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This is to certify that the
dissertation entitled

PREPARATION OF OPTICALLY ACTIVE
a-HYDROXYSILANES

presented by
IL HWAN AN

has been accepted towards fulfillment
of the requirements for the

PhD. degree in CHEMISTRY

Wgwaflareflfi

Major Professor’s Signatbfi

Low 7/3. 74910

Date

MSU is an Aflinnative Action/Equal Opportunity Employer

 

PLACE IN RETURN Box to remove this checkout from your record.
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Preparation of Optically Active a-Alkoxysilanes
By
IL HWAN AN

A DISSERTATION

Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of

DOCTOR OF PHILOSOPHY
Chemistry

2010

ABSTRACT
PREPARATION OF OPTICALLY ACTIVE a-ALKOXYSILANES
By

ll Hwan An
We have studied on developing new method for the generation of optically
active a-hydroxysilanes. The ring opening of epoxy alcohols bearing a TMS
group with both aluminum and boron hydrides provided the unfavoured1,2-diol .
This result shows that silicon plays an important role in determining the
regioselectivity and that cyclic boronic esters are formed in the ring opening
reaction. The scope and limitation of enzymatic kinetic resolution of q-
hydroxysilanes in combination with different solvents, temperatures and
acetylation reagents were investigated. The reactions are sensitive to the
structures of both the silyl group and the organic side chain. In the non enzymatic
kinetic resolution, the absolute stereochemical outcomes complement our

enzymatic results.

ACKNOWLEDGEMENT

First, I would like to express my appreciation to Professor Robert E
Maleczka for his thoughtful and kind guidance for the last six years. I learned a
lot of things from him that I need to be an independent researcher. I feel
extremely lucky to be his student.

Also, I would like to thank former and current group members. All of them
are very nice to me and they are really diligent and smart people. I also enjoyed
the experience of working with them.

I could not have finished my PhD study without the love and support from
my parents, Mr. Kyoungsik An and Mrs. Youngae Lee. I would also like to
dedicate this humble thesis to my beloved wife, Hua Shao and my son, Edward

lnkyoo An.

iii

TABLE OF CONTENTS

LIST OF TABLES ................................................................................................ vii
LIST OF FIGURES ............................................................................................. viii
LIST OF SCHEMES ............................................................................................. ix
CHAPTER 1
INTRODUCTION
1.1 Synthesis of a-Hydroxysilianes ............................................................. 1
1.1.1 Retro Brook Rearrangement ................................................. 1
1.1.2 Swern Oxidation and Alkylation ............................................ 2
1.1.3 Nucleophilic Addition ............................................................. 2
1.2 Application of of a-Hydroxysilianes ....................................................... 3
1.2.1 Peterson Olefination ............................................................. 3
1.2.2 1,4-Addition to «mp-Saturated Ketones .................................. 4
1.2.3 Friedel-Craft Type Alkylation ................................................. 4
1.2.4 [2,3]-Wittig Rearrangement ................................................... 5
1.2.5 [1 ,4]-Wittig Rearrangement ................................................... 6
1.3 Synthesis of Acylsilanes ....................................................................... 6
1.3.1 Swern Oxidation of a-Hydroxysilanes ................................... 7
1.3.2 Palladium-catalyzed Acylation of hexamethyldisilane ........... 7
1.3.3 Silylation of Dithianes ............................................................ 8
1.4 Application of Acylsilanes ..................................................................... 9
1.4.1 SiIa-Stetter Reaction ............................................................. 9
1.4.2 Nucleophilic Addition to Acylsilanes ...................................... 9
1.4.3 Aldol Reactions ................................................................... 10
1.5 Requirement of Optically Pure a-alkoxysilane for [1,4]-Wittig
Rearrangement Study ........................................................................ 10
CHAPTER 2
SYNTHESIS OF OPTICALLY PURE q-HYDROXYSILANE - PRIOR ART ......... 12
2.1 Reduction of Acylsilanes .................................................................... 12
2.2 Enzymatic Kinetic Resolution ............................................................. 15
CHAPTER 3
ATTEMPTED PREPARATION FOR OPTICALLY ACTIVE a-HYDROXYSILANE
BY RING OPENING OF EPOXYALCOHOL ....................................................... 19
3.1 Introduction ......................................................................................... 19
3.2 Ring Opening of Epoxyalcohol ........................................................... 20
CHAPTER 4
ENZYMATIC KINETIC RESOLUTION OF q-HYDROXYSILANES ..................... 28

iv

4.1 Introduction ......................................................................................... 28

4.2 Mechanism of Kinetic Resolution ....................................................... 29
4.3 Enzymatic Kinetic Resolution of d-Hydroxysilanes ............................. 30
4.4 Determination of Absolute Stereochemistry ....................................... 37
4.5 Determination of °/oee using 2QSi NMR ............................................... 39
4.6 Conflict Optical Rotation Value of (R)-19 ............................................ 42
4.7 Reduction of Optically Pure Acetate ................................................... 45
CHAPTER 5
ENZYMATIC KINETIC RESOLUTION OF METHYLATED d-HYDROXYSILANE ..
......................................................................................................... 47
5.1 Introduction ......................................................................................... 47
5.2 Kinetic Resolution of Rac-24 .............................................................. 48
5.3 Determination of Absolute Stereochemistry ....................................... 51
5.4 Formation of Acetylated Hemiacetal ................................................... 53
5.5 Future Work ........................................................................................ 60
CHAPTER 6
PREPARATION OF HYDROXYSILANES BY d-HYDROXYSILANES KINETIC
RESOLUTION WITH PHOSPHABICYCLOOCTANE (PBO) ............................... 61
6.1 Attempted Preparation of a-Hydroxysilane ......................................... 61
6.2 Non Enzymatic Kinetic Resolutions — Prior Art ................................... 65
6.3 Preparation of Phosphabicyclooctane Catalyst (58) ........................... 67
6.4 Kinetic resolution of by Phosphabicyclooctane Catalyst (58) ............. 69
CHAPTER 7
DESIGNED AND SYNTHESIZED A SERIES OF NOVEL N-BOC AMINES ....... 73
APPENDIX
EXPERIMENTAL DETAILS ................................................................................ 76
Materials and Methods ............................................................................. 76
Standard Reaction Method ....................................................................... 76
Ring Opening Reaction ............................................................................ 76
Synthesis of 1,3-Diol 6 (Scheme 31) ............................................. 79
Ring Opening of 5 with Red-AI (Scheme 33) ................................. 81
Kinetic Resolution of a-Hydroxysilanes with Novozym 435 ...................... 82
Preparation of a-Hydroxysilanes .................................................... 82
Acylation of d-Hydroxysilanes ........................................................ 88
Kinetic Resolution of o-Hydroxysilanes with Novozym 435 ........... 92
29Si NMR Experiment (Table 5) ..................................................... 93
[(110 value Experiment for 1-(DimethylphenylsilyI)-2-propen-1-
ol (19) (Scheme 42) ....................................................................... 96
Reductive Cleavage of Optically Active Acetates .......................... 98
Mosher’s Ester Analyses (Figrue 6 and Figure 12) ........................ 98
Chiral GC and HPLC Analyses .................................................... 100

GC Analyses ................................................................................ 101

Enzymatic Kinetic Resolution of Methylated a-Hydroxysilanes .............. 102
Kinetic Resolution of Rec-24 and Rac-3 ...................................... 102
Identification of Acetal 33 ............................................................. 105
Mosher’s Ester Analyses (Figure 13) ........................................... 107

Resolution of d-Hydroxysilanes via Norephedrine Cabamate (Scheme

59) .......................................................................................... 108

Kinetic Resolution of d-Hydroxysilanes using PBO Catalyst .................. 109
Synthesis of 58 (Scheme 63) ....................................................... 109
Preparation of a-Hydroxysilanes .................................................. 115
Acylation of a-Hydroxysilanes ...................................................... 116
Kinetic Resolution of a-Hydroxysilanes with PBO Catalyst
..................................................................................... 119
GO Analyses ................................................................................ 120
Chiral GC and HPLC Analyses .................................................... 121

Designed and Synthesized a series of Novel N-Boc amines (Figure

17).. ....................................................................................................... 121

vi

LIST OF TABLES

Table 1 Buynak’s Asymmetric Reductions ......................................................... 13
Table 2 Kinetic Resolution of rac-3 ..................................................................... 33
Table 3 Kinetic Resolution of d-Hydroxysilanes .................................................. 36
Table 4 Enantiomeric Ratio by 298i NMR ............................................................ 41
Table 5 Retention Times of Optically Pure 19 .................................................... 44
Table 6 Reduction of Optically Pure Acetate (S)-18 ........................................... 45
Table 7 Kinetic Resolution of d-Hydroxysilanes .................................................. 48
Table 8 Test Reaction for Kinetic Resolution of Rec-49 ..................................... 69
Table 9 Kinetic Resolution of d-Hydroxysilanes .................................................. 71
Table 10 29Si and 1H Experiments for Rac-22 .................................................... 94
Table 11 29Si and 1H Experiments for Rac-3 ...................................................... 95
Table 12 29Si and 1H Experiments for Rac—25 .................................................... 95
Table 13 ”Si and ‘H Experiments for Rac-27 .................................................... 96

vii

LIST OF FIGURES

Figure 1 Transition State Model for the Reduction of Acylsilanes by (—)- IpchCI.
14

Figure 2 Possible Transition State for Ring Opening with Red-AI ...................... 24
Figure 3 a-Hydoxysilane ..................................................................................... 28
Figure 4 Kinetic Resolution ................................................................................ 28
Figure 5 Failed d-Hydroxysilanes ....................................................................... 35
Figure 6 Determination of Absolute Stereochemistry of (R)-3 ........................... 38
Figure 7 Kazlauska’s Rule ................................................................................. 39
Figure 8 Difficulty Determinating %ee ................................................................ 40
Figure 9 298i NMR of Rae-27 with Eu(tfc)3 ......................................................... 41
Figure 10 298i NMR Spectrum of R3 with Eu(tfc)3 ............................................. 42
Figure 11 Conflict [a]D Values ............................................................................ 43
Figure 12 Determination of Absolute Stereochemistry of (R)-19 ........................ 43
Figure 13 Determination of the Absolute Stereochemistry of (S)-24 .................. 51
Figure 14 Kazlauskas’ Rule for Rae-24 .............................................................. 53
Figure 15 Dynmaic Kinetic Resolution ................................................................ 60
Figure 16 Our Substrates for Kinetic Resolution ................................................ 67
Figure 17 Synthesized N-Boc Amines ................................................................ 74
Figure 18 Retention Times of d-Hydroxysilanes ............................................... 101
Figure 19 Retention times of Acetated Product ................................................ 102
Figure 20 Retention times of a-Hydroxysilanes ................................................ 120
Figure 21 Retention times of Acetated Products .............................................. 120

viii

LIST OF SCHEMES

Scheme 1 Preparation of o-Hydroxysiliane by Retro Brook Rearrangement ........ 1

Scheme 2 Preparation of d-Hydroxysiliane by Swern Oxidation .......................... 2
Scheme 3 Preparation of a-Hydroxysiliane with PhMeZSiLi ................................. 3
Scheme 4 Peterson Olefination using a-Hydroxysilane ........................................ 3
Scheme 5 Regioselective 1.4-Addition of Protected a—Hydroxysiliane ................. 4
Scheme 6 FrideI-Craft Type Alkylation ................................................................. 5
Scheme 7 MeLi-promoted [2,3]-Wittig Rearrangement ........................................ 5
Scheme 8 [1 ,4]-Wittig rearrangement ................................................................... 6

Scheme 9 Preparation of Acylsilanes from o-Hydroxysilans by Swern Oxidation 7

Scheme 10 [1 ,4]-Wittig rearrangement ................................................................. 8
Scheme 11 Preparation of Acylsilanes by Dithianes ............................................ 8
Scheme 12 Thiazolium-Catalyzed Stetter Reaction ............................................. 9
Scheme 13 Nucleophilic Addition to Acylsilanes .................................................. 9
Scheme 14 An Aldol Reaction with an Acylsilane ............................................... 10
Scheme 15 [1 ,4]-Wittig Rearrangement ............................................................. 11

Scheme 16 Preparation of Optically Pure 1-(DimethylphenylsinI)-2-proen-1-ol .12

Scheme 17 Chiral Lithium Amide Reduction ...................................................... 14
Scheme 18 Asymmetric Hydrogenation with Ruthenium Catalyst ...................... 15
Scheme 19 Kinetic Resolution of 1-Trimethylsilylpropanol ................................. 16
Scheme 20 Hydrolysis and Acylation using Enzyme .......................................... 16
Scheme 21 Kinetic Resolution of 4-TMS-3-butyn-2-ol ........................................ 17
Scheme 22 Our Synthetic Plan for Optically Active a-Hydroxysilane ................. 19

ix

Scheme 23 Synthesis of Compound 4 ............................................................... 20

Scheme 24 Regioselective Opening of Epoxyalcohol ........................................ 21
Scheme 25 Ring Opening Reaction with Red-AI ................................................ 22
Scheme 26 Ring Opening Reaction for Epoxyalcohol ........................................ 22
Scheme 27 Ring Opening Reaction for Epoxysilane .......................................... 22
Scheme 28 Ring Opening Reaction of Similar Substrates with LAH .................. 23
Scheme 29 Ring Opening Reaction using Red-AI .............................................. 23
Scheme 30 Ring Opening Reaction using Super-Hydride .................................. 24
Scheme 31 Synthesis of 1,3-Diol (11) ................................................................ 25
Scheme 32 Formation of Ethylboronic Ester ...................................................... 26
Scheme 33 Observed Product ........................................................................... 27
Scheme 34 Kinetic Resolution of Secondary Alcohol ......................................... 29
Scheme 35 Kinetic Resolution of Secondary Alcohol with Pseudomonas sp. ....29
Scheme 36 Mechanism of Kinetic Resolution .................................................... 30
Scheme 37 Kinetic Resolution of 4-TMS-3-butyn-2-ol with Amano AK .............. 31
Scheme 38 Kinetic Resolution of 1-Trimethylsilyethanol in Ionic Liquid ............. 32
Scheme 39 Solvent Effect in Kinetic Resolution ................................................. 32
Scheme 40 Possible Structure in Mosher Ester Analysis ................................. 37
Scheme 41 Enzymatic Kinetic Resolution of d-Hydroxysilane ............................ 39
Scheme 42 Reduction of Acylsilane 29 .............................................................. 44
Scheme 43 Reduction of Optically Pure Acetate by DIBAL ................................ 46
Scheme 44 Kinetic Resolution of with Amano AK .............................................. 47
Scheme 45 Kinetic Resolution with CRL ............................................................ 47

Scheme 46 Kinetic Resolution with Amano PS-D l ............................................. 48

Scheme 47 Kinetic Resolution with Amano PS-C ll ............................................ 48
Scheme 48 Comparison of Absolute Stereochemistry ....................................... 52
Scheme 49 GC data for Kinetic Resolution of Rae-24 ........................................ 54
Scheme 50 GO data for Kinetic Resolution of Rae-3 .......................................... 55

Scheme 51 Kinetic Resolution of Sterically Hindered Secondary Alcohol 34 ..... 56

Scheme 52 Enzymatic Resolution of Rae-3 with Amano PS-D I lipase and
Hydrolysis of 33 ................................................................................................... 57

Scheme 53 Possible Mechanism for Formation of Acetylated Hemiacetal 33....58

Scheme 54 Synthesis of Acetal 33 ..................................................................... 59
Scheme 55 Possible Rearrangement of 18 ........................................................ 60
Scheme 56 Dynamic Kinetic Resolution of Rac-14 ............................................ 61
Scheme 57 Racemization of (S)-14 .................................................................... 61

Scheme 58 Resolution of a-Hydroxystannes via Norephedrine Carbamate ....... 62

Scheme 59 Attempted Resolution of d-Hydroxysilane by Kells’ Protocol ........... 64
Scheme 60 Kinetic Resolution with Planar-Chiral DMAP Derivate 51 ................ 65
Scheme 61 Kinetic Resolution with Catalyst 56 ................................................. 66
Scheme 62 Kinetic Resolution with PBO Catalyst 58 and 61 ............................. 66
Scheme 63 Preparation of Catalyst 58 ............................................................... 68
Scheme 64 Regioselective Borylation of 71 and 73 ........................................... 73
Scheme 65 Regioselective 1,4-Addition of Protected d-Hydroxysiliane ............. 74

xi

Chapter 1. Introduction

a-Hydroxysilianes have emerged as an important functional group in
organic synthesis."2'3""5 Many reactions involving a-hydroxysilanes proceed by
activation of the silyl group thanks to high Si-O and Si-F bond energies. The
carbon-silicon bond is relatively long and tends not hinder reactions. Silyl groups
can also stabilize an d-anion and a B-cation and exchange with other metals.
These features make the silyl group a powerful C-C bond forming tool in organic
synthesis.
1.1. Synthesis of a-Hydroxysilianes
1.1.1. Retro Brook Rearrangement3""5"6

Many procedures have been developed for the preparation of o-
hydroxysilianes. In 1985, Danheiser and coworkers reported that reacting an
(LB-unsaturated alkylsily ether with base can initiate retro Brook rearrangement
(Scheme 1). An allyl alcohol is converted to the corresponding trimethylsilyl ether
followed by retro Brook rearrangement with t-BuLi to produce the 1-
hydroxyalyltrimethylsilane in 86% yield. This method is useful for preparation of
d-hydroxysilianes bearing vinyl and alkyne groups.

Scheme 1. Preparation of d-Hydroxysiliane by Retro Brook Rearrangement

1) n-BuLi (1.0 equiv)
TMSCI (1.0 equiv)

 

\ THF, -78 °C TMS
\/\OH =
\
2) t-BuLi (1.2 equiv) Keg/C)».
0

\ —78°C /

[ vows

 

1.1.2. Swern Oxidation and Alkylation7'8'9

q-Hydroxysilianes also can be prepared by Swern oxidation of
(trimethylsilyl)methanol followed by alkylation. Nucleophiles can include Grignard
reagents such as PhMgBr or alkyl lithiums such as n-BuLi. In the first step,
(trimethylsilyl)methanol is oxidized to afford formyltrimethylsilane (Scheme 2).
When (2-phenylethynyl)-Iithium is used as a nucleophile, the condensation
product 3-phenyI-1-(trimethylsilyI)-2-propyn-1-ol was obtained in 76% yield.

Scheme 2. Preparation of d-Hydroxysiliane by Swern Oxidation

oxalyl chloride (1.1 equiv)
DMSO (1.1 equiv)
Et3N (5.0 equiv)

II

o
HOVTMS
HJLTMS

 

 

ether, -78 °C

PhCECLi (5.0 equiv) l

—78 °c
OH
/TMS
P“ (76%)

1.1.3. Nucleophilic Addifion‘0'11'12

An alternative approach to d-hydroxysilianes is direct addition of a silyl
group to aldehydes or ketones. Dimethylphenylsilyl lithium (PhMeasiLi) is readily
available from chlorodimethylphenlysilane and lithium metal (Scheme 3).
PhMezsiLi can react with various aldehydes such as hexanal, benzaldehyde,
cyclohexanecarboxaldehyde to afford o—hydroxysilianes. Unfortunately,
trimethylsilyllithium (TMSLi) cannot be prepared by this method because it is not

stable.

Scheme 3. Preparation of a-Hydroxysiliane with PhMGQSil—i

 

0 PhMeZSiLi (1.1 equiv) 0”
Q/tkH = G/kSiPhMez
THF, -78 °c tort
(67%)

1.2. Application of of a-Hydroxysilianes
1.2.1. Peterson Olefination“14

o-Hydroxysilanes can be used for formation of olefins. As mentioned
before, the silyl group on a-hydroxysilanes can be easily removed by formation
the strong Si-O bond and this can be used for olefin synthesis (Peterson

Olefination, Scheme 4).

Scheme 4. Peterson Olefination using d-Hydroxysilane

 

 

 

"'C5H11 H —78 °c, THF 0”
(73%)
1) Mg (4.0 equiv) PPh3 (1.2 equiv)
EtZO, reflux CCl4/T HF, reflux
O 2) CuBrSMez (1.0 equiv)
_ -78 °C n-C5H11 SiMezPh
"0an ....0 - 7g
SiMezPh 3) ”'C4HQCOCI (1.0 equiv)
—10 °C (85%)
1) MeLi (1.5 equiv)
THF, —78 °C
2) KH, rt
- e H -c H
SIMezPh O _ n 4 9
n-C5H11 H Me n-C4H9 n‘C5H11 Me
(60%)

Grignard reagents derived from organochlorides are transmetalated with
copper and this substance attack the acylchloride to form the a-silyl ketone.
Addition of a nucleophile to the carbonyl group followed by elimination under
basic condition affords olefinic product
1.2.2. 1,4-Addition to a,[3-Saturated Ketones‘s'16

Silyl groups can also be easily removed by CsF to form aryl a-alkoxy
anions. These newly formed weak nucleophiles can undergo 1.4-addition to form
C-C bonds. For example, the regioselective 1,4-addition of MOM protected (0-
hydroxybenzyl)trimethylsilane to cyclopentenone shown in Scheme 5 was
reported.

Scheme 5. Regioselective 1,4-Addition of Protected a-Hydroxysiliane

 

o
iMOM O CsF (0.1 equiv)
+ >
Ph TMS C? DMF, rt OMOM
(1.0 equiv) (1.5 equiv) Ph
(68%)

1.2.3. Friedel-Craft Type Alkylationz'17

Silyl groups can also stabilize a B-cation. Vinyl silanes prepared from d-
hydroxysilanes can undergo FriedeI-Craft acylation type reactions to afford c.8-
saturated ketones. The copper-mediated allylic substitution reaction allows for
the stereoselective preparation of alkenylsilanes bearing a chiral center (Scheme
6). Importantly, the chirality is almost completely transferred to the product
during the reaction. The formed alkenylsilane can undergo Friedel-Craft acylation

type reaction to afford the o,[3-saturated ketone.

Scheme 6. Fridel-Craft Type Alkylation

CICOC6F5 (1.4 equiv)
DMAP (0.1 equiv)

 

OH pyridine (1.4 equiv) (3st
U a 0 0
/
“33 Etzo. 0 °C TBS/k)
(92%ee) (95%, 92 %ee)

i-PrZZn (2.4 equiv)
CuCn2°LiCI (1.2 equiv)
THFzNMP (2:1),

11 -50 °C

 

AICI3 (1.2 equiv)
tBu \ t-BuCOCI(1.2 equiv) _
- WIT" 1 \ i-Pr

0 CHZCIZ, —78 °c
(65%, 90%ee) (81%, 90 %ee)

 

_.|
W
a;

1.2.4. [2,3]-Wittig Rearrangement18

Our group also uses d-hydroxysilanes as Wittig rearrangement precursors.
Because the silyl group can stabilized the negative charge at the a-position or
exchange with a metal, two Vlfittig rearrangement routes are possible (Scheme 7).

Scheme 7. MeLi-promoted [2,31-Vthig Rearrangement

MeLi (1.4 equiv)

THF, rt, 16 h
‘o/ivii' OH

A 2' then H20 PhJWMe

Ph 2 TMS 3-
\ Me /' (75%)
10V?"
2'
Ph 2 Li

Si/Metal exchange generates a negative charge on the a-position of the d-
alkoxysilane and the intermediate can act as a nucleophile. ln [2,3]-Wittig

rearrangements, the silyl group can exchange with methyl lithium to form a

5

negative charge on the a to oxygen. This negative charge attacks C3 position to
give [2,3]-Wittig rearrangement product.
1.2.5. [1 ,4]-Wittig Rearrangement19

We have also reported on [1,4]-WIttig rearrangements of a-alkoxysilianes
derived from allyl d-hydroxysilane. In this case, the negative charge is stabilized
by the silyl group and the allyl group and [1 ,4]-Wittig rearrangement products are
obtained as major products (Scheme 8).

Scheme 8. [1,4]-Wittig rearrangement

1. MeLi (1.4 equiv)

10Aph THF, rt, 16 h 0

 

. 4
3 H then H20 (50%)

1|
\ 1O/\Ph /
49y”

 

3 6)
0A.». “1.8:“ $18-$10). . 0
’- ’ ' 9 Ph 1
4%TMS 7 TMS
3 H 2) Mel Me
(73%)

1.3. Synthesis of Acylsilaneszo'z1

Acylsilanes are carbonyl derivatives which have the silicon directly
attached to the carbonyl group. Acylsilanes have unusual reactivity because of
the silicon located a to the carbonyl group. They can act as acyl anion precursors
and ordinary ketones. Also, the Brook rearrangement is common in the reaction

of acylsilanes with nucleophiles. The use of acylsilanes in organic synthesis has

increase significantly due to the discovery of new reactions and improvements in
acylsilane syntheses.
1.3.1. Swern Oxidation of a-Hydroxysilanes‘o'zz' 23
Functionalized acylsilanes can be simply prepared by Swern oxidation of
q-hydroxysilanes, which are prepared by Swern oxidation of
trimethylsilylmethanol followed by alkylation (Scheme 9). Interestingly, this
method uses the same chemistry for the synthesis of a-hydroxysilanes shown in
Chapter 1.1.3. In the first step, (trimethylsilyl)methanol is oxidized to afford
formyltrimethylsilane. When phenyl magnesiumbroimde is used as a nucleophile,
the condensation product (d-(trimethylsilyI)-benezenemethanol) was obtained in
46% yield. Oxidation to the corresponding acylsilane affords
phenyl(trimethylsinI)-methanone in 68% yield.

Scheme 9. Preparation of Acylsilanes from a-Hydroxysilans by Swern Oxidation

oxalyl chloride (1.1 equiv)
DMSO (1.1 equiv)

 

 

 

 

Et3N (5.0 equiv) O
ether, —78 °C H TMS
oxalyl chloride (1.1 equiv) fygflgcar (5-0 equrv)
DMSO (1.1 equiv)
j]: Et3N (5.0 equrv) OH
P“ TMS ether, -78 °c Ph TMS
(68%) (76%)

1.3.2. Palladium-catalyzed Acylation of hexamethyldisilanez"'25

Benzyoltrimethylsilanes can be prepared by palladium catalyzed acylation

reactions from hexamethyldisilane with aryl chlorides (Scheme 10). The reaction

could provide ortho, meta, and para substitued benzyoltrimethylsilanes. However,
ortho substituted products were obtained with lower yields. 4-Methyl-benzoyl
chloride was treated with palladium catalyst and hexamethyldisilane to afford (4-
methylphenyl)(trimethylsinI)-methanone in 81% yield.

Scheme 10. Preparation of Acylsilanes by Hiyama Type Reaction

Me3SiSiMe3 (1.1 equiv)
[(n3-C3H5)PdCl]2 ( 5 mol%)

0 P(OEt)3 (1o moi%) 0
110 °c

(81%)

 

1.3.3. Silylation of Dithianes25'27

Silylation of dithiane compounds followed by hydrolysis gives acylsilanes
(Scheme 11). This dithiane route provides a general method for preparation of
acylsilanes bearing aryl and alkyl substituents. In the first step, dithiane is
prepared by protection of aldehydes. Deprotonation of the dithianes followed by
addition of TMSCI and deprotection of dithianes affords acylsilanes.

