34 (s, 3 H), 1.39-1.75 (m, 3 H), 1.6~ (q, J=:

7.3 liz, 2 H), 1.67(q, ) = 7.3 Hz, 2 H), l.Y4-2.04 (m, ] H), 2.01 (ddd, J = 12.2, IO .7, 3.4 Hz, 1 H),

3.00 (s, 1 H), 4.87 Cdt, } = 10.7, 4.4 Hz, 1 H), 7.12-7.29 (01, 5 H); HR-EIMS II1/Z

358.2531, M+ calcd [or C21 H3403 358.2508.

(-)-8-Phenylmenthyl

3,3-cyclopenta-2,3-oxiranecarboxylate

17. Thegeneral procedure was followed using f-BuOK (34 mg 0.30 I11mol), 3a (91 mg, 0.29mmol), and cyclopentanone (0.05 mL, 0.6 mmol).

Preparati\'e TLC (silica gel,hexanel AcOEt 13/1) o[ the crude product afforded 17 as a mixture of dia tereomers(colorless oil, 49 mg, 45%, 80~ de): for the major diastereomer: I H NMR (270 MHz,CDCI3) 8 O.77-l.14 (m, 3 H), 0.87 (d, J = 6.3 Hz, 3 H), 1.23 (s, 3 H), 1.3 j (s, 3 H),

47

1.40-2.00 (m, 4 H), 1.57-1.62 (m 2 H), 1.62-1.66 (m 2 H), 1.76-1.87 (m, 4 H),
2.05 (ddd, ) = 12.2, 10.7,2.9 Hz, 1 H), 3.01 (,' 1 H) 4.86 (dt, ) = 12.2, 10.7,4.4
Hz, 1 H), 7.12-7.28 (m, 5 H): HR-EIMS m/z 356.2346, M+ caIcd for C23 H 3203

356.2352.

(-)-8-Phenylmenthyl

3,3-cyclohexa-2,3-oxiranecarboxylate

18.

The

general procedure was followed using ,-BuOK (36 mg, 0.32 ml11ol), 3a (93 mg, 0.30mmol), and cyclohexanone (0.05 mL, 0.5 11111101).

Preparative

LC (silica gel,hexane/ AcOEt 13/1) of the crude product afforded 18 as a mixtll re of dia tereomers(colorless oil, 50 mg, 45%, 960/0 de): for the major diastereomer: ] H NMR (270 MHz,CDCI3) 8 0.74-1.10 (m, 3 H), 0.86 (d, J = 6.8 Hz, 3 H), 1.24 (s, .3 H), 1.24-1.34 (111,2 H), 1.34 (s, 3 H), l.37-l.75 (m, 3 H), l.52-l.57 (m, 2 H), 1.65-1.72 (m, 6 H),
1.93-2.02 (m, 1 H), 2.02 (ddd, ) = 12.2, 10.7,3.4 Hz, 1 H), 2.96 (s, 1 H), 4.88 (dt, J= 10.7,4.4 Hz, 1 H), 7.13-7 .30 (m, 5 H); 13 C NMR (68 MHz, CDC 13) 8 21.5, 24.4,

24.6, 25.1, 25.6, 26.7, 27.4, 28.2, 31.1, 34.2, 34.7, 39.8, 41.L1·, 50.1, 59.2, 64.4,
75.8, 125.0, 125.2, 127.7, 150.5, 167.3;

HR-EIMS 111/Z 370.2543, M+ calcd for

C24H3403 370.2508.

(-)-8-Phenylmenthyl

3,3-diphenyl-2,3-oxiranecarboxylate

19.

The

general procedure was followed using ,-BuOK (39 mg, 0.35 mI1101), 3a (107 mg, 0.35mmo1), and benzophenone (92 mg, 0.50 mmol).

Preparativ..., TLC (silica gel,hexane/ AcOEt 13/1) of the crude product afforded 19 as a mixture or diastereomers(colorless oil, 71 mg, 450/0, 77O/C de): for the major diastereomer: 1H NMR (270 MHz,CDCI3) 8 0.28 (4 J = 12.2 Hz, 1 H), 0.56-0.98 (m, 2 H), 0.69 (d, J = 6.3 Hz, 3 H),
1.17 (s, 3 H), 1.18-1.52 (m, 4 H), 1.33 (s, 3 H), 1.80 (ddd, J = 12.2,10.7,3.4 Hz, 1H), 3.65 (s, 1 H), 4.60 (dt, ) = 10.7,3.9 Hz, 1 H), 7.07-7 ,.26 (10, 5 H), 7.28-7.31

48

(m.5 H), 7.46-7.52 (m, 5 H); HR-EIMS 1l1/z. 454 .2531

M+ calcd for

31H3403454 .2508.

(-)-8- Phenyl menthyl

3,3-cyclohexa-2- methyl-2,3-ox iranecarboxylate

20. The general procedure was followed using t-BuOK (68 mg, 0.60 mmol), 4 (103
mg, 0.28 mmol), and cyclohexanone (33 mg, 0.34 m111(1). Preparalive TLC (. ilica gel ,hexane/ AcOEt ] 3/l) of the crude product afforded a mixture o[ 2R- and 2S-21 as acolorless oil (7 mg, 180/0,36%; de): IH NMR (270 MHz, CDCI3) 80.84- 2.09 (m, 30
H), 4.84 (dl, J = 10.7,4.4 Hz, major-O-CH), 4.98 (dt, J = 10.7, 4.4 Hz, minor-OCH), 7.15-7.20 (m, 1 H), 7.26-7.31 (m, 4 H); HR-EIMS IIllz 384.2662, M+ calcd for
C25H3603 384.26()4.

(-)-8-Phenylmenthyl 3-phenyl-N-phenyl-2,3-aziridine 21.

The generalprocedure [or Darzens reaction was followed using t-BuOK (86 mg, 0.77 mmol), 2a(101 mg, 0.33 mmol), and N-benzylideneaniline (85 mg, 0.47 mmol). Preparative TL(silica gel, hexane/ AcOEt 13/1) afforded cis-21 (major diastereonl'"'r) and a mixtur ofcis-21 (minor diastcreomer) togelher with trans-21 (diastereomeric mixture) (57 mg,
38%, ciS/frons l.5/1.0, cis: 41 % de, trans: >850/0 de): cis-21 (pure diastereomer): 1H
NMR (270 MHz, CDCI3) 8 0.41-0.54 (m, 1 H), 0.67 (d, J = ().3 Hz, 3 H,

H3),0 .73-0.92 (m, 2 H), 0.97-1.13 (m, 1 H), l.14-1.31 (m, I H), 1.20 (s, 3 H,
C(CH3)2), 1.34 (s, 3 H, C(CH3)2), l.54-1.62 (m, 1 H), 1.67- I.7R (m, 1 H), l.922'()2 (m, 1 H), 2.34 (d, J = 7.1 Hz, 1 H, 3-H), 3.33 (d, J = 7.1 Hz, 1 H, 2-H), 4.71
(dt, J = 10.8,4.7 Hz, 1 H, -O-CH), 6.95-7 . 15 (m, 3 H), 7.21-7.42 (m, 12 H); FAB ElMS mlz 454.2697, M+H calcd for C31 H3602N 454.2746; tro/1.\'-21 (diastereomericmixture) and cis-21 (minor diaslereomer): 1H NMR (270 MHz, CDC13) 8 0.59-2.16(m 17 H), 2.15 (d , J = 2.7 Hz, traIH-major-3-H), 2.75 (d, J := 2.4 Hz, trans-minor-3-49-H), 2.90 (d J = 6.5 Hz, cis-minor-3-H), 3.53 (d, J = 6.5 Hz, cis-minor-2-H), 3.55 (d ,) = 2A Hz fral1s-rninor-2-H), 3.61 (d, J = 2.7 Hz, tl'al1s - major- 2- H), 4.61 (dt, J =10.8, 4.4 Hz, Iral7s-minor-O-CH), 4.78 (dt, J = 10.7, 4A Hz, fral7s ·- major-O-CH), 4.82
(dt, J = 10.8 , 4.7 Hz, cis-minor-O-CH), 6.64-7.31 (m, ll;; HI;

FAB-EIMS m/z

454.2757, M+H cald for C31 H3602N 454.2746.

(-)-8- Ph eny I me n thy I 3- (p - methoxyp heny I )-2,3-oxira neca rboxy I a te

22.

PTLC (silica gel, hexane/ AcOEt 13/1) afforded the mixture of cis- and fl'nl7s-22 (49%,
cis/frons 4.3/1.0, cis: 64% dc, frans : 35% de):cis-22:

1H NMR (270 MHz, CDCl3)

8 0.8-2.3 (m, 17 H), 2.49 (d, J = 2.0 Hz, minor-2-H), 2.74 (d, .J = 2.0 Hz, major-2-H),
3.78 (s, 3 H, OMe), 3.88 (d, .J = 2.0 Hz, 1 H, 3-H), 4.6-4.7 (m, 1 H, -O-CH), 7.2-7.4(m,9 H): fral1s-22:

1H NMR (270 MHz, CDC13) 8 0.8-2.3 (m, 17 H), 2.65 (d, .J =4.9 Hz, minor-2-H), 3.42 (d, J = 4.4 Hz, major-2-H), 3 .76 (s, 3 H. OMe), 3.95 (d, J =4.4 Hz, minor-3-H), 4.11 (d, J = 4.9 Hz, major-3-H), 4.6-4.7 (m 1 H, -O-CH), 7.2I

7.4 (m, 9 H).

( - ) - 8 - Ph e n y I men thy I

3 - (p - met h y 0 x y P hen :y I ) - 3 - met h y I - 2 , 3 -oxiranecarboxylate 23. PTLC (silica gel, hexane/ AcOEt L3/1) a.fforded the mixtureof cis- and frans-diastereomer (31 %, cis/ frans 4.4/1 ,(»: cis-23 (major diastereomer):
1H NMR (270 MHz, CDCl3) 8 1.0-2.1 (m, 8 H), 0.69 (d, J =: 6.4 Hz, 3 H, Me), 1. L1(s, 3 H, Me), 1.25 (s 3 H, Me), 1.66 (s, 3 H, 3-Me), 2.08 (dt, J = 11 A, 3.8 Hz, 1 H),
3.29 (s, 2-H), 3.77 (s, 3 H, OMe), 4.4-4.6 (m, 1 H, -O-CH), 7.2-7.4 (m, 9 H); frans23 (major diastereomer):

1H NMR (270 MHz, CDC13) 8 1.0-2.l (m, 13 H), 0.88 (d, J= 6.34 Hz, 3 H, Me), 1.74 (s, 3 H, 3-Me), l.86 (dt, J = 13.3, 3.3 Hz, 1 H), 3J)6 (s, 2H), 3.82 (s, 3 H, OMe), 4.4-4.6 (m, 1 H, -O-CH), 7.2-7.4 (m, 9 H)

50

(-)-8-Phenylmenthyl

3 - (p - met h yip hen y I ) - 3 - n1 e thy I - 2 , 3 -oxiranecarboxylate 24. PTLC (. ilica gel hexanel AcO t 13/1) ,,{lord d the mixtureof cis- and fral1s-24 (54%, cis/frolls 4.2/1.0); cis-24 (major diastereomer):

1H NMR(270 MHz, CDCl3) 8 O.6X (d, J = 4.1, lO.Y Hz, 3 H, IVle) , l.O-l.X (m, X H) 1.12 (s, 3
H. Me), 1.26 (s, 3 H, Me), 1.66 (s, 3 H, 3-Me), 2.31 (, , 3 H, Me) . 3.23 (" 1 H, 2-1 I),
4.52 (dt, J = 4.1 Hz, 10.9 Hz, 1 H, -O-CH), 7.2-7.4 (m, Y H):
diastereomer):

fral1s-24 (major

1H NMR (270 MHz, CDC]3) 8 0.88 (d, J = 6.3 Hz, 3 H, Me), 1.0-1.8(m, 11 H), 1.42 (s, 3 H, Me), J .74 (s, 3 H, 3-Me), 2.35 (s, 3 H, ~1e), 3.03 (s, 1 H, 2H), 4.4-4.6 (m, 1 H, -O-CH), 7.2-7.4 (m, 9 H).

(-) - 8 - P hen y 1m e n th y I

3 - (111 - met h yIp hen y I ) - 3 - met h y I - 2 , 3 -oxiranecarboxylate 25. PTLC (siUca gel, hexanel AcOEt 13/ I) afforded the mixtureof cis- and frnns-25 (830/0, cis/frans 5.411.0):

cis-25 (major diastereomer):

1H NMR(270 MHz, CDCl3) 8 0.68 (d, J = 6.4 Hz, 3 H, Me), 1.] 3 (s " 3 H, Me), 1.27 (s, 3 H,Me), 1.67 (s, 3 H, 3-Me), 1.1-2.1 (m, 8 H), 2.42 (s, 3 H, Me), 3.31 (s, 2-H), 4.52 (dt,
J =4.4,10.8 Hz, 1 H), 7.2 -7.4 (m, 9 H); frans-25 (major diasteleom r):

IH NMR(270 MHz, CDC)3) 8 1.75 (s, 3 H, 3-Me), l.1-2.1 (m, 8 H), 2.3{) (s, 3 H, Me) , 2.99
(s. 1 H, 2-H), 4.4-4.6 (m, 1 H, -O-CH), 7.2-7.4 (m~ 9 1-1).

(-)-8-Phenylmenthyl

3-(11'1-methoxyphenyl)-3-methyl-2,3-oxiranecarboxylate 26. PTLC (silica gel, hexanel AcOEt 13/1) afforded the mixtureof cis- and fral7s-26 (870/0, ciS/frans 10/1.0): cis-26 (major diastcreomer): I H NMR(270 MHz, CDCl3) 8 0.69 (d, J = 6.3 Hz, 3 H, Me), 1.12 (s, 3 H, Me), 1.26 (s, 3 H,Me), 1.67 (s, 3 H, 3-Me), 1.1-2.1 (m, 8 H), 3.31 (s, 1 H, 2··H), :1.80 (s, 3 H, OMe) ,4.54 (dt, J = 4.2, )0.6 Hz, 1 H), 7.2-7.4 (m, 9 H); f(ol7s-26 (major diastereomer):I H-NMR (270 MHz, CDCI3) 8 0.88 (d, J = 6.8 Hz, 3 H, Me), 1.29 ( ,3 H, Me), 1.42

51

(s. 3 H, Me),

1.75 (s, 3 H, 3-Me), 1.1-2.1 (m, 8 H), 3.09 (s, 1 H. 2-11), 3.92 (s, 3 H,

OMc), 4.4-4.6 (m, 1 H, -O-CH), 7.2-7.4 (m, <) II).

3-Phenyl-l,3-butanediol 27. To a suspension or LiAIH4 (80 mg, 2.1 mmol) in
THF (4 mL) at 0 °C was slowly added a solution of cis-12 (lOS mg, 0.27 mmol). The
reaction mixture was stirred at 0 °C and warmed to 25°C. After 1'7 h, lh mixlure wascooled at () °C. To the mixture, were carefully added ether (30 mL) and waler (1 mL).
The formed precipitate was filtered and sufficiently wa hed with El20. The combinedorganic layer was washed with water and dried over anhydrous Na2~)04 and evaporated.
The crude product was purified with preparative TLC (silica gel, hexane/ AcOEt 10/3) and27 was afforded as a colorless oil (34 n1g, 76%, I aJ25 0 = -65.8 (c 0.137, benzene)[lil. 16 : (+)-(3R)-27: la]25 0 = +66.7° (maximum, benzene)]): I H NMR (270 MHz,COCI3) 8 1.57 (s, 3 H), 2.00 (ddd, J = 14.7,5 .3,3.9 Hz, I H), :~. to (ddd, J = ]4.7,
8.6,4.4 Hz, 1 H), 2.85 (bs, 1 H), 3.60-3.44 (m, 1 H), 3.80 (bs, ) H), 3.80-3 .64 (m,1 H), 7.27-7.20 (m, 1 H), 7.37-7.31 (m, 2 H), 7.44-7.40 (m, 2 H); HR- IMS III/Z
166.1010, M+ ca1cd for CIOH1402 166.0994.

(- )-8- Phenyl menthyla- (l-cycloh exeny I)-a-hydroxy.acetate

28.

The

mixture of 18 (3 L7 mg, 0.855 111mol) and MS 4A (5.6 g) in benzene was rel1uxed. After
12 h, the mixture was cooled and filtrated. The precipitate was sufficiently washed with
CH2CI2. The filtrate was evaporated. Preparative TLC (Si02, hexane/ AcOEt 9/1) of thecrude product afforded 28 (166 mg, 520/0): IH NMR (270 MHz, COC]3) 80.80-1.10(m 3 H), 0.87 (d, J = 6.8 Hz, 3 H), 1.22 (s, 3 H), 1.31 (s, 3 H), 1.41-1.75 (m, 8 H),
1.94-2.08 (m, 5 H), 4.20 (d, J = 3.4 Hz, 1 H), 4.88 (dl, J = 10.7,4.4 Hz, 1 H), 5.75S.80 (m, 1 H), 7.16-7.22 (m, 1 H), 7 .24-7.35 (m, 4 H); 13 C NMJ> (68 MHz, COC I3)

8 21.6, 21.9, 22.1, 23.4, 25.0, 25 .8, 26.9, 27.2, 31.3, 34.3, 39.8,41.4,50.2,76.3,

52

76.7.125.2,125.4,128.0,128.2,134.1,151.0,172.1: HR-EIM

m/z37 0.2550,M+

calcd for C24H3403 370.2508.

1-(1-Cyclohexenyl)-1,2-ethanediol 29.

To a SlI, pension 0[" LiAIH4 (552 mg,

14.6 mmol) in THF (5 mL), was added a solution of 28 (303 mg, 0.82 I11mol) in TH(4mL) at () °C. The reaction mixture was stirred at 25°C for 12 h. After cooling at 0 °C,
water was carefully added to the mixture. The formcd precipitate was filtered andwashed with CH2CI2.
evaporated.

The organic layer was dried over anhydrollS MgS04 andPreparative TLC (silica gel, hexane/ AcOEt 2/1) or the crude productafforded diol 29 along with (-)-8-phenylmenthol (153 mg, 85%). A pure sample of 29
was obtained by recyclc-HPLC (J AIGEL-1 Hand 2H, CHCI3) as a colorless crystal (15mg, 13%) (la]25 0 = -27.0 (c 0.196, CHCI3) llit. 17 (IR)-29: lal 25 0 = -28.1°]): IH
NMR (270 MHz, CDCI3) 8 1.54-1.83 (m, 4 H), 1.84-1.93 (m, 2 H), 1.94-2.11 (m, 4H), 3.53-3 .81 (m, 2 H), 4.05-4 .15 (m, 1 H), 5.75-5.85 (m, 1 H); 13 C NMR (68MHz, COC}3) 8 22.4, 22.5, 24.S, 24.9, 63.4, 76.2, 124.0, 136.7;
142.0994, M+ caIcd for CSH 1402 142.0994.

53

HR- -'lMS mlz

Supplementary Material
1Hand/or 13C NMR spectra of 7, 12,18,27 and 29 are shown below.

54

o

Me

'.

.

I'h

Chart 1. I H NMR spectrum of geometric and diastereomeric mixrure of 7

'1

HK I I

dc-o'- v
5.58

Me.-L MePhr-

mlXlure u f cu - Ind Irolu -7

;'
4.'2

If')
If')

1.00

~LLLLJ~~JI~~~,I~I
r-

9.00
ppm

8.00

7.00

6.00

5.00

4.00

3.00

2.00

1.00

I
I
~u.U

"I

0

,'>1e

o
H

'

I,

H

~.

Chart 2. 1JC NMR spectrum of geometric and diastereomeric mixture of 1

OC-O"

Ph

Me -L
, Me

Ph
mixtur e o( cu - ~nd " ON- 7

\.D

VI
I

,11..1""

..

oI'

'1'

I I

I I I

I

I I 1

1 ....... J~
.....

"'I"

1_ .1

,',

...I

''If'

'I/'

', ...

.. L

J,_L ..1~n'~''1'"'"'' ,...

I 1 I I I I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I 1 1 1 1 I I I 1 1 I 1 1 I 1 I 1 Iii I 1 1 1 1 I I 1 1 1 I I 1 I

200.00 190.00 180.00 170.00 160.00 150.00 140.00 130.00 120.00 110.00 100.00 90.00

ppm

80.00

....

.J..I

.JJ.

I

"

""""1' '''''''''''r..... ,I
~

...

'

.....

I I I I I I I I I I I 1 1 1 I I I. 1 1 1 I 1 I I I I 1 I 1 I I I I I I
70.00

60.00

50.00

40.00

30.00

20.00

10.00

Me

o

(J

:>~-o·i
H

Me

I

Chart 3.

I H NMR spectrum of cis-12 (major diaslereomer)MePh
cu ·l: ( ma lor I1j ..,te~omer )

1.47
./

J
10.72

r-

V)

1.00

~

I
ppm

9.00

8.00

'7nn

0.t9

Me
I

p, ,H 2 'Ph~_O"\.ic:...

Chart -'.

I)C NMR spectrum of cis-12 (major diastereomer)

r. Ie
rler)

,

-

,I

I

I

00
t.r)

....

.-U.

'r

.

"

,

',...,

"Jnr

.1

II

,\

'r

200.00190.00 180.00 170.00 160.00 150.00 140.00 130.00 120.00 110.00 100.0090.00
ppm

"

80.00

•• ,

70.00

''I'

~

80.00

........

