Asymmetric Synthesis Using Novel Cationic Diether-CoordinatedLewis Acids and Stereoselective Synthesis of Piperidones
and 1,2-Amino Alcohols

Novel Cationic Diether-Coordinated Lewis Acids,
and Stereoselective Synthesis of Chiral Piperidones and
1,2-Amino Alcohols by the Reaction of uSilyloxyimines

Thesis submitted to Hiroshirrta University
for the Degree of Doctor of Science

Kaori Ishimaru
January, 1997

Acknowledgements

The author expresses her sincere gratitude to Professor Kin-ya Akiba,
Hiroshima University, for his guidance, help, encouragement, and full
support throughout her graduate study.

She is especially grateful to Associate Professor Yohsuke Yamamoto,
Hiroshima University, for his guidance, suggestions, and cooperation
throughout the course of this work.

She wishes to thank Professor Katsuo Ohkat.a and Research Associate
Satoshi Kojima, Hiroshima University for his suggestions andencouragement.

She wishes to thank Professor Toshifumi Hirata and Associate Professor
Shunsuke Izumi, Hiroshima University, for the use of their refrigerator
room.

She thanks Associate Professor Koji Yamada, Hiroshima University, formeasurement of powder X-ray diffraction.

She thanks members of K.-y. Akiba's Laboratory who shared period tostay with her, especially Mr. Kazutaka Tsuru, Keiji Monda, and Wataru
Satoh.

She heartly appreciates her family for their encouragement and patiencethroughout the course.

Asymmetric Synthesis Using Novel Cationic Diether-CoordinatedLewis Acids and Stereoselective Synthesis of Piperidones and 1,2Amino Alcohols
CONTENTS

Chapter 1. Asymmetric Synthesis Usinlg Novel Cationic
Coordinated Lewis Acids
1-1.

Introduction

Diether-

11-2. Cationic Lewis Acids for [4+2]Type Cycloadditionof a-Chiral Aldimines

12

1-3. Development of Novel Cationic Le\\ris Acids
Coordinated by a Chiral Diether Ligand

18

1-4. Attempt to Develop Novel Lewis Acids Bearinga Monoether-Coordinated Ligand

31

1-5. Aldol Reaction by Using the Novel (:ationic Lewis Acids

39

1-6. Synthesis of the Modified Chiral Ligands

44

1-7.

Structure of Chiral Diether-Coordinated Titanium
Complexes

47

1-8. Summary

51

1-9. Experimental Section

52

1-10. References

74

Chapter 2. Stereocontrol in [4+2]Type Cycloaddition of Imines
Bearing a-Hydrogens with 2-Silyloxy-l,3-butadienes

2-1. Introduction

77

2-2. [4+2JType Cycloaddition of Imines bearing a-Hydrogens

82

2-3. [4+2JType Cycloaddition of a-Silyloxyimines

84

2-4. Summary

98

2-5. Experimental Section

99

2-6. References

122

Chapter 3. Stereoselective Synthesis of 1,2-Amino Alcohols by
Nucleophilic Addition of Organometallic Reagents to (lSilyloxyimines
3-1. Introduction

124

3-2. Nucleophilic Addition of Organometallic Reagents to an (lSilyloxyimine

131

3-3. Summary

138

3-4. Experimental Section

139

3-5. References

149

Chapter 1.

Asymmetric Synthesis Using Novel Cationic
Diether-Coordinated Le'wis Acids

1-1. Introduction
Various Lewis acids with chiral ligands have been utilized for many asymmetricinductions. 1- 2 For example, metal halides and alkoxides bearing chiral diamines (eq1-1),3 amino alcohols (eq 1-2),4 and diols (eq 1-3)5 have been found to be useful as
catalysts. In these cases, the Lewis acidity of the complexes are not so strong but
stereochemically stable chiral centers at carbon atoms in the ligands control thestereoselectivity of the reactions.

(eq 1-1-1)

RMgBr + PhCHO
toluene(R=CH 3(CH 2)S-' Ar=3,5-xylyl-,70 %ee
71 % yield)

PhCHO(eq 1-1-2)(R 2 =Et, 98 %ee, 99 % yield)

-1-

R1
2

R1CHO + R 2Zn

R2

X~H

..

(eq 1-2)

H

Rl=n-C6H13, M~CHCH2' cycLo-C 6 H ll , Ph
{ R 2=Me, Et(78-1 00 o/.~ee, 70-100 % yield)

2i5

SiPh3

::::-,.1

+

H

A°

1

C6Fs

o;:AIMe

~

°

.&

SiPh3

OH

,,~
- - - - - - I..~ PhS,.Jt...~C6Fs(eq 1-3-1)-78°C(88 %ee, 90 % yield)

Ph

Ph

PhJO-J:OH
Me""o ''1/ OH

=<

SMe

SMe

• TiCI 2(OIPr)2

A:
Ph Ph

-----------~.~

toluene-petroleum ether(88 %ee, 74 % yield)

Ceq 1-3-2)

251::::-,.

)= +

°

~

I

O,/TiCI 2

0
OH

.&

H~COOMe--M-S-4-A--~~~II,""'~COOMe(eq 1-3-3)(95 (7'oee, 72 % yield)-30°C

Recently, Alexakis reported novel systems such as 1 derived from N-substitutedchiral diamines based on the conception that the methyl substituent on the nitrogenshould be oriented trans to the substituent R' on the neighboring ring carbon because-2-

of the sterlc hinderance between R' and Me substituents, and the stereogenic center
which controls the stereoselectivity becomes the nitrogen atom (chirality transfer) (eq1-4).61(eq 1-4)(>99 %ee (S), 74 % yi eld)

RLi

The idea of the chirality transfer by use of organolithiUlm or magnesium reagents
coordinating to the chiralligands has also been used for the nucleophilic addition toaldehydes (eq 1-5),7-10 but a few examples have been reported thus far as shown
below.

-3-

PhCHO+(eq 1-5)

RM

RM

ligandMe2Mg

Mr;}_('e
MeO

BuLi

ee(%)

configuration

ref.

20

S

7,8

40

R

9

95

R

10

OMe

Me2NCH\_-{H2NMe2
MeO

OMe

BuLi

More recently, Tomioka et. al. reported enantioselective conjugate addition oforganolithium reagents to an a,,B-unsaturated aldimine by use of a C2 symmetricchiral diether, 11 and the corresponding aldehyde was obtained in 94 % ee (R=Ph) byusing (R,R)-1 ,2-diphenylethane-l ,2-diol dimethyl diether (eq 1-6). They proposed
the model A for the structure of the active species. The model shows that the diether
forms a five-membered chelate complex with the organolithium reagent and the lonepair of the nitrogen atom of the aldimine coordinates to the lithium atom. It was
assumed that four substituents of the ligand would take an all-trans arrangement
because of the steric factors which would lead chirality transfer from chirality of the
carbon atoms On the backbone to the oxygen atoms.

-4-

Q
RLi

H+

QHO

P}-f - CO~~A(eq 1-6)

"f /.

MeO

OMe

.0'.0'In spite of these interests, stronger Lewis acids with chiral diether ligands have notbeen reported yet. In this Chapter, the author wishes to describe the generation of
cationic Lewis acids 16 as shown in Scheme 1-1 hoping that these will be reactive
enough to employ unactivated substrates or reactants.

In the Lewis acids, thecoordinating diether as shown in 16 suppresses polymerizaltion of the cationic species
and coordination site for the substrate in octahedral geometry should be available by
abstraction of a chloride ion from 14 or 15 with silver ion. As described above, thefour substituents of the diether ligand would take an all-trans arrangement.

Ph

o
PhCHO
------..

Clt,

:

)-H
\

/~"":
+ M~ ~~O~Ph

C",..-I""

0

X /14: X=Cl{ 15: X=Oalkyl

16

Scheme 1-1.

-5-

17

..... PhIn the course of our study, Corey et. al. reported a novel chiral super-Lewis acidic
catalyst as show n in 2 or 3. 12 The application of the oxazaborinane system 2 toDiels-Alder reaction of less reactive 1,3-cyclohexadiene or isoprene with 2bromoacrolein was unproductive.

However, using the catalyst 3, the reaction

proceeded to give products in excellent yield. The results strongly suggest that thesecationic metal species should have applicability as Lewis acids.

"2

3
In the Coreis Lewis acid, abstraction of a bromide (or halogen) was
accomplished by using the strongly cationic silver salt as Ag+B[C6H3 -3,5-(CF3)2J4(AgTFPB 4, TFPB: tetrakis[3,5-bis(trifluoromethyl)phenyl]borate) prepared fromNaTFPB. It might be difficult to use other silver ions (AgBF4, AgOTf etc) for
abstraction of the halogen because cationic BR2+ were very unstable. If the othermetal species are used in which the abstraction of the halogen is easy , there will be noneed to use AgTFPB which is difficult to prepare. In addition, the author thought theamine substituent in the Lewis acid might make the strong Lewis acidity weaker so as-6-not to polymerize cationic species or not to decompose reactants. The results should
show the possibility that even weaker neutral Lewis acid would become stronger
Lewis acid by the abstraction of the halide anion. The novel idea will widen thechemistry of Lewis acids.

In the coordination chemistry of the cationic species which would have thepossibility to be Lewis acids, Lambert et. al. reported rather stable R3Sn+X- species(R=Me, Bu, Ph, X=CI04, B(C6F5)3H) in 1992.1 3 They prepared tin cations asshown in eq 1-7.

R3SnH + Ph 3CCI0 4 ~ R 3SnCI0 4 + Ph 3CH
R 3SnCI + AgCI0 4 ~ R 3SnCI0 4 + AgCIR3SnH + B(C6F 5)3• R 3SnB(C6 F5 )3 H[(eq 1-7)(R=Me, Bu)
In 1994, Sakurai et. al. reported the BU3Sn+TFPB- 5 (TFPB: tetrakis[3,5bis(trifluoromethyl)phenyl]borate), and when a small amount of ether was added tothe solution of the BU3Sn+TFPB- at -70°C (eq 1-8), 119Sn signal shifted to higher
field (5~ 8356 at -20°C, after addition of ether, 6~ 8 165 at ·-20 °C).14 The result
showed the formation of ether complex of tributyltin cation, and ether-coordination ispossible by formation of cationic species.

CD2CliEt20

BU3SnH + Ph3CTFPB~[Bu3Sn-OEt2tTFPB- + Ph 3 CH

Ceq 1-8)

6

In the case of neutral metal species coordinating ether, Denmark reported that
Et2Zn or (XCH2)2Zn (X: iodide, chloride) coordinating 1,2-dimethoxyethane wasobserved by 1Hand 13C NMR spectra in benzene-d6 and "7 could be isolated todetermine the structure by X-ray analysis. 15 They also prepared the complexes 8 and-7-9 in solution but the corresponding diether complexes with Zn(CH2Cl)2 could not be
prepared.

0

Phr--('h

/
\

,

Zn

0/

\

Ph....::~/CH 2 1OMe

MeO
CH 2 1"Zn(CH
I Ih
2

7

8

1\

OMe

MeO

"Zn(CHI Ih
2

9In the case of titanium (IV) or Sn (IV) compounds which are well-known Lewis
acids, some of diether-coordinated complexes have been reported. Examples areshown below.

-8-

Examples of Diether-Coordinated Ti(IV) or Sn(IV) Complexes (Sumof the bond angles around the indicated oxygen atom is shown inparenthesis.)Q
Sp2 (358.3°, 359.4°)

18b l718e20

18d l9(O)
CI, +. . . . . CIC(/tf\..CI(Of

sp3-sp2(351.4°, 359.9° and 355 .9°, 360.1°)
18f21

-9-

From these X-ray structures, chelation of the ether oxygen to Lewis acidic central
atoms such as Ti(IV) usually renders the hybridization of the oxygen to an sp2 mode
from sp3, thus losing the chirality at the oxygen. Recently reported X -ray structuresof Ti(0-i-Pr)CI3(Et20)(PhCHO) (10) and Ti(0-i-Pr)CI3(THF)2 (11) clearly showedthat the oxygen atoms of diethyl ether and THF coordinating to the Ti(IV) center were
almost sp2 hybridized (the sum of the bond angles of the oxygen atoms: 359.3 0 in
10, 359.8 0 in 11).2 3 On the other hand, however, ab initio calculations of chelatecomplexes of CH3TiC13 with (S)-2-hydroxypropionaldehyde (12) and (S)-2methoxypropionaldehyde (13) showed the oxygen atom of the hydroxy group in 12
was practically sp2 hybridized whereas some chiral induction on the oxygen atomfrom the carbon center was observed in 13 (Scheme 1-2).24 To design the chirality!ransfer, it was necessary that the ether oxygen atoms were sp3 hybridized or nearly
sp3. Thus the experimental examination of the structures of Ti(IV) chiral diether

complexes (14 or 15) was of interest before these compounds were utilized as chiral
Lewis acids.

Scheme 1-2.

-10-

CI

\

t --

CI2

0

--,..,. ...... Phl"'O~""PhX /14: X=CI{ 15: X=O-alkyl

16

17

In addition, the applicability of the cationic Lewis acids for some reactions is alsoquite important. In this Chapter the author wishes to report on the development of thenovel cationic Lewis acids bearing diethers derived from (R,R)-l ,2-diphenylethane1,2-diol. At the beginning of the Chapter, the development of the cationic Lewis
acids without the ligands is described. Application for aldol reactions by using thenovel cationic Lewis acids and X-ray structures of six-coordinate titanium complexes

14c and lSa are also described.

-11-

1-2. Cationic Lewis Acids for [4+2]Type Cycloaddition of a-Chiral
Aldimines

At the beginning of the study, cationic Lewis acids without ligands were
investigated. The author selected the [4+2]type cyc1oaddition of an a -chiral aldimine
60c derived from (S)-valine with a 2-silyloxy-l,3-butadiene 57a because no productwas obtained when TiC14 was used as a Lewis acid at -30°C in i-PrCN as shown in eq
1-9 although the reaction of the aldimine 60a derived from (S)-ethyllactate proceeded
under the reaction conditions (see Chapter 2).

~SitBUM92
578 TBAF----30°C'H"~/-+
H~
~~"
I ~
OH

(S}-valine

FIt'

OH

CH 2A1

CH2Ph

648

64b

(eq 1-9)

no product

9Si B0=N
H'CH Ph2i-PrCN

-30°C

60a

H~
I

A1

H OH
CH 2 Ph61b
87 % yield( S)-ethyllactate

To circumvent the problem, the activated Lewis acids such as the cationic titanium
compounds were the candidates for the reaction. Recently, Suzuki et. al. reported new
glycosidation by use of Cp2ZrCI2-AgCI04 Ceq 1-10).25 They succeeded in highly pselective glycoside formation.

-12-

Ac

~

CP2 ZrCI 2
AgCI04F+ ROH- - - - -

OMe

OMe

AC~C\
- IbM:OR(eq 1- 10)

OMe

Mukaiyama et. al. reported the activated Lewis acids for the Beckmann
rearrangement of benzophenone oxime deri vati ves as shown in eq 1-11. 26 They havebeen using these Lewis acids for other systems until now.

1) reflux 7h)=NOTMSPhCONHPh(eq 1-11)2) H2O

catalyst (20 mol%)yield (%)

SnCI4+AgSbF6

71

2

TiCI 4+AgSbF 6

24

3

SbCI 5 +Ag SbF6

78

4

TiCI4

2

5

SnCI4

0

6

Ag SbF 6

19

entry

Akiba et. al. reported the effects of counter ion and solvent on the rate of the silver
ion promoted-rearrangement of 4-aryl- or 4-alkenyl-3-bromo-3,4-dihydro-2-pyrones asshown in eq 1-12.27 The rearrangement with AgSbF6 in dichloromethane proceededsmoothly at room temperature and completed within 15 min to afford the product inhigh yield. The combination of weakly coordinating hexafluoroantimonate as a counter-13-

anion and weakly donating dichloromethane as a solvent was crucial for the activity ofthe silver cation.
~R

D
~

I

o

Br

AgX
Ceq 1-12)0RX

solvent

conditions

conversion (%)

p-tolyl

SbF6

dichloromethaner.t., 15 min

100

p-tolylSbF6

acetonitrile

r.t., 24 h84

p-tolyl

BF4dichloromethaner.t., 24 h

71

p-tolylBF4acetonitrile

reflux, 12 h79

I-propenyl

SbF6

dichloromethaner.t., 15 min100

I-propenyl

BF4acetonitrile

reflux,7 h

81

It seems that the selection of neutral Lewis acids and silver ions for cationic Lewis
acid-promoted reactions might be difficult if the substrate is easy to decompose bystrongly activated cationic species. In the [4+2]type cycloaddition, the usilyloxyaldimines were easily to polymerize under some conditions so that carefulselection was necessary.
As a model reaction of eq 1-9, the u-silyloxyaldimine derived from (S)-ethyllactate
was selected in the reaction. The methods and results are shown in Scheme 1-3 andTable 1.

-14-

9Si BLewis Acid~'cH2A1
60a

IMethod

1160a
AgXJsol vent..

~

ASilBUMe2

TiCLt

~

- - - - - - I..

Ph~

57a TBAF
..

H

HI/

...

Ph

"/1/

N

¥._

I

+

H OH
CH2Ph

H

~
:\H
,...: N

P~

61a

.'

I H OHCH 2Ph61b

IMethod 21
9Si Et/"\. -N- H/- 'CH Ph
2

AgX+TiCI 4- - - - - - i..
~~SiIBUMe2~

P

57a TBAF......

0

H~H
1/.
N

Ph

Isolvent.,'«'-+I H OHC H2 Ph

61a

Scheme 1-3.

Table 1-1. [4+2]Type Cycloaddition of an a-Silyloxyaldimine 60a
Derived from (S)-Ethyl Lactate.
entry X

solvent

1

BF4

CH2C12

2

OCOCF3

CH2C12

3

CI04

CH2C12

4

OTf (0.8 equiv.

CH2C12

method 61a:61b

conditions

yield (0/0)

o °C, 20 min

27

o °C, overnight

0

13:87

o °C, 20 min

93

36:64

o °C, 20 min

64

5:95

1

to aldimine)

-15-

5

CH2Cl2

28:72

o °C, 20 min

57

OTf (3 equiv. to CH2C l2

19:81

o °C, 20 min

61

OTf (1.1 equiv.
to aldimine)

6

aldimine)

7

CH2C12

2

34:66

o °C, 20 min

82

i-PrCN2

10:90

o °C, 30 min

79

OTf (3 equiv. to CH2Cl2

2

15:85

o °C, 20 min

80

2

4:96

o °C, 20 min

33

CH2CI2*a 2

15:85

o °C, 20 min

58

OTf (1.5 equiv.
to aldimine)8

OTf (1.5 equiv.
to aldimine)

9

aldimine)
10

SbF6 (2 equiv.

C H 2 Cl 2

to aldimine)
11

SbF6

The ratios of 61a:61b were determined by 1H NMR spectra.
*a Five times amount of the solvent was used compared with that in other entries.

The product 6th might be obtained by way of chelation pathway in the case of
TiCl4 (Chapter 2), so higher selectivity of 6tb might suggest that more active Lewis
acids were formed. ZnCI2-AgSbF6 and ZnBr2-AgSbF6 were also investigated but noselectivity was observed (31 % yield). In Table 1-1, using AgSbF6 gave highselectivity as in entry 10 but in low yield. Higher 6tb selectivities seem to be observedby using more cationic silver ions, but the resulting highly cationic titanium ion mightalso decompose the aldimine. The reactions did not appear to require the super-cationic
Lewis acids. Method 2 was better way to obtain products than the method 1 (61 0/0
yield in entry 6, and 80 % yield in entry 9).

-16-

H".~r\~+H~/'~
I

TiCI 4 / AgOTf"f>=N
H'CH2A1

0 H
CH 2A1

60c

Ai'

64a

H 0 H
CH 2A164b

The results were applied for the [4+2]type cycloaddition of an a-chiral aldimine
derived from (S)-valine with a 2-silyloxy-l ,3-butadiene. The addition of 1 equiv of
AgOTf to the mixture was quite effective in activating TiCl 4 and only 64b was obtainedin 49 % yield (64a:64b=<2:>98) at -30°C in i-PrCN. It is unclear what is theactivated species, but TiCI3+ -TiCl4 polymer might be the Lewis acid in this system.

-17-

1-3. Development of Novel Cationic Lewis Acids Coordinated by a
Chiral Diether Ligand
A. Preliminary Examination in [4+2]Type Cycloaddition of aSiJyloxyaldimines
The crural diether ligands were prepared as shown in Scheme 1-4. Osmiumoxidation of trans-stilbene by use of dihydroquinjdine 4-chlorobenzoate afforded(R,R)-1,2-diphenylethane- 1,2-diol (R,R)-19. 28 The optical pure compound was
obtained after recrystallization of the crude products from EtOH. (S,S)-1,2Diphenylethane-1,2-diol (S,s)-19 was prepared by using dihydroquinine 4chlorobenzoate and Os04.2 8 The resulting diol (R,R)-19 was treated with NaH and
Me2S04 to give (R,R)-l ,2-diphenylethane-1 ,2-diol dimethyl diether (R,R)-20a,11and dibenzyl diether (R,R)-20b could be prepared by using NaH and BzIBr. Other
dialkyl diethers could not be obtained by the similar methods, so the (R,R)-l ,2diphenylethane-1,2-diol (R,R)-19 was treated with KOH-DMSO followed by alkyl
iodide at room temperature to give dialkyl diethers in excellent yields. 29

Ph

P~

OS04
~

dihydroquinidine
4-chlorobenzoate

P'}--(HO

NaH, Me 2S0 4

OH

. 'K

89%

Ph

Ph

MeO

OMe

(R,R)-20a(R,R)-19~ NaH,BzIB~ P~-f

70%

85 %

BzlO

OBzl

(R,R)-20b

OS04

PH.f
HO

dihydroquinine
4-chlorobenzoate

n-Alkyl IodideP}-f

DMSO-KOH

RO

h

>90%

OH

(S ,5)-19

Scheme 1-4.

-18-

{

OR

(R,R)-20c: R=Et
(R,R)-2Od: R=n-Pr(R,R)-20e: R=n-Bu

As a part of the ongoing project, [4+2]type cycloaddition of an aldimine 60a with 2silyloxy-l,3-butadiene 57a was carried out to test the cationic Lewis acids which wereprepared in situ (Table 1-2). Based on the results in Section 1-2, the best method toprepare the cationic Lewis acids was decided as shown in eq 1- 13.

AgX +chiralligand I dichloromethane
TiCl4 ~sitBuMe 2~
57a TBAF

CiSiEi"-/):N'CH2Ph
H
60a

0

0

N .
:AN H Hfr)?
"" ~+(eq 1-13),..'

I HOH Ai I HOH
CH 2PhCH 2PhIdichloromethane

61a

61b

j

Table 1-2.
entrychiralligand

temperature

1(R,R)-20a2

61a : 61 b

yield (% )

O °C

87:13

70

(R,R)-20a-30 °C

76:24

74

3

(5,5)-20a

o °C

87:13

76

4

(R,R)-19

o °C

BF4

5

(R,R)-20a

o °C

OTf

50:50

6

(R,R)-20a

O °C

SbF 6

27:73

7

(R,R)-20a

O °C

BF4

29:71

55

8

(R,R)-20a-30 °C

SbF 6

9:91

:J5

9

(R,R)-20a-30 °C

BF4

50:50

76

10

(5,5)-20a

o °C

BF4

50:50

52

11

4°C

X

0

30:70

-19-

40

In Table 1-2, the selectivity by using (R,R)-20a- TiCl4 without silver ions was thesame as that with (S,S)-20a-TiCl4 (entries 1 and 3). The use of chiral diolligand(R,R)-19-AgBF4-TiC14 gave no product (entry 4). The large effect of the counter

anion of the silver salts on the selectivity was observed when the chiral diether ligand(R,R)-20a was used (entried 5, 6, and 7) and strongly cationic silver ion such as

AgSbF6 led to higher selectivity of 61b (61a:61b=27:73, entry 6). The ratio of
61a:61b (27:73) in the reaction with (R,R)-20a was different from that with (S,S)20a (50:50) when the same silver salt was used (entries 7 and 10). The results suggestthat the chirality of the chiralligands affect the selectivity of the products.
Table 1-3. Effect of the Aging Time on the
Stereoselectivity.
entry

chiralligand

temperatureX

aging time

61a : 61 b

yield (%)

1(S,S)-20a

o °C

BF4

<10 sec.

<2:>98trace

2(S,S)-20a

O°C

BF4

10min

36:65

3

(S,S)-20a

o °C

BF4

1h

65:35

ffi

In the reaction as in Table 1-2, to a stirred solution of the chiralligand and silver salt

was added TiCl4 and the mixture was stirred for 1 min. Then 60a and 57a was added
to the mixture successively. However, the reaction time of the chiral ligand, silver salt
and TiC14 (aging time, 1 min in Table 1-2) might be important for the generation of thecationic Lewis acids. The effect of the aging time in the reaction with (S,S)-20aAgBF4-TiCl4 on the selectivity was examined and the results are shown in Table 1-3.
As shown in Table 1-3, the author found that the aging time significantly affected thediastereoselectivity. Longer aging time produced 61a with higher selectivity in the caseof (S,S)-20a-AgBF4-TiCI4. The origin of the selectivities is unclear and should bequite complicated because of the chiral induction from the chirality of the aldimine at the-20-

a-position. However, the results show the large possibility for utilizing the novel
cationic Lewis acids. In the next section, other reactions by using the novel cationic
Lewis acids are described.

B. Examination in Diels-Alder Reaction
The author selected Diels-Alder reaction of methacrolein with cyclopentadiene to
examine the enantioselectivity induced by the chirality of the chiralligand in the Lewis
acids (eq 1-14, Table 1-4). The reaction was carried out according to the literature 30
except for the preparation of novel Lewis acids. To detennine the enantiomeric excessof the exo products, the cycloadducts were converted to the acetals such as 23 (eq lI S). In addition to the study of TiCI4-Ag+ system, other Lewis acids were examined

for the reaction.

==<HO

+

0

Lewis acid

I exo I

Iendol

~CHO

4

21-R

22-S

~

+

h

22-R

HC(O Etb

benzene, r.t. 3 h

f~9~?!-fto23(eq 1- 15)-21 -(eq 1-14)

k o

CHO

21 -S

~CHO

CHO

Table 1-4.
aging conditionsee (%)

exo:endo

yield (%)

ZnBr2

0

88:12

00

• r.t. 0 min

0

87:13

00

3

r.t. 30 min

0

89:11

75

4

r.t. 1 h

0

89:11

73

5

r.t. 2 h

0

90:10

79

entry

2

ZnCI 2+( 5, S)-20a

AgBF4

6

(5,S)-20a
ZnBr2+AgBF 4• r.t. overnight

0

90:10

83

7

ZnBr2+Ag SbF 6(S,S)-20a• r.t. overnight

0

94:6

ffi

8

ZnBr2+Ag SbF 6(S,S)-20a• CICH2CH2CI

0

81:19

<20

9

SnCI 2+Ag SbF 6(S,S)-20a reflux• reflux

0

88:12

<20

10

TiCI4+AgSbF6(S,S)-20a• r.t. overnight

0

65:35

40

11

TiCI 4+AgSbF 6• r.t. overnight

0

93:7

40

12

SnCI 2+( S, S)-20a. -78°C, 20min

0

92:8

72.

13

SnCI 2+AgSbF 6 -

0

88:12

<20

14

nBU3SnCI+AgSbF6 -

0

91 :9

00

15

Ph 3SnCI+AgSbF 6

0

91:9

ffi

(R,R)-20b
Ag SbF 6.

(R,R)-20b
reflux(R,R)-20b -78°C-78 oC, 20min(R,R)-20b--78°C, 20min*The reaction was carried out in dichloromethane except for the entry 8.