Scheme 11. Preparation of Acylsilanes by Dithianes

HSCH2CH2CH23H (1.1 equiv)
o BF3-Et20 (1o moi%) (\I

 

 

)L = s s
H CHZCIZ, rt X...
(90%)
n-BuLi (1.0 equiv)
TMSCI (1.0 equiv)
HgCl2 (2.2 equiv) ”25 °C
0 H90 (1.5 equiv)
)L = s s
2 LMS MeOH, reflux 7<TMS
( 5 0) (78%)

1.4. Application of Acylsilanes
1 .4.1. Sila-Stetter Reaction28'29

Stetter reactions between acylsilanes and (LB-conjugated ketones can be
catalyzed by thiazolium to afford 1,4-dicarbonyl products (Scheme 12). In this
reaction, acylsilanes are tunable and various substituted (LB-conjugated ketones
produce their corresponding products. The reaction proceeds via 1,4-addition to
chalocone (dB-conjugated ketone). Acetyltrimethylsilane reacts with 1,3-
diphenyI-2-propen-1-one to afford 1,3-diphenyI-1,4,-pentanedione.

Scheme 12. Thiazolium-Catalyzed Stetter Reaction

 

 

 

 

I
1) catalyst (30 mol%) BC?
DBU (0.3 equiv) A (+3
0 o i-PrOH, THF, 70 °c m S N-Et
+ :‘
/u\TMS Ph/VLPh 2) H20 ph ph
(2.0 equiv) (70%)
LHO catalyst

 

1.4.2. Nucleophilic Addition to Acylsilanesao'm

Acylsilanes can be considered as aldehyde equivalents because a silyl
group can be removed easily by fluoride ion. Addition of a nucleophile to
acylsilanes affords a-hydroxysilanes (Scheme 13) and the large silyl group may
increase stereodifferentiation.

Scheme 13. Nucleophilic Addition to Acylsilanes

n-BuLi (2.0 equiv) TBAF
TMS - -
Ph/I\[( = Pthn Bu > Ph/lyn Bu
0 DMF, rt

 

 

%
THF, —78 °c Ho TMS HO “‘H
(92%) (89%)
dr= >100:1 dr= >100:1

The silyl group can be converted to a hydrogen by TBAF. In this reaction,
alkyl lithiums and Grignard reagents can be act as nucleophiles and thus various
d-hydroxysilanes can be formed and converted to alcohols.

1.4.3. Aldol Reactions” 33

Lithium enolates from various acylsilanes can react with aryl and alkyl
aldehydes to afford B-hydroxyacylsilanes, which can be converted to [5-
hydroxycarboxylic acid by oxidation (Scheme 14). During the reaction, the large
silyl group may also increase the syn preference. Aldol reaction between 1-
(dimethylphenylsilyl)-1-propanone and benzaldehyde followed by oxidation
affords B-hydroxy-a—methyI-benzene propanoic acid in 68% yield.

Scheme 14.‘ An Aldol Reaction with an Acylsilane

1) LDA (1.0 equiv)
o THF, —78 °C OH O

\JLDMPS Ph/IW/lLDMPS

2) PhCHO (1.0 equiv)

 

3) H202. NaOH
MeOH, rt

OH O
Ph OH

(68%)
syn/anti=9: 1

1.5. Requirement of Optically Pure a-alkoxysilane for [1 ,4]-Wittig
Rearrangement Study

As shown before, our group studied the [1,4]-Wittig rearrangement of d-
alkoxysilanes. In the course the research, we became interested in determining

the stereochemical consequences of these silyl-Wittig rearrangements. Past

10

results showed that the syn isomer reacts faster than the anti isomer. We also
wondered if this reaction occurs with retention or inversion of configuration at the
migrating center. To answer this question, there was need to access optically
pure d-hydroxysilianes (Scheme 15). A bottleneck in the synthesis of substrate 2
was the availability of enantiopure compound 3.

Scheme 15. [1 ,4]-Wittig Rearrangement

 

Ph Ph
10/1\ Io/iN
3
Ph NH v
A A (19 equiv) 4 3 2 TMS 4 3 2 TMS
OH 0 '3 anti-2
Ss/l\rus =
TMSOTf (5 mol%) Ph Ph
rac—3 i
cyclohexane, rt . /\
(79%, anti/syn=1:1 ) 1C) 1 I? 1
4%1105 4MTMS
syn-2

[1 ,4]-\Mttig rearrangement

"stereochemical outcome ’2"
O

4
PhNTMS
1

My research focused on development of method for preparation of optically pure

d-hydroxysiliane for [1 ,4]-Wittig rearrangement.

11

Chapter 2. Synthesis of Optically Pure a-Hydroxysilane - Prior Art
2.1. Reduction of Acylsilanes

The preparation of optically pure d-hydroxysilane compounds is still
challenging. A literature search revealed asymmetric reduction as the most
common approach to such compounds. Specifically, organoborane hydride
additions,34 asymmetric hydrogenations,35 chiral lithium amide reactions,36 and
biocatalytic transformations 37 of acylsilanes have afforded a variety of d-
hydroxysilanes with high levels of enantioselectivity.

Scheme 16. Preparation of Optically Pure 1-(DimethylphenylsinI)-2-proen-1-o|

DMPSCI (1.5 equiv)

 

 

 

DMAP (0.5 equiv)
Et3N (2.0 equiv)
HOV 4’ DMPSOM
CH2C|2, rt (86%)
LiCl (3.0 equiv)
. . , s-BuLi (2.2 equiv)
1) tnfluoroacettc anhydnde THF, —78 °C
(1.5 equiv) v
DMSO (2.0 equiv)
o CHZCIZ, —78 °C OH
7 /
DMPs’LK/ 2) Et3N (3.0 equiv) DMPS

(89%)

1) (+)-IpczBCI (1.2 equiv)
THF, rt
2) diethanolamine (4.0 equiv)

 

ll
(3H

DMPSV
(93 %ee)

In many of these examples, the starting acylsilanes are generated by the

oxidation of racemic q-hydroxysilanes, which themselves are produced via Brook

12

rearrangement-based processes (Scheme 16). 38 Among the asymmetric
reagents for acylsilane reductions, chiral borane reagents are most commonly
used. However, most of the work on the synthesis of d-silyl alcohols has been
done with 0-3in benzyl and allyl alcohols in which the silicon bears bulky groups
such as t-Bu, Ph, or i-Pr and the terminal sp2 carbon is substituted. Such trends
are evident in the work of Buynak and coworkers, who explored the reduction of
acylsilanes by (—)-lpc2BCl.34 Table 1 shows their results. Comparing entries 1, 2
and 3 to entries 4, 5 and 6, one can see that if acylsilanes have a big silyl group
such as a triphenylsilyl, the corresponding products are obtained in high optical
purity. As the size of the silyl group gets smaller (from triphenyl to dimethyl
phenyl to triethyl), enantioselectivity is deceased. Cleary, a—hydroxysilanes
bearing a TMS group are missing from the table.

Table 1. Buynak’s Asymmetric Reductions34

(-)-|pc2BCl (1.51 equiv)

 

 

 

 

i THF, rt, overnight ‘ HO“ H
R S'R1R2R3 then diethanolamine (3.17 equiv) S'R1R2R3
rt, 2.5h
Entry d-Hydroxysilane %ee Entry d-Hydroxysilane %ee
HO H HO H
1 41. 97 4 ‘1 83
vSiPh3 vSiMezPh
2 H01 H 95 5 {CD/‘4” P“
-/ — 89
Me/(SiPhg, S'\ h— Me
HO H HO H
3 4'“ 97 6 "‘ 80
\ SiPh3 V9133

 

13

Products from the reduction of acylsilanes using (—)-Ipc2BCl have the R
configuration. The proposed reaction mechanism involves a six-membered
transition state with the small group occupying the axial position and the large
group in the equatorial position so as to minimize unfavorable steric effects ’
(Figure 1).

Figure 1. Transition State Model for the Reduction of Acylsilanes by (—)-IpczBCl

I lpq ’CI q

WET)

11161
L

RS _

 

 

Another possible asymmetric reagent for acylsilane reductions is chiral
lithium amides (Scheme 17).36 The mechanism for these reactions is not clearly
understood yet. However, it has been proposed that the bulkier phenyl group
occupies the equatorial position and the carbonyl group forms a complex with
lithium. This explains the formation of (S)-alcohols as the major products. As
such, for optimal results a large difference in the size of the two substituents
flanking the carbonyl is best.

Scheme 17. Chiral Lithium Amide Reduction

Ph H
NAt-Bu

N Li
[T] (1.2 equrv) _

 

 

 

- 7
0 OH P ’H Ptnqt B”
> h / 0..N .
Ph/lLTMS THF Ph/kTMS \Ié \L1'
0 SIMe3 N
-80 °c, 30 min (64 /o. 81 %ee) We

14

Optically pure d-hydroxysilanes can also be obtained by asymmetric
hydrogenation. Recently, Ohkuma reported Tol-binap/pica ruthenium (ll)
catalyzed asymmetric hydrogenation of a-hydroxysilanes (Scheme 18).35
(Acetyldimethylsilyl)-benzene was reduced to 1-(dimethylphenylsilyI)-ethanol with
good enantiomeric excess. However, this protocol still required large silyl groups
such as DMPS or TBS for good enantioselectivity. There were no examples

ofsubstrates bearing a TMS group.

Scheme 18. Asymmetric Hydrogenation with Ruthenium Catalyst

H2 (10 atm) DO Arz / I
catalyst (0.1 mol%) P\ (El/N \
O t-C4H90K (1.1 mol%) OH P/ C|\N
)L = A Ar2 H2

Me DMPS EIOH, 23 00 Me DMPS
(85%, 93 %ee)

 

 

Ar = 4-CH3C6H4
. catalyst

 

 

 

2.2. Enzymatic Kinetic Resolution

Enzymatic Kinetic Resolution of a-hydroxysilanes would be a useful
method to prepare optically pure d-hydroxysilanes. Although the kinetic
resolution of secondary alcohols via esterification has been extensively explored
with various lipases, kinetic resolution of d-hydroxysilane is less studied. To the
best of our knowledge, only a few reports on the enzymatic kinetic resolution a-
hydroxysilanes exist and in those reports only a limited number of substrates

have been examined.

15

For example, Uejima et aI. resolved 1-trimethylsilylpropanol with excellent
enantioselectivity by a hydrolase-promoted esterification in 1993 (Scheme 19).39
No other substrates were tested.

Scheme 19. Kinetic Resolution of 1-Trimethylsilylpropanol

Lipoprotein Lipase (100 mg/mmol)

 

OH 5-phenylpentanoic acid (1.0 eq) (3H
TMS 2,2,4-trimethylpentane \/\TMS
30 °C . (95 %ee)

49 %conversion

In 2004, Guintchin and Bienz found that treatment of (:t)-1-
[(dimethyl)(phenyl)silyl]but-2-yn-1-ol with a variety of lipases (lipases from
Pseudomonas Fluorescens, Candida cylindracea, Aspergilus niger,
Chromobacterium viskosum or hog pancreas) failed to give any acylated material.
Partial success was realized when they reacted the corresponding racemic
acetate with A. niger (Scheme 20).40

Scheme 20. Hydrolysis and Acylation using Enzyme

OH enzyme

............ > noreaction
vmylacetate

0A0 lipase from A. niger (246 mg/mmol) OH
/DMPS 01.24.22.062 11 /°MPS

(23%, 97 %ee)

\
g

 

Marshall and coworkers also reported lipase-mediated resolutions of
secondary propargyl alcohols bearing silyl substituents that lead to high
enantiomeric purity (Scheme 21).“ Even though the substrates in this study are
not q-hydroxysilanes, their data indicate the ability of Amano AK to catalyze the
esterifcation of silyl containing substrates. In practice, the kinetic resolution of

16

rac-16 gave acylated (R)-17 and unreacted (S)-16. Without further purification,
both (R)-17 and (S)-16 were subjected to succinic anhydride so as to esterify (S)-
16. (R)-17 was isolated in 45% yield and (S)-18 in 43% yield. Independently,
treatment of (R)-17 and (S)-18 with DIBAL afforded (S)-16 and (R)-16 in good
yield with good %ee’s.

Scheme 21. Kinetic Resolution of 4-TMS-3-butyn-2-ol

Amano AK (28 mg/mmol)

TMS -
Vin Iacetate (7.7 equiv)
HO/ y >m/m Ho/TMS
pentane, 3 A MS

 

Me rt, 72 h
rec—16 (R)-17 M(S)-16
succinic anhydride (0.6 equiv)
Et3N (0.9 equiv)
DMAP (1 mol%)
reflux, 4 h ()

 

 

TMS - TMS TMS
DI BAL 1.2 UIV
HO/ < ( eq ) ACO/ + R0/
5

hexane, —78 °C

 

Me
(S)-16 (R)-17 (S)-18
(87%, >94 %ee) 41% (isolated) R=CO(CH2)ZCOZH
43% (isolated)
TM
110/ S DIBAL (1.2 equiv) l
llglle hexane, —78 °C
(R)-16

(83%, >94 %ee)

As shown in this chapter, optically pure d-hydroxysilanes can be prepared
by acylsilane reductions or enzymatic kinetic resolution of a-hydroxysilanes. In
the case of the acylsilane reductions, the size of the two groups flanking on the
carbonyl group should be very different. In the most examples, large TBS or TPS

groups have been used in the reaction. Kinetic resolution would provide the

17

optically pure a-hydroxysilanes bearing a small TMS group. A few of examples
do show that d-hydroxysilanes bearing a small TMS group can be resolved with
excellent %ee, however, these are few in number and of limited structural

diversity.

18

Chapter 3. Attempted Preparation for Optically Pure a-Hydroxysilanes by
Ring Opening of Epoxyalcohol
3.1. Introduction

As mentioned in Chapter 2, several methods exist for the preparation of
optically active a-hydroxysilanes. Among these methods the reduction of
acylsilanes is the most common, but such reactions typically require large silyl
groups (larger than TMS). Kinetic resolution of a-hydroxysilanes, as well as other
methods, have not been widely studied in terms of substrate scope. Owing in
part to what we viewed as a limited number of available methods and our
anticipated need for various optically active d-hydroxysilanes for our Wittig
studies (vide supra), we set out to develop new approaches to these compounds
and/or to advance existing protocols.

Scheme 22. Our Synthetic Plan for Optically Active d-Hydroxysilane

Via Ring Opening Reaction

Sharpless
asymmeric
TMSWOH --?.'°.°.’E'9?i'?.”.--_ , TMS 3% OH
4 (28,3S)-5 or
(2R,3R)-5
I regioselective
; ring opening
TMSY\ elimination TMS 0” OH
\ .0 ................... W O,
OH OH TMS\/'\/OH
(S)-3 or (S)-6 or (S)-9 or
(RI-3 (R)-6 (12)-9

Given our particular need for allylic d-hydroxysilanes, one new approach
envisaged involved asymmetric epoxidation of TMS substituted allylic alcohols

19

followed by ring opening and elimination of the intermediates to install the double
bond in the allylic o-hydroxysilane (Scheme 22). This synthetic plan is relatively
simple and relies on well established Sharpless asymmetric epoxidations to
install chirality through reagent control. Another useful feature is that the final
vinyl group or the primary hydroxyl on the intermediate 1,3-diol, could be used for
introduction or other functional groups via cross metathesis or other methods.
Importantly, our synthetic plan also allows us to address a synthetic
question pertaining to the regioselectivity of the proposed epoxide opening.
While TMS groups and free alcohols are known to direct epoxide openings, to
our best knowledge, there is no report on the regioselectivity of Red-Al hydride
delivery to an epoxyalcohol bearing a silyl group as present in 6. Therefore,
investigating the reaction of 5 with Red-Al will provide new information as to the
relative directing strengths of these two groups.
3.2. Ring Opening of Epoxyalcohol

Scheme 23. Synthesis of Compound 4

 

1) EtMgBr (2.7 equiv)
H-—Ej THF, 10 °C : TMS :
OH OTMS
7 2) TMSCI (2.7 equiv)

5 °C to reflux

3) 1.4 M H2804

 

 

20°C
Red-Al "
TMSWOH 7 TMS :
4 Et20,2to 20°C 8 o‘ H
(57%) (80%)

20

The starting material (4) for this chemistry was prepared as shown in
Scheme 23. Propagylic alcohol reacted with ethylmagnesium bromide to form the
dianion, which was quenched with TMSCI to afford trimethyI-[3-
[(trimethylsilyl)oxy1-1-propyn-1-yl]-silane. Deprotection of the alcohol followed by
reduction of the triple bond with Red-AI afforded the requisite allyl alcohol 4.

Before implementing our synthetic plan on optically active material, the
feasibility and regio chemistry of the key reaction in question was studied with
(:)-epoxyalcohol 5 (Scheme 24). Epoxidatlon of allylic alcohol (4) was readily
accomplished by treatment with 2.0 equivalents of m-CPBA in CH2CI2 to obtain
the epoxyalcohol (5) in 66% yield.

Scheme 24. Regioselective Opening of Epoxyalcohol

 

m—CPBA (2.0 equiv)
TMSWOH = TMS\([D>\/OH
4 CH2C12, 0 01:3 5
(66%)
' ring opening

I

TMS\|/\ elimination TMS OH OH
\ 4» ------------------- W or
OH OH TMSvK/OH

3 6 9
We then explored conditions for the regioselective ring opening of the
epoxyalcohol to furnish the desired 1,3-diol (6). Red-Al has been reported to
react with epoxy alcohols in 1,2-dimethoxyethane to open the epoxide from the

less hindered side and furnish the corresponding 1,3-diol (Scheme 25).“2

21

Scheme 25. Ring Opening Reaction with Red-Al

\I/VOH
DME, 0 to 25 °c 0“

1,3-diol
(61 %)

Red-Al (1.05 equiv) mu

 

t-Bu\(l)>\/OH

The reaction is thought to involve an initial complexation of the aluminum
species with the alcohol followed by internal hydride delivery (Scheme 26).
Because 5-exo ring formation is preferred over the 6-endo alternative, the
product is a 1,3-diol.

Scheme 26. Ring Opening Reaction for Epoxyalcohol

X

I

’X
o Red-AI “"1 02 attack

802N011 —_. R\<(\/ _—_. R 0..
3 1 0 j/\/
OH
5-exo > 6-endo 1,3-diol

Interestingly, Liu reported complementary regioselectivity with DIBAL. If an
epoxide bears only a silyl group, the regioselectivity is explained by the transition
state shown in Scheme 27.43 Silicon is partially pentancoordinated and hydride is
directed to the sterically more crowded carbon to give the product.

Scheme 27. Ring Opening Reaction for Epoxysilane

{-BUZ
o DIBAL Al Ph 3.
Ph 3' H' ‘o “—"’ 3 '\/\OH
3 ' Phasill

A similar ring opening reaction of epoxyalcohol bearing silyl group with a
reducing reagent was reported by Manual and coworkers in 1993. However, they

used LAH instead of Red-Al. This report shows that LAH can open the

22

epxoyalchol bearing the silyl group regioselectively (Scheme 28).44 In the
reaction, observed product is the 1,2-diol.

Scheme 28. Ring Opening Reaction of Similar Substrates with LAH

Me‘s/:L Me‘ 0 Me‘s/:[OH
I ' I
Ph/ [ah/8| Ph’

 

 

OH m-CPBA 0H LlAlH4 OH
+ : + > +
Me‘sij CH2012 Me. :9, Et20 Ma .20”
I o - '
2 , 20 0 SO ,30,
Ph "OH Phi ”OH Ph “OH

With this information, we first decided to react Red-Al and our substrate. A
DME solution of compound 5 was treated with 1.05 equivalent of Red-AI at 0 to
25 0C for 4.5 h. The 1,2-diol (9) was exclusively obtained in 60% yield (Scheme
29), and the expected 1,3-diol was not observed under those conditions.

Scheme 29. Ring Opening Reaction using Red-Al

 

O Red-Al (1 .05 equiv) OH
TMSWOH . > TMS\/‘\/OH
5 DME, 0 to 25 C, 4.5 h 9

1,2-diol (60%)
This experiment showed that silicon overrides the directing effects of the
OH group. The possible transition state for our ring opening reaction with Red-AI
is shown in Figure 2. To obtained the 1,2-diol, the hydride might be strongly
coordinated to silicon (a) or the substrate might form a six-membered ring by
silicon-hydride coordination (b). In both cases, the silicon plays an important role

for the ring opening reaction with Red-AI.

23

Figure 2. Possible Transition State for Ring Opening with Red-Al

 

 

 

 

— H R2 - I- p 7

\Al/ M s
e I ,
/ \ 3 \

/H‘ O H
\‘ "I \
Me3Si—‘—l\/OH X2Al—O
(a) (b)
Si group >> OH group six-membered ring

Whereas Red-Al did not afforded 1,3-diol, we wondered if the
, regioselectivity in the epoxide ring opening reaction would be changed by using a
larger or less coordinating hydride source to maximize the steric effect between
silyl group and the reducing reagent. Super-Hydride (LIB(CzH5)3H) containing
three ethyl groups was selected.

Scheme 30. Ring Opening Reaction using Super-Hydride

TsCl (1 .05 equiv)

 

 

Et3N (2.5 equiv)

LiB(C2H5)3H (2 equiv) TMS OH DMAP (3 mol%)
0 A _ complex
TMSWOH ' OH 0 ’ mixture

THF, rt, 1 h CH2CI2, 0 C to rt
5 1o
1,3-diol (91%)
(presumed product)

Treatment of a THF solution of compound 5 with 2.0 equivalents of Super-
Hydride at room temperature for 1 h gave an unknown product (Scheme 30). The
‘H and 13C NMR spectra obtained were not identical to 1,2-diol (9). We
postulated that the product might be the desired 1,3-diol, resulting from opening
of the epoxide from the less hindered side. However, structural determination

was complicated by an impurity that remained after silica gel column

24

chromatography. Moreover, the next proposed step, tosylation of the primary
hydroxyl group, of ‘presumed-compound (10)’, was not achieved.

Other attempts at reacting the impure and presumed 10 also failed. For
example, in an effort to form the acetal, the presumed 1,3-diol (10) was treated
with 4.0 equivalents of benzaldehyde dimethyl acetal and 0.6 equivalent of
camphor-10-sulfonic acid in CHgCIg at room temperature or 10 equivalents of 2,2-
diemthyoxypropane and 0.01 equivalent of camphor-10-sulfonic acid in CH20I2 at
room temperature. In the end through, no acetal was formed. Likewise,
presumed 1,3-diol 10 did not acylate upon treatment with 2.3 equivalents of
acetyl chloride and 2.3 equivalents of triethylamine in THF at room temperature.

Scheme 31. Synthesis of 1,3-Diol (11)

TBSCI (1.2 equiv)

 

 

OH lm (2.5 equiv) OTBS
vms DMF, rt VTMS
3 11
(78%)
1) BH3 (4.0 equiv)
THF, 0 °c to rt
2) NaOH, 30% H202
rt
0
OH OH 55/" HF OH ores
TMS CH3CN, rt TMS
6 12
(82%) (45%)

At this point, we doubted our tentative assignments of 10 as the 1,3—diol.
To address this question directly, 1,3-diol 6 was prepared independently as
illustrated by Scheme 31. Protection of d-hydroxysilane 3 with TBSCI followed by
hydroboration/oxidation afforded compound 12. The last step was removal of the

TBS group under acidic conditions to form the 1,3-diol compound. Comparing the

25

spectroscopic data of 1,3-diol (6) and presumed-compound (10) showed that the
compounds were in fact different.

As this point we considered the work of Vidari and coworkers who, in 1989
reported similar reactions between Super-Hydride and 1,2-diols (Scheme 32).“
They showed that Super-Hydride could be used not only as a reducing reagent,
but also as a reagent for the protection of 1,2-dlols. This reaction is general,
allowing for the preparation of cyclic ethylboronic esters from acyclic 1,2-diols in
high yield. In the reaction, Super-Hydride abstracts hydrogen from the 1,2-diol
and forms an O-B bond. Ethane is released and the ethylboronic ester is
obtained.

Scheme 32. Formation of Ethylboronic Ester
10H LIBIC2H5)3H (11 6911:) 10:13 _/
OH THF, 0 °C to rt 0

(75%)

 

o
LiEt3BH [-H2] H [‘EtH]

G

e
O-BEt3 ® [-EtH] 0‘ @
Li ,BEtZ LI
OH 0

We recognized that presumed product 10 (Scheme 30) also could be a

II

boronic ester of the type Vidari reported. Conformation of this was made possible
by purifying compound 10 by distillation. One compound was obtained and the
IR, 1H, 130 and "B NMR, COSY, HMQC and HRMS spectra revealed that the
product was ethylboronic ester 13 (Scheme 33). IR of compound 13 showed that
there were no hydroxyl groups and “B NMR showed the presence of a boron. To

26

further elucidate the structure, the boron was removed with sodium hydroxide to
form 1,2-diol (10). We compared the 1H NMR spectrum of compound 10 formed
by Red-Al with that of compound 10 from 13. They were identical and supported
the structure of compound 13.

Scheme 33. Observed Product

 

 

LIB(CzH5)3H
O (2 equiv) > NaOH OH
TMSWOH ’ 0’3. ’ = TMS OH
THF, rt. 1 h TMS\/K/O 0 °C t° It \A/
5 13 10
(72%) (84%)

We have studied the ring opening of epoxy alcohols bearing a TMS group
with both aluminum and boron hydrides. In all cases, formation of the 1,2-diol
was favored. This result shows that silicon plays an important role in determining
the regioselectivity and that cyclic boronic esters are formed in the ring opening
reaction. Unfortunately, we did not obtained the 1,3-diol needed for the
preparation of optically active d-hydroxysilanes. Therefore, we decided to move

to the enzymatic kinetic resolution of d-hydroxysilane as described in Chapter 4.

27

Chapter 4. Enzymatic Kinetic Resolution of a-Hydroxysilanes
4.1. Introduction

So far, our efforts toward accessing enantiopure d-hydroxysilanes had
proven unsuccessful, therefore our attention turned to kinetic resolution (Figure
3). As shown in Chapter 2.2, enzymatic kinetic resolution is an alternative
method for preparing a-hydroxysilanes. The advantage of enzymatic
esterifications or ester hydrolyses is that they provide ready access to both a-
hydroxysilane enantiomers.

Figure 3. d-Hydoxysilane

R2 OH

R1 \ SIR3
R3

A kinetic resolution is “T he achievement of partial or complete resolution
by virtue of unequal rates of reaction of the enantiomers in a racemate with a
chiral agent (reagent, catalyst, etc.)”.46 Enzymes are widely used in kinetic
resolutions. Because enzymes have a chiral active site, one enantiomer of the
racemates is transformed to the product at a faster rate than the other. This
process is illustrated in Figure 4 where R and S are substrate enantiomers, R’
and S’ are corresponding product enantiomers and E is enzyme. After the
reaction, R’ and S are recovered.

Figure 4. Kinetic Resolution

 

kR(fast)

 

28

One of the most developed enzymatic kinetic resolutions is the
esterification of secondary alcohols (Scheme 34). Treatment of racemic
secondary alcohols with acylating reagents and an enzyme can give two
products. One is the unreacted secondary alcohol and the other is the acetate.

Scheme 34. Kinetic Resolution of Secondary Alcohol

 

i
R R > R AR + R /LR
1 2 acylating reagent 1 2 1 2

For example, Pseudomonas sp. resolves (3E)-4-phenyl-3-buten-2-ol to
afford unreacted (S)-alcohol and (R)-acetate in good yields with excellent
selectivity (Scheme 35).47 The (R)-alcohol was acylated in 47% yield with 95 %ee,
while the (S)-alcohol was recovered in 50% yield with 95 %ee.