50.00

.,.

J"'I'Il"'Tl"

40.00

~

r

30.00

..-"
20.00

,
10.00

Me

PhAH O'Me

Chart 5. IH NMR spectrum of trans-12 (major dias[crcomcr)

OC-o'

Mc-L

Me

Pit

Iran.r·12 ( major diulercomcr)

I

23.91

1 t.S2

0\

tn

1.00
-----/.r---

I
ppm

9.00

8.00

7.00

8 00

.c;:

nn

O.ts

PhAH 2'Me:\oic

oc-o . .
M

Chart 6.

I) C

NMR spectrum of trans-12 (major diastereomer)

Me
Ph{TolU·l: (major tliule:rc:omer)o\D

1'1 I I I i i i I I I i i I I i i i i i i i i i i i i i i I I i i I I i i i i i i i i i I i i i i i i i i i I i i I i i i
200.00 190.00 180.00 170.00 180.00 150 nn 14n nn 11n nn 1.,n nto

ppm

I I

¥e

,,0

Chart 7. IH NMR spectrum of trans-12 (minor dias[ercomcr)

o 0\.feA'c-{) +~Ph

H

Me Ph Me'''''1\.1-12 (minor diurcreomer)

J2.08

•

-/

12.67

\0

1.00

~

Me

o

~\)1.

'

oc-o . .

0Chart 8. IH NMR spectrum of 18 (major diasrcreomer)

25.40
~

(

Me-L MeI
I

Ph

18 (major diulcrcomcr)

I

!
J

J
I

/

I

r

N

\D

4.6

1.00

0.8

_.----- -------------¥c0o

I / ' i~\ '"H!

~C-O' .JMe

I

Chart 9. DC NMR spectrum of 18 (major diastereomer)

I

Me

Ph
IS (major dlutcrcomer)--('1"'.

\0

I
I

~
,
I

2 C

BC

I

I

l8C

PC

..

c::1'1
I '

I

lSC

16C

~--

1

.-

..

I

14C

I

. I

I

lJC

12C

110

I

iCC

I

;C

I

I

80

7C

€~

5~

:..

.-

---

- -

I

4e

I

JC

I

I

2C

tC

CD

a

o

CD

a

o

"-I

a
o

CJI

a
o

CII

a

o

~

o
o
(')
::r'

S

~

ell

0

::r:

0

~tu
en

"0
~

n

~

III

0

3

0

0
-..
N

~

~

o
o

c

...
oo

65

~
.

H/

'.

OH

Chart 12. lJC NMR spectrum of 29

OH

I

29

\0
\0

I

I

ppm

~

I I I II I I

I

I I I II I

I

I I I II

150.00140.00130.00120.00110.00100.00III

I

I I I I

I

90.00

80.00

I

I

I

I I I I

I Iii

Iii

70.00

80.00

50.00

iii

iii

40.00

iii

30.00

Iii

iii

20.00

10.

References
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Ensley H. E.:

Parnell , C. A.; Corey, E. J. 1. Org. Chem., 1978,43, 1610.
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Chapman, B. 1. Synthesis. 1995, 475. (b) Denmark, S. E.; Schnute, M. E.;
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Whitesell, 1. K.; Lawrence R. M.; Chen, H.-H. 1. Org. Chell/., 1986,51,4779.
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Maddaluno, 1. F.; Gresh, N.;

Giessner-prettre, C. 1. Org. Chem., 1994,59, 793.

de Pa eual -Teresa, B .;Gonzalez, 1.: Asensio, A.; Houk, K. N. 1. Am. Chem. Soc., 1995,117,4347.
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6. Corey, E. 1.; Ensley, H. E. 1. Am. ChelJ1. Soc., 1975,97,6908. Deprez, P.;
Royer, J.; Husson, H.-P. Tetrahedron Asymm., 1991,2, 1189.
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Ihara, M.;

Takahashi, M.; Niituma, H.; Taniguchi, N.; Yasui, K.; Fukumoto, K. 1. Org.
Chem. 1989,54,5413. Ihara, M.; Takaha hi, M.; Taniguchi, N.; Yasui, K.;
Fukumoto, K.; Kametani, T . 1. Chem. Soc., Perkin Trans. I, 1989,897. Ojima,
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Left .. 1990,31,4289. Basavaiah, D.; Bharathi, T. K. Tefr(ihedrol1 Left. 1991,
32.3417. Ojima, 1.; Habus, 1.; Zhao, M.; Georg, G.I.; layasimghc, L.R. 1. Org.
Chem ., 1991,56, 1681. Ihara, M.; Takahashi, M.; Taniguchi, N.; Yasui, K.;

67

Niitsuma. H.; Fukumoto, K. J. Che11l. Soc., Perkin Trans. 1, 1991, 525. Ahiko,A.: Liu, 1.-F. 1. Org. Chelll., 1996,61,2590.

8. Oou, D.-M.: Liu, Y.-C.: Chen, C.-S. 1. Org. Chel17., 1993,58, 1287.

9. Clark, C.: Hermans, P.; Meth-Cohn, 0.; Moore, C.· Taljaard, H.
0 . 1. Che1l1. Soc., Chem. COI11I11UI1., 1986, 1378.

.; van Vuuren,

Meth-Cclhn , 0.; Moore, C.;

Taljaard, H. C. 1. Chem. Soc., Perkin Trans. 1.1988,2663. YoshimitslI, T.;Ogasawara, K. 1. ChelJ1. Soc., Chem. Commun., 1994, 2197.

nders. D.; Zhu,

J.: Raabbe, O. AngeH'. Che1l1. Int. Ed. Engl., 1996, 35, I 725.
10. Newman, M. S.; Magerlein, B. 1. Organic Reaction, lohn&:Wiley, New York,1945, Vol. 5, P 413. Ballester, M. Chel11. Rev., 1955,55,283 . Borch, R. F.

Tetrahedron Lett., 1972,3761. Raux-Schmitt, M.-C.; Seydcn-Penne, J.; Wolfe,

S. Tetrahedron, 1972,28,4965. Bansal, R. K.; Sethi, M. K. Bull. Chem. Soc.
lpn., 1980,53, t197.
II.

Zimmerman, H. E.; Ahramjian, L. 1. Am. Chem. Soc., 1960,82, 5459.
Morrison, 1. D.: Mosher, H. S. Asymmetric Organic Reagents; Pr ntic -Hall Inc .;N. J., 1971; Chapter 4, p 152 ..

12. Mukaiyama, T.; Haga, T., Iwasawa, N. Chem. Left., 1982, 1601. Abdel -Magid,
A.; Pridgen, L. N.; Eggleston, D. S.; Lantos, 1. 1. Am. Chell!. Soc., 1986, 108,4595. Baldoli, C.; Buttero, P. D.; Maiorana, S. Tetrahedron, 199{), 46, 7823.

Corey, E. 1., Choi, S. Tetrahedron Lett., 1991, 32, 2857 . Pridgen, L. N.; AbdelMagid, A. F.; Lantos, I.; Shilcrat, S.; Eggleston, D. S. 1. Org. Chem., 1993,58,5107. Takahashi, T.; Muraoka, M., Capo, M.; Koga, K. Chel77. Pharm. Bull.,
1995,43, 1821.

13. Dahn, H.; Loewe, L. Chimica, 1957, 1 J, 98. Paln1er, J. T. Chern. Abst., 1990,
J 12, 198431 p, Eur. Pat. Appl. EP 342,904.

14. Tucker, J. A.; Houk, K. N.; Trost, B. M. 1. Am. Chen1. Soc., 1990, 1J 2, 5465.

6815. Cantril1, A. A.' Hall, L. D.: Jarvis, A. N.; Osborn, H. M. 1.' Raphy, J.; Sweeney
1. B. Che111. C0111111lf17. 1996, 2631. Han en, K. B.: Finney, N. S .. Jacobsen, E.

N . Angew. Chem. Jnt. Ed. Eng/. , 1995,34, 676.

16.

Hosokawa, T.: Yagi, T.; Ataka, Y.; Murahashi, S. -I. Bull. Chem. Soc. lpn.,
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Mitsui, S.; Imaizumi, S.; Senda, Y.; Konno, K. Chem Jnd.

(London), 1964, 233.
17. Sabol, J. S.; Cregge, R. J. Tetrahedron Lett., 1990,31,27 . Vankar, P. S.;
Bhattacharya, I.; Vankar, Y. D. Tetrahedron: Asymmetry, 1996, 7, 1683.
18. Ko, K.-Y.: Frazee, W. 1.; Eliel, E. L. Tetrahedron, 1984,40,1333.

19. Borch, R. F. Tetrahedron Left., 1972, 376l.
20. Yamamoto, Y.; Maruyama, K. Tetrahedron Left., 1980,21. 4607. Murata, S.;

Suzuki, M.: Noyori, R. 1. Am. Chem. Soc., 1980,102, 3248. Yamamoto, Y.;
Yatagai, H.; Naruta, Y.; Maruyama, K. l. Am. Chem. Soc., 1980,102, 7107.
Danda, H.; Hansen, M. N.; Heathcock, C. H. 1. Org. Chl'I11., 1990,55, 173.
Walker, M. A.; Heathcock, C. H. 1. Org. Chem., 1991,56, 5747.
21. Li, Y.; Paddon-Row, M. N.; Houk, K. N. 1. Am. Chem. Soc., 1988,1/0, 3684.
Li, Y.; Paddon-Row, M. N.; Houk, K. N. 1. Org. Chem., 1990,55 481.
22. House, H. 0.; Trost, B. M. 1. Org. Chem., 1965,30, 1341. Moreland, D. W.;

Dauben, W. G. l. Am. Soc. Chelll., 1985, 107, 2264.
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1995,60, 7934.

24.

Sisido, K.; Nakanishi, 0.; Nozaki, H. 1. Org. Chem., 1961,26 , 4878.
Yanagisawa, H.; Fujimoto, K.; Shimoji, Y.; Kanazaki, T.; Mizutari, K.; Nishino,
H.; Shiga, H.; Koike, H. Chon. Pharm. Bull., 1992,40, 2055.

25. Jurczak, 1.: Zamojski, A. Rocz. Chem., 1970,44, 2257. Grigg, R.; Markandu,
1.: Perrior, T.: Surendrakulllcr, S.; Warnock, W. J. Tetrahedron, 1992,48,6929.

6926. Whitesell, J. K.; Bhattacharya, A.; Buchanan, C. M.~ Chen, H. H.; Deyo, D.;James, D.; Liu, C.-L.: Minton, M. A. Tetrahedron, 1986,42, 2lJ93 . SolladieCavallo, A.; Khiar, N. Tefrahedron Left., 1988, 2Y, 2189.
27. Gou, D.-M.; Liu, Y.-C.; Chen, C.-S. 1. Org. Chell1., 1993,58, 1287.
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29 . Kogure, K.; Nakagawa, K.; Fukawa, H. Agric. BioI. Chell1., 1976,4(), 1547.
30. Mosandl, A.: Lchensm.-Untcrs. Forsch, Z. 1983,177, 129.
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1988. 2663.

70

Chapter 2

Stereoselectivity in the FormaLti,()n of
2,5-Disubstituted Tetrahydro]pyran by
Intramolecular Hetero-Michclel Addition

Introduction
The cnolates of N -acyl-oxazolidinones have demonstrated good levels ofdiastereoselection in asymmetric induction of various reactions of the enolate(alkylation 2, acylation 3 , hydroxylation 4, a-amination 5 , aldol addition reactions 1,6, andso on). The Evans' chiral oxazolidinone auxiliaries are well suited for use as chiralglycine synthons. The utility of these chiral auxiliaries has been studied during thesynthesis of MeBmt, the rare amino acid from cyclosporin A (Fig 1).1

Fig 1

The diastereoselecti vi ty can be explained by facial selecti ve approach of theelcctrophilc to the oxazolidinyl enolate (Scheme J). If the metal is not coordinated withthe oxazolidinone carbonyl oxygen (Scheme Ia), the attack of an electrophil occurs fromthe Re face of the enolate double bond. This is explained as being the result of
equilibration o[ the oxazolidinyl enolate to the conformation which place the dipoles o[the carbonyl group and the enolate opposite to each other. If the metl1 is coordinated, theattack occurs [rom the Si [ace to give the diastereomeric product due to the sterichindrance by isopropyl group as shown in Scheme 1b.

71

(a) Non-chelation m(xlcl

()

OM

O)lN~

}--

S ialllack

II ~~ OM"x

;N~
(r{~

o

(b) Chelation model

M

if '0

)L~

o

_

0

E+
)l N ~- - .- 0.

_(~

Si al~1ck}--

E

Scheme 1

Although stereoselective synthesis of 2,3- or 2,6-disuhstituted pyran derivatives havebeen much investigated,7 less attention has been accorded to the st reoselcctive
construction of 2,5-disubstituteu tetrahydropyran ring. The reason ror the less attention
may be due to rarity of 2,5-disubstituted tetrahydropyrans in natural prouucts.

11 '

7'

3'

Rhopaloic acid A(+ )-laFig 2

Rhopaloic acid A (+)-1 a (Fig 2) which was isolated from a marine sponge,
Rhopn/oeides s17. is one or the 2,5-uisubstituted tetrahydropyran in natural compound72

and the structure was identified as (2~,5a,3E,7 £)-( +)-a-m "\thylene-5-( 4,8, 12-trimethyl3,7, I l-tridecatrienyl)-tetrahydro-2H-pyran-2-ace tic acid. 8 Til

2,5-disuhstituted

tetrahydro-2H-pyranyl-acrylic acid derivative is a novel slructul' in the natural products.
Rhopaloic acid A inhibited gastrulation of starfish embryos and also exhibited potent
cytotoxicities in vitro against human myeloid K-562 cells, human MOLT-4 I ukemia cells
and murine L 1210 leukemia cells. The interesting biological activity or this compound
may be raised fron1 the structural feature which is a hydrophilic 2- tetrahydropyranyl acrylic acid moiety tethered a hydrophobic isoprenoid entity,Y

Some sesterterpenes

related to Mamoalide having pyran and furanone ring as hydrophilic entitie showed
themsel ves to be potent inhibitor of phospholi pase A2Ya Some interesti ng phenomena
concerncd with the hydrophobic effect in DNA cleavage shown hy alk(en)yl -di andtrihydroxybenzenes have been discussedYb With respect to the hydrophilic part, theacryllc acid moiety is also found in compounds such as Conconadine LOa and Oerin lOb ,and the related 2-mcthylcne y-lactone group in many bioactive natural products .
Furthermore, a 2,5-disubstiluled tetrahydro-2H-pyran -2-ac ryJic acid struclur is nov I in
natural products. Thc potential of (+ )-la and its ana logou. as bio1(lgical probes as w 11
as the interesting structural features provided the inc ntive for the the ynth tic
undertaking described here. This chapter describes the asymmetric induction in theformation of the 2,5-disubstituted tetrahydropyrans hy the Evans' oxazolidinone
methodology and stereose1cctive synthesis of Rhopaloic acid A and ils related compounds
are described.

73

Results and Discus Jon))
sjI

C2-0 hond cleavage

'i'

R

2

-

.
.
g
WillI rcaclIolI('HO

J>R~~y(,02Et=====>~

C02H

Intramolecular lI etero-MII;hael Addition CH1
a: R = homofarncsyl
b: R = gcranyl

OTB'S CH X
2

'

. 2·

2
allylaliol1(2£,6£)- farnesol.,.<--~orR

RVC02Mc

geraniol

<====

6

R

l . . . . . . . / / ...-'-:'I', "" C02Mc

CH20TBS
3- II
ij
R~CH 20H

CH20TBS
45o0O)lN~R~R..

(R}- 7 a'/ Bn

Scheme 2
The construction of the 2,S-disubstituted tetrahydropyrans 1 could he achi ved by the
intramolecular hetero-Michael addition reaction of a,~- un, aturaled est r derivativ s 2. It
may he favor in synthesis of compounds having acrylic acid moiety that the cyclizatlon
and a-methylene introducUon are carried out simultaneously due, to high reactivity of theacrylate moiety to various reagents. Retrosynthetic cleave of the indicated bond in 1
together with the double bond migration furnishes the unsaturated ester 2 as a cyc1izationprecursor (Scheme 2). The predictable Wittig reaction of :3 could accomplish theformation of the a,~-unsaturated carhoxylate derivative to give the precursor 2. A
selccti ve oxidation of the termi nal alcohol of 4 could give 3. C 111 pound 4 could beformed by reduction, protection of alcohol, and regioselcctive hydroboraUon-oxidationfrom 5.

Compound 5 could conceivably be formed in one step through adiastereoselecLi ve allylation of 6.

Com pound 6 could be fa::>hioned by way of74homologation steps from (2E.6E)-l'arnesol or geraniol. The "vans' a ymmetric allylationof (S)- and (R)-7a could be applied to the stcreosclccliv synthesis of (2S,5R)- and(2R,5S)-1 by way of (R)- and (S)-8, rcspecti vely.

Scheme 3 demonstrates three carbon homologation of (2E,6E)-farnesol to afrord ester
6a. Brominalion of (2E,6E)-farnesol with MsCl-LiBr 11a afforded (2E,6E)-farne yl
bromide 9a along with ca. 500/0 of (2Z,6E)-farnesyl bromide 9a. 12 Hromination reactionof (2E,6E)-farnesol with Me2S-NBS lIb also gave a 85: 15 mixture of the geometricisomers of (2E,6E)-farnesyl bromide 9a and (2Z,6E)-farnesyl bromide 9a. On the other
hand, treatment or (2E,6E)-farnesol with PPh3 and CBIA at () °C offordeu almost only
(2E,6E)-farnesyl bromide 9a «2E,6E)/(2Z,6E) >95/5).13 The brolllide 9a was lIsed forthe following reaction wilhout further purification. For the purpose of three carbon
homologation, conjugate addition of the organoc(}pper reagent generated from thebromide 9a with acrolein was allempted. 14 TreaLment of th~ bromide 9a withmagnesium did not afford the corresponding Grignard reagent but gave thecOITesponuing dimer.

