Overview of Synthesizing

Merrilactone A= Contents =I. Beginning
II. Danishefsky's RouteIII. Hirama & Inoue's Route
IV. Frontier's Route
V. Conclusion

6th / Feb./ 2008
Literature Seminar ~ B4 part ~Takafumi Yukawa

I. Beginning
Merrilactone AO

extractionOHOOOO

Merrilactone A

only 0.004% yield

Illicium merrillianum¾ Biological Feature• Neurotrophic• Neuritogenetic• possibility for treatment of neuro-degeneration deseases(Alzheimer’s and Perkinson’s)• potential alternative for nerve growth factor (NGF) andother expensive peptidal reagents¾ Chemical Featurevery interesting and challenging compound
Densely Oxygenated !

Highly compact and caged skeleton !

oxetane
15O

8O

17HO

10

2

96

12

3O

11O

4O

51413

dilactone
It is important to synthesize Merrilactone A in the place of both chemistry and biology.

History
Isolation
RacemicChiral

2000

Y. Fukuyama et al. Tetrahedron Lett. 2000, 41, 6111.
V. B. Birman and S. J. Danishefsky J. Am. Chem. Soc. 2002, 124, 2084.
M. Hirama, M. Inoue et al. J. Am. Chem. Soc. 2003, 125, 10772.
G. Mehta and S. R. Singh Angew. Chem. Int. Ed. 2006, 45, 953.

Chap. II
Chap. IIIA. J. Frontier et al. J. Am. Chem. Soc. 2007, 129, 498.
Z. Meng and S. J. Danishefsky Angew. Chem. Int. Ed. 2005, 44, 1511.
M. Inoue et al. Angew. Chem. Int. Ed. 2006, 45, 4843.
M. Inoue et al. J. Org. Chem. 2007, 72, 3065.

Chap. IV

2001

2007

2002

2003

2004

2005

2006

Hirama, Inoue

Racemic

Chap. III

Mehta

isolateFrontier

Danishefsky
First Synthesis

chiralStrategy for Synthesis ~~ How to construct the five rings (A~E) ~~Danishefsky's Route :

DCA

B

O

E

Hirama and Inoue's Route : B and CDAE

HOA and C

B

DE

O

Frontier's Route :

O

E
B
A

C

D O

O

1 / 15

II. Danishefsky's Route
Retrosynthetic Analysis
O
O

O

O

O

O

Oxetane formation

iiii

O

O

O

HO2C

O

v
ORO

O
O

HOvi
OR

Ovii

O

1O

O

O

OR

OR
O

iv

OR

HOO

H

O

X

O

O

OR

O
O

Oii

OR

O

OO

O

2HOO

OROHO

Diels-Alderviiiixxxi

Key Reaction
1Diels-Alder ReactionDiels-Alder reaction didn't directly proceed with the retro-synthesized compounds.
OROOR

directDiels-AlderOOOO

necessary to conduct
further reactions

more powerful dienophile
ORORO

O

O

OOO

HOO

OCO

DO

Scheme 1Methylene blue : elimination of oxygen

15, 1716, 19 : reduction under very mild condition with high chemoselectivity (Synthesis 1987, 647)

ex )
OOH

ClCO2Et

XO
X

X : Cl, Br, NO2

THF / NaBH4 (3.0 equiv.) /drop addition of MeOH
1 h, 10 °C ;OOOEt

1N HCl~ 80 %OHX

only carboxylic acid is reduced in thepresence of halogen and nitro group.
2 / 152Oxetane Formation

Largely, three methods are known for building-up oxetane¾ Payne Rearrangement
R1O

R3R3OHstrong baseprotic solvent

R2 R4 R5

R1R2 OHO

R5R4This time, the situation has been slightly changed
forming oxetane ring structure.
(Fukuyama et al. Tetrahedron, 2001, 57, 4691)

POINT

•
•

C7-OH is located near C1.
Strong base will open lactone ring.

C7-OH attacks C1 producing four-membered ring, not C2 doing five-membered ring.
Acid condition solves this problem, for tertiary C1 carbon is likely charging plus.