Scheme 35. Kinetic Resolution of Secondary Alcohol with Pseudomonas sp.

Pseudomonas sp. (50 %wt)

 

OH vinyl acetate (4.0 equiv) (3H OAc
: - +
MeMPh hexane, 3 A MS MeA/‘Ph Me / Ph
'1' 3 h (47%, 95 %ee) 50%, 95 %ee

50 %conversion
4.2. Mechanism of Kinetic Resolution
Enzymes determine the enantioselection through their chiral active site
and also proceeded the acylation process. Acylation of secondary alcohols
involves a serin, histidine, aspartate triad (Scheme 36).“ Serine is activated by
the hydrogen bonding of the three amino acids and the nucleophilicity of oxygen
on serine increases (a). The oxygen attacks the carbonyl group of the acylating

reagent to form transition state (b). The alcohol (R1OH) is then released (c) and

29

the secondary alcohol attacks the carbonyl group on serine. Finally, the acetate
is afforded and the enzyme is released for the next catalytic cycle (d).

Scheme 36. Mechanism of Kinetic Resolution

JOL
R1\ 0
O
9 8.. I R2
Asp—(1.9,.H. A ..... H-q Asp-((9)1. /\ /H ..o\
0' N_N Ser B. N-’@5~N Ser
Hls His
(13)
(a)
R3 it (PH
R4/'\O R2 R1

4.3. Enzymatic Kinetic Resolution of a-Hydroxysilanes

As shown in Chapter 2.2, the kinetic resolutions of silicon containing
alcohols have been also reported before and 1-trimethylsilylpropanol, 1-acetate-
1-(dimethylphenylsilyl)-2-butyn-1-o| and 4-trimethylsilyl-3-butyn-2-ol were
resolved successfully. We decided to apply the conditions that had previously
been employed during the kinetic resolution of 4-trimethylsilyl-3-butyn-2-ol

because the reaction provided both enantiomers with excellent enantiomeric

30

excess and kinetic resolution of secondary alcohols with Amano AK are well
known (Scheme 37).

Scheme 37. Kinetic Resolution of 4-TMS-3-butyn-2-ol with Amano AK

/ TMS
110/

 

Me
(S)-16
TM S Amano AK (28 mg/mmol) 1) acetylation (87%, >94 %ee)
/ vinyl acetate (7.7 equiv) 2) column chromatography
HO / = = 4-
Me pentane, 3 A MS 3) reduction TMS
rt, 72 h /
rac-16 HO /
tile
(R)-16

(83%, >94 %ee)

Owing in part to the limited literature precedent (see Chapter 2.2), we set
out to conduct our own study on the enzymatic kinetic resolution of 01-
hydroxysilanes that varied at both the silicon and the organic group flanking the
carbinol.

Initially, three different enzymes (Amano AK lipase, Amano PS lipase, and
Novozym 435) were investigated in the kinetic resolution of ' (:t)-1-
hydroxyallyltrimethylsilane (rec-3). Reactions were run in a sealed tube filled with
substrate, enzyme, vinyl acetate, and 3A molecular sieves as a mixture in
pentane. The results of these screening experiments are summarized in Table 2.

In all cases, (S)-3 reacted faster than (R)-3, as determined by a Trost-
modified Mosher analysis of the unreacted alcohol using O-methylmandelate
(vide infra, Chapter 4.4).49 However, Zong and coworkers reported the remaining
alcohols were 8 enantiomers in Novozym 435 catalyzed esterifications of 1-
trimethylsilylethanol in both organic solvents and ionic liquids (Scheme 38).50

31

Although Novozym 435 and vinyl acetate were used in our study and Zong’s
study the product reported by Zong exhibits an opposite sense of absolute
stereochemistry to that seen by us. These results obviously show that solvents
can play an important role in the stereochemical course of enzymatic kinetic
resolutions.

Scheme 38. Kinetic Resolution of 1-Trimethylsilyethanol in Ionic Liquid

Novozym 435 (32 mg/mmol)
OH vinyl acetate (4.0 eq) OH

A TMS = /L TMS

C4MII‘I‘IPF6, 45 °C
97 %ee

6 h 50 %conversion

 

Interestingly, the sense of our enantioselection was similar to that
observed by Uejima in the resolution of 1-trimethylsilylpropanol with lipoprotein
lipase in water-saturated 2,2,4—trimethylpentane (Scheme 19)”.

Scheme 39. Solvent Effect in Kinetic Resolution

 

 

 

 

cyclohexane _
N02
RO(O)C C(O)OR Pseudomonas sp. lipase
20 °C
N
H
R = t-BuC(O)OCH2 = RO(O)C S C(O)OH
diisopropyl ether
N
H
99 %ee

Scheme 39 shows one of the most drastic examples of solvent influence
on the enantioselectivity of an enzymatic kinetic resolution. As reported by Hirose

32

and coworkers in 1992, 5‘ in Pseudomonas sp. lipase resolution of
dihydropyridine dicarboxylates, (R)-monoester was obtained with 88 %ee in
cyclohexane and (S)-monoester was obtained with 99 %ee in diisoproyl ether. In
this reaction, the solvents influence the absolute enantioselectivity, however, the
cause of such solvent effects on enantioselectivty is not been fully understood.

Table 2. Kinetic Resolution of rec-3

 

 

 

 

OH 1 5—5 0 0:33:3in acetate 9H OAC
vrms ' ' A vms + vms
3 A MS, pentane, rt-38 °C
rec-3 (R)-3 (S)-18
130 mg Amano AK 130 mg Amano PS 15 mg Novozym
Lipase/mmola Lipase/mmolb 435/mmol°
Time (S)-18 Time (S)-18 Time (S)-18
Entry (h) (%ee)c Entry (h) (%ee)c Ent'y (h) (%ee)c
1 23 73 1 22 88 1 8 99
2 96 81 2 24 93 ' 2 13 99
3 1 20 80 3 48 94 3 22 99
4 1 68 80 4 96 92 4 27 98
5 1 92 82 5 1 69 96 5 33 98

 

aReactions using Amano AK Lipase were performed at rt with 5.0 equiv of vinyl acetate in

pentane containing 3A molecular sieves.

bReactions using Amano PS Lipase and Novozym 435 were performed at 38 °C with 1.5 equiv of

vinyl acetate in pentane containing 3A molecular sieves.

°The absolute configuration was assigned by Mosher analysis and chiral GC analysis determined

the %ee.

It was clear that Amano AK (130 mg/mmol of Amano AK, 5.0 equivalents

of vinyl acetate, pentane, 3 A molecular sieve) could effectively resolve a-

33

hydroxysilanes with synthetically useful levels of enantioselectivity. However, 130
mg of Amano AK per mmol of rec-3 was necessary and the reaction time was
over 192 n. Thus, we continued to our kinetic resolution study in the search of
better results. Amano P8 was therefore investigated in the kinetic resolution of
rac-3. Rac-3 was treated with 130 mg of Amano PS and 1.5 equivalent of vinyl
acetate in pentane with 3 A molecular sieves. The desired acetate was afforded
in 169 h with 96 %ee.

In our kinetic resolution study, Novozym 435 provided even better result. It
was superior to Amano AK lipase and Amano PS lipase in that it afforded the
best selectivity and shortest reaction times. Also, only 15 mg of Novozym 435 per
mmol of rec-3 was need in the reaction. As such, the best conditions to emerge
out of these first experiments were to place a sealed tube containing a pentane
solution of the rac-3, 15 mg Novozym 435/mmol rac-3, 1.5 equivalent of vinyl
acetate, and 3 A molecular sieves under a nitrogen atmosphere into an oil bath
heated to 38 °C for 33 h. This protocol afforded (S)-acetic acid 1-(trimethylsilyl)-
allyl ester (S)-18 in 30% isolated yield with 98 %ee as well as unreacted (R)-3,
which was isolated in 33% yield with 73 %ee.

Additional testing showed that increasing the amount of vinyl acetate (up
to 5 equivalents) did not improve the selectivity or yield. Likewise, lowering the
Novozym 435 loading to 10 mg/mmol rec-3 only resulted in longer reaction times,
lower yields, and little change in the selectivity. Notably, if Novozym 435 was

excluded no formation of the acetate product was observed.

34

On the basis of the above results, we applied our established procedure to
a series of a-hydroxysilanes. The results from these reactions are summarized in
Table 3. Unfortunately, substrate scope proved narrow. Exchanging the TMS
group for a dimethylphenylsilyl (DMPS) group (19) improved the performance of
the reaction (entry 2), whereas the terf-butyldimethylsilyl (TBS) analogue (21)
failed to react (entry 3). Substrates with an additional methyl group at either the
01- or B-vinyl positions (entries 4 and 6) did not acylate at 38 °C, even with
increased catalyst loadings.

As Novozym 435 is stable at 70-80 °C,52 rec-22 was exposed to higher oil
bath temperatures. At 78 °C and with increased catalyst loading, (E)-1-
(trimethylsiIyI)-2-buten-1-ol (rec-22) did react, albeit slowly and with low yield and
poor selectivity (entry 5). Other solvents, including CH2C12, THF, benzene,
toluene, and t-amyl alcohol, were examined, but none proved superior to pentane
for the resolutions of 22 and 24.

All other d-hydroxysilanes screened (Figure 5) failed to react. Even raising
the amount of Novozym 435 to 130 mg/mmol of silane, upping the equivalents of
vinyl acetate, and/or running the reactions at elevated temperatures did not
promote acylation.

Figure 5. Failed d-Hydroxysilanes

Me OH Me OH OH OH
WTMS Wows Ph/|\TMS PhADMPS
25 26 27 28

35

00:0. 00$ 0.: 00.50.00 02: 0:0 0.0E0::0c0 05 02000. 0: 0:0E0t0 0300008000 0:0 0.500.020E0E0 =4.s

no.0. 0.30.9: 0.: 0: .0200.0 09000.0: 0.: .0 20:08. .00:00 mc_.00E00 .5 005.0000 003 000\e 0:0 >00_E0z000.0.0 05.0000 0... Ho

.000\° 05 005E000 0.02000 0...... .0 00 .0.E0 05.0 0:0 0.02000 .0502). .5 00:90.00 00.5 b:0.E0c000.0:0 05.0000 0c...a

000.000 0:0 .92 <0 93000 35> .0 >500 m; .mmv E>N0>0z 00:02.0 3.0.0250 003 00.000 0 c. :3. 0.03 20:000.“:w

 

00:000. 0:

8.0. 000.

8:000. 0..

00:00.0. 0:

020. 00.0

010. .08

 

29> 0\0
0.0.85.0.

en
0.2
0.: 5.500. o: 0... 00 t m. 22./WW 0
:0
0| ~20. 0e. . .0 0. mm 0. a 0
ms... / 0.2
0... 8.58.8 0E 0.0. we. 0. :Jo\/\ .0
K
.0... 8:68. oc 0:. 00 em 0. 09/) 0
IO
2.
08A 0...... s09. .00.. 00 as m. wa:o/.\/ 0
:0
n
.0? 0-0.. 008 02 mm mm 0. 2E / _
IO
0 0.03 o\o 0000\0 -
000 \o 0c0__m>x0.0>I 000.04.08.02. .0... 2. m9. E>~0>0z 000.0086? 0 bEm.
9002.6. .9: Am. 0E0... 0E. ._. .0EEBE 05:05

 

003.620.31-30 00:280.”. 0:006. .m 0.00...

36

4.4. Determination of Absolute Stereochemistry

As previously mentioned, the absolute stereochemistry of unreacted q-
hydroxysilanes was determined by Mosher ester analysis.31 These remaining a-
hydroxysilanes from the kinetic resolution of rec-3 were treated with (R) or (S)-a-
methoxyphenylacetic acid (MPA), DCC and DMAP in CHgClg. For such a reaction
there are four possible derivatives; the (R)-MPA-(R)-ester, (S)-MPA-(R)-ester,
(R)-MPA-(S)-ester, and (S)-MPA-(S)—ester (Scheme 40).

Scheme 40. Possible Structure in Mosher Ester Analysis

(R)-(—)-a-methoxyphenylacetic acid (0.8 equiv) shielded

(‘DH DCC(O.8 equnv) Hawk: oz‘KéLh CH3(
v Ha—/Sl
TMS CHZCIZ, rt
(R)-MPA—(R)-ester
(S)-(+)«nu-methoxyphenylacetic acid (0.8 equiv)

9H occ (0.8 equiv) Haiku; Ojkngcmz)
v a—/Si
TMS CH2CI2, rt

shielded
(S)-MPA-(R)-ester

(R)-(—)-a-methoxyphenylacetic acid (0.8 equiv) shielded H

. O
OH DCC(O.8 equw) ‘ §OJ¥IOCH3 (3)
vms H P“

_ CHzClz, l‘t Ha
(S) 3 (R)—MPA—(S)-ester

 

 

(S)-(+)-a-methoxyphenylacetic acid (0.8 equiv) Hl-ll O
OH 000 (0.8 equnv) )Sim- OCH3
shielded

(S)—MPA-(S)-ester
From the Mosher model, it is assumed that the methoxy, carbonyl and H

(from the q-hydroxysilane) are in the same plane. lf R—3 is the unreacted q-

37

hydroxysilane, we consider equations (1) and (2). In case of (R)-MPA-(R)-ester,
the phenyl group shields Ha of the vinyl group and the Ha peak moves upfield in
the 1HNMR (Eq. 1). For the (S)-MPA-(R)-ester, the H, of the methyl group on
silicon is shielded by the phenyl group and H, moves upfield in the 1HNMFl (Eq.
2). Thus, the ASHa of 8(R)-MPA-(R)-ester—8(S)-MPA-(R)-ester is negative and
the A5Hb by 6(R)-MPA-(R)-ester—6(S)-MPA-(R)-ester should be positive. Were
unreacted q-hydroxysilane 3 of the S absolute stereochemistry an opposite
chemical shift and A5 values would be observed (Eq 3 and 4). Therefore, the
AESHa from 6(R)-MPA-(S)-ester—5(S)-MPA-(S)-ester would be positive and the
AaHb from 5(R)-MPA-(S)-ester—6(S)-MPA-(S)-ester would be negative.

The 1HNMl-‘l spectra of the two derivatives were compared. ASH,l was
—O.118 and ASHb was +0.189. Therefore, we assigned the absolute
stereochemistry of the remaining q-hydroxysilane as R (Figure 6). The same
procedure was applied to the q-hydroxysilane remaining after the kinetic
resolution of rec-19. Again, the absolute stereochemistry was assigned as R.

Figure 6. Determination of Absolute Stereochemistry of (R)-3

O-MPA
! I,Me

SI‘M
Ha KH 9
-0.118 b+0,1a9
5(R)-MPA-(R)-ester - 5(S)-MPA-(R)-ester
The assigned absolute stereochemistry of the a-hydroxysilanes from the
enzymatic kinetic resolution are those that would be expected by an empirical

rule called “Kazlauskas’ rule”.54 Kazlauskas’ rule predicts which alcohol will react

faster in an acylation of secondary alcohols. This rule is based on size

38

differences of the substituents at the stereocenter (one large and one medium
group). According to their size, substituents are placed in two different pockets.

Kazlauskas’ rule can be illustrated as shown in Figure 7. The secondary
alcohol arranges itself with the larger group on the right and medium group on
the left. After the reaction, the alcohol with the OH group orientated toward the
back of the plane is unreacted and the alcohol with the OH group orientated to
the front of the plane is acylated. The size difference between the two
substituents is important for reliably predicting absolute stereochemistry. Usually,
lager size differences give better predictability and enantioselectivity.

Figure 7. Kazlauska’s Rule

9H
.—. =
OH
Lipase
(WE _ Acyl Donor +
raC ’Acy|

 

@336)
We can clearly see that rec-3 follows Kazlauskas’ rule (Scheme 41). The
mediumsize vinyl group is placed on the left side and lager TMS group is on the
right side. After the reaction, (R)-3 remains and (S)-3 was acylated. Kazlauskas’

rule was also applied to the kinetic resolution of rac-19.

Scheme 41. Enzymatic Kinetic Resolution of q-Hydroxysilane

 

Vii-I enzymatic kinetic resolution 9H \/(')\A°
TMS = VTMS + \ TMS
rac—3 (R)-3 (S)-18

39

4.5. Determination of %ee using ”Si NMR
One of the problems we met during the project was to determine
enantiomeric excess of the products. Chiral HPLC and 60 are useful tools in
terms of accuracy and generality, but their use can be time consuming and not
always workable. For example, rec-25 did not give good separation under the
HPLC and 60 conditions we explored (Figure 8).
Figure 8. Difficulty Determinating %ee

Me OH

\ TMS
25

Mosher ester analysis can be also used for this purpose. However, a-
hydroxysilanes were sensitive to the conditions of ester formation and erosion of
enantiomeric excess was observed in all cases. As such we continued to search
for alternative methods. In 1999, Picard and coworkers reported the use of
lanthanide shift reagent to q-C-silylated amines and alcohols for determination of
enantiomeric excess using 2QSi NMR (Figure 9).55 In the presence of Eu(tfc)3,
rec-27 shows two peaks with ratio of 50.32497.

We applied this 29Si NMR analysis to some of our substrates. We ran a
series of spectra in the presence of 1-20 mol% of the chemical shift reagent in
order to find the optimal conditions. Table 4 shows the best results. Applying this
method to rec-27, 3 and 25 allowed for the determination of the enantiomeric
excess with reasonable accuracy and precision. In the case of rec-22, partial
separation of the two peaks was observed but it was not baseline, limiting the

use of 298i NMR in this instance.

40

Figure 9. 293i NMR of Rae-27 with Eu(tfc)3

 

r 1

 

 

\ . {3 EU

 

 

OH

Ph/k TMS
rac-27

 

 

 

 

 

111
E
3
0)
K
(L

WJ

f u I I I I I I I I m y I I u t v

3 2 2.7 2.5

 

 

Table 4. Enantiomeric Ratio by 29Si NMR

 

 

q-Hydroxysilanes Eu(tfc)3 (mol%) A5 (ppm) Ratio
OH
rec-27
OH
vms 10.1 0.0102 52.22472
rec-3
Me OH
rec-25
OH
Me“ TMS 12.0 0.0051 overlapped
rec-22

 

To check the accuracy of these measurements, the enantiomeric excess

of non racemic mixture 3 was measured by chiral GC and 29Si NMR (Figure 10).

41

The results were in good agreement. Even though this 2‘E’Si NMR method has

substrate limitations, the enantiomeric excess can be determined quickly and

 

 

reliably.
Figure 10. 298i NMR Spectrum of R-3 with Eu(tfc)3
60 %ee
Eu(tfc)3 (10.1 mol%)
\ S)” = by 298i NMR
\/\TMS
(R)-3 CDCI3
(61 %ee by chiral GC) _

 

 

V I I r T V I Y r ‘I’ U I ‘r I V Y I

1.17 1.15

4.6. Conflict Optical Rotation Value of (R)-19

During the kinetic resolution reaction of rec-19, [0].; results that were
inconsistent with previous reports were obtained. We measured the optical
rotation of the remaining alcohol (Figure 11) and a negative value ([a]o = —8.9 (c
1.04, CHCI3)) was obtained (R—19-a). However, assuming Kauzlaskas’ rule and
that the unreacted alcohol should be of the R configuration, this negative rotation
for (R)-19 would be in conflict with a previous report”56 Namely, Woerpel
described the preparation of (S)-19 by reduction of 1-(dimethylphenylsilyl)—2-
propen-i-one with (+)-lpczBCl and reported a negative [q]o value for the S
enantiomer (R-19-b). Curiously, Marsden reported the preparation of (R)-19

42

using (—)-lpchCl and he also reported a negative [q]o rotation for his R
enantiomer (R-19-c). Obviously, having negative [dlo values for both R and S
enantiomers is improbable.

Figure 11. Conflict [0].; Values

OH OH OH
vows VDMPS vows
(R)-19-a (S)-19-b (R)-19-c
(99 %ee) (93 %ee) (91 %ee)
[a]D = —8.8 (c 1.04, CHCI3) [ab = —10.5 (c 0.50, CHCI3) Mo = —6.8 (c nla, n/a)
Our result Woerpel's result Marsden's result

Mosher ester analysis of our material after the kinetic resolution of rac-19
indicated that the unreacted alcohol was (R)-19 and (S)-19 was acylated (Figure
12). However, Mosher ester analysis is an empirical method, and given the
conflicting literature, we sought a more definitive conformation of our assignment.

Figure 12. Determination of Absolute Stereochemistry of (R)-19

O-MPA
H I‘Me
—0.086 H +0192

5(R)-MPA-(R)-ester - 5(S)-MPA-(R)-ester
In a private communication, we learned that Woerpel and Marsden did not
have any material left to recheck the [ab values of their materials. To make
matters more confusing the original paper on the preparation of optically pure 19,
which was referred to by Woerpel and Marsden, did not report any [(119
values.”56 Thus we were left with no choice other than to repeat the previously
reported reductions (Scheme 42). Acylsilanes (29) were prepared by Swern

oxidation of rec-19 (1.5 equivalent of trifluoroacetic anhydride, 2.0 equivalents of

43

DMSO and 3.0 equivalents of EtaN in Cchlz, -78 °C). (R)-19 and (S)-19 were
prepared by reduction of 29 using (-)-lpcp_BCI and (+)-IpczBCl. In our hands, (R)-
19 gave a negative [q]o and (8)49 gave a positive [0].). This result is consistent
with our [q]o value of (R)-19 prepared by enzymatic kinetic resolution.

Scheme 42. Reduction of Acylsilane 29

 

(—)-lpczBC| (1.5 equiv) (2H
/ 5 VDMPS
THF, rt (R)-19 (87 %ee)
0 [min = -8.1 (c 1.24, CHCI3)
VLDMPS
29 OH

\ (+)-IpczBCl (1.5 equiv) v
> DMPS

(3)49 (82 %ee)

THF, rt
[0t]D = +7.2 (0 0.67, CHCI3)

Table 5. Retention Times of Optically Pure 19

 

 

. f , ,
Preparation method or HPLC Condition Retention time
optically pure 19 (min)
(—)-lpchCl reduction Column: OD-H 9.0
. Eluent: 0.5 °/o IPA/hexane
(+)-IpczBCl reduction Flow rate: 1.0 mU mi n 8.1
. - - 38
Kinetic resolution (Woerpel S condition) 9.0

 

We also compared our enzymatically generated (R)-19 with both (4»)-
lpchCl and (—)-lpchCl reduction products following the HPLC conditions
described in Woerpel’s paper (Table 5).38 The retention time of enzymatic
product (R)-19 is the same as that of the (-)-|pcp_BCl reduction product (R)-19.

We thus confirmed the absolute configuration of remaining q-hydroxysilane as R

44

enantiomer and [0].) value of (R)-19 is negative. (S)-19 prepared by Woerpel
should have a positive [0].; rotation.
4.7. Reduction of Optically Pure Acetate

As the advantage of a resolution is the ability to access both enantiomers,
we next investigated procedures for converting the enantioenriched acetates into
their corresponding chiral d-hydroxysilanes. Experimenting on (S)-18, a variety of
reagents were investigated, but many of these lead to erosion of enantiomeric
excess (Table 6). The most efficient results were achieved with DIBAL. For
example, when essentially enantiopure (S)-18 (98 %ee) was treated with 1.0
equivalent of DIBAL in hexane at -78 °C, the corresponding (S)-1-
hydroxyallyltrimethylsilane ((S)-3) was obtained in 78% isolated yield with only
modest loss of %ee (99:1 to 9455.5 er).

Table 6. Reduction of Optically Pure Acetate (S)-18

 

reagent
\/C')\AC solvent 0H
\ > \
TMS temperature TMS
(S)-18 (98 %ee) time (S)-3

 

Entry Reagent Equiv Solvent Temp (°C) Time (h) %ee Yield (%)

 

1 K2003 5.0 MeOH 20 4 85 -
2 LAH 1 .2 Eth Reflux 2 80 -
3 KCN 1 .0 MeOH rt 24 76 -
4 LiOH 5.0 MeOH-Hgo 20 5 85 -
5 Red-AI 1.05 THF 0 to rt 1.75 81 -
6 DIBAL 1 .1 CHQC|2 —78 3 84 -
7 DIBAL 1 .0 Hexane —78 3 89 78

 

45

The same procedure could be applied to (S)-20, with even less loss of
enantiopurity. In this way, (8)49 was obtained in 81% yield with 93 %ee
(Scheme 43).

Scheme 43. Reduction of Optically Pure Acetate by DIBAL

 

OAc DIBAL (1 .0 equiv) OH
vows hexane V \ DMPS ’
(S)-20 (99 %ee) —78 °C. 3 h (3)49 (81 %, 93 %ee)

46

Chapter 5. Enzymatic Kinetic Resolution of Methylated q-Hydroxysilanes
5.1. Introduction

In an attempt to overcome the poor reactivity exhibited by the methylated
substrates (Table 3, entries 4 to 6), we turned to commercially available enzymes
that are known to effect the transesterification of secondary alcohols. Several
such enzymes are documented in the literature.

For example, Amano AK resolves a-methyl-benzeneethanol to afford the
(S)-unreacted alcohol and the (R)-acetate in good yields with good enantiomeric
excesses (Scheme 44).57 The acetate was obtained in 42% yield with 97 %ee
and the (S)-alcohol was recovered in 52% yield with 81 %ee.

Scheme 44. Kinetic Resolution of with Amano AK

Amano AK (72 mg/mmol)

 

OH vinyl acetate (16.2 eq) ‘ 9H + 0 Ac
Ph rt ’ /'\/Ph /'\/Ph
h
68 52%, 81 %ee 42%, 97 %ee

Similarly, CRL was reported for the efficient kinetic resolution of
tetrahydro-2-pheyI-2H-pyran-4-ol to afford the unreacted alcohol and the
corresponding acetate (Scheme 45).58

Scheme 45. Kinetic Resolution with CRL

 

OH CRL (35 mg/mmol) OH OAC
vinyl acetate (16.0eq) g
> +
cyclohexane, rt 0
ph o 5 h Ph 0 Ph‘“ 0
37%, 98 %ee 37%, 95 %ee

Also there are some examples of the dynamic kinetic resolution of

secondary alcohols with a ruthenium cocatalyst. Using a ruthenium racemization

47

catalyst and PS-D l as an acylating catalyst, a series of secondary alcohols were

resolved with excellent enantioselectivities and in good yields (Scheme 46).59

Scheme 46. Kinetic Resolution with Amano PS-D l

 

Amano PS-D I (80 mg/mmol) ’ O-H-O

p-CIC5H4OAc (6.7 eq) Ph pt.
OH catalyst (10 mol%) OAc Ph \ P“ P“ / Ph
A/OT' ' /'\/0Tr Ph 0 CJ-‘t'u-H-R'u, CO Ph

toluene, 70 °C CO CO
91%. 99 %ee catalyst

 

 

 

L

Kim and coworkers have also reported a novel ruthenium catalyst that can
racemiz allylic alcohols (Scheme 47).60 In the presence of this catalyst, Amano
PS-C ll catalyzed transesterification using p—ClCeH4OAc as an acylating reagent
afforded (R)-acylated product in 84% yield with >99 %ee.