75

1. Mg, Cl1Br-~v1e , ", IlMPA
'//
~r-~

2. acrolein

~

R~

OTMS

OH _ a_' -~:./" I3r(2E,6E)-farnesold

RCH 20H
13aej

RCH 2Br14a

9a

RC0 2Me __._c_12aR = homofarnesyl

l'

~~~

g

02M

I

lOa

02 Me

h
RCH 2C0 2H - - -RCII 2C0 2Me
16a
6a

II
RXC02MC
C0 2MeR' = farnesyl
11

R

Scheme 3 Reagents and conditions: (a) PPh3, CBr4 , CH2CI2 , O°C; (b) NaH, CH2(C02Me)2, THF,
25°C. 78 % (over two steps); (c) NaCl , H20, DMF, reflux , 91 %; (d) LiAIH4 . THF, 25°C, 91 %; (e)PPh3. CB r 4. C H 2C I2 , 0 0C. 92%; (0 NaCN, DMF, 25°C, 87 %; (g) KOH , H20 , reflux, SW'h; (h)K2C03 , Mel, DMF, 25°C, 98% .

At this point, our strategy was changed to successive homologation starling from thebromide 9a. Treatment of the bromide 9a with dimethyl malonate (6.2 equiv) in thepresence of NaH (ca. 1 cquiv) afforded dimethyl ester lOa in 7R%.15 The bromid 9areacted with dimethyl malonate (2 equiv) in the pre ence of NaH (ca. 2 equiv) to formlOa in low to moderate yield (10-640/0) along with difarnesyl-substituted malonate 11 (737 0/c) depending on the reaction conditions. Compound 11 was a dialkylated productthrough reaction of the bromide 9a with the enolate of monoalkylated malonate.
Demethoxycarbonylation of lOa under neutral conditions (NaCl in moist DMF) afforded
e ter 12a in 91 % yield.
Reduction of 12a with LiAIH4 afforded the primary lllcohol 13a in quantitative yield.
Brominatinn of the alcohol 13a with Ph3P-CBr4 gave bromide 14a in 92 ~) yield.

76

Treatment of Grignard reagent generat d from the bromide 14a with carbon dioxide did
not afford the desired carboxylic acid 16a but the dimeric product 17 along with theprotonatcd product 18 was obtained. Therefore, the bromide 14a was convert d using
NaCN in OMF to afford the nitrile 1 Sa (87(Yc)).

I lydrolys 'is of 1 Sa under basic

conditions afforded the carboxylic acid 16a and esterification of 16a with MeIlK2C03 16
gave methyl ester 6a in 86% yield over two steps.
cx-Allylation of the carbonyl group in the ester 6a afforded mctJlyl 2-homofarnesyl-4pentenoate Sa in 81 % yield (Scheme 4). In the presence of lithium aluminum hydride
5a underwent reduction to give the primary alcohol 19a (88%) which could be protected
subsequently in the [orm of tfrt-butyldimethylsilyl (TBS) ether 20a (870/0).
Hydroboration-oxidation of the terminal olefin with 9-BBN-H202 gave regioselcctively
4a in 790/0 yield. Swern oxidation of 4a afforded the aldehyde 3a (800/0), while with

PCC and POC it gave 3a in lower yield (480/0 and 360/0, respectively).
a
RCH 2C0 2Me
6a

•

R~

~

R~

C0 2Me

112

Sa

19a

R = homofarnesyl

R~CHO~ eb

R~OH

CH 20TBSCH 20TBS

3a

4a

II

!

c

4

d

R~
CH 20TBS20a

Scheme 4 Reagents and conditions: (a) LDA, THF, -78 °e, thcn allyl brom ide, -78 to 25°C, 81 ~ ;(b) LiALH4, THF, 0 °C. 88%; (c) TBSCI imidazolc, DMF, 25 °e, 87%; (d) 9-BBN, THF, 0 to 25 ° ,then NaOH. 30% aq. H202, 25°C, 79%; (c) (COC12)2, DMSO, Et3N, CH2C12, -60°C, 80%.

The two carbon homologation of geraniol was practiced by the same procedure as
described above (Scheme 5).

77

~ OI-I _ll_,b__..
geraniol

RCH2C0 2 Me

_C_ _ _~~R~

R = geranyl

CH 20lI

6b

19h

~f

R~CH~_ R"'~OH
CH 20TBSCH 20TBS3b41>

Scheme 5 Reagents and conditions: (n) PPh3 , CBr4 , CH2CI2. 0 °C then NaH, CI f2( 02Me)2, TH ,25°C. 88o/c (over two steps); (h) NaCI. H2 0 , reUux , 85 %; (c) LOA, THF, -7H ° Lhen allyl hromide,-20 to -10°C, 82%; (d) LiAIH4 , THF, 0 dc. 91 %; (e) TBSCl, imidazole, DMF, 25°C, 98(Yn; (0 9-BBN. THF. 0 to 25 °C then NaOH. 30% <14. H202, 25 °C, 80%; (g) DI\lSO (COC1 2)2, Et3N,
CH2CI 2, -60 °C. 84%.

Next, the Evans' asymmetric alkylation of N-acyl-oxazolidinone wa utilized forasymmetric induction in the aldehyde 3a (Scheme 6) . Treatment 01 carboxylic acid 16a
with pivaloyl chloride followed by N-lithio-(S)-4-benzyl-2-oxazolidinone afforded (S)7a. The lithium enolate of (S)-7a was treated with allyl bromide at ··20 to - 10°C to give(R)-8a as a pure diastereomer (61 % yield, 99%) de) . !7 The optical purity of thallylation product (R)-8a was established by deprotection or the chiral auxiliary unc,!{yield) followed by conversion of the alcohol (R) -19a into its benzoate. The benzoate
was analyzed on a DAICEL-OD CHIRAL column (hexane! AcOEt 400!1, Fig 3).
According to the chelation model of the enolate intermediate, the ab (11 ute configuration of(R)-8a was predicted to be 2R. 5 Conversion of (R)-8 into (R)-3a was done by theabove procedure. Following protection of the alcohol (R) - 19a with (L terf-buthyldimethyl
silyl group, the silyl ether (R)-2()a was subjected to regiuseleclive h:fdroboration with 9BBN reagent followed by oxidation with H202 to give (R)-4a (927') . Swern oxidationof (R)-4a wa converLed to (R)-3a in 80% yield. In order to synthesize (S)-3a, (R) -4bcnzyl-2-oxazolidinone in stead or (S)-4-bcnzyl-2-oxa/.oIidinone was used as a chiralauxiliary. Treatment of the carboxylic acid 16a with pivaloyl chloride in the presence of
Et3 N and addition of N -lithio-(R)-4-benzyl-2-oxazolidinone to the resulting acid78

anhydride gave (R)-7a (YSo/c·). Treatment of (R)-7a with LOA in tetrahydrofuran at -78°C and quenching the resulting amide enolate with allyl hromide gave (S)-8a (76o/n). The
configuration at C-2 position or (S)-8a was expected to be (S) by the ch lation modc1
intem1ediate. Reduction of (S)-8a with lithium borohydride in l1lethc.' nol afforded alcohol(S)-19a in 60o/n yield. The chiral auxiliary was recovered in 76% yield. The alcohol(S)-19a was converted to its benzoate and the diasLercoselccli vity of the asymmetricallylation using (R)-4-benzyl -oxazolidinone was evaluated by the chiral HPL

analysis

Succcssiv~ conversion of (S)-of the benzoate derivative (99o/r) ee) as shown in Fig 3.
19a afforded the aldehyde (S)-3a.

o

a

R

~
"-.../ -. N

0
~

,u+,

LJ

16 a ----I.~

0 -'

0

,,'" S
Bn

b

0

R~~O

'0

"[R~NAOl------' ~R\-J

Bn,,'"(.))- 7 a

0

1/

}_-.I
Bn"

(m-8a

R = homoramcsyl
R~CHO

R~

d
-..---

CH 20TBS

H 20H(R)- 20a(R)-19 a16a(R)- 7aR = homo[arnesyl

R~CHO
CH 20TBS(5}20a(S)- 3aCH 20H(.5)-19 a

Scheme 6 Reagcnts and conditions: (a) Et3N, pivel , THF, 0 °e thcn N-lilhio-oxazoliuin-2-onc, THF,
-78 to 25 °e. 87 % [or ('5) -7a. gyre [or (R)-7a; (b) LDA, THF. -78 °e Lhcn allyl bromidc, -20 LO -10 °e,
61o/r [or (R)-8a, 76% for (S)-8a; (c) LiAIH4, THF. 0 °e, 88(f{-; (d) TBSCl, imidazole, DMF, 25°C,
74% [or (R)-20a. 59(Ye [or CS')-20a; (c) LiBH4 , THF, McOH, () to 2S °e , 59 670.

79

colullln : DAICEL IlIRAL-OD
solvent: hex.ane/2-propanol 4()()/1

(R)
(S)

TIME

fNTEG

18.98725.56739.3275
37.6496~:8:j ~?

i(R)~t;':s,irae-benzoate(S)column: DAICEL CIIIRAL-OD
solvent: hexanc/2 -prupanol 400/ I

9. 1 5 C:

1 :3.275_---------------=================.1 1 :' • ~:~.~.
17.:::17

TIME

20. 0 t: 3

15.327.-, 1 A 4 -,c. 1 ~, '1 : t-, .L

C •

(R)
(S)

22.68398.40/0 ec. S)t,·) j ( - (i

IITIEG
90.9060
0.6932(R)

25. 5 4~:(R)- benzoate

column: ,DAICEL CIIlRAL-OD
solvent: 11exanc/2-propanol gOO/ 1

(R)
(S)

INTEG
1.8039TIME
18.73964 . 1297

24.62794.80/0 cc.. . .. . __. _ _ _ . 1

,",

.~

i'

c. t, • I

i

-! C'
( .'

(R)

29 ' Q55

31.455(S)-hanzoale

Fig 3. IIPLC allalysis of r({c-, U{)-, nlld (,)')-hcnzoatc derivatives

80

24.~· 'jO

A Wittig -Horncr-Emmon.

reaction h twn th'lld hyde 3a and(EtO)2P(O)CH2C02Et took place smoothly to give E-cx,~-lInsaturated ester 21 as anonly single isomer in 93%) yield (Scheme 7).18 Treatment of the aldehyde 3a withdimethyl malonate in the presence of NH3+CH2CH2NH3+·(CH3C02-)2 afforded thecx,~-unsaturated ester 22 in 41 % yield (Scheme 7).

Scheme 7

R~~C02l

R~CHO

CH20TBS

CH20TBSh.3= 16.1 Hz

3a2]

R = homofarncsyl

R~CHO
CH20TBS

NH3+CH2CH2NH3 +·( CH 2C0 2- )2 R~,,___,./"~:~~~~/C02Mc----------------~.
CH 2(C0 2Mc h. 4J %

3a

~I

I

CH20TBS

C02Mc

22

R = hOlTlofarnesyl

Scheme 8

R~CHO
CH 20TBS3a: R = homofamcsyl

2 a: R = homofarncsyl

3b: R=geranyl

2b: R=gcranyl

Table 1.

entry
1

2
3
4
5
6
7
8

The modified Wittig-Horner-Emmons reactions o_f-:-3_a_a_n~d-:-:-3~b~_substrate
reaction conditions
Z
E ~o...,...d_L_lc_t__y_lc_ld~(9(---:...)_
3a
0 °C, 3 h
1.3
1.0
2a
54
3a
25°C, 18 h
Z-only2a58(R)-3a25°C, 17 h
Z-only(1\')-2a54(R)-3a0 °C, 3 h
1.0
2.4(R)-2a57(S)-3a25°C, 18 h
Z-only(S)-2a253bO°C,3h
2.0
1.0
2b
83
3b
25°C, 14 h
3.0
1.0
2b
63
3b
25°C, 4.5 days10
1.0
_2_b_ _ _7_4_ _81

cx , ~ - Un s aturate d cs ters 2a and 2b were obtained by th e modi fied Wittig-Horner-

Emmons reaction of the aldchydc 3a and 3b with (EtO)2 P(O)C(:= Il2) 0 2Et in thpresence of NaSCHMc2 (Schem e 8) .19 The geometric ratio of the product depended on
the reaction conditions (Table 1) . When the rcaction of 3a was stirred at () °C for 3 h, areaction mixture of (2) - and (E) -2a was obtained in 54 1() yield (21 E = 1.3: 1.0, entry 1).
The reaction of 3a at 25 °C for 18 h afforded only (Z)-2a as the thermodynamicallycontrolled product in 580/0 yield (entry 2). The reaction of (R) - and (S) -3a and 3b
showed to be Z-selectivity except entry 4 (entries 3-8). Chart 1 and 2 show 1Hand 13
NMR spectra of Z-2a, respectively (see supplementary material). Chart 3 and 4 show
1Hand 13C NMR spectra of E-2a, respectively (see supplementary material) . Chart 5
and 6 show 1Hand 13C NMR spectra of Z-2b , respectively (see supplementarymaterial) . Chart 7 and 8 show I Hand 13C NMR spectra of E-2b, respectively (seesupplementary material) . The characteristic signals assigned to protons of position 3,4 ,CH(CH3)2 , CH2S, CH20Si , and vinyl position in IH N~v1R spectra of 2a,b aresummarized in Table 2. The characteristic signals assigned to carbon of po, ition 1
CH20Si, OCH2CH3 , CH=C, and CH=C in 13C NMR spectra are summari!. d in Table~. The geometry of 2a was assigned by comparison of 1H NMR chemical 'hift of vinyl

proton 19: The 3-H vinyl proton (8 6.81) of the major product appeared ca . 0.8 ppm
downfield relative to that (8 5.97) of the minor product. On the other hand , the 4-J-I
methylene proton (8 2.47) or the minor product was appeared at lower magnetic field
than that (8 2.26) of the major one. On the basis of anisotropic effect of ester group, themajor product was assigned as Z-geometry and that of the minor product as E,
respectively. Furthermore, the relative stereochemistry of the product was confirmed by
DIF-NOE (Fig 4): when 3-H proton of the E-isomer was irradiiated, the intensity of the2-CH2-S signal was enhanced by 8.2O/C .

82

0%

R

C0 2El"~CH 2 - SCHMc2

CH 20TBS

2-2a
Fig 4.

Table 2.
CDC I 3)posilion3

DIF-NOE data of 2a

The characteristic signals in 1 H Nl\1R spectra of 2a,b (8 in
2-2a

£-2a

Z-2b

E-2b
6.81 (l, J =5.97 (l, J =6.80 (l, J =S.9S (l, J
7.6 Hz, 1 H)
7.3 Hz, I H)
7.3 H;r" 1 H)
7.3 Hz, 1 H)
4
2.26 (ld, J = 7.R, 2.47 (ld, J = 7.8, 2.27 (ld, J =7.3, 2.48 (ld, J = 7.3,
7.3 Hz, 2 H)
7.3 Hz, 2 H)
7.3 Hz. 2 H)
6.8 Hz, 2 H)
CH(CH3)2 2.95 (scp, J =2.85 (scp, J =2.92 (scp, J =2.84 (scp, J =6.8 Hz, 1 H)
6.6 Hz, 1 H)
6.4 Hz~ 1 H)
6.8 Hz, 1 H)
CH2S
3.47 (s, 2 H)
3.39 (S, 2 H)
3.46 (s, 2 H)
3.38 (s, 2 H)
CH20Si3.47-3.52
3.47-3.53
3.20-3.40
3.47 (d, J =(m, 2 H)(m, 2 H)(m, 2 H)
4.9 Hz, 2 H)
5.05-5.15
5.05-5.21
5.10-5.20
vinyl
S.10-S.20(m, 3 H)(m, 3 H)(m, 2 H)(m, 2 H)

Table 3.
CDC)3)

The characteristic signals in 13C NMR specltra ·of 2a,b (8 inpOSition

2-2a

1

16S.0

E-2a
166.9

6S.0

6S.0

60.7
124.3, 124.4

CH20SiOC H 2 CH 3
CH=C

124.S, 144.8
CH=C=

124.7, 131.2]34.9, 13S.0

Z-2b

£ -2b

60.4

166.9
64.8
60.6

166.8
64.8
60.3

124.2 (x2)
124.4, 143.3
124.6, 129.0
131.2, 134.9

124.3, 124.4
144.6
129.S, 131.1
136. ]

122.6, 124.3
143.2
129.0, 131.1
136.0

83

_

.

----

-

R~yC02Et
I 12 CIIMe 2

1120Il2 1. 22. ami 2
21
22
Z-2a
L-2a
Z-2b
23
24

25a
25 b

23 , 24, and 25

Z-26a

R = homofarncsyl, R I = C02El, R2 = H
R = homofamcsyl, Rl = C02Mc, R2 = C02Mc
R = homofarncsyl , R I = C02El, R2 = CH2SCHMc2
R = homofarncsyl, R I = CH2SCHMc2, R 1 = C 0 2 El
R = gcranyl, R 1 =C02El, R2 = CH2SCHMc2
R = homo[arbcsyl. R3 = CH2C02El
R = homofarncsyl. R3 = CH(C02Mc)2R = homofamcsyl , R3 = C(=CH2)C02El
R = gcrallYI. R3 = C(=CH2)C02El

The intramolecular hctero-Michael additions of 21, 22, and 2 were summarized inTable 4 (Scheme 9). Exposure of the a,~-unsaturated ester 21 with TBAF to remove thesilyl group afforded 23 in 770/0 yield, the cis/trans ratio heing 30:70 (entry I). Treatmentof 22 with TBAF also afforded 24 in 13% yield (cis/trans = ca. 2:3, entry 2). Treatmentof £-2a with the methylaUon reagent MeI-AgBF4 followed by de 'ilylation or the si1ylgroup afforded preferentially frons ethyl pyranyl acrylate rac-25a in 31 o/t-) yield (cis/trans= 6:94, entry 3). Z-2a, Z-(R)-2a, Z-(S)-2a, and Z-2b also gave pref rentiaJly fransethyl acrylate 25 (entries 4-7). Chart 9 and 10 how] Hand 13

NJ\1R spectra of fran.\' -25a, respectively (see supplementary material). Chart 11 shows 111. NMR spectrum ofcis-25a (see supplementary material).

Chart 12 and 13 show 1Hand 13

NMR spectraof 25b, respectively (see supplementary material). The charact.eristic signal a. igned toproton of position 2, 6, 3", and vinyl in 1H NMR spectra of 25a,h are ummarized inTable 5. Table 6 shows the characteristic signals assigned to carbons of position 2, 6,
1", 2", 3", CH=C, and CH=C in 13C NMR spectra of 25a,b. T e cyclizations were
found to be kinetically controlled and irreversible. Recently, similar hetero-Michacl
addition studies of ,,(-oxygenated a,~-unsaturated esters have been r,~ported, the reaction
also being found to be kinetically controlled.2 0 In spite of various attempts for84

Table 4.

Formation of 2,S-disubstituted tetrah~droE~ran from 21, 22, and 2
rp:::Iop.nt,
rnnriltl('m,---0----- :::Inri_ u _ - - u _ _ u ,. u ____ _ ,I
pntrv

substrate

1

21

TBAF(6 equiv), 25 °e, 5 h

2

22

TBAF(3 equiv), 24 h

3

E-2a

1. Mel (3 equiv), AgBF4 0.3 equiv), 25 °e, 2h

C!Stra!?snrnrinrt
r - _.-. -vip 1ri (0/,..,')

3

7

23

77

ca. 2

3

13

6

94

24
rac-2Sa31

595

rac-2Sa37

4

96(2S,5R)-2Sa

35

2

98

(2R ,5S)-2Sa

33

15

85

rac-2Sb

24~,J - -

- -

,

'

"

2. TBAF (4.4 equiv), 25 °e, 11 h
4

Z-2a

1. Mel (4 equiv), AgBF4 0 .2 equiv), 25 °e, 2 h

2. TBAF (3 equiv), 25 °e, 11 h
5Z-(R)-2a

1. Mel (2 equiv), AgBF4 0 .1 equiv), 25 °e, 5 h\f'1

2. TBAF (5.6 equiv), 25 °e, 13 h
6Z-(S)-2a

1. Mel (excess), AgBF4 (3.8 equiv), 25 °e, 5 h

2. TBAF 03 equiv), 0 °e o 6 h, then 25 °e, 15 h
7Z-2b

1. Mel (23 equiv), AgBF4 0.7 equiv), 25 °e, 3 days

2. TBAF (2.4 equiv). 25 °e, 1.5 daysrf)

methylation (MeOTf then TBAF: MeI -AgBF4 then TBAr, AcOH; MeI-AgBr4 then
TBAF, AcOH, H20), yields of the pyranyl acrylate formation wer

not improved.

Expo ure of Z-2a with TBAF did not give pyran derivative 25a bUI gave 2-26a in ~n(Ynyield. Cyclization reaction of 2-26a in the presence of NaH was uns uccessful.

Table 5.

The characteristic signals of 1 H NMR spectra of 25a,b

~
5

R

3"

2

2"C02H1"

25a: R = homofarncsyl
25b: R = gcranyl

position
2

frans-25a

cis-25afrol1s ··25b

4 .12 (d, J =9.8 Hz, 1 H)
3. 16 (t, J =11.2 Hz, 1 H)
4.03 (ddd, J = 11.2,
3.9, l.5 Hz, 1 H)
5.88 (t, J =l.5 Hz, 1 H)
6 .23 (bs, 1 H)

3.85-3.95

5.06-5 . 15(m, 3 H)

5.03-5.14(m, 3 H)

4.13 (d, 1 =Y.3 Hz, 1 H)
3.17 (t, J =11.2 z, 1 H)
4.02 (ddd, J = 1 1.2,
3.9, 2.0 Hz, 1 H)
5.87 (d, J =l.0 Bz, 1 H)
6.23 (d, 1 =1.0 Hz, 1 H)
5.00-5.10(111, 2 H)~-~------~~~~------------~~~~----~

6

3"

vinyl

(m, 1 H)3.64-3.70(m, 2 H)----------~~~------------~~--~------~.

o.

Table
position

2
6
1"
2"
3"
CH=C

CH=C

~~-----------~-----------

The characteristic signals of tralls-25a,b in 13C NlVlR spectra
frans-25atrnl1s-25b

75 .6
74.0
166.1
142 .3124.4
123 .9124.2 (x2)131.2, 135.0
135 .3

75.6
73.8
166.0
142.3
124.9
121.7
124.3
131.4
136.4

A signmcnt of 6-ax-H at 8 3.16 in the 1 H NMR spectrum of fral1s - 25a wasdetermined from the following coupling constants (Fig 5): J5,6-ax := 11 .2 Hz, 15 6-eq =86

3.9 HI..

h r lativ stereoch mistry or 1ral1s-25a y a. confirmcd hy nhanccmcnt or

inten. it of til 2-H signal at 8 4. 12 hy IO</(J upon irradIation of th 6-ax-ll al 8 3. 16
through DIF-NOE 111 asurem nts.
H
3"

.16 :IX. 6 cq= 11.2 HI.
}c:" 6 ax = J 1.2 III.
is , 6-l'q = 3.9 lIz
16-cq , 4 ell = 1.5 HI.

H

Fig 5. DIF-NOE data of tralls-25a

The stereochcmistry in thc formation of pyranyl acrylatc formation was rationalizcd byinvoking a model of a chair-likc transition statc in which the long-chain alkyl group ilocated at the equatorial position (Schcme to) . Intcrmediatc II i:) dLfavored by 1,3diaxial repulsion betwecn thc acrylatc moiety and protons and the reaction takes placemainly via transition state Ito givc frans isomer.
Scheme

to

__
JR3
]
R ~()
H
frans
21. 22.
and 2] .. . .

nc~from 21: R = homofamcsyl, RI = H. R2 = C02 E l, R3 = C H2C02 Et[rom 22 : R = homofarnesyl. R J = C02Mc, R2 = C02Mc , R3 = CH(C02 Mc )2[rom E-2a: R = homofarncsyJ, R 1 = C02Et, R2 = CH2S+(Mc)CHMc2, R3 =: C(=CH2)C02Et[rom 2-2a : R = ilomofarnesyl, R 1 = CH2S+(Mc)CHMc2, R2 == C0 2 E t. R3 =: C(=C H2)C02El
from Z-2b : R = geranyl. Rl = CH2S+(Mc)CHMc2, R2 = C02 Et , R3 =: C(=CH2)C02 El

87

The introduction or a-methylene into tetrahydropyran acrylic esters 23 and 24 wasattempted (Scheme II) .

Treatment of 23 with Ll A rolI()w(~ d by ( H20)n or

Eshcenmoser's salt 21 was ineffective in the introduction of a-methylene. Exposure of
23 with magnesium methyl carbonate (CH30C02IVlg0CH3·XC02)22 was also
ineffective. Reaction of 24 with (CH20)n in the presence of K2C03 did not afford thetetrahydropyran derivative 27. Treatment of a,~ - unsaturated ester 21 with TBAF in thepresence of (CH20)n or Eshcenmoser's salt could not afford the desired product 28.
Scheme 11

R = homofamesyl
24)
RdC02Et if
X__.__ _

R = homofcU11esyl
18

TBAF / EschcllIllOSl.!['S saltC<) 2 ~tJt

28
X = OHorNMc 2

25a

Attempt for construction of a teterahydropyran 2-acetic acid moiely b fore introducing
a-methylene moiety was also done (Scheme 12). Treatment of 3a with methyl acrylate
in the presence of DABCO (Baylis-Hillman reaction 23 ) did not give the desired alcohol
29 and the starting aldehyde 3a was not recovered.

88Scheme 12

Oil

R~~/C02MC

R~CHO

DABCO

CH 20TBSmcthyl acrylatc
CHPTBS3an29

R = homofa111csyl

Oxidation of Z-2b with mCPBA followed by rearrangement in the prescnce or(EtO)3 P gave the alcohol 3() (500/0 yield ovcr two stcps) which was trcated with
NCS/PPh3 to afford 25b in 130/0 yicld (cis/frons = 32 : 68, Schemc 13).2 4 Chart 14
shows 1H NMR spcctrum of 30 (scc supplemcntary matcrial). Thc charactcristic signals
in 1H NMR spctrum of 30 was assigned as following: 8 2.50··2.80 (bs, 1 H): hydroxy
proton, 3.40-3.50 (m, 2 H): CH20Si, 4.35 (td, J = 18.5,0.4 Hz, 1 H): 3-H, 5.77 (s, 1H), and 6.22 (s, 1 H): ex-methylene .
Scheme 13

CH20TBS CH2SCHMc2 2. (EtO,»P, MeOH, reflux, 24 11, 55%
R = gcrany!
Z-2b

30

Scheme 14

Rd

C02Et

hydrolysis

R = homo[arnesyl
25a89

cis:/rans = 32:68

Next, hydrolysis of a -meth ylene tetrahydropyranyl acryli c cs t "' [ 25a wa examined(Scheme 14). Results of the hydrolysis are summarized in Table 7. Hydroly, is of ra c25a with aqueous KOH afforded ra c- l with retention of ster ochemisLry (e ntry I ) .

However, the other hydrolysis conditions were ineffective (enlry 2-()): Hydrolysis underhasic condition in organic solvent (OMF, EtOH) and hydrolysL under n ut.ral condition sgave a compound in which a-methylene signal of 1H NMR disappeared (entry 2-4) .
Reaction of rac-25a with CeC13·7H20 did not occur (entry 5, 6) . Hydrolysis of(2S ,SR)- and (2R,SS)-25a in aqueous KOH or LiOH afforded (2S ,SR) - and (2R,SS)-Ia(cntry 7 and 8). The assignment of relative stercochemistry of tral7,\- 1a was as igned on
the basis of the same considerations as those for 25a: is , 6-- axial = 11 .2 I z, is , 6 equatorial = 3.9 Hz: when 6-axial-H was irradiated, the intensity enhancement of 2-H by
6.9% was observed. The 1Hand 13C NMR and mass spectra of th ~ carboxylic acid 1aand the ethyl ester 25a were identical with those recorded on samples of natural (+)Rhopaloic acid A (+)-la and its ethyl estcr derivative ~ respectively. Chart 15 and 16
show I Hand 13C NMR spectra of la, respectively ( ee supplementary material) .

hart

17 and 18 show H-H COSY and HMQC spectra of la, r specti vely (s c supplem ntarymaterial). Chart 19 shows MS spectrum of 1a (see supplementary mat rial) .

hart 20and 21 show I Hand 13C NMR spectra of natural product. Rhopaloic acid A (+) -1a ,respccti vely (see supplementary material). Chart 22 shows MS pectrum of natural
product Rhopaloic acid A (see supplementary material).
1Hand 13C NMR pectral data of the natural (+) -la and synthetic la are summarizedin Table 8. In H-H COSY spectrum, correlations of 6-H-ax with 6-H-eq , 2-H with 3-H,
vinyl proton with 2'-H, 6'-H, and lO'-H were ob crved.

In HMQC spectrum,

correlation of 6-H with C6 (74.0 ppm), 2-H with C2 (76.3 ppm) , and 3" -H with C3"026.7 ppm).

90

Table 7.

Hydrolysis of ethyl ester 25a

Clitrysubstrate1

rac-25aiCo.gCllts a..lid cOliditioliS
aq. KOH~ reflux, 14 h

cis;]'cu-w

productyield (7v \496

rac-la34

cis:trans = 4 : 962

rac-25aaq. KOH, EtOH, reflux, 24 hl,4-addition?

3

roc-25aNaCl, H20, DMF, 100°C, 48 h

1,4-addition?

4

rac-25a

NaOH, iPrOH, reflux, 22 h

1,4-addition?

5

rac-25a

CeC13·7H20, MeOH, reflux, 22 h

trace

6

rac-25a

CeC13·7H20, H20, reflux, 15 h

no reaction

7 (2S,5R)-trans-25a

aq. KOH, reflux, 22 h

only trans(2S,5R)-1 a

56

8 (2R .5S)-trans-25a

a~iOH, 25°C, 26 h

only trans(2R,5S)-la60

0\NMR Data of natural (+ )-la and synthetic la(S()()MHz in CDC(3)natural (+)-laa
ynlhetic 1a
8Hc
8Hb
8C
8e
post lion
4.12(ct,
4.11 (d,
76.0
76 .3
2
.1= 12.2 Hz, 1 H)
J = 10. 1 Hz, I H)
1.28 (m I H)
32.1
1.30 (m, 1 H)
31.8
3
1.95 (m, I H)
1.94 (m, I H)
1.20 (m, I H)
1.22 (m, I H)
30.4
30.2
4
1.92 (m, I H)
1.91 (m, 1 H)
1.50 (m)1.60 (m, 1 H)
35.3
35.2
S
73.9
3.1S (t,3.18 (t,74.06J = I I. 2 Hz, 1 H)
) = 11.0 Hz, I H)
4.04 (ddd, ) = 11.0,
4.07 (ddd, ) = 1 1.7,
3.9, 2.0 Hz, 1 H)
3.8, 1.6 Hz, 1 H)
1.20 (m)32.S
1.15 (m, 2 H)
I'
32.4
2'
1.99 (m)2S.0
2.00 (m, 2 H)
24.9
5.10 (m)124.2
5.IO(m)
124.0
3'
4'
13S.0
135.0
1.99 (m)1.99 (m)
S'
39 .7
39.7
2.06 (m)6'
26 .6
2.06 (m)26.6
S.10 (m)
124.1
124.2
5.10 (m)
7'
8'
135.3
135.5
9'
1.99 (m)1.99 (m)39.7
39.7
2.06 (m)10'
2.06 (m)26.8
26.8
5.10 (m)
II'
124.4
124.4
5.10 (m)12'131.2
J 31.3
1.68 (s, 3 H)
13'
25.7
1.68 (s, 3 H)
25.7
14'
1.60 (s)16.0
1. 60 (s)16.0
1.60 ( )IS'
1. 60 (s)
16.0
16.0
16'
I. 60 (s)17.7
1. 60 (s)17.7
I"170. I
168 .6
2"
140.7
141.9
3"
5.89 ( , 1 H)
125.8
126.7
5.88 (brs, 1 H)
6.36 (s, 1 H)
6.31 (bI's, 1 H)

Table 8.

L

a The spectral dale') was reported in ref 8.
b TIle proton of C02 H was observed at 10.0 ppm as broad singlet.
C The proton of C02H was not ohserved due to broadening.

Optical rotation valuesor (2S,5R)- and (2R,5S) -2Sa, and (2S,SR)- and (2R,SS)-la

were summarized in Scheme 15: (2S,5R)-2Sa: laj2S D ··46 (c 0.044, CHCl3), (2S,5R)1a: laj25 D -37.6 (c 0.315, CHCI3), (2R,5S)-2Sa: fal 2S

o +43.1 (c 0.116, CHC13),and (2R,SS)-la: la]25 0 +39.0 (c 0.241, CHCl3).8 Judging from the above values, it isuggested that the absolute configuration of the natural Rhopaloic acid A ([ a]25 0 +40 (c0.47, CHCI3)) and its ethyl ester ([ al 25 0 +46 (c C)'08S8, CHCI3)) is (2R,SS).

92

Scheme 15

+,
itt?

C0 Et

R

2

H

R

II

3
~~~'5S
0"H(2S.5R)-la(2S.5R)-2Sa[a)25 n -46 (c OJ)44. CIICI)[ aJ25 0 -37.6 (c 0.315, CII(1)