In spite of the extensive investigation of the reaction under various conditions
besides the conditions cited in Table 1-4, enantioselectivity of the exo compounds in thereaction was not observed. The change of the aging time in the reaction of ZnCI2(S,s)-20a-AgBF4 resulted in no change of the enantioselectivities (entries 2-5). In-22-

addition, no effect of the counter anion of the silver salt in the reaction of ZnBr2(S,S)-20a-AgBF4 was observed (entries 6 and 7). Although formation of precipitates
which could be AgX (X=CI or Br) was noticed after addition of the silver salt in many
reactions, the author suspected that the cationic species were not formed. To overcome
the problem, the reactions of ZnBr2-(S,S)-20a-AgSbF6, SnCI2-(S,S)-20aAgSbF6, and SnC12-(R,R)-20b-AgSbF6 were carried out under reflux conditions(CH2C12 or CICH2CH2Cl) but the decomposition of the chiralligands occurred(entries 8, 9, and 13). In addition, stronger Lewis acidic TiCI4-(S,s)-20a-AgSbF6
system which was prepared at r.t. decomposed the chiral diethers (entries 10 and 11).
Other Lewis acids such as Et2AICl, Ti(O-i-Pr)3Cl were tried under various conditions
but stereoselectivity was not observed.
To determine the reaction conditions for preparation of the Lewis acids, the amountsof AgCI and the recovered chiralligands were examined (eq 1-16 and eq 1-17). It isdifficult to identify the metal cation directly but the presence of the metal cation might besupported if the resultant AgCI was identified and the quantity was determined. In thereaction of SnCl2 with AgSbF6, the precipitates were observed even at -78°C, andthese were identified as AgCI by powder X -ray diffraction (Fig 1-1). The AgCI wasrecovered in 75 % yield when (R,R)-20a was used as a chiralligand (eq 1-16). Afterthe abstraction of the chloride ion from SnCI2, the mixture was treated with H20 andwas extracted with dichloromethane. The solvent was evaporated and 1H NMR of therecovered ligand was examined. In the case of (R,R)-20a, the chiralligand did notdecompose at all, but when (R,R)-20b was used, the peaks in the 1H NMR spectrum
were quite complex after formation of the cationic Lewis acid. The result shows thechiral dibenzyl diether ligand (R,R)-20b is unstable under the reaction conditions.

-23-

SnCl 2 (0.4 mmol)+

AgSbF6 (0.4 mmol)

P~Jh
~_

MeO

OMe

AgCI (75 %)(eq 1-16)• AgCl(15%)(eq 1-17)~

CH 2C1 2 , -78°C(R,R)-20a

SnCl 2 (0.4 mmol)

+

P}-(h
BzlO

OBzl

AgSbF6 (0.4 mmol)
CH 2C1 2 , -78°C(R,R)-20b

-24-

60

40

20

Fig. 1-1. Powder X-ray Diffraction of Agel formed in the Reaction of
Eq 1-16.

Based on the results in Table 1-4, it seemed better to select other reactions because
reaction points in the Diels-Alder reaction were far away from the carbonyl oxygenmetal coordinating bond compared to the case in hetero Diels-Alder reactions (Scheme
1-5). To lay groundwork for the novel cationic Lewis acids, closer reaction points
should be necessary. The author examined the hetero Diels-Alder reaction of
benzaldehyde and Danishefsky's diene in the next section.

O-----~I~...... ....

H

o~
M

I

Reaction Points

Scheme 1-5.

-25-

C.Examination in Hetero Diels-Alder Reaction

The reaction of benzaldehyde with Danishefsky's diene was carried out according to
the literature 31 after preparation of the novel Lewis acids (eq 1-18). The enantiomeric
excesses of the products 24 were detennined by Daicel OD column (hexane/iPrOH=501l, flow rate=1.0ml / min, tR=25 min (S) , tR=32 min (R)). The results areshown in Table 1-5.
Lewis acid
MS4A

A

AgSbF6 chiral diether

PhCHO_ .....t _ _ _--'tl--_~.. -780C
aging conditions(eq 1-18)

24-R

24-S

Table 1-5.

entry

Lewis acidligandsolvent

aging conditions

yield

24-R:
24-S

Ti(O-i-Pr)3CI(R ,R)-

CH2Cl220a2

Ti(O-i-Pr)3CI(R ,R)-

n-Bu3SnCl(R ,R)-

CH2Cl2

Ph3SnCI(R ,R)-

35-78°C - -50 °C,

51:49

20

52:48

33

51:49

61

2h
CH2C12

20a
4

50:50

overnight

20a
3-78°C,(0/0)-78°C,
overnight

CH2C1220a-78°C,
overnight

-26-

5

CP2TiCI(R ,R)-

CH2Cl2Ti(O-i-Pr)3C1(R ,R)-

51 :4940

overnight

20a
6-78°C,

hexane-78°C,2h

50:50

10

hexane-42°C,2h

52:48

15

CH2Cl2-42 °C, 2h

55:45

30

hexane-42 °C, 2h

55:45

15

20a
7

Ti(O-i-Pr)3CI(R ,R)-

20a
8

TiC4

(R ,R)-

20a
9

SnCl2

(R ,R)-

20a
10

TiC4

(S)-2S* 1 CH2Cl2-42°C,2h

52:48

20

11

TiC4

(R ,R)-

toluene-42°C,2h

53:47

28

CH2Cl2-42 °C,

69:31

35

60:40

20

20a
12

TiC14

(R ,R)-

overnight

20a
13

SbCl5

(R ,R)-

CH2Cl2overnight

20a
14

TiC14

(R ,R)--42°C,

CH2 Cl 2-23°C, Ih

64:36

45

CH2Cl2-23°C, Ih

60:40

40

CH2C l2-23°C,5h

58:42

69

CH2C12-42°C,

72:28

50

70:30

55

20a
15*5

TiC14

(R ,R)-

20a
16

ZnCl2

(R ,R)-

20a
17

TiC14

(R ,R)-

20a*4
18

TiC14

2(R ,R)-

overnight
CH2Cl220c*2,3,4-42°C,
overnight

-27-

19

TiCI3(OTt)

2(R ,R)·C H 2C l2

20a*3,420

TiCI2(OTt)22(R ,R)--42 ec,

60:40

40

50:50

40

overnight
CH2Cl220a *3,4-42 ec,overnight* 1. (S)-2S: (S)-binaphthol dimethyl diether*2. (R~)-20c : (R,R)-hydrobenzoin diethyl diether*3.2 equiv. of chiral diether to Lewis acid was used
*4. 2 equiv. of AgSbF6 to Lewis acid was used
*5. no molecular sieves 4A

To avoid accidental H20 in the reaction, molecular sieves 4A was added except forentry 15. Small effect of the molecular sieves 4A on the selectivity was observed as inentry 14 (64:36) compared with entry 15 (60:40). One drop of 2,6-di-tert-butyl-4methylpyridine was used to avoid the small amount of strong H+. After someexperiments, the author found that excess 2,6-di-tert-butyl-4-methylpyridine led tolower selectivities. Surprisingly, when large amount of 2,6-di-tert-buty 1-4methylpyridine in dichloromethane was added to the AgSbF6 in dichloromethane at r.t.,
AgCl was precipitated. The abstraction of chloride ion of dichloromethane might haveoccurred. In entries 1-7, no selectivities were observed when relatively weak Lewis
acids such as Ti(O-i-Pr)3CI, n-Bu3SnCl, Ph3SnCI, and Cp2TiCI were used.
However, when TiC14 or SnCl2 was used as a Lewis acid with (R~)-20a, lowselectivities were observed (entries 8, 9, and 11). Chiral binaphthol dimethyl diether(S)-2S in the place of (R,R)-20a did not give better result (entry 10). In order to

optimize the reaction conditions, we chose CH2Cl2 as a solvent and TiCl4 as a Lewis
acid because the reaction with TiC14 in CH2C12 gave slightly better result than that intoluene (entries 8 and 11). Longer aging time was effective to obtain 24-R selectively(55:45 in entry 8 vs. 69:31 in entry 12), although the yield was still unsatisfactory. The
aging reaction at higher temperature (-23 ec) for 1 h gave fairly good results (entry 14,-28-

64:36,45 % yield). The best result was obtained as a ratio of 77:28 in 50 % yield
when 2 equiv. of AgSbF6 to TiC14 was used with the long aging time (entry 17).
Under similar conditions, SbCI5, ZnCI2, TiCI3(OTf), and TiCI2(OTf)2 did not give
better results than TiC14 (entries 13, 16, 19, and 20). TiBr4 and TiJ4 were also tried
but no selectivity was observed.
Based on these results, it seems that TiCl4 is the best candidate as a Lewis acid andthe conditions of generation of the cationic species are crucial for the selectivity. Thus,
the author tried to isolate TiC14-chiral diether complexes. The stability of thesecomplexes had not been estimated, but these were prepared under the conditions as in
eq 1-19 and identified by 1H NMR in dry CDCI3.

PJ--(hMeO

OMe(R,R)-20a

TiCl 4..

hexane.. PJ--(hMeO

CH 2 Cl 2
-20°C

OMe

(eq 1-19)~/

TiCl 4(R,R)-26ayellow powder

After trying to obtain the complex as a solid under various conditions, the following
procedure was the method of choice: To a stirred solution of (R,R)-20a indichloromethane at -20°C was added TiCl4 very slowly. Then dry n-hexane wasadded to the mixture to give yellow precipitates which were washed with dry n-hexane
after filtration. The complex was quite moisture sensitive, so the manipulations wereconducted under AI atmosphere. Using the complex (R,R)-26a, the hetero DielsAlder reaction of benzaldehyde with Danishefsky's diene was carried out and the results
are shown in Table 1-6.

-29-

Table 1-6. Hetero Diels-Alder Reaction by Use of the Complex (R ,R)26a.
entry

solvent

aging conditions

24-R:
24-S

CH2Cl2-20°C, overnight, 1.5 equiv. of AgSbF6

yield(0/0 )

74:26

49-20°C, 1 day

50:50

55

to the complex
22x(CH2CI2hexane) *a

3

CH2C l2-hexane-20°C, 4 h

57.5:42.5

34

4

CH2Cl2-20°C, 10 h, the amount of the cationic56.5:43.5

45

Lewis acid was 0.1 equiv. tobenzaldeh~de*a: Twice amount of the solvent was used compared with that in other entries.

24-R was obtained in a ratio of 74:26 in 49 % yield (entry 1) when 1.5 equiv. of

AgSbF6 was reacted with the complex (R,R)-26a at -20°C overnight. The result wasalmost comparable but slightly better than that without isolation (entry 17 in Table 1-5).
The reaction under the diluted conditions did not afford 24·R selectively (entry 2).

In section 1-5, the author applied the novel cationic Lewis acids for the aldol reactionof benzaldehyde and silyl enol ether. Searching for the utility of these Lewis acids isvery important. Before the application, the author also tried to examine monoethercoordinated TiCl4 system in the next section.

-30-

1-4. Attempt to Develop Novel Lewis Acids Bearing a MonoetherCoordinated Ligand

The monoether-coordinated novel cationic Lewis acids are shown in eq 1-20 which is
exemplified by the hetero Diels-Alder reaction of benzaldehyde with Danishefsky's
diene. The ether moiety in 32 could strongly coordinate to the Ti atom by abstractionof the chloride anion with the silver cation. Addition of benzaldehyde to the cationic
Lewis acid would lead the transition state as in 33 in which the chirality transfer fromthe carbon chiral center in the backbone to the ether oxygen would occur.

\r

H~

OR

~OH

QR
. ~OTiCI3

R'RI

RI RI

29-31

32

PhCHO

Ag+

~ +!p-

Cf-i "
CI

~TMS
H+
Me
f ~

8'

0

H

tv1e
33

0

~

(eq 1-20)

24

Recently, Rebieve et. al. reported Diels-Alder reaction of methacrolein withcyclopentadiene as shown in eq 1-21, and they succeeded to obtain products with highselectivity by using dialkoxy ligands (R=H in eq 1-21,73 %ee (-), 90 % yield) but thestereoselectivity was much lower when monoether ligands were used (for example,
R=Me in eq 1-21, 20 %ee (+), 90 % yield).3 2 They reasoned that the replacement of
the hydroxy group in the Lewis acid by an OMe moiety prevented the chelate formation
because of steric interference with the vicinal phenyl group. However, the author
thought the another possibility that the selectivities in the reaction by using the-31-monoether chiralligands might result from poor Lewis acidity of the neutral central
atom and coordination of the ether to the metal might be difficult. The author hoped thatthe novel strongly activated cationic Lewis acids as shown in eq 1-20 would circumventthe problem of the chelation.

JrH(eq 1-21)

The monoether-coordinated ligands were easily prepared from commercially available(S)-ethyllactate, (S)-valine, and (S)-mandeIic acid as shown in Scheme 1-6. The
reaction of chiral esters with Grignard reagents afforded the chiral diols, and theresulted chiral diols were alkylated with methyl iodide to give the chiral methyl ether
ligands. 1,1-Dinaphthyl alcohol29c was prepared by the reaction of (S)-ethyllactatewith BzIBr followed by the reaction with naphthyllithium.

-32-M9+ PhBr

QH

OH
:
OH

~OEt _ 3_P_hM_9_B_r __o

NaH, Mel

:Xh

78%

29a

THF

89%
[a]o -130 (c=2.1, EtOH)(S)-ethyl lactate\

NaH. BzlBr

OBzl
OH
:

:Xh

ll1F
53%

t
(X)

[a]o -45 (c=0 .96,CHCI 3 )/I

NaH, BzlBr

OBzl

~OH

•

THF

Et 2 0!

Y);

OH(S)-valine

.

NaN02
H2SO4

OH
:
OH

Y);

H2SO4

29c

./\
napll naph

91%
NH2

29b

OH

~OEt

EtOH

0

59%

65%

Mg+PhBr

3PhMgBr

QH•

61%

NaH, Mel

~OH

9Me
• ~OH

ll1F

PIl PhI _./\

30

PIl Ph73%

Mg+PhBrOH
ptiyOHoOH
ptiyOEt
EtOH

o3PhMgBr•

NaH, Mel

QH
p~OH

61%p~~h

ll1F

QMe
•

~OH
P _./\

31a

Pn Ph

93%

35%

[a]o -237 (c=1,CHCI 3 )\NaH. BzlBr

QBzl

ll1F

p~OH

60%

Scheme 1-6.

-33-

PIl Ph31b

The hetero Diels-Alder reaction of benzaldehyde with Danishefsky's diene wascarried out under various conditions by use of TiCI4-AgSbF6-chiral monoether ligand
system. The enantiomeric excesses of the products were determined by Daicel OD
column (n-hexane / i-PrOH = 50/ 1). At the beginning, the conditions to prepare thecomplexes were investigated. In method 1, the complexes were prepared by reaction of
the ligand with TiCl4 Ceq 1-22), and n-BuLi was used for abstraction of H+ of thehydroxyl group in the method 2 Ceq 1-23).

YTMS

Lewis acid Me 0--/1 ~PhCHO------------------~.~

OMe(Method 1)

H+?(H ---11,,TiCI4~

AgSbF 6-20 0C

~

-'p™S
PhCHO

(Method 2)

9Me

~OH

Meo-# ~

n-BuLi~(eq 1-22)

evaporated
in vacuo

TiCI 4

C H 2 CI 2~~

-20 °C -40 °C..

AgSbF 6AiAlo--II'fTMS
PhCHO

Me

'I ~

...

H+
~

~

(eq 1-23)

After a lot of experiments, the author found that n-BuLi (0.9 equiv. to the ligand)
was necessary to prepare the complex because only a small amount of the products was
obtained in the method 1. Other bases such as NaH were unproductive. In 1H NMR
in dry CDCl3, the signal of methyl protons of the methoxy group shifted to downfield
when titanium chloride was added to the ligand in solution as shown below. This factindicates the coordination of the methoxy group to the Ti atom occurred. Two couplesof the peaks were observed in the complex and the author reasoned that polymer-34-

complexes might exist. Attempt to isolate the Ti complex as solids failed because it wasan oil.

1H NMR in dry CDCI3~OR
Ph

proton 1 (ppm)Rproton 2 (ppm)-TiCI 3

5.27
4.90

3.84
3.40

-H

4.29

3.38

Ph

In order to optimize the reaction conditions, the effect of Lewis acids, the counter

anion of the silver salt, aging time, and the chiral monoether ligand were examined(Table 1-7). In these reactions, 0.9 equiv. of n-BuLi and TiC14 were used as describedabove to avoid the generation of cationic species other than 33 except for entry 6.

-35-

OR

~H

n-BuLi (0.9equiv. to theligand)C H 2CI 2 MCI 4 (0.9
AgSbF6 (2 equiv. toorequiv. tothe ligand)toluenethe ligand)- - - - -._. -20 °C - - - - - -- . 20 minoa, b

R' R'/ hexanel29a: R=Me, R'=Ph
29c: R=Bzl, R'=naph

JTMS

PhCHO

Meo--J~H+(eq 1-24)

Table 1-7.
chiral ligand

solvent

24-R:24-S

yield (%)

TiCI 4+AgSbF 6

29ahexane-CH 2Cl 2

65:35

48

2

TiCI 4+AgSbF 6

29chexane-CH 2Cl 2

54.5:45.5

48

3

SnCI 4+AgSbF 6

29ahexane-CH 2Cl2

52:48

55

4

TiCI4+AgCI04

29a

hexane-CH2Cl2

53.5:46.5

OO*a5

TiCI4+AgOTf

29ahexane-CH2Cl2

51:49

58

6

2(TiCI 4+AgSbF6)

29ahexane-CH 2Cl 2

50:50

E£)*c

7

TiCI 4+Ag SbF6

29ahexane-toluene

50:50

47

8

TiCI 4+AgSbF 6

29ahexane-CH 2Cl 2

54:46

47*b

entry

catalyst*a*a. stirredfor1hb*. stirredfor10min*c. Twice amount of TiCI 4 and AgSbFs compared to the general method was used.

The use of silver hexafluoroantimonate underwent the reactions with higher
selectivity (entry 1) in comparison with the use of other silver salts (entries 4 and 5).
Excess use of cationic species resulted in no stereoselectivity (entry 6). By the use ofhexane-toluene as a solvent, the selectivity was not observed (entry 7). The use of
SnCl4 instead of TiCl4 resulted in low selectivity (entry 3). The products in 30 %eewere obtained in entry 1, but partial decomposition of the chiral ligand was also
observed. In addition, extensive decomposition of the chiralligand was observed in the-36-case of the benzyl-protected ligand 29c (entry 2). In order to avoid the decomposition,
abstraction of chloride at lower temperatures might be necessary but it was rather
difficult. Therefore, other ligand systems 30 and 31a derived from (S)-valine ormandelic acid bearing a bulky substituent at the a -position of the alcohol were used (eq1-25, Table 1-8).

OR

N~OH

n-BuLi (0.9
TiCI 4 (0.9.
tthequiv . toeqUlv, a e C H CI
2 2ligand)the ligand)----------~.

RI RI/ hexane{3): R=Me, R'=Ph, RM=i-Pr
31a: R=Me, R'=Ph, RU=Ph

PhCHO

-20°C

AgSbF6 (2 equiv. toth e I'Igan d)•

20 ml'noa

yTMS
Me~ ~
H+
(eq 1-25)

Table 1-8.
catalyst (20 mol%)ligandsolvent

24-R :24-Syield (%)

TiCI 4 +AgSbF6

3)

hexane-CH 2CI2

50:50

57

2

TiCI 4 +AgSbF 6

31ahexane-CH 2CI2

50:50

3

TiCI 4 +AgSbF6

31a

hexane-CH 2Cl 2

50:50

entry

45 *a
51

*a , stirred for 1h

When the ligands 30 and 31a were used in the reaction, no selectivity was observed(entries 1-3, Table 1-8). This was unexpected results for the author because the chiraltransfer would be easier than the case of 29a because of the bulkiness of the asubstituent (Scheme 1-7).

-37-

Ph

Ph

vs.

bulkier

Scheme 1-7.

The author found that the ligands 30 and 31a decomposed completely when thesechiralligands were tried to be recovered. Even when these complexes were prepared at
low temperature (-78°C), total decomposition of the chiralligands was observed. The
cationic complexes must be very unstable under the reaction conditions.
In summary, the stereoselectivities up to 30 % ee were observed in hetero Diels-

Alder reaction of benzaldehyde with Danishefsky's diene by use of the novel cationicchiral monoether-TiCI4-AgSbF6 system (entry 1 in Table 1-7). However, theinstability of the chiralligands under the conditions to generate cationic species
prevented further elaboration of the system.

-38-

1-5. Aldol Reaction by Using the Novel Cationic Lewis Acids

A. Reaction with TiCl4-Chiral Diether Complexes

Various titanium complexes «R,R)-26a-e) could be prepared from (R,R)-20
with TiCl4 and isolated under Ar as yellow powder (Scheme 1-8). Preparation ofthese complexes needs careful experimental manipulation as mentioned before. The
TiC14-chiral diether complexes are thermally unstable and should be stored at -20 cC.
The complexes bearing longer alkyl chains as ether substituents such as n-hexyl could
not be isolated as solids.

TiC4(R,R)-20a: R=Me
(R,R)-20b: R=Bzl(R,R)-20c: R=Et
(R,R)-20d: R=n-Pr(R,R)-20e: R=n-Bu(R,R)-26a: R=Me
(R,R)-26b: R=Bzl(R,R)-26c: R=Et
(R,R)-26d: R=n-Pr(R,R)-26e: R=n-Bu

Scheme 1-8.
The aldol reaction of benzaldehyde and silyl enol ether 35 was canied out (Scheme
1-9)33 and the enantiomeric excesses of the products were determined by Daice! AS
column. After a lot of examinations concerning the aging time, the best result was
obtained when the aging time was ca.15-20 min at -20 cC. The results are shown in
Table 1-9.

-39-

(R,R)-26
34

Scheme 1-9.
Table 1-9. Aldol Reaction of Benzaldehyde and SHyl Enol Ether(35) By Using Titanium Tetrachloride-Diether Complexes «R,R )-26).

entry

R

36-R:36-S byield (0/0)

1a

Et

75:25

81

2a

n-Pr

76.5:23.5

76

3

Me

76.5:23.5

80

4

Et

77:23

86

5

n-Pr

78:22

82

a The complexes were prepared in situ.
b Enantioselectivity was determined by HPLC analysis (Daicel AS column, iPrOH:n-hexane=5:95) .

-40-

The reactions using the complexes (R,R)-26 without abstraction of a chloride ion
by silver hexafluoroantimonate proceeded to give aldol products in high yields but
without selectivity. It is necessary to abstract a chloride ion by the silver salt forstereoselection. 36-R could be obtained selectively in ratios of 75:25-78:22 (36R:36-S) when these complexes were used with silver hexafluoroantimonate. There

were little effects of the diether substituents on the selectivity, but the author reasoned
the chain-like ether substituents (n-alkyl substituents) extended toward the quasiequatorial direction in the coordinated conformation and did not affect the chiralenvironments. To overcome the problem, bulkier dibenzyl diether was used but its
TiCl4 complex was very unstable and decomposition occurred even at -20°C. In
addition to the reactions with the isolated complexes, the author also investigated thereactions with the complexes prepared in situ (entries 1 and 2) and found that there
was no change of the selectivity compared with the case of the isolated complexes.
The fact suggests the reaction will proceed selectively by the use of the complexes
prepared in situ without isolation of the complexes.

B. Reaction with TiCI3(OR)-Chiral Diether Complexes

TiCI3(OR)-chiral diether complexes (R,R)-37 were also prepared from (R,R)20 with TiCI3(OR) (eq 1-26, eq 1-27, and Scheme 1-10) and the aldol reaction was
carried out by using the complexes. Ti(OR)4 could be prepared from Ti(O-i-Pr)4 andROH at 130°C while the resulting isopropanol was distilled out (eq 1-26).3 4
TiCI3(OR) was prepared by disproportionation of titanium tetraalkoxide and titanium
tetrachloride at low temperatures. Attempt to prepare TiCI3(OR) at higher
temperatures underwent polymerization of titanium compounds which could not be
dissolved in the solvent. The appropriate temperature to prepare these TiCI3(OR)strongly depended on the substituents R (eq 1-27). These Ti(OR)4 and TiCI3(OR)were prepared and used under Ar. The chiral diether complexes (R,R)-37 could be
prepared by the similar method of TiCl4 complexes. However, TiCI3(O-an1yl)-chiral-41-diether complexes could not be prepared probably because of the steric hinderance of
the amyl substituent. TiCI3(OBzI) was tried to prepare, but decomposition occurred
even at -78°C.

Ti(O-i-Pr)4

+

4ROH

-------I~~

Ti (0 R)4+

4i-PrO H(R=neopentyl, cyclohexyl, diisopropylmethyl)(eq 1-26)

Ti(OR)4+(eq 1-27)

Pj-{h
R2o..

(R 1=alkyl-O-)

.,OR2
'~(

CI 3 X(R,R)-20a: R2=Me(R,R)-20b: R2=Bzl(R,R)-20c: R2=Et(R,R)-20d: R2=n-Pr(R,R)-20e: R2=n-Bu(R,R)-37a: R2=Me, R1=i-PrO(R,R)-37b: R2=Et, R1=i-PrO(R,R)-37c: R2=Et, R1 =EtO
(R,R)-37d: R2=Et, R1=cyclohexyloxy(R,R)-37e: R2=Et, R1=neopentyloxy(R,R)-37f: R2=Me,R 1=diisopropylmethyloxy

Scheme 1-10.

The aldol reaction by using these complexes proceeded smoothly to give products inexcellent yields as shown in Table 1-10. In addition, 36-R was the major product inall cases. The substituent R 1 was smaller, the selectivity of 36-R was higher. Judging
from the selectivities, the author proposes the reaction intermediate 38 in the reaction
with (R)l.)-37 (Scheme 1-11). In 38, strongly coordinating R 1 group prefer tooccupy the trans site to the weakly coordinating benzaldehyde. The strong electrondonating property of the R 1 group weakens the coordination of the benzaldehyde
reSUlting in the lower selectivity in the aldol reaction in comparison with the-42-corresponding TiCl4-chiral diether system. The modification of the chiral ligand
system will give higher selectivities, but still the novel cationic system is fo und to have
utility for some reactions.

OIMS~ Ph 35

H~

0

HO---I"~ p~ Ph + p M Ph
36-R

36-S

(R,R)-37

38

Scheme 1-11.

Table 1-10. Aldol Reaction of Benzaldehyde and Silyl Enol Ether (35)
By Using Titanium Alkoxytrichloride-Diether Complexes «R ,R)-37).

entry

Rl

R2

36-R :36-S byield (%)

1

O-i-Pr

Me

57.5:42.5

962

O-i-Pr

Et

61:39

95

3

O-cyclohexyl

Et

54:46

82

4

O-neopentyl

Et

57:43

88

5a

O-neopentyl

Et

55 :4581

6O-diisopropy lmethy 1

Me

52:48

91

7

O-ethyl

Et

61:39

93

a Reaction was carried out in dichloromethane-isobutyronitrile.
b Enantioselectivity was determined by HPLC analysis (Daicel AS column, i-PrOH :n-hexane=5:95).

-43-

1-6. Synthesis of the Modified Chiral Ligands

The author also synthesized the modified chiral hydrobenzoin for the chiralitytransfer system. The author selected (R,R)-1 ,2-bis(3,5-di-tert-butylphenyl)ethane-l ,2diol 44 which had not been synthesized yet. The model of the cationic Lewis acids 45
is shown in Scheme 1-13 and the author anticipated that the bulky tert-butyl substituentswould control the conformation of the benzaldehyde and would control the direction of
the nucleophilic attack toward the coordinated aldehyde.
The chiral diol 44 was prepared as follows: Friedel-Crafts alkylation of toluene
with t-BuCI in the presence of AICl3 afforded 1,3-di-tert-butyl-5-methylbenzene 39 35
and the resulting 39 was reacted with NBS to give 40 36 in 64 % yield. 39 was
oxidized to aldehyde 42 37 and the Wittig reaction of phosphonium bromide 41 and 42
afforded 43 38 which was obtained as a cis-trans mixture in a ratio of 1:25 in 56 0/0
yield. Some isomerization procedures were tried but yields were not good. The author
decided to conduct the next procedure without isomerization. Osmium oxidation of 43
by Sharpless method 28 was the best way to obtain the diol 44. Other reaction
conditions were tried but the products could be obtained in quite low yields . The
optical purity of the diol 44 was determined by Daicel column OD and it was 45 %ee(R). The optical resolution is possible by use of the column. The new chiral diol will

widen the utility as a chiralligand not only for the novel cationic Lewis acid system but
also for the Lewis acid system bearing the chiral diol.

-44-

NBS

CH2Br

CCI~

.J-.:,-

u6 ~4 t-B~t-BU

t-BuC~%AICI 3 t-B~ I t-Bu

31 %

39

40

1) NBS~)P2 :HO2) tetramine
H 0-EtOH
2~

t-BNt-Bu

42

47 %

+

. uCi

CH 2 PPh 3

PPh 3

40
94%

t-B

~

-B(
t-Bu

Wittig41
56 0/042
t-Bu
t-Bu t-Bu

t-Bu

0504

t-B

:B~~-

hydroquinidine-

4-chlorobenzoate

43

31 0/0Scheme 1-12.

-45-

O-t-BU

H

HO

44

OH

Scheme 1-13.