Scheme 47. Kinetic Resolution with Amano PS-C II

Amano PS-C II (144 mg/mmol)

 

 

 

 

p-CleH4OAc (1.5 equiv) f ‘

Et3N ( 1 equiv)

OH catalyst (4 mol%) OAc /4R'u/ 'Ru-

- I s ,
MeM Ph - MeMPh \ H ('3'
CH2Cl2, 3 A MS
rt 48 h 84%, >99 %ee
. catalyst

 

>99 %conversion

5.2. Kinetic Resolution of Rae-24

We tested Amano AK, Amano PS-D I, Amano PS-C II and CRL in the
kinetic resolution of 2-methyl-1-(trimethylsiIyI)-2-propen-1-ol (rac-24) (Table 7).
Amano AK, Amano PS-C II and CRL afforded some level of reactivity but the
reaction times were long and enantioselectivity was low. Amano PS-D I gave the

best results in terms of enantioselectivity.

48

 

.0. :

.3:

 

 

 

0. 00 00 - m. as 80 “.1: 0.0.80_>:_> _ 0-0a 80:3 5
.0: .3:
1 N N
n 00 00 Z 9. 000 _0 :0 20.80.23 _ 0.0. 2.22 0
.0: .3:
3
o. E .0 00 t 9. m: 0:0 .9 90.82.63 _ 0-0. 80:2 0
.50: .0:
0:030
0: so 00 00 S E 80 Z 3.0.1.060 5.0. 80:... s
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>
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50

As shown in entry 12, the optimized conditions were rec-24, 288 mg
Amano PS-D I/mmol rec-24, 3.0 equivalents of vinyl acetate and 3 A molecular
sieves in toluene under a nitrogen atmosphere at room temperature in a sealed
tube. Acetate (R)-3O was obtained in 13% yield with 87 %ee, with the alcohol (8)-
24 being recovered in 19% yield with 99 %ee. Again, adjustments in the amount
of Amano PS-C l lipase and vinyl acetate and/or solvent did not improve the
resolution results. If Amano PS-D l was excluded, no formation of acetate
product was observed.

From these reactions, we made two important observation. First, (S)-24
was unreacted and (R)-24 was acylated in the reaction. Second, the yield of both
products was lower than those from the kinetic resolution with Novozym 435.

5.3. Determination of Absolute Stereochemistry

Again, the absolute stereochemistry of the unreacted o-hydroxysilane 24
was determined by Mosher ester analysis (Figure 13).31 Interestingly, the
stereochemical preference was opposite to that observed during the resolution of
rec-3 with Novozym 435.

Figure 13. Determination of the Absolute Stereochemistry of (S)-24

O-MPA
.,Me
S"Me
H H
-0.1 59 +0.183

5(R)-MPA-(R)-ester ' 6(R)-MPA-(S)-ester
Scheme 48 shows the absolute stereochemistry of the remaining a-
hydroxysilane and acetated product after the kinetic resolution. In the case of the

kinetic resolution of rac-24 with Amano PS-D I, the unreacted a-hydroxysilane

51

was the S enantiomer (Eq 1). However, the R enantiomer was recovered after
the kinetic resolution of rec-3 with Novozym 435 (Eq 2). To more directly
compare the selectivity of Amano PS-D I vs. Novozym 435, rec-3 was resolved
with Amano PS-D I in the presence of 1.5 equivalent of vinyl acetate in toluene at
room temperature (Eq 3). After ~18 h, rec-3 was completely consumed and
acetate (S)-18 was formed in 41 °/o yield with 97 %ee.

Scheme 48. Comparison of Absolute Stereochemistry

 

 

Amano PS-D l
(288 mg/mmol substrate),
OH vinyl acetate (1.5 equiv) OH 9A0 (1)
— +
TMS 3 A MS, toluene TMS YTMS
rec-24 rt (3)-24 (R)-30
Novozym 435
CH (15 mg/mmol substrate), OH O A c
Vk vinyl acetate (1.5 equiv) ‘ g + v 2
\ TMS ’ VTMS TMS ( )
rec-3 3 A MS. Pentane (R)-3 (S)-18
38 °C
Amano PS-D I
OH (288 mg/mmol substrate), 0 Ac

 

vinyl acetate (1.5 equiv)
vTMS > v (3)

3 A MS, toluene TMS
rec-3 rt, ~13 h (8)48
(41%, 97 %ee)

It seems that rec-24 does not follow Kazlauskas’ rule. However, rec-24 is
different from rac-3 in term of the size of substituents. Rae-24 has a methyl group
on the o-position of the vinyl group (isopropenyl group). Unfortunately, we could
not find an A value of the isopropenyl group so as to make the direct size
comparison of the two groups (A value of TMS= 2.5). For an indirect comparison
of the two groups, a similar isopropyl group was selected and it has a smaller A

value than TMS (A value of isopropyl= 2.1). We could not decide which group

52

between TMS and isopropyl group is larger. However, if we assume that the
isopropenyl group is larger than the TMS group, Kazlauskas’ rule could be apply
to the kinetic resolution of rec-24 (Figure 14). Importantly, what can be
concluded though is that the observed absolute stereochemistry is highly
influenced by even relatively small changes to the side chain structure of the a-
hydroxysilane.

Figure 14. Kazlauskas’ Rule for Rae-24

OH
—. i —
‘ 00- w

 

OH OH
Lipase (3)-24
TMS = _ Acyl Donor +
,Acyl
rec-24 rac 0 OAc
._—> =
00 “W
(R)-30

5.4. Formation of Acetylated Hemiacetal

As mentioned before, the kinetic resolution of rac-24 afforded products in
low yield (Chapter 5.2). The low yields of (R)-30 and (S)-24 were partly due to
formation of unknown compounds as main products of the reaction. While the
reactions of rec-3 and rac-24 with Amano PS-D l afforded different
stereochemical outcomes, they were similar in that both afforded side products.
After the kinetic resolution of rec-24, three newly formed peaks (3.6 min, 7.1 min
and 7.2 min, ratio= 18:43:38) were observed for the unreacted o-hydroxysilane
and acetate product by GC (Scheme 49). Similarly, GC of the crude material
gave three peaks at 2.6, 6.2, and 6.4 minutes (ratio= 22:38:48) for the acylated

products peak from the kinetic resolution of rac-3 (Scheme 50).

53

 

 

 

 

 

 

 

 

 

 

 

 

 

 

0.25 m. _ . _ m. _ m _ ..
l7 4
.012... I
.z x)
W IO
.9
.9 w r
.7
9
wEP/W/
/
U<O
.0. -
m
.00.... 5M. .33. n 0. .t
- t 00:
ms”? m. 0:029 .22 < m 05F”.
:_E 0.0 + :_E N0 + :_E 0N + /_\/ A /_\/
0<O .2000 m. 5 0.0000 _3:_> 10
.9000030 6:559: 00m.
_ 0-00 o:0E<

0.80 .o 55.280: 5.052 a. 0.00 00 .8 05050

54

0055.: 0.3 0.0 m.~

w p u -

 

 

 

 

 

 

 

 

 

 

.8
9
\ .99 ms:
9
05.54% .9 9
w :0
0<0
.1.
V.
7. _
OMAN: VNIAW v r_ N—. w .t glows

 

0:029 .02 < m

.2300 0. : 0.0.80 35>
o< :0 .2238 05505 000.
_ 0.00 805<

0 III"

vuémm .0 :o=:_ommm 030:5. :2 0.00 0.0 .9. 0E050w

55

 

We decided to elucidate the structure of the side product of the kinetic
resolution of rec-3. Acetate (S)-18 was easily removed from the crude material by
rotary evaporation. However, a mixture (2.6 min, 6.2 min and 6.4 min on GC) of
unknowns was inseparable by silica gel column chromatography or fractional
distillation. Furthermore, the compound that eluted at 2.6 min partially
decomposed during silica gel column chromatography (ratio of 2.6 min:6.2
min:6.4 min = 9:32:59).

A possible explanation for the byproducts from the enzymatic kinetic
resolution of rec-3 is formation of an acylated hemiacetal by reaction between the
starting racemic q-hydroxysilanes and the aldehyde formed from the acylating
reagent. Recall that all of rec-3 was consumed in the reaction with Amano PS-D l.
Forthermore, Hogberg and coworkers reported the kinetic resolution of sterically
hindered secondary alcohols with vinyl acetates gave acylated hemiacetal as the
major product (Scheme 51).61 Usually, more sterically hindered substrates form
these acetals in such reactions.

Scheme 51. Kinetic Resolution of Sterically Hindered Secondary Alcohol 34

 

Boehringer Chirazyme L-2 i
OH (1.3 mg/mmol substrate), 0 OAC
“ vinyl acetate (20 equiv) “
O. octane O.
rt
34 35
(47%)

We tentatively assigned the structure of the impure material from the
kinetic resolution of rec-3 based on ‘H, ‘30, HMQC, HMBC, TOCSY, COSY, IR,

and HRMS analysis. These data suggested that the peaks occurring at 6.2, and

56

6.4 minutes was diastereomers of 33. Treatment of the impure acetal 33 with C18
silica gel in CHaCN at room temperature gave (R)-3 with 64 %ee in >33% yield
(Scheme 52). This result showed that (R)-3 is converted to the acetal 33 during

the kinetic resolution.

Scheme 52. Enzymatic Resolution of Rec-3 with Amano PS-D l lipase and

 

Hydrolysis of 33
Amano PS-D | lipase i
OH (228 mg/mmol substrate), Ci) OAc OAc
vin Iacetate 1.5e uiv

vms y ( q ) > vms + vms

rec-3 3 A MS, pentane, 33 (3)43

rt, ~18 h (41%, 97 %ee)
CH
C -Si0 '

18 2 VTMS

MGCN, l't (RH,

(>33%, 64 %ee)

The formation of acylated hemiacetal 33 can be explained by the following
mechanism (Scheme 53). The reaction initially affords (S)-18. During the reaction,
aldehyde 36 is also produced by enol-keto tautomerization of the enol side
product (from (b) to (c) in Scheme 36). Compound 36 can react with both (R) and
(S)-3 at different rates. It is assumed that acetylation of (S)-3 is faster than
formation of hemiacetal (S)-37, because (S)-18 is recovered in good yield with
excellent enantiomeric excess. In the case of (R)-3, formation of hemiacetal is
faster than acetylation. Subsequently, hemiacetal 37 forms (from (R)-3), which

can be esterified to give (R,R)- and (R, S)-33.

57

 

 

”1%”: 8-8%
25M) 95/“) A
o<0/_\m + o<o/\m
8.5% a 8-39
227) msP/_\/ ll
20 o + o<0/\o

63° 3 5&3
on ~19

t
6529 .92 < m

 

wSF/W/ A

O o<O

928m :63
88: _ 9mm 895.

on .mfiooflEoI no§boo< ,6 SEES". .2 EmEmcoos. o_n_mmon_ .mm oEocow

I
O um

58

To further support our conclusion, we independently prepared 33 by the
reduction of 18 with DIBAL followed by acylation of the resultant hemiacetal
(Scheme 54).62 Interestingly, this newly prepared material had the same impurity
profile of 33 made during the kinetic resolution of rac-3. A GC of the material
gave peaks at 2.6, 6.2 and 6.4 minutes, albeit in a different ratio (1:59:40). The
material was also spectroscopically similar to that formed during the kinetic

resolution. We confirmed the formation of acetal 33 in the kinetic resolution of

 

 

rec-3.
Scheme 54. Synthesis of Acetal 33
pyridine (3.0 equiv)
o OAl(i-Bu)2 DMAP (20 equiv) i
0k DIBALH (2.0 equiv) 0 A020 (6.0 equiv) 0 OAc
v t v : v
TMS CHZCIZ, -78 °c, 45 min TMS CH2CI2. TMS
18 35 -78 °C, 29 h 33

The last unknown side product from the kinetic resolution of rec-3 was a
compound that eluted at 2.6 min on GC. However, this side product is not
separable by silicagel column chromatography or by fractional distillation. We
thought that the side product might be a rearrangement product from acetate 18
(Eq 1, Scheme 55), because an extra CH3 (from the acetate), TMS and vinyl 1H
NMR peaks were presented in the 1H NMR spectrum of the crude material. With
this information, compound 31 was prepared from commercially available 32 (Eq
2) and its GC retention time was determined. This established that 31 was not
the side product from the enzymatic kinetic resolution. We still do not know the

structure of this minor side product.

59

Scheme 55. Possible Rearrangement of 18

rearrangement o

 

 

o o ,
kgws AOMTMS (1)
18 31
pyridine (1.1 eq) 0
HOMTMS aceticanhydride(1.1eq) t AOMTMS (2)
32 rt 31

(retention time by G0: 5.4 min)

5.5. Future Work

Our research shows the viability of the enzymatic kinetic resolution of o-
hydroxysilanes to prepare optically pure o-hydroxysilanes. However, kinetic
resolution allows for a maximum of only 50% yield of a single enantiomer. In our
study, unreacted o-hydroxysilane was recovered in 43% and the acetate was
isolated in 37%. To overcome the maximum of 50% yield in kinetic resolution, a
dynamic kinetic resolution (DKR) can be used (Figure 15). During a DKR, R and
S enantiomers react at different rates but they are in equilibrium by way of a
racemization event that happens during the kinetic resolution. In this way, all the
starting material can be used and the product can be obtained in 100% yield.

Figure 15. Dynmaic Kinetic Resolution

 

 

[ kR(fast) ]
R + E > R'

 

fl racemization

S + E ---------------- *9

60

For example, Backvall and coworkers have studied the dynamic kinetic
resolution of rec-14 with ruthenium-catalysts (Scheme 56).52 In this case, (R)-15
was obtained in 80% with >99 %ee.

Scheme 56. Dynamic Kinetic Resolution of Rac—14

Novozym 435 (30 mg/mmol)

 

 

p-CIC5H4OAC (3.0 equiv) r O-H-O ‘
R at 2 m |°/) Ph Ph
0“ U‘C ( ° ° OAc Ph Ph
/k : /'\ Ph \ / Ph
Ph toluene, 70 °C, 48 h Ph Ph QC.Rzu-H--R.u,CO Ph
rec-14 (R)-15 CO CO
80%, >99 %ee _ Ru-catalyst

 

 

 

In the reaction, the ruthenium catalyst is used for racemization. During the

reaction, the S enantiomer is racemized and the R/S ratio is reequilibrated

(Scheme 57).
Scheme 57. Racemization of (S)-14
OH Ru'H O H OH
3 M 9' ———> /U\ + R’u -——> )\
/\Ph /\ Ph ‘H Ph
(3)-14 Ph rac-14

DKR is one of the methods to maximize the yield of the kinetic reaction.
We already optimized the conditions for the enzymatic kinetic resolution a-
hydroxysilanes. Applying ruthenium catalysts for racemization to our system

would allow us to obtained higher throughput of a single enantiomer.

61

Chapter 6. Preparation of a-Hydroxysilanes by Kinetic Resolution with
Phosphabicyclooctane (P80)
6.1. Attempted Preparation of a-Hydroxysilane

We had investigated the scope and limitation of enzymatic kinetic
resolution of o-hydroxysilanes in combination with different enzymes, solvents,
temperatures and acylating reagents. However, the substrate scope was not as
broad as we had hoped. Therefore we sought even more methods to prepare
enantiomerically pure methylated d-hydroxysilanes.

Scheme 58. Resolution of a-Hydroxystannes via Norephedrine Carbamate

 

4-02NC6H40(O)CI O
\/CID\H (1.5 equiv) OJLO-p-NOZPh
S”B”3 hexane/CH3CN (1 :1) SnBua
39 ,1 4o

1) (1 S,2R)-(+)-norephedrine

(1.3 equiv)
hexane/CH3CN (1:1), 0 °C
2) silica gel column

 

 

% chromatography
1) AlH3 (1.8 equiv) O
OMOM THF, reflux JL OH
= O N
SI‘IBU3 _ H
(3)43 2) MOMC|(1.5equ1v) SnBU3 Ph
(50%, 94 %ee) iP'ZNEt (2'? 9‘1””) 41 (35%)
CH2C|2. 0 C 10 ft higher Rf
+
it
‘ OH
O N
\ASnBu3
42
lower Rf

One of our trials was the resolution of rec-24 via (1 S,2R)-(+)-norephedrine
carbamate. Kelly et al. reported the successful resolution of q-hydroxystannes via

62

(18,2R)-(+)—norephedrine carbamates in a two-phase acetonitriIe-hexanes
solvent system.63 In this case, o-hydroxystannes (39) were converted into mixed
carbonates with p-nitrophenyl ohIoroformate (Scheme 58). Treatment the
carbonate (40) with (18,2R)-(+)-norephedrine then afforded the carbamates (41
and 42). Diastereomers 41 and 42 were separable by silica gel column
chromatography. Isolated 41 was converted back to optically pure MOM
protected o-hydroxystanne by reduction with AIH3 followed by protection of
alcohol. The optically pure protected o-hydroxystannes (S)-43 was obtained in
60% yield with 94 %ee.

We decided to apply this protocol to our methylated o-hydroxysilane (rac-
24), which could not be resolved by enzymatic kinetic resolution with Novozym
435. The modified Kells’ procedure was performed on rec-24 (Scheme 59).64 In
doing so, we substituted ethyl ohIoroformate for p-nitrophenyl ohIoroformate.
Thus, stirring a mixture of a-hydroxysilane 24, ethylchloroformate, and pyridine in
hexane/acetonitrile at 0 °C for 2 h, and then quenching with water, afforded the
carbonate derivate 45 in 46 %yield. The first step of this reaction proceeded well.
However, the subsequent step, which involves the replacement of the carbonate
functionality with a carbamate. did not proceed and only 45 was recovered. The
failure of the second step may be due to the poor leaving ability of the ethoxide
group.

To try and overcome this problem p-nitrophenyl ohIoroformate (47) was
employed in step one of the reaction, affording the mixed carbonate (48) as a

dirty white solid after 45 minutes. A mixture of this crude carbonate 48, (1S,2R)-

63

(+)-norephedrine, and diisopropyl amine, in hexane/acetonitrile (1:1 v/v) was
stirred at room temperature for 24 h, followed by aqueous workup to give-the
corresponding carbamate as an inseparable mixture of diastereomers (46al46b)
by silica gel column chromatography. The difficulty in separation forced us to
abandon this route.

Scheme 59. Attempted Resolution of o-Hydroxysilane by Kells’ Protocol

 

0
OH O pyridine (3.0 equiv)
M + A JL = 0%A
\ TMS 0 c1 hexane/MeCN (1 :1) /\/k
0°C,2h \ TMS
24 44 45(45%)

(1 S,2R)-(+)-norephedrine
(1.3 equiv)
i-PerEt (3.0 equiv)
hexane/MeCN (1 :1)

4------

OH JL OH
MTMS O ”/Y

(S)-24 46a
AlH
+ 4- ------------- 3- ----------- +
0 s
Q“ O/ILN ' OH
MTMS ; H Ph
MTMS
(R)-24 46b
inseparable
diastereomers
it
NO
i O 2 o O-p-NOzPh
Cl 0 Mulls
47 48

64

6.2. Non Enzymatic Kinetic Resolutions - Prior Art

We turned our attention to non-enzymatic catalytic kinetic resolutions. Several
non-enzyme catalysts for kinetic resolution of secondary alcohols are
documented in the literature.

Fu and coworkers reported the kinetic resolution of secondary alcohols
with a planar-chiral derivative of 4-(dimethylamino)pyridine (DMAP) 51 (Scheme
60). 65 2,2-Dimethyl-1-pheny|propan-1-ol (rec-49) was resolved to unreacted
alcohol (R)-49 and acetylated product (S)-50 with excellent enantiomeric excess.
A similar protocol was applied to the resolution of a series of racemic allylic
alcohols. After kinetic resolution of rec-52, the remaining (R)-52 was obtained
with good enantiomeric excess.

Scheme 60. Kinetic Resolution with Planar-Chiral DMAP Derivate 51

catalyst 51 ( 1 mol%)

 

 

 

 

 

 

ACZO (0.7 equiv)
0H Et3N (0.7 equiv) 0H 9A0
Ph t-Bu = Ph/kt-Bu + PhAt-Bu r MezN
rec-49 t-amyl alcohol, 0 °C (3)49 (R)-50
51 %conversion (92 %ee) (88 %ee) \N F'e
catalyst 51 ewe
A020 R
0” Et3N 9” OAc R=Ph
Et 5 Y3 + Y3 _ catalyst 51
t-amyl alcohol, 0 °C
rec-52 63 %conversion (R)-52 (S)-53
93 %ee

In 2000, Spey and coworkers reported on the development of catalyst 56
for the kinetic resolution of sterically hindered secondary alcohols (Scheme 61 )65
Treatment of 1-naphthol (rec-54) with 56 and isobutyric anhydride afforded (R)-

54in 43% with 97 %ee as well as (S)-55 in 56 % with 73 %ee.
65

Scheme 61. Kinetic Resolution with Catalyst 56

catalyst 56 ( 1 mol%)

 

 

isobutyric anhydride
(1.4 equiv) _ r 4
I
0” Et3N (0.7 equiv) OH (300 Pr 0
“DC ’ " D

toluene, -78 °C \

rec-54 55 %conversion (R)-54 ( S) _55 Ph | /

(43%, 97 %ee) (55%. 73 %ee) N
catalyst 56

 

 

 

Phosphabicyclooctanes had also previously proven successful in the
resolution of alcohols bearing a t-butyl group (35) and allylic alcohols (36)
(Scheme 62).67 In the both cases, unreacted alcohols and acetated products
were obtained in reasonable enantiomeric excess.

Scheme 62. Kinetic Resolution with PBO Catalyst 58 and 61

 

catalyst 58 (4 mol%)
OH benzoic anhyride (2.5 equiv) OH OC(O)ph
> + I
Ph/kt-Bu toluene, rt Ph t-Bu PhAt-Bu
rec-49 53% conversion (8)49 (R)-57

(88 %ee) (78 %ee)
catalyst 61 (5 mol%)

 

 

OH isobutyric anhyride (2. 5 equiv) 00(0)"Pr
th to'uene' .40 OC >Yl\/\Ph “WW1
rec-59 48% conversion (3)-59 (R)'60
(66 %ee) (71 %ee)
H H H H
PI: P0,”: t-Bu
58 51 t-BU
k PBO catalyst

 

 

 

66

Given the structural similarities to our silyl substrates, we hypothesize that
planar-chiral DMAP derivative or phosphabicyclooctanes could provide a novel
route to optically active a-hydroxysilanes (Figure 16). We first chose to

investigate the resolution of a-hydroxysilanes via phosphabicyclooctane (PBO)

 

catalyst.
Figure 16. Our Substrates for Kinetic Resolution
r 1
OH OH OH OH OH
vms vows vres Me/\/I\TMS Vms
3 19 21 22 Me24
Me OH Me OH OH OH
WTMS Wows Ph/kTMS PhADMPS
25 25 27 28

 

 

 

6.3. Preparation of Phosphabicyclooctane Catalyst (58)67

We decided to prepare catalyst 58 by the following procedure (Scheme
63). The synthesis of catalyst 58 initiated with transesterification of 62 followed
by triflation to give 64. 2,2-Dimethylcyclopentane formed its enolate with LDA and
the enolate reacted with triflate 64 in THF (transition state 68). During the
alkylation, the enolatelithium may be coordinated to the oxygens of 64. To
minimize steric effects, the hydrogen should occupy the place below the
cyclopentane. After alkylation of 64, the ester was converted to the
corresponding alcohol by LAH. Cyclization of the 1,4-diol 65 followed by

oxidation to the corresponding sulfate gave 66.

67

Scheme 63. Preparation of Catalyst 58

methyldiglycol (3.2 equiv)

 

 

 

 

 

CH3 OCH AI(OiPr)3 (17.0 equiv) CH3 0 o
HO)\n/ 3 = HO/kll/ \/\O/\/ \
O reflux O
62 63
(58%)
pyridine
(2.0 equiv)
triflic anhydride
(2.0 equiv)
1) n-BuLi (0.7 equiv) o
diisopropylamine (0.7 equiv) CH3 V CH20'2' 0 C
H toluene, 0 °C
OH 2) 2,2-dimehtylcyclopentanone O
65 (0.6 equiv), —78 °C
3) LiAlH4 (7.9 equiv) ‘54
1) SOCI2 (1.6 equiv) —78 °C
CCI4, reflux
2) RUC'3O3H20 1) H2PPh (1.8 equiv)
(6 mol /°) . n-BuLi (1.1 equiv)
NaIO4 (2.0 equiv)v THF —78 °C
0 C 2) n-BuLi (1.2 equiv)
H -78 °C
IO >
0,302 3) H3B-THF (3.0 equiv)
rt

66

 

 

 

 

 

68

 

67
(7.8% from 63)

pyrrolidine
reflux

 

H H
PH,”

58
(92%)

Ph

The next step is a double SN2 reaction. The first SN2 reaction happens at
the less sterically hindered primary carbon on 66. In second 8N2 reaction, the
phenyl group should be away from the reaction center to give the endo-phenyl
diastereomer (transition state 69). 3H3 was installed for purification and
determination of the diastereomeric ratio (67). The final product (58) was

obtained by removal of the BH3 group.

6.4. Kinetic Resolution of a-I-lydroxysilanes by Phosphabicyclooctane
Catalyst (58)

In our hands, catalyst 58 prepared in this manner contained a small
amount (60:1) of the P-epimer after removal of the BH3 group. Fortunately,
recrystalization of 58 in CH3CN at -20 °C afforded material that was
diastereomerically pure by NMR.

Table 8. Test Reaction for Kinetic Resolution of Rec-49

 

 

 

catalyst 58 (8.5 mol%)
OH benzoic anhyride (2.5 equiv) OH OC(O)Ph
1: + I
PhAt-Bu solvent, temp Ph/|\t-Bu phAt-3u
rec-49 time, %conversion (S)-49 (R)-57

58 . .. ,, (S)-49
Entry (m ol%) Solvent Time (h) Temp( C) Conv( A) (% e e)
1 8.5 heptane 1.6 (5 ) r.t. 50 (53) 58 (87)
2 4.0 toluene 5.5 (12) r.t. 47 (53) 55 (88)
3 4.0 toluene 19.5 (65) —40 51 (45) 61 (78)

4 4.0 toluene 26 —30 59 85

 

alThe number in parenthesis are reported by Vedejs and coworkers

bThe chiral HPLC analysis determined the %ee.

69

To test synthesized catalyst 58, we ran the same reactions reported
before by Vedejs. Applying this catalyst to the resolution of rec-49 under
previously reported conditions gave lower %ee’s than expected (Table 8). We
obtained (S)-49 with 58 %ee at 50% conversion (Entry 1). In contrast, the
literature reported that the kinetic resolution of rec-49 afforded (S)-57 with
87 %ee at 53% conversion (Entry 1 in parenthesis). Changing the conditions did
not improve selectivity in the reaction (Entries 2 and 3).

At —40 °C, a white solid was observed during the reaction (Entry 3). We
presume that at this temperature the benzoic anhydride did not completely
dissolve in the toluene. So we increased the temperature to -30 °C and the
kinetic resolution of the rec-66 was tested. This modification improved the
outcome of the reaction affording up to 85 %ee at 59% conversion (Entry 4).
Notably, the reaction was slow especially past 50% conversion. Nonetheless,
more than 50% conversion was necessary to get higher enantiomeric excesses
of 49.

Confident in the quality of the catalyst and our own protocol, we set out to
screen the resolutions of a set of a-hydroxysilanes (Table 9). The distinction
between a t-Bu and TMS group became immediately apparent (compare entry 2
in Table 8 to entry 1 in Table 9). While we were able to achieve the first
resolution of an a-hydroxysilanes with catalyst 58, after 47% conversion the

unreacted 27 possessed an enantiomeric excess of only 46 %ee (Entry 1).