H

H

R~
H

R~
H

C0 2Et

11'

7'

3'

====>

2R

2" CO..,HH)" ~Rhop,lloic acid A 8(-~ · ) - la

C0 2H

(2R.5S) -la(2R.5S)-25a[a4&~02Hr\) +·n.) (c 0.116. CIIC!3)[af5lJ +39.0 (c 0.241, Clle!3)

R = homofarncsyl

In this study, a stereoselective formation of 2,5-disubstitutcd tetrahydropyran ring
having acrylate moiety at C2 and geranyl or homo[arnesyl group at C5 by means of
intramolecular hetero-Michael addition was achieved. Application of this methodology tostcreosclccti ve synthesis of (+)-, (- )-en t-, and (±)-roc-la was s.ucCl~eded. On the basisof stereochemical considerations in the asymmetric synthesis of (+)-1a and ( )-1a, it i.
determined that the configuration of the natural Rhopaloic acid A is 2R and 5S,
respectively.

93

Experimental Section

All reactions wcre carried out under N2. TH

was distilled aft r r lluxing over

Nalbenzophenone prior to use. CH2Cl2 was distilled overaH2 h'vfore use. NaH wasused after washed with hexane. Silica gel 60F254 was u ed for preparative thin layer
chromatography (PTLC). NMR spectra were recorded on a JEOL (JSX-270 or a JEOL
Lamhda 50() instrument and 1H NMR spectra were ohserved in CDCl3 solution withTMS as the internal reference. 13C NMR spectra were observed in CDC13 solution withTMS as the internal reference. IR spectra were recorded on a JASCO IRA-l H in tnunentand MS spectra were recorded on a JEOL SX-l 02A instrument under electron ionization(EI) conditions. EI data were obtained by using 70 eV electrons. Optical rotations wererecorded on a JASCO DIP-370 polarimeter.

Methyl (4E ,8E)-2-(methoxycarbonyl)-S,9, 13-trime lt hyl-4,8, 12tetradecatrienoate lOa. To a solution of (2E,6E)-farnesol (30.8 g, 139 111mol) andPPh3 (43.6 g, 166 mmol) in CH2C12 (150 mL) at 0 ° ,was added CBr4 (6 .6 g, 193mmol) in one portion and the mixture was stirred at 0 °C for 6 h. The r action mixture
was 4ucnched with aqueous NaHC03 and the organic layer wa washed with water andbrine and concentrated. Hexane was added to the crude product 9a and the ~ oJuble
portion was filtered. The filtrate was concentrated to afford bromide 9a (51 .0 g) as apale yellow oil. The product 9a was more than 95% pure (2E,6E)-isomer in which asmall amount of (2Z,6E)-isomer was contained as an impurity. The I:.:rude product 9a
was uscd for the next reaction without further purification: 1H NMR (270 MHz,CDC13) 8 1.60 (s, 6 H, vinyl-CH3), 1.68 (s, 3 H, vinyl-CH3), 1.73 (s, 3 H, vinylCH3), 1.95-2.20 (m, 8 H, 4-H, 5-H, 8-H, 9-H), 4.02 (d, J = 8.3 Hz, (2E,6E)-I-H),
4.10 (d, J = 8.3 Hz, (2Z,6E)-1-H), 5.05-5.15 (m, 2 H, 6-H, lO·-H), 5.54 (L, 1= 8.3

Hz, 1 H 2-H)

94

To a mixture of NaH (7.35 g, 184 I11mol, 60%J oil u, pension washed withchcxanes) in THF (120 mL) at () DC, was slowly added dim thylll1a Jonate (100 mL, 875mmol) in THF (100 mL). The reaction mixture was stirred at 25 °C for 3 hand THF(100 mL) was added to the mixture in order to dissolve the formed precipitate. The

solution was cooled to 0 °C and the crude farnesyl bromide 9a (5l.0 g) in Til (100 mL)
was added over 1 h. After stirring for 10 h, the resulting residue wa qu nched withaqueous NH4Cl and the resulting mixture was extracted with EQO. The combinedorganic layer was washed with water and brine, dried over anhydrous MgS04, filtered,and evaporated. The crude product was purified by bulb to bulb distillation (200-210 ° ,I mmHg) and dimethyl ester lOa was obtained as a pale yellow oil. (:16.4 g, 780/(l fr m
(2E,6E)-farnesol).

An analytical sample was obtained by column chromatographic

separation on silica gel (eluted with 170/0 EtOAc in hexane: Rf := 0.41) ; IR (thin film)
Vrnax 2900, 1720, 1420, 1320, 1200 1140;

1H NMR (270 MHz, CDC13) 8 l.57 ( , 3H. vinyl-CH3), 1.58 (s, 3 H , vinyl-CH3) , 1.62 (s, 3 H, vinyl-CH3), 1.66 (s, 3 H,

vinyl-CH:n, 1.93-2. 10 (m, 8 H, 6-H, 7-H, 10-H, 11 - I), 2.61 (t, J = 7.3 lIz, 2 H , 3-H), 3.36 (t, J = 7.3 Hz, 1 H, 2-H), 3.71 (s, 6 H, OMe), 5.03-5.12 (m, 3 II, 4-H, 8-H,
12-H):

13C NMR (68 MHz, CDCI3) 8 15.9, 16.0, 17.6 , 25.C1, 26.5, 26.7, 27.5,

39.6(x2), 51.8, 52.3(x 2), 119.3, 123.8,124.3 ,131.2,135.7,138.7, 169.5(x2);HR-

ElMS m/z 336.2336, M+ calcd for C20H3204 336.2301' Anal. Calcd for C20H3204:
C, 71.39: H, 9.59. Found C, 71.39; H , 9.59.

(4E ,SE)-(2-Methoxycarbonyl)-S,9-dinlethyl-4,S-decad ienate

lOb. The

reaction conditions for preparation of lOa were followed using geraniol (5'()6 g, 32.8mmol), PPh3 (10.1 g, 38.7 mmol), CBr4 (16.1 g, 48.5 mmol), NaH (1.58 g, 39.6mmol) and CH2(C02Mc)2 (15.0 mL, 131 mmol) . Purification with bulb to bulb
distillation (140-150 DC, 1 mmHg) afforded lOb (7.74 g, 87.80/0) as a colorless oil: Rf=
0.53 (silica gel, 170/c EtOAc in hexane);95

1H NMR (270 MHz, CDC13) 8 1.59 (s, 3 H ,vinyl-CH3), 1.63 (, 3 H, vinyl- H3), 1.68 (d, 3 H, J = 0.97 HI, villyl- H3), 1.972.03 (m, 4 H, 6-H, 7-H), 2.61 (t, 2 H, J = 7.42 Hz, 3-H), 3.38 (t, I. H, J = 7.42 Hz, 2H) , 3.73 (s, 6 H, OMe) , S.03-S.()7 (m 2 H 4-H,8-H); 13

IS .8, 17 .4, 2S.4, 26.3, 27.4, 39.S, S1.7, S2.1 (x2),169.4 (x2): HR EI-MS /77/z 268.1671, M+calcd for

NNIR (oS MHz,119.~,

DCI3) 8123.8, 131.1 , 138.4,

lSH2404 ,2(i8. 167S .

(6E, 1OE, 15E, 19E )-13, 13- Di (methoxycarbonyl)-2,6, 11),16,20,24-

hexamethyl-2,6,10,15,19,23-pentacosahexene 11. To a mil(tur of NaH (1l.2g, 281 mmol) in THF (600 mL) , was added dimethyl malonate (26. ') mL, 228 111mol) in
THF (600 mL) at 0 °C and the mixture was stirred for 3 h at 2S °C. To the solution, wasadded 9a (32.9 g, 115 mmol) in THF (1S0 mL) over a 1 h period.. After stilTing [or 18 h
at room temperature the mixture was quenched with aqueous NH4CI and the resulting
mixture was extracted with Et20. The combined. extracts were washed with water andbrine, dried over anhydrous MgS04, filtered and concentratcd. The resulting residuc
was purified by column chromatography (silica gcl, 170/(' EtOAc in hexan ) to afford lOa(4.82 g, 12%) and 11 (7.76 g, 120/0) as a pale yellow oil, respectively. An analyticalsample of 11 was obtained by column chromatographic cparation on i1ica g 1. Rf =0.44 (silica gel, 170/0 EtOAc in hexane): IR (thin film) Vmax 290(1, 28S0, 1720, 1430,
1370, 1200, 1170, 900; 1H NMR (270 MHz, CDC13) 8 I.S8 (s , IS H, vinyl-CH3) ,1.68 (s, 9 H, vinyl-CH3), \.93-2.14 (m, 16 H, 4-H, S-H, 8-H, 9-H, I7 -H, 18-H, 21H, 22-H), 2.60 (d, J = 7.3 Hz, 2 H, 12-H , 14-H), 3.69 (s, 6 H, O~r1c), S.OO (t, J = 7.3
Hz 2 H, II-H, lS-H), S.OS-5.18 (m, 4 H, 3-H, 7-H, 19-H, 23··H); HR- IMS mlz
540.4183, M+ calcd for C3SHS604 S40.4179.

Methyl (4E ,8E)-5,9 13-trimethyl-4,8,12-tetradecatrienoate

12a.

A

mixture of lOa (36.4 g, 108 mm01), NaC1 (1S.3 g, 261 11111101), and watcr (3.9 mL, 217mmol) in DMF (I (X) mL) was rclluxcd . After 20 h, the solution wa cooled to 2S °C and96

quenched wiLh water. The re ulting mixture was extracted with Et20. The combinedorganic layer was dried over anhydrolls Mg 04, and filLered, and evaporated.
Purification by bul b Lo bul b disti llation (175-180 ° ,1m mHg) (,I' the crude productafforded methyl ester l2a as a pale yellow oil (27.6 g, 91 0/0):

Rf = 0.55 (silica gel,

17% AcOEt in hexane); IR (thin film) Vmax 2900, 1740, 1440, 1360, 1200, 1160; 1H
NMR (270 MHz, CDC]3) 8 1.59 (s, 6 H, vinyl-CH3), 1.62 (s, 3 H, vinyl-CH3), 1.67
(s, 3H, vinyl-CH3), 1.93-2.11 (m, 8 H, 6-H, 7-H, IO-H, II-H), 2.30-2.35 (m, 4 H, 2-

H, 3-H), 3.66 (s, 3 H, OMe), 5.04-5 .1 4 (m, 3 H, 4-H, 8-H, 12-H);

13C NMR (68MHz, CDCI3) 8 15.8, ] 7.5, 23.4, 25.5, 26.4, 26.6, 34. I, 39.~i, 39.6, 51.2, 67.8,

122.2, 123.9, 124.3, 131.0, 134.9, 136.6, 173.7; HR-EIMS mlz 27R.2246, M+ caled
for C18H3002 278.2246.

Methyl (4E ,8E)-5,9-dimethyl-4,8-decadienoate 6b. The reaction conditions[or preparation of lOa was followed using lOb (7.48 g, 27 .9 mmol), NaCI (1.66 g,

27.9 I11mol), H20 (l.02 g, 56.8 mmol). Purification with bulb to bulb distillation (110120°C, 1 mmHg) afforded 6b (4.98 g, 84.90/0) as a colorIes oil: Rf= 0.69 (silica gel,170/(' EtOAc in hexane): 1H NMR (270 MHz, CDCI3) 8 l.59 (s, 3 H, vinyl-13), 1.61(s, 3 H, vinyl-CH3), 1.68 (s, 3 H, vinyl-CH3), 1.97-2.04 (m, 4 H, 6-H, 7-H), 2.322.33 (111,4 H, 2-H, 3-H), ~.67 (s, 3 H, OMe), 5.07-5,()9 (m ., 2 H, 4-H, 8-H); 13
NMR (68 MHz, CDCI3) 8 15.8, 17.5, 23.4, 25.5, 26.5, 34.1, 39.5, 5t.3, 122.1,
124.1, 131.2, 136.6, 173.8; HR ElMS mlz 210.1618, M+ calcd for

13H2202210.1620 .

(4E ,8E)-5,9,13-Trimethyl-4,8,12-tetradecatrien-l .. ol

13a.