-46-

1-7. Structure of Chiral Diether-Coordinated Titanium Complexes

The titanium complexes (R;l)-26 and (R;l)-37 were prepared and isolated as
mentioned above. The complexes were quite unstable, but it was of interest to confirm
the structures because there was a possibility that the complexes were polymer. In tills
section, the author wishes to report the X-ray structures of (R,R)-26d and (R,R)37a. To confirm these structures, the crystals suitable for X-ray analysis wereprepared by recrystallization from dichloromethane and n-hexane in a freezer (-20°C).
The crystals of (R;l)-26 were thermally unstable as mentioned above but could be
handled under an Ar atmosphere in a glove bag at room temperature for a short period.
A single crystal of (R;l)-26d in a sealed capillary was used for X-ray diffraction
measurements at ca. -5°C, but even at this low temperature significant decomposition
took place during the measurement. Thus, the obtained data were not quite good
(R=9.50/o) but the position of the atoms could be determined. In contrast, crystals of(R,R)-37a were stable at room temperature and X-ray diffraction of a single crystalof (R,R)-37a could be measured at room temperature in a sealed capillary without
any problems. The obtained data showed very good quality (R=3.8 0/0). The ORTEP
drawings of (R,R)-26d and (R;l)-37a are shown in Figures 1-2 and 1-3, and theselected bond distances and angles are listed in Table 1-11. These structures show
six-coordinate geometry around the titanium center. To our delight the substituents (npropyl in (R,R)-26d and methyl in (R,R)-37a) on the ether oxygen atoms areoriented trans to the phenyl group on the neighboring carbon although these oxygen
atoms are not completely sp3 hybridized (the sum of the bond angles around theoxygen atoms are 347.4° and 355.6° in (R,R)-26d, and 345.7° and 347.1 ° in (R,R)37a).
The structure of (R,R)-37a is consistent with the reported principle that thestrongest ligand (Ti-O-i-Pr in (R,R)-37a) prefers a trans position to the weakest
ligand (Ti-O(ether)). The bond distance of Ti-O(isopropoxide) (1.707(5) A, d inTable 1-11) is comparable to the reported distances 1.742(6) A in [Ti(Oi-Pr)C15]2-,-47-

1.726(4) A in Ti(O-i-Pr)CI3(THF)2, 1.721(2) A in Ti(O-i-Pr)CI3(Et20)(PhCHO),
and 1.702(4) A in [Ti(O-i-Pr)CI2(Jl-CI)(OC(OMe)C6H5)]2.39 The distance between
Ti and the ether oxygen (2.226(5) A, a in Table 1-11) trans to the isopropoxide was
longer than that between Ti and the cis ether oxygen (2.138(4) A, b in Table 1-11).
The strong trans influence of the isopropoxide ligand has also been pointed out inTi(O-i-Pr)C13(Et20)(PhCHO) 10 and Ti(O-i-Pr)CI3(THF)2 11.23

Figure 1-2.

ORTEp· drawing of (R,R) -26d showing the thermal

ellipsoids at the 30 % probability level.

-48-

Figure 1-3.

ORTEP drawing of (R ,R)-37a showing the thermal

ellipsoids at the 30 % probability level.

-49-

Table 1-11. Selected Bond Lengths and Bond Angles for (R ,R) - 2 6 dand (R ,R )-37 a.

CI R

Ie \g0 ;

ab
ac
~Ti:b
.
ad
X
"0
'Ph
ae
f / h 26d: X=CI, R=n- Praf
CI R
37a: X=O-i-Pr,
ag
R=Me
ai
37a
26d
gi
bond lengths (A)bea
2 .1 4(2)2.226(5)bdb
2 .09 (2)2.138(4)bec2.21(1)
CII/,,c

'.

d
e
f

I

'!--~Ph2.22(1)2.30(1)2.27(1)2.267(3)1.707(5)2.315(3)2.339(3)

bf

bj
bh
jh

-50-

37a
26d
bond angles (deg)74.2(7)73.6(2)99.2(6)91.8(2)164.9(6)169.0(2)84.6(5)83.3(2)
83.7(2)84.8(5)119.8(4)120(2)
117(1)
115.3(4)110.6(5)111(2)
165.0(2)173 .4(6)95.5(2)90.7(6)86.3(2)87.8(6)83.3(2)85 .1(6)115.6(4)120(1)
117.9(4)
125(2)
113.6(5)111(2)

1-8. Summary

The exploitation of novel cationic Lewis acids was performed. From theexperiments as described above, the author found that titanium(IV) chloride andtitanium(IV) alkoxytrichloride were suitable for the asymmetric aldol reaction. In
addition, the titanium complexes (R,R)-26d and (R,R)-37a were isolated and thestructures were determined by X-ray analysis. These results will widen the chemistryof Lewis acids because the novel cationic Lewis acids will develop the potential for thereaction of unactivated substrates or reactants.

OTMS

J
35
~Ph

HQ
-

'Q

HO
0

----l.~ Ph"'~Ph + PhA....-A- ph
36-R

R 1 =CI or alkoxy2

R =alkyl

-51-

36-5

1-9. Experimental Section
General.
1H NMR spectra were recorded at 400 MHz (JEOL EX4(0) in CDCI3 . Chemical
shifts (b) are reported in ppm down field from internal tetramethy lsilane or fromresidual chloroform (b=7.26). The preparation of aldimines are described in Chapter
2. Monoether chiralligands were prepared according to the literature 32 and [a]D wereconsistent with the data in the literature. All reactions were conducted under Ar except
for the Os04 oxidation procedures.

[4+2JType Cycloaddition of Aldimine 60c with 2-S:ilyloxy-l,3butadiene 57a by Use of Cationic Lewis Acid.
To an isobutyronitrile (2 mL) solution of 60c (0.15 mL, 0.45 mmol) was added
isobutyronitrile (4 mL) solution of titanium tetrachloride (0.08 ml, 0.68 mmol) andsilver triflate (0.17 g, 0.69 mmol) at -30°C under nitrogen. Following the addition of

57a (0.45 mL, 1.8 mmol), the mixture was stirred at -30°C for 1 day. The reaction
mixture was poured into aq NaHC03 followed by extraction with CH2CI2 . The
combined organic layers were dried over MgS04, and the solvent was evaporated. The
residue was dissolved in THF and 1.8 mmol of TBAF (in THF solution) was added tothe solution. The reaction mixture was stirred for 10 h, quenched with water, extractedwith CH2Cl2, and the combined organics were dried over MgS04. After the solvent
was removed in vacuo, the crude product was separated by recycle HPLC (J AI LC
908, JAIGEL-IH and 2H, 1,2-dichloroethane). 74 mg, (49 0/0)

64b: colorless oil. IH NMR (CDCI3): b 0.60 (d, J = 6.3 Hz, 3H), 1.06 (d, J = 6.3
Hz, 3H), 1.70-1.85 (m, IH), 2.36-2.45 (m, IH), 2.70-2.85 (m, 2H), 2.98-3.10 (m,IH), 3.20-3.25 (m, IH), 3.62 (d, J = 14.0 Hz, IH), 3.58-3.63 (m, IH), 3.90 (d, J =14.0 Hz, IH), 4.63-4.70 (m, IH), 7.20-7.75 (m, 10H).

-52-

General Procedures for Diels-Alder Reaction of Mrethacrolein with
Cyclopentadiene.
To a stirred solution of the cationic Lewis acid (Lewis acid: AgSbF6: crural
diether=I:0.8:1, aging conditions are described in 1-3-B) was added methacrolein (lequiv. to the chiral diether) and cyclopentadiene (3 equiv. to thle chiral diether) at -78°C
and stirred for ca. 6 h. After usual work-up, the ratio of exo:endo was determined by
1H NMR. The product was acetalized according to the literature. 30

Diels-Alder adduct 21 (exo).

= 12.2 Hz), 0.94 (s, 3 H), 1.20-1.62 (m, 2 H), 2.75-2.82(m, 2 H), 3.17 (dd, 1 H, ) = 11.7, 4.0 Hz), 6.02-6.05 (m, 1 H), 6.21-6.24 (m, 1
IH NMR 0.68 (d, 1 H, )H), 9.60 (s, IH).
The peak of aldehyde proton of endo compound 22 is b 9.32 ppm.

Acetal 23-exo-1= 12.2,2.6 Hz), 0.82 (s, 3 H), 1.14 (d, 3 H, J = 6.5
Hz), 1.29 (d, 3 H, J = 6.5 Hz), 1.13-1.49 (m, 2 H), 1.15 (d, 3 H, J = 8.8 Hz),IH NMR 0.71 (dd, 1 H, )1.70-1.79 (m, 2 H), 2.63 (s, 1 H), 2.70 (s, 1 H), 3.87-3.92 (:m, 1 H), 4.19-4.30 (m,IH), 4.64 (s, 1 H), 6.02-6.10 (m, 2 H),.

Acetal 23-exo-2
1H NMR 0.71 (dd, 1 H, J = 11.7, 2.4 Hz), 0.84 (s, 3 H), 1.10-1.15 (m, 2 H), 1.17
(d, 3 H, J = 6.3 Hz), 1.33 (d, 3 H, J = 6.3 Hz), 1.57 (d, 1 H, J = 8.3 Hz), 1.64
(dd, 1 H, J = 12.2, 3.4 Hz), 1.76 (dt, 1 H, J = 12.2, 6.3 Hz), 2.72 (s, 2 H), 3.823.92 (m, 1 H), 4.22-4.32 (m, 1H), 4.68 (s, 1 H), 6.07-6.10 (m, 2 H),.

General Procedures for Hetero Diels-Alder Reaction of Benzaldehydewith Danishefsky's Diene by Using Monoether-Coordinated Titanium
Complex.

-53-

To a stirred solution of 29a (0.24 g, 1 mmol) in hexane (3 mL) was added n-BuLi(0.57 rnL, 0.9 mrnol) at 0 °C and the mixture was stirred for 15 min. CH2Cl2 (10 mL)
and TiCl4 (0.1 mL, 0.9 mrnol) was added to the solution and the temperature wascooled to -20°C. After stirring for 10 min, AgSbF6 (0.69 g, 2 mmol) in CH2Cl2 wasadded to the mixture and stirred for 20 min. Benzaldehyde (0.1 mL, 1 mmol) andDanishefsky's diene (0.39 rnL, 2 mmol) was added successively to the mixture andstirred for several hours. The work-up procedure was the same as that in theliterature. 31 The crude products were purified by column chromatography (hexane /CH3COOEt = 3 /2), and the enantiomeric excesses were detennined by Daicel OD
column (n-hexane / i-PrOH = 50/ 1).

General Procedure for the Preparation of Chiral Diethers.
(R,R)-l ,2-diphenylethane-1 ,2-dioI 28 and (R,R)-l ,2-diphenylethane-l ,2-diol

dimethyl ether3 were prepared according to the literatures. Other diethers wereprepared by modified Johnstone's method 29 as follows; To D:MSO (l00 mL) was
added powdered KOH (22 g) at r.t.. After stirring for ca. 5 min, (R,R)-l ,2diphenylethane-l,2-diol 10.6 g (50 rnmol) in DMSO (50 mL) and alkyl halide ( 199mmol) were added to the solution successively (alkyl halide was added very slowly
because of the exothermic reaction). The reaction mixture was stirred for 1 day at r.t.
and was treated with H20. The mixture was extracted with dichloromethane, and the
combined organics were washed with water. After the solvents were evaporated, thecrude products were purified by column chromatography (Merck silica gel 7734: ether /n-hexane = 1 / 5).

(R ,R)-1,2-Diphenylethane-l,2-diol Dimethyl Diether (R,R )-20a.

IH NMR 3.34 (s, 6 H), 4.70 (s, 2 H), 7.13-7.27 (m, 10 H).

(R,R)-1,2-Diphenylethane-l,2-diol Dibenzyl Diether (R ,R)-20b.

-54-

IH NMR 4.38 (d, 2 H, J = 12.0 Hz), 4.58 (d, 2 H, J = 12.0 Hz), 4.59 (s, 2 H),
7.10-7.35 (m, 10 H) .

(R,R )-1,2-Diphenylethane-l ,2-diol Diethy I Diether (R,R) - 20c.

IH NMR 1.26 (t, 6 H, J

= 6.8 Hz), 3.50-3.59 (m, 4 H), 4.55 (s, 2 H), 7.17-7.40(m, 10 H).

(R,R )-1,2-Diphenylethane-l ,2-diol

IH NMR 0.99 (t, 6 H, J

Di-n -propyl Dielther (R,R) - 20d.

= 7.2 Hz), 1.65-1.72 (m, 4 H), 3.39-3.49 (m, 4 H), 4.53

(s,2 H), 7.16-7.50 (m, 10 H).

General Procedures for the Preparation of TiCl4-Diether Complexes.
To a stirred solution of diether (19 mmol) in dry dichloromethane (15 mL) was
added TiCl4 (12.7 mmol) very slowly at -20°C. After stirring for a few minutes, dry
n-hexane (ca. 50-100 mL) was added to the solution. The yellow precipitates were
filtered by using glass wool and washed with dry n-hexane. The (R,R)-l ,2diphenylethane-l,2-diol dialkyl diether (yellow powder) was collected under argon andwas dried in vacuo (The powder was unstable at r.t. and moisture sensitive so that
rapid manipulation was necessary !).

TiCI4-(R ,R)-1,2-Diphenylethane-l,2-diol Dimethyl Diether Complex(R,R)-26a.

IH NMR 3.81 (s, 6 H), 5.20 (s, 2 H), 7.20-7.40 (m, 10 H).
TiCI4-(R ,R)-1,2-Diphenylethane-l,2-diol Diethyl Di,!ther Complex(R,R)-26c.

IH NMR 0.87 (t, 6 H, J = 6.6 Hz), 4.12-4.16 (m, 2 H), 4.61-4.64 (m, 2 H), 5.46(s, 2 H), 7.25-7.40 (m, 10 H).
TiCI4-(R ,R)-1,2-Diphenylethane-l,2-diol Di-n -propyl Diether Complex(R,R)-26d.

-55-

IH NMR 0.56 (t, 6 H, J

= 7.4 Hz), 1.88-1.91 (m, 2 H), 1.43-1.51 (m, 2 H), 3.81-

3.89 (m, 2 H), 4.42-4.48 (m, 2 H), 5.42 (s, 2 H), 7.18-7.31 (m, 10 H).

TiCI4-(R ,R)-1,2-Diphenylethane-l,2-diol Di-n -butyl Diether Complex(R,R) -26e.

IH NMR 0.59 (t, 6 H, J = 7.3 Hz), 0.76-1.19 (m, 4 H), 1.34-1.45 (m, 2 H), 1.741.88 (m, 2 H), 3.88 (dt, 2 H, J = 4.9, 11.7 Hz), 4.45 (dt, 2 H, J = 4.9, 11.7 Hz),5.40 (s, 2 H), 7.20-7.28 (m, 10 H).

General Procedures for the Preparation of Ti(OR)4.
Ti(OR)4 were prepared according to the literature 34 except for Ti(OEt)4.

Ti C13( O-i- propy I)
1H NMR 1.55 (d, 6 H, J

= 5.8 Hz), 5.16-5.20 (m, 1 H).

TiCI3(OEt)
IH NMR 1.64 (t, 3 H, ]= 7.0 Hz), 4.90-4.95 (m, 2 H).

TiCI3(0-cyclohexyl)
1H NMR 1.41-1.54 (m, 4 H), 1.86-1.94 (m, 4 H), 2.00-2.11 (m, 2 H), 4.95-5.05(m, 1 H).

TiCI3(0-neopentyl)
1H NMR 1.10 (s, 9 H), 3.85-3.91 (m, 2 H).

TiC I3(0-diisopropylmethyl)
1H NMR 1.08 (d, 6 H, ]= 6.5 Hz), 1.17 (d, 6 H, J = 6.5 Hz), 2.07-2.16 (m, 2 H),

4.50 (t, 1 H, J = 5.8 Hz).

General procedures for the preparation of TiC13(OR)-diether complexes were similar
to those for TiC14-diether complexes.

-56-

TiCI3(O-i-Pr )-(R ,R)-1,2-Diphenylethane-l,2-diol Dimethyl Diether
Complex (R,R)-37a.
IH NMR 1.56 (d, 3 H, J = 5.8 Hz), 1.59 (d, 3 H, J = 5.8 Hz), 3.56 (s, 3 H), 3.79
(s,3 H), 5.01 (d, 1 H, J = 9.9 Hz), 5.10 (d, 1 H, J = 9.9 Hz), 5.38-5.45 (m, 1 H),
7.09-7.24 (m, 10 H).
TiCI3(O-i-Pr)-(R,R )-1,2-Diphenylethane-l,2-diol Diethyl Diether

Complex (R,R)-37b.
1H NMR l.03-l.11 (m, 6 H), l.47 (d, 3 H, J = 6.4 Hz), l.49 (d, 3 H, J = 6.4 Hz),3.65-3.80 (m, 1 H), 3.95-4.05 (m, 1 H), 4.15-4.25 (m, 1 H), 4.40-4.50 (m, 1 H),
5.12 (d, 1 H, J = 8.0 Hz), 5.26 (d, 1 H, J = 8.0 Hz), 5.29-5.33 (m, 1 H), 7.00-7.20(m, 10 H).

TiCI3( 0 Et)-(R,R )-1,2-Diphenylethane-l,2-diol Dietltlyl Diether
Complex (R,R)-37c.
1H NMR l.20-l.28 (m, 6 H), 1.64 (t, 3 H, J = 6.8 Hz), 3.81-3.85 (m, 1 H), 4. 154.19 (m, 1 H), 4.39-4.43 (m, 1 H), 4.61-4.66 (m, 1 H), 5.15 (q, 2 H, J = 6.8 Hz),5.29 (d, 1 H, J = 10.3 Hz), 5.39 (d, 1 H, J = 10.3 Hz), 7.10-7.40 (m, 10 H) .

TiCI3 (O-cyclohexy I)-(R,R )-1 ,2- Di pheny lethane-l ,2-diol Diethy I
Diether Complex (R,R)-37d.
IH NMR 1.20-l.50 (m, 10 H), l.70-2.05 (m, 4 H), 2.25-2.33 (m, 2 H), 3.85-3.93(m, 1 H), 4.15-4.26 (m, 1 H), 4.37-4.50 (m, 1 H), 4.60-4.72 (m, 1 H), 5.23 (d, 1
H, J = 8.0 Hz), 5.30-5.40 (m, 1 H), 5.42 (d, 1 H, J = 8.0 Hz), 6.95-7.60 (m, 10
H).

Ti Cl3 ( 0 -n e 0 pen t y I) - (R ,R ) -1,2 -Dip he n y let han e -1,2 -d i 0 I Die thy I Die the rComplex (R ,R)-37e.
1H NMR 1.15 (s, 9 H), 1.25-1.35 (m, 6 H), 3.83-3.88 (m, 1 H), 4.18-4.22 (m, 1
H), 4.36-4.41 (m, 1 H), 4.62-4.67 (m, 1 H), 4.88 (s, 2 H), 5.33 (d, 1 H, J = 9.8
Hz), 5.40 (d, 1 H, J = 9.8 Hz), 7.05-7.35 (m, 10 H).

-57-

TiCI3(O-diisopropylmethyl)-(R ,R)-l ,2-Diphenylethane-l,2-diol
Dimethyl Diether Complex (R ,R)-37f.
1H NMR 1.16 (d, 3 H, J = 6.8 Hz), 1.23 (d, 3 H, J = 7.3 Hz), 1.35 (d, 3 H, J =6.8 Hz), 1.40 (d, 3 H, J
H), 4.60 (t, 1 H, J

= 6.8 Hz), 2.22-2.29 (m, 2 H), 3.59 (s, 3 H), 3.83 (s, 3= 5.3 Hz), 5.03-5.06 (bm, 1 H), 5.20-5.22 (bm, 1 H), 7.10-7.40(m, 10 H).

General Procedures for Aldol Reactions of Benzaldehyde with SHyl
Enol Ether by Using Titanium Complex.
To a stirred solution of the titanium complex (1.3 mrnol), molecular sieves 4A (30mg), and 2,6-di-tert-butyl-4-methylpyridine (1 drop) in dry CH2Cl2 (3 mL) was added
silver hexafluoroantimonate (1.9 mrnol) in dry CH2Cl2 (2 mL) at -20°C. After
stirring for 15 min, the temperature was cooled to -78 °C and the mixture was stirred
for 20 min. Benzaldehyde (1.3 mrnol) and silyl enol ether (2.5 mrnol) were added tothe solution successively and the mixture was stirred overnight at the same
temperature. The reaction mixture was quenched with 1M HC!, and the mixture was
extracted with ether. The organics were dried over Na2S04, and the solvents were
evaporarted to give crude aldol products. The products were purified by column
chromatography (Merck silica gel 7734: gradient elution, CH3COOEt / n-hexane = 1 /5 -100/ 0). The products were identified according to the literature. 10 The
enantioselectivity was determined by HPLC (Daicel Chiralcel AS, i-PrOH:n-hexane =5:95).

General Procedure for Aldol Reaction of Benzaldehyde with SHyl Enol
Ether by Using Titanium Complex Prepared in situ.
To a stirrded solution of diether (1.5 mmol), molecular sieves 4A (30 mg), and 2,6di-tert-butyl-4-methylpyridine (1 drop) in dry CH2Cl2 (3 mL) was added 1 mmol oftitanium tetrachloride at -20°C. After stirring for 2 min, silver hexafluoroantimonate-58-

(1.5 mmol) in dry CH2Cl2 (2 mL) was added dropwise to the :~olution at -20 °C. Afterthe mixture was stirred for 15 min, the temperature was cooled to -78 °C and thereaction mixture was stirred for 20 min. The procedures of the aldol reaction were thesame as above.

Synthesis of (R,R )-1,2-Bis(3,S-di-tert-butylphenyl)e~thane-l,2-diol

Preparation of 1,3-Di-tert-butyl-S-methylbenzene

44.

39~.

To a stirred solution of toluene 96 mL (0.9 mol) and t-BuCI 196 mL (1.8 mol) was
added dropwise AICl3 4.7 g (0.035 mol) over half day and the reaction mixture wasstirred for 1 day. The mixture was poured into ice-HCI ag. slowly and the organics
were evaporated. The crude product was purified by vacuum distillation (78-80 °C /1.4 mmHg). colorless oil, 170.3 g (31 0/0)
1H NMR 1.40 (s, 18 H), 2.40 (s, 3 H), 7.08 (s, 2 H), 7.30 (s, 1 H).

Preparation of 1-(Bromomethyl)-3,S-di-tert-butylbenzene 40.
A mixture of 147 g (0.7 mol) of 1,3-di-tert-butyl-5-methylbenzene 39, 128 g (0.7mol) of N-bromosuccinimide, and 200 mL of CCl4 was heated under reflux for 18 h.
The mixture was allowed to cool to r.t. and was filtered through Celite. The filtrate
was concentrated and the residual oil was distilled through a Vigreux column (120-125°C / 6 mmHg). colorless oil, 128 g (64 %)1H NMR 1.40 (s, 18 H), 4.55 (s, 2 H), 7.30 (s, 2 H), 7.45 (s, 1 H).

Preparation of 3,S-Di-tert-butylbenzyl Phosphonium Bromide 41.
A mixture of PPh3 (122 g, 0.47 mol) and 1-(bromomethyl)-3,5-di-tert-butylbenzene
40 (128 g, 0.47 mol) in toluene (1 L) was heated at 80°C for 2 h and cooled to r.t..
The mixture was concentrated and the residual solid was washed with ether. The whitesolid was dried in vacuo to give the product. white powder, 237 g (94 0/0)
1H NMR 1.36 (s, 18 H), 7.70-7.73 (m, 3 H), 10.00 (s, 1 H).

-59-

Preparation of 3,5-Di-tert-butylbenzaldehyde 42.
A solution of 131 g (0.64 mol) of 39, 171 g (0.96 mol) of N-bromosuccinimide,
and 0.57 g of benzoyl peroxide in 400 mL of CCl4 was heated! to reflux for 4 h. After
filtration, the solvent was evaporated. The residue was added to a solution of 246 g(1.8 mol) of tetramine in H20 (170 mL) and EtOH (170 mL), and the solution washeated to reflux for 4 h. Then 114 mL of concentrated HCI was added to the mixture
and refluxing was continued for 30 min. The organic product was isolated as usual toyield a residue which was recrystallized from petroleum ether to give the aldehyde 42.
colorless crystals, 66 g (47 0/0)
IH NMR 0.75 (s, 18 H), 4.88 (d, 2 H, J

= 14.2 Hz), 6.50 (s, 2 H), 6.95 (s, 1 H),

7.31-7.46 (m, 15 H).

Preparation of (E)-1,2-Bis(3,5-di-tert-butylphenyl)ethene 43.
A vigorously stirred suspension of the phosphonium salt 4]l (0.44 mol) in THF(lL) was added dropwise n-BuLi (265 mL, 0.44 mol) at 0 DC. The dark-red solution
was stirred for 10 min, the aldehyde 42 (97 g, 0.44 mol) in THF solution (ca. 1 L)
was added to the solution at -10 DC. The mixture was allowed to warm to room
temperature over 0.5 h, and stirred for a further 0.5 h. The mix.ture was concentrated,
treated with ether, and the resulting suspension was filtered through a short column(silica gel). Evaporation of the elute gave a crude product which was purified bycolumn chromatography. white powder, 100 g (56 %)1H NMR 1.37 (s, 36 H), 7.12 (brm, 1 H), 7.25 (brm, 1 H), 7.30-7.38 (m, 6 H).

Preparation of (R,R )-1 ,2-Bis(3,5-di-tert- buty Ipheny l)ethane-l ,2-diol44.
To a stirred solution of 43 (0.84 g, 2.1 rnmol), N-methylmorpholine-N-oxide in
H20 solution (0.72 g, 3.1 mmol), hydroquinidine-4-chlorobenzoate (47 mg, 0.10mmol) in acetone was added Os04 (ca. 2.5 mg) at 0 DC. The mixture was stirred for 4
DC for 33 h and usual work-up gave the crude product. The crude product was purified-60-

by recrystallization (EtOH). white powder, 0.38 g (33 0/0), [a]D=+2.4. When the 38
g of 43 was used, the [a]D was changed and 45 % ee of 44 was obtained (Daicel OD
column).
1H NMR 1.18 (s, 36 H), 4.66 (s, 2 H), 7.18 (s, 4 H), 7.26 (s, 2 H).

X-ray Structure Determination of 26d and 37a.
Crystal data and numeric details of the structure determinations are gi ven in Table 4.
Crystals in sealed capillaries suitable for X-ray structure detemunation were mounted
on a Mac Science MXC3 diffractometer and irradiated with graphite-monochromated
Mo Ka radiation (A. = 0.71073 A) for data collection. Lattice parameters were
determined by least-squares fitting of 31 reflections with 44° < 28 < 50° and 40° < 28

< 50° for 26d and 37a, respectively. Data were collected with the 28/ro-scan mode.
All data were corrected for absorption.3 9 The structures were solved by a direct
method with the SIR 92 program40 in the Crystan-GM package. Refinement on F
was carried out by full-matrix least squares. All non-hydrogen atoms were refinedwith anisotropic thermal parameters except for C(7) and C(8) in 26d. These carbon
atoms were refined with isotropic thermal parameters. All hydrogen atoms in 26d and

37a were included in the refinement on calculated positions (C·-H = 1.0 A) riding on
their carrier atoms with isotropic thermal parameters. All the computations werecarried out on a Indigo 2 computer. Crystallographic data, bond distances and angles,
and atomic coordinates are shown in Table 1-12 (26d and 37a), 1-13, 1-14, 1-15(26d), 1-16,1-17,1-18 (37a).

-61-

Table 1-12. Selected Crystallographic Data for 26d and 37a.

No

26d

37a

formulaC20H2602Cl4Ti

Cl9H2S03Cl3Ti

mol wt

488.1

455.7

cryst syst

orthorhombic

orthorhombic

space group

P2j2j2j

P2j2j2j

cryst dimens, mm

0.85 x 0.55 x 0.25

0.55 x 0.50 x 0.35

a,A

13.42 (1)13.656 (2)b,A

15.84 (1)14.748 (3)c,A

10.982 (9)11.047 (2)u, deg90

90p, deg90

90"f, deg

90

90

V, A3

2334 (3)2225 (7)Z

44

Deale, g cm- 3

1.39

1.36

abs coeff, cm- l

75.58

68.105-62-

F(OOO)

1008

944

radiation; A, A

Cu Ka, 1.54178

Cu Ka, 1.54178

temp,OC

-5±1

23±1

28 max, deg

130

1310

scan rate, deg/min

2 .5

1.0

linear decay, 0/0

10data collected+h,+k,+l+h ,,-k,+l

total data coIled, obsd

22 19, 1138 (I> 3 0 (I) )2177, 1662 (I>30(I))

R int

0 . 189

0 .023no of params refined

234

260

R, Rw, sa

0.095, 0.107, 4.356

0.038, 0.039, 1.230

max shift in final cycle

0.4495

0.975

final diff maE, max, e/A3

0.81

0 .36

a Function minimized was sum [w(lFoI2_IFcI 2 )2] which w= l.O/[(aIFoI2+0 .0003IFoI2]. R= L[(IIFol IFcll)ILIFol. RW=[LW(IFol-IFcl)21LIFoI2) 112 .