7O

53.. 9: 855.9% 2.0.228 Sq: ace cc .920 9?.

 

 

 

 

 

 

2
v 9 EE on 9:93: md w520/_\:Ioo v
:o
2
Q m em 5 F 88.9 9m 255/) m
. :o
a
Q 2 S e N 8822 em 2‘7.) N
:0
R
0? RV EE 0.. 0:029 0.0 wEHJ\:a w
:0
63°C as goé 88.822248
mcm=m>x9u>Ié coo oE_._. Eczom mm 9.355. bEw
a... 8298 . 5 E t 82
co m m m m E028 m m
N 4.. N /«\F A N /_\F
:0 + en. 0 . :0
4i 3:8 m NV 0900ch
r u c an 22.98

 

 

 

mocm=m>xofi>lé .6 cozaowmm 039:? .m cam...

71

The corresponding allylic alcohol behaved similarly affording S-3 in
19 %ee after 47% conversion (Entry 2). Interestingly, the stereochemical
preference was opposite to that observed during the resolution of rec-3 with
Novozym 435.

To examine a change in both steric bulk of the silyl and carbon substituent,
as well as the hybridization of the carbon substituent, we examined rec-19 and
rec-70 (Entries 3 and 4). Both of these substrates responded poorly providing
the o-hydroxysilanes with 5 %ee and 4 %ee respectively.

While reaction optimization remains necessary, these results are
significant in that they represent the first kinetic resolution of a-hydroxysilanes
with phosphabicyclooctanes and in that the absolute stereochemical outcomes

complement our enzymatic results.

72

Chapter 7. Designed and Synthesized a series of Novel N-Boc amines

During my PhD studies on the generation of optically active 01-
hydroxysilanes, I also became involved in a short term side projects when these
projects demanded additional and immediate attention. For example, during a
study on the C-H activation/borylation of protected anilines, our group working in
collaboration with Professor Mitch Smith (MSU) found that 71 borylated at the 2-
position (Scheme 64).

Scheme 64. Regioselective Borylation of 71 and 73

 

 

o o
H. L ,t-Bu BzPin2(1.5 mol%) H. A ,t-Bu
N 0 [|r(OMe)(COD)]2(3.0 mol%) N 0
; PinB
dtbpy. THF, 25 °c
CN CN
71 72
o o
H ’u\ B2Pin2(1.5 mol%) H /u\
N CH3 [lr(OMe)(COD)]2(3.0 mol%) N CH3
dtb ,THF, 25°C .
py PlnB
CN CN
73 74

This was unexpected because Ir-catalyzed borylations are generally
governed by sterics. For example, NHAc substrate (73) borylates at the 3-
position under the same conditions.68 In an attempt to understand the observed
regioselectivity, l was called upon to rapidly synthesize of novel N-Boc anilines

(Figure 17). My compounds are currently being used to complete this study.

73

Figure 17. Synthesized N-Boc Amines

 

NHBoc NHBoc NHBoc NHBoc

Q
2_
\/

N HAC COzMe OC(O)NM62 0M6

NHBoc NHBoc NHBoc

@-

CF3 CI
CF 3 OMe OC(O)NMez
N HBoc NHBoc
OC(O)NM32 N: M82

 

 

L

Conclusion

We have studied on developing new method for the generation of optically
active d-hydroxysilanes. The ring opening of epoxy alcohols bearing a TMS
group with both aluminum and boron hydrides provided the unfavoured1,2-diol .
This result shows that silicon plays an important role in determining the
regioselectivity and that cyclic boronic esters are formed in the ring opening
reaction. The scope and limitation of enzymatic kinetic resolution of o-
hydroxysilanes in combination with different solvents, temperatures and
acetylation reagents were investigated. The reactions are sensitive to the
structures of both the silyl group and the organic side chain. In the non enzymatic
kinetic resolution, the absolute stereochemical outcomes complement our

enzymatic results.

74

Appendix. Experimental Details
Materials and Methods

Tetrahydrofuran was freshly distilled from sodium/benzophenone under
nitrogen. Benzene and chlorotrimethylsilane were freshly distilled from calcium
hydride under nitrogen. Benzene—dB, DMSO-dS, and chloroform-d were
purchased from the Cambridge Isotope Labs and used without further purification.
Deionized water was used unless othenlvise noted. Enzymes were purchased
from Aldrich or Novozym. (Amano PS: Lipase from Burkholderia cepacia),
Novozym 435: Lipase B from Candida antarctica immobilized on acrylic resin,
Amano AK: Lipase from Pseudomonas Fluorescens, Amano PS-D I: Lipase from
Pseudomonas cepacia immobilized on diatomite, Amano PS-C ll: Lipase from
Pseudomonas cepacia immobilized on ceramic, CRL: Lipase from candida
rugosa or candida cylindracea)

All other commercial reagents were used without purification unless
otherwise noted. Flash chromatography was performed with silica gel 60 A (230—
400 mesh) purchased from Silicycle. TLC was performed on aluminum backed
TLC plates by Silicycle. All other yields refer to chromatographically and
spectroscopically pure compounds. Melting points were determined on a
Thomas-Hoover Apparatus, uncorrected. Infrared spectra were recorded on a
Nicolet IR/42 spectrometer. 1H, 11B, 13C, 298i and 31P NMR spectra were
recorded on 300 and 500 MHz spectrometer with chemical shifts reported
relative to the residue peaks of solvent chloroform (25 7.24 for 1H and 5 77.0 for

13C). The enantiomeric excess (ee) values were determined on an Agilent 1100

75

series HPLC using a Chiralcel OJ, OD or OD-H columns or on a Varian 3900 GC
using a B-dex tm 325 column. Optical rotations were measured on a Perkin—
Elmer 341 polarimeter. High-resolution mass spectra (HRMS) were obtained on
a Waters QTOF Ultima mass spectrometer at the Michigan State University Mass
Spectrometry Facility by Luis Sanchez.
Standard Reaction Method

All reactions were carried out in oven-dried glassware, with magnetic
stirring, and monitored by thin-layer chromatography with 0.25-mm precoated
silica gel plates, unless otherwise noted. Visualization of reaction progress was
achieved by UV lamp, phosphomolybdic acid stain or potassium permanganate
stain.

Ring Opening Reaction

 

3-(TrimethylsinI)-2-propyn-1-ol (8)64
TMS—:—\
8 0” A solution of Mg turnings (4.87 g, 0.2 mol) in THF (100 mL)

 

was stirred while maintain the reaction temperature below 50 °C and
bromoethane (14.9 mL, 0.2 mol) was added dropwise over 3 h. The reaction
mixture was stirred for 1 h at 50 °C and cooled to 0 °C. A solution of propargyl
alcohol (4.16 mL, 72 mmol) in THF (4.2 mL) was added dropwise over 2.25 h
below 10 °C. The reaction was stirred overnight and cooled to 0 °C. TMSCI (25.4
mL, 200 mmol) was added dropwise by addition funnel while the reaction
temperature below 25 °C. The reaction mixture was heated to reflux for 2 h, the
suspension cooled to room temperature and aqueous H2804 (1.4 M, 80 mL)

added over 0.75 h. The reaction mixture was stirred for 5 min and extracted with

76

ether. Combined organic phases were washed with water and brine and dried
over MgSO4. After filtration and evaporation, the residue was purified by

distillation to afford 8.0 g of 8 (80%).

 

(3E)-4—(TrimethylsilyI)-3-buten-1-oI (4)54

4

To a cold (0 °C), stirred solution of sodium bis(2-

methoxyethoxy) aluminum hydride (7.35 mL, 37.6 mmol) in
ether (20 mL) under nitrogen conditions was added a solution of 8 (3.4 mg, 26.8
mmol) in ether (9 mL) dropwise over 1.3 h. The reaction mixture was stirred for
10 min and the cold bath was removed. The reaction mixture was stirred for an
additional 1 h at room temperature and then cooled back down to 0 °C. The
reaction was quenched by addition of aqueous H2804 (3.4 M, 50 mL) and
extracted with ether. Combined organic phases were washed with water and
brined and dried over MgSO4. After filtration and evaporation, the residue was
purified by silica gel column chromatography using EtOAc/hexane (1 :99) to afford

1.1 g of 4 (56%).

 

0 3-(Trimethylsilyl)-2-oxiranemethanol (5)

TMS/<l/\OH

5 To a cold (0 °C), stirred solution of allyl alcohol 4 (8.7 g, 67

 

mmol) in CHQCIQ (470 mL) under nitrogen conditions was added a solution of m-
CPBA (23.1 g, 134 mmol) in CH2CI2 (470 mL) via syringe and stirred at 0 °C.
After the complete consumption of the starting allyl alcohol, the reaction mixture
was filtered to remove precipitated m-chlorobenzoic acid. After evaporation, the
residue was purified by silica gel column chromatography using hexane/EtOAc

(9:1) to afford 5.5 g of 5 as a pale yellow oil (58%). 1H NMR (300 MHz, CDCI3) 8

77

3.94 (ddd, J = 12.4, 5.0, 2.2 Hz, 1 H), 3.57-3.47 (m, 1 H), 3.01—2.97 (m, 1 H),
2.23 (d, J = 3.5 Hz, 1 H), 0.03 (s, 9 H); 130 NMR (75 MHz, CDCI3) 8 54.2, 55.8,

48.9, —3.2. The spectroscopic data were consistent with the literature values.69

 

0H 3-(TrimethylsinI)-1,2-propanediol (9)

TMS\)\/OH 1) by Super-Hydride70

To a cold (0 °C), stirred solution of 13 (223 mg, 1.2 mmol) in
THF (1.2 mL) was added sodium hydroxide (101 mg, 2.5 mmol) in water (1.0 mL).
After stirring for 1 h at 0 °C and 2 h at 25 °C, the reaction mixture was diluted
with water and extracted with ether. Combined organic phases were washed with
brine and dried over MgSO4. After filtration and evaporation, the residue was
purified by silica gel column chromatography using EtOAc/hexane (7:3) to afford
150 mg of 9 (84%). 1H NMR (500 MHz, CDCI3) 8 3.89—3.82 (m, 1 H), 3.52 (d, J =
10.9 Hz, 1 H), 3.31 (m, 1 H), 0.78 (dd, J = 14.5, 8.1 Hz, 1 H), 0.68 (dd, J = 14.5,
5.1 Hz, 1 H), 0.04 (s, 9 H); ”C NMR (125 MHz , cock.) 8 71.1, 59.7, 22.3, —0.1;
IR (neat) 3370 cm‘1The spectroscopic data were consistent with the literature
values.71
2) by Reel-Al72
To a cold (0 °C), stirred solution of epoxyalcohol 5 (185 mg, 1.2 mmol) in
dimethoxyethane (7 mL) under nitrogen conditions was added a Red-AI (0.38 mL
of a 3.5 M solution in toluene, 1.3 mmol) dropwise. The reaction was allowed to
warm to room temperature and stirred for 4.5 h. The reaction mixture was diluted
with ether and quenched with addition of 5% HCI (3 mL). The phases were

separated and the aqueous phase was extracted with ether. The combined

78

organics were washed with water and brine and then dried over MgSO4. After
filtration and evaporation, the product was purified by distillation to afford 120 mg
of 9 (63 %).
3) by Dihydroxylationm

A mixture of t-Butyl alcohol (25 mL), water (25 mL) and AD-mix-alpha (7.0
g) was stirred at room temperature. The reaction mixture was cooled to 0 °C and
some of the dissolved salts precipitated. Allyltrimethylsilane (0.79 mL, 5.0 mmol)
was added at once and the heterogeneous slurry was stirred vigorously at 0 °C
for 38 h. Solid sodium sulfite (7.5 g) was added at the same temperature. The
reaction mixture was allowed to warm to room temperature and stirred for an
additional 1 h. The reaction mixture was diluted with CH20I2. The phases were
separated and the aqueous phase was extracted with CH2CI2. Combined organic
layers were washed with brine and dried over MgSO4, After filtration and
evaporation, 224 mg of 9 were obtained (30%).

Synthesis of 1,3-Diol 6 (Scheme 31)

OTBS [1-[[(1,1-Dimethylethyl)dimethylsinl]oxy]-2-propen-1-
v ms yl]trimethylsilane (11)
1 1

To a solution of 1-hydroxyallyltrimethylsilane (391 mg, 3.0

 

 

mmol) in DMF (4.5 mL) was added TBSCI (0.6 mL, 3.7 mmol) and imidazole (1.0
mL, 7.5 mmol). The reaction mixture was stirred for 24 h before being quenched
by addition of water (5 mL) and diluted with EtOAc. The phases were separated
and the aqueous phase was extracted with EtOAc. Combined organic layers

were washed with saturated aqueous NaHCOa and brine and dried over MgSO4,

79

After filtration and evaporation, the residue was purified by silica gel column
chromatography using hexane to afford 11 as a pale yellow but the columned
material contained impurity. After second silica gel column chromatography, 574
mg of the impure 11 were obtained and in the next step without further
purification. 1H NMR (500 MHz, CDCI3) 8 5.90 (ddd, J = 17.0, 10.5, 5.3 Hz, 1 H),
5.00 (dt, J = 17.0, 2.1 Hz, 1 H), 4.92 (dt, J = 10.6, 2.0 Hz, 1 H), 3.97 (dt, J = 5.3,
1.9 Hz, 1 H), 0.93 (s, 9 H), 0.02 (d, J = 3.2 Hz, 5 H), 0.01 (s, 9 H); 130 NMR (125
MHz, 00013) 6 139.6, 109.6, 69.0, 25.8, 18.2, -4.0, -4.4, -5.1; IR (neat) 1270

cm“; HRMS (El) (m/z) calcd for C12HggBOSi2 [M+CHaCN+NH4]* 303.2288, found

 

303.2282.
OH ores 3'«tert'auty'd"“ethll'SI'i!|)<>xy)-3-(trlmethylsllyl)propan-1-o|
TMS (12)74
12

 

To a cold (0 °C), stirred solution of 11 (245 mg, 1.0 mmol) in
THF (4 mL) under nitrogen conditions was added BH3 (4.0 mL of a 1.0 M solution
in THF, 4.0 mmol) dropwise. After stirring for 3 h, aqueous NaOH (4 mL of a 2 N
solution) was added dropwise to maintain gentle H2 evolution. 30 % H20) (4 mL)
was then added and the mixture was stirred at room temperature for 30 min. The
reaction mixture was diluted with H20 and extracted with CHCI3. Combined
organic phases were washed with brine and dried over MgSO4. After filtration
and evaporation, the residue was purified by silica gel column chromatography
using EtOAc/hexane (1:4) to afford 0.119 g of 12 as a colorless oil (45%). 1H
NMR (300 MHz, CDCI3) 8 3.85-3.61 (m, 2 H), 3.65 (dd, J = 5.8, 4.9 Hz, 1 H),

2.02—1.90 (m, 1 H), 1.77-1.66 (m, 1 H), 0.87 (S, 9 H), 0.08 (S, 3 H), 0.03 (S, 9 H),

80

 

0.01 (s, 3 H); 13c NMR (75 MHz, cock.) 8 55.3, 52.4, 35.7, 25.5, 18.7, -2.1, -3.7,
—4.0; IR (neat) 3340 cm“; HRMS (El) (m/z) calcd for C12H3002Si2 [M+H]*

263.1863, found 263.1859.

 

OH OH 1-(Trimethylsilyl)-1,3-propanediol (6)

TMS To a solution of 12 (118 mg, 0.45 mmol) in CH3CN (1 mL) was
added: solution of 5 % aqueous HF (0.1 mL) in CH3CN (0.5 mL) at room
temperature. The reaction mixture was stirred for 40 min and then quenched by
the addition of saturated aqueous NaHC03. The reaction was diluted with ether.
The phases were separated and the aqueous phase was extracted with ether.
Combined organic phases were washed with brine and dried over M9304. After
filtration and evaporation, the residue was purified by silica gel column
chromatography using hexane/ethyl acetate (1 :4) to afford 55 mg of 6 (82%) as a
colorless OH. 1H NMR (300 MHZ, CDCla) 5 3.94-3.72 (m, 2 H), 3.58 (dd, J = 11.2,
2.5 Hz, 1 H), 1.82-1.75 (m, 1 H), 1.70-1.50 (m, 1 H), 0.02 (s, 9 H); "’0 NMR
(125 MHz, CDCI3) 6 66.0, 63.4, 35.0, -3.4; IR (neat) 3322 cm"; HRMS (El) (m/z)
calcd for C6H15028i [M+H]" 149.1003, found 149.0998.

Ring Opening of 5 with Red-AI (Scheme 33)

 

((2-Ethyl-1 ,3,2-dioxaborolan-4-yl)methyl)trimethylsilane
(13)75

To a solution of 5 (2.2 g, 15.6 mmol) in THF (1 mL) under

 

 

nitrogen conditions was added Super-Hydride (1.5 mL of 1.0 M solution in THF,
31.3 mmol) dropwise via syringe pump (1.4 mL/hr). The reaction mixture was

stirred for 2.5 h at room temperature before being quenched by addition of water

81

(10 mL). The reaction was extracted twice with ether. The combined organics
were washed with saturated aqueous NaHC03 and brine and then dried over
M9804. After filtration and evaporation, the residue was purified by fractional
distillation (20 mmHg, 38 °C) to afford 2.253 g of 13 (77%) as a colorless oil. 1H
NMR (500 MHz, CDCI3) 5 4.56-4.44 (m, 1 H), 4.20 (dd, J = 8.7, 7.6 Hz, 1 H),
3.62 (dd, J = 8.7, 7.5 Hz, 1 H), 1.07 (dd, J = 14.2, 6.8 Hz, 1 H), 0.92 (t, J = 7.8 Hz,
3 H), 0.85 (dd, J = 14.2, 7.7 Hz, 1 H), 0.75 (q, J = 7.7 Hz, 2 H), 0.02 (s, 9 H); 13c
NMR (125 MHz, cool.) 8 75.3, 73.0, 25.4, 7.7, 0.1; “8 NMR (150 MHz, CDCI3)
5 43.5. IR (neat) 1340 cm"; HRMS (El) (m/z) calcd for C3H1gBOZSi [M+H]+
187.1326, found 187.1322.

Kinetic Resolution of a-Hydroxysilanes with Novozym 435

Preparation of a-Hydroxysilanes

 

1-Hydroxyallyltrimethylsilane (3)6

To a cold (-78 °C), stirred solution of allyl alcohol (5.4 mL, 80.0

 

mmol) in HF (60 mL) under nitrogen conditions was added n-BuLi (52.8 mL of a
1.6 M solution in hexane, 84.0 mmol) dropwise via a syringe. Upon complete
addition of base, the reaction mixture was stirred for 1 h. Next, TMSCI (10.1 mL,
80.0 mmol) was added dropwise via a syringe. Following this addition, the
reaction mixture was stirred for 1.5 h and then t-BuLi (56.8 mL of a 1.7 M solution
in hexane, 97.0 mmol) was added dropwise via a syringe. After stirring for an
additional 1.5 h, the reaction was quenched by the addition of saturated aqueous
NH4C| and then diluted with ether. The phases were separated and the aqueous

phase was extracted with ether. The combined organics were washed with brine

82

and dried over anhydrous Na2$O4. After filtration and evaporation, the residue
was purified by silica gel column chromatography using EtZO/hexane (1:9) to
afford 5.4 g of 3 as a colorless oil (51%). 1H NMR (500 MHz, CDCI3) 8 5.00 (ddd,
J = 17.2, 10.7, 5.3 Hz, 1 H), 5.04 (ddd, J: 17.2, 2.1, 1.6 Hz, 1 H), 4.96 (ddd, J =
10.7, 1.9, 1.6 Hz, 1H), 3.99-3.97 (m, 1 H), 1.35 (br s, 1H), 0.03 (s, 9 H); 13C NMR
(125 MHz, CDCI3) 5 139.9, 109.4, 69.0, -4.3. The spectroscopic data were

consistent with the literature values.6

 

OH 1-(Dimethylphenylsilyl)-2-propen-1-oI (19)

%DMPS The reaction was carried out on allyl alcohol (2.7 mL, 40.0

 

mmol) as described in the preparation of 3 except that
chlorodimethylphenylsilane (7.0 mL, 42.0 mmol) was used as the silylating agent
and that following its addition, the reaction mixture was stirred for 1.25 h and that
after the t—BuLi addition, it was stirred for an additional 2.0 h. This modified
protocol afforded 3.2 g of 19 as a pale yellow oil (42%). 1H NMR (500 MHz,
CDCI3) 5 7.5—7.54 (m, 2 H), 7.39-7.33 (m, 3 H), 5.98 (ddd, J = 17.2, 10.7, 5.3 Hz,
1 H), 5.07—5.03 (m, 1 H), 5.00-4.97 (m, 1 H), 4.21 (ddd, J: 5.3, 2.1, 2.1 Hz, 1 H),
1.28 (br s, 1 H), 0.34 (s, 1 H), 0.32 (s, 1 H); 130 NMR (125 MHz, CDCI3) 8 139.3,
135.0, 134.2, 129.5, 127.8, 110.0, 68.4, -5.8, —5.1; IR (neat) 3420 cm“; HRMS
(El) (m/z) calcd for C11H150$i [M]" 192.0970, found 192.0963. The spectroscopic

data were consistent with the literature values.56

 

(1 ,1 -Dimethylethyl)dimethyl(2-propen-1 -yloxy)-silane
Moms
75 A mixture of allyl alcohol (4.0 mL, 60 mmol), TBSCI (10.8 g,

72.0 mmol) and imidazole (6.1 g, 90.0 mmol) in DMF (20 mL) under nitrogen

83

conditions was stirred for 1 h at room temperature. The reaction mixture was
extracted with ether. Combined organic phases were washed with water and
brine and dried over MgSO4. The residue was purified over silica gel column
chromatography using EtQO/hexane (1 :25) to afford 8.5 g of the desired product
as a colorless oil (83%). 1H NMR (500 MHz, CDCI3) 8 5.93 (ddt, J = 17.1, 10.4,
4.6, 1 H), 5.25 (dddd, J: 17.1, 1.9, 1.9, 1.9 Hz, 1 H), 5.06 (ddd, J: 10.5, 1.8, 1.8
Hz, 1 H), 4.16 (dt, J = 4.5, 1.8 Hz, 2 H), 0.09 (s, 9 H), 0.06 (s, 6 H). 13C NMR
(125 MHz, CDCI3) 5 137.5, 113.9, 64.1, 25.9, 18.4, -5.2. The spectrosc0pic data

were consistent with the literature values.76

 

1-[(1,1-Dimethylethyl)dimethylsilyl]-2-propen-1-o| (21)77

OH
%TBS To a cold (—78 °C), stirred solution of (1,1-

 

dimethylethyl)dimethyl(2-propen-1-yloxy)silane (8.3 g, 48.6
mmol) in THF (200 mL) under nitrogen condition were added
tetramethylethylenediamine (13.1 mL, 88.0 mmol) and then sec-BuLi (59.7 mL,
1.4 M in cyclohexane, 84.0 mmol) dropwise. The reaction mixture was warmed
up to —40 °C and then stirred for 3.5 h. It was recooled to -78 °C and the reaction
was quenched by the addition of AcOH (17.9 mL, 314.0 mmol) in THF (53 mL).
The reaction mixture was warmed to room temperature and extracted with ether.
Combined organic phases were washed with water and brine and dried over
MgSO4. The residue was purified over silica gel column chromatography using
EtOAc/hexane (1 :30) to afford 0.7 g of 21 as a colorless oil (9%). 1H NMR (500
MHZ, CDCI3) 5 6.05 (ddd, J = 17.2, 10.7, 5.3 Hz, 1 H), 5.06 (ddd, J = 17.2, 2.1,

1.6 HZ, 1 H), 4.97 (ddd, J: 10.7, 3.5, 1.6 Hz, 1 H), 4.16 (ddd, J: 5.3, 2.1, 2.1 HZ,

84

 

1 H), 0.94 (s, 9 H), 0.11 (s, 3 H), -0.05 (s, 3 H); 13c NMR (125 MHz, CDCI3) 8
140.7, 109.4, 67.6, 26.0, 17.0, -7.6, -9.2. The spectroscopic data were

consistent with the literature values.78

 

OH (ZE)-1-(TrimethylsilyI)-2-buten-1-oI (22)

Me/V‘ TMS The reaction was carried out as described for the preparation
22

 

of 3 except that (2E)-2-buten-1-ol (5.7 mL, 67.5 mmol) served
as the alcohol and reaction times following the addition of TMSCI and t-BuLi
addition were 2.5 h and 2.0 h, respectively. This modified protocol afforded 5.3 g
of 22 as a pale yellow oil (54%). 1H NMR (500 MHz, CDCI3) 8 5.51-5.42 (m, 2 H),
3.86 (doublet of pentets, J = 6.8, 1.4 Hz, 1 H), 1.68 (dt, J = 6.3, 1.4 Hz, 3 H), 1.27
(br s, 1 H), 0.01 (s, 9 H); ”C NMR (125 MHz, CDCI3) 8 132.4, 122.2, 58.4, 17.8,
-4.2; IR (neat) 3416 cm"; HRMS (El) (m/z) calcd for C7H1GOSI [M]" 144.0970,

found 144.0970. The spectroscopic data were consistent with the literature

 

values.79
' OH 2-Methyl-1-(trimethylsiIyI)-2-propen-1-o| (24)
TMS The reaction was carried out as described for the preparation of
Me
24

 

3 except that 2-methyl-2-propen-1-ol (6.6 mL, 79.0 mmol)
served as the alcohol and that following the addition of TMSCI the reaction stirred
for 1.0 h, before t-BuLi (55.6 mL 1.7 M in hexane, 95.0 mmol) was added
dropwise via syringe. After stirring for an additional 3 h at -33 °C, the cold bath
was removed and a solution of acetic acid (5.4 mL, 95.0 mmol) in THF (5 mL)
was added. After the reaction mixture was stirred for 30 min, saturated aqueous

NaHCOa (60 mL) and pentane (100 mL) were added. Workup and

85

chromatography as previously described afforded 9.1 g of 24 as a colorless oil
(81%). 1H NMR (500 MHz, CDCI3) 8 4.77 (oct, J = 0.8 Hz, 1 H), 4.74 (dq, J = 3.0,
1.5 Hz, 1 H), 3.86 (s, 1 H), 1.59 (t, J = 0.7 Hz, 3 H), 1.29 (br d, J = 2.50, 1 H),
0.05 (s, 9 H); "’0 NMR (125 MHz, CDCI3) 8 148.3, 105.3, 71.5, 20.7, —3.4. The

spectral data were consistent with literature values.80

 

Me OH (ZE)-1-(Trimethylsily)-2-hexene-1-ol (25)

WTMS The reaction was carried out as described for the
25 preparation of 3 except that (2E)-2-hexen-1-ol (2.3 mL, 20.0

mmol) served as the alcohol, sec-BuLi (17.1 mL 1.4 M in cyclohexane, 24.0
mmol) was used in place of t-BuLi, and reaction times following the addition of
TMSCI and s-BuLi addition were 2.5 h and 2.0 h respectively. This modified
protocol afforded 1.9 g of 25 as a pale yellow oil (57%). 1H NMR (500 MHz,
CDCI3) 5 5.57 (dddd, J = 1.3, 1.3, 6.6, 15.4 Hz, 1 H), 5.47 (dddd, J = 1.5, 6.8, 6.8,
15.1 Hz, 1 H), 3.89-3.87 (m, 1 H), 2.02-1.97 (m, 2 H), 1.37 (sext, J = 7.3 Hz, 2
H), 1.27 (br s, 1 H), 0.87 (t, J = 7.4 Hz, 3 H), 0.01 (s, 9 H); ‘30 NMR (125 MHz,
CDCI3) 5 131.4, 127.5, 68.4, 34.6, 22.8, 13.6, —4.2. The spectral data were

consistent with literature values.81

 

Me 0,, 1-(Dimethy|phenylsilyl)-1-bexanol (25)

Wows Chlorodimethylphenylsilane (9.7 mL, 57.9 mmol) was
26 added to a rapidly stirring mixture of lithium wire (0.9 9,

135.0 mmol (fine cut)) in THF (60 mL) at room temperature. The reaction mixture
was stirred for 31 h at room temperature, giving a deep red solution of PhMBzSiLI.