¾ Peternò-Büchi Reaction ([2+2] Photocycloaddition)

Review : J. Chem. Soc., Perkin Trans. 1, 2001, 2983

ex ) Greaney's synthetic study (Org. Lett. 2005, 7, 3969)
AO

CE
BHOOO

E

B
A

COOcf ) oxetanocin synthesis (Synthesis 1998, 5, 683)

oxetanocin

••

POINT

generally low yield
difficult to control the position of olefin and carbonyl group¾ From 1,3-Diol

Synthesis 1995, 5, 533

cf ) Taxol Synthesis

POINT

Installation of 1,3-diol moiety should be prior to oxetane formation.
3 / 15

Total Synthesis
ORing C, DSynthesis

22HOOOCDOO(23 : α, 24 : β)Desired23, 24 : Claisen rearrangement by Johnson ortho protocol (J. Am. Chem. Soc. 1970, 92, 741)
R1

R1

R1

R1

CH3C(OEt)3 +R2

HO

EtO
EtO

R2O

EtO

O

EtO

R2

R2O

cf ) Danishefsky developed this strategy for asymmetric synthesis. (Angew. Chem. Int. Ed. 2005, 44, 1511)
ClClOMeOMeClOOClOAB

CO2Me

CO2MeO

COH
OH

cat. (S,S)-[CoIII(salen)]-OAc-78 °C, 2 days; -25 °C, 2days HO
THF
y. 86 %, 86 %eeOOO

MeO2COHDNTBSO

E

N
Co

t-Bu

Ring A
Synthesis

OO

AO

O

O
OAc
t-Bu
t-Bu

t-Bu
(S,S)-[CoIII(salen)]-OAc

HOO

O

23, 24(from 24)

iodolactonization

dead end !

O
Ring B
Synthesis

HOB

OO(from 23)

C-allylation
by Keck reaction

OO

27

selenenylation andbromoselenenylationoxidativedeselenenylation

free radical cyclization

4 / 15O
Ring E
Synthesis

EHOOOOO

toal 20 steps
10.7 % overall yield< Free Radical Cyclization >Free radical cyclization is another key reaction for all synthesis route.
Danishefsky

Hirama and Inoue

Frontier(90%)
AIBN, Bu3SnH, PhH, reflux; p-TsOH, H2O (one pot)

O
Important method to construct ring B

General Feature

HOB

OO

react under mild conditions
attack the closest reactive site
irreversible

OO

undamage the other functional groups
high regio and stereoselectivity
retro reaction doesn't occur

Frontier Molecular Orbital
The reaction is accerated as LUMO becomes lowerby the effect of electron withdrowng group.

rxn rate : EWG = -CHO > -CO2R > -Ph

5 / 15

III. Hirama and Inoue's Route
Retrosynthetic Analysis
OHOOHOOOOOO

HOO

Oi

O

Oii

OH

Oiii

OO
OHv

ORiv
OH

OR

OR
OH
viii

OHvi

OR
O

ClO

vii

Desymmetrization
by Transannular Aldol Reaction

O

OR

OR

OR
OR

OR

OR

HOO

O

ORORO

OROR

HOClixxOxi

Key Reaction
Desymmetrization by Transannular Aldol Reaction
Advantage of taking desymmetrization strategy¾ making the process shorter¾ possibility to achieve enantioselectivity by desymmetrization
OM

HOROROOR enantioselective
OR deprotonation
OOOH(-)-5OO

HOROROH

OROR(+)-5Desired

diastereoselective
C-C bond formation

OHOROROMOOH(-)-13H
OROROOHOR
ORUndesired (+)-13Condition Check

optimization of base reagent

optimization of protecting group(DCB)

6 / 15

Possible Mechanism

From condition checkbdcabdHa

Hc

Table 1entry 1 and 2 : LiN(TMS)2 was better than DBU in selectivity
entry 2 and 3 : high selectivity under lower rxn temp.

Diastereoselectivity is achieved under kinetic control.
Table 2entry 1~ 4 : selectivity was changed under protecting group

Diastereoselectivity depends on the size ofortho-substituent.

The mechanism (shown left) can be supported.

Explanation of Possible Mechanism
1. Only 2 protons circled (a and c) in the chart
Ha O
will actually be deprotonated and stableHbcis- enolate (4A and ent-4A) should be formed.
2. After deprotonation, steric interaction occurs
between C7-O bond and C14 in theconformation of 4A to generate 4B.
Hd H O
3. Enolate flips downward kinetically before
cstabilization by chelation like 4C.