To a

Suspension of LiAIH4 (4.38 g, lIS 11111101) in THF (100 mL) at 0 °e, was slowly added
methyl ester 12a (27.6 g, 99 111111(1) in THF (100 I11L). The reaction mixLure was stirred
at 25°C for 1 h and ether and water was slowly added Lo the mixture at 0 °C. The formed97

precipitate was filtered and sufricienlly washed witht20. The filtrate wa extractedwith Et20 and the combined organic layer was wash d with water emd brine, dried overanhydrous MgS04, filtered, and evaporated. Purification by bulb to bulh distillation(I RO-J YO °C, J mmHg) of the crude product was afforded 13a as a pal yellow oil (22.5g, 91 0/0). An analytical sample was obtained by PTLC on silica gcl ( luted with 170/<)
EtOAc in hexane: Rf = O.25)~
1140:

IR (thin film) vmax 3300, 2YOO. 2850, 1440, 1380,

1H NMR (270 MHz, CDC]3) 8 1.60 (s, 6 H, vinyl-CH3), 1.6 L (s, 3 H, vinyl-

CH3), 1.68 (s, 3 H, vinyl-CH3), 1.94-2.20 (m, 12 H, 2-H, 3-H, (i-H, 7-11, to-H, 11H), 3.62 (t, J = 6.6 Hz, 2 H, I-H), 5.04-5.18 (m, 3 H, 4-H, 8-H, 12-H), the hydroxyl
proton was not observed due to the broadening of the signal;

IJC NMR (68 MHz,CDCI3) 8 15.9 (x2), 17 .6, 24.2, 25.6,26.5,26.7, 32.6, 39.6 (x2), 62.5, 123.7,
124.1,124.3,131.1,134.9,135.6; HR-EIMS m/z 250.2299, M+ calcd for C17H3001
250.2297; Anal. Calcd for C 17H300: C, 8l.54; H. 12.07. Found C, 81.34; H, 12.33.

(4E,8E)-5,9,13-Trimethyl-4,8,12-tetradecatrienyl

bromide14a. To asolution of 13a (22.5 g, 90 I11mol) and triphenylphosphine (28.8 g, 110 I11mol) inCH2C12 (lOO mL) at 0 °C, was added carbon tetrabromide (45.0 ~r, 136 mmol) in one
portion. The mixture was stilTed at 0 °C for 1 h and quenched with water. The resulting
mixture was extracted with CH2C12 and the combined organic layer was washed withwater and brine, dried over anhydrous MgS04, filtered, and evaporated. Hexane wasadded to the crude product and the soluble portion was eparaled and evaporated.
Distillation by hulb to bulh (L 70-180 °C, 1 mmHg) of the resulting Gi] afforded 14a as apalc yellow oil (25.8 g, 92o/cl). The oil was purified by column chromatography on silicagel (eluted with hexane: Rf = 0.44);
1260. 700;

IR (thin film) Vmax 2900. 1430, 1380, 1360,

1 H NMR (270 MHz, CDCI3) 8 1.60 (s, 6 H, vinyl-CH3), 1.63 (s, 3 H,

vinyl-CH3) 1.68 (s, 3 H, vinyl-CH3), 1.84-1.93 (m, 2 H, 2-H), 1.97-2.19 (m, 10 H,
3-H, 6-H, 7-H, lO-H, Ii-H), 3 .39 (t, J = 6.6 Hz, 2 H, i-H), 5.04-5.15 (m, 3 H, 4-H,

98

R-H, 12-H);

13C NMR (68 MHI. CDCI3) 8 16.0, 16.1 , 17 .6. 25 .6, 26.3, 26.4 26.7,

32.8, 33.4, 3Y.7 (x2), 122.4, 124.0, 124.3, 131.9, 135.0, 136.7;

HR-EIMmlz

312.1476, M+ caIcd forC17H2979Br 312.1453.

(5E, 9E)-6,1 0,14- Trimethyl-5,9, 13-pentadecatriencnitril e 15a.

A sampleof sodium cyanide (5.60 g, 114 11111101) was added to a solution of 14a (22.2 g, 71mmol) in DMF (100 mL). The reaction mixture was stirred at 25°C for 1 h. The mixture
was quenched with water and the resulting mixture was extracll~d with Et20. The
combined organic layer was washed with water and brine, dried over anhydrou MgS04,
filtered . and evaporated. The crude product was purified by bulb to bulb distillation(180-1 YO DC, 1 mmHg) and 15a was obtained as a pale yellow oil (15 .9 g, 870/0). An
analytical sample was obtained by column chromatographic separation on silica gel(eluted with 17% EtOAc n hexane: Rf = 0.59); IR (CH2CI2) vmax 2900,2850,2250,
1425, 1370:

1H NMR (270 MHz, CDCl3) 8 1.59 (s, 6 H, vinyl-CH3), 1.62 (s, 3 H,

vinyI-CH3), 1.67 (s, 3 H, vinyl-CH3), 1.68-1.72 (m, 2 H, 3-1I), \.93 -2.20 (m, to II,
4-H, 7-H, 8-H, II-H, 12-H), 2.31 (t, J = 7.1 Hz, 2 H, 2-H), 5.03 -5.14 (m, 3 II, 5-11,
9-H,I3-H);

13C NMR (68 MHz, CDC13) 8 15.9, 16.0, 16.2, 17.6,25.4,25.6,26.4

26.5,26.6,39.6 (x2), 119.7,121.7,123.8,124.2,131.1,135.1,137.6;

HR-EIMSmlz 259 .2283, M+ calcd for C18H29N 259.2300: Anal. Cellcd for C1SH29N:

83.33: H, 11.27, N, 5.40. Found C, 83.28; H, 11.37; N, 5.32.

(5E,9E)-6,10,14-Trimethyl-5,9,13-pentadecatrienoic Acid

16a.

To a

solution of 15a (15 .9 g, 61 mmol) in EtOH (lOa mL), was added a solution of KOH(36.7 g, 655 mmol) in water (100 mL). The mixture was rel1uxcd f(.r 30 h and cooled to
25°C. The ethanol was evaporated by rotary evaporator and the residue was extractedwith CH2CI2. The aqueou phase was acidified with conc. HC) and extracted with
El20. The comhined Et20 layer was washed with water and brine, dried over anhydrous99

MgS04. The filtratc wa evaporatcd to givc 16a as a palc ycllow oil (14.9 g, 8%)).
The oil was eparatcd by column chromatography on silica gel (elutcd with 17% tOAc
in hexane: Rf = 0.23); IR (CH2C12) Vmax 2900, 1700, 1420, 1380, 1220;

1H NMR(270 MHz, CDCl3) 8 ] .6 1 (s, 9 H, vinyl-CH3), 1.69 (s, 3 H, vinyl - ~H3), 1.69-1.71(m, 2 H, 3-H), 1.94-2.18 (m, 10 H, 4-H, 7-H, 8-H, Il-H 12-H), 2.36 (t, J = 7.6 Hz,
2 H, 2-H), S.06-S.17 (m, 3 H, S-H, 9-H, ] 3-H), 10.00-11.00 (bs, 1 H);

13C NMR(68 MHz, CDCI3) 8 16.0 (x2), 17.6,24.7,25.6,26.5 ,26.7,27 I 31.4,39.7 (x2),123.1 , 124.1 , 124.4, 131.2, 135.0, 136.3 , 180.4; HR-EIMS l/1/z :~78 .2254 , M+ calcd
for C 18H3002 278.2246.

Methyl (5E ,9E)-6,1(),14-trimethyl-5,9,13-pentadec31trienoate 6a. To a
mixture of 16a (8.19 g, 29.4 mmol) and K2C03 (12.2 g, 88.3 mmclI) in DMF (30 mL),
was added Mel (6.0 mL, 96.4 mmol) and thc rcsulting solution was stirrcd at 25°C for 3
h. The mixturc was qucnchcd with watcr and thc resulting mixture was cxtractcd with
Et20. The combined organic laycr was washcd with watcr and brinc, dried withanhydrous MgS04, filtered, and cvaporated. Thc crudc product was puriri d by bulb tobulb distillation (160-170 DC, 1 mmHg) and 6a was obtaincd as a palc ycllow oil (8.40g,98%). An analytical sample was obtaincd by column chromatographi '': scparaLion on silicagel (eluted wiLh 17% EtOAc in hcxane: Rf= 0.53); IR (thin film) vmax 2900, 2850,
1730, 1420, 1360, 1160;

1H NMR (270 MHz, CDC}3) 8 1.60 ( , 6 H, vinyl -Mc),

1.62-1.67 (m, 2 H, 3-H), l.68 (s, 6 H, vinyl-Me), 1.94-2.19 (m , 11) H, 4-H, 7-H, 8-H,
II-H. 12-H), 2.30 (t, J = 7.6 Hz, 2 H, 2-H), 3.66 (s, 3 H, O!vlc) , S.06-5.l7 (m, 3 H,
5-H 9-H, 13-H); HR-ElMS mlz. 292.2442, M+ caled. [or C 19H3202 292.2402.

(4S ,5' E ,9' E) - 3- (1 '- Oxo -6' ,10' , 14' - tri m eth y 1- 5' ,9' ,13'-pentadecatrienyl)-4-(phenylmethyl)-2-oxazolidinone (S)-7a. To a olution of
16a (3.1S g, 11.3 mmol) and Et3N (1.6 mL, 11.5 I11mol) in THF (20 mL) , was added100

PivCI (1.4 mL, I 1.4 mmo1) at 0 °C to give anhydridc. The r action mixtur was stilT d
at 0 °C for 30 min and white precipitate was formed. To the suspen ion at -78 ° ,waslowly added N-lithio-(S)-4-benzyl-2-oxazolidinone which was prcpared from stirring ofa solution of (S)-4-benzyl-2-oxazolidinone (2.0 g, 11.3 m11101) in TI IF (30 mL) and a
1.57 M solution of n-BuLi in hexane (7.9 mL, 12.6 111mol) at -7R 0(., f{ r 30 min and the
mixture was allowed to warm to ambient temperature over 15 h. Aqueous NH4 1 wasadded to the reaction mixture and the resulting mixture was extracled with Et20. The
combined organic layer was washed with water and brine, dried over anhydrous Mg 04,
filtered, and evaporated. The residue was separated by column chromatography on silicagel (eluted with 170/0 EtOAc in hexane: Rf= 0.3) to give (S)-7a as a colorless oil (4.27
g, 87~' ):[cx]25 D +35.3 (c 0.61, CHCI3);

1670, 1420, 1360, 1340, 1240, 1180;

IR (thin film) Vmax 2900,2850, 1760,

1H NMR (270 MHz, CDC]3) 8 1.61 (s, 6 H,

vinyl-CH3), 1.63 (s, 3 H, vinyl-CH3), 1.69 (s, 3 H, vinyl-CH3), 1.70-1.81 (m, 2 H,
3'-H), 1.95-2.15 (m, J 0 H, 4'-H, 7'-H 8'-H, 11'-H, 12'-H), 2.77 (dd, J = 13.2, 9.8
Hz, 1 H, benzyl position), 2.85-3.05 (m, 2 H, 2'-H), 3.31 (dd, J == 13.2, 2.9 Hz, 1 H,
henzyl position), 4.15-4.25 (m, 2 H, 5-H), 4.64-4.74 (m, 1 H, 4-H), 5.05-5.25 (m, 3H, 5'-H, 9'-H, I3'-H), 7.15-7.25 (m, 2 H), 7.25-7.45 (m, 3 H);

13C NMR (68 MHz,COCI3) 8 15.9, 16.0, 17.6,24.3,25.6,26.6,26.7 ,27.2,35.0,37.9, ]9.7 (x2), 55.1,
66.0, 123.3, 124.1, 124.3, 127.2, 128.9 (x2), 129.4 (x2), 131.1, 134.9, 135.3
136.1, 153.3, 173.3;

HR-EIMS mlz 437.2932, M+ cakd for C28 H3y03N 437.2930;

Anal. Calcd [or C28H3903N: C,76.85: H,8.98; N,3.20. Found

,76.66; H,9.16;

N. 3.18.

(4R ,5'E ,9'E)-3-(1 '-Oxo-6' ,10' ,14'-trimethyl-5' ,9',13'-pentadeca trienyl)-4-(pheny Imethyl)-2-oxazolidinone (R )-7 a.

The reaction

conditions [or preparation of (S)-7a were followed using 16a (2.6 g, 9.3 mlTIol),
pivaloyl chloride (1.4 mL, 11 mmol), Et3N (1.6 mL, 11 mmol), (R)-4-benzyl-2-

101oxazolidinone (l.8 g, 10 mmol) and a 1.6 M solution or nBuLi in h xane (6.4 mL, 10mmol). Column chromatographic separation (silica g I, 17 (If, EtOAc in hexan ) of thecrude product afforded (R)-7a as a colorless oil (3 .9 g, 95o/c): [(x.j25 o -35.5 (c 3.9,
CHCl3)·(7 E, llE)w 4- (Methoxycarbony 1)-8, 12, 16- tri methyl-I, 7,11,15heptadecatetraene Sa. To a solution of (i-Pr)2NH (1.4 mL, ] 0.7 I1ll11ol) in THF (J ()mL) at -78 °C, was added a 1.63 M solution of 17-BuLi in hexane (4.9 mL, 8.0 mmo1)
over 5 min. The solution was stirred at 0 °C [or 30 min. Arter the s(llution wa cooled to-78°C, a solution of 6a (1.94 g, 6.65 mmol) in THF (7 mL) was added to the solution.
The mixture was stirred at -78°C for 30 min and allyl bromide (2.9 mL, 33.5 mmol) was
added to it.

The reaction n1ixture was allowed to warm from -78°C to ambient

temperature over 18 hand 4uenched with aqueous NH4Cl. The resulting mixture was
extracted with Et20. The combined organic layer was washed with water and brine,
dried over anhydrous MgS04, filtered, and evaporated. The crude product was purifi dwith bulb to bulb distillation (L 7 5-185 °C, 1 mmHg) and Sa wa:; obtain d a a pal
yellow oil 0.78 g, 81 0/0).

An analytical sam pIc was obtain d by column

chromatographic separation on silica gel: Rf = 0.67); lR (thin film) Vmax 2900, 2850,
1730, 1420, 1360, 1150;] H NMR (270 MHz, COC13) 8 1.45-\.60 (m, 2 H, 5-H),

1.56 (s, 6 H, vinyl-Me), 1.65 (s, 6 H, vinyl-Me), 1.92-2.13 (m, 10 H, 6-H, 9-H, IO-H,
13-H, 14-H), 2. 13-2.49 (m, 3 H, 3-H, 4-H), 3.63 (s, 3 H, OMe) 4.93-5.20 (m, 5 H,
I-H, 7-H, II-H, I5-H), 5.62-5.82 (m, I H,2-H);

HR-EIMS /11/z .332.2708, M+ calcd

for C22H3602 332.2715.

(6E,1 OE)-4-(Methoxycarbony 1)-7,11 wdimethy 1-1,6,1 O-(lodeca triene

5b.

The reaction conditions for preparation of Sa were followed using 6b (1.00 g, 4.75mmol), nBuLi (5.76 mmol), i-Pr2NH (0.85 mL, 6.48 mmol) and allyl bromide (1.65102mL, \9.0 mmol). Purification with hulh to hulh dL tillation (12(1-130 ° , 1 mmHg)

afforded 5b (0.98 g, R2.3%) as a pale yellow oil: Rf = 0.75 (siJica g I, 17 ~ EtOAc in
hexane): 1H NMR (270 MHz, COCI3) 8 1.60 (s, 6 H, vinyl-CHJ), 1.6R (d, J = 0.97
Hz, 3 H, vinyl-CH3), 1.98-2.08 (m, 4 H, 8-H, 9-H), 2. 17-2.40 (111, 4 II, l-H, 5-H),

2.40-2.50 (m, 1 H, 4-H), 3.65 (s, 3 H, OMe), 4.99-5'()9 (m, 4 H, I-H, 6-H, IO-H),
5.74 (ddt, J= 17.110.3,6.8 Hz, 1 H, 2-H); 13C NMR (6R MHz, CDCI3) 8 IS .6, 17 .S,25.5 , 26.4,30.0,35.6,39.6, 4S.4, S1.1, 116.5, 120.7 , 124.0, 13l.1 , 13S.4, 137 .2,
175.S: HR-EIMS /I1/z. 2S0.1947, M+ calcd for C t6H2602 2S0.1933 ..

( 4 S ,2' R ,5' E ,9' E) - 3 - [1 ' - 0 x 0 - 2 ' - (2" - pro pen y I ) -6' , 1 () , , 1 4' - t rim e th y IS' ,9' ,13' -pentadecatrienyl]-4-(phenylmethyl)-2-oxazolidi11tone(R)-8a.

To

a solution o[ (i-Pr)2NH (2.6 mL, 19.8 11111101) in THF (12 mL) at -78 °C, was slowly
added a 1.6 M solution of I1-BuLi in hexane (9.7 mL, 15.2 111mol). 'fhe reaction mixture
was wanned to 0 °C and stirred. After 30 n1in, the mixture was agclin cooled to -78 °C.
To the cooled solution, was added a solution of (5)-7 (6.05 g, 13 . ~: 111111(1) in TH · (12mL) and the mixture was stirred at -78°C [or 30 min.

A sample of allyl hromide (6.0mL, 69.3 m111o]) was added to the reaction mixture. The reaction mi , tur was wan11ed to-20°C and stirred at -20 to -10 °C [or 6 h. The mixture was quenched with aqueous
NH4CI and the resulting mixture was extracted with Et20. The combined organic layer
was washed with water and hrine, dried over anhydrous Mf.S04, filtered, andevaporated. Silica gel column chromatography o[ the crude product afforded (R)-8a as acolorless oil (3.79 g, 61 %): Rf = 0.S2 (silica gel, 17(10 AcOEt in hexane);+44.1 (c 3.9, CHCI3);ra] 2S 0

IR (thin [ilm) Vlnax 2900, 1770, 1680, 1430, 1370, 1340,

1230, 1200, 1090,900; 1H NMR (270 MHz, CDCI3) 8 I.S8 (s, 3 H, vinyl-CH3), I.S9
(s, 6 H, vinyl-CH3), 1.68 (s 3 H, vinyl-CH3), 1.74-1.87 (m , 2 H, 3'-H), 1.93-2.11(m, 10 H, 4'-H, T-H, 8'-H, II'-H, 12'-H), 2.28-2.38 (m, L H, l" -H), 2.42-2 .53 (m,1 H, 1"-H), 2.66 (dd, J = 13.2, LO.O Hz, 1 H, benzyl proton), 3.30 (dd, J = 13.2, 3.4

103

Hz, I H, henzyl proton), 3.88-3.97 (m, 1 H, 2'-H), 4.08-4.20 (m, 2 H, 5-H), 4.624.73 (m, 1 H, 4-H), 5.02-5 .14 (m, 5 H, 3"-H, 5'-H, 9'-H, I3'-H), 5.76-5.9L (m, 1 H,
2"-H), 7.21 -7.36 (m, 5 H);

13C NMR (68 MI Z, CD 13) 8,16.0 (x2), 17.6,25.6,

25.7,26.6,26.7,31.4,36.9,38.1,39.7 (x2), 41.9,55.5,65.8,117.1,123.5,124.1,
124.4, 127.2, 128 .9 (x2), 129.4 (x2), 131.2, 135 .0, 135.2, 1]5.4, 135.8 , 153 .0,
175.9:

HR-EIMS /11/z. 477.3266, M+ calcd for C3IH4303N 477.3243; Anal. Calcd

for C31H4303N: C, 77.95; H, 9.07; N, 2.93. Found C, 77.75; H, 9.10; N, 2.81.

( 4 R ,2' S ,5' E ,9' E) - 3 - [ 1 ' - 0 x 0 - 2' - (2" - pro pen y I ) -6' , 1 () , , 1 4' - t rim e thy IS' ,9' ,13' -pentadecatrienyl]-4-(phenylmethyl)-2-oxazolidinone (S)-8a. The

condition for (R)-8a were followed using (R)-7a (3.8 g, 8.78 I11mol), i-P r2NH (1.7 I11L,
12.0 mmol), a 1.6 M solution of nBuLi in hexane (6.3 mL, LO. l mmol), and allyl
bromide (3 .2 mL, 37.0 mmol). Column chromatography on silica gel (eluted with 90/0
AcOEt in hexane) of the crude product afforded (S)-8a as a colorkss oil (3.2 g, 760/0) :lal 25 0 -45.6 (c 1.4, CHCI3).

(7 E, J 1 E)-4- Hyd roxymethyl-8, 12, 16-tri methyl-I, 7,11 , 15-

heptadecatetraene 19a. To a suspension of LiAIH4 (1.96 g, 51.g mmol) in TH(50mL) at 0 DC, was slowly added a solution of 5a (11.0 g, 33.2 mmDl) in TH (50 mL)
and the mixture was stirred at°ec.

After 3 h, water (1 mL) was carefully added to the

mixture at 0 ec, followed by sat. NaOH (1 InL). The resulting suspension was filtered.
The filtrate was partitioned between water and Et20 and thoroughly , ,xtracted with Et20.
The combined extracts were washed with water and brine, dried over anhydrous MgS04,
filtered, and evaporated . The crude product was purified with bulb to bulb distillation
090-200°C, 1 mmHg) to give 19a as a pale yellow oil (8 .89 g, 88<70) . The product was
further purified hy column chromatography on silica gel (eluted with 170/0 AcOEt inhexane: Rf = 0.15):

IR (thin film) Vmax 3500, 2900, 2850, 1440, 1380, 1030, 990,

104

910:

IH NMR (270 MHz, CDCI3) 8 1.25-1.46 (m, 2 H, 5-H), 1.60 (5, 9 H, vinyl-

CH3), 1.68 (5, 3 H, vinyI-CH3), 1.60- 1.65 (m, 1 I I, 4-H), 1 . 93-:~ . 15 (m, 10 H, 6-H,
9-H, 1()-H, I3-H , 14-H) , 2.13 (t, J = 6.8 Hz, 2 H, 3-H), 3.54 (d, J = 5.9 Hz, 1 H,
CH20H), 3.55 (d, J = 5.4 Hz, 1 H, CH20H), 4.99-5.14 (m, 5 1 , I-H, 7-Il, II -H, 15H) , 5.75-5.90 (m, 1 H, 2-H), the hydroxy proton wa
broadening of the signal;

not ohserved duto the13C NMR (68 MHz, CDCI.3) 8 15.9, 17.6, 25. 1, 25.2, 25.6,

26.5, 26.7, 30.7, 3() .9, 35.6, 3<) .7, .3 9.9, 65.3, 1 I 6. 1, I 24. 1, I 24 .3 (x 2) , 11 l. 1,
134.9, 135.2,137 .0, ; HR-EIMS 1I11z. 304.2799, M+ calcd for C21H360 304.2766.