This PhMeZSiLi solution was then added dropwise via cannula to a cold (-78 °C)

86

stirred solution of hexanal (0.7 mL, 5.8 mmol) in THF (6 mL). The reaction
mixture was stirred for 30 min at the same temperature before being quenched
by addition of saturated aqueous NH4CI solution. The reaction was extracted
twice with ether. The combined organics were washed with water and brine and
then dried over MgSO4. After filtration and evaporation, the residue was purified
over silica gel column chromatography using Et20/hexane (1 :9) to afford 0.6 g of
25 as a pale yellow oil (44%). 1H NMR (500 MHz, CDCI3) 8 7.55-7.53 (m, 2 H),
7.37-7.34 (m, 3 H), 3.50—3.47 (m, 1 H), 1.55—1.47 (m, 3 H), 1.30—1.18 (m, 6 H),
0.85 (t, J = 7.04 Hz, 3 H), 0.32 (s, 3 H), 0.31 (s, 3 H); ”C NMR (125 MHz, CDCI3)
5 136.8, 134.1, 129.2, 127.9, 65.5, 33.4, 31.7, 26.5, 22.6, 14.0, —5.3, -5.7. The

spectral data were consistent with literature values.82

 

0H a-(TrimethylsilyI)-benzenemethanol (27)7

Ph/k TMS

27

DMSO (0.7 mL, 11.0 mmol) was added dropwise by syringe to
a stirred a cold (-78 °C) solution of oxalyl chloride (0.8 mL, 10.5
mmol) in anhydrous ether under nitrogen. The reaction mixture was warmed to -
35 °C and then stirred for 1 h. The reaction mixture was then cooled back down
to —78 °C and (trimethylsilyl)methanol (1.2 mL, 10.0 mmol) was added dropwise.
The reaction mixture was warmed to -35 °C and stirred for 2 h. The reaction
mixture was again cooled to —78 °C and triethylamine (6.9 mL, 50.0 mmol
(freshly distilled over CaH2)) was added dropwise. The reaction mixture was
stirred for 2 h at the same temperature and then warmed to 0 °C and stirred for 4
h. The reaction mixture was recooled to —78 °C and bromophenylmagnesium

(9.0 mL, 50.0 mmol) was added dropwise. After the reaction mixture was stirred

87

for 2 h at —78 °C, water (20 mL) and ether (90 mL) were added and the mixture
was allowed to warm to room temperature. The phases were separated and the
aqueous phase extracted with ether. Combined organics were washed with brine
and dried over anhydrous M9804. After filtration and evaporation, the residue
was purified over silica gel column chromatography using EtQO/hexane (1:9) to
afford 0.8 g of 27 as a colorless oil (47%). 1H NMR (500 MHz, CDCI3) 5 7.30-
7.26 (m, 2 H), 7.18-7.13 (m, 3 H), 4.51 (s, 1 H), 1.65 (br s, 1 H), 0.00 (s, 9 H);
"’0 NMR (125 MHz, CDCI3) 8 144.2, 128.1, 125.8, 124.9, 70.5, —4.2. The

spectral data were consistent with literature values.83

 

OH a-(DimethylphenylsiIyI)-benzenemethanol (28)

Ph/LDMPS

28

The reaction was carried out as described for the preparation of

26 except that that PhMGzSILI was formed over 36 h and

 

benzaldehyde (0.4 mL, 4.3 mmol) served as the aldehyde. This modified protocol
afforded 0.4 g of 28 as a colorless oil (40%). 1H NMR (500 MHz, CDCI3) 8 7.47-
7.45 (m, 2 H), 7.39—7.31 (m, 3 H), 7.25-7.21 (m, 2 H), 7.15—7.12 (m, 1 H), 7.08-
7.05 (m, 2 H), 4.59 (s, 1 H), 1.54 (br s, 1 H), 0.28 (s, 3 H), 0.25 (s, 3 H); 1"c NMR
(125 MHZ, CDCI3) 5 143.5, 135.9, 134.3, 129.4, 128.0, 127.8, 125.9, 125.1, 70.0,
-5.4, —6.3. The spectral data were consistent with literature values.81

Acylation of a-Hydroxysilanes

 

OAc Acetic acid 1-(trimethylsilyl)-allyl ester (18)

\ TMS To a solution of 1-hydroxyallyltrimethylsilane (0.6 g, 4.81 mmol)
18
and pyridine (0.3 mL, 4.8 mmol) was added acetic anhydride

(0.4 mL, 4.8 mmol). The reaction mixture was stirred at room temperature

88

overnight. The reaction mixture was diluted with 820, and then sequentially
extracted with 1M HCI, saturated aqueous NaHCOa and brine. The ethereal layer
was dried over MgSO4, filtered, and evaporated to afford 0.5 g 18 as a pale
yellow oil (57%). 1H NMR (500 MHz, CDCI3) 8 5.83 (ddd, J = 17.0, 10.9, 5.8 Hz, 1
H), 5.17 (ddd, J: 5.8, 1.8, 1.8 Hz, 1 H), 4.98 (ddd, J: 9.3, 1.7, 1.7 HZ, 1 H), 4.96
(m, 1 H), 2.07 (s, 3 H), 0.07 (s, 9 H); ”C NMR (125 MHz, CDCI3) 8 170.7, 134.9,
111.3, 70.5, 20.9, —4.0; IR 1734 (s) cm"; HRMS (El) (m/z) calcd for CeH1502$i
[M]+ 172.0920, found 172.0923. The spectral data were consistent with literature

values. 8‘

 

0A Acetic acid 1-(dimethylphenylsinI)-prop-2-enyl ester (20)
C

\ DMPS Applying the acylation procedure described in preparation of 18
2° to 1-(dimethylphenylsilyI)-2-propen-1-ol (0.4 g, 2.5 mmol)
afforded 0.5 g of 20 as a pale yellow oil (85%). ‘H NMR (500 MHz, CDCI3) 8
7.53-7.50 (m, 2 H), 7.40—7.33 (m, 3 H), 5.82—5.75 (m, 1 H), 5.39 (ddd, J = 5.7,
1.9, 1.9 Hz, 1 H), 4.98 (ddd, J = 4.5, 1.5, 1.5 Hz, 1 H), 4.95-4.94 (m, 1 H), 2.04 (s,
3 H), 0.34 (d, J = 0.8 Hz 5 H); 130 NMR (125 MHz, CDCI3) 8 170.7, 135.5, 134.9,
134.3, 129.8, 128.1, 112.1, 70.2, 21.2, —5.3, —5.4; IR (neat) 1740 cm 7‘; HRMS
(El) (m/z) calcd for C13H1802Si [M]" 234.1076, found 234.1078. The spectral data

were consistent with literature values.34

 

OAc Acetic acid 1-(trimethylsilyI)-but-2(E)-eny| ester (23)

Me/vTMS Applying the acylation procedure described in preparation
23
of 18 to (2E)-1-(trimethylsilyl)-2-buten-1-oI (0.7 g, 5.0

mmol) 0.5 g of 23 as a colorless oil (61%). 1H NMR (500 MHz, CDCI3) 5 5.49—

89

5.39 (m, 2 H), 5.09-5.05 (m, 1 H), 2.02 (s, 3 H), 1.55 (dd, J = 4.8, 1.1 Hz, 3 H),
0.00 (s, 9 H); ”’0 NMR (125 MHz, CDCI3)5170.7, 127.5, 124.5, 70.3, 21.0, 17.8,
—3.9; IR (neat) 1742 cm"; HRMS (El) (m/z) calcd for C9H1302Si [M]+ 186.1076,

found 186.1079. The spectral data were consistent with literature values.80

 

i OAc Acetic acid 2-methyI-1-(trimethylsinI)-allyl ester (30)

TMS Applying the acylation procedure described in preparation of 18
Me

30 to 2-methyI-1-(trimethylsiIyl)-2-propen-1-oI (0.1 g, 0.7 mmol)

 

L

afforded 0.07 g of 30 as a pale yellow oil (55%). 1H NMR (500 MHz, CDCI3) 5
5.01 (s, 1 H), 4.72-4.71 (m, 1 H), 4.59—4.57 (m, 1 H), 2.05 (s, 3 H), 1.71-1.59 (m,
3 H), 0.06 (s, 9 H); 13C NMR (125 MHZ, CDCI3) 5 170.7, 143.3, 107.9, 72.7, 21.0,
20.7, -3.3; IR (neat) 1770 cm“; HRMS (El) (m/z) calcd for ConOzSi [M]+
186.1076, found 186.1078. The spectral data were consistent with literature

values.85

 

0A Acetic acid 1~(t-butyldimethylsiIyl)-prop-2-enyl ester
c .

v7.33 Applying the acylation procedure described in preparation of 18

76 to 1-[(1,1-dimethylethyl)dimethylsilyl]-2-propen-1-ol (100 mg,

0.5 mmol) afforded 78 mg of the desired product as a pale yellow oil (63%). 1H
NMR (500 MHZ, CDCI3) 5 5.85 (ddd, J = 16.8, 11.0, 5.6 HZ, 1 H), 5.37 (td, J: 5.6,
1.9 Hz, 1 H), 4.97 (td, J = 7.3, 1.6 Hz, 1 H), 4.94 (d, J = 1.8 Hz, 1 H), 2.07 (s, 3
H), 0.90 (s, 9 H), 0.00 (s, 3 H), —0.02 (s, 3 H); 13C NMR (125 MHz, CDCI3) 5
170.5, 135.5, 111.1, 58.7, 25.8, 21.1, 15.9, -7.5, -8.5; IR (neat) 1750 cm“;

HRMS (El) (m/z) calcd for C11H22028i [M]" 214.1389, found 214.1389.

90

 

Acetic acid 1—(trimethy|silyl)-hex-2(E)-eny| ester
Me OAc

WTMS Applying the acylation procedure described in preparation of
77

 

18 to (2E)-1-(trimethylsilyl)-2-hexene-1-ol (517 mg, 3.0
mmol) afforded 573 mg of the desired product as a pale yellow oil (89%). 1H
NMR (500 MHz, cock.) 8 5.45 (m, 2 H), 5.10 (dd, J = 4.8, 1.7 Hz, 1 H), 2.02 (s, 3
H), 1.97 (m, 2 H), 1.35 (dt, J = 14.7, 7.5 Hz, 2 H), 0.85 (t, J = 7.4 Hz, 3 H), 0.00 (s,
9 H); ”C NMR (125 MHz, CDCI3) 8 170.7, 129.7, 125.5, 70.3, 34.5, 22.5, 21.1,
13.5, —3.9; IR (neat) 1740 (s) cm“; HRMS (El) (m/z) calcd for C11H220281 [Mr

214.1389, found 214.1389.

 

Me OAc 1'AcetatO-1~(dlmethylphenylsllyI)-1-hexanol

WDMPS Applying the acylation procedure described in preparation
78 of 18 to 1-(dimethylphenylsilyl)-1-hexanol (70 mg, 0.29

mmol) afforded 57 mg of the desired product as a colorless oil (69%).‘H NMR
(500 MHZ, CDCI3) 5 7.51-7.49 (m, 2 H), 7.36-7.32 (m, 3 H), 4.94 (dd, J = 10.8,
3.7 HZ, 1 H), 1.98 (s, 3 H), 1.61-1.12 (m, 8 H), 0.83—0.79 (m, 3 H), 0.30 (d, J =
5.8 Hz, 5 H); “’0 NMR (125 MHz, CDCI3) 8 171.1, 135.1, 134.0, 129.3, 127.7,
68.4, 31.4, 30.9, 26.6, 22.4, 20.9, 13.9, -4.9, -5.2. The spectral data were

consistent with literature values.16

 

0A 1-Acetatae-a-(trimethylsiIyI)-benzenemethanol
C

ph TMS Applying the acylation procedure described in preparation of
79

 

18 to o-(trimethylsilyI)-benzenemethanol (270 mg, 1.5 mmol)

afforded 309 mg of the desired product as a pale yellow oil (93%). 1H NMR

91

(500 MHz, c0013) 8 7.30 (m, 2 H), 7.18 (m, 3 H), 5.71 (s, 1 H), 2.15 (s, 3 H), 0.04
(s, 9 H); ”C NMR (125 MHz, CDCI3) 8 170.7, 140.1, 128.1, 125.0, 125.2, 71.5,
21.1, —3.9; IR (neat) 1746 (s) cm“; HRMS (El) (m/z) calcd for C12H1802$i [M]+

222.1076, found 222.1076.

 

0A 1-Acetate- a-(dimethylphenylsinl)-benzenemethanol
C

ph DMPS Applying the acylation procedure described in preparation of
80 18 to c-(dimethylphenylsilyl)-benzenemethanol (93 mg, 0.38
mmol) afforded 72 mg of the desired product as a pale yellow oil (65%). 1H NMR
(500 MHz, CDCI3) 5 7.43-7.35 (m, 3 H), 7.33-7.29 (m, 2 H), 7.22-7.18 (m, 2 H),
7.15—7.11 (m, 1 H), 7.00—6.97 (m, 2 H), 5.84 (s, 1 H), 2.05 (s, 3 H), 0.30 (s, 3 H),
0.25 (s, 3 H); 130 NMR (125 MHz, 00013) 8 170.5, 139.4, 135.0, 134.3, 129.5,
128.0, 127.6, 126.1, 125.4, 76.7, 71.0, 21.0, -5.3, -5.6; IR (neat) 1747 (s) cm“;
HRMS (ESI+) (m/z) calcd for C17H2102$i [M+H]+ 285.1311, found 285.1317.
Kinetic Resolution of a-Hydroxysilanes with Novozym 435
Resolution of (i)-1-hydroxyallyltrimethylsilane (3) (Table 3, entry 1)
Novozym 435 (30 mg; 15 mg/mmol (rac)-alcohol) and vinyl acetate (0.3
mL, 3.0 mmol) were added to a tube containing a mixture of (1)-1-
hydroxyallyltrimethylsilane (3) (261 mg, 2.0 mmol) and activated 3A molecular
sieves in pentane (1.0 mL). The tube was purged with N2 and sealed. The sealed
tube was placed in a 38 °C an oil bath and the reaction mixture was stirred with
the reaction progress being monitored by GC (VF-1ms column). After ~50% of

the starting material was consumed, the reaction mixture was filtered through a

pad of Celite 503, concentrated, and purified by silica gel column

92

chromatography using Etgomexane (1 :9) to afford optically active acetate (S)-18
(104 mg, 30%, [a]n = —17.5 (c 1.03, CHCI3, >98 %ee)) and unreacted optically
active alcohol (R)-3 (86 mg, 33%, [o]D = -7.1 (c 1.05, CHCla, 73 %ee)).
Resolution of (1)-1—(dimethylphenylsilyl)-2-propen-1-ol (19) (Table 3, entry
2)

Applying the kinetic resolution procedure described on rec-3 to (1)-1-
(dimethylphenylsilyI)-2-propen-1-ol (19) (385 mg, 2.0 mmol) afforded after ~49%
conversion optically active acetate (S)-20 (174 mg, 37%, [a] p = -10.1 (c 1.26,
CHCl3, 99 %ee)) and unreacted optically active alcohol (R)-19 (167 mg, 43%,
[ab = —8.8 (c 1.04, CHCI3, 99 %ee)).

Resolution of (:t)-(2E)-1-(trimethylsilyI)-2-buten-1-ol (22) (Table 3, entry 5)

Applying the kinetic resolution procedure described on rec-3 to (:t)-(ZE)-1-
(trimethylsinI)-2-buten-1-ol (22) (300 mg, 2.1 mmol) at 78 °C, afforded after
~46% conversion acetate 23 (46 mg, 12%, (all chromatographic and
spectroscopic attempts to resolve the enantiomers and thus determine the %ee
failed) and unreacted optically active alcohol (R)-22 (34 mg, 11%, [010 = +4.1 (c
1.12, CHCI3, 9 %ee)).
295i NMR Experiment (Table 5)

Representative procedure for rec-3

Rec-3 (20 mg) was dissolved in CDCI3 (2.0 mL) and Eu(tfc)3 (42 mg) was
dissolved in CDCI3 (4.2 mL). The rec-3 solution (0.375 mL) was placed in a NMR
tube and then the Eu(tfc)3 solution (5-20 mol%) was added. CDCI3 was added to

up to totally 0.75 mL. The tube was sealed under nitrogen with cling-film and

93

 

shaken briskly by hand to ensure complete dissolution. After 30 min, the 29Si
NMR spectrum was collected at room. Refocused-decoupled INEPT sequence

was applied. The Fle were Fourier transformed and phased automatically, the

same phase corrections being applied for each sample.

The experiment results

Table 10. 29Si and 1H Experiments for Rec-22

 

 

. Eu(t‘fc)3 295i A5 . 1H
o-HydroxySllanes (mol%) NMR (ppm) Ratlo NMR
1 2 Not _ _ Not
' separated separated
3 0 Not _ _ Not
' separated separated
6 0 Not _ _ Not
' separated separated
9 0 Not _ _ Not
' separated separated
/\)O\H 10 0 N°t - — N°t
Me \ TMS ' separated separated
rec-22
Partial Not
12.0 separation 0.0051 Overlapped separated
13.0 Pan'ef' 0.0054 Overlapped N°t
separation separated
1 4. 6 Not _ _ Not
separated separated
17 1 Not _ _ Not
' separated separated

 

94

Table 11. 29Si and 1H Experiments for Rec-3

 

 

 

 

. Eu(tfc)3 298i A5 . ‘H
a-HydroxySllanes ("101% 1 NMR (ppm) Ratlo NMR
50 Nm _ Nm
' separated separated
Not
OH 10.1 Separated 0.0102 52.2:472
\/|\ separated
\ TMS
1804 15.1 Not _ Not
separated separated
20.1 Not _ Not
separated separated
Table 12. 29Si and 1H Experiments for Rec-25
. Eu(tfc)3 298i . 1H
d-Hydroxysuanes (mol%) NMR A5 (ppm) Ratio NMR
0 9 Not _ _ Not
' separated separated
2 4 Not _ _ Not
' separated separated
4 8 Not _ _ Not
' separated separated
Partial Not
w 7.2 Separated 0.0078 Overlapped separated
\ TMS Not
rec-25 9.7 Separated 0.0073 48.0520
separated
12.8 Not _ _ Not
separated separated
15.4 Not _ _ Not
separated separated
20.1 Not _ _ Not
separated separated

 

95

 

Table 13. 29Si and 1H Experiments for Rec-27

 

, Eu(tfc)3 29s: As - ‘H
a-Hydroxysflanes (mol%) NMR (ppm) Ratlo NMR
OH
)x 101 Separated 0 0075 52147.9 Not
358-2st - ' ' ’ separated

 

The best result was obtained for rec-27 with 10.1 mol% of Eu(tfc)3, rec-3
with 10.1 mol% of Eu(tfc)3, rec-25 with 9.7 mol% of Eu(tfc)3 and rec-22 with 12.0
mol% of Eu(tfc)3 (Table 10 to Table 13). For rec-27, rec-3 and rec-25, this
experiment gave good separation. However, rec-22 showed just partially
separated two peaks. During the experiment, we also collected the 1H NMR for
these substrates at room temperature. Unfortunately, none of them showed any
separated peaks.

[0].; value Experiment for 1—(DimethylphenylsinI)-2-propen-1-oI (19)

 

(Scheme 42)
o 1-(Trimethylsily|)-2-propen-1-one (29)
VLDMPS To a cold (-78 °C), stirred solution of trifluoroacetic
29

 

anhydride (1.0 mL, 7.5 mmol) in CH2CI2 (8 mL) under
nitrogen conditions was added a solution of DMSO (0.71 mL, 10 mmol) in CH2CI2
(6 mL) dropwise via syringe. After stirring for 0.5 h at the same temperature, a
solution of 19 (962 mg, 5 mmol) in CH20I2 (8 mL) was added over 20 min by
syringe. The reaction mixture was stirred for 1 h at -78 °C and Et3N (2.0 mL, 15
mmol) was added dropwise. After stirring for 1 h at the same temperature, the

reaction mixture was diluted with water (15 mL), allowed to warm to room

96

 

temperature and extracted with CH2CI2. Combined organic phases were washed
with water and brine and dried over MgSO4. After filtration and evaporation, the
residue was purified over silica gel column chromatography using EtOAc/hexane
(5:95) to afford 29 (735 mg) but the columned material contained impurity.
Without further purification, the material was used for the next step. 1H NMR
(500 MHZ, CDCI3) 5 7.58-7.55 (m, 2 H), 7.44—7.38 (m, 3 H), 6.44 (dd, J = 17.9,
10.8 Hz, 1 H), 6.00 (dd, J = 17.9, 0.8 Hz, 1 H), 5.88 (10.8, 0.8 Hz, 1 H), 0.55 (s, 6

H). The spectral data were consistent with literature values.38

 

OH (R)-1-(Dimethylphenylsilyl)-2-propen-1-ol (R-19)

i
vows To a solution of (-)-IpczBCl (288 mg, 0.89 mmol) in THF (3 mL)
(R)-19

 

was added a solution of 1-(trimethylsilyl)-2-propen-1-one (113
mg, 0.59 mmol) in THF (1 mL) dropwise at room temperature. The reaction
mixture was stirred for overnight at room temperature and THF was removed in
vacuo. The residue was dissolved in 320 (5 mL) and diethanolamine (180 pL,
1.89 mmol) was added. The reaction mixture was stirred for 2.5 h at room
temperature, filtered and extracted with ether. The combined organics were
washed with water and brine and dried over Nast4. After filtration and
evaporation, the residue was purified by silica gel column chromatography using

EtQO/hexane (1:9) to afford 52 mg of (R)-19 (42%). [ojo = -8.1 (c 1.24, CHCI3,

 

87 %ee)
OH (S)-1—(DimethylphenylsilyI)-2-propen-1-oI (S-19)
vows The reaction was carried out on 29 (141 mg, 0.74 mmol) as
(S)-19

 

described in the preparation of (R)-19 except that (+)-IpchCl

97

 

(358 mg, 1.1 mmol) was used as the reducing reagent. This modified protocol

afforded 59 mg of (S)-19 (41%). [010 = +7.2 (0 0.67, CHCI3, 82 %ee)

8.4.6. Reductive Cleavage of Optically Active Acetates
Reduction of (S)-18 (Table 6, entry 7)

A solution of compound (S)-18 (138 mg, 0.8 mmol, >98 %ee) in hexane (3
mL) was cooled to —78 °C. To that cold solution, DIBAL (0.8 mL of a 1.0 M
solution in hexane, 0.8 mmol) was added dropwise. The reaction mixture was
then stirred at the same temperature for 2.5 h. The cold bath removed and the
reaction mixture was quenched with saturated aqueous Rochellet Salt (1.5 mL)
and diluted with ether. The phases were separated, the aqueous phase extracted
with ether, and the combined organics were dried over Na2804. After filtration
and evaporation, the residual oil was purified by silica gel column
chromatography using Et20/hexane (1 :9) to afford 82 mg of (S)-18 (78%; [010 =
+8.3 (5 1.21, CHCI3, 89 %ee).

Reduction of (S)-20 (Scheme 43)

Applying the conditions described for (S)-18 to (S)-20 (73 mg, 0.3 mmol)
in hexane (1.5 mL) using 1.1 equiv of DIBAL (0.3 mL of a 1.0 M solution in
hexane, 0.3 mmol) afford 49 mg of (S)-19 (81%; [an = +8.2 (0 1.12, CHCI3,
93 %ee).

Mosher’s Ester Analyses (Figrue6 and Figure 12)

(R)-1-Hydroxya|Iyltrimethylsilane Mosher esters

 

To a solution of (R)-1-hydroxyallyltrimethylsilane (46

mg, 0.35 mmol), (R)-(—)-0l-methoxyphenylacetic acid

 

98

(47 mg, 0.28 mmol) and DCC (65 mg, 0.31 mmol) in CH20I2 (3.5 mL) under
nitrogen was added DMAP (4 mg, 0.032 mmol) in a single portion. The reaction
mixture was stirred at room temperate for 4 h. The precipitate formed was
removed by filtration and the filtrate was washed with cold 1M HCI, saturated
aqueous NaHCOa and brine. The organic layer was dried over MgSO4, filtered,
and evaporated to afford the crude Mosher ester, which was immediately
analyzed by 1H NMR (300 MHz, coma, pertinent peaks only) 8 5.75-5.52 (m, 1

H), -0.04 (d, J = 0.8 HZ, 9 H).

 

 

 

\ H 0 Applying the same procedure to (RH-
\1111 OCH3 . .
—/s1 0 H hydroxyallyltnmethylsrlane (46 mg, 0.35 mmol) and (S)-
\ Ph
. 82 (+)-a-methoxyphenylacetic acid (47 mg, 0.28 mmol)

afforded the crude Mosher ester, which was immediately analyzed by 1H NMR
(300 MHZ, CDCI3, pertinent peaks only) 5 5.89-5.74 (m, 1 H), —0.22 (d, J = 0.7
Hz, 9 H).

(R)-1-(DimethylphenylsiIyl)-2-propen-1-ol Mosher esters

 

\

OCH3
—SiJ\0)l\(“Ph
Ph/ \ H

83

(dimethylphenylsilyI)-2-propen-1-ol (72 mg, 0.37 mmol)

 

\ H 0 ]Applying the Mosher’s procedure to (R)-1-

2 and (R)-(—)-o-methoxyphenylacetic acid (50 mg, 0.30
mmol) (7 h reaction time) afforded the crude Mosher ester, which was
immediately analyzed by 1H NMR (300 MHz, CDCI3, pertinent peaks only) 5

5.71—5.58 (m, 1 H), —0.27 (d, J = 2.8 Hz, 6 H).

 

Applying the Mosher’s procedure to (R)-1-

(dimethylphenylsilyl)-2-propen-1-ol (72 mg, 0.37 mmol)

 

99

 

and (S)-(+)-a-methoxyphenylacetic acid (50 mg, 0.30 mmol) (7 h reaction time)
afforded the crude Mosher ester, which was immediately analyzed by 1H NMR
(300 MHZ, CDCI3, pertinent peaks only) 5 5.79—5.66 (m, 1 H), —0.08 (d, J = 4.3
Hz, 6 H).

Chiral GC and HPLC Analyses

1-Hydroxyallyltrimethylsilane (3)

CC Column: B-dex tm 325 (30 m x 0.25 mm x 0.25 pm film thickness).
Program 30 to 150 °C, at 5 °C/min, hold at 150 °C for 2 min. t,»(R) enantiomer
(min) = 10.0 min, t,»(S) enantiomer (min) = 9.8 min.