-63-

Table 1-13.

Bond Distances of 26d.

Intramolecular Distances (A) with e.s.d. inparentheses
atom

atom

Til
C14
Til
C13
Til
Cl1
Til
C12
Til
02
Til
01
02
C8
02
C4
01
C7
01
C8
01
C1
C9
C14
C9
C10
C9
C7
C11
C9
C15
C20
C15
C16
C15
C8
C15
C19
C15
C17
C10
C14
C14
C12
C14
C13
C10
C12
C10
C11
C20
C19
C20
C18
C16
C17
C7 --- C8
C12 --- C11
C12 --- C13
C4 --- C5
C11C13
C19 --- C18
C19 --- C17
C18 --- C17
C1
C2
C1
C3
C5
C6
C2
C3

distance
2.297 (9)2.274 (9)2.211 (9)2.223 (10)2.087 (18)2.140 (16)1.45 (4)1.48 (4)1.49 (3)2.37 (3)1.51 (4)1.37 (4)1.33 (4)1.47 (4)2.35 (4)1.36 (4)1.44 (4)1.50 (4)2.36 (5)2.40 (4)2.31 (4)2.27 (5)1.37 (5)2.37 (5)1.38 (5)1.40 (5)2.33 (6)1.41 (5)1.53 (4)1.39 (6)1.32 (5)1.50 (5)2.39 (5)1.23 (6)2.31 (6)1.44 (6)1.43 (5)2.36 (6)1.50 (6)1.31 (6)-64-Table 1-14. Bond Angles of 26d ..
Intramolecular Angles (degrees) with e.s.d. lnparentheses
atom

atom

atom

C14
Til
C13
Til
C14
Cl1
C14
Til
C12
Til
C14
02
Til
C14
01
Til
C13
Cl1
C13
Til
C12
C13
Til
02
Til
C13
01
Cl1
Til
C12
Cl1
Til
02
Cl1
Til
01
C12
Til
02
Til
C12
01
02 --- Til --- 01
Til --- 02 --- C8
Til --- 02 --- C4
C8 --- 02 --- C4
Til --- 01 --- C7
Til --- 01 --- C8
Til --- 01 --- C1
C7 --- 01 --- C8
C7 --- 01 --- C1
C8 --- 01 --- C1
C14
C9
C10
C14
C7
C9
C14 --- C9 --- C11
C10 --- C9 --- C7
C10 --- C9 --- C11
C7 --- C9 --- C11
C20
C15
C16
C20
C8
C15
C20
C15
C19
C17
C20
C15
C16
C15
C8
C16
C15
C19
C17
C16
C15
C8 --- C15 --- C19
C8 --- C15 --- C17
C19 --- C15 --- C17
C9 --- C14 --- C10
C9 --- C14 --- C12
C9 --- C14 --- C13
C10 --- C14 --- C12
C10 --- C14 --- C13
C12 --- C14 --- C13
C9 --- C10 --- C14
C9 --- C10 --- C12
C9 --- C10 --- C11
C14 --- C10 --- C12

angle
168.5
92.4
94.8
87.8
84.6
93.6
94.3
85.1
84.8
95.9
173.4
99.2
90.7
164.9
74.2
120.0
125.1
110.5
116.6
86.0
119.7
38.8
111.1
149.8
118.1
122.2
87.8
119.4
30.3
149.5
122.3
118.4
31.9
89.9
119.0
90.4
32.5
150.0
151.5
58.1
30.5
92.9
124.6
62.4
94.2
31.9
31.4
89.4
120.4
58.0

-65-

(4 )
(4 )
(4 )
(6 )
(5 )
(4 )
(4)
(6 )
(5 )
(4 )
(6 )
(6 )
(6 )
(6 )
(7 )
(14)
(16)
(20 )
(13)
(9 )
(17)
(13)
(19)
(17)
(24)
(23)
(19)
(24)
(17 )
(21 )
(25 )
(25)
(18)
(20 )
(21 )
(19)
(15)
(21 )
(20)
(15)
(14)
(19)
(26 )
(13)
(20 )
(17 )
(15)
(19)
(28 )
(12)

C14
C12
C15

C10
C10
C20

C11
C11
C19

89.0 (22)31.0 (19)117.2 (29)Intramolecular Angles (degrees) with e.s.d. In
parentheses (contd)
atom

atom

atom

C15
C20
C18
C19
C20
C18
C15
C16
C17
01 --- C7 --- C901 --- C7 --- C8
C9 --- C7 --- C8
C14
C12
C10
C14
C12
C11
C14
C12
C13
C10
C12
C11
C10
C12
C13
C11
C12
C13
02
C8
01
02
C8
C15
02
C8
C7
01
C8
C15
01
C8
C7
C15 --- C8 --- C702
C4 --- C5
C9 --- C11 --- C10
C9 --- C11 --- C12
C9 --- C11 --- C13
C10
C11
C12
C10
C11
C13
C12
C11
C13
C15
C19
C20
C15
C19
C18
C15
C19
C17
C20
C19
C18
C20
C19
C17
C18
C19
C17
C14
C12
C13
C14
C13
C11
C12
C11
C13
C19
C20
C18
C17
C20
C18
C19
C17
C18
01 --- C1 --- C2
01 --- C1 --- C3
C2 --- C1 --- C3
C16
C15
C17
C19
C15
C17
C18
C15
C17
C16
C19
C17
C16
C18
C17
C18
C19
C17
C4
C6
C5
C1 --- C2 --- C3

angle
91.9
25.5
114.1
117.2
103.7
114.0
59.6
90.3
33.3
30.7
92.9
123.5
79.7
116.8
110.7
148.0
37.5
111.8
115.9
29.2
89.0
61.6
118.3
90.8
27.5
30.9
94.3
61.9
125.0
92.8
32.8
114.9
85.9
29.0
29.5
90.8
119.8
112.6
100.1
28.9
33.4
60.1
87.3
93.3
120.6
27.4
112.5
119.0

-66-

(22)
(20)
(24 )
(20)
(19)
(21 )
(13)
(21 )
(17)
(16)
(22)
(30)
(14)
(20)
(20 )
(19)
(12)
(22)
(24)
(16)
(21 )
(13)
(29 )
(22)
(17)
(16)
(29)
(14)
(35)
(22 )
(25)
(27)
(19)
(18)
(21 )
(25)
(38)
(28)
(21 )
(21 )
(15)
(13)
(22)
(21 )
(29)
(21 )
(28 )
(37)

C1 --- C3 --- C2

32.1 (22)-67-

Table1-15.

AtomicCoordinates

of

26d.

positional parameters and equivalent isotropic thermal
parameters with e.s.d. in parentheses

atom

x

Til

1.0697 ( 3 )-0.0179 (3 )0.2794

(4 )

0.047

(3 )

C14

0.9237 (5 )0.0526 ( 6 )0.2393

(6 )

0.073

(5 )

C13

1.2185 (5 )-0.0676 ( 5 )0.3479(8 )0.066 ( 5 )Cl1

1.1243 ( 6 )-0.0002

C12

1.0055 (7 )-0.1456 ( 5 )021.0267 (13)-0.021701

U (eq)zy

0.0911 ( 7 )

0.077

(6 )

0.2487

(9 )

0.087

(6 )

(9 )

0.4619

(15)

0.05

(1 )

1.1171 (11)0.0996 ( 9 )0.3562

(15)

0.03

(1 )

C9

1.1028 (18)0.2018 (15)0.5314(23)

0.04 (2 )C15

0.9694 (16)0.0660 (16)0.6395(25)

0.04 (2 )C14

1.195 (2 )0.198 (2 )0.584 (2 )

0.04

(2 )

C10

1.055 ( 2 )0.276 ( 2 )

0.533

0.06

(2 )

C20

0.8715 (18)0.0730 (22)0.6093

(28)

0.07

(2 )

C16

1.0027 (18)0.06270.7645 (27)

0.05

(2 )

C7

1.0601 (19)0.1308 (16)0.4632

0.045

(7 )

C12

1.191 (2 )0.336 (2 )0.641 ( 3 )

0.06

(2 )

C8

1.0434 (17)0.05130.5398

0.044

(7 )

C4

1.017 (2 )-0.100 (2 )

0.536

(3 )

0.07

(2 )

C11

1.098 ( 3 )0.345 (2 )

0.587

(3 )

0.08

(2 )

C19

0.803

(2 )

0.080 (3 )

0.705

(4: )

0.09

(3 )

C13

1.240 (2 )

0.263

(2 )

0.644 (3 )

0.07

(2 )

C18

0.825 ( 3 )0.089 (3 )0.812 ( 4 )

0.09

(3 )

Cl

1.146 (2)0.171 (2 )

0.273

(3 )

0.07

(2 )

C17

0.927

(3 )

0.077 (2 )0.851 (3 )

0.07

(3 )

C5

0.916 (2 )-0.140 (2 )0.537 (3 )

0.07

(2 )

C2

1.247 ( 3 )0.164 ( 3 )0.230 (3 )

0.11

(3 )

C6

0.919

(3 )

-0.231 ( 3 )0.575 (3 )

0.10

(3 )

C3

1.320 (3 )(3 )0.307 ( 5 )

0.13

(4 )

0.173

(6 )

(18)

(17)

-68-

(3 )

(23)

(23)

Table 1-16.Bond Distances of

37a.

Intramolecular Distances (A) with e.s.d. In
parentheses
atom

atom

Cl1 --- Til
C12 --- Til
C13 --- Til
01
Til
02
Til
03
Til
C1
01
C2
02
C3
C4
C3
C5
01
C3
C3
02
C4
C11
C4
01
C4
02
C5
C6
C5
C9
C5
C10
C6
C7
CB
C7
C7
C9
CB
C9
CB
C10
C9
C10
C11
C12
C11
C13
C11
C15
C11
C16
C12
C13
C12
C14
C12
C16
C13
C14
C13
C15
C14
C15
C14
C16
C15
C16
C17
C18
C17
C19
c17
03
C18
03
C19
03

distance
2.267 (3)2.339 (3)2.315 (3)2.226 (5)2 . 138 (4)1.707 (5)1.471 (8)1.455 (8)1.495 (9)1.513 (9)1.464 (8)2.382 (8)1.524 (9)2.355 (7)1.455 (8)1.382 (10)2.388 (12)1.382 (10)1.412 (12)1.378 (15)2.386 (14)1.364 (15)2.389 (14)1.384 (14)1.372 (9)2.382 (10)2.393 (10)1.372 (9)1.363 (10)2.375 (10)2.359 (10)1.387 (12)2.373 (12)1.350 (12)2.361 (11)1.378 (11)1.408 (19)1.39 (3)1.414 (14)2.352 (16)2.40 (3)-69-Table 1-17.

Bond Angles of 37a.

Intramolecular Angles (degrees) with e.s.d. inparentheses
atom

atom

atom

angle

C4
C3
C5
C4
C3
01
C4
C3
02
C5
C3
01
C5
C3
02
01
C3
02
C3
C4
C11
C3
C4
01
C3
C4
02
C11 --- C4 --- 01
C11 --- C4 --- 02
01
C4
02
C3
CS
C6
C3
CS
C9
C3
C5
C10
C6
C5
C9
C6
C5
C10
C9
C5
C10
CS
C6
C7
C6
C7
C8
C6
C7
C9
C8
C7
C9
C7
C8
C9
C7
C8
C10
C9
C8
C10
C5
C7
C9
C5
C9
C8
C5
C9
C10
C7
C9
C8
C7
C9
C10
C8
C9
C10
C5
C10
C8
C5
C10
C9
C8
C10
C9
C12
C4
C11
C13
C4
C11
C4
C11
C15
C4
C11
C16
C13
C12
C11
C12
C15
C11
C16
C12
C11
C15
C13
C11
C16
C13
C11
C16
C11
C15
C13
C12
C11
C14
C11
C12
C16
C11
C12
C14
C13
C12
C16
C13
C12
C16
C12
C14
C12
C11
C13
C14
C11
C13
C15
C11
C13
C14
C13
C12
C15
C12
C13

111.7
105.4
35.6
112.2
146.8
81.9
110.6
36.8
107.7
146.9
111.6
83.0
120.3
149.4
119.0
90.3
120.6
30.4
119.4
119.0
89.7
29.4
120.9
91.0
29.9
60.7
90.4
30.3
29.7
91.0
120.7
89.9
119.3
29.4
120.3
149.6
150.8
121.2
29.3
88.9
118.5
59.6
89.2
29.6
121.1
90.5
30.7
30.6
90.4
59.8
29.5
89.9
60.4
119.4
90.0

-70-

(5 )

(5 )
(3 )
(5 )
(S )
(4 )
(5 )
(3 )
(5 )
(5 )
(5 )
(4 )
(6 )
(6 )
(7 )
(6 )
(7 )
(5 )
(8 )
(8 )
(6 )
(6 )
(10)
(7 )
(6 )
(4 )
(7,)
(5 )
(6 )
(6 )
(9 )
(6 )
(8 )
(6 )
(6 )i
(5 )
(5 )
(6 )
(4 }I
(5 )
(6 )
(3 )
(5 )
(4 )
(7 )
(5 )
(4)
(5 )
(5 )
(4 )
(4 )
(6 )
(3 )
(7 )
(6 )

C14 --- C13 --- C15
29.5 ( 5 )Intramolecular Angles (degrees ) with e.s.d. lnparentheses
atom

atom

atom

angle

C12
C14
C13
C12
C14
C15
C12
C14
C16
C13
C1 4
C15
C1 3
C1 4
C1 6
C15
C1 4
C16
C11
C15
C13
C11
C15
C14
C11
C15
C1 6
C13
C15
C1 4
C13
C15
C16
C14
C15
C16
C11
C16
C1 2
C11
C16
C14
C11
C16
C15
C12
C16
C14
C12
C16
C15
C14
C16
C15
C18
C17
C19
C18
C17
03
C19
C17
03
C17
C18
03
C17
C19
03
C1
01
C3
C1
01
C4
C1
01
Til
C3
01
C4
C3
01
Til
C4
01
Til
C2
02
C3
C2
02
C4
C2
02
Til
C3
02
C4
C3
02
Til
C4
02
Til
C17
03
C18
C17
03
C19
C17
03
Til
C18
03
C19
C18
03
Til
C19
Til
03
CII
Til
C12
Cl1
C13
Til
Cl1
01
Til
Cl1
02
Til
Cl1
Til
03
C13
Cl2
Til
Cl2
Til
01
Cl2
02
Til
Til
03
C12
01
C13
Til
Cl3
02
Til
03
C13
Til
02
01
Til
01 --- Til - - - 03

30.0
90.2
59.7
12 0 .2
89.7
3 0. 460 . 09 0 .329 .530 . 48 9. 411 9 . 830 . 791 .2
12 0 . 960 . 490 .2
29.8
127 . 9112 . 9117 . 6
33.6
31.5
110.6
148.2
119.8
37.7
115.3
83.9
150.0
113.6
117.9
36.7
88.0
115.6
33.5
30.9
162.9
63 . 9
129.6
166.2
92.0
95.4
91.8
165.0
99.1
165.2
83.7
83.3
94.7
83.3
86.3
96.8
73.6
169.0

-71-

(4 )
(6 )
(3 )
(7 )
(5 )
(5 )
(3 )
(6 )
(4 )
(5 )
(6 )
(8 )
(4 )
(5 )
(7 )
(4 )
(5 )
(5 )
(1 6 )(1 3 )(1 1 )
(8 )
(7 )
(5 )
(5 )
(4 )
(3 )i
(4 }I
(2 )
(5 )
(5)
(4)
(3 )
(3 )
(4 )
(8 )
(7 )
(7 )
(7 )
(6 )
(5 )
(1 )
(1 )
(2 )
(2 )
(2 )
(1 )
(2 )
(2 )
(2 )
(2 )
(2 )
(2 )
(2 )
(2 )

02 --- Til --- 03

95.5

-72-

(2)

Table 1-18.

Atomic Coordinates of

37a.

positional parameters and equivalentisotropic thermal parameters with e.s.d. inparentheses

atom

x

y

z

U (eq)

Til

0.53285 ( 8 )0.13993(7 )0.59754 (10)0.0426 (7 )01

0.4254 ( 3 )0.2142(3 )0.7121 (4 )

0.042

(2 )

02

0.3995 ( 3 )0.0643(3 )0.5901 (4 )

0.039

(2 )

03

0.5975 ( 3 )0.0683(3 )0.5063

(4 )

0.060

(3 )

C1

0.4298 ( 6 )0.3137 ( 4 )0.7197

(8 )

0.063

(5 )

C2

0.4053(6 )-0.0311 (5 )0.5572(8 )0.056 (4 )C30.3238 ( 4 )0.1835 (4 )0.7016 ( 6)

0.038

(3 )

C4

0.3295 (5 )0.0829 (4 )0.6863

(6)

0.038

(3 )

C5

0.2631 ( 5 )0.2095 (4 )0.8106 ( 6 )

0.044

(3 )

C6

0.3016 ( 6 )0.2022 (5 )0.9258 ( 6 )

0.055

(4 )

C7

0.2436 (8 )0.2265 ( 5 )1.0264 (7 )

0.074

(6 )

C8

0.1493(8 )0.2565 ( 6 )1.0072 (9 )

0.082

(6 )

C9

0.1114 (7 )0.2614 ( 6 )0.8931

(10 )

0.083

(6 )

CIO

0.1675 ( 6 )0.2377(5 )0.7936

( 8)

0.065

(5 )

Cl1

0.2289(4 )0.0438 (3 )0.6576

(5 )

0.032

(3 )

C12

0.1792(5 )0.0714 ( 4 )0.5562

( 6)

0.046

(4 )

C13

0.0887(5 )0.0379 ( 5 )0.5296 ( 7 )

0.059

(4 )

C14

0.0461 ( 5 )-0.0252(5 )

0.6065 ( 8 )

0.068

(5)

C15

0.0940 ( 6 )-0.0530 ( 6 )

(7 )

0.065

(5 )

C16

0.1859 ( 5 )-0.0192

0.7319 ( 6 )

0.055

(4)

C17

0.6744 (8 )0.0182 (11)0.4524

(12 )

0.128

(9 )

C18

0.7624 (10)0.0229 (19)0.5186 (16 )

0.17

(1 )

C19

0.6500 (12 )-0.0423(15 )0.3609

(15)

0.17

(1 )

Cll

0.65406 (14)0.23849 (15)0.64592(18)

0.071 (1 )C120.55908(12)

0.05533(12)0.77370

(16)

0.056

(1)

C13

0.46717(15)0.22832(12)0.44462

(14)

0.062

(1 )

(5 )

-73-

0.7067

1-10. References

1) Recent reviews and reports : Ager, D. J.; Prakash, I.; Schaad, D . R. Chem . Rev.

1996,96, 835. Cooke, J. W. B.; Davies, S. G.; Naylor, A. Tetrahedron 1993,49,7955.

Donnelly, D. M. X.; Fitzpatrick, B. M.; O'Reilly B. A.; Finet, J. -Po

Tetrahedron 1993,49, 7967. Enders, D.; Reinhold, U. Angew. Chem. Int. Ed.
Engl. 1995,34, 1219. Deng, J.; Hamada, Y.; Shioiri, T. 1. Am. Chem. Soc. 1995,

117, 7824. Gennari, C.; Pain, G.; Moresca, D. 1. Org. Chem. 1995,60, 6248.
2) Handbook of Enantioselective Catalysis, Vols. 1, 2 Brunner, H.; Zettlemeier, W.
eds.; 1993, VCH, Weinheim.

Chiral Auxiliaries and Ligands in Asymmetric

Synthesis Seyden-Penne, J. ed.; 1995, John Wiley & Sons, New York. Asymmetric
Synthetic Methodology Ager, D. 1.; East, M. B. eds.; 1995, CRC Press, Boca Raton.

3) Tomioka, K.; Nakajima, M.; Koga, K. Tetrahedron Lett. 1987,28, 1291.
Yoshioka, M.; Kawakita, T.; Ohno, M. Tetrahedron Lett. 1989,30, 1657.
4) Soai, K.; Yokoyama, S.; Ebihara, K.; Hayasaka, T. 1. Chem. Soc., Chern.

Commun. 1987, 1690.

Chaloner, P. A.; Renuka Perera, S. A. Tetrahedron Lett.

1987,28, 3013.
5) Maruoka, K.; Hoshino, Y.; Shirasaka, T.; Yamamoto, H. Tetrahedron Lett. 1988,

29,3967. Mikami, K.; Terada, M.; Narisawa, S.; Nakai, T. Synlett 1992,255.
6) Alexakis, A.; Lensen, N.; Tranchier, J.-P.; Mangeney, P.; Feneau-Dupont, J.;
Declercq, J. P. Synthesis 1995, 1038. Alexakis, A.; Kanger, T.; Mangeney, P.;
Rose-Munch, F.; Perrotey, A.; Rose, E. Tetrahedron: Asymmetry

1995,6, 47.

Alexakis, A.; Frutos, J. C.; Mutti, S.; Mangeney, P. 1. Org. Chern. 1994,59, 3326.
Alexakis, A.; Mangeney, P.; Marek. 1.; Rose-Munch, F.; Rose, E.; Semra, A.;
Robert, F. 1. Am. Chem. Soc. 1992, 114, 8288.

Alexakis, A.; Sedrani, R.;

Normant, J. F.; Mangeney, P. Tetrahedron: Asymmetry 1990, 1, 283.

7) Cohen, H. L.; Wright, G. F. 1. Org. Chem. 1953, 18, 432.
8) French, W.; Wright, G. F. Can. 1. Chem. 1964,42,2474.

-74-9) Seebach, D.; Kalinowski, H. -O.; Bastani, B.; Crass, G.; Daum, H.; DOff, H.
Dupreez, N. P.; Ehrig, V.; Langer, W. ; Nlissler, C.; Oei, H. A.; Schmidt, M. Helv.
Chim. Acta, 1977,60, 302.
10) Mazaleyrat, 1. P.; Cram, D . 1. J. Am. Chem. Soc. 1981, 103, 4585.
11) Tomioka, K.; Shindo, M.; Koga, K. J. Am. Chem. Soc. 1989,111, 8266.
Shindo, M.; Koga, K.; Tomioka, K. J . Am. Chem.
Tomioka, K. Synthesis 1990, 541.

SIOC.

1992, 114, 8732.

Tomioka, K.; Shindo, M.; Koga, K.

Tetrahedron Lett. 1993, 34, 681.
12) Hayashi, Y.; Rohde, 1. 1.; Corey, E. 1. J. Am. Chern. Soc. 1996, 118, 5502.
13) Lambert, 1. B.; Kuhlmann, B. J. Chem. Soc., Chem. Commun. 1992,931.
14) Kira, M,; Oyamada, T.; Sakurai, H. J. Organomet. Chern.. 1994,471, C4-C5.
15) Denmark. S. E.; Edwards, 1. P.; Wilson, S. R. 1. Am. Chern. Soc. 1992,114,
2592.
16) Guolin, G.; Zuohua, P.; Zeying, Z. Wuli Huaxue Xuebao (Acta Phys.-Chirn.
Sin) 1986,2, 278.
17) Sobota, P.; Mustafa, T. L. Polyhedron 1989, 8, 2013.
18) Sobota, P.; Ejfler, 1. Szafert, S.; Szczegot, K.; Sawaka-Dobrowlska, W. 1.
Chern. Soc., Dalton Trans 1993, 2353.
19) Olejnik, Z.; Utko, L. 1.; Sobota, P. Acta Cryst., C (Cr. Str. Cornm.) 1996,52,
847.
20) Fowles, G. W. A.; Lester, T. E.; Wood, 1. S. J. 1norg. l'vucl. Chern. 1969,31,657.
21) Iiskola, E.; Pelkonen, A.; Kakkonen, H. J.; Ahlgren, M. Acta Cryst., C (Cr. Str.
Cornm.) 1993,49, 1607.
22) Yatsenko, A. V.; Aslanov, L. A.; Burtsev, M. Y.; Kravchenko, E. A. Zh. Neorg.
Khim. 1991, 36, 2031.
23) Gau, H.-M.; Lee, C.-S.; Lin, C .-C.; Jiang, M.-K.; Ho, Y.-C.; Kuo, C.-N . 1.
Am. Chem. Soc. 1996, 118, 2936.
24) Jones, V.; Frenking, G.; Reetz, M. F. Organometallics 1993, 12, 2111.

-75-25) Matsumoto, T.; Maeta, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron Lett. 1988,
29, 3567.
26) Mukaiyama, T.; Harada, T. Chern. Lett. 1991, 1653.
27) Kume, T.; Akiba, K. l. Org. Chern. 1989,54, 1935.
28) McKee, B. H.; Gilheany, D. G.; Sharpless, K. B. Organic Synthesis 1991, 70,47.
29) Johnstone, R. A. W.; Rose, M. E. Tetrahedron 1979,35, 2169.
30) Furuta, K.; Shimizu, S.; Miwa, Y.; Yamamoto, Y. l. Org. Chern. 1989,54,
1481.
31) Gao, Q.; Ishihara, K.; Maruyama, T.; Mouri, M.; Yamamoto, H. Tetrahedron

1994, 50, 979.
32) Rebieve, F.; Riant, 0.; Kagan, H. B. Tetrahedron: Asymrnetry 1990, 1, 199.
33) Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992,33, 6907.

Ishihara, K.; Maruyama, T.; Mouri, M.; Gao, Q.; Furuta, K.; Yamamoto, H. Bull.
Chern. Soc. lpn. 1993, 66, 3483.
34) Bradley, D. C.; Mehrotra, R. C.; Wardlaw, W. l. Chern. Soc. 1951,2027 .
35) Geuze, J.; Ruinard, C.; Soeterbroek, J.; Verkade, P. E.; Wepster, B. M. Recl.

Trav. Chirn. Pays-Bas, 1956, 75, 301.
36) Kopecky, K. R.; Yeung, M. Can. l. Chern. 1988,66,374.
37) Newman, M. S.; Lee, L. F. 1. Org. Chern. 1972,37, 4468.
38) Wallace, T. W.; Wardell, I.; Li, K.; Leeming, P.; Redhouse, A. D. l. Chern.

Soc., Perkin Trans 1 1995, 2293.
39) Walker, N.; Stuart, D. Acta Crystallogr. 1983, A39, 158.
40) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.; Giacovazzo, C.;

Guagliardi, A.; Polidori, G. l. Appl. Cryst. 1994,27, 435.

-76-

Chapter 2.
Stereocontrol in [4+2]Type Cycloaddition ofImines Bearing a-Hydrog{~nswith 2-Silyloxy-l,3-butadi{~nes2-1. Introduction

Nucleophilic addition reactions to aldimines have found widespread application in thesynthesis of nitrogen-containing natural products. 1-3 These are seen in various alkaloids,
and the examples are Elaeocarpus alkaloids elaeokanine A (46), B (47), the fungal
neurotoxin slaframine (48), lupinine (49) , lysergic acid (50), palustrine (51),anhydrocannabisativene (52) 1, ipalbidine (53)2b, and (S)-anabasin (tobacco alkaloid, 54)3
as shown below .

co

Me

46

48

47

51

50

HO

54

53

-77-

49

52

In addition, dipeptide mimics of CD4, the cellular receptor of HIV -1 has beensynthesized recently.4omimicry of the Thr45-Lys46
segment of CD4

55
mirnicry of the Phe43-Lys46 segment of CD4

However, the synthetic utility of reactions of aldimines bearing a-hydrogens with
nucleophiles has been hampered by deprotonation of the a-hydrogens. 5 To overcome thisproblem, Akiba et.al. and others have used soft nucleophiles such as copper reagents with
Lewis acids as shown in Chapter 3. 6 ,7 As the approach for synthesizing piperidones orpiperidines, some workers have reported on reactions with activated aldirnines (eq 2-1),1 ,811 highly nucleophilic Danishefsky's diene (eq 2_2),2,12-15 catalytic activation by Lewis
acids (eq 2_3),3,16,17 or thermal intramolecular irnino Diels-Alder reaction (eq 2-4).1 bi) with activated aldirnines
R'OOCy,H

II
N'COR

+

~

~COOR'~~N"R- ~"R-~-I(eq 2-1-1)8'COR

R=Me, Ot-Bu, OBzI, OCH 2CCl 3
R'=Me, Et{
R"=MeO, TMSO, SPh(eq 2-1-2) lOa, lOb
-HCl

-78-

~)n

;c.L~ycooMe(eq 2-1-3 ) 11A(diastereomeric ratio 93:7 - 12.:88, 35-900/0 yield)

CQ(eq 2-1-4)lboCI

PhCOCH=N~CI'r('yCOPh

Ceq 2-1- 5) Ib~N,~CI~)..CI

cc

R"

v

Pivo~NyR
OPiv

R'

K ..