DesiredOROR

Undesired

Moreover, Hirama and co-workers succeeded in synthesizing chiral Merrilactone A by using chiral basein desymmetrization process. (J. Org. Chem. 2007, 72, 3005)
Asymmetric Desymmetrization

Condition Check

Apply to Total Synthesis

7 / 15

Total Synthesis
ORing B, CSynthesis

HOBOOOCO[2+2] photocycloaddition

metathesis
by Grubbs’ catalyst
first generation

keyCriegee oxidation

1011 : attack from down side because of the steric effect of DCB
ClClO Cl
MgBrO

OCl O
10attack from down side

Ring ASynthesis

OOAO

HOOODBU

free radical cyclization

8 / 15

ORing DSynthesis

O

HOODOO

19β

Methylation byEschenmoser’s reagent

19

20 : stereoselective enolization
C3 protons are hidden by DCB or ethyl moiety.

C1 proton can be regioselectively deprotonated.

2132 : oxidation of ketal (Tetrahedron lett. 1978, 19, 419)

reaction mechanismOO
HOEtO H
BF3HOOOOOOOClO
ClAt this stage, the problem is how to reduce C7 carbonyl group.
At first, they use DIBAL-H for compound 22 (model substrate), but desired product wasn't selectively obtained.

Desired22 24 : reduction by DIBAL-H

24

25 : Ag2CO3/Celite oxidation

Undesired(Synthesis, 1979, 401)

mechanism

Celite : easy to separate Ag residue from productKetal blocks the attack of hydridefrom downward
Undesired products (26, 27)

advantage
very mild condition (neutral)disadvantage
excess amount of Ag2CO3 is needed
low selectivity

Then, try another reductant : Birch reduction.
9 / 153431 : Birch reductionSodium cation is chelated
as shown in the chart above

high stereoselectivity

31, 36

37 : regioselective oxidation

Ioxidation easily

IIDesiredcf ) if the alcohol is protected by TBS, the structure is changed that TBSO directs pseudo-equatorial way.

IVUndesiredIII

oxidation easily

O
Ring ESynthesis

37EHOO

OOO

38 : epoxidation by dimethyldioxirane (DMDO) (Chem Rev. 1989, 89, 1187)
reaction mechanism

total 23 steps
3.0 % overall yield

not commercially available ; preparation by oxidation of acetone is inefficient (y. ~ 3%).
however, advantage is larger.
byproduct is only acetone
good selectivity despite of high reactivity
inexpensive for preparation

10 / 15

IV. Frontier's Route
Retrosynthetic Analysis
OHOO

OO

O

HOO

OO
O

Oi

Ref. J. Am. Chem. Soc. 2008, 130, 300

ii

O

OR

O

X
ROO

ORO

O

ORO

ORO

O

iv

Nazarov Cyclization

v

H
R

R

Riii

OO

vi

vii

Key Reaction
Nazarov Cyclization
Lewis acid-catalyzed Nazarov cyclization

general Lewis acids : .FeCl3, BF3 Et2O, SnCl4, Cu(OTf)2, PdCl2(MeCN)2, AlCl3, Sc(OTf)3, etc

Eisenberg and Frontier developed more powerful Lewis acid ; Ir (III) complex.
synthesis of Ir (III) complex
Ph2POCIr4Ir (III) comlex(Inorg. Chem. 2002, 41, 2095)

MeI (excess)P
Ph2

Iabcdex)FeatureStrongLewis Acid••

increase the reactivity
lessen byproducts under mild condition

mechanism

11 / 15

Reactivity compared to Cu(OTf)2

active spieces
substrates coordinate to Ir (III) by O, O' chelation.

ordicarbonyl type (2a)1 : Ir (III) complex

monocarbonyl type (2c, 2d)(Tetrahedron 2005, 61, 6193)

compound 2a, 2c, 2d
short reaction time
low temperaturehigh yield

possible structure of Ir (III) chelation

Ir (III) complex is superior
to Cu(OTf)2cyclization can't proceed
in this binding

compound 2b
Cyclization didn't proceed with 2b.
The possible chelate structure is shown right.
In Merrilactone synthesis, 15j is the substrate for the key reaction forming ring C.
OTIPSOO

Ir (III) complex

TIPSO

OTBS CH2Cl2 , rt
87 %TMSOTMS

15j

O

HOOTBSOO
23j

AOO
CO

TIPS : triisopropylsilyl

However, Ir(III) complex can not be the only catalyst of Nazarov cyclization. TIPS+ produced is also thought to be a catalyst.
This presumption is suggested by these experiments.