Acetic acid 1-(trimethylsilyI)-allyl ester (18)

CC Column: B-dex tm 325 (30 m x 0.25 mm x 0.25 pm film thickness).
Program: 30 to 150 °C, at 5 °C/min, hold at 150 °C for 2 min. Results: t,»(R)
enantiomer (min) = 12.9 min, HS) enantiomer (min) = 13.0 min.
1-(Dimethylphenylsilyl)-2-propen-1-ol (19)

HPLC column: Chiralcel OJ. Eluent: IPA/hexane (90:10), 0.18 mL/min.
Results: t,~(R) enantiomer (min) = 23.6 min, t,»(S) enantiomer (min) = 30.9 min.

HPLC column: Chiralcel OD-H. Eluent: IPA/hexane (95:5), 1.0 mL/min.
Results: t,»(R) enantiomer (min) = 9.0 min, t,»(S) enantiomer (min) = 8.1 min.
Acetic acid 1-(dimethylphenylsinI)-prop-2-enyl ester (20)

HPLC column: Chiralcel OJ. Eluent: IPA/hexane (90:10), 0.18 mL/min.
Results: HR) enantiomer (min) = 31.2 min, HS) enantiomer (min) = 35.4 min.

(2E)-1-(Trimethylsily|)-2-buten-1-o| (22)

100

 

GC Column: B-dex tm 325 (30 m x 0.25 mm x 0.25 um film thickness).
Program: 30 to 150 °C, at 1 °C/min, Results: HR) enantiomer (min) = 29.2 min,
HS) enantiomer (min) = 29.9 min.
2-Methyl-1-(trimethylsilyl)-2-propen-1-ol (24)

CC Column: B-dex tm 325 (30 m x 0.25 mm x 0.25 pm film thickness).
Program: 45 °C for 20 min, 45 to 150 °C, at 2 °C/min. Results: t,»(R) enantiomer
(min) = 27.7 min, t,-(S) enantiomer (min) = 28.1 min.

Acetic acid 2-methyI-1-(trimethylsinI)-allyl ester (30)

GO Column: B-dex tm 325 (30 m x 0.25 mm x 0.25 pm film thickness).

Program: 45 °C for 20 min, 45 to 150 °C, at 2 °C/min. Results: HR) enantiomer

(min) = 36.0 min, tr-(S) enantiomer (min) = 35.8 min.

GC Analyses
Figure 18. Retention Times of o-Hydroxysilanes
OH OH OH OH
V‘TMS vows V‘Tes Mev TMS
3 19 21 22
(2.2 min) (9.8 min) (3.6 min) (3.6 min)
OH lMe Ol-l Me OH OH
YTMS WTMS WDMPS Ph/‘\TMS
24 25 25 27
(3.5 min) (6.4 min) (13.0 min) (8.5 min)
OH
/I\ HOMTMS decane
Ph DMPS
28 32 (4.8 min)
(14.7 min) (3.5 min)

GC Column: VF-1ms column (15 m x 0.25 mm x 0.25 pm film thickness).

Program: 50 °C for 2 min, 50 to 200 °C, at 10 °C/min.

101

Figure 19. Retention times of Acetated Product

OAc OAc OAc OAc
VTMS vows Mme TMS
18 20 23 30
(4.1 min) (11.0 min) (5.5 min) (5.3 min)
/\/\ OAc Me OAc Me OAc

AcO / TMS
V185 WTMS WDMPS

31 75 77 78

(5.4 min) (5.8 min) (7.9 min) (13.7 min)

OAc OAc
Ph/k DMPS Ph/'\ ms

79 80

(15.2 min) (9.8 min)

GC Column: VF-1ms column (15 m x 0.25 mm x 0.25 pm film thickness).
Program: 50 °C for 2 min, 50 to 200 °C, at 10 °C/min.
Enzymatic Kinetic Resolution of Methylated a-Hydroxysilanes
Kinetic Resolution of Rec-24 and Rec-3
Amano PS-C II resolution of rec-24 (Table 7, entry 1)

A mixture of rec-24 (144 mg, 1 mmol), p-CICeH4OAc (256 mg, 1.5 mmol),
Eth (0.13 mL, 1.0 mmol) and PS-C II (144 mg) in CH2CI2 under nitrogen
conditions was stirred at room temperature. The reaction mixture was stirred with
the reaction progress being monitored by GC (VF-1ms column). After stirring for
64 h, temperature was increased to 40 °C and stirred for an additional 145 h.
After ~8% of the starting material was consumed, the reaction mixture was
filtered through a pad of Celite. Analysis of the filtrate was analyzed by GC (VF-

1ms column) using decane as an internal standard indicated that the optically

102

active acetate (R)-30 to be formed in 2% yield (66 %ee) and the unreacted
optically active alcohol (S)-24 was formed in 14% yield (2 %ee).
Amano AK resolution of rec-24 (Table 7, entry 2)

A mixture of rec-24 (144 mg, 1 mmol) and Amano AK (72 mg) in vinyl
acetate (1.5 mL) under nitrogen conditions was stirred at room temperature. The
reaction mixture was stirred with the reaction progress being monitored by GC
(VF-1 ms column). After stirring for 65 h, temperature was increased to 40 °C and
stirred for an additional 144 h. After ~13% of the starting material was consumed,
the reaction mixture was filtered through a pad of Celite. Analysis of the filtrate
was analyzed by GC (VF-1ms column) using decane as an internal standard
indicated that the optically active acetate (R)-30 to be formed in 13% yield
(21 %ee) and the unreacted optically active alcohol (S)-24 was formed in 81%
yield (>1 %ee).

CRL resolution of rec-24 (Table 7, entry 3)

A mixture of rec-24 (144 mg, 1 mmol), CRL (30 mg), vinyl acetate (1.4 mL,
16.0 mmol) in cyclohexane (3 mL) under nitrogen conditions was stirred at room
temperature. The reaction mixture was stirred with the reaction progress being
monitored by GC (VF-1ms column). After stirring for 16 h, temperature was
increased to 40 °C and stirred for an additional 169 h. The temperature was
increased to 60 °C and stirred for an additional 167 h. After ~9% of the starting
material was consumed, the reaction mixture was filtered through a pad of Celite.
Analysis of the filtrate was analyzed by GC (VF-1 ms column) using decane as an

internal standard indicated that the optically active acetate (R)-30 to be formed in

103

5% yield (9 %ee) and the unreacted optically active alcohol (S)-24 was formed in
57% yield (>48 %ee).
Amano PS-D I resolution of rec-24 (Table 7, entry 12)

To a sealed tube containing a solution of racemic 2-methyl-1-
(trimethylsilyl)-2-propen-1-ol (24) (144 mg, 1.0 mmol) and activated 3A molecular
sieves in toluene (1 mL) was added PS-D l (288 mg) and vinyl acetate (0.3 mL,
3.0 mmol). The tube was purged with N2 and sealed. The tube was purged with
N2, sealed, and the reaction mixture was stirred with the reaction progress being
monitored by GC (VF-1ms column). After ~44% of the starting material was
consumed, the reaction mixture was filtered through a pad of Celite. Analysis of
the filtrate was analyzed by GC (VF-1ms column) using decane as an internal
standard indicated that the optically active acetate (R)-30 to be formed in 13%
yield (87 %ee) and the unreacted optically active alcohol (S)-24 was formed in
19% yield (>99 %ee).

Amino PS-D I resolution of rec-3 (Scheme 48, eq 3)

PS-D l (288 mg) and vinyl acetate (0.14 mL, 1.5 mmol) were added to a
tube containing a mixture of racemic 1-hydroxyallyltrimethylsilane (0.13 g, 1.0
mmol) and activated 3A molecular sieves in toluene (1 mL). The tube was
purged with N2, sealed, and the reaction mixture was stirred with the reaction
progress being monitored by GC (VF-1ms column). After ~100% of the starting
material was consumed, the reaction mixture was filtered through a pad of Celite

503. Analysis of the filtrate was analyzed by GC (VF-1 ms column) using decane

104

 

as an internal standard indicated that the optically active (S)-18 to be formed in

41% yield (97 %ee) as well as presumed 33 and an impurity.

Identification of Acetal 33
Hydrolysis of acetal 33 by C13 silica gel (Scheme 52)

PS-D l (2.88 g) and vinyl acetate (1.4 mL, 15.0 mmol) were added to a
sealed tube containing a mixture of racemic 1-hydroxyallyltrimethylsilane (1.39 g,
10.6 mmol) and activated 3A molecular sieves in toluene (10 mL). The sealed
tube was purged with N2 and the mixture was stirred at room temperature and
monitored by GC. The tube was purged with N2, sealed, and the reaction mixture
was stirred with the reaction progress being monitored by GC (VF-1ms column).
After ~100% of the starting material was consumed, the reaction mixture was
filtered through a pad of Celite 503, concentrated, and subjected to silica gel
column chromatography using Et2O/hexane (1 :9), which afforded a mixture of
(S)-18, presumed acetal 33 and an unidentified impurity. Compound (S)-18 was
removed by rotary evaporation, leaving 117 mg acetal 33 and the impurity. This
mixture provided the following data: Major (GC peak at 6.4 min) 1H NMR
(500 MHz, CDCI3) 5 5.96 (q, J = 5.3 Hz, 1 H), 5.92-5.87 (m, overlapped), 5.07-
4.96 (m, 2 H), 3.83—3.80(m, 1 H), 2.00 (s, 3 H), 1.38 (d, J = 5.3 Hz, 3 H), 0.03 (s,
overlapped); 130 NMR (125 MHz, CDCI3) 5170.6, 137.8, 110.7, 98.1, 78.3, 21.4,
21.1, -4.2; IR (neat) 1740 cm"; Minor (GC peak at 6.2 min) 1H NMR (500 MHz,
CDCI3) 5 5.92—5.87 (m, overlapped), 4.93-4.88 (m, 2 H), 3.93—3.89 (m, 1 H),
2.05 (s, 3 H), 1.40 (d, J = 5.2 Hz, 3 H), 0.04 (s, overlapped); 13c NMR (125 MHz,
CDCI3) 8 170.8, 135.2, 112.5, 95.1, 74.5, 21.2, 20.9, -4.0 ; IR (neat) 1740 cm";

HRMS (ESI+) (m/z) calcd for C3H1708i [M + H - CHaCO2H]" 157.1049, found
105

 

157.1052. These data suggest that the peaks occurring at 6.2, and 6.4 minutes
are diastereomers of 33. In addition the structure of acetal 33 was consistent
with HMQC, HMBC, TOCSY, and COSY data acquired on the mixture. Acetal 33
and the impurity (48 mg) were dissolved in CH2,CN (2 mL) to which C13 silica gel
(500 mg) was added. The mixture was stirred at room temperature for 20 min,
filtered, concentrated, and purified by silica gel column chromatography using
Et2O/hexane (1 :9) to afford 10 mg of (R)-3 as a colorless oil (>33%, 64 %ee).

Possible rearrangement product (Scheme 55)

 

(2E)-1-acetate-3-(trimethylsilyI)-2-propen-1-ol (31)
ACOMTMS
31 To a solution of (2E)-3-(trimethylsilyl)-2-propen-1-ol (11 uL,

 

0.76 mmol) and pyridine (68 uL, 0.84 mmol) was added acetic anhydride (80 pL,
0.84 mmol). The reaction mixture was stirred at room temperature overnight. The
reaction mixture was diluted with 320, and then sequentially extracted with 1M
HCI, saturated aqueous NaHCOa and brine. The ethereal layer was dried over
MgSO4, filtered, and evaporated to afford 134 mg 31 as a pale yellow oil (100%).
1H NMR (500 MHz, CDCI3) 5 6.04 (dt, J = 18.7, 5.0 Hz, 1 H), 5.92 (dt, J = 18.7,
1.5 Hz, 1 H), 4.57 (dd, J = 5.0, 1.5 Hz, 2 H), 2.08 (s, 3 H), 0.05 (s, 9H). “’0 NMR
(125 MHz, CDCI3) 5 170.7, 139.3, 133.5, 66.9, 20.9, -—1.5; IR (neat) 1745 (s) cm‘

1; HRMS (El) (m/Z) calcd for C3H1GO2SI [M]+ 172.0920, found 172.0920.

 

. J\ Synthesis of acetal 33 (Scheme 54)62
\ 0 OAc To a cold (—78 °C), stirred solution of (3:)-1-trimethylsilylallyl
TMS
33 acetate (18) (155 mg, 0.9 mmol) in CH2CI2 (5 mL) under

 

L

nitrogen condition was added DIBAL (1.8 mL of a 1.0 M solution in hexane, 1.8

106

mmol) dropwise. The resulting reaction mixture was then stirred for 45 min and
after which pyridine (0.2 mL, 2.7 mmol), a solution of DMAP (221 mg, 1.8 mmol)
in CH2CI2 (2 mL), and acetic anhydride (0.5 mL, 5.4 mmol) were added dropwise.
After stirring an additional 29 h, the reaction mixture was warmed to 0 °C and
stirred for 0.5 h. The reaction mixture was quenched by addition of saturated
aqueous NH4CI and sodium potassium tartrate at 0 °C. The resulting solution
was warmed to room temperature, stirred for additional 0.5 h and then diluted
with CH2CI2. Phases were separated and the aqueous phase extracted with
CH2CI2. The combined organics were washed with ice cooled 1 M sodium
bisulfate, saturated aqueous NaHCOa, and brine to afford 61 mg (< 31%) of
presumed acetal 33.

Mosher’s Ester Analyses (Figure 13)

(8)-2-Illlethyl-1-(trimethylsiIyI)-2-propen-1-ol (8) Mosher esters

 

  
     

 

( l H c To a solution of (S)-2-methyI-1-(trimethylsilyl)-2-
._\- OCH
%ONth 3 propen-1-ol (30 mg, 0.21 mmol), (R)-(-)-o-
H
85 methoxyphenylacetic acid (28 mg, 0.17 mmol) and

DCC (39 mg, 0.19 mmol) in CH2C|2 (2.0 mL) under nitrogen was added DMAP (2
mg, 0.019 mmol) in a single portion. The reaction mixture was stirred at room
temperate for 7 h. The precipitate formed was removed by filtration and the
filtrate was washed with cold 1M HCI, saturated aqueous NaHCOa and brine. The
organic layer was dried over MgSO4, filtered, and evaporated to afford the crude
Mosher ester, which was immediately analyzed by 1H NMR (300 MHz, CDCI3,

pertinent peaks only) 5 1.67 (s, 3 H), -0.19 (s, 9 H).

107

 

 

Applying the Mosher’s

procedure to (rac)-2-methyI-1-

 

 

(trimethylsinI)-2-propen-1 -oI
(100 mg, 0.69 mmol) and (R)-(-)-a-methoxyphenylacetic acid (94 mg, 0.56
mmol) (7 h reaction time) afforded the crude Mosher ester, which was
immediately analyzed by 1H NMR (300 MHZ, CDCI3, pertinent peaks only) 5
1.67 (s, 3 H), 1.51 (s, 3 H), 0.00 (s, 9 H), —0.19(s, 9 H).

Resolution of a-Hydroxysilanes via Norephedrine Cabamate (Scheme 59)64

 

1
J

(E)-Ethyl(1-(trimethylsilyl)but-2-en-1-yl)carbonate (45)

 

 

o
JACK Ethylcholoformate (1.13 g, 10.4 mmol) was added to cold
\ “TMS J, (0 °C) solution of 24 (1.0 g, 5.9 mmol) in

 

hexane/acetonitrile (1:1 WV, 20 mL), followed by pyridine (1.7 mL, 20.8 mmol),
and the reaction stirred at 0 °C for 2 h. The reaction was quenched by the
addition of water (30 mL), diluted with CH30N (50 mL), and then hexanes (150
mL). Layers separated and the hexane/acetonitrile layer was washed with brine
(30 mL), dried with Na2SO4, and concentrated under reduced pressure to give
the crude product, which was employed in the second step without further
purification. To a solution of the crude carbonate in hexane/acetonitrile (1 :1 WV,
30 mL) at 0 °C, was added (1R,2S)-(+)-norephedrine (1.369, 9.0 mmol), followed
by diisopropylethylamine (3.6 mL, 20.8 mmol). The reaction was allowed to warm
to room temperature overnight, and then quenched by the addition of water.
Phases were separated and the organic phase (hexane/acetonitrile) washed with

brine, dried with Na2SO4, and concentrated under reduced pressure to yield the

108

desired product as a colorless oil. The second step did not go, and after
purification by silica gel column chromatography on using EtOAc/hexane (3:97),
632 mg of 45, the product of the first step, was obtained as a colorless oil. 1H
NMR (300 MHz, CDCI3) 5 5.58—5.41 (m, 2 H), 4.87—4.85 (d, J = 6.3 HZ, 1 H),
4.18—4.11 (q, J: 7.1 Hz, 2 H), 1.67 (d, J: 5.5 Hz, 3 H), 1.27 (t, J: 7.1 HZ, 3 H),
0.03 (s, 9 H); 130 NMR (75 MHz, cock.) 8 155.7, 127.1, 125.5, 74.5, 53.8, 17.9,
14.3, -4.0; IR (neat) 1744 cm"; HRMS (El) (m/z) calcd for c.0H2003Si [M+H]"

216.1182, found 216.1184.

 

' o ‘ (El-p-Nitrophenyl(1-(trimethylsilyl)but-2-en-1-yl)-

o o-p-No2Ph carbonate (48).
2 48 4
mmol) as described in the preparation of (R)-19 except that p-

 

The reaction was carried out on 24 (300 mg, 2.0

 

nitropheylchloroformate (629 mg, 3.1 mmol) was used to form carbonate. This
modified protocol afforded 294 mg of 48 (46%). 1H NMR (300 MHz, CDCI3) 5
8.25-8.23 (d, J = 9.1 Hz, 2 H), 7.37-7.34 (d, J = 9.3 Hz, 2 H), 5.58-5.51 (m, 1 H),
5.59—5.50 (m, 1 H), 4.99-4.96 (d, J = 7.7 Hz, 1 H), 1.72 (d, J = 6.3 Hz, 3 H), 0.09
(s, 9 H); 130 NMR (75 MHZ, CDCI3) 5 155.9, 152.9, 145.2, 127.4, 126.2, 125.2,
121.8, 77.1, 17.9, -4.0; IR (neat) 1753 cm“; HRMS (FAB+) (m/z) calcd for
C14H13NOSSi [M-Hj“ 308.0955, found 308.0957.

Kinetic Resolution of a-Hydroxysilanes using PBO Catalyst

Synthesis of 58 (Scheme 63)

 

CH3 (28)-2—(2-methoxyethoxy)ethyl ester-2-

HONOwo/VO\
O

hydroxy-propanoic acid (63)
53
109

Methyl (8)-lactate (33.0 mL, 0.34 mol), di(ethylene glycol) methyl ether (138 mL,
1.1 mol) and Al(OfPr)3 (1.2 g, 5.8 mmol) were stirred under nitrogen conditions
and refluxed until 8 mL of methanol was collected (65 °C, 1 atm). The crude
material was purified by distillation under reduced pressure (117-120 °C, 1-2
torr) but obtained product contained impurity. The impure 63 was purified by
redistillation (97 °C, 1 torr) to afford 38.6 g of 63 as a colorless oil (58%). [olo = —
11.9 (c 5.56, EtOAc). 1H NMR (500 MHz, CDCI3) 5 4.34—4.26 (m, 3 H), 3.72-3.69
(m, 2 H), 3.63—3.60 (m, 2 H), 3.54—3.51 (m, 2 H), 3.35 (s, 3 H), 1.40 (d, J = 6.9
Hz, 3 H); 13C NMR (125 MHz, CDCI3) 5 175.6, 71.8, 70.5, 68.9, 66.7, 64.5, 59.0,

20.3. The spectral data were consistent with literature values.67

r (58,55$,BaS)-2,2-dioxide-hexahydro-5,8,8-trimethyI-4H-
1521/ cyclopenta[d]-1,3,2,-dioxathiepin (55)
0
0,802 To a cold (0 °C), stirred solution of 63 (12.3 g, 34.4 mmol) in
k 55

CH2CI2 (180 mL) under nitrogen conditions was added triflic

 

 

 

anhydride (11.9 g, 70.8 mmol) dropwise over 5 min. The reaction mixture was
stirred for 5 min at 0 °C and pyridine (5.6 mL, 70.2 mmol) was added dropwise
over 5 min at 0 °C. The reaction mixture was stirred for an additional 5 min at the
same temperature before removal of ca 213 of the solvent by rotary evaporator.
Hexane was added and extraction with water. The water layers were washed
with hexane and the combined hexane layers were dried over MgSO4. After
filtration and evaporation, 14.2 g of impure ethoxyethoxyethyl (8)-c-

trifluoromethyl-sulfonyloxypropionate (64) was obtained. As the literature

110

 

mentioned, the crude material was used for the next step without further
punflcafion.

To a cold (0 °C), stirred solution of diisopropylamine (3.5 mL, 25.4 mmol)
in toluene (200 mL) under nitrogen conditions was added n-BuLi (15.8 mL of 1.6
M solution in hexane, 25.2 mmol) and stirred for 5 min. The reaction mixture was
cooled to -78 °C and 2,2-diemthyl cyclopentenone (2.9 mL, 23.2 mmol) was
added dropwise over 5 min. The reaction mixture was stirred at the same
temperature for 1.2 h and then impure 64 (14.2 g, 44 mmol) was added dropwise
over 5 min. After stirring for 1 h, the reaction mixture was allowed to warm to -
55 °C and stirred for an additional 23 h. The reaction mixture was recooled to -
78 °C, THF (150 mL) was added dropwise over 1 h and a suspension of LiAlH4
(10.3 g, 272 mmol) in THF (120 mL) was added by syringe. After stirring for 20 h
at —78 °C, the reaction mixture was warmed to -35 °C and stirred for 3 h. The
cold bath was removed and warmed to room temperature. The reaction was
quenched with saturated NH4CI and the phases were separated. The aqueous
phase extracted with ether, and the combined organics were dried over Na2SO4.
After filtration and evaporation, the residue was purified by silica gel column
chromatography using EtOAc/hexane (4:6) to afford (1S,58)-5-((2’S)-1’-
hydroxyprop-2’-yl)-2,2-dimethyl-1-cyclopentanol (65) containing an impurity. After
subsequently the impure material to two additional silica gel columns, 2.9 g of the
impure 65 was obtained and it was used for the next step without further

punficafion.

111

 

 

To a solution of lmpure 65 (1.04 g, 6.0 mmol) in CCI4 (12 mL) under
nitrogen conditions was added SOCI2 (0.71 mL, 9.7 mmol) and refluxed for 1 h.
The reaction mixture was cooled to room temperature, the solvent was removed
by N2 stream and the residue was dissolved in mixture of CH30N, CCI4 and water
(8 mL: 8 mL: 12 mL). The reaction mixture was cooled to 0 °C and RuCla-H2O (11
mg, 0.4 mmol) and NalO4 (2.6 g, 12.1 mmol) were added. After stirring for 5 min
at 0 °C, the reaction mixture was stirred for an additional 1 h at room temperature.
The reaction was quenched by the addition of water and then diluted with ether.
The phases were separated and the aqueous phase was extracted with ether.
The combined organics were washed with brine and dried over anhydrous
MgSO4. After filtration and evaporation, the residue was purified by silica gel
column chromatography using Et2O/hexane (2:8) to afford 66 containing an
impurity. After subsequently the impure material to two additional silica gel
columns, 633 mg of impure 66 was obtained and it was used for the next step
without further purification. 1H NMR (300 MHz, CDCI3) 8 4.09 (d, J = 10.1, 1 H),
3.92-3.85 (m, 1 H), 3.48 (dd, J=12.1, 3.4 HZ, 1 H), 1.54—1.02 (m, 5 H), 1.00 (s, 3
H), 0.83 (s, 3 H), 0.68—0.53 (m, 1 H), 0.21 (d, J = 6.8 Hz, 3 H).The spectral data

were consistent with. literature values.67

 

‘ (1R,2R,4S,58)-4,8,8-Triemthyl-2-(phenylphospha)-bicyclo-
[3.3.0]octane borane complex (67)

To a cold (0 °C), stirred solution of phenylphosphine (5.0 mL

 

 

 

a of 10 wt% solution in hexane, 3.1 mmol) in THF (21 mL) under

nitrogen conditions was added n-BuLi (1.8 mL of 1.6 M solution in hexane, 3.0

112

 

mmol) dropwise. After stirring for 5 min at 0 °C, a solution of impure 66 (633 mg,
2.7 mmol) in THF (14 mL) was added dropwise at —78 °C. After stirring for an
additional 15 min, the cold bath was removed and the reaction mixture was
warmed to room temperature. After stirring for 15 min at room temperature, the
reaction mixture was recooled to —78 °C and n-BuLi (2.0 mL of 1.6 M solution in
hexane, 3.3 mmol) was added dropwise. The reaction mixture was stirred for 15
min at -78 °C, warmed to room temperature and stirred for an additional 2 h.
After addition of borane-THF (8.1 mL of 1.0 M solution in THF, 8.1 mmol), the
reaction mixture was stirred for 1 h at room temperature. The solvent was
removed by N2 stream and aqueous 1M HCI (21 mL) was added. The reaction
was diluted with CH2CI2. The phases were separated and the aqueous phase
was extracted with CH2CI2. The combined organics were washed with brine and
dried over anhydrous Na2SO4. After filtration and evaporation, the residue was
purified by silica gel column chromatography using toluene/hexane (1 :1) to afford
444 mg of 67 as a white crystal (7.8 % from 63). HPLC column: Chiralpak AS.
Eluent: EtOH/hexane (025299.75), 1.0 mUmin. Results: 11.1 min (single peak).
1H NMR (500 MHz, CDCI3) 8 7.82-7.77 (m, 2 H), 7.45-7.41 (m, 3 H), 2.54 (d, J =
10.4 Hz, 1 H), 2.56—2.40 (m, 2 H), 2.30—2.20 (m, 1 H), 2.1—1.84 (m, 2 H), 1.52-
1.39 (m, 3 H), 1.17 (d, J = 5.3 Hz, 3 H), 0.98 (s, 3 H), 0.48 (s, 3 H); "‘0 NMR
(125 MHz, CDCI3) 5 132.8 (cl, J = 9.1 Hz), 131.1 (d, J = 2.1 Hz), 128.68 (d, J =
41.5 Hz), 128.60 (d, J '= 9.7 Hz), 56.8 (d, J = 30.0 Hz), 54.8 (d, J = 2.45 Hz), 44.5
(d, J = 5.5 Hz), 44.2 (s), 43.2 (d, J = 4.8 Hz), 35.9 (d, J = 35.9 Hz), 30.6 (d, J =

4.4 Hz), 29.1 (d, J = 4.5 Hz), 24.5 (d, J = 24.5 Hz), 20.5 (d, J = 9.9 Hz); 118 NMR

113

(150 MHz, coca) ) 8 -31.2- -38.2 (m); 3‘P NMR (200 MHz, CDCI3) 8 330-309
(m); IR (neat) 2358 cm"; HRMS (ESI+) (m/z) calcd for C15H2eBP [M+Na]*
283.1766, found 283.1763; [djp = +291 (0 2.18, EtOAc); mp = 138-139 °C. The

spectral data were consistent with literature values. 67

 

(1S,2R,4S,5S)-4,8,8-TrimethyI-2-phenyl-2-phosphabicylco-
[3.3.0]ocatane (58)

A solution of 67 (435 mg, 1.6 mmol) in pyrrolidine (24 mL) was

 

 

 

refluxed for 4 min 30 sec and cooled to room temperature for 20
min. Pyrrolidine was removed by N2 stream and the residue was filtered through
silica gel in toluene under nitrogen conditions. The columned material contained
a small amount (60:1) of the P-epimer of 58 by 31P NMR. Recrystalization of the
material in CH2,CN at —20 °C afforded 379 mg of diastereomerically pure 58 as a
white crystal (92%). 1H NMR (500 MHz, Caps) 8 7.57-7.53 (m, 2 H), 7.11-7.03
(m, 3 H), 2.61 (dd, J = 26.7, 9.2 Hz, 1 H), 2.27 (dd, J = 14.4, 5.7 Hz, 1 H), 2.21-
2.03 (m, 2 H), 1.83-1.74 (m, 1 H), 1.53 (ddd, J: 19.4, 14.4, 11.0 HZ, 1 H), 1.35—
1.17 (m, 3 H), 0.98 (d, J = 5.3 HZ, 3 H), 0.98 (s, 3 H), 0.71 (s, 3 H); ”C NMR
(125 MHz, C6D5) 5 139.0 (d, J = 31.6 Hz), 134.4 (d, J = 20.3 Hz), 128.3 (d, J =
21.9 Hz), 128.2 (s, it might be overlapped with C505), 58.5 (d, J = 24.6 Hz), 56.0
(d, J = 3.4 Hz), 45.3 (d, J = 3.4 Hz), 44.0 (d, J = 1.5 Hz), 43.9 (cl, J = 4.6 Hz),
36.3 (d, J = 8.8 Hz), 31.3 (d, J = 3.4 Hz), 30.1 (s), 25.6 (d, J = 5.5 Hz), 21.5 (d, J
= 3.4 Hz); 3‘13 NMR (200 MHz, 060,) 8 —1.7 (s); IR (neat) 1455 cm"; HRMS

(ESI+) (m/z) calcd for CieH24P [M+H]” 247.1616, found 247.1618; [Clo = —15.1 (c

114

 

1.07, THF); mp = 49 °C. The spectral data were consistent with literature values.