II

04P
OPiv
iV

Q-R

H

R=

~
o

R'= rvie, H{ R"=~le, H

(t
N

etc.

-79-

~

A'

Ceq 2-1-6) 3ii) with highly nuc1eophilic Danishefsky's diene

R

O

N""'"

o

(eq 2_2_1)12b

R'

R=Ph, BzI
{ R'=Ph, i-Pr, PhCH=CH- etc.

R2

==<X
R1

Me

OTMS

Rl=H, Me

32-100% yield2(eq 2-2-2)13

R =H, Me{R 3 =Ph, i-Pr
R 4 =Ph, Bzl

H

)=N

/Bzl

yOTMS
+

PH

~R

OMe

,

~ b
~

'

0

"B-OAr

1:

O

+

•

P

(R=H, Me)

N~

O

0

~N~

EIOOCJe.~ OTMS___EIOOCo-;

TMSO

0

-80-

I

R

(eq 2_2_3)ISaN
Bn(eq 2_2_4)2b

iii) catalytic activation by Lewis acid

d';';
R

ely

PhCH= NR

1) Lewis acids•

2) NaHC0 3 aq

OTMS

Ph

+

~~

OTMS

( Lewis acid=BF 3 -Et2 0, AICI 3 , Et2AICI, ZrCI 4 , TiCJ4 )(eq 2_3)17c

iv) thennal intramolecular imino Diels-Alder reaction

COOMe

COOMe

(eq 2_4)lb

-NOMe
67%

3:2 mixture of diastereomers

In spite of the usefulness of these cyclization, efficient r4+2]type cyc1oaddition ofunactivated 2-silyloxy-l ,3-butadienes with unactivated aldimines bearing a-hydrogens has
not been reported . In this Chapter, the effective use of tri lmethylsilyl triflate for the
cyc1oaddition of aldimines bearing a-hydrogens is describced at the beginning. I8 In
addition, the author wishes to describe stereocontrol in [4+2]type cyc1oaddition of a silyloxyaldimines bearing an a-hydrogen with 2-silyloxy- l ,3-bultadienes.

-81 -2-2. [4+2JType Cycloaddition of Imines Beari ng (X- H y drogens
The reaction of aldimines 56a-56c with 2-silyloxy- l,3-butadiene 57a in the presenceof silyl triflate 58 gave good yields of cycloadducts 591 after deprotection w ith
tetrabutylammonium fluoride (TBAF) (Scheme 2- 1, Table 2- 1).

silyl triflate

>=N

H

58

"cH2Ph56
a = Et{ b = n-Prc = i-Pr

59-trans

59-cisScheme 2-1

Table 2-1. Diastereoselectivity in [4+2]Type Cycloaddition of Aldimine (56).

entry
1
2
3

4
5

R
Et
n-Pr
i-Pr
n-Pr
n-Pr

silyl triflate trans: cis
TMSOTf89: 11TMSOTf
87:13
TMSOTf
98:2
TBDMSOTf 88: 12
TIPSOTf
90:10

yield~%)

49
52
75
58
60

The relative stereochemistry between C(2) and C(6) substituents of these diastereomers
was determined by NOESY spectrum after assignment by 2D-COSY spectrum. Higher

trans selectivity was observed by increasing the bulkiness of the a - substituents of the-82-

aldimine (58a (R I =Et), 58b (R 1=n-Pr), and 58e (R I =i-Pr)~ the diastereomeric excess was
78 % (entry 1, 49 % isolated yield), 74 % (entry 2, 52 % isolated yield), and 96 % (entry

3,75 % isolated yield), respectively). Other silyl triflates were also tried to obtain transisomers selectively, but there was a little change in the ratio and less selective (entries 4 and5).

From these preliminary results, high frans selectivities could be anticipated in [4+2]type
cyc1oaddition of chiral aldimines 60a-60e which could easily be prepared from
corrunercially available (S)-ethyllactate and (S)-valine, and it is interesting to investigate theselectivities among four possible isomers (2 kinds of 2,6-trans isomers and 2 kinds of 2,6-

cis isomers).

In the next section, stereoselective synthesis of 2,6-disubstituted-4-

piperidones by [4+2Jtype cyc1oaddition of chiral aldimines with 2-silyloxy-l,3-butadienes
is described.

~BZI~SiE+-

r~CH2Ph *~CH2Ph
60a

60b

60c

\/
(S)-ethyl lactate(S)-valine-83-2-3. [4+2JType Cycloaddition of a-Silyloxyaldimines(A) Preliminary Observations
The a-silyloxyaldimines (60a, 60c) and a-benzyloxyaldimine 60b were easily
prepared from commerciaIly available (S)-ethyllactate or (S)-valine as shown below.

9H
/yOEt
0

PTBDMSTBDMSCI"~OEt

imidazole
Dfv1F(51-ethyl lactate

9H
/Y0Et
0

0

DIBAL-HQTBDMS
"/yH

78%

0

<?SiE+-

BzINH2-- ~~CH2Ph
MS4A

60a

92%

S8%

NaH, BzlBr

"

THF

QBzl
/yOEt

DIBAL-H

0

81%

PBzl

~H
0

9BzI

B;zINH 2-- ')=~CH2Ph
MlS4A

85%

SOb
49%

(51-ethyl lactate

~H2

:

Y'b

OH

(51-valine

NaN02

"

H2SO4

PH
:
OH

Y'b

65%

H2SO4
EtOH

PH
:
OEt

Y'b

59%

TBDMSCI
imidazole

DMF

T8DMS
yyOEt

-- 9

0

91%

DIBAL-H77%

QT8DMS:H

Y'b

BzINH2MS4A
57%

9Si E+-~~CH2Ph60c[4+2]Type cyc1oaddition of aldimine 60a with 2 equiv of 2-siilyloxy-l ,3-butadiene
57a was conducted by the use of trimethylsilyl triflate in dichloromethane at 4 °C

(Scheme 2-3).

As expected from the effect of bulkiness of the a-substituent inaldimines 56, only the two 2,6-trans diastereomers (61a and 61b) were obtained as a
77:23 mixture in high yield (entry 1, Table 2-2). 2,6-Cis isomers were not detected atall. The stereochemistry of the major diastereomer 61a was determined by X-ray-84-

analysis as an intramolecular hemiketal (Figure 2-1) and the relative stereochemistry ofminor diastereomer 61b was confirmed to be trans between the a-hydroxyethyl groupand the phenyl group by DIFNOE experiments. Proton irradiation of the C-6 methinegroup (-NCHPh-CH2-: 8 3.80) of the ring resulted in intensity enhancement of signalsof the methine proton (8 4.48, 7.7 0/0) and the methyl protons (8 1.20, 5.6 0/0) of thehydroxyethyl group, and no enhancement was observed of the signal of the C-2 methinegroup (8 3.10).

TBAF

u

~ . 'H~l'rYaH
CH 2 Ph61b

P~H + P1{~H
CH2 PhCH 2 Ph61c

61d
not detected

Scheme 2-3

Figure 2-1. X-ray Crystallographic Structure of 61a.

-85-

Table 2-2. Effect of Lewis Acid on [4+2JType C:ycloaddition of an
Aldimine (60a) with 2-Siloxy-l,3-butadiene (57a).

Lewis acid57a

61a:61byield(%)

TMSOTf2eg to imine

77:23

90

2

H3SiOTf

2eg to imine

55:45

91

3

TIPSOTf

2egtoimine

56:44

64

4

Zn(OTf)2

2eg to imine

92:8

34

5

BF3 oEt20

2eg to imine

45:55

45

6

ZnCl2

2eg to imine

37:63

78

7

ZnBr2

2egtoimine

47:53

76

8

SnCl4

2eg to imine

37:63

24

9

TiC4

2eqtoimine

19:81

50

10

Ti(Oi-Pr)42eg to imine

11

Zn(OTf)2

4eg to imine

77:23

98

12

TiCl4

4eg to imine

30:70

86

entry

0

*All reactions were carried out at 4 °C for 1-7 days in dichloromethane under nitrogen.
TMS: trimethylsilyl

TIPS: triisopropylsilyl-86-

DIF NOE experiment of 61 b

To achieve a higher degree of asymmetric induction from the a-chirality, weinvestigated the reaction with other Lewis acids under similar conditions (Table 2-2,
entries 2-10). Parent silyl triflate (entry 2) and triisopropylsilyl trilflate (entry 3) did notshow good selectivities in comparison with TMSOTf. Among a series of Lewis acids, it
was interesting that the major product in the case of Zn(OTf)2 (entry 4) was 61a while
the major one by using TiCl4 was 61b (entry 9). Therefore, we tried to optimize
reaction conditions with these Lewis acids and an increase in the amount of 57a to 4
equiv was found to be effective (entries 11 and 12). In the reaction with TiCI4, we
found that the following procedure gave the best results: To a stirred solution of
aldimine 60a was added TiC14 and 57a successively. Since longer reaction time (20min) of aldimine 60a with TiCl4 before addition of 57a did not give products at all, it
was necessary to add 57a immediately after TiC14 was added to aldimine 60a.

-87-

~

:W-

~SiIBUMe2

H

oSi

E1-

57a

N~

Me

I ~~~LA.

CH 2 Ph

61a

Felkin-Anh model~OSiIBuMe2

M~~
N, OSiE.t

I ":',T1C1.

PhCH 2

'

~ ~

57a

Hr)
.
'
H
Rl~ I XOH

4

CH 2 IPhChelation model

61b

Figure 2-2

Formation of 61a as in the case of Zn(OTf)2 or TMSOTf can be explained by the
non-chelation pathway and 61h as with TiCl4 by chelation model (Figure 2-2). The
stereochemical outcome with Zn(OTf)2 was a surprise for us but we reasoned that the
fonnation of non-chelation product 61a with Zn(OTf)2 might be originated from theinsolubility of Zn(OTf)2 in dichloromethane. In the regular procedure, 57a was added
immediately after addition of aldimine 60a within 5 sec to a solution of Zn(OTf)2'Thus, the complexation of Zn(OTf)2 with aldimine 60a was slow in the solvent and thenon-chelation reaction with 57a took place before chelation of the catalyst toward thesilyloxy group occurs.

There might be a possibility concerning dissociation ofpolymeric Zn(OTf)2' In fact, the yield of the chelation product (61b) was increased(61a:61b = 62:38) when the mixture of Zn(OTf)2 and aldimine 60a was stirred for 30
min before addition of 57a.

-88-

(B) Cyc1oaddition by Using Zn(OTf)2
Based on the results in the section A, we expected that even less polar solvents suchas n-hexane would be more effective in the reaction with Zn(OTt)2' The results of thesolvent effect with Zn(OTt)2 are shown in Table 2-3. To our delight, the diastereomer

61a could be obtained with high selectivity (61a:61b = 89: 11) in 93 % yield when
Zn(OTt)2 was used at 4 °C in dry n-hexane with 4 equiv of 57a (entry 1). In contrast,
the reaction with TMSOTf revealed no dependence on solvents although temperatureeffects were observed. In the final analysis, the best conditions to obtain 61a wereshown in entry 1.

M~ 57• a TBAF • H.....
________
08itBuMe2

9, 8i8-

Lewis AcidrN...CH2PhP,

CH 2CI 2

4°C

P

60a

0

UA
.
I ~H
.... HCH 2 Ph+~l'(.:taH
CH 2 Ph

61a

Table 2-3.

H

61b

Solvent Effect with TMSOTf or Zn(OTf)2 as a Lewis Acid.

entrysolvent

Lewis acidconditions

61a:61b yield(%)

1n-hexaneZn(OTt)2

4°C, 2 days

89: 1193

2n-hexaneZn(OTt)2

r.t., 1 day

94:6

53

3

tolueneTMSOTf4°C, 3 days

78:22

97

4

CH2C12Zn(OTt)2

4°C, 4 days

77:23

98

5

C H 2 CI 2

TMSOTfr.t., 3 days

66:34

76

6

C H 2C l 2

TMSOTf-78°C, 7 da~s 51:49

39

-89-

(c) TiC14-Catalyzed Cycloaddition
Based on the chelation model, the use of a benzyl group instead of a TBDMS groupfor protection of a hydroxyl group was anticipated to yield 62b with higher
diastereoselectivity because chelation with TiCl4 would become more facile (Scheme 24). The benzyl-protected aldimine 60b was prepared and used in the reaction undersimilar conditions. The results are shown in Table 2-4. In spite of the use of 4 equiv of
57a, yields were not good except for the case of TMSOTf (2 equiv of diene was used)and no product was obtained by using TiCl4 (entries 1, 2, and 3, Table 2-4) because
decomposition of 60b had occurred. Benzyl group smaller than silyl group might notprotect the a-hydrogen from deprotonation. In addition, chelation-product 62b was theminor product in all the cases. Therefore, it turns out that the bulky t-butyldimethylsilylgroup is required for suppressing the decomposition of the aldimine effectively.

~sitBuMe2

9Bz1

Lewis Acid

0=~
H
CH Ph

57a TBAF

2

SOb

Scheme 2-4-90-Table 2-4.

entry

[4+2JType Cycloaddition of a-Benzyloxyaldimine 60b.

62a:~~2b

Lewis Acidsolvent

temperature (OC)TiC14

C H 2Cl2

4

0

2

TiCl4

CH2Cl2

-20

0

3

TiCl4

C H 2C l2

-78

0

4

ZnC l2CH2Cl2

4

84:16

25

5

Zn(OTf)2

C H 2Cl2

4

70:30

51

6

TMSOTf

CH2Cl2

4

78:22

95

yield(%)

A bulkier triisopropylsilyl-protected aldimine was used in the reaction with TiCl4 at 4
°C in dichloromethane and the ratio was 40:60 (61a:61b) in 75~'10 yield. The selectivityof 61b formation was lower compared with the case of the t-butyldimethylsilyl-protected
aldimine (61a:61b = 30:70, Table 2-2, entry 12). The inferior selectivity of 61b
formation might be attributed to the difficulty of chelation by the bulky triisopropylsilylgroup. These results might suggest the presence of equilibrium between the N,Ochelated TiCl4 complex and the N-coordinated complex, and thus, the selectivity
observed with the t-butyldimethylsilyl-protected aldimine 60a might be related with theequilibrium ratio of these species. In order to confirm the ass1llmption, we examined
temperature and solvent effects in the reaction with TiCl4 (Table 2-5), under the
speculation that the N,O-cyclic chelated TiC14 complex should be preferable to the Nacyclic complexed compound at low temperatures and in polar so1vents. No product was
obtained in acetonitrile but the result might be due to nucleophilic attack of diene 57 at theacetonitrile cyano carbon. However, the use of bulkier isobutyronitrile and pivalonitrile-91-

as polar solvents was effective in affording 61b selectively (entries 2 and 3). The best
result was obtained (61b was obtained exclusively in 870/0 yield, entry 10) by using low
melting isobutyronitrile (mp -72°C) at -30 °C. The reversed selectivity observed in nhexane (entry 9) may be ascribed to heterogeneous reaction conditions as was describedin the reactions with Zn(OTf)2. Without the deprotection procedure, cycloadducts
retaining enol silyl ether functionality and the t-butyldimethylsilyl group could be
isolated. Thus, the t-butyldimethylsilyl group was not eliminated in the reaction with
TiCl4 under these conditions so the high selectivity is not a consequence of tbutyldimethylsilyl group elimination in 60a.

-92-

Table 2-5.

Solvent

and Temperature Effect on the Stereoselectivity of

61b Formation by Use of TiCI4.

entry

61a :61b

solvent

conditions

yield(% )CH3CN

4°C, 1 day

2;-PrCN

4°C, 1 day

24:76

67

3

t-BuCN

4 °C, 1 day

18:82

60

4

CH2Cl24°C, 1 day

24:76

65

0

+sulfolane
5

CH2Cl24°C, 1 day

30:70

86

6

Et20

4°C, 1 day

53:47

96

7

CCl4

4°C, 1 day

49:51

71

8

toluene

4 °C, 1 day

68:32

90

9

hexane4°C, 1 day>98:<212

10;-PrCN-30°C, 1 day<2:>9887-93-

(D) The Scope for the [4+2JType Cycloaddition
The reaction of 60a with 57b derived from mesityl oxide as shown in Scheme 2-5
was examined. The structural assignment for 63a was carried out by X-ray crystal
structure determination (Figure 2-3). The reactions using Zn(OTf)2 and TMSOTf gave a
mixture of 63a and 63b in the same ratio (43:57, Table 2-6, entries 2 and 3), andtriisopropylsilyl-protected aldimine did not improve the ratio in the presence of TMSOTf
at 4 °C in dichloromethane. However, 63b could be obtained with high selectivity with
TiCl 4 in i-PrCN (entry 1, Table 2-6).

oo, .. ...,,(
H
.Me~
+ M~
I OH
.

M

60a

I OH
CH 2 Ph

63a

M~

CH2 Ph63b

Scheme 2-5

Figure 2-3. X-ray Crystallographic Structure of 63a.

-94-

Table 2-6. [4+2JType Cycloaddition of Aldimine 60a with 57b.

entry

solvent

Lewis acidconditions

63a:63b yield(%)

i-PrCN

TiCl 4-30°C, 1 day 9:91

65

2

hexaneZn(OTf)2

4°C, 2 days

43:57

75

3

CH2Cl2TMSOTf4°C, 1 da~

43:57

80

When the aldimine 60c bearing a bulkier isopropyl group at the a-position was
subjected to cyc1ization with 57a followed by subsequent treatment with TBAF,
cyc10adducts (64a and 64b) could be obtained as expected (Table 2-7 and Scheme 2-6).
The structural determination could be carried out similarly as mentioned above, andFigure 2-4 shows the X-ray structure of 64a. In this case, non-chelation product 64a
could not be obtained selectively (entries 1 and 2) similar to the case with 2-silyloxy-l ,3butadiene 57b. In addition, no product was observed in isobutyronitrile at -30°C
although 64b could be obtained predominantly at 4 °C in dichloromethane (entry 3).
Thus, the reaction was sluggish probably because of the steric hinderance of the i-Pr
group in 60c. Therefore, we tried to activate TiCl 4 by the use of silver ions. Various
silver ions (AgCI04, AgSbF6, and AgOTf) and conditions (the order of addition,
temperature etc.) were examined to prepare active Lewis acids. After some experiments,
we found that addition of 1 equiv of AgOTf to the mixture was quite effective in
activating TiCl 4 and only 64b was obtained in 49 % yield at -30°C in i-PrCN (entry 5).
The active Lewis acid might be the TiCI3+ -TiCl4 polymer catalyst judging from theexperiments in Chapter 1.

-95-

?SiEt'Y>=~
H
CH Ph

o

Hf>~+ H~

Lewis Acid

2

Ptl

60c

I

H OH
CH 2 Ph

ptf'

64a

I

H OH
CH 2 Ph64b

Scheme 2-6

Table 2-7. [4+2JType CycIoaddition of Aldimin€! 60c with 57a.

solvent

Lewis acidconditions

64a:~~4byield(%)

CH2Cl2TMSOTf4°C, 7 days

43:57

91

2

CH2Cl2Zn(OTf)2

4°C,7 days

49:51

59

3

CH2Cl2TiCl44°C, 11 days 30:70

91

4

i-PrCN

TiC14-30°C, 1 day -05

i-PrCN

TiCI4-AgOTf -30°C, 1 da~ <2:>98

entry

-96-

49

02

Figure 2-4. X-ray Crystallographic Structure of 64a.

The mechanism of [4+2]type cycloadditions involving aldimines is quite complex anda stepwise mechanism 20 and a concerted mechanism 16 have been suggested. Recently,
Akiba et.al. reported on [4+2]type cycloaddition of diene 57 to chromone 21 andcoumarin 22 activated by TBDMSOTf (t-butyldimethylsilyl triflate) and it was concluded
that only the former proceeded through a silyloxyallyl cation intermediate based on a
successful trapping experiment by the use of sterically hindered 57b. Therefore, in orderto gain insight on the mechanism of the reaction of 60a with 57b catalyzed by TMSOTf,
the mixture was quenched after stirring for 15 min at 0 °C. However, only cyclic
products 63 were obtained in 63% yield and no acyclic products were isolated. In
addition, only cyclic products 61 were isolated in 200/0 yield wnen the reaction of 60a
with 57a was carried out at 0 °C for 1 min in the presence of TMSOTf. These results
suggest that the reaction proceeds through a concerted mechanism or a stepwise
mechanism in which cyclization of cation intermediates is fast.

-97-

2-4. Summary

Trans-2,6-disubstituted-4-piperidones were synthesized by [4+2Jtype cyc1oadditionof chiral aldimines (60) with 2-silyloxy-l ,3-butadienes (57) in the presence of Lewis
acids. In the cycloaddition, only two 2,6-trans isomers (chelation and non-chelation
products) were observed and no cis compounds were detected regardless of the Lewis
acid used. Chelation-controlled products 61b, 63b, and 64b were obtained selectively
by the use of TiCI4-i-PrCN and 61a was obtained with high selectivity when TMSOTf
or Zn(OTf)2 was used as a Lewis acid at 4°C. The cyclization of aldimines bearing uhydrogens will be widely applied to synthesize natural products especially containing apiperidone fragment.

-98-2-5 Experimental Section

1H NMR spectra were recorded at 400MHz (JEOL EX4(0) in CDCl3 in the presenceof TMS as an internal standard. Melting points were taken on a rnicro melting point
apparatus ( Yanagimoto model) and are uncorrected. High-resolution mass spectra wererecorded on a JEOL SX-I02A spectrometer. Elemental analyses were performed on a
Perkin-Elmer 2400 CHN elemental analyzer. All reactions were conducted under anargon atmosphere.

Preparation of Ethyl (S)-N -2-[(tert-Butyldimethylsilyl)oxy]propylidene
Benzylamine.

(S)-2-[ (tert-Bu tyldimethylsilyl)oxy] propionate

To a stirred solution of 12.8 g (188 mmol) of imidazole and 18.8 g (125 nunol) of (butyldimethylsilyl chloride in dry DMF (25 mL) was added 11.0 rnL (97 nunol) of (S)ethyl lactate at r.t.. The reaction mixture was stirred for 8 h, quenched with H20 (30mL), and extracted with ether (150 mL). The collected organic layers were washed with

H20 (100 rnLx 10), dried over MgS04, and the solvent was evaporated. The crude
product was distilled (b.p. 95-105 °C / 2 mmHg, 20 g, 92% yield).
IH NMR (CDC}3) 0.06 (s, 3 H), 0.09 (s, 3 H), 0.90 (s, 9 H), 1.26 (t, 3 H, J = 7.0Hz), 1.38 (d, 3 H, J

= 6.8 Hz), 4.10-4.23 (m, 2 H), 4.29 (q, 1 H, J = 6.8 Hz).

(S)-2- [(tert- B u ty Idimethy Isily I)oxy] propanal

To a stirred solution of 8.53 rnL (34 nunol) of ethyl (S)-2-[(tertbutyldimethylsilyl)oxy]propionate in dry CH2C12 (36 mL) was added slowly 36.3 rnL(36.3 nunol) of diisopropylaluminum hydride (1.0 M in hexane solution) at -78°C. The
reaction mixture was stirred for 20 min, dry MeOH (3.6 mL) was added to the solution at-78°C, then the mjxture was stirred for 1.5 h at r.t.. After stirring, inorganic precipitate-99-was filtered through Celite and the filtrate was evaporated. The crude product was
purified by distillation (b.p. 83-85 °C /25 mmHg, 5.0 g, 780/0 yield).
1H NMR (CDC13) 0.06 (s, 3 H), 0.09 (s, 3 H), 0.90 (s, 9 H), 1.27 (d, 3 H, J = 7.1
Hz), 4.10 (q, 1 H, J

= 7. 1 Hz), 9.62 (s, 1 H).

(S )-N - 2- [ (I ert - B u t y Idi methy Isily I)oxy] propylidene Benzy lamine
To a stirred rrlixture of 2.4 mL (22 mmol) of benzylarrli ne and 20 g of molecular sieves
4A in dry ether (40 mL) was added 3.5 g (1 8 mmol) of (S)-2-[(tertbutyldimethylsilyl)oxy] propanal at r.t .. The reaction mixture was stirred at r.t. for 3 h
and molecular sieves 4A was fil tered off. The solvent of the fi ltrate was evaporated andthe crude product was purified by vacuum distillation (b.p. 11 6- 120 °C /0.7 mmHg, 3.0g, 580/0 yield).
1H NMR (CDCI3) 0.06 (s, 3 H) , 0.09 (s, 3 H), 0.90 (s, 9 H), 1.22 (d, 3 H, J = 6.8
Hz) , 4.29 (m, 1 H) , 4.49 (s, 2 H), 7.15 -7.26 (m, 4 H) , 7.57 (d, 1 H, J

= 5.4 Hz).

Preparation of (S)-N -2-[ (tert-Butyldimethylsilyl)oxy ]-3-methylbutylidene
Benzylamine.

(S)-2-Hydroxy-3-methylbutanoic Acid
To a stirred solution of 4.6 g (427 mmol) of (S)-valine in H20 (330 mL) was added
dropwise slowly 2 N H2S04 (213 mL) by use of dropping funnel at 0 °C. After thevaline dissolved into the solution, 2 N NaN02 (213 mL) was added dropwise to thesolution. The rate of the additions of both reagents should be similar. After reaction
mixture was stirred for 3 h at 0 °C and for 12 h at r.t., the mixture was extracted with
CH3COOEt (100 mLx3). The collected organic layers were dried over Na2S04 and thesolvent was evaporated. The crude product was purified by recrystallization (ether /hexane, mp 64-65 °C, 650/0 yield).

-100-Ethyl (S)-2-Hydroxy-3-methylbutanoate
To a stirred solution of 19 g (161 mmol) of (S)-2-hydroxy-3-methylbutanoic acid and990/0 EtOH (130 mL) was added slowly 4 mL of conc. H2S04 at. r.t.. The reaction
mixture was refluxed for 12 h, and the solvent was evaporated. Then, the crude mixture
was extracted with ether (150 mL), washed with sat.NaHC03 ag. (l00 mLx2), and thecollected organics were dried over Na2S04. After the solvent was evaporated, crude
product was purified by distillation (83-84 °C / 30 mmHg, 14 g, 59%).
1H NMR (CDCI3) 0.84 (d, 3 H, J = 6.9 Hz), 1.00 (d, 3 H, J = 6.9 Hz), 1.28 (t, 3 H,

] = 6.8 Hz), 2.00-2.12 (m, 1 H), 2.77 (d, 1 H, J =6.0 Hz), 3.95(m, 1 H), 4.10-4.25(m, 2 H).

Ethyl (S)-2-[ (tert-Butyldimethylsily I)oxy] -3-methyl-bu tanoate
To a stirred solution of 7.9 g (116 mmol) of imidazole and 10.7 g (71 nunol) of tbutyldimethylsilyl chloride in dry DMF (30 mL) was added 8.1 mL (58 nunoI) of ethyl(S)-2-hydroxy-3-methylbutanoate at Lt .. The reaction mixture was stirred for 8 h,quenched with H20 (30 mL), and extracted with ether (150 mL). The collected organic
layers were washed with H20 (lOO mLxl0), dried over MgS04, and the solvent wasevaporated. The crude product was distilled (b.p. 127-129 °C / 24mmHg, 14 g, 91 %yield).
1H NMR (CDCI 3) 0.02 (s, 3 H), 0.04 (s, 3 H), 0.90 (s, 9 H), 0.85-0.95 (m, 6 H), 1.25
(t,3 H, J = 7.3 Hz), l.96-2.08 (m, 1 H), 3.92 (d, 1 H, J = 4.9 Hz), 4.10-4.21(m, 1
H).

(S)-2- [(tert-B u tyldimethysily I )oxy] -3-methy I bu tanal

To a stirred solution of 13.8 g (53 mmol) of ethyl (S)-2-[(tert-butyldimethylsilyl)oxy]3-methyl-butanoate in dry CH2Cl2 (50 mL) was added slowly 60 n1L (60 mmoI) of
diisopropylaluminum hydride (1.0M in hexane solution) at -78°C. The reaction mixture
was stirred for 20 min, dry MeOH (5.6 mL) was added to the solution at -78°C, then the-101-

mixture was stirred for 1.5 h at r.t.. After stirring, inorganic precipitate was filteredthrough Celite and the filtrate was evaporated. The crude product was purified by
distillation (b.p. 98-100 °C / 18 mmHg, 8.8 g, 770/0 yield).
1H NMR (CDCI3) 0.05 (s, 6 H), 0.93 (s, 9 H), 0.85-1.00 (m, () H), 1.90-2.08 (m, 1
H), 3.71 (dd, 1 H, J

= 2.1, 4.9 Hz), 9.59 (d, 1 H, J = 2.1 Hz).