(6E, 1 OE)-4-hydroxymethyl-7, 11-di methyl-l ,6, 10-dodccatriene

19b.

The reaction conditions for preparation of 19a were followed using Sb (2.81 g, 11.2mmol) and LiAIH4 (0.70 g, L8.6 mmol). Purification with column chromatography on
si lica gel (eluted with 13~ AcOEt in hexane) afforded 17b (20.2 g, 91.0 ~) as acolorless oil: Rf = 0.38 (silica gel, 170/0 EtOAc in hexane); 1H NMR (270 MHz,CDCI3) 8 1.65 (s , 6 H, vinyl-CH3), 1.68 (d, J = 0.98 Hz, vinyl- ]-13), 2.0 I -2. 13 (m 9H, 3-H, 4-H, 5-H, 8-H, 9-H), 3.55 (d, J = 5.4 Hz, 2 H, CH20H), 5.00-5.10 (m 3 H,
I-H, 6-H). 5.16 (tq, J = 7.3, l.0 Hz, I H, 10-H), 5.83 (ddt, J = 17 . 1, 10.3, 6.8 Hz, 1
H, 2-H), the hydroxy proton was not observed due to broadening of the signal: I
NMR (270 MHz, CDCl3) 8 16.0, 17.6, 25.6, 29 .3, 35.5, 39.8 . 41.1, 65.4, 116.1 ,122.3, 124.2,131.3 , 136.5 , 137.1: HR ElMS mlz 222.1975, ~f1+ '",a1cd for

15H260222.1984.

(4R,7 E, 11 E)-4-Hydroxymethyl-8,12, 16-trimethyl-,1,7,11,15-

heptadecatetraene (R)-19a. The reaction conditions for preparation of 19a were

followed using (R)-8a (6.15 g, 13 mmol) and LiAIH4 (1.08 g, 29 rnmol) . The productwas purified by column chromatography on silica gel (eluted with 17O/r. EtOAc in hexane,
Rf= 0.15) and (R)-19a (3.66 g, 87o/r.)) was obtained: lcx]25 D -4.8 ( c 2.0, CHC I3)·105

(4S,7E,1 1E)-4-Hydroxymethyl-8,12,16-trinlethyl-l,7,11 15-

heptadecatetraene (5)-19a. To a ,olution of (S)-8a (2.4 g, 8.0 mmol) in dry MeOH
(1.1 mL) at 0 °C, was slowly a solution of LiBH4 (520 mg, 24 mm ')1) in THF (19 OlL).
The reaction mixture was stirred at () °C for 3 h and quenched with aqueous NH4Cl. Th
aqueous layer was extracted with Et20 and the combined organ.ic extracts w re washedwith water and brine, dried over anhydrous Na2S04 and concentrated.

Columnchromatographic separation of the crude product (silica gel, 170/0 EtOAc in hexane, Rf =O.IS) gave (R)-4-benzyl-2-oxazolidinone (white crystal, 860 mg, 76O/r,) and (S)-19a as acolorless oil (973 mg, 60Ok,): la]2S D +4.5 (c 3.4, CHCl3).

(7 E, 11 E)-4-(tert- B u tyldi methy lsi loxy methyl )-8, 12, 16-trimethyl-

1,7,11,15-heptadecatetraene 20a. To a mixture of 19a (1.58 g, 5.20 mOlal) andimidazole (67 L mg, 9.86 mOlol) in DMF (7 mL) at°°C, was added TBSCI (1.14 g, 7.55mmol). The reaction mixture was stirred at () °C for 3 h and quench d with aqucou 'NH4Cl. The aqueous layer was extracted with ether. The com bined

xtracts w r

washed with water and brine, dried over anhydrous MgS04, filtered, and evaporat d.
The residue was separated with column chromatography on silica gel (eluted withhexane) to give 20a as a pale yellow oil (1.89 g, 87o/r). An analytical ample wasobtained by PTLC on silica gel (eluted with hexane: Rf = 0.8)~2900,2850, 1440, 1380, 1250, 1090,900, 830, 770~

IR (thin film) Vm ax

I H NMR (270 MHz, CDC13) 8

0.03 (s, 6 H, CH3-Si), 0.89 (s, 9 H, (CH3)3C-Si), 1.25-1.44 (m, 2 H, 5-H), 1.50-

I.S9 (m, 1 H. 4-H), 1.60 (s, 9 H, vinyl-CH3), l.68 (s, 3 H, vinyl-CH3), l.95-2.17(m, 12 H, 3-H, 6-H, 9-H, 10-H, I3-H, 14-H), 3.48 (d, J = 5.9 Hz, ] H, CH20S i ),3.49 (d, J = 5.4 Hz, 1 H, CH20Si), 4.9S-S.0S (m, 2 H, 1-H), 5.08-S.15 (m, 3 H, 7-H,

ll-H, IS-H) 5.7-S.8S (m, 1 H, 2-H);

13C NMR (68 MHz, CDCI3) 8 -5.4 (x2), 16.0,

17.7, 18.3, 25.3 (x2), 2S.7, 25.9 (x3), 26 .6, 26.8, 29.7, 30.6, 3S.5, 39.7, 40.0, 64.9,

106115.7. 124.3 , 124.4, 124.7, 131. 2, 134.9 (x 2) , 137 .4 ;HR- 11\1/Il/;'

418 .3666 , M+

ca1cd for C27HSOOSi 418.3631; Anal. Cedcd for C27HSOO<;;i: C, 77.43; H, 12.03 .
Found C, 77.46: H, I 1.88.

(6E,1 ()E )-4-(tert- B u ty Id i methy lsi Iy loxy nlcthy I)-7, 11-d i mcth y 1-1 ,6, 1 ()-dodecatriene 20b. The reaction conditions for 20a were followed using 19b (2.29 g,
jO.3 mmol), imidazole (l.40 g, 20.6 I11mo1) and TBSCI (1.70 g, 1 \. 3 111m(1). Purified
with bulb to bulb distillation (190-200 °C, 1 mmHg) afforded 20b (3.78 g, 97.7 I11m01):

Rf = 0.88 (silica gel, 170/0 AcOEt in hexane); 1H NMR (270 MHz, CDCI3) 8 0.03 (s, 6H, CH3-Si), 0.89 (s, 9 H, (CH3)3CSi), 1.S9 (s. 3 H, vinyl-CH3), 1.60 ( , 3 H, vinylCH3), l.68 (d, J = 0.97 Hz, 3 H, vinyl-CH3), l.90-2.20 (m, 9 H, 3-H, 4-H, 5-H, 8H, 9-H), 3.47 (d, J = 5.37 Hz, 2 H, CH20Si), 4.96-5.15 (m, 4 fI, I-H, 6-H, 10-H),
5.78 (ddt, J = 17.1,10.3,6.8 Hz, I H, 2-H); 13C NMR (270 W{Hz, CDCI3) 8 -S.4(x 2), 16.1, 17.7, 18.3, 2S.7, 26.0 (x3), 26.7, 28 .9, 3S.3, 39.9, 41.4, 64.7, 1IS.7,
122.8, 124.4, 131.2, 136.0, 137.4; HR ElMS m/z 336.2852 M+ Celled for21 H400Si

336.2848.

(4R,7 E, 11 E)-4-(tert-B u ty Idi nlethy Isiloxy methy 1)-8,12,16- tri methy 1-

1,7,11,15-heptadecatetraene (R)-20a.

The reaction conditions for 20a were

followed using (R)-19a (J.07 g, 3.S 11111101), TBSCI (637 mg, 4.23 mm(1) and imidazole(532 mg, 7.8 mmol). The crud product was separated with column chromatography on
silica gel (eluted with hexane) to give TBS ether (R)-20a (1.08 g, 740/0) as a pale yellow
oil. An analytical sample was obtained by PTLC on silica gel (eluted with hexane: Rf =n.8): [O,]2S 0 +2.6 (c 3.0, CHC13).

(4S,7 E, 11 E)-4-(tert-Bu tyldimethylsiioxymethyl)-8, 12,16- tri methyl-

1,7,11,15-heptadecatetraene (S)-20a.

107

The reaction conditions for 20a werefollowed using (5)-19a (356 mg 1.17 111111(1), TB' 1 (212 mg, 1.40 11111101) andimidazole (223 mg, 3.28 I11mol). Column chromatographic s paration (silica gel,hexane) of the crude product afforded (S)-20a (289 mg, 59%) as a c,,)lorless oil: l aJ25 0-4.7 (c 2.98, CHC13).

(7 E, 11 E)-4-(tert- B u tyldi methylsi loxymethy I )-8,12, 16-tri nlethyl-

7,11,lS-heptadecatriene-l-ol 4a. To a solution of 20a (1.8() g, 4.52 mmol) in

THF (5 mL) at 0 °C, was added or a 0.5 M solution of 9-BBN in THF (13.6 mL, 6.8mmo1) and the mixture was sUrred at 0 °C to ambient temperature over 18 h. The solution
was cooled to () °C and water was added to the solution. To the resulting mixture at () °C,
were added a solution of NaOH (631 mg, 15.8 mm(1) in water (3 mL) and 300/0 aq.
H202 (1.65 g, 14.6 mm(1) and the reaction mixture was stirred at () °C to ambient
temperature. After 18 h, Water was added to the mixture and the aqueous layer was
extracted with dichloromethane. The organic layer was collected, washed with water andbrine, dried over anhydrous MgS04, filtrate, and evaporat d.. The oily residue wasseparated with column chromatography (silica gel, EtOAdhexane 1/5). 4a was obtain d
a a pale yellow oil (1.55 g, 79 rc) . An analytical sample was obtained by PTL on silicagel (eluted with 170/0 AcOEt in hexane: Rf = O.3)~
1440, 1380, 1250, 1060, 830,770;

IR (thin film) Vmax 33()O, 2880,

IH NMR (270 MHz, COCI3) 8 0.04 (5, 6 H,

CH3-Si). O.R9 (s, 9 H, (CH3)3C-Si), 1.23-1.52 (m, 7 H, 2-H, 3··H, 4-H, 5-H), 1.60
(s. <) H, vinyl-CH3), 1.68 (s, 3 H, vinyl-CH3), 1.95-2.15 (m, 10 H, 6-H, 9-H, IO-H,
13-H, 14-H). 3.50 (l. J = 5.4 Hz, 2 H, I-H), 3.62 (t, J = 6.8 Hi~, I H,

H2-0-Si),

3.64 (t, J = 6.8 Hz, 1 H CH2-0-Si), 5.07-5.14 (m, 3 H, 7-H, Il-H, I5-H), thehydroxyl proton was not observed due to the broadening of the sig'lal~

13C NMR (68MHz, CDCl3) 8 -5.5 (x2), 15 .9, 17.6, 18.3,25.3 (x2), 25.6, 2~;.9 (x3), 26.4 (x2),28.1,32.2,19.7,39.9,41.9,63.3,65.4,124.2,124.4, 124.7, 131.1, ]34.8, 134.9~

108

HR-EIMS m/z 436.3771, M+ calcd for C27H5202 i 436.371'7; Anal.
C27H5202Si: C, 74.24; H, 12.00. Found

aIed for,74.39; II, J 2.08.

(6E, lIE )-4-(tert-B u tyldi methylsi Iyloxymethyl )-7, I1-d Hnlethyl-

dodecadiene-l-ol 4b. The reaction conditions for 4a were followed u ing 20b (3.00

g, 8.91 mm01), 9-BBN (26 mL, 13.0 1111110]), NaOII (1.43 g,. 35.7 1111110]) and 30%
H202 (5.30 g, 88.2 11111101). Purification with bulb to bulh distillaLion (230 0 ,1 I11111Hg)
afforded 4b (2.72 g, 86.1 11111101): Rf = 0.40 (silica gel, 170/0 EtOAc in hexane); IH
NMR (270 MHz, CDC]3) 8 0.03 (s, 6 H, CH3-Si), 0.89 (s, 9 H, ( H3)3 Si), 1.271.64 (m, 6 H, 2-H, 3-H, 5-H), 1.59 (s, 6 H, vinyl-CH3), 1.68 (~;, 3 H, vinyl-CH3),
1.90-2.00 (m, 1 H, 4-H), 1.95-2.08 (m, 4 H, 8-H, 9-H), 3.47 (d, J = 5.4 Hz, 1 H,
CH20Si), 3.48 (d, J =5.4 Hz, CH20Si), 3.62 (t, J = 6.6 Hz, 2 H, I-H), .5.06-5.15(m, 2 H, 6-H, IO-H), the hydroxy proton was not observed due to the broadening of thesignal: 13C NMR (270 MHz, CDCI3) 8 -5.5 (x2), 16.0, 17.6, ]~;.2, 25.6, 25.9 (x3),26.7,26.9,29.3,30.2 41.0,63.2,65.2, L22.6, 124.3, 131.2, 13~i.9; HR- 1M

III/Z

354.2943, M+ caIed for C21 H4202Si 354.2954.

(4R,7 E, 11 E)-4-(tert- B u ty Idi methy lsi loxymethy 1)-8:1 12,16- tri nlethy 1-

7,11,15-heptadecatriene-l-ol(R)-4a.

The reaction conditions for 4a were

followed using (R)-20a (1.38 g, 3.3 mmol), 9-BBN (0.5 M in THF solution) (7.2 mL,
3.6 ml1101), NaOH (389 mg, 9.73 11111101) and 30o/c) aqueous H202 (692 mg, 6.11 mmol).
The resulting oily product was separated with column chromatography (silica gel, 17O/C
EtOAc in hexane) to give alcohol (R)-4a (1.0 g, 6901£-),92% yield based on the recoveryof (R)-20a) and the starting material (R)-20a (364 mg) was recovered. An analyticalsample wa obtained hy PTLC on silica gel (eluted with 17% EtOAc in hexane: Rf=0.3): [cxJ25 D +8 .8 (c 0.3 CHCl3).

]09

(4S,7 E, II E)-4-{tert- B u tyldi nlethylsily loxymcthyl)- 8,12,16- tri nle thyl7,11,15-heptadecatriene-l-ol(8)-4a.

The reaction conditions for 4a were

followed using (S)-20a (289 I11g, 0.69 11111101), a 0.5 M solution or 9-BBN in THF (1.5mL, 0.75 mmol), NaOH (110 mg, 2.75 mmol) and 30% aqueous 11202 (204 mg, 1.8
O1mol). Column chromatographic separation of the crude product afforded (S)-20a(78.9 mg, 260/(') as a colorless oil: fa]25 0 -4.8 (c 1.47, CHCI3)·(7 E, I 1 E) - 4 - (t e r t - But YId i nl e thy lsi IYlox y met h y I) - 8, 12,1 (, - t rim e thy 17,11,15-heptadecatriene-l-al 3a. To a solution or (COCI)2 (0.38 mL 4.36 m111(1)in CH2Cl2 (50 mL) at -60°C, was added a solution or DMSO (0.6:\ mL, 8.88 ml11ol) in
CH2CI2 (10 mL). After 15 min, a solution of 4a (1.92 g, 4.40 n 111(1) in

H2C12 (5mL) was added to the mixture at -60°C and the reaction mixture WilS stirred ror 30 min.
To the mixture, was added Et3N (3.1 mL, 22.2 mmo]) and the reaction mixture wasstirred at -60 to -10°C for 5 h. The reaction mixture was quenched with aqueous NH4Cl
and the resulting mixture was extracted with CH2CI2. The combined organic layer waswashed with water and brine, dried over MgS04, filtered, and evaporated· Th crud
product was separated with column chromatography (silica geltOAc/h xane liS)afforded 1.52 g (80o/c:,) of 3a as a pale yellow oil and 228 mg (12Stl) or 4a (9\ o/i-) yield
based on the recovery of 4a). An analytical sample was obtained bJ PTL

on silica gel(eluted with 170/0 AcOEt in hexane: Rf= 0.4): IR (thin film) Vmax 2YOO, 1720, 1440,
1380. 1250, 1080, 830, 770:

1H NMR (270 MHz CDC13) 8 0.( 14 (s, 6 H, CH3-Si),

O.8Y (s, Y H, (CH3)3C-Si), 1.23-1.44 (m, 3 H, 4-H, 5-H), 1.45- L55 (m, 2 H, 3-H),
1.60 (s, 9 H, vinyl-CH3), 1.68 (s, 3 H, viny]-CH3), 1.94-2.]12 (m, 1() H, 6-H, 9-H,
10-H, 13-H, 14-H), 2.45 (td, J = 7.7, 1.7 Hz, 2 H, 2-H), 3.47 (00, J = 10.0, 5.6 Hz, 1
H, CH2-0-Si), 3.55 (dd, J = ]0.0,4.6 Hz, 1 H, CH2-0-Si), 5.05·· 5.14 (m, 3 H, 7-H,

II-H. 15-H), Y.76 (t, J = 1.7 Hz, 1 H, I-H);

13C NMR (68 MHz, CDC]3) 8 -5.5(x2), 16.0, 17 .7. 18.2,23.6,25.3 (x2), 25.7, 25.9 (xl), 26.6, 26.7, 31.0,39.5,39.7

110

(x2), 41.5, 64.9, 124.2, 124.3, 124.4, 131.2, 134.9, 135.1, 202.9:

HR-EIMS mlz

434.3542, M+ calcd for C27H5002Si: 434.35RO· Anal. ,aIcd for .27115002Si: C,
74.59~ H,

11.59. Found C, 74.36; H, 1 1.80.

(6E, llE)-4-(tert-B u tyldi methylsi Iyloxymethy I )-7, 11-dii methyl-

dodecadien-l-al 3b. The reaction conditions for 3a were followed using 4b (2.04 g,

5.78 mmol), (COCI)2 (0.65 111L, 7.49 mmol) . DMSO (0.85 mL, 12.0 mmol) and Et3N
(4.0 mL. 28.7 11111101). Purification with column chromatography on silica gel (eluted
with 5o/c AcOEt in hexane) afforded 3b (1 .71 g, 84.3 Di< J) as a col(trleoil: Rf= 0.75

(silica gel, 17O/c AcOEt in hexane); 1H NMR (270 MHz, CDCI3) j) 0.03 (s, 6 H, CH3Si), 0.89 (s, 9 H, (CH3)3C-Si), 1.50-1.80 (m, 4 H, 3-H, 5-J-I), [.60 (s, 6 H, vinylCH3), 1.68 (s, 3 H, vinyl-CH3), 1.94-2.29 (m, 5 H, 4-H, 8-H, 9-H), 2.46 (td, J = 7.3,
2.0 Hz, 2 H, 2-H), 3.45 (dd, J = 10.0, 5.6 Hz, I H, CH20Si), 3.50 (dd, J = 9.8, 4.8
HZ,1 H, CH2Si), 5.06-5.13 (m, 2 H, 6-H, IO-H), 9.75 (t, J = ~~.O Hz, 1 H, CHO);
13C NMR (270 MHz, CDCI3) 8 -5.5 (x2), 16.1, 17 .6, 18.2,23.4,25.6,25.9 (x3),26.6,29.2,39.8,40.7,41.7,64.8,122.2, 124.2, 131.2, 136.3, 20L6; HR- 1M

mlz

352.2789, M+ calcd for C21H4002Si 352.2798.

(4R,7 E, 11 E)-4-(tert- B u ty Id i methylsilyl oxy methyl)-,8, 12,16- tri nlethyl-

7,11,15-heptadecatriene-l-al(R)-3a.

The reaction conditions [or 3a were

followed using (R)-4a (1.92g, 4.40 010101), (COCI)2 (0.38 mL, 4.36 m1110]), DMSO
(0.63 mL, 8.9 mmol) and Et3N (3.1 mL, 22.2 mmol). The crude product was separated
with column chromatography (silica gel, 170/0 AcOEt in hexane) to afford aldehyde (R)3a as a pale yellow oil (1.52 g, 80o/c, 91 % yield based on the recovery of (R)-4a) and
228 mg (120/0) of the recovered (R)-4a. An analytical sample was obtained by PTLC on
silica gel (e]uted with 17% AcOEtin hexane: Rf= 0.4): la1 25 D +7.7 (c 3.7, CHC]3)·111

(45,7 E, 11 E)-4- (tert- B u tyldi methy IsHy Ioxynlethyl)-8, 12, 16- tri methyl-

7,11,15-heptadecatriene-1-al(S)-3a.

The r action conditions for 3a were

followed lIsing (S)-4a (I 16 mg, 0.27 mmol), DMSO (0.1 mL, 1.4 111111(1), ( 01)2(0.05 mL, 0.6 mmo1) and Et3 N (0.20 mL, 1.4 I11mo1). PTLC or the crude productafforded (S)-3a (50.8 mg, 44%) as a colorIc soil: [a1 25 D -4.7 (c 2.98,

H 13).