67

 

1 P-epimerization of 58 experiment

H The reaction was carried out on 67 (5.1 mg, 0.502 mmol) as
p

“‘Ph described in the preparation of (1S,2R,4S,5S)-4,8,8-trimethyI-2-

H
phenyl-2-phosphabicylco-[3.3.0]ocatane except that the reaction mixture was

 

 

refluxed for 2 h. 1H NMR (300 MHz, 0606) 8 755-752 ppm and 7.47-7.43 ppm
(ratio of 15:10), 2.35 pm and 2.25 ppm (ratio of 10:15); 3‘P NMR (120 MHz,
C5D5) 5 —2.01 ppm and -15.74 ppm (ratio of 1.0: 1.6).

Preparation of a-Hydroxysilanes

 

r OH a-(Dimethylphenylsilyl)cyclohexanemethanol (70)

06H11/‘\0Mps Chlorodimethylphenylsilane (24.8 mL, 148 mmol) was added

 

L 7° to a rapidly stirring mixture of lithium wire (3.2 g, 466 mmol
(fine cut)) in THF (120 mL) at room temperature. The reaction mixture was stirred
for 28 h at room temperature, giving a deep red solution of PhMe2SiLi. This
PhMe2SiLi solution was then added dropwise via cannula to a cold (-78 °C)
stirred solution of cyclohexanecarboxaldehyde (2.4 mL, 20 mmol). The reaction
mixture was stirred for 30 min at the same temperature and allowed to warm to
0 °C. The reaction mixture was stirred for an additional 1.5 h at the same
temperature before being quenched by addition of saturated aqueous NH4CI
solution. The reaction was extracted twice with ether. The combined organics
were washed with water and brine and then dried over MgSO4. After filtration and

evaporation, the residue was purified over silica gel column chromatography

115

 

using Et2O/hexane (1:25) to afford 3.5 g of 70 as a pale yellow oil (73%). 1H NMR
(500 MHz, CDCI3) 8 7.58—7.54 (m, 2 H), 7.35-7.34 (m, 3 H), 3.33 (d, J = 5.9 Hz,
1 H), 1.85-1.49 (m, 6 H), 1.25—0.99 (m, 6 H), 0.36 (d, J = 4.8 HZ, 6 H); 13C NMR
(125 MHZ, CDCI3) 5 138.0, 134.2, 129.3, 128.0, 71 .1, 42.2, 31.0, 29.7, 26.6, 26.5,
26.4, —3.5, —4.0. The spectral data were consistent with literature values.35

Acylation of a-Hydroxysilanes

 

1-Benzoate-a-(1 ,1 -dimethy|ethyI)-benzenemethanol

OC(O)Ph

Ph f-Bu To a solution of c-(1,1-dimethylethyl)-benzenemethanol (100 mg,
88

 

0.60 mmol) and pyridine (50 pL, 0.61 mmol) was added benzoic
anhydride (139 mg, 0.61 mmol). The reaction mixture was stirred at 80 °C for 48
h. The reaction mixture was diluted with 320, and then sequentially extracted
with 1M HCI, saturated aqueous NaHCOa and brine. The ethereal layer was dried
over MgSO4, filtered, and evaporated. The residue was purified by silica gel
column chromatography using EtOAc/hexane (5:95) to afford to 103 mg the
desired product (53%). 1H NMR (500 MHz, CDCI3) 8 8.11-8.08 (m, 2 H), 7.58—
7.53 (m, 1 H), 7.47-7.42 (m, 2 H), 7.35-7.32 (m, 2 H), 7.30—7.25 (m, 2 H), 7.25-
7.22 (m, 1 H) 5.70 (s, 1 H), 1.01 (s, 9 H); 13c NMR (125 MHz, CDCI3)5165.5,
138.4, 132.8, 130.6, 129.5, 128.3, 127.69, 127.64, 127.5, 83.4, 35.4, 26.2. IR
(neat) 1722 cm"; HRMS (ESI+) (m/z) calcd for C13H2oO2 [Mt-Na]+ 291.1351,

found 291.1358.

 

Phenyl(trimethylsilyl)methyl benzoate

 

116

 

 

The reaction was carried out on 27 (100 mg, 0.55 mmol) as described in the
preparation of 1-benzoate-o-(1,1-dimethylethyI)-benzenemethanol except that
the reaction mixture was stirred for 24 h at 50 °C. The residue was purified by
silica gel column chromatography using EtOAc/hexane (5:95) to afford to 35 mg
the desired product (22%). 1H NMR (500 MHz, CDCI3) 5 8.13—8.09 (m, 2 H),
7.78-7.53 (m, 1 H), 7.49-7.43 (m, 2 H), 7.31-7.25 (m, 2 H), 7.25-7.20 (m, 2 H),
7.19-7.14 (m, 1 H) 5.91 (s, 1 H), 0.08 (s, 9 H); "*0 NMR (125 MHz, CDCI3) 8
166.2, 140.0, 132.8, 130.6, 129.5, 128.4, 128.2, 126.1, 125.1, 72.1, -3.7. IR
(neat) 1720 cm"; HRMS (ESI+) (m/z) calcd for C17H2oO2Si [M+Na]" 307.1130,

found 307.1136.

 

OC(O)Ph 1'(Trlmethy|3Ilyl)a||y| benzoate

TMS The reaction was carried out on 3 (200 mg, 1.5 mmol) as
90

\

 

described in the preparation of 1-benzoate-o-(1,1-
dimethylethyl)-benzenemethanol except that the reaction mixture was stirred for
14 h at 50 °C. The residue was purified by silica gel column chromatography
using Et2O/hexane (5:95) to afford to 173 mg the desired product (48%). 1H NMR
(500 MHz, CDCI3) 8 8.07-8.04 (m, 2 H), 7.57-7.52 (m, 1 H), 7.45-7.41 (m, 2 H),
5.94 (ddd, J = 17.1, 10.8, 5.6 Hz, 1 H), 5.43 (dt, J = 5.6, 1.8 Hz, 1 H), 5.10-4.99
(m, 2 H), 0.11 (s, 9 H); 130 NMR (125 MHz, CDCI3) 8 155.1, 134.8, 132.7, 130.5,
129.5, 128.3, 111.4, 70.9, —3.8; IR (neat) 1720 cm“; HRMS (ESI+) (m/z) calcd

for C13H1902Si [M+H]+ 235.1154, found 235.1159.

 

The reaction was carried out on 70 (113 mg, 0.45 mmol) as

OC(O)Ph

051111 DMPS described in the preparation of 1-benzoate-o-(1,1-
91

 

117

 

dimethylethyl)-benzenemethanol except that the reaction mixture was stirred for
48 h at 50 °C. The residue was purified by silica gel column chromatography
using EtOAc/hexane (10:90) to afford to 109 mg the desired product (68%). 1H
NMR (500 MHz, CDCI3) 5 8.02—8.00 (m, 2 H), 7.58—7.51 (m, 3 H), 7.45—7.41 (m,
2 H), 7.35—7.31 (m, 3 H), 5.10 (d, J: 7.1 Hz, 1 H), 1.77—1.52 (m, 6 H), 1.17—0.93
(m, 5 H), 0.37 (d, J = 17.1 Hz, 6 H); 13C NMR (125 MHz, CDCI3) 5 166.6, 136.8,
133.9, 132.5, 130.7, 129.4, 129.2, 128.3, 127.8, 73.6, 40.4, 30.7, 30.0, 26.16,
25.11, 25.0, -3.4, -4.0; IR (neat) 1713 cm“; HRMS (ESI+) (m/z) calcd for

ngHzaOzSI [M+N1‘14]+ 370.2210, found 370.2202.

 

OC(O)Ph 1-(Dimethyl(phenyl)silyl)allyl benzoate

\ ”DMPS The reaction was carried out on 18 (200 mg, 1.04 mmol) as
described in the preparation of 1-benzoate-q-(1,1-dimethylethyl)-
benzenemethanol except that the reaction mixture was stirred for 46 h at 50 °C.
The residue was purified by silica gel column chromatography using
EtOAc/hexane (10:90) to afford to the desired product but the columned material
contained impurity. After second silica gel column chromatography, 160 mg of
impure product was obtained. 1H NMR (500 MHz, CDCI3) 5 8.04—8.00 (m, 2 H),
7.57-7.52 (m, 3 H), 7.45-7.41 (m, 2 H), 7.38-7.32 (m, 3 H), 5.87 (ddd, J =17.1,
10.8, 5.5 Hz, 1 H), 5.52 (dt, J: 5.5, 1.8 Hz, 1 H), 5.05—4.95 (m, 2 H), 0.40 (d, J =
2.0 Hz, 5 H); 13c NMR (125 MHz, CDCI3) 8 155.3, 135.4, 134.8, 134.3, 133.0,
130.7, 129.8, 129.7, 128.6, 128.1, 112.1, 70.6, —5.0, —5.3; IR (neat) 1717 cm"1‘
HRMS (ESI+) (m/z) calcd for CiaH24O2Si [M+NH4]+ 314.1578, found 314.1576.

Kinetic Resolution of a-Hydroxysilanes with PBO Catalyst

118

 

 

Resolution of (:l:)-a-(1,1-dimethylethyl)-benzenemethanol (49) (Table 8, entry
4)

To a cold (—30 °C) solution of 58 (3.3 mg, 4 mol%) in toluene (1.0 mL)
under nitrogen conditions was added (1)-0-(1,1-dimethylethyl)-benzenemethanol
(55 mg, 0.33 mmol) and benzoic anhydride (189 mg, 0.83 mmol). The reaction
mixture was stirred with the reaction progress being monitored by GC (VF-1ms
column). After ~59% of the starting material was consumed, the reaction mixture
was filtered through a pad of Celite. Analysis of the filtrate was analyzed HPLC
(Chiralcel OD) and indicated that the optically active (8)-49 to be formed with
85 %ee.

Resolution of (:I:)-a-(trimethylsilyl)-benzenemethanol (Table 9, entry 1)

Applying the kinetic resolution procedure described on rec-49 to (1)-o-
(trimethylsilyI)-benzenemethanol (27) (18 mg, 0.1 mmol) with 58 (1.5 mg, 6
mol%) at room temperature afforded after ~47% conversion unreacted optically
active alcohol with 46 %ee.

Resolution of (:I:)-1-hydroxyallyltrimethylsilane (Table 9, entry 2)

Applying the kinetic resolution procedure described on rac-49 to (:i:)-1-
hydroxyallyltrimethylsilane (3) (13 mg, 0.1 mmol) with 58 (1.2 mg, 5 mol%) at
room temperature afforded after ~47% conversion unreacted optically active
alcohol (8)-3 with 19 %ee.

Resolution of (1)-1-(dimethylphenylsilyl)-2-propen-1-ol (Table 9, entry 3)

Applying the kinetic resolution procedure described on rec-49 to (:i:)-1-

(dimethylphenylsilyl)-2-propen-1—ol (19) (21 mg, 0.1 mmol) with 58 (1.4 mg, 5

119

 

 

mol%) at room temperature afforded after ~54% conversion unreacted optically
active alcohol (8)-19 to be formed with 5 %ee.
Resolution of (:l:)-a-(dimethylphenylsilyl)-cyclohexanemethanol (Table 9,
entry 4)

Applying the kinetic resolution procedure described on rec-49 to (1:)-o-
(dimethylphenylsilyl)-cyclohexanemethanol (38 mg, 0.16 mmol) with 58 (3.5 mg,
8.5 mol%) in heptanes at room temperature afforded after ~43% conversion

unreacted optically active alcohol 70 to be formed with 5 %ee.

GC Analyses
Figure 20. Retention times of o-Hydroxysilanes
OH OH )0:
Ph/kTMS PhXt-Bu C6H11 DMPS
27 49 70
(8.5 min) (8.4 min) (14.5 min)

GC Column: VF-1ms column (15 m x 0.25 mm x 0.25 urn film thickness).
Program: 50 0C for 2 min, 50 to 200 °C, at 10 °C/min.

Figure 21. Retention times of Acetated Products

OC(O)Ph OC(O)Ph OC(O)Ph OC(O)Ph OC(O)Ph
Ph t-Bu Ph TMS \ TMS 05H" DMPS \ DMPS
88 89 90 91 92
(15.8 min) (15.9 min) (9.7 min) (15.2 min) (16.6 min)

GC Column: VF-1ms column (15 m x 0.25 mm x 0.25 um film thickness).
Program: 50 °C for 2 min, 50 to 200 °C, at 10 °C/min.
Chiral GC and HPLC Analyses

q-(TrimethylsiIyl)-benzenemethanol (27)

120

 

HPLC column: Chiralcel OD. Eluent: IPA/hexane (3:97), 1.0 mUmin.
Results: 8.3 min, 10.3 min (absolute stereochemistry is not determined yet).
a-(1,1-Dimethylethyl)-benzenemethanol (49)

HPLC column: Chiralcel OD. Eluent: IPA/hexane (3:97), 1.0 mL/min.
Results: HS) enantiomer (min) = 7.8 min, HR) enantiomer (min) = 12.2 min.
a-(DimethylphenylsilyI)-cyclohexanemethanol (70)

HPLC column: Chiralcel OD. Eluent: IPA/hexane (1:400), 1.0 mUmin.
Results: 11.1 min, 13.2 min. (absolute stereochemistry is not determined yet)

8.8. Designed and Synthesized a series of Novel N-Boc amines (Figure 17)

NHBOC 1,1-Dimethylethyl ester-[44acetylamino)phenyl]-carbamic acid
A mixture of 4’-aminoacetanilide (5.0 g, 33.3 mmol), Boc2O (9.4 g,
NHA 43-3 mmol), Zn(CIO4)2-6Hzo (0.52 g. 1.55 mmol) in t-BuOH (50 mL)
C
93

 

under nitrogen conditions was stirred for 20 h at 30 °C. The solvent
was removed in vacuo and the residual solid was extracted with brine and
CH2CI2. The combined organics were washed with water and brine and then
dried over MgSO... After filtration and evaporation, the residue was washed with
ether and hexane to afford 2.02 g of the desired product as a white crystal (23%).
1H NMR (500 MHz, DMSO) 8 9.75 (br s, 1 H), 9.18 (br s, 1 H), 7.45-7.30 (m, 4 H),
1.98 (s, 3 H), 1.45 (s, 9 H); ‘30 NMR (125 MHz, DMSO) 8 157.7, 152.7, 134.5,
133.8, 119.4, 118.4, 78.7, 28.1, 23.7; IR (neat) 3425, 3334, 1595, 1550 cm";
HRMS (ESI+) (m/z) calcd for C13H13N203 [M+Na]+ 273.1207, found 273.1215.

The spectral data were consistent with literature values.86

121

m Methyl 4-((tert-butoxycarbonyl)amino)benzoate

A mixture of methyl 4-aminobenzoate (5.0 g, 33.1 mmol), 80020

CO M (93 9, 43.0 mmol). Zn(CI04)2;6H20 (0.51 g, 1.55 mmol) in CH2CI2
2 e

591—1 (50 mL) under nitrogen conditions was stirred for 47.5 h at 30 °C.

 

 

The solvent was removed in vacuo and the residual solid was washed with
hexane and CH2CI2. The desired product was purified by recrystalization using
EtOAc/hexane to afford 3.01 g of the desired product as a white crystal (36%). 1H
NMR (500 MHz, CDCI3) 5 7.97-7.93 (m, 2 H), 7.43-7.39 (m, 2 H), 6.65 (s, 1 H),
3.85 (s, 3 H), 1.50 (s, 9 H); 130 NMR (125 MHz, CDCI3) 8 155.5, 152.1, 142.5,
130.8, 124.4, 117.3, 81.2, 51.8, 28.2; IR (neat) 3408, 3331, 1711, 1597 cm“;

HRMS (ESI+) (m/z) calcd for C(3H17NO4 [M+Na]+ 274.1055, found 274.1049.

 

r NHBoc 4'((t°"'3“t°"3“’a"”"Y'I‘M"iIIOIIDheflyl dimethylcarbamate87

To a solution of N-Boc-4-hydroxyaniline (1.5 g, 7.1 mmol) in
pyridine (2.2 mL) was added dimethyl carbamyl chloride (0.85

OC(O) NMez
95

 

   

mL, 9.3 mmol) at room temperature. The reaction mixture was
stirred for 46.7 h at room temperature and dimethylcarbamyl chloride (0.85 mL,
9.3 mmol) and pyridine (3.0 mL) were added. The reaction mixture was warm to
50 °C and stirred for 21 h at the same temperature. The reaction was diluted with
EtOAc and 1M HCI. The phases were separated and the aqueous phase was
extracted with EtOAc. The combined organics were washed with brine and dried
over anhydrous MgSO4. After filtration and evaporation, the residue was washed
with hexane and purified by recrystalization using EtOAc/hexane. The material

was dried over vacuum at 50 °C to afford 1.3 g of the desired product as a white

122

 

crystal (55%). mp = 182 °c; 1H NMR (500 MHz, cock.) 8 7.30 (d, J = 8.5, 2 H),
7.03—5.99 (m, 2 H), 5.41 (br s, 1 H), 3.05 (s, 3 H), 2.98 (s, 3 H), 1.49 (s, 9 H);
130 NMR (125 MHz, CDCI3) 8 155.0, 152.7, 145.8, 135.4, 122.0, 119.3, 80.4,
35.5, 35.4, 28.3; IR (neat) 3425, 3298, 1595, 1505 cm"; HRMS (ESI+) (m/z)

calcd for C14H20N2O4 [M+H]+ 281.1501, found 281,149.

 

1 ,4-Dihydro-1-benzoxazin-2-one-2H-388

o
m/KO To a solution of ethylchloroformate (3.1 mL, 3.5 g) and
95 pyridine (2.6 mL, 32.5 mmol) in CH3CN (35 mL) was added 2-

‘
J

 

 

 

aminobenzyl alcohol (4.0 g, 32.5 mmol). The reaction mixture was stirred for 17 h
at room temperature and refluxed for 4.5 h. The solution was diluted with CH2CI2
and brine. The phases were separated and the aqueous phase was extracted
with CH2CI2. The combined organics were washed with brine and dried over
anhydrous MgSO4. After filtration and evaporation, the crude material was
dissolved toluene (35 mL) and DBU (0.97 mL, 6.5 mmol) was added. The
reaction mixture was refluxed for 2.4 h and the solvent was removed in vacuo.
The residue was diluted with CH2CI2 and brine. The phases were separated and
the aqueous phase was extracted with CH2CI2. The combined organics were
washed with brine and dried over anhydrous MgSO4. After filtration and
evaporation, the residue was washed with hexane and purified by recrystalization
using CH2CI2/hexane to afford 1.5 g of the desired product as a white crystal
(31%). 1H NMR (500 MHz, CDCI3) 8 7.51 (br s, 1 H), 7.25—7.23 (m, 1 H), 7.11-
7.09 (m, 1 H), 7.07-7.02 (m, 1 H), 5.79-5.75 (m, 1 H), 5.30 (s, 2 H); 1"c NMR

(125 MHZ, CDCI3) 5 153.1, 135.5, 129.2, 124.2, 123.3, 117.9, 114.0, 68.6; IR

123

(neat) 1716 cm”; HRMS (ESI+) (m/z) calcd for CgH3N102 [M+H]+ 150.0555,

found 150.0549. The spectral data were consistent with literature values.89

 

3-((tert-Butoxycarbonyl)amino)phenyl dimehtyl-
carbamate88

To a solution of N-Boc-3-hydroxyaniline (2.0 g, 9.5 mmol)

 

 

in pyridine (3.0 mL) was added dimethyl carbamyl chloride (1.14 mL, 12.4 mmol).
After stirring for 86 h at 50 °C, the reaction was diluted with EtOAc and 1M HCI.
The phases were separated and the aqueous phase was extracted with EtOAc.
The combined organics were washed with brine and dried over anhydrous
MgSO4. After filtration and evaporation, the residue was washed with hexane and
purified by recrystalization using EtOAc/hexane to afford 1.0 g of the desired
product as a white crystal (40%). mp = 139 °C; 1H NMR (500 MHz, CDCI3) 5 7.32
(br s, 1 H), 7.2 (t, J = 8.14 Hz, 1 H), 7.01-5.98 (m, 1 H), 5.79-5.75 (m, 1 H), 5.47
(br s, 1 H), 3.05 (s, 3 H), 2.97 (s, 3 H), 1.48 (s, 9 H); 13c NMR (125 MHz, CDCI3)
5 154.7, 152.4, 152.0, 139.2, 129.3, 116.3, 115.0, 112.1, 80.6, 36.6, 36.4, 28.3;
IR (neat) 3308, 1707, 1512 cm"; HRMS (ESI+) (m/z) calcd for Ct4H2oN2O4
[M+H]+ 281.1501, found 281.1499.

m 1,1-Dimethylethyl ester-N-[4-(trifluoromethyl)phenyI]-carbamic
acid90

To a solution of 4-(trifluoromethyl)aniline (0.75 mL, 6.0 mmol) in

CF3
A; dioxane (3 mL) added to a solution of NaOH (0.24 g, 6.0 mmol) in

 

 

water (6 mL). The reaction mixture was cooled to 0 °C and a solution of 80020

(1.3 g, 6.0 mmol) in dioxane (3 mL) was added dropwise. After stirring for 43 h at

124

 

 

room temperature, the reaction mixture was cooled to 0 °C and solutions of
NaOH (0.24 g, 6.0 mmol) in water (6 mL) and 80020 (1.3 g, 6.0 mmol) in dioxane
(3 mL) were added. The reaction mixture was stirred 73 h at room temperature.
The phases were separated and the organic layers were sequentially extracted
with 1M HCI, saturated aqueous NaHCOa and brine. The organic layer was dried
over MgSO4, filtered and evaporated. The residue was washed with hexane to
afford 584 mg of the desired product as a white crystal (37%). mp = 120 °C; 1H
NMR (500 MHZ, CDCI3) 8 7.53-7.50 (m, 2 H), 7.45—7.43 (m, 2 H), 5.58 (br s, 1
H), 1.51 (s, 9 H); 13c NMR (125 MHz, CDCI3) 8 152.3, 141.5, 125.2 (q, J = 3.8
Hz), 124.7 (q, J = 32.7 Hz), 124.2 (q, J = 271.3 Hz), 117.8, 81.2, 28.2. The
spectral data were consistent with literature values.91

1 ,1 -Dimethylethyl ester-N-(4-methoxyphenyI)-carbamic acid92

 

 

NHBoc
I \ To a solution of 5-amino-2-methoxypyridine (2.0 g, 16.1 mmol) in
N /
0M6 dioxane (8 mL) was added to a solution of Boc2O (4.5 g, 20.9
_99_, mmol) in dioxane (8 mL). The reaction mixture was stirred for 22 h

at room temperature. The reaction mixture was sequentially extracted with 1M
HCI, saturated aqueous NaHCOa and brine. The organic layer was dried over
Na2SO4, filtered and evaporated. The residue was purified by silica gel column
chromatography using from 100% CH2CI2 to 100% acetone but the columned
material contained impurity. After evaporation, the residue was purified by
sublimation (0.2 atm, 85 °C) to afford 863 mg of the desired product as a white
crystal (23%). mp = 81 °C; 1H NMR (500 MHz, CDCI3) 8 7.97 (d, J = 2.7 Hz, 1 H),

7.79 (br S, 1 H), 6.60 (d, J: 8.8 Hz, 1 H), 6.30 (br S, 1 H), 3.87 (s, 3 H), 1.48 (S, 9

125

 

H); 13c NMR (125 MHz, CDCI3)5160.5, 153.2, 137.5, 131.5, 128.9, 110.5, 80.7,
53.4, 28.2; IR (neat) 3325, 1725, 1701 cm"; HRMS (ESI+) (m/z) calcd for
C11H16N203 [M+H]+ 225.1239, found 225, 1240. The spectral data were

consistent with literature values.93

 

NH 13 1 .1-Dimehtylethyl esmf-[4-meth0Xy-3-(trifluoromethyl)-
0C

phenyllcarbamic acid94
CF3 To a solution of 5-methoxy-3-trifluromethyaniline (2.0 g, 10.4
OMe
100

mmol) in THF (7.5 mL) was added to Boc2O (2.5 g, 11.5 mmol).

 

L

The reaction mixture was refluxed overnight, cooled and the solvent was
removed in vacuo. The residue was purified by silica gel column chromatography
using EtOAc/hexane (1 :9) to afford 2.8 g of the desired product as a white crystal
(92%). mp = 138 °C; 1H NMR (500 MHz, DMSO) 8 9.40 (br s, 1 H), 7.78 (s, 1 H),
7.59 (d, J = 8.3 Hz, 1 H), 7.15 (d, J = 9.0 Hz, 1 H), 3.81 (s, 3 H), 1.45 (s, 9 H); ”C
NMR (125 MHz, DMSO) 8 152.8, 151.9, 132.4, 123.5 (q, J = 272 Hz), 123.4 (br
s), 116.6 (q, J = 29.9 Hz), 116.3 (br s), 113.4, 79.2, 56.1, 28.0; IR (neat) 3323,

1699 cm". The spectral data were consistent with literature values.

 

' NHBoc ‘ 4—((tert-Butoxycarbonyl)amino)-2-chlorophenyl dimethyl-

carbamate88

0' The reaction was