(S)-N -2-[ (tert-Butyldimethylsilyl)oxy ]-3-methylbutylidene

Benzylamine

To a stirred mixture of 4.9 mL (44 mmol) of benzylamine and 20 g of molecular sieves
4A in dry ether (40 mL) was added 8.8 g (41 mmol) of (S)-2-[(tertbutyldimethysilyl)oxy]-3-methylbutanal at r.t.. The reaction mixture was stirred at r.t.
for 3 h and molecular sieves 4A was filtered off. The solvent of the filtrate was
evaporated and the crude product was purified by vacuum distillation (b.p. 120-125 °C /0.1 mmHg, 7.1 g, 57% yield).
1H NMR (CDCI3) 0.04 (s, 3 H), 0.10 (s, 3 H), 0.95 (s, 9 H), 0.95-1.01 (m, 6 H),
1.87-1.97(m, 1 H), 3.97 (t, IH, J = 5.9Hz), 4.64 (s, 2 H), 7.25-7.40 (m, 5 H), 7.66
(d, I H, J = 6.4 Hz).

Preparation of (S)-N-2-Benzyloxypropylidene Benzylamine.

Ethyl (S)-2-Benzyloxypropionate
To a stirred solution of 11 g (285 mmol) of NaH in dry THF (30 mL) was added 27 mL(238 mmol) of (S)-ethyllactate at 0 °C. The reaction mixture was stirred for 30 min at 0°e, benzyl bromide (34.8 mL, 292 mmol) and TBAI (1.01 g, 2.9 mmol) in dry THF (20mL) was added to the solution slowly and stirred for 14 h at r.t.. The mixture wasquenched with H20 (40 mL), and extracted with ether (300 mL). Then, the collectedorganic layers were dried over MgS04, and the solvent was evaporated. The crude
product was purified by distillation (b.p. 86-90 °C / 20 mmHg, 42 g, 850/0 yield).

-102-

1H NMR (CDCI3) 1.30 (t, 3 H, J = 6.8 Hz), 1.43 (d, 3 H, J == 6.8 Hz), 4.04 (q, 1 H,

J = 6.8 Hz), 4.21 (dq, 2 H, J = 2.7,6.8 Hz), 4.50 (d, 1 H, J == 12.3 Hz), 4.71 (d, 1
H, J = 12.3 Hz) , 7.28-7.37 (m, 5 H) .

(S)-2- Benzyloxypropanal

To a stirred solution of 30 mL (156 mmol) of ethyl (S)-2-benzyloxypropionate in dry
CH2Cl2 (100 mL) was added slowly 162 mL (162 mmol) of diisopropylaluminum
hydride (1.0 M in hexane solution) at -78°C. The reaction mixture was stirred for 20
min, dry MeOH (16.5 mL) was added to the solution at -78°C, then the mixture wasstirred for 1.5 h at r.t.. After stirring, inorganic precipitate was filtered through Celite
and the filtrate was evaporated. The crude product was used for next reaction without
purification (21 g, 81 % yield).
1H NMR (CDCI3) 1.31 (d, 3 H, J = 7.3 Hz) , 3.85-3.90 (m, 1 H), 4.58 (d, 1 H, J =11.7 Hz), 4.64 (d, 1 H, J = 11.7 Hz), 7.24-7.36 (m, 5 H), 9.65 (d, 1H, J = 1.5 Hz).

(S)-N -2-Benzyloxypropylidene

Benzylamine

To a stirred mixture of 4.6 mL (42.4 mmol) of benzyl amine and 20 g of molecularsieves 4A in dry ether (40 mL) was added 5.6 g (35 mrnol) of (S)-2-benzyloxypropanal
at r.t.. The reaction mixture was stirred at r.t. for 3 h and molecular sieves 4A wasfiltered off. The solvent of the filtrate was evaporated and the crude product was
purified by vacuum distillation (4.1 g, 49% yield).
IH NMR (CDCI3) 1.38 (d, 3 H, J = 6.4 Hz), 3.85 (d, 1 H, J = 19.0 Hz), 4.10-4.18(m, 1 H), 4.52-4.64 (m, 3 H), 7.26-7.37 (m, 10 H), 7.71 (d, 1 H, J = 5.3 Hz).

Typical Procedures for TiCl4-catalyzed [4+2JType Cycloadditions:
Titanium tetrachloride (0.38 mmol) and 1.36 mrnol of 57a were added to 0.34 mmolof 60a in dry isobutyronitrile (2.8 mL) at -30°C under nitrogen.

After stirring at -30°C for 1 day, the reaction mjxture was poured into aq NaHC03 followed by extraction-103-with CH2CI2 . The combined organic layers were dried over ~1gS04, and the solvent
was evaporated. The residue was dissolved in THF and 1.3 mlmol of TBAF (in THF
solution) was added to the solution. The reaction mixture was stirred for 10 h,quenched with water, extracted with CH2CI2, and the combined organics were driedover MgS04. After the solvent was removed in vacuo, the crude product was separated
by recycle HPLC (JAI LC 908, lAIGEL-IH and 2H, l,2-dichloroethane).

Typical Procedures for Zn(OTf)2-catalyzed [4+2]Type Cycloadditions:
To a stirred solution of 0.38 mmol of Zn(OTf)2 in dry hexane (4.1 mL) was added
0.34 mmol of 60a at 0 °C under nitrogen. Following the addition of 57a (1.36 mmol),the mixture was stirred at 4 °C for 3 days. The resulting mixture was poured into aq
NaHC03 and extracted with CH2CI2. After the combined organic layers were driedover MgS04, the solvent was evaporated. The residue was dissolved in THF and 1.3
mrnol of TBAF (in THF solution) was added to the solution. The reaction mixture wasstirred for 10 h, quenched with water, extracted with CH2CI2, and the combinedorganics were dried over MgS04. After the solvent was removed in vacuo, the crude
product was separated by recycle HPLC (J AI LC 908, 1AIGEL-I Hand 2H, 1,2dichloroethane ).
Typical procedures for runs using TMSOTf were almost the sarne as for TiCl4 exceptthat dichloromethane or toluene was used as a solvent.

61a: colorless crystals (ether / n-hexane). mp 147-148 °C. IH NMR (CDCl3): 0
l.20 (d, J = 6.4 Hz, 3 H), 1.56 (brs, I H), 1.81-2.08 (m, 4 H), 3.10 (d, J = 4.4 Hz, 1H), 3.18 (d, J = 14.2 Hz, 1 H), 3.63 (d, J = 14.2 Hz, 1 H), 3.80 (dd, J = 5.4, 10.8
Hz, 1 H), 4.48 (q, J = 6.4 Hz, 1 H), 7.22-7.60 (m, 10 H)..

Anal. Calcd for

C20 H 23 N0 2: C, 77.64; H, 7.49; N, 4.53. Found: C, 77.89; H, 7.66; N, 4.58.

-104-

6tb: colorless oil. 1H NMR (CDCI3): 8 1.04 (d, J = 5.8 Hz, 3 H), 1.55 (brs, 1
H), 2.30 (dd, J = 15.1,3.9 Hz, 1 H), 2.58-2.95 (m, 4 H), 3.47 (d, J = 13.5 Hz, 1 H),
3.7~-3 . 90 (m, 2 H), 4.52 (dd, J =10.7,3.9 Hz, 1 H), 7.13-7.39 (m, 10 H). HRMS:

mJz Calcd for C20H23N02: 309.1729. Found: 309.1753.

62a: colorless oil. IH NMR (CDCI3): 8 1.31 (d, J = 6.4 Hz, 3 H), 2.41 (dd, J =14.9, 3.4 Hz, 1 H), 2.66 (dd, J = 15.3, 6.3 Hz, 1 H), 2.74-2.77 (m, 2 H), 3.06-3.10(m, 1 H), 3.50-3.59 (m, 1 H), 3.55 (d, J = 13.7 Hz, 1 H), 3.88 (d, J = 13.7 Hz, 1 H),
4.36 (d, J = 11.7 Hz, 1 H), 4.52 (d, J = 11.7 Hz, 1 H), 4.90 (dq, J = 4.9, 6.4 Hz, 1
H), 7.20-7.50 (m, 15 H).

HRMS: mlz Calcd for C27H29N02: 399.2199. Found:399.2202.

62b: colorless oil. 1H NMR (CDCI3): 8 1.17 (d, J = 6.4 Hz, 3 H), 2.50-2.55(m,4 H), 3.01-3.03 (m, 1 H), 3.48 (d, J = 13.6 Hz, 1 H), 3.63 (d, J = 13.6 Hz, 1 H),
3.96-4.03 (m, 1 H), 4.26-4.35 (m, 1 H), 4.42 (d, J = 11.5 Hz, 1 H), 4.63 (d, J = 11.5
Hz, 1 H), 7.05-7.45 (m, 15 H). HRMS: mlz Calcd for C27H29N02: 399.2178.
Found: 399.2188.

63a: colorless crystals (ether / n-hexane). mp 106-107°C. 1H NMR (CDCl3): 8
0.94 (d, J = 6.8 Hz, 3 H), 1.06 (s, 3 H), 1.37 (s, 3 H), 1.60 (brs:, 1 H), 2.20-2.31 (m,2 H), 2.65-2.83 (m, 3 H), 3.35 (d, J = 17.1 Hz, 1 H), 3.88-3.91 (m, 1 H), 4.24 (d, J= 17.1 Hz, 1 H), 7.22-7.47 (m, 5 H).

Anal. Calcd for C16H23N02: C, 73.53; H,

8.87; N, 5.36. Found: C, 73.38; H, 8.84; N, 5.76.

63b: colorless oil. 1H NMR (CDCl3): 8 0.96 (d, J = 6.3 Hz, 3 H), 1.30 (s, 3H), 1.32 (s, 3 H), 2.17-2.59 (m, 4 H), 3.13 (dt, J = 8.6, 4.3 Hz, 1 H), 3.52 (dq, J =8.6, 6.3 Hz, 1 H), 3.80 (d, J = 15.8 Hz, 1 H), 4.00 (d, J = 15 .8 Hz, 1 H), 7.24-7.42(m,5 H). HRMS: mlz Calcd for C16H23N02: 261.1729. Found: 261.1725.

-105-

64a: To an isobutyronitrile (2 mL) solution of 60a (0.15 mL, 0.45 mmol) was
added isobutyronitrile (4 mL) solution of titanium tetrachloride (0.08 ml, 0.68 mmol)and silver triflate (0.17 g, 0.69 mmol) at -30°C under nitrogen. Following the additionof 57a (0.45 mL, 1.8 mmol), the mixture was stirred at -30°C for 1 day. The reaction
mixture was poured into aq NaHC03 followed by extraction with CH2CI2. The
combined organic layers were dried over MgS04, and the solvent was evaporated. The
residue was dissolved in THF and 1.8 mmol of TBAF (in THF solution) was added tothe solution. The reaction mixture was stirred for 10 h, quenched with water, extractedwith CH2CI2, and the combined organics were dried over MgS04. After the solvent
was removed in vacuo, the crude product was separated by recycle HPLC (JAI LC 908,
JAIGEL-IH and 2H, 1,2-dichloroethane). Subsequent recrystaUization from ether / nhexane gave 64a (74 mg, yield 49 %) as colorless crystals.
1H NMR (CDCI3): 8 0.75 (d, J = 6.3 Hz, 3 H), 1.05 (d, J = 6.3 Hz, 3 H), 1.45-1.55(m, 1 H), 1.86-2.10 (m, 4 H), 3.16 (d, J = 14.2 Hz, 1 H), 3.15-3.25 (m, 1 H), 3.60
(d, J = 14.2 Hz, 1 H), 3.70-3.85 (m, 1 H), 4.15-4.25 (m, 1 H), 7.15-7.60 (m, 10 H).
Anal. Ca1cd for C22H27N02: C, 78.30~ H, 8.06~ N, 4.15. Found: C, 78.30~ H, 8.27;
N,4.08.

64b: colorless oil. 1H NMR (CDCI3): 8 0.60 (d, J = 6.3 Hz, 3 H), 1.06 (d, J =6.3 Hz, 3 H), 1.70-1.85 (m, 1 H), 2.36-2.45 (m, 1 H), 2.70-2.85 (m, 2 H), 2.98-3.10(m, 1 H), 3.20-3.25 (m, 1 H), 3.62 (d, J = 14.0 Hz, 1 H), 3.58-3.63 (m, IH), 3.90
(d, J = 14.0 Hz, 1 H), 4.63-4.70 (m, 1 H), 7.20-7.75 (m, 10 H).

Crystal Structure of 61a, 63a, and 64a.

Crystallographic data for 61a: C20H23N02, FW = 309.0, orthorhombic, space group
P212121, a = 11.380(2) A, b = 25.362(2) A, c = 6.016(2) A, V = 1736.4(7) A3, Z =4, D cal = 1.18 g/cm 3, Il = 0.42 cm- 1. T = 297 K. Final R = 0.054 (Rw= 0.063) for-106-

1389 observed reflections with F>3cr(F). Crystallographic data for 63a: C 16H23N02,
FW = 261.4, monoclinic, space group P21/n, a = 15.878(4) A, b = 7.721(2) A, c =13.083(4) A,

f3 = 111.53(2)0,V = 1492.1(7) A3, Z = 4, D cal == 1.16 g/cm3, Jl = 0.42

em-I. T = 297 K. Final R = 0.071 (Rw= 0.094) for 1645 observed reflections with
F>3cr(F). Crystallographic data for 64a: C22H27N02, FW = 337.0, Trigonal, spacegroup P3221, a = 10.478(2) A, b = 10.478(2) A, c = 31.20(1) A, V = 2966(2) A3, Z =6, D cal = 1.13 g/cm 3 , Jl = 0.39 cm- 1. T = 297 K. Final R = 0.076 (Rw= 0.066) for
1242 observed reflections with F>3cr(F).
Crystals suitable for X -ray structure determination were mounted on a Mac Science
MXC3 diffractometer and irradiated with graphite-monochromated Mo Ka radiation (A= 0.71073 A) for data collection. Lattice parameters were determined by least-squares

fitting of 21-31 reflections with 27°<28<32°,19°<28<30°, and 24°<28<35° for 61a,
63a, and 64a, respectively. Data were collected with the 28/co scan mode. The
structure was solved by a direct method with a program, Monte Carlo-Multan. 25
Refinement on F was carried out by full-matrix least-squares. All non-hydrogen atoms
were refined with anisotropic themal parameters. All hydrogen at.oms in 61a and 63a
could be found on a difference Fourier map~ these coordinates were included in therefinement with isotropic thermal parameters. The hydrogen atoms in 64a were
included in the refinement on calculated positions (C-H = 1.0 A) riding on their carrier
atoms with isotropic thermal parameters. All the computations were carried out on a
Titan-750 computer using the crystan-G program. Atomic coordinates, bond distances
and angles, and crystallographic data show Table 2-8, 2-9, 2-10, 2-11 (61a), 2-12, 213,2-14,2-15 (63a), 2-16, 2-17, 2-18, and 2-19 (64a).

-107-

Table2-8Intramolecular Distances (A) with E~.s.d. lnparentheses
atom

atom

distance--c 4
0 2--c 20
0 2
--c 4
N 1
--c 7
N 1
--c 6
N 1
--c 2
C 2 --c 14
C 2 --c 3
C 3 --c 4
C 4 --c 5
C 5 --c 6
C 6 --c 20
C 7 --c 8
C 8 --c 9
C 8 --c 13
C 9 --c 10
C 10 --c 11
C 11 --c 12
C 12 --c 13
C 14 --c 15
C 14 --c 19
C 15 --c 16
C 16 --c 17
C 17 --c 18
C 18 --c 19
C 20 --c 21

1.387 ( 6 )1.435 (7 )1.458 ( 6)1.472 (7 )1.474 ( 6 )1.488 (7 )1.525 (7 )1.543 ( 8)1.512 ( 8 )1.517 ( 8 )1.518 ( 8 )1.534 ( 8 )1.505 ( 8)1.36 (1 )1.394 (9 )1.41 (1 )1.41 (2 )1.32 (2 )1.36 (1)1.373 ( 8 )1.404 ( 8 )1.390 (9 )1.36 ( 1 )1.38 ( 1 )1.389 ( 9)1.523 ( 9 )

o 1

-108-

Table 2-9Intramolecular Angles (degrees) with e.s.d. inparentheses
atom
C 20
C 7
C 7
C 6
N 1
N 1
C 14
C 4
o 1
o 1
o 1
o 2
o 2
C 3
C 4
N 1
N 1
C 5
N 1
C 9
C 9
C 13
C 8
C 11
C 12
C 11
C 12
C 15
C 15
C 19
C 14
C 17
C 16
C 17
C 18
0 2
0 2
C 21

atom
--0 2
--N 1
--N 1
--N 1

atom

angle

--c 4
--c 6
--c 2
--c 2
--c 14
--c 3
--c 3
--c 2

109.6
113.0
109.6
113.1
108.7
112.7
109.7
113.4
109.2
109.1
117.3
109.7
102.0
109.1
99.3
108.5
114.9
101.0
112.4
117.9
121.2
120.9
121.4
117.0
121.3
120.6
121.7
118.6
122.0
119.4
120.8
120.7
119.5
120.4
119.9
109.9
104.6
114.2

--c 2
--c 2
--c 2
--c 3
--c 4 --0 2--c 4 --c 3--c 4 --c 5--c 4 --c 3--c 4 --c 5--c 4 --c 5--c 5 --c 6--c 6 --c 5--c 6 --c 20--c 6 --c 20--c 7 --c 8--c 8 --c 13--c 8 --c 7--c 8 --c 7--c 9 --c 10--c 10 --c 9--c 11 --c 10--c 12 --c 13--c 13 --c 8--c 14 --c 19--c 14 --c 2--c 14 --c 2--c 15 --c 16--c 16 --c 15--c 17 --c 18--c 18 --c 19--c 19 --c 14--c 20 --c 21--c 20 --c 6--c 20 --c 6

(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(5 )
(4 )
(5 )
(6 )
(5 )
(6 )
(7 )
(9 )
(9 )
(9 )
(8 )
(5 )
(5 )
(5 )
( 6)
(7 )
(6 )
(7 )
( 6)
(5 )
(4 )
(5 )

-109-

***** torsional angles *****# ns1,atm1,ns2,atm2,ns3,atm3( 1 H 20 )no. 1

( 1 C 20

( 1 C 6

# ns1,atm1,ns2,atm2,ns3, a tm3( 1 C 20 )no. 2

( 1 C 6

( 1 H 6ang l e be tween pl ane n o. a a n d n o . bab

ang l e1

2

91 . 14***** torsional ang l es *** * *# ns1,atm1,ns2,atm2,ns3,atm3( 1 H 6

no. 1

( 1 C 6

( 1 C 5

# ns1,atm1,ns2,atm2,ns3,atm3
no. 2( 1 C 6

( 1 C 5

( 1 H 5 B)

# ns1,atm1,ns2,atm2,ns3,atm3

no. 3( 1 C 6

( 1 C 5

( 1 H 5 A)

angle between plane no. a and no. babangle

a

b

angle

a

b

angle

1

2

l'

3

77.80

2

3

51.97

129.77***** torsional angles *****# ns1,atm1,ns2,atm2,ns3,atm3( 1 C 2

( 1 H 2

no. 1

( 1 C 3

# ns1,atm1,ns2,atm2,ns3,atm3
no. 2( 1 H 3 A)

( 1 C 3

( 1 C 2

# ns1,atm1,ns2,atm2,ns3,atm3
no. 3( 1 H 3 B)

( 1 C 3

( 1 C 2angle between plane no. a and no. b
a

b

angle

a

b

angle

a

b

angle

1

2

142.90

1

3

24.60

2

3

118.30-110-

Table 2-10
Positional parameters and equivalentisotropic thermal parameters with e.s.d. inparentheses

atom

x

y

z

B(eq)

o1
o2

-0.1562 ( 3 )-0.2192 (3 )0.0081 ( 3 )0.0236 (4 )-0.0160 ( 5)-0.1227 (4 )-0.0988 (5 )-0.1020 (4 )0.0214 (6 )0.0299 ( 5 )0.1293 ( 6 )0.137 (1 )0.038 ( 1 )-0.058 (1 )-0.0639 ( 6)0.1528 ( 4 )0.1886 ( 5 )0.3070 ( 6 )0.3900 ( 6)0.3556 ( 6 )0.2376 ( 5 )-0.2129 ( 5 )-0.3255 ( 6 )-0.030 ( 6 )-0.023 ( 6)-0.024 ( 5 )-0.327 ( 6 )-0.108 ( 5 )0.102 ( 6)0.050 (5 )-0.040 ( 6)-0.162 ( 6)0.191 (6 )-0.133 ( 8)0.130 ( 6 )0.209 ( 6)0.411 ( 6)0.474 ( 6)-0.329 ( 6)-0.202 ( 5 )0.210 (7 )0.056 ( 6 )0.330 ( 6)-0.139 (7 )-0.396 ( 6 )-0.205 ( 6 )-0.0264 ( 1 )0.0552 (2 )0.1216 ( 2 )0.0850 ( 2 )0.0283 ( 2 )0.0258 ( 2 )0.0575 ( 2 )0.1126 ( 2 )0.1765 ( 2 )0.2149 ( 2 )0.2187 ( 3 )0.2537 ( 4 )0.2861 ( 3 )0.2829 ( 3 )0.2480 ( 3 )0.0850 ( 2 )0.1006 ( 2 )0.1001 ( 3 )0.0839 ( 3 )0.0668 ( 3 )0.0664 ( 3 )0.1094 (2 )0.1251 ( 3 )0.013 (2 )0.045 (2 )0.100 (2 )0.112 ( 3 )0.141 ( 2 )0.181 (2 )0.004 (2 )0.181 (2 )0.051 (2 )0.193 ( 3 )0.305 (3 )0.109 (2 )0.053 (3 )0.048 (3 )0.085 ( 3 )0.161 ( 3 )-0.028 ( 2 )0.253 (4 )0.308 (2 )0.108 (2 )0.249 ( 3 )0.113 ( 3 )0.132 ( 3 )-0.0226 (6 )-0.1496 (6 )-0.0615 (6 )-0.2524 (9 )-0.199 (1 )-0.0492 (9 )0.1600 (9 )0.062 (1 )-0.138 (1 )0.052 (1 )0.177 (1 )0.359 (2)0.400 (2 )0.275 (2)0.105 (2 )-0.3201 (9 )-0.528 ( 1 )-0.585 ( 1 )-0.437 (1 )-0.229 (1 )-0.170 (1 )-0.083 (1 )0.037 (1 )-0.33 (1 )0.23 (1 )-0.39 (1 )0.20 (1)0.17 (1 )-0.23 ( 1)
-0.11 (1 )-0.24 (1 )0.27 ( 1)
0.13 (1 )0.31 (2 )-0.63 (1 )-0.03 (1 )-0.12 (1 )-0.49 (1 )0.09 ( 1)
0.11 (1 )0.43 (2 )0.53 (1 )-0.74 (1 )0.03 (1 )-0.05 (1 )-0.21 (1 )

3.8 (1 )
4.3 (1 )
3.3 (1 )
3.3 ( 2 )3.8 (2 )3.3 (2 )3.3 (2 )3.4 (2 )4.4 (2 )4.2 (2 )5.7 (2 )8.0 (3 )
8.6 (4 )
8.6 (4 )
6.5 ( 2 )3.5 (2 )4.2 (2 )5.2 ( 2 )5.2 (2 )5.8 (2 )4.8 (2 )4.0 (2 )5.5 (2 )3.81 (0 )3.34 (0 )3.33 (0 )5.54 (0 )3.45 ( 0 )4.44 ( 0 )3.81 (0 )4.08 (0 )3.34 (O )5.70 ( 0 )8.64 (0 )4.21 (0 )4.81 (O )5.76 CO)5.17 (0 )5.54 (0 )4.08 (0 )7.98 (0 )4.08 (0 )4.08 (0 )6.52 (O )5.54 (0 )3.99 (0 )

N 1
C 2
C 3
C 4
C 5
C 6
C 7
C 8
C 9
C 10
C 11
C 12
C 13
C 14
C 15
C 16
C 17
C 18
C 19
C 20
C 21
H 3 A
H 5 A
H 2
H 21A
H 6
H 7
H 3 B
H 38
H 5 B
H 9
H 12
H 15
H 19
H 18
H 17
H 21B
H 47
H 10
H 31
H 24
H 13
H 21C
H 20

0

-111-

Table2-11

No
formulamol wteryst syst
space group
eryst dimens, mm

a,A
b, A
c, A
u, deg~, degy, degV , A3Z
Deale, g em- 3
abs eoeff, cm- 1

F(OOO)
radiation; A, A
temp,OC
28 max, degscan rate, deg/min
linear decay, %data collected
total data collcd, unique,obsd
R int
no of params refined

R, R w , sa
max shift in final cycle
final diff map, max, el A3

C20H23N02309.0
orthorhombic
P2121210.55 x 0.50 x 0.30
11.380 (2)25.362 (4)6.016 (2)9090901736.4 (7)
4
1.18
0.42
664
Mo Kcx, 0.71073
23 ± 150
2.0-h,+k,+l1847, 1794, 1389 (F>3a(F)0.02
283
0.054,0.063,2.13
0.50
0.19

a Function minimized was sum [w(IFoI2_IFcl 2 )2] which
w=1.0/[( (JIFoI2+0.0003IFoI2].
R=L[(IIFol-IFcll)/LIFol. RW=[LW(IFol-IFcI)2/LIFoI2] 1/2.