.

TIPS+ BArf-Ir(III) complex TIPSOTf

entry

CF3

reaction
f-0

BAr : 2 B

1

CF3 4
entry 0 : using Ir (III) for general substrate (unprotected by TIPS)
entry 1 : using Ir (III) for 15j (protected by TIPS)
entry 2 : using TIPSOTf for general substrateentry 3 : using TIPS+ BArf- for general substrate2.

3Possibility

entry 0 : Ir (III) complex works as a catalyst.
entry 2 : TIPSOTf doesn't work as a catalyst.
entry 3 : TIPS+ BArf- works as a catalyst.

1. Ir (III) initiates and catalyzes.
2. Ir (III) initiates only and TIPS+ catalyzes, in stead.
3. Both Ir (III) and TIPS+ catalyze.

Total Synthesis
They examined three procedures, and only No.3 was gone well.
O

1.

OTIPS
O

O

TIPSO

O
O

O
TMS

2

TMS

3O

2.

OTIPS

TIPSO
O
TMS

O

OTBS

15i

TMS

TIPSO
TMS

O

O

O

23i

O

31
O

O
O

TMS

23jOO

Merrilactone A

33

OTBS

OO

OTBS

OOTIPS

OTBS

15j

O

OTBS

OO

3.

O

O

OTBS

O

45

12 / 15

O
Ring A, CSynthesis

OHOO

CAOO

key reaction

23j

7

8 : lactonization by higher-order stannylcupratehigh stereo- and regioselectivity
compared with general stannylcuprate
1,4-addition of tributylstannane
high temp. : E-isomer (3'b)
low temp. : Z-isomer (4'b)

1015
The metal is strongly chelated by the amide moiety.

make it possible not to overadd to the substrate,
producing a tertiary alcohol.

cf )

O

TIPSO

OTIPS

O

OOO

TMS

O
TMS

2O

O

3Using a variety of Lewis acids, all attempts were failed and only hydrolyzed compound 13 was obtained.

O
Ring B, DSynthesis

HOB

OOO
DO

13 / 15

23i

44 : selective desilylation of alkyne

RTMS

Ag

AgNO3

R

TMS H2ORAg

KCN / H2O

R

Ag

R

H

N C

23i

44 : free radical cyclization
OTIPS

AIBN
Bu3SnH

Bu3Sn

OTIPS

OTBS

O

OTBS

O

TsOH
H2O

H

OTIPS
OTBSOcf ) When Me group was pre installed (31), desired lactone formation didn't proceed.
OOOO
O

OTBS

O
31

OO
33

FailedWhat is the difference ?

In the case of R=H, stabilization makes the equilibrium shift rightward.

ORing ESynthesis

EHOO

OO
O

48

total 17 steps,
14.4 % overall yield48

33 : methylation

14 / 15

V. Conclusion
see Mr. Kuramochi's lit. seminar

Evaluate these three routes by Baran's 8 rules
By Baran, short synthesis is defined as follow.

short synthesis : maximized C-X(C) bond forming, minimized redox and protection-deprotection.
This time, three total synthesis are summerizedRouteTotalSteps

Yield
(%)

C-X
Forming(steps)

Ratio
(%)

Redox(steps)

Ratio
(%)

protection &deprotection(steps)

Ratio(%)

Danishefsky

20

10.7

1050

2103

15

Hirama & Inoue

23

3.3

1252

730

3

13

Frontier

17

14.4

1059

212318Frontier's route will be good.
Danishefsky : Formation of A ring by Diels-Alder is difficult. Stereoselective direct Diels-Alder would be nice.
Hirama & Inoue : After desymmetrization, formation of ring B was problematic.
Frontier : Smart synthesis, but asymmetric Nazarov cyclization should be the key for asymmetric total synthesis.

15 / 15