E th YI (2E, 9 E , 13 E ) - 6 - ( t er t - but y I dim e thy lsi I Ylox y I met h y I ) - 1 0 , 1 4 , 1 8-

trimethyI-2,9,13,17-octadecatetraenoate 21. To a slIspensioll of NaH (to.2 mg,
0.26 mmol) in THF (0.5 mL) at 0 DC, was slowly added a solution of(EtO)2P( O)CH2C02Et (79.9 mg, 0.36 mm(1) in THF (0.5 mL). Arter the reaction
mixture was stirred at 0 DC for 30 min, a solution of 3a (32.9 mg, (1.076 mmol) in THF(0.5 mL) was added to the solution. The mixture was, tirred at 25 DC for 4 handquenched with aqueous NH4Cl. The aqueous layer was extracted with ether. The
combined organic layer was washed with water and brine, dried oyer MgS04, filtered,and evaporated. The crude product was purifjed with preparative TL(silica g 1, 17 ~EtOAc in hexane) and 21 was obtained as an only cis geometric i~;om r (colorless oil,
35.5 mg, 930/('):

Rf = 0.73 (silica gel, 170/0 EtOAc in hexane);IR (thin film) Vmax

2900, 2870, 1710, 1650, 1430, 1360, 1250, 1170, lOYO, 830, 770;

1H NMR (270MHz, CDCI3) 8 0.03 (s, 6 H, Si-CH3), 0.89 (s, 9 H, vinyl-CH3), 1.29 (t, J = 7.1 Hz,
3 H, OCH2CH3), 1.30-1.54 (m, 5 H, 5-H, 6-H, 7-H), 1.60 (s, 6 H vinyl- H3), 1.68
(s. 6 H, vinyl-CH3), 1.91-2.13 (m, 10 H, 8-H, II-H, 12-H, 15-H, 16-H), 2.16-2.27(m, 2 H. 4-H), 3.43-3.57 (m, 2 H, CH2-0-Si), 4.18 (q, J = 7. JI Hz, 2 H, 0

H2 H3),

5.04-5 . 18 (m, 3 H, 9-H, 13-H, 17-H), 5.81 (d, J = 16.1 Hz, 1 H, 2-H), 6.92-7.06 (m,I H. 3-H): HR-EIMS mlz. 504.4019, M+ calcd for C31 H5603Si 504.3999.

Methyl(9E,13E)-6-(tert-butyIdimethylsiIyloxymethyl)-2-methoxycarbonyl-1 0, 14, 18- tri methy 1-2,9, 13, 17 -nonadeca tetranoate

112

22.

To a olution of dimethyl malonate (0.1 mL, O.8S mmol) in MeOH (I mL), were added
H3N+CH2CH2NH3 +·2Ac- (catalytic amount) and 3a (104 mg, 0.24 mmol). The
mixture was stirred at 25°C ror 23 h and quenched with aqu ous NH4 1. MeOH was
evaporated by rotary evaporator and the remaining aqueous layer was ex tracted withether. The com bined organic layer was washed wi th water and brine, dried overanhydrous MgS04 , filtered, and evaporated. The crud product was purified withpreparative TLC (silica gel, 170/0 EtOAc in hexane) and 22 was obtained as a colorless oil(53.7 mg , 41 o/n): Rf = 0.55 (silica gel, J 7% AcOEt in hexane) ; I H NMR (270 MHz,
CDCI) 8 0.03 (s, 6 H, Si-CH3) , 0.89 (s, 9 H, Si-C(CH3)3) , l . lO-I. 71 (111, 5 H, 5-H,
6-H, 7-H), 1.60 (s , 6 H, vinyl-CH3), 1.68 (s, 6 H, vinyl-CH3), ] .9~-2.15 (m, ]0 H,
8-H, II-H, 12-H, I5-H , 16-H), 2.30 (td, J = 8.3 Hz, 2 H, 4-H), 3.43-3.47 (m, 2 H,
CH2-0-Si), 3.78 (s, 3 H, OMe), 3.82 (s, 3 H, OMe), 5.06-5.17 (m, 3 H, 9-H, I3-H,
17-H), 7.03 (t, J = 8.3 Hz, 1 H, 3-H);

HR-EII\1S mlz 548.3886 , M+ caled for

C32H5605Si 548.3897.

Eth yl(2E , 9 E , 1 3 E)-

and(2Z, 9 E ., 1 ] E ) - 6 - ( t e r t -butyldi methy Isilyloxy meth yl )-2-(2" -propanethiometh yl).l 0,14,18trimethyl-2,9, 13,17 -nonadecatetraenoate (E)- and (Z)-2a.

o a su. pensionof NaH (12.9 mg, 0.32 111mol) in THF (1 mL) at 0 °C, were added 2-propanethiol (0.05
mL, 0.54 m(1101) and a solution of (EtO)2P(O)C(=CH2)C02Et (93 ..3 mg, 0.32 n111101) in
THF (I mL). After the mixture was stirred at 0 °C [or 1() min, a sollJtion of 3a (135 111g,
OJ I mmol) in THF (l mL) was added and the reaction mixture wa stirred at () °C for 1

h. Aqueous NH4Cl was added to the reaction mixture and the aqueous layer wa
extracted with CH2CI2. The combined organic layer was washed v/ith water and brine,
dried over anhydrous MgS04, filtered, and evaporated. The crude product was purjfkd
with PTLC (silica gel, AcOEUhexane 1110, developed twice) and 4:'.7 mg (26q{) of (£)2a and 60.9 mg (33~) of (2)-2a were obtained as a colorless oil: [( r (£)-2a: Rf = 0.66

113

(silica gel, 17 cl(> AcOEt in hexane);

1H NMR (270 MHz,D 13) I~ 0.03 (s, 6 H,

H3-Si), 0.89 (s, 9 H, (CH3)3C-Si), 1.25 (d, J = 6.8 Hz, 6 H, (CH3)2CH), l.31 Ct, J = 7.2
Hz, 3 H, OCH2CH3) , 1.18-1.37 (m, 4 H, 5-H, 7-H), 1.54-1.64 (111, I H, 6-H), 1.60
(s, 9 H, vinyl-CH3), 1.68 (s, 3 H, vinyl-CH3), 1.95-2.15 (m, 1() II, 8-H II -H, 12-H ,I5-H, 16-H), 2.47 (td, J = 7.8,7.3 Hz, 1 H, 4-H), 2.85 ( ep, J = 6.6 Hz, 1 H,
CH(CH3)2), 3.39 (s, 2 H, CH2-S), 3.47-3.53 (m, 2 H, CH20Si), 4.24 (q, J = 7.2 Hz,
2 H, OCH2CH3), 5.05-5.21 (m, 3 H, 9-H, I3 -H, 17-H), 5.97 (t, J = 7.3 lIz, 1 H, 3H):

13C NMR (68 MHz, CDC]3) 8 -5.4 (x2), 14.3 , 16.0, 17.7, 1:~.3, 23.2, 25.3 (x2),

25 .7, 25.9 (x 3), 26.6 (x2), 26.7, 26.8, 26.9, 30.7, 30.9, 34.2, 34.5, 39.7, 39.9, 60.4,
65 .0, 124.2 (x2) , 124.4, 124.6 , 129.0, 131.2, 134.9, 143.3, 166.9; HR-EIMS mlz
592.4371, M+ calcd for C35H6403SiS 592.4345; for (Z)-2a: Rf = 0.61 (silica gel,
17o/c AcOEt in hexane); IR (thin film) vmax 2900, 2850, 1700 1435, 1360, 1240,
1080, 830,770;

1H NMR (270 MHz, CDCl3) 8 0.04 (s, 6 H, SjCH3), 0.89 (s, 9 H,

SiC(CH3)3, 1.28 (d, J = 6.8 Hz, 6 H, CH(CH3)2, 1.30 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 1.35-1.56 (m, 5 H, 5-H, 6-H, 7-H), 1.61 ( , 9 H, vinyl - H3), 1.69 (5, 3H, vinyl-CH3), 1.93-2.12 (m, 10 H, 8-H, II-H, 12-H, 16-H, 117-H), 2.26 (td, J = 7 .3,
7.8 Hz, 2 H, 4-H), 2.95 (sep, J = 6.8 Hz, I H, CH(CH3)2), 3.47 ( , 2 H,

H2),

3.47-3.52 (m, 2 H, CH20Si), 4.21 (q, J = 7.0 Hz, 2 H, OCH2CH 3), 5.05 -5.15 (m, 3
H,9-H, I3-H, 17-H), 6.81 (t, J = 7.6 Hz, 1 H, 3-H); 13C Ntv1R (68 MHz, CDCl3) 8-5.4 (x2), 14.2, 16.0, 17 .7, 18.3,23.4,25.3 (x2), 25.7, 25.9 (X1), 26.2, 26.4, 26.5,
26.7, 26.8, 30.3, 31.0, 34.8, 35.5, 39.7, 39.9, 60.7, 65.0, 124.3, 124.4, 124.5,
124.7, 131.2, 134.9, 135.0, 144.8, 165 .0; HR-EIMS 11117. 592.4378, M+ calcd for
C35H6403SiS 592.4345.

E th y I (2Z, 6 R ,9 E , 13 E ) - 6 - (t e r t - but y I dim e thy lsi I)' lox y met h y I ) - 2 - (2II -propanethiomethyl)-l 0,14, 18-trimethyl-2,9, 13, 17 -nonadeeatetraenoate Z(R)-2a. To a llspension of NaH (150 mg, 3.74 ml1101) in THF C; mL) at 0

114

ec, wereadded2-propanethiol(O .3R

mL,

4.10

mmol)

and

a

solutionof(EtO)2P(O)C(=CH2)C02Et (885 mg, 3.69 mm(1) in THF (I mL). Aft r th mixture
was stirred at 0 °C for 10 min, a solution of (R)-3a (1.55 g, 3.57 m11101) in TH (3 mL)
was added and the reaction mixture was stirred at 25 °ror 17 h. Aqueous NlI4 .1 wasadded to thc reaction mixture and the aqueous layer was extracted with

H2C12 . The

combined organic layer was washed wiLh watcr and brin ,dried over anhydrous MgS04,
filtered, and evaporated.

The crude product was purified with PTLC ( i11ca gel,

AcOEtJhcxane 1/ 10, dcveloped twice) and only Z-(R)-2a was ohtained as a colorless oil
0.17 g, 540/(1): [aj25 o +3.2 (c O. 18, CHC13).

Ethyl(2Z ,6R ,9E, 13E)-

and(2E ,6R ,9E, 13E )-6-(tert-butyldi methy Isily loxymethyl)-2-(2" -propaneth iomethyl)-1 (), 14, 18trimethyl-2,9,13,17-nonadectetraenoate Z- and E-(R)-2~a.

To a su pcnsionof NaH (79.2 mg, 1.98 mmol) in THF (2 mL) at 0 DC, were added 2-propanethiol (0.2mL, 1.95 mmol) and a solution of (EtO)2P(0)C(=CH2) 02 t (4RO mg, 2.00 mmol) in
THF (1 mL). After the mixture was stirred at 0 °C for I() min, a solution of (R) -3a (SOO
mg, 1.84 mmol) in THF (2 mL) was added and the reaction mixtllrt~ was till' d at 0 °Lfor 3 h. Aqueous NH4Cl was added to the rcaction mixture and th-~ aLjueous lay r w' ,extracted with CH2CI2. The comhined organic laycr was washed v/ith water and brine,
dried over anhydrous MgS04, fjltered, and evaporated.

he cfude product was purificd

with PTLC (silica gel, AcOEtJhexanc 1110, dcveloped twice) to give a mixture of Z- andE-(R)-2a as a colorless oil (615 mg, 670ft, EIZ = 1:2.4).

Ethyl (2Z ,6S ,9E, 13E )-6-(tert- bu ty Id i methy lsi Iy I oxy methy 1)- 2-(2 "_propanethiomethyl)-l 0,14, 18-trimethyI-2,9, 13,17 -nonadt'ctetraenoate

Z-(S)-2a. The feaction conditions for Z-(R)-2a were followed usillg (S)-3a (50.8 mg,

0.12 mmol). NaH (l Y.9 mg, 0.50 mmol), 2-propanethiol (0.08 mL, 0.80 mmol). PTLC

115

of the crude product afforded Z-(5)-2a (17.4 mg 25(~) as a color1c , oil: [a1 25 0 + 1.6(c 2.24. CHC I 3)·

E thy I (2Z ,8 E , 1 2 E ) - 6 - (t e r t - but YI d i n1 e thy lsi I Ylox y met h y I) - 2 - ( 2 t t propa nethiomethyl)-9, 13-dimethyl-2,8, 12-tetradecatri enoate

Z -2b.

The

reaction condition for Z- and £-(R)-2a were followed using 31b (1.41 g, 3.99 mI11(1),NaH(180.0mg,

4.5mmol).

2-propanethiol(0.40(Et20)2P(=O)C(=CH2)C02El (1.05 g, 4.43 mmol).

mL,

4.4

I11mol),Purification with column

chromatgraphy on silica gel (eluted with 30/0 EtOAc in hexane) afforded Z- and E-2b
(1.51 g, 74.3o/(), EIZ = 1:8 .5): for Z-2b: Rf= 0.78 (silica gel, 17% AcOEl in hexan );1H NMR (270 MHz, CDCI3) 8 OJ)3 (s, 6 H, CH3-Si), 0.89 (s, 9 H, ( H3)3CSi), 1.28
(d, J = 6.4 Hz, 6 H, SCH(CH3)2), 1.29 (t, J = 6.8 Hz, 3 H, OCH2CH3), 1.40-1.60(m. 3 H, 5-H, 6-H), 1.60 (s, 6 H, vinyl-CH3), 1.68 (s, 3 H, vinyl-CH3), 1.90-2.15(m, 6 H, 7-H, lO-H, iI-H), 2.27 (ld, J = 7.3 ,7.3 Hz, 2 H, 4-H \ 2.92 (sep, J = 6.4

Hz, 1 H, SCH), 3.46 (s, 2 H, CH2S), 3.20 -3.40 (m, 2 H,

H20;)]), 4.22 (4 J = 6.R

Hz. 2 H, OCH2CH3), 5.10-5.20 (m, 2 H, 8-H, 12-H), n.80 (l, J = 7.3 III" 3-H)~ 13 NMR (68 MHz, CDCI3) 8 -5.5 (x2), 14.2, 16.1, 17.6, \8.2, 21.4 (x2), 25 .6, 25 .9

ex3). 26.1, 26.5, 26.6, 29.2 29.9, 35.5, 39.8,41.0, 60.6, 64.8, 124.3, 124.4, 129.5,]31.1,136.1,144.6,166.9, HR-EIMS mlz 510.3570, M+ caled for

29115404

510. 3563: for (E)-2b: Rf = 0.76 (silica gel, 17% AcOEl in hexane); 1H NMR (270

MHz CDC13) 8 0.03 (s, 6 H CH3Si), 0.89 (s, 9 H, (CH3)3C',i), 1.24 (d J = 6.8 Hz,
6 H, SCH(Cli3)2), 1.31 (l, J = 6.8 Hz, 3 H, OCH2CH3), 1.40-1. 0 (m, 3 H, 5-H, 6H), 1.60 (s, 6 H, vinyl-CH3), 1.68 (s, 3 H, vinyl-CH3), 1.9-2.1 (m, 6 H, 7-H, to-H,] I-H), 2.48 (td, J = 7.3, 6.8 Hz, 2 H, 4-H), 2.84(sep, .I = 6.8 1 Z, 1 H, SCH), 3.38 (s,2 H, CH2S), 3.47 (d, J = 4.9 Hz, 2 H, CH20Si), 4.19 (q, J = 6.8 Hz, 2 H,
OCH2CH3), 5.10-5.20 (m, 2 H, 8-H, 12-H), 5.95 (L, J = 7.3
NMR (68 MHz, CDCI3) 8 -5.5 (x2)

116z, I H, 3-H); 13C

14.2, 16.0, 17.6, 18.2,22.9,23.2,25.6,25.9

(x3), 26.7, 27.1, 29.1, 30.5 , 34.1 34.4,39.8 41.0,60.3,64.8,122.6,124.3,129 .0,
13l.1 , 136.0 , 143.2, 166.8 ~HR-EIMS

1I1/Z.

495 .3336, M + - C H 3 caIed for

C29H5404SSi 495.3328.

Ethyl (3 'E, 7'E)-5-(4' ,8' ,12'-trimethyl-3' ,7', 11 '-~ridecatrienyl)­
tetrahydro-2H-pyran-2-acetate 23. To a solution of 21 (22.4 lllg 0.045 mmol) in
THF (0 .5 mL), was addcd a 1.0 M solution of TBAF in THF (0.3 mL, 0.3 mmol) . Thc
rcaction mixturc was stirred at 25°C [or 5 hand quenchcd with aqucous NH4 1. Thc
aqucous laycr was cxtracted with cthcr and thc organic layer was combincd. Thc
combined organic laycr was washed with watcr and brinc, dricd o\'cr Mg '04, filtercd,
and evaporated. The crude product was purified with prcparativc TLC (silica gel, 170/0
AcOEt in hcxanc) and a mixturc of cis- and trol1s-23 was obtained a~' a colorless oil (L3.4
mg, 77O/C , cis/trrl11s = 3:7); Rf = 0.79 (silica gel, 17o/rl AcOEt in hexane); IR (thin film)
Vmax 2900, 2850, 1730, 1440, 1370, 1280, 1180, 1090:

I H N1V1R (270 MHz, CDC 13)

8 1.25 (t, J = 7.3 Hz, 3 H, OCH2CH3), 0.82- 1.56 (m , 7 H, 3-1 I, 4-11, 5-11 , 1'_II),
1.57 (s 6 H, vinyl-CH3), 1.59 (s, 3 H, vinyl-C1I3) , 1.67 ( ,3 H, vinyl - 1-13), 1.842.10 (m , 10 H, 2'-H, 5'-H , 6'-H, 9'-H, IO'-H), 2.31-2.61 (m, 2 H,

H2 02 ~ t), 3.05

(t J = 11 .2 Hz, tral1s-6-ax-H), 3.56-3.96 (m, 2-ax-H, 6-cq-H, c;s-6-ax -H), 4.14 (q, J =7.3 Hz, 2 H, OCH2CH3), 5.05-5.18 (m, 3 H, 3'-H, 7'-H, ] 1'_H);

HR-EIMS I17/Z

390.3154, M+ caIed for C25H4203 390.3134.

Methyl (3 'E, 7' E)-a- methoxycarbonyl-5-( 4' ,8' , 12' ,. tri methyl-3', 7',11 'tridecatrienyl)-tetrahydro-2H -pyran-2-acetate 24. To a solution of 22 (53.7
mg, 0.1 mmol) in THF (0.5 mL) at 25 °C, was added a 1.0 M solution of TBA in THF(0.5 mL, 0.5 mmol) and the reaction mixture was stirred at 25 °C. After 24 h, aqueous
NH4CI was addcd to the reaction mixture and the aqucous layer was extracted with cther.
The com bincd organic laycr was washed with watcr and brine, dricd over anhydrous

117

MgS04, filtered, and evaporated. Th crud product was purified with pr parative TL(silica gel, 17o/r, AcOEt in hexane) and a mixtur of cis- and f,.011S-24 wa, obtained as acolorless oil (5.77 mg, 13% , cis/fUI11S = 1:3):
hexane):Rf = 0 .51 (silica gel, L7o/r, AcOEt in

I H NMR (270 MHz, CDCI3) 8 0.84-1.8\ (m , 7 H , I ' ·H, 3-H , 4 -H, 5-H),

1.57 (s, 6 H, vinyl-CH3), 1.60 (s, 3 H, vinyl-CH3), 1.68 (s, 3 H, vinyl- H3), 1.862.20 (m, 10 H, 2'-H, 5'-H, 6'-H, 9'-H, IO'-H), 3.06 (t J = 11.2 Hz I II fral1s-6 - ax H), 3.48 (d, J = 8.8 Hz, \ H, CH(C02Me)), 3.73 (5, 3 H, OMe), 3.76 (s, 3 HOMe),
3.80-3.98 (m, 2 H, 2-H, 6-eq-H, cis-6-ax-H), 5.06 -5.18 (m, 3 H , 3'-H 7'-H, II'-H);
HR-EIMS m/z 434.3018, M+ calcd for C26H4205 434.3032.

Ethyl(3' E ,7' E ) - ex. - met h y len e - 5 - ( 4' ,8' , 12' - t r i ml e thy 1- 3 ' ,7' ,tridecatrienyl)-tetrahydro-2H -pyran-2-acetate 25a.