-112-

Table 2-12
Intramolecular Distances (A) with e.s.d. lnparentheses
atom

atom

--c 4
o 2 --c 16
N 1
--c 6
N 1
--c 2
N 1
--c 7
C 2 --c 14
C 2 --c 15
C 2 --c 3
C 3 --c 4
C 4 --c 5
C 5 --c 6
C 6 --c 16
C 7 --c 8
C 8 --c 9
C 8 --c 13
C 9 --c 10
C 10 --c 11
C 11 --c 12
C 12 --c 13
C 16 --c 17
0 1

distance
1.227
1.431
1.456
1.473
1.475
1.528
1.534
1.557
1.481
1.483
1.541
1.536
1.514
1.374
1.402
1.369
1.358
1.359
1.402
1.524

(5 )
( 6)
(4 )
(5 )
(5 )
(6 )
(7 )
(7 )
(6 )
(6 )
(7 )
(5 )
(6 )
(7 )
(5 )
(7 )
(7 )
(9 )
(7 )
( 6)

-113-

Table2-13

Intramolecular Angles (degrees) with e " s.d. In
parentheses
atom

atom

angle

--c 2
C 6 --N 1 --c 7
C 2 --N 1 --c 7
N 1 --c 2 --c 14
N 1 --c 2 --c 15
N 1 --c 2 --c 3
C 14 --c 2 --c 15
C 14 --c 2 --c 3
C 15 --c 2 --c 3
C 4 --c 3 --c 2
0 1--c 4 --c 3
0 1--c 4 --c 5
C 3 --c 4 --c 5
C 4 --c 5 --c 6
N 1 --c 6 --c 16
N 1 --c 6 --c 5
C 16 --c 6 --c 5
N 1 --c 7 --c 8
C 9 --c 8 --c 13
C 9--c 8 --c 7
C 13 --c 8--c 7
C 10 --c 9--c 8
C 11 --c 10 --c 9
C 10 --c 11 --c 12
C 11 --c 12 --c 13
C 12 --c 13 --c 8
0 2--c 16 --c 17
0 2--c 16 --c 6
C 17 --c 16 --c 6

112.3

C 6

atom

--N 1

(3 )

114.6 (3 )115.4 (3 )110.4 ( 3 )109.7 (3 )
110.3

(4 )

107.7 ( 4 )110.6 ( 4 )108.1 ( 4 )111.0 (4 )122.9 ( 4 )121.6 ( 4 )115.4 ( 4 )110.1 ( 4 )113.4 ( 3 )112.9 ( 3 )111.6 ( 4 )114.0 ( 4 )117.3 ( 4 )123.3 (3 )119.2 ( 4 )122.0 ( 4 )121.2 ( 6 )118.6 ( 5 )121.7 (4 )119.2 ( 5 )111.7 (4 )109.1 ( 4 )111.1 (4 )-114-

Table 2-14
positional parameters and equivalentisotropic thermal parameters with e.s.d. inparentheses

atom

x

y

z

B (eq)

0 1
0 2

0.0909 ( 3 )0.1152 (2 )0.1113 (2 )0.1200 ( 2 )0.1658 (3 )0.1184 ( 3 )0.1033 (4 )0.0611 ( 3 )0.1952 (3 )0.2023 ( 3 )0.1304 (3 )0.1378 (4 )0.2172 ( 4 )0.2902 ( 4 )0.2846 ( 3 )0.1741 ( 4 )0.0258 ( 3 )0.0432 ( 3 )-0.0488 ( 4 )-0.007 ( 3 )0.232 ( 4 )0.038 ( 3 )0.341 ( 4 )0.329 (4 )0.248 ( 4 )0.159 (4 )0.198 ( 3 )0.162 ( 3 )0.077 (4 )0.078 ( 4 )0.218 ( 4 )0.235 (4 )0.032 (4 )-0.064 (4 )-0.102 (4 )-0.011 ( 4 )0.000 (4 )0.104 (3 )-0.046 (4 )0.068 ( 3 )0.178 ( 4 )0.137 (4 )0.6252 ( 4 )-0.0269 ( 4 )0.2626 (4 )0.4482 (5 )0.5459 ( 6 )0.5102 ( 5 )0.3245 ( 5 )0.2327 ( 5 )0.1602 (6 )0.0593 ( 5 )0.0334 (7 )-0.0651 (7 )-0.1426 (7 )-0.1181 ( 6 )-0.0204 (6 )0.4730 (8 )0.5269 ( 6 )0.0402 ( 5 )0.0144 (8 )0.283 ( 6 )0.496 ( 7 )-0.026 ( 6 )-0.179 ( 8 )-0.003 (7 )0.217 ( 6 )0.262 (7 )0.070 ( 6 )0.672 ( 8 )-0.084 ( 7 )0.091 ( 7 )-0.225 ( 7 )0.443 ( 8 )0.636 (7 )-0.102 ( 8 )0.039 ( 8 )0.460 (7 )0.547 (7 )-0.147 ( 7 )0.106 ( 8 )0.310 ( 6 )0.584 ( 9 )0.386 ( 8 )

(3 )
(2 )
0.3564 ( 2 )0.3844 ( 3 )0.314~~ ( 4 )0.195B ( 4 )0.1657 (4 )0.2399 ( 3 )0.4034: (4 )0.5055 ( 3 )0.5384 ( 4 )0.6284 ( 4 )0.6892 ( 4 )0.6603 (4 )0.5676 (4 )0.5070 (4 )0.3592 ( 4 )0.2102 ( 4 )0.1188 ( 4 )0.219 ( 3 )0.345 ( 4 )0.277 ( 4 )0.701 ( 5 )0.543 ( 4 )0.423 (4 )0.179 (4 )0.344 (4 )0.328 (4 )0.646 (4 )0.496 (4 )0.756 ( 5 )0.524 ( 5 )0.394 (4 )0.092 ( 5 )0.149 ( 5 )0.387 (4 )0.285 ( 5 )0.164 (4 )0.057 ( 5 )0.093 ( 5 )0.520 (5 )0.552 (5 )

7.9 ( 1 )
6.4 (1 )4.24 ( 9 )
5.0 ( 1 )6.0 ( 1 )
5.6 (1 )
5.9 ( 1 )
4.4 ( 1 )
5.3 (1 )
4.8 ( 1 )
6.2 (1 )
7.3 ( 2 )7.0 ( 2 )6.5 (2 )6.1 (1 )
7.4 (2 )6.4 ( 2 )5.4 ( 1 )
7.4 ( 2 )4.19 ( 0 )5.68 ( 0 )5.06 (0 )6.62 ( 0 )5.96 (0 )5.01 ( 0 )5.47 ( 0 )5.01 ( 0 )5.68 ( 0 )7.03 (0 )5.93 (0 )6.89 (0 )7.31 ( 0 )6.05 ( 0 )7.11 ( 0 )7.11 ( 0 )6.05 ( 0 )6.05 ( 0 )4.77 ( 0 )7.11 ( 0 )5.47 ( 0 )7.31 ( 0 )7.31 ( 0 )

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H 6
H 3 A
H 16
H 12
H 13
H 7 A
H 5 A
H 7 B
H 3 B
H 10
H 9
H 11
H 14A
H 15A
H 17A
H 17B
H 15B
H 15C
H 2
H 17C
H 5 B
H 14B
H 14C

N
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C

-115-

0.12670.180~)

Table2-15

No

formulamol wteryst syst
space group
eryst dimens, mm

V, A3

C16H23N02
261.4
monoclinic
P211n
0.75 x 0.60 x 0.25
15.878 (4)7.721 (2)13.083 (4)90
111.53 (2)901492.1 (7)Z

4Deal c , g cm- 3

1.16
0.42
568
Mo Ku, 0.71073
23 ± 1
50
2.0

a,A
b, A
c, A
u, deg~, degy, degabs coeff, cm- 1
F(OOO)
radiation; A, A
temp,OC
28 max, degsean rate, deg/min
linear decay, %data collected
total data collcd, unique,obsd
R int
no of params refined
R, R w , sa
max shift in final eycle
final diff map, max, el A3+h,-k,±l2998, 2627, 1645 (F>3cr(F)0.05
242
0.071, 0.094, 1.99
1.46
0.23

a Function minimized was sum [w(IFoI2_IFcl 2 )2] which
w=I.0/[(crIFoI2+0.0003IFoI2].
R=l:[ (1IFol-IFcll)/LIFol. Rw= [l:w(IFol-IFcI)2/LIFoI2] 1/2.

-116-

Table 2-16
Intramolecular Distances (A) with e.s.d. lnparentheses
atom

distance

--c 4
--c 4
--c 20
N 1
--c 7
N 1
--c 2
N 1
--c 6
C 2 --c 14
C 2 --c 3
C 3 --c 4
C 4 --c 5
C 5 --c 6
C 6 --c 20
C 7 --c 8
C 8 --c 9
C 8 --c 13
C 9 --c 10
C 10 --c 11
C 11 --c 12
C 12 --c 13
C 14 --c 15
C 14 --c 19
C 15 --c 16
C 16 --c 17
C 17 --c 18
C 18 --c 19
C 20 --c 21
C 21 --c 23
C 21 --c 22

1.40 (1 )1.427 ( 8 )1.474 ( 8 )1.46 (1 )1.469 ( 9 )1.47 (1 )1.50 (1 )1.54 (1 )1.53 (1 )1.53 ( 1 )1.52 (1 )1.550 ( 9 )1.48 (1 )1.36 (1 )1.39 (1 )1.37 (2 )1.38 (1 )1.36 (2 )1.37 (1 )1.37 ( 1 )1.41 (1 )1.38 (1 )1.37 (2 )1.40 (1 )1.40 (1 )1.55 (1 )1.53 (1 )1.54 (1 )

atom

o 1
o 2
o 2

-117-

Table2-17Intramolecular Angles (degrees) YI,i th e. s . d . ln
parentheses
atom
C 4
C 7
C 7
C 2

atom
--0 2
--N 1
--N 1
--N 1

atom

--c 20
--c 2
--c 6
--c 6
--c 14
--c 3
--c 3
--c 2

--c 2
--c 2
C 14 --c 2
C 4
--c 3
0 1
--c 4 --0 2
0 1--c 4 --c 5
0 1--c 4 --c 3
0 2--c 4 --c 5
0 2--c 4 --c 3
C 5--c 4 --c 3
C 6--c 5 --c 4
N 1--c 6 --c 5
N 1--c 6 --c 20
C 5--c 6 --c 20
N 1--c 7 --c 8
C 9--c 8 --c 13
C 9--c 8 --c 7
C 13 --c 8
--c 7
C 8
--c 9 --c 10
C 9--c 10 --c 11
C 12 --c 11 --c 10
C 11 --c 12 --c 13
C 12 --c 13 --c 8
C 15 --c 14 --c 19
C 15 --c 14 --c 2
C 19 --c 14 --c 2
C 14 --c 15 --c 16
C 17 --c 16 --c 15
C 16 --c 17 --c 18
C 19 --c 18 --c 17
C 18 --c 19 --c 14
0 2--c 20 --c 21
0 2--c 20 --c 6
C 21 --c 20 --c 6
C 23 --c 21 --c 22
C 23 --c 21 --c 20
C 22 --c 21 --c 20
N 1
N 1

angle
110.6 (4 )111.9 (7 )112.0 ( 5 )113.4 ( 5 )111.8 ( 5 )110.3 (7 )110.5 ( 5 )112.0 ( 5 )111.0 ( 5 )112.2 ( 8 )112.2 ( 6 )102.6 ( 5 )109.7 (7 )108.7 ( 5 )98.6 (7 )108.1 ( 5 )112.5 (7)102.5 ( 6 )112.9 ( 8 )115.2 ( 8 )123.0 (7 )121.8 ( 8 )125.2 ( 8 )
118 ( 1)119 (1 )121.5 ( 9 )121.0 ( 9 )118.3 (7 )121.8 ( 9 )119.9 ( 6 )
122 ( 1)
119.4 ( 8 )120.5 ( 8 )
119 (1 )120.2 (7)110.7 ( 6 )102.3 ( 5 )113.4 (7 )111.7 (7 )109.8 ( 8 )106.4 (7 )-118-

Table 2-18
positional parameters and equivalentisotropic thermal parameters with e.s.d. In
parentheses
atom

x

y

z

B (eq)

0 1
0 2
N 1
C 2
C 3
C 4
C 5
C 6
C 7
C 8
C 9
C 10
C 11
C 12
C 13
C 14
C 15
C 16
C 17
C 18
C 19
C 20
C 21
C 22
C 23
H 2
H 3 A
H 6
H 7 A
H 15
H 11
H 19
H 7 B
H 3 B
H 5 A
H 5 B
H 20
H 21
H 9
H 10

0.1879 (5 )0.0262 (4 )0.2339 ( 6 )0.1727 ( 6)0.2013 ( 7 )0.1706 ( 8 )0.2693 (8 )0.1946 (8 )0.1989 ( 9 )0.300 (1 )0.449 (1 )0.546 (1 )0.491 ( 1 )0.342 (1 )0.247 ( 1 )0.2344 ( 8 )0.3831 (9 )0.4409 (9 )0.348 (1 )0.194 (1 )0.1384 ( 8 )0.0290 ( 8 )-0.0310 ( 9 )-0.054 ( 1 )-0.175 ( 1 )0.0627100 (0.1291800 (
0.1696000 (0.1889900 (
0.4615100 (0.5487300 (0.0256500 (0.0880700 (
0.3021100 (0.3736900 (
0.2703300 (-0.0328000 (0.0292700 (
0.4996300 (0.6572300 (0.3021000 (0.1366200 (0.5554700 (
0.4018200 (0.1243400 (-0.0897800 (0.0464800 (-0.1220400 (-0.2133400 (-0.2472700 (-0.1583000 (- 0.7560 ( 5 )-0.7586 (4 )-0.4609 ( 6 )- 0.4434 ( 6 )-0.5251 (7 )-0.6780 (8 )-0.6604 ( 8 )-0.6144 ( 8)-0.3947 ( 8 )-0.3619 ( 9 )-0.288 ( 1 )-0.248 ( 1 )-0.290 ( 1 )-0.362 ( 1 )-0.398 ( 1 )-0.2836 ( 8 )-0.1893 ( 9 )-0.0433 ( 9 )0.0101 (8 )-0 . 0821 (9 )-0.2281 (8 )-0.7249 (8 )-0.8670 (9 )-0.826 ( 1 )-0.988 (1 )-0.5089000 (-0.5705600 (-0.6614000 (-0.2964200 (-0.2275000 (-0.2588900 (-0.2714000 (-0.4665200 (-0.4722800 (-0.5798100 (-0.7533599 (-0.6791700 (-0.9189700 (-0.2649000 (-0.1812600 (-0.3886600 (-0.4536100 (0.0192200 (0.1204900 (-0.0459299 (-0.9103400 (-0.7438700 (-0.7857499 (-1.0782501 (-0.9498700 (-1.0039901 (- 0.162B (2 )-0.1113 ( 1 )-0.0663 ( 2 )-0.106B (2 )- 0.1432 (2 )-0.1292 ( 2 )-0.0909 ( 2 )- 0.0575 (2 )-0.0304: (2 )0.0066 (2 )0.0026 (3 )0.0359 (4 )0.0766 (3 )0.0824 ( 3 )0.0483 ( 3 )-0.1182 (2 )-0.1226 (2 )-0.1345 (2 )-0.1424 ( 2 )-0.1387 (3 )-0.1254 (2 )-0.0653 (2 )-0.0381 (3 )0.0074 ( 3 )-0.0575 ( 3 )-0.1038200 (-0.1737200 (-0.0247000 (-0.0364·400 (-0.1149900 (

7.2 (2 )5.7 (2 )5.9 (2 )5.0 (3 )5.3 ( 3 )5.6 ( 3 )6.7 (3 )5.9 (3 )7.2 ( 3 )
6.8 ( 4 )11.6 ( 5 )13.5 ( 6 )
9.8 (5 )9.6 (5 )
8.7 (4 )
5.3 ( 3 )6.6 ( 3 )7.4 (4 )
7.7 ( 4 )
7.6 ( 4 )
6.3 (3 )6.2 ( 3 )7.7 (4 )11.0 ( 5 )11.7 (5 )4.50 (0 )4.81 ( 0 )5.12 ( 0 )6.14 ( 0 )6.03 ( 0 )9.34 ( 0 )5.54 (0 )6.14 ( 0 )4.81 ( 0 )5.72 (0 )5.72 ( 0 )5.37 ( 0 )6.96 ( 0 )11.43 ( 0 )13.48 (0 )8.56 (0 )7.59 (0 )6.88 ( 0 )7.19 ( 0 )6.86 ( 0 )9.25 ( 0 )9.25 ( 0 )9.25 ( 0 )11.24 ( 0 )11.24 ( 0 )11.24 ( 0 )

H 12
H 13
H 16
H 17
H 18
H 22A
H 22B
H 22C
H 23A
H 23B
H 23C

-119-

o .1005~)00-0.1245800-0.0193600-0.1483600-0.0980700-0.0854100-0.0565300-0. 0384~)00-0.0269400
0.0296200

o .1119~iOO

0 . 0538000-0.1371700-0.1515800-0.1461300
0.0283000
0.0194600
0.0078600-0.0397600-0.0558600-0.0870600

(
(
(
(

(
(

(
(
(
(

(
(
(
(
(
(
(
(
(
(

(

H 1

0.0901600 (-0.8049299 (- 120--0.1784099 (5.18 (0)Table2-19

No
formulamol wteryst syst
space group
eryst dimens, mm
a,A
b, A
c, A
u, deg~, degy, degV, A3

C22H27N02
337.0
trigonal
P3221
0.70 x 0.50 x 0.20
10.478 (2)10.478 (2)31.20 (1)90
90
120
2966 (2)Z

6Deale, g cm- 3

1.13
0.39
1092
Mo Ku, 0.71073
23 ± 150
4.0

abs coeff, cm- 1

F(OOO)
radiation; A, A
temp,OC
28 max, degsean rate, deg/min
linear decay, %data collected
total data coIled, unique,obsd
R int
no of params refined

R, R w , sa
max shift in final cycle

final diff map, max, el A3+h,+k,+l2172,2047, 1242 (F>3a(F)0.02
227
0.076, 0.066, 2.29
3.34
0.27

a Function minimized was sum [w(IFoI2_IFcl 2 )2] which

w=I.0/[(aIFoI2+0.0003IFoI2].
R=L[("Fol-IFc")ILIFol. RW=[LW(IFol-IFcI)2/LIFoI2] 1/2.

-121-

2-6. References

1) Weinreb, S. M. Acc. Chern. Res. 1985,18, 16. Weinreb. S. M.; Staib, S. S.
Tetrahedron 1982,38, 3087.
2) Danishefsky, S. 1.; Langer, M. E.; Vogel, C. Tetrahedron L4ett. 1985,26, 5983.
Danishefsky, S. 1.; Vogel, C. 1. argo Chern. 1986,51, 3916.
3) Pfrengle, W.; Kunz, H. 1. argo Chem. 1989,54,4261.
4) Boumendjel, A.; Roberts, 1. C.; Hu, E.; Pallai, P.V. 1. argo Chern. 1996,61, 4434.
5) Volkmann, R. A.; Davis, 1. T.; Meltz, C. N. 1. Arn. Chern. Soc. 1983,105, 5946.
Scully, F. E. 1. argo Chern. 1980,45, 1515.
Stork, G.; Dowd, S. 1. Am. Chent. Soc. 1963,85,2178.
Hosomi, A.; Araki, Y.; Sakurai, H. 1. Arn. Chern. Soc. 1982,104,2081.
6) Wada, M.; Sakurai, Y.; Akiba, K.-y. Tetrahedron Lett. 1984., 25, 1079.
7) Yamamoto, Y. Angew. Chern. Int. Ed. Engl. 1986,25, 947.
8) lung, M. E.; Shishido, K.; Light, L.; Davis, L. Tetrahedron Lett. 1981,4607.
9) Danishefsky; S. 1.; Langer, M. E.; Vogel, C. 1. Arn. Chern. Soc. 1976,98, 6715.
10) Larsen; S. D.; Grieco, P.A. 1. Arn. Chern. Soc. 1985,107, 1768.
Grieco, P. A .; Bahsas, A. 1. argo Chern. 1987,52, 5746.
11) Waldmann, H. Angew. Chern .. Int. Ed. Engl. 1988,27, 274.
12) Danishesky, S. 1.; Kerwin, 1. F., lr. 1. argo Chern. 1982,47, 3183.
Kerwin, 1. F., lr.; Danishesky, S. 1. Tetrahedron Lett. 1982,23,3739.
13) Brandstadter, M. M.; Ojima, 1. Tetrahedron Lett. 1987,28,613.

14) Midland, M. M.; McLoughlin, 1. 1. Tetrahedron Lett. 1988, .29, 4653.

15) Hattori, K.; Yamamoto, H. 1. argo Chern. 1992,57, 3264.
Hattori, K.; Yamamoto, H. Synlett 1993, 129.
16) Vacca, 1. P. Tetrahedron Lett. 1985,26, 1277.

17) Veyrat, C.; Watski, L.; Seyden-Penn, 1. Tetrahedron Lett. 1986,27, 2981.
Le Coz, L.; Wartski, L.; Seyden-Penn, 1. Tetrahedron Lett. 1989,30,2795.
Le Coz, L.; Veyrat-Martin, C.; Wartski, L., Seyden-Penn, 1.; Bois, C.; Philoche--122-Levisalles, M . 1. Org. Cllent. 1990,55,4870.
18) Akiba, K.-y.~ Motoshima, T.~ Ishimaru, K., Yabuta, K.~ Hirota, H.~ Yamamoto, Y.

Synlett 1993, 657.
19) Preliminary communication has been reported: Ishimaru, K.~ Watanabe, K.; Yamamoto,Y.; Akiba, K.-y. Synlett 1994,495.
20) Ishimaru, K.; Tsuru, K.; Yabuta, K.; Wada, M.; Yamamoto, Y.; Akiba, K.-y.

Tetrahedron, 1996,52,13137.
21) Waldmann, H.; Braun, M. 1. Org. Chern. 1992,57,4444.
22) Lee, Y.-G.; Ishimaru, K.; Iwasaki, H.; Ohkata, K.; Akiba, K.-y. 1. Org. Chern. 1991,
56,2058.
23) Ohkata, K.; Lee, Y.-G.; Utsumi, Y.; Ishimaru, K.; Akiba, K.-y. 1. Org. Chern. 1991,
56,5052.
24) Li, W.-R.~ Ewing, W. R.; Harris, B. D.; Jouillie, M. M. 1. .Am. Chern. Soc. 1990,

112,7659.
25) Coppens, P.; Hamilton, W. C. Acta Crystallogr. 1970, .A26., 71.

-123-

Chapter 3.

Stereoselective Synthesis of 1,2-Amino Alcohols
by Nucleophilic Addition of Orgallometallic
Reagents to a-Silyloxyimin.es

3-1. Introduction
There are a number of natural products containing a 1,2-amino alcohol unit
which is found also in many important drugs. 1a-e For exaITlple, Statin 65 and
AHPPA 66 (3-amino-2-hydroxy-5-phenylpentanoic acid) are essential componentsof pepstatin and aphatinin, respectively, and both are natural peptidic inhibitors ofacidic proteases such as renin and HIV -I-protease) The biological activity ofthese analogues is found to depend strongly on the relative and absolutestereochemistry of y-amino-p-hydroxy acid functionality.

R=i-Bu: statin 65{ R=Bn: AHPP A 66

Recently, haptens (67a,b, 68a,b, 69a,b) containing a 1,2-amino alcohol
functionality were synthesized with the goal of generating antibodies for thehydrolysis of ester and amide. 3

67a: R=SH
67b: R=CH 2C0 2H

68a: R=N-·hydroxysuccinimide
68b: R=OH

o

0

N~'R

H

69a: R=N-hydroxysuccinimide
69b: R=OH-124-

Other examples containing a 1,2-amino alcohol unit in natural products areshown below.
OH~~~OMe)J~OMe
HOdenopamineOH

r\O~W~1~ OMe
V
1# OMebevantolol

In addition, 1,2-amino alcohols have been used as chiral sources in many
asymmetric induction reactions involving metal reagents as shown in Table. 4a ,5Reagent(equiv.)

Substrate(equiv.)

ee(%)

Et2Zn

PhCHO

98 (R)

Et2Zn

PhCHO

100 (R)2

Me2CuLi

PhCHO

16.5 (R)

JNM.

Et2Mg

t-BuCHO

20 (R)

n-Bu4AlLi

PhCOC0 2Me

43

Me4Ti

O-N02C 6 H 4CHO

90 (R)

Chiral Auxiliary0~...cOH

I-J<

P

H

OH

JNM.
H

P H OH

H

2

P

P

H

OH

J:NM.

2

~ OH
Ph

PXOH
NHS0 2 Ar+Me2CHOH-125-

To synthesize these amino alcohols, some kinds of strategies have beenreported. 1 Examples are shown as follows;(i) nucleophilic addition of organometallic reagents (Grignard, lithium reagents,
trialkylsilyl cyanide / Lewis acid, alkyl titanium reagents 1b, boron enolates 2d ) toa-amino aldehydes which were prepared from chiral amino acids (eq 14))( preparation of starting materials)
NBn2

nucleophile(R')- - - -..-

R

,.·l

~OH

T

+

(eq 14-1) Ib

R'chelation productnon-chelation productnon-chelation product---R'MgX, R'2CuLi, R'CeCI 2, R'3SiCN /' ZnBr2' R'Li, R'Ti(NEt2h{ chelation product---TiCl 4 / R'2Zn, SnCl 4 / R'SiMe3' TiCI 4 / R'3SiCN(eq 14_2)2d
R=Me, Bn, s-Bu, i-Pr, i-Bu
H .,B
L'=

H

H "tH ----Me or

Me'~Me

-126-

H

B

H:Y'~Me

Me'~
Me

~

~

NHCbz

1. Eu(fodh,lOkbar.
Y

NHCbz+ OHC~OTBDPS - - -___
_

OMe

I

2. PPTS, MeOH

OH

HO

6

NHCbz

OTBDPS"~OTBDPS

~

+

OMe

0
'-../

OMe

OH

I'~'-"~'-"...COOH/"'-...

(eq 14_3)le

H2N

Ie

i) BuLiii) Et 2 AICICO

PPh 3l,lrFe.~

o

co

~F~G

t:!Bn2iii) ~H

OH

o

0

V

(eq 14_4)2aii) epoxy-ring opening (eq 15)o

ZHN(CH2)~OH

LiAIH4•OHZHN(CH2)~ J..

/\

1\ 'V OH(eq 15_1)lc

H NHBoc

H NHBoc(syn)i) NaN 3

acetoneH 20(eq 15-2)3ii) K 2C0 3
MeOH-H 20

62%

-127-

(regioselectivity; 94:6)

NaH, THF

OH-~·R~O
BnNy
OH

o

R~OH

(eq 15_3)4bNHBniii) elimination of halogen by azide~r

p~COOMeOAci) NaN 3 / DMF

NHBoc

p~COOMeii) H 2, Pd-C
Boc20 / EtOAc(eq 16)2c

OAciv) reduction of amino acid and oxime derivatives, and hydroboration(eq 17-1)4b

p~

J

N

i) Dibalii) PhMgBriii) NaHC03 • HP.

R

H3 0 +•COOMe,

H2N~PhOHOH(eq 17_2)4b

NH2

OH

(690/0 )p~PhOH(eq 17_3)4bd.e.=93%(eq 17-4)lg-128-v) vicinal oxyamination of olefins by Sharpless method
NR'
II

OS03

(eq 18)lfvi) biological reduction

o

A

PH

0

A

NH

Ph~COOEt

Hansenula polymorph a
SC 13865
PH•

NH

Ph~COOEt(eq 19)1hOHo(99% optical purity)
taxol side-chain synthonvii) Michael addition of an alkoxide
R1

R2

"==<

N0 2

i) BnONaii) AcOH

N0 2.. R 0 l R2
OBn

NH2

.. R~

H 2, Pd-C

OH

R2(eq 20)li

d.e.= ::::90: 10
R l=Me, Et, i-Pr, phenyl, phenethyl{

R 2=Me, Et, Ph, CsH 11
R 3 =BzI, phenethyl, phenylpropyl, Me

One of these strategies, nucleophilic addition to imines will be presented.
However, stereoselective synthesis of 1,2-amino alcohols by the addition of
nucleophiles to imines has been rather troublesome especially with enolizable
imines. 6 To circumvent the problem, Abba et.a!. had devised an efficient method
for nucleophilic addition of soft nucleophiles such as copper reagents with Lewis
acids to aldimines bearing a-hydrogens)

The use of organocoppereBF3complexes for the addition affords adducts in good yield whereas no product was
obtained when Grignard reagents were used.

-129-

RI=Ph, Et
R 2=n-Bu, phenethyl, benzyl

1

R=n-Bu, Me, phenethyl

From the results, the author decided to apply the reagents to chiral aldimines.
The crural aldimine 60a could be easily prepared from commercially available (S)ethyl lactate as shown in Chapter 2, and it is interesting to examine thediastereoselectivities due to the asymmetric induction from t.he chirality at aposition of the aldimine. In this Chapter, stereoselective synthesis of 1,2-amino
alcohols by the nucleophilic addition of organocuprate·BF3 complexes andorganolitruum reagents to an a-silyloxyimine is described. And anti or syn adducts
could be obtained stereoselectively by the choice of organometalHc reagents.

-130-

3-2. Nucleophilic Addition of Organometallic I~eagents to an
a-Silyloxyimine

At the beginning, reactions of di-n-butylcuprateeBF3 complex to a-silyloxyaldimine
60a was carried out to give anti-l ,2-amino alcohol 68b-anti diastereoselectively( anti:syn = >98:<2 ) in 80% yield after treatment with TBAF (Scheme 3-1). In addition,

reaction with n-BuLi 67b proceeded to give syn isomer 68b-syn predominantly( anti:syn = 19:81, 490/0 yield). It is interesting that each diastereomer could be obtainedwith high selectivity.

9 H n-Bun-BU2CuLie BF3 (G5b) TBAF'----1

.-

QSI~

NHBzl

/=~

G8b-anti

H

9H n-Bu)
+-~
(

NHBzl

Bzl

60a

n-BuLi (G7b)

..

TBAF

...

H

9 n-Bu(+ QH
~
NHBzl

)

~H::~

68b-syn

Scheme 3-1

These structures of 1,2-amino alcohols were determined by differential NOE spectrumof corresponding oxazolidin-2-ones 69b prepared by the reaction of the amino alcoholwith diethyl carbonate (Scheme 3-2).13 In the case of the oxazolidin-2-one derivative ofanti isomer 68b-anti, an NOE was observed between Ha and Hb (5.8%) whereas no
NOE was observed for the syn derivative 68b-syn .

-131-

OH
:

r

5.8%

NaOEt
n-Bu

(EtObCONHBzl

hexaneNOE:~=( ,Hb~

CH2C,6HS

n-Bu
68b-anti

QH:

69b-anti

NaOEt
n-Bu

(EtObCONHBzl

hexane~Ha~::10
Ml

n-B

~

~
Hb

CH 2CfiH s

no NOE
68b-syn69b-syn

Scheme 3-2

Other nucleophiles were also examined and the results were shown in Scheme 3-3 andTable 3-1. The table shows wide applicability of the reaction.