11 ' -

To a olution of 2-2a(69.2 mg. 0.12 mmo1) in CH2C12 (l mL), were added Mel (0.2 mL, 3.21 m11101) andAgBF4 (35.7 mg, 0.18 mmol). The reaction mixture was stirred al. 25°C for 22 handfiltered. After the filtrate was evaporated, THF (0.5 mL) and a J..() )\11 solution of BA
in THF (0.5 mL, 0.5 mmo1) were added to the oil and the mixture: was stirred at 25 0for

20 h. Aqueous NH4CI was added to the reaction Illi xture and the aqu ous lay r was
extracted with CH2CI2 and the organic layer was collected. The COl nhined organic layer
was washed with water and brine, dried over anhydrous Mf.S04

filtered, andevaporated. The crude product was purified with PTLC (silica geL AcOEUhexane 1/5)
and mixture of cis- and fl"([I7.\"-25a (14.9 mg, 320/0, cis/lral1s = 6:9,t) was afforded a, acolorless oil: For frons-25a:

Rf= 0.75 (silica gel, I 7 (/c) AcOEt in hexane); IR (thinlayer) Vmax 2900, 2850, 1705, 1435, 1370, 1280, 1250, 1170, J 140, 1080, 1020; IH

NMR (270 MHz CDCI3) 8 0.87-1.35 (m, 4 H, 1'-H, 3-ax-H 4-ax-H), 1.30 (t, J = 7.3
Hz, 3 H. OCH2CH3), 1.60 ( , 9 H, vinyl-CH3), 1.68 ( , 3 H, villyl-CH3), 1.64-1.74(m. 1 H, 5-H), 1.89-2.1 () (01 ,12 H, 3-eq-H, 4-cq-H, 2'-H, 5'-H, 6'-H, 9'-H, 10'-H),
116 (L J = 11.2 Hz. 1 H 6-ax-H), 4.()3 (ddd., J = 11.2,3.9, 1.:; Hz, 1 H, 6-eq-H),118

4.12 (d ) = y.g Hz, 1 H, 2-H), 4.22 (lj ) = 7.3 I-V:, 2lJ, 0

H2CI-(3), 5.06-S.15 (m 3

H. 3'-H, T - H

11 '-H), 5 .88 (L ) = 1.5 Hz, 1 H, (X-m thyl ne), 6.23 (b , 1 H, (X-methylene):

13C NMR (6g MHz, CDC]3) 8 14.2, \0 .0 , \7 .7, 2,L9, 25.7, 20.7, 2o.g(x2), 30.S, 32.3, 32.S, 3S.3, 39.7 (x2), 60.6, 74.0, 75.6, 123.9, 124.2 (x2), 124.4,
131.2, 13S.0, 13S.3, 142.3 , 166.1 ;HR-EIMS m/z 402.3151, M+ calcd forOCl :,) 8 l. 14-1.76 (m, S

C26H4203 402.3134: For cis-25a: 1H NMR (270 MHz,H, I'-H, 3-ax-H, 4-ax-H , S-H), 1.29 (t, J = 7.3 Hz, 3 H, OCH2CH3) , I .S9 (s. Y H,
vinyl-CH3), 1.67 (s, 3 H, vinyl-CH3), 1.96-2. I 5 (m, 12 H, 3-eq-H, 4-elj-H, 2'-H, 5'H. 6'-H, 9'-H, 10-H), 3.64-3.70 (m, 2 H), 3.85-3.YS (m, 1 H), 4.22 (4, ) = 7.3 Hz, 2
H. OCH2CH3), 5.03-5.14 (m, 3 H, 3'-H, T-H, 11 '-H), S.88 (s, J H, a -methylene),
6.23 (s, 1 H, a-methylene): HR-EIMS m/z 402.3156, M+ citlcd for C26H403
402.3134.

E thy I (2S, 5 R ,3 ' E ,7 ' E ) - a - me thy Ien e - 5 - ( 4 ' ,8' , 12 t rim e th y 1- 3 ,7' ,I -tridecatrienyl)-tetrahydro-2H -pyran-2-acetate (2S ,5R')- :~5a.

I

Th

11

I -

r actionconditions for 25a were followed lIsing (R) -2a (100.5 mg, 0.17 11111101), AgBF4 (40.6
mg, 0.21 mmol), Mel (0.2 mL, 3.2 mmol) and TBAF (0.5 mL or 1.0 M TBAF in THF).
The crude products were separated with PTLC to give 'r((l7s-(2S,5R) -25a (24.8 mg,

36o/c, cisltrans = 4:96) as a colorless oil: Rf = 0.75 (silica gel, 17~) EtOAc in hexane);[0.]25 0 -46 (c 0 .0436, CHC13).

Ethyl (2R ,5S,3' E, 7 'E )-a-methylene-5-( 4',8',12' -trimethyl-3', 7',
tridecatrienyl)-tetrahydro-2H -pyran-2-acetate (2R ,5S)-25a.

11 1_

The reaction

conditions for preparation of 25a were followed using (S)-2a (l7A mg, OJ)29 mmol),Mel (0.4 mL, 6.4 mmol), AgBF4 (21.8 mg, 0.11 mmol) and a 1.0 Jv1 solution of TBA
in THF (0.4 mL). Column chromatographic separation of the crude product afforded119tr(ll1 s-( 2R ,5S)-25a (3.92 mg, 3 3~) , cis/frans = 2:98) as a colorless oil: la 125 D +43. 1 (c0. 116, CHC I3)·

Ethyl (2'E ,6'E)-a-methylene-5-(3' ,7'-dimethyl··2' ,6'-octadienyl)tetrahydro-2H-pyran-2-acetate

25b.

The reaction condition s for 25a wasfollowed using (Z)-2b (1 06.l mg , 0 .209 I11mol) , M I (0.30 111L, 4. 81 111mo]). AgBF4(68 .5 mg, 0 .35 mmo]) and a 1.0 M solution of TBAF in THF (0.5 mL, 0.5 11111101).
Purification with PTLC (silica gel , 13 0/0 AcOEt in hexane) alJonJed 25b (16.6 mg

24.30/(', cis/trans = 4: 1) as a colorless oil: Rf = 0.74 (silica gel , J 7 ~7 AcOEt in hexane);J H NNfR(270 MHz" CDC}3) 0 1.10-1.50 (m, 2 H, 3-ax -H, 4-·ax ··H), 1.30 (t, J = 6.8

Hz, 3 H, OCH2CH3), 1.5-1.8 (m, 2 H, l'-H), 1.58 (s, 3 H, vinyl-CH3) , 1.60 (s, 3 H,
vinyl-CH3) , l.68 (s, 3 H, vinyl-CH3), 1.82-1.97 (m, 1 H, 5-H), 1.90-2 .10 (m , 6 H , 3cq-H , 4-eq -H , 5'-H, 6'-H) , 3.17 (t, J = 11.2 Hz, I H, 6-ax-H) , 4·.02 (ddd , J = 11.2,
3.9, 2.0 Hz, ] H, 6-eq-H) , 4 . 13 (d , J = 9 .3 Hz" 1 H, 2-H) , 4.22 (q J =6.8 Hz, 2 H,
OCH2CH3) , 5.00-5. 10 (m , 2 H , 2'-H, 6'-H) , 5 .87 (d , J = 1.0 Hz, 1 H, a -methyl ne ),6.23 (d, J = 1.0 Hz, 1 H, a -methylene);

13C NMR (68 MHz,D 13) 0 14.2, 16. 1,

17.7 , 25.7 , 26 .6,30.4, 30.8, 32.4, "1,6.7 , 39.8, 60.6 , 73 .8, 75 .6, 121.7 , 124.3 , 124.9 ,131.4 , 136 .4, 142.3. 16G.O:

IIR -EIMS m/z. 320.2336, M+ ca1cd 1'01'

20II"1,2

3

320.2351.

Ethyl (8E, 12E )-6-(tert- bu ty Idi methylsi Iy I oxy methyl) -3-h yd roxy -2- 0.methy lene- 9, 13-d i meth y 1-8,12- tetradecadienoa te 30.

A sample of mCPBA(111.4 mg , 0 .65 mmol) was added to a solution o[ 2b (271.4 mg , n.53 mmol) in
CH2Cl2 (5 mL) at 0 °C. The reaction mixture was stirred at 2S °C [or 4 days andquenched with aqueous Na2S20~. The resulting mixture was extracted with CH2C 12
and organic layer was combined . The combined organic layer was washed with aqueous
NaHC03 and water, dried over anhydrous MgS04, filtered and evaporated . The crude120

product was purified with PTLC (Si02, 170/0 AcOEt in h xane) to giv ,ulfoxide (191.2
mg, 680/r):

1H NMR (270 MHz, CD 13) 8 0.03 (s, 6 H, Si-CH3), O.R9 ( , 9 H,

SiC(CH3)3), 1.33 (s, J = 6.R Hz, 6 H, S H( H3)2), 1.36 (t, J = 7.1 HI., 3 H,
OCH2CH 3), 1.60 (s, 6 H, vinyl-CH3), l.6R (s, 3 II , vinyl- H3), 1.40- 1.60 (m, 3 II ,5-H, 6-H), 1.90-2. 05 (m, 6 H, 7-H, IO-H, II -H), 2.37 (td, J = '7.7,7.7 lIz, 2 H, 4H) , 2.80 (scp, J = 6.8 Hz, 1 H, SCH(CH3)2), 3.59 (d. J = 1.95 H~~, 2 H,

H2S), 3.78

(d, J = 12.7 Hz, 1 H, CH20Si), 4.22 (q, J = 7.3 Hz, 2 II , OCH2C 3),7.18 (t, J = 7.7
Hz, 1 H, 3H); HR-EIMS mlz 526.3506, M+ Calcd for C29H5404~)iS 526.3512.
0.05 mL (0.42 mmol) of (MeO)3P was added to a solution of the sulfoxide (271.4
mg, 0.53 mmol) at 0 °C. The reaction mixture was stirred at 25°C fClr 12 h and quenchedwith aqueous NaHC03. The resulting mixture was extracted with CH2CI2. The
combined organic layer was washed with water, dried over anhydrous MgS04, filteredand evaporated. The crude product was purified with PTLC (Si02, 17 0/0 AcOEt inhexane) to give 30 (49.4 mg, 55 0/0) :j H NMR(270 MHz, CDCI3) 8 0.02 ( , 6 H,

SiCH3), 0.88 (s, 9 H, SiC(CH3)3) , 1.11 (t, J = 7.1 HI" OCH2CBJ) , 1.30- 1.70 (m, 5
H, 4-H, 5-H, 6-H), 1.58 (s, 3 H, vinyl-CH3), 1.60 (s, 3 II , vinyl- H3) , 1.68 (s, 3 H,
vinyl-CH3), 1.90-2.10 (m, 6 H, 7-H, IO-H, II -H), 2.50-2.80 (bs, I H, OIl) , 3.403.50 (m, 2 H, CH20Si), 4.22 (q, J = 7.2 Hz, 2 H, OCH2CH3) , 4.35 (ld, J = 18.5. 0.4
Hz, 1 H, 3-H), 5.77 (s, 1 H, a-methy1cne), 6.22 (s, 1 H, a -methylene); HR- IMS mlz
452.3317, M+ calcd for C26H4804Si 452.3322.

Preparation of 25b from 30.

To a solution of 3() (90.2 mg, 0.20 m11101) in

C H 2 Cl2 (2 mL) at 0 °C, were added PPh3 (65.9 mg, 0.25 mmo]) and N chlorosuccinimide (42.6 mg, 0.32 m11101) in one portion. The reaction mixture was
warmed to 25°C and tilTed. Arter 17 h, the reaction mixture was quenched with water.
The resulting mixture was extracted with CH2C12. The combincu organic layer wasdried over anhydrolls MgS04, filtered and evaporated. The crude product was purified

121

with PTLC (Si02, 17% AcOEt in h xane) to give 2Sb (10.8 m.g, 17%, cis/frons =32:6R).

(3' E ,7' E ) - a - Me th y len e -5 -( 4 ' ,8' , 12 ' - t r i me thy 1- 3' ,7' , t 1 ' -tridecatrienyl)-tetrahydro-2H-pyran-2-acetic acid rae-la o To a solution of
25a (2S.4 mg, 63.2 I1mo1, ciS/frons = 4:96) in H20 (1 mL), was added KOH (113 mg,
2.0 mmol). The reaction mixture was refluxed for 14 h. After the reaction mixture wa
cooled to 2S °C, it was acidified with 1 N aq. HCl. To the mixture, was added ether andthe aqueous laycr was extracted. The combined organic layer wm. wa hed with waterand brine, dried over anhyurous MgS04, filtered, and evaporated. The crude productwas purified with column chromatography (60/o-wt. water silica gel, 170/0 EtOAc in
hexane) and a mixture of cis- and fral1s-rac-la was obtained as a colorless oil (7.98 mg,
340/c, cis/tral1s = 4:96): Rf = 0.13 (silica gel, 17% EtOAc in hexane); frans-rac-la: IR(thin film) vmax 3S00-3000, 2900, 28S0, 1680, 1620, 1430, 1370, 1280, 1160, 1 140,
IORO. 9S0, 830:

I H NMR (270 MHz, CDC!3) 8 O.RS-1.23 (m, 4 H, I '-H, 3-ax-11, 4-ax-H), 1.23-1.47 (m, 1 H, S-ax-H), 1.60 (s, 9 H, vinyl-Me), 1.68 (s, 3 H, vinyl-M ),1.90-2.10 (m, 12 H, 3-eq-H, 4-eq-H, 2'-H, S'-H, 6'-H. 9'-H, 10'-H), 3.1 R (t, J = 11.2
Hz, 1 H, 6-ax-H), 4.07 (ddd, J = 11.7,3.9,2.0 Hz, 1 H, 6-eq-H), 4.12 (u, J = 12.2
Hz, 1 H. 2-ax-H), S.OS-S.lS (m, 3 H, 3'-H, T-H, I i'-H), S.89 (s, 1 H, a-methylene),
6.36 (s, 1 H, a-methylene), the carbonyl proton was not ob erved due to the broadcningof the signal:

13C NMR (12S MHz. CDC13) 8 16.0 (x2), 17.7, 2~·.9, 2S.7, 26.6, 26.8,

30.2,31.8,32.4, 3S.2, 39.7 (x2), 74.0, 76.3, 124.0 124.1, 124.4, 126.7, 131.3,
13S.0, 13S.S 140.7, 168.6;

HR-EIMS m/z 374.2810, M+ calcd for

24 H 3803

374.2821.

(2S ,SR ,3'E ,7'E)-a-Methylene-S-(4' ,8' ,12'-trimethyl .. 3' ,7', t 1 '-t rid eca tri e ny I) - tetr ah yd ro- 2H - py ran-2-acetic acid (2S. SR )-e Ill-l a.

122

The

reaction conditions for rac-Ia were fol1owed using (R) -25a (6.04 mg , 15 J-ltnol, only
frans isomer), KOH (113 mg 2.0 mmol). The crude product wa . purified with column

chromatography (6o/a-wt. water silica gel, 17 % EtOAc in hexane) to give Iral1s-(2. ,5R)1a (3.15 mg, 56o/i:

1):

l aJ25 D -37.6 (c 0.315, CHCI3)·(2R ,5S ,3'E ,7'E)-a-Methylene-5-(4' ,S', I2'-trinlethyl .. 3' ,7' ,11 '-tridecatrienyl)-tetrahydro-2H -pyran-2-acetic acid (2R ,5S)-1a. A mixure of(S)-lral1s-25a was stirred at 25°C for 26 h and worked up. The crude product was

purified with column chromatography (6%-wt. water silica gel, 170/0 EtOAc in h xane) togive fral1s-(2R,SS)-1a (2.9S mg, 600/0): [aJ 2S D +39.0 (c 0.241, CHC I3)·

General method on determination of optical purity of CR) -19 a:(4R ,7£, II £)-4-CBenzoylhydroxymethyl)-S,12,I6-trimethyl-l,7, 11,15-

heptadecatetraene.

To a solution of (R)-19a (S8.0 mg, 19l )..1n101) in CH2 12 (0.5mL) at () DC, were added Et3N (0.1 mL, 718 ~m()l) and Bz 1 (0.05 mL, 431 )..11). Th
reaction 111 ix ture was stirred at 25°C for 18 h and the mix ture was qllench d wi thaqueous NH4Cl. The aqueous layer was extracted with Et20 and the comhined organic
layer was washed with water and brine, dried over anhydrous MgS04, filter d, andevaporated. Preparative TLC (silica gel, 17% EtOAc in hexane) of the crude productafforded henzoale as a colorless oil (68 mg, 87%): Rf == 0.62 (silica gel 171(J AcO t inhexane): [a]2S D +S.4 (c O.4S, CHCI3): IR (thin film) Vmax 2900, 2R50, 1720, 1440,
137S. 1310,1260,1100,700:
H),

IH NMR (270 MHz, CDCI3) () 1.43-1.52 (m, 2 II, 5-

I.S7 (s. Y H, vinyl-CH3), 1.65 (s, 3 H, vinyl-CH3), 1.86-2.13 (m, II H, 4-H, 6-

H. Y-H, 10-H, 13-H, 14-H), 2.20 (t, ) = 6.8 Hz, 2 H, 3-H), 4.23 (d, ) = 5.9 Hz, 2 H,
CH2-0Bz), S.02-S.1S (m, S H, I-H, 7-H, lI-H, IS-H), S.72-S.87 (m, 1 H, 2-11),
7.37-7.43 (m, 2 H), 7.S2-7.S7 (m, I H), 8.02-8.08 (m, 2 H)'

13C NMR (68 MHz,

CDCI,3) 8 16.0 (x2), 17.7, 2S.2, 25.7, 26.6, 26.7,31.0,35.8,37.0,39.7 (x2), 67.0,

123116.7,124.0,124.1,124.4, 12R.3 (x2), 129.5 (x2), 130.5, 13l.2, 132.8,135.0,
135.5, 136.1, 166.6;

HR-EIMS II1/Z 408.3028, M+ cakd for C28H4002 408.3067.

The optical purity of the henzoate was determined hy HPLC analysis (DAICELCHIRAL-OD column (hcxane-EtOAc 400: 1). The enamtiomeric exccss was 98o/r, cc.

124Supplementary Material
rac-, (R)-, and (S)-Bcnzoate derivatives and I Hand/or] 3C NMR and/or MS spectraof 2a ,b, 25a,b, 30, and In are shown below.

125

Ol -

n Vl
o _'
"

'1:1

~

n

:r

~

CTI

~

::r:

~

~
Vl

g
~

a
0

........

~
N

~

----

126

•

OTBS

s'jPr

~CO:EI

Chart 2. 13 C NMR spectrum of 2-2a

e-

N

I

j

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References and Notes
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150

Acknowledgments

The author expresses his gratitude to Professor Kats uo Ohkata for his ducation ,continuous guidance, and full support at Hiroshima UnivcL ity.
The author is grateful to Dr. Satoshi Kojima for hi education and guidance at
Hiroshin1a University.
The author is thankful to Dr. Yoshikazll Hiraga and Dr. Kazumlasa Okada for theirsupport through this work.
The author is thankful to Mr. Jyunji Kimura, Mr. Mun taka Tok masu , Mr.
Yoshihiro Shinohara, Ms. Asan1i Sasaoka, Ms. Yuko Ohba, Ms. Kyoko Takezono, Ms.
Hiroko Nishitani, and other members of Tenn-nennbutsuyuuki rec;;earch group at
Hiroshima University for their support for this work.
The author thanks Associate Professor Shinji Ohta (Hiroshima U 1iversity) for spectraof natural (+ )-Rhopaloic aicd A and its ethyl ester.
The author wishes to thank Profes or Kin-ya Akiba, Associlat Pn fcssor YOhSllk
Yamamoto, and other members of Hann-nouyuki re arch group at Hiroshima Univ rsity
for their support for work.
The author thanks the Instrument Center for Chemical An llysl. at Hiroshima
University for NMR, n1ass , optical rotation analysis.

151List of Publications(1) Monomeric IO-Sb-5 Pcntacoordinate Organoantimony Monohalide and Their

Permutational Behavior.
Kojima, S.; Takagi, R.; Nakata, H.; Yamanloto, Y.: Akiba, K.-y. Chem. Lett.,
1995, 857-858.
*(2) Asymmetric Darzens Condensation of Ketones with a-Chloroacetates by Mean of(-)-8-Phenylmenthyl Auxiliary.
Ohkata, K; Kimura. J.; Shinohara, Y.; Takagi, R.: Hiraga, Y. Chem. Co 111m un. ,1996, 2411-2412.
(3) Excellent Z-Selective Olefin Formation Using Pentacoordinate :;pirophosphoranes
and Aldehydes. Wittig Type Reaction via Hexacoordinate Intermediates.
Kojima, S.; Takagi, R.; Akiba, K.-y. 1. Am. Chem. Soc., 1997, 119,5970-5971.
*(4) Synthesis of Norsesterterpene rac- and ent-Rhopaloic Acid A.
Takagi, R.; Sasaoka, A.; Kojima, S.; Ohkata, K. Chem. Commun., 1997, 18871888.
*(5) Stereoselectivity in the Formation of 2,5-Disubstituted Tetrahydropyrans by
Intramolecular Hetero-Michael Addition.
Takagi, R.; Sasaoka, A.; Kojima, S.; Ohkata, K. J-leterocyc1es, 1997,45,23132316.
*(6) Asymmetric Induction in Darzens Condensation by Means of (- )-8-Phenylmenthyland (-)-Menthyl Auxiliaries.
Takagi, R.; Kimura, J.; Shinohara, Y.; Ohba, Y.; Takezono, K. Hiraga, Y.;
Kojima, S.; Ohkata, K. 1. Chem. Soc .. Perkin Trans. 1, 1 199~;, in press.
*(7) Stercoselective Synthesis of (+ )-Rhopaloic Acid A and (-)-ent- and (±)-racRhopaloic Acid A.
Takagi, R.; Sasaoka, A.; Nishitani, H.; Kojima, S.; Hiraga, Y., Ohkala, K. 1.
Chem. Soc., Perkin Trans. 1, 1998, il1 press.
*.

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152