R 2 CuLi· BF3 (65)RCu. BF3 (66)

TBAF

9H R

,---- ----. I
qSi:::+( R= n-Bu, n-Oct, Me,
phenethyl, Ph)

68-anti

/==~
H
Bzl
60a

NHBzl

RLi (67)

TBAF( R= n-Bu, n-Oct, Me,
phenethyl, Ph)

9H R
1"HBZI
68-synScheme 3-3

-132-

(

\+

QH R )/y~NHBzl

Table 3-1 . Stereoselectivities of Addition of Organometallic Reagents to
60a

entry

nucleophile

product

anti :synyield

JHa,Hb (Hz)(%)

antilsyn
3.4

1

Me2CuLi-BF3

6Sa>98:<2

78

2

MeLi

68a

18:82

41

3

MeCu-BF 3

68a>98:<2

93

3.4

3.4

6.4

( 2.0 equiv.)
4n-Bu2CuLi-BF3

68b>98:<280

5n-BuLi

68b

19:81

43

6

n-BuCu-BF 3

68b>98:<2

52

7.8
3.4

( 2.0 equiv.)
7n-Bu2CuLi

68b

8(n-Octyl)2CuLi-BF3

68c>98:<285

9(n-Octyl)Li68c

11 :8971

10(PhCH2CH2)2CuLi-

68d>98:<2

75

0
3.4
4.4
3.6

BF3
11

PhCH 2CH 2Li

68d

10:90

54

12

Ph 2CuLi-BF 3

68e

95:5

58

13

PhLi

68e

20:80

67

14

Ph 2CuLi

G8e

-133-

0

4.4
4.4
8.3

Notable is the fact that fairly unreactive Ph2CuLieBF38 is also effective. The highlevels of diastereoselectivities were not nuc1eophile dependent and only a small amount of
the corresponding syn isomer was obtained in the case of Ph2CuLi eBF3 (entry 12).
OrganocoppereBF3 complexes were also effective if two equivalents of these complexes
were used (entries 3 and 6: with one equivalent of the complex, the yield was lower). 10
BF3 played an essential role for the addition, and organocuprates themselves did not give. any products in the absence of BF3 (entries 7 and 14).7 Recently, Lipshutz et.al. havediscussed about the role of BF3 eEt20 in reaction of lower order organocuprates. 9 They
found that the structure of an originally formed cuprate (R2CuLi or RR'CuLi) is changed
significantly upon exposure to BF3eEt20 based on their low-temperature NMR
experiments, and the peaks could be assigned to be R3Cu2Li, RLi and dimeric (RCuLi)2
at -80°C in THF. In our experiment, the formation of organocuprateeBF3 complex prior
to the reaction was also essential since the addition of organocuprate to the solution of

60a and BF3 was unproductive. The result shows that only activation by BF3 eEt20 of
the aldimine does not maximize both reaction-rate and yield.
Reactions of 60a with organolithium reagents 67 proceeded to give syn isomers
predominantly (anti: syn = 10:90-20:80) (entries 2, 5, 9, 11 and 13).1 1 From the table,
there was no large difference about the selectivities even when aromatic or aliphatic
lithium reagents were used. Thus each diastereomer could be prepared selectively only
by changing the choice of organometallic reagents.

-134-

The relative stereochemistry of the 1,2-amino alcohols of 68 [a) R=Me, b) R=n-Bu,e) R=Ph] could be assigned according to an empirical rule, i.e., coupling constants of anti
isomers (1=3.4 -4.4Hz) are smaller than those of syn isomers (1=6.4-8.3Hz,Table 12).1 2
However, in the case of 68 [c) R=n-octyl, d) R=phenethyl], the coupling constants werevery similar, i.e., 3.4-3.6Hz (anti) and 4AHz (syn), and one cannot be confident on theassignment of relative stereochemistry.
In order to confirm the assignment, oxazolidin-2-one 69c 14 was prepared fromcorresponding 1,2-amino alcohol (68c) as shown in Scheme 3-4. When Ha wasirradiated, an NOE was observed for Hb of 69c-anti (7 AO/o). Also, X-ray
crystallographic structural analysis of 68e-anti was carried out, slLlpporting theassignment of relative stereochemistry by the coupling constant (Figure 3-1).

yCtyl
QH

LiH MDS(i mb eO

NHB zl
68c-anti

69c-anti

Scheme 3-4

Figure 3-1. X-ray crystal structure of 68e-anti.

-135-

The syn addition of organolithium reagents can be explai ned by the chelation modeland the anti selectivity with organocuprate-BF3 complexes can be accounted for by the
Felkin-Anh model (Scheme 3-5).
~

H

Hm_OSi_B_____.

M
)1V

QH
.

I

Y

Felkin-Anh model

68-anti

CH 2 PhR

NHB zl

QH

..

:

~

R

NHBzl
68-synScheme 3-5

The quite high anti selectivities are surprising in light of the fact that the addition of
BuCu-BF3 and BU2CuLi-BF3 to Ph(Me)CH-C(H)=NPr gives a rather low
diastereoselectivity (4: 1, Scheme 3-6).1 5

pJyH

BU2CuLi-BF3

.-

80%

N,
Pr

pJyBU
HN,
Pr

+

Ph~BU
HN,
Pr

80

20

(Cram)(anti-Cram)

Scheme 3-6-136-

The difference can be rationalized as follows. The Felkin-Anh conformer 16 shown in
Scheme 3-5 should playa predominant role in the reaction of 6031 because of the electronwithdrawing effect of the oxygen atom and the bulkiness of the silyloxy group comparedwith the methyl group. In contrast, smaller difference of the steric and electronic effects
between the phenyl and the methyl substituents in Ph(Me)CH-C(H)=NPr may lead toseveral conformers responsible for the addition.

-137-

3-3. Summary

1,2-Amino alcohols were synthesized by addition of organocuprate·BF3 65 (R=nBu, n-octyl, Me, phenethyl, Ph), organocopper-BF3 66 (R=Me, n-Bu), andorganolithiums 67 (R=n-Bu, n-octyl, Me, phenethyl, Ph) to an (J.-silyloxyaldimine 60a
derived from commercially available (S)-ethyllactate. The reactions withorganocuprate-BF3 65 and organocopper-BF3 66 led to the anti isomers almost
exclusively (anti:syn=>98:<2 for R=n-Bu, n-octyl, Me, phenethyl and anti:syn=95:5
for R=Ph, 52-93% isolated yields) and the syn isomers could be obtained with highstereoselectivities by using organolithiums (anti:syn= 10:90-20:80, 41-71 % isolated
yields ).

R2 CuLi- BF3 (65)
TBAF
RCu. BF3 (66)---

QSI. ::::+-'----1( R= n-Bu, n-Oct, Me,
phenethyl, Ph)

NHBzl

68-anti

/==~
H
Bzl
GOa

9H R

RLi (67)

TBAF( R= n-Bu, n-Oct, Me,
phenethyl, Ph)

9H R~HBZI\+
68-syn-138-(

3-4. Experimental Section

1H NMR spectra were recorded at 400MHz (lEOL EX4(0) in CDC]3 in the presenceof TMS as an internal standard. Melting points were taken on a rnicro melting point
apparatus ( Yanagimoto model) and are uncorrected. Thin-layer chromatography (TLC)
was perfonned with Merck silica gel GF-245 plates. All reactions were conducted under
an argon atmosphere . Aldimine 60a was prepared as shown in Chapter 2.17

General Procedure for the Addition of OrganocuprateeBF3 with an a,Silyloxyimine (60a).

To a stirred solution of 5.04 mrnol of RLi in dry THF (20 mL) at -30°C was added
0.51 g (2.67 mmol) of CuI over a period of 5 min and the reaction mixture was stirred for
20 min at -30°C. After the solution was cooled to -78 °C and was stirred for 20 min,
BF3eEt20 (0.33 mL, 2.67 mrnol) was added dropwise over a period of 5 min. The
solution was stirred for 15 min at the same temperature, then 0.75 mL (2.52 mmol) of
imine 60a was added to the solution and the reaction mixture was allowed to wann toroom temperature and stirred overnight. The reaction was quenched with 30 mL ofaqueous NaOH (100/0). After the mixture was filtered through Celite, the filtrate was
extracted with ether (50 mL x 3). The combined organic layer was dried over anhydrous
Na2S04. After filtration, the solvent was evaporated to give the t-butyldimethylsilyl
protected product which was purified by TLC (i-PrNH2:hexane = 1:30).
To a stirred solution of t-butyldimethylsilyl protected amino alcohol containing a
mixture of anti and syn isomers in THF (1.0 mL) was added TBAF in THF (1M, 0.46
mL, 0.46 mmol) at 0 °C and the reaction mixture was stirred for 2 h at 0 °C and at room

temperature for 1 day. The mixture was treated with H20 (30 mL) and was extractedwith ether (50 mL x 3). The combined organic layer was dried over anhydrous Na2S04.

-139-

After filtration, the solvent was evaporated and the residue was chromatographed (TLC,
etherli-PrNH2 = 100: 1) to give 1,2-amino alcohol.

General Procedure for the Addition of Organolithiunl Reagents to 60a.

To a stirred solution of the imine 60a (0.75 rnL, 2.52 mmol) in dry hexane (20 rnL) at-78°C was added 2.77 mmol of RLi solution in hexane over a period of 5 min and thereaction mixture was allowed to warm to room temperature and stirred for one day,followed by treatment with 30 rnL of aqueous NaOH (l00/0). The: mixture was extractedwith ether (50 rnL x 3), and the combined organic layer was dried over anhydrous
Na2S04. After filtration, the solvent was evaporated and the residue waschromatographed (TLC, i-PrNH2:hexane = 1:40) to give t-butyldimethylsilyl protected
product. Desilylation was carried out by similar procedures described above.

(2S ,3R )-3-Benzylamino-2-heptanol(68b-anti).

The product could be purified by recrystallization (ether / hexane = 111). mp 92.2-92.7°C, 1H NMR (CDC13) 0.90-1.11 (m, 3H), 1.07 (d, 3H, J = 6.4 Hz), 1.24-1.65 (m,7H), 2.35-2.45 (m, IH), 2.50-2.55 (m, 1H), 3.80 (s, 2H), 3.88 (dq, IH, J = 3.4, 6.4
Hz), 7.20-7.40 (m, 5H). Anal. Calcd for C14H23NO: C, 75.97; H, 10.47; N, 6.33.
Found: C, 75.83; H, 10.67; N, 6.24.

(2S ,3S) -3- B enzy lamino-2- heptanol(68b -s y n).

The product could be purified for NOE spectra by separation with recycle HPLC (1,2dichloroethane). 1H NMR (CDC13) 0.87-0.94 (m, 3H), 1.18 (d, 3H, ] = 6.4 Hz), 1.30l.65 (m, 7H), 2.32-2.45 (m, 2H), 3.47 (dq, 1H, J = 7.8, 6.4 Hz), 3.71, 3.87 (ABq,-140-

2H, ] = 12.7 Hz), 7.25-7.40 (m, 5H). This was converted to oxazolidinone (69b-syn).

(lR ,2S)-I-Benzylamino-l-phenyl-2-propanol(68e-anti).

The product could be purified by recrystallization (ether / hexane = 111). mp 84.0-85.0°C, 1H NMR (CDCI3) 0.98 (d, 3H, ] = 6.4 Hz), 3.29 (d, IH, J = 9.3 Hz), 3.54, 3.69
(ABq, 2H, ] = 13.2 Hz), 3.74 (dq, IH, ] = 9.3,6.4 Hz), 7.22-7.39 (m, 10H). Anal.
Calcd for CI6HI9NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.30; H, 7.94; N,
5.69.

(IS ,2S)-I-Benzylamino-l-phenyl-2-propanol(68e-s.yn).

The product could be purified by recrystallization (ether / hexane = 11 1). mp 77.5-79.0°C, IH NMR (CDCI3) 1.01 (d, 3H, ] = 6.4 Hz), 3.65, 3.77 (ABq, 2H, ] = 13.2 Hz),3.70 (d, IH, ] = 4.4 Hz), 4.01 (dq, IH, ] = 4.4,6.4 Hz), 7.23-7.39 (m, 10H). Anal.
Calcd for CI6HI9NO: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.26; H, 7.87; N,
5.64.

(2S ,3R )-3-Benzylamino-2-butanol(68a-anti).

The product could be pqrified by recrystallization (ether / hexane = 111). mp 84.0-85.0°C, 1H NMR (CDCI3) 1.01 (d, 3H, ] = 6.4 Hz), 1.10 (d, 3H, ] == 6.4 Hz), 2.72 (dq,IH, ] = 3.4, 6.4 Hz), 3.81 (s, 2H), 3.84 (dq, IH, ] = 3.4, 6.4 Hz), 7.24-7.36 (m, 5H).
Anal. Calcd for CIIHI7NO: C, 73.70; H, 9.56; N, 7.8l. Found: C, 73.84; H, 9.61;
N,7.51.

-141-

(2S ,3S )-3- Benzylamino- 2- bu tanol(68a-s y n).

IH NMR (CDCI3) 1.11 (d, 3H, J = 6.4 Hz), 1.18 (d, 3H, J == 6.4 Hz), 2.41 (dg, IH,

J = 8.3, 6.4 Hz), 3.34 (dg, IH, J = 8.3, 6.4 Hz), 3.70, 3.94 (ABg, 2H, J = 13.2 Hz),7.22-7.38 (m, SH). HRMS(M+l) 180.1380 (calcd for CI1H17NO 180.1388).

(2S ,3R )-3-Benzylamino-2-undecanol(68c-anti).

The product could be purified by recrystallization (ether / hexane = 111). mp 86.0-87.0
DC, 1H NMR (CDCI3) 0.88 (t, 3H, J = 6.8 Hz), 1.09 (d, 3H, J = 6.4 Hz), 1.10-1.S0(m,14H), 2.S2-2.S6 (m, IH), 3.81 (s, 2H), 3.87 (dg, IH, J = 6.4, 3.4 Hz), 7.20-7.40(m, SH). Anal. Caled for C18H31NO: C, 77.92; H, 11.26; N, S.OS. Found: C,
78.18; H, 11.24; N, S.08.

(2S ,3S)-3-Benzylamino-2-undecanol(68c-sy n).

IH NMR (CDCI3) 0.89 (t, 3H, J = 6.8 Hz), 1.19 (d, 3H, J = 6.8 Hz), 1.10-1.60(m,14H), 2.36 (dt, IH, J = 4.4, 6.8 Hz), 3.47 (dg, IH, J = 4.4, 6.8 Hz), 3.72, 3.87
(ABg, 2H, J = 12.7 Hz), 7.21-7.38 (m, SH). HRMS(M+l) 278.2466 (caled for
C18H31NO 278.2484).

(2S ,3 R ) - 3 -Ben z y 1ami n 0 - 5 -P hen y 1- 2 -pen tan 0 I( 6 8 d -ant i) .

The product could be purified by recrystallization (ether / hexane:= 111). mp 87.0-87.S
DC, 1H NMR (CDCI3) 1.11 (d, 3H, J = 6.4 Hz), 1.68-1.80 (m, 2H), 2.S0-2.7S (m,3H), 3.76, 3.80 (ABg, 2H, J = 13.2 Hz), 3.91 (dg, IH, J = 3.6, 6.4 Hz), 7.10-7.35(m, 10H). Anal. Caled for C18H23NO: C, 80.25; H, 8.61; N, 5.20. Found: C,
80.48; H, 8.69; N, 5.2S.

-142-

(2S ,3S)-3-Benzylamino-S-phenyl-2-pentanol(68d-syn).

IH NMR (CDC}3) 1.21 (d, 3H, J = 6.4 Hz), 1.70-1.81 (m, IH), 1.86-1.98 (m, IH),
2.44 (dt, IH, J = 4.4, 7.3 Hz), 2.62-2.75 (m, 2H), 3.57 (dq, IH, J = 4.4, 6.4 Hz),
3.73,3.86 (ABq, 2H, J = 12.7 Hz), 7.10-7.35 (m, 10H). HRMS(M) 269.1786 (caled
for C 18H23NO 269.1780).

(4R ,SS )-cis-3-Benzy 1-4-n -butyl-S -methyl-l ,3-oxazolidin-2-one(69b-anti) .

69b-Anti was prepared from 68b-anti using diethyl carbonate and EtONa in hexane.
The product was purified with recycle HPLC (l,2-dichloroethane). When Ha wasirradiated, NOE was observed for Hb (5.8%) (Scheme 3-2). IH NMR (CDC}3)0.80 (t, 3H, J = 7.3 Hz), 1.26 (d, 3H, J = 6.3 Hz), 1.10-1.60 (m, 6H), 3.44 (dt, IH, J= 3.4, 6.3 Hz), 3.98 (d, IH, J = 15.6 Hz), 4.53 (quintet, IH, J = 6.3 Hz), 4.73 (d, IH,
J = 15.6 Hz), 7.15-7.30 (m, 5H). HRMS(M) 247.1568 (caled for C15H21N02

247.1572).

(4S ,5 S ) -trans -3 -B en z y 1- 4 -n -but y 1-5 -met h y 1-1,3 -ox a z 0 lid i n -2 -one

(6 9 b -syn).

69b-Syn was prepared from 68b-syn using diethyl carbonate and EtONa in hexane.
The product was purified with recycle HPLC (1 ,2-dichloroethane). When Ha wasirradiated, NOE was not observed for Hb (Scheme 3-2). 1H NMR (CDCl3) 0.79 (t, 3H,
J = 7.9 Hz), 1.07-1.55 (m, 6H), 1.23 (d, 3H, J = 5.9 Hz), 2.98-3.04 (m, IH), 3.95 (d,IH, J = 15.1 Hz), 4.18 (quintet, IH, J = 5.9 Hz), 4.73 (d, IH, J = 15.1 Hz), 7.05-7.30(m,5H). HRMS(M) 247.1572 (caled for C15H21N02 247.1572).

-143-

(4R ,5S)-cis-3- BenzyI-5 -methyl-4-n -octy 1-1 ,3-oxazolildin-2-one(69c-anti) .

69c-Anti was prepared from 68c-allti using lithium hexamethyldisilazide andcarbonyl diimidazole. The product was purified with recycle HPLC (1,2dichloroethane). When Ha was irradiated, NOE was observed for Hb (7.40/0) (Scheme
3-4). 1H NMR (CDCI3) 0.88 (t, 3H, J = 6.8 Hz), 1.33 (d, 3H, J = 6.6 Hz), 1.23-1.56(m. 14H), 3.51(dt, IH, J = 3.4,6.6 Hz), 4.05 (d, IH, J = 15.6 Hz), 4.60 (quintet, IH,
J = 6.6 Hz), 4.80 (d, IH, J = 15.6 Hz), 7.26-7.36 (m, 5H). HRMS(M) 303.2180(caled for C19H29N02 303.2199).

Crystal Structure of 68e-anti.

Crystallographic data for 68e-anti: CI6HI9NO, FW =241.3, orthorhombic, spacegroup P212121, a = 13.662(2) A, b = 18.822(3) A, c = 5.261(1) A, V= 1352.8(4) A3,
Z = 4, Deal = 1.18 g/cm 3 , J.1 = 0.40 cm- 1. A Crystal suitable for X-ray structure
determination was mounted on a Mac Science MXC3 diffractometer and irradiated withgraphite-monochromated Mo Ka radiation (A = 0.71073 A) for data collection. Lattice
parameters were determined by least-squares fitting of 31 reflections with 25°<28<30°.
Data were collected with the 28/0) scan mode. The structure was solved by a direct
method with a program, Monte Carlo-Multan. 18 Refinement on F was carried out by
full-matrix least-squares. All non-hydrogen atoms were refined with anisotropic themalparameters. All hydrogen atoms could be found on a difference Fourier map; thesecoordinates were included in the refinement with isotropic thermal parameters. All thecomputations were carried out on a Titan-750 computer using the crystan-G program.
The final cycle of full-matrix least-squares refinement was based on 1155 reflections [F>-144-3.00cr(F)] and 221 variable parameters with R(Rw) = 0.039 (0.044). Bond distances
and angles, atomic coordinates, and crystallographic data are shown in Tables 3-2, 3-3,
3-4, and 3-5.

-145-

Table3-2Intramolecular Distances (A) with e.s.d. lnparentheses
atom

o 1

atom

--c 2
N 1 --c 1
N 1 --c 10
C 1 --c 4
C 1 --c 2
C 2 --c 3
C 4 --c 9
C 4 --c 5
C 5 --c 6
C 6 --c 7
C 7 --c 8
C 8 --c 9
C 10 --c 11
C 11 --c 16
C 11 --c 12
C 12 --c 13
C 13 --c 14
C 14 --c 15
C 15 --c 16

distance
1.436
1.471
1.475
1.523
1.546
1.512
1.377
1.377
1.389
1.366
1.369
1.393
1.509
1.378
1.384
1.382
1.370
1.360
1.399

(3 )
(3 )
(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(4 )
(5 )
(5 )
(4 )
(4 )
(5 )
(4 )
( 5)
(6 )
(7 )
( 6)

-146-

Table3-3Intramolecular Angles (degrees) with e.s.d. In
parentheses
atom

atom

atom

--c 10N 1 --c 1 --c 4
N 1 --c 1 --c 2
C 4--c 1 --c 2
0 1--c 2 --c 3
0 1--c 2 --c 1
C 3--c 2 --c 1
C 9--c 4 --c 5
C 9--c 4 --c 1
C 5--c 4 --c 1
C 4--c 5 --c 6
C 7--c 6 --c 5
C 6--c 7 --c 8
C 7--c 8 --c 9
C 4--c 9 --c 8
N 1 --c 10 --c 11
C 16 --c 11 --c 12
C 16 --c 11 --c 10
C 12 --c 11 --c 10
C 13 --c 12 --c 11
C 14 --c 13 --c 12
C 15 --c 14 --c 13C 14 --c 15 --c 16
C 11 --c 16 --c 15
C 1

--N 1

angle
113.0 ( 2 )112.7 ( 2 )111.5 ( 2 )110.4 (2 )107.3 ( 2 )110.2 ( 2 )114.9 (2 )118.2 ( 2 )123 . 3 ( 2 )118.3 ( 2 )121.0 (3 )120.4 ( 3 )119.3 (3 )120.4 (3 )120.7 ( 3 )116.3 ( 2 )118.2 ( 3 )120.7 ( 3 )121.1 (3 )121.2 ( 3 )120.1 (4 )119.6 (4 )120.6 ( 4 )120.2 ( 4 )

-147-

atom
0 1
0 2

1
C 2
C 3
C 4
C 5
C 6
C 7
C 8
C 9
C 10
C 11
C 12
C 13
C 14
C 15
C 16
C 17
H 6
H 3 A
H 16
H 12
H 13
H 7 A
H 5 A
H 7 B
H 3 B
H 10
H 9
H 11
H 14A
H 15A
H 17A
H 17B
H 15B
H 15C
H 2
H 17C
H 5 B
H 14B
H 14C
N

Table 3-4
Positional parameters and equivalentisotropic thermal parameters with e.s.d. inparenthesesxyz

0.0909 (3 )0.1152 (2 )0.1113 (2 )0.1200 ( 2 )0.1658 ( 3 )0.1184 ( 3 )0.1033 (4 )0.0611 ( 3 )0.1952 ( 3 )0.2023 ( 3 )0.1304 ( 3 )0.1378 ( 4 )0.2172 ( 4 )0.2902 (4 )0.2846 (3 )0.1741 (4)0.0258 (3 )0.0432 ( 3 )-0.0488 (4 )-0.007 ( 3 )0.232 (4 )0.038 ( 3 )0.341 (4 )0.329 ( 4)0.248 ( 4)0.159 ( 4 )0.198 ( 3 )0.162 ( 3 )0.077 ( 4 )0.078 (4 )0.218 ( 4 )0.235 (4 )0.032 ( 4 )-0.064 ( 4 )-0.102 (4 )_-0.011 (4 )0.000 ( 4 )0.104 ( 3 )-0.046 (4 )0.068 ( 3 )0.178 (4 )0.137 ( 4 )0.6252 (4 )-0.0269 ( 4 )0.2626 (4 )0.4482 ( 5 )0.5459 ( 6 )0.5102 ( 5 )0.3245 ( 5 )0.2327 ( 5 )0.1602 ( 6 )0.0593 ( 5)0.0334 (7 )-0.0651 (7 )-0.1426 (7 )-0.1181 ( 6 )-0.0204 ( 6 )0.4730 ( 8 )0.5269 (6 )0.0402 (5)0.0144 ( 8 )0.283 (6 )0.496 ( 7 )-0.026 ( 6)-0.179 ( 8 )-0.003 (7 )0.217 ( 6 )0.262 (7 )0.070 ( 6 )0.672 ( 8 )-0.084 (7 )0.091 (7 )-0.225 ( 7 )0.443 ( 8 )0.636 (7 )-0.102 ( 8 )0.039 (8 )0.460 (7 )0.547 ( 7 )-0.147 (7 )0.106 ( 8 )0.310 ( 6 )0.584 ( 9 )0.386 ( 8 )-148-

0.1267 (3 )0.18015 (2 )0.3564 ( 2 )0.3844 ( 3 )0.3144 ( 4 )0.1958 (4 )0.1657 (4 )0.2399 (3 )0.4034 (4 )0.5055 ( 3 )0.5384 ( 4 )0.6284 (4 )0.6892 (4 )0.6603 ( 4 )0.5676 ( 4 )0.5070 ( 4 )0.3592 ( 4 )0.2102 ( 4 )0.1188 (4 )0.219 ( 3 )0.345 ( 4 )0.277 (4 )0.701 ( 5 )0.543 (4 )0.423 (4 )0.179 ( 4 )0.344 (4 )0.328 ( 4 )0.646 ( 4 )0.496 (4 )0.756 ( 5 )0.524 ( 5 )0.394 ( 4 )0.092 ( 5 )0.149 ( 5 )0.387 ( 4 )0.285 (5 )0.164 ( 4 )0.057 ( 5 )0.093 ( 5 )0.520 ( 5 )0.552 ( 5 )B(eq)7.9 ( 1 )
6.4 (1 )4.24 ( 9 )
5.0 ( 1 )6.0 ( 1 )
5.6 (1 )
5.9 ( 1 )
4.4 ( 1 )
5.3 (1 )
4.8 ( 1 )
6.2 (1 )
7.3 ( 2 )7.0 ( 2 )6.5 ( 2 )6.1 ( 1 )
7.4 ( 2 )6.4 ( 2 )5.4 ( 1 )
7.4 ( 2 )4.19 ( 0 )5.68 ( 0 )5.06 ( 0 )6.62 ( 0 )5.96 (0 )5.01 ( 0 )5.47 ( 0 )5.01 ( 0 )5.68 (0 )7.03 (0 )5.93 ( 0 )6.89 ( 0 )7.31 ( 0 )6.05 ( 0 )7.11 ( 0 )7.11 ( 0 )6.05 ( 0 )6.05 ( 0 )4.77 ( 0 )7.11 (0 )5.47 ( 0 )7.31 ( 0 )7.31 ( 0 )Table3-5Noformulamol wtcryst syst
space group
cryst dimens, mm

a,A
b, A
c, A
u, degp, degy, degV , A3Z

Deale, g cm- 3
abs coeff, cm- 1
F(OOO)
radiation; A, A
temp,OC
28 max, degscan rate, deg/min
linear decay, %data collected
total data coIled, unique,obsd
R int
no of params refined
R, R w , sa
max shift in final cycle
final diff map, max, e/A3

C16H19NO
241.3
orthorhombic
P2121210.90 x 0.35 x 0.20
13.662 (2)18.822 (3)5.261 (1)9090901352.8 (4)
4

1.18
0.40
520
Mo Ku, 0.71073
23 ± 150
1.0+h,-k,+l1475, 1410, 1155 (F>3a(F)0.00
221
0.039, 0.044, 1.49
0.26
0.20

a Function minimized was sum [w(IFoI2_IFcl 2 )2] which
W= 1.0/[ (aIFoI2+0.0003IFoI2].

R=L:[ (IIFol-IFcll)/LIFol. Rw= [L:w(IFol-IFcI)2/LIFoI2] 1/2.

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3-5.

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List of Publications

1*

Kin-ya Akiba, Toshihiro Motoshima, Kaori Ishimaru, Kazutaka Watanabe, Hiroshi
Hirota and Yohsuke Yamamoto[4+2]Type

Cycloadditionof

Aldimines

Bearinga-Hydrogens

2-Silyloxy-1,3-butadienes Catalyzed by Trimethylsilyl Triflate, Synlett,

with

1993,

657-659.
2*

Kaori Ishimaru, Kazutaka Watanabe, Yohsuke Yamamoto and Kin-ya Akiba
Stereocontrol in [4+2]Type Cycloaddition of an Aldimine Derived from (S)-Ethyl
Lactate with 2-Sily loxy-1 ,3-butadienes, Synlett, 1994, 495-498.

3*

Kaori Ishimaru, Kazutaka TSUfU, Katsunori Yabuta, Makoto Wada, Yohsuke
Yamamoto and Kin-ya Akiba
Stereoselective Synthesis of 1,2-Arnino Alcohols by Addition of Organocuprate· BF3
Complexes and Organolithium Reagents to an a-Silyloxyaldimine Derived from(S)-Ethyl Lactate, Tetrahedron, 1996,52, 13137-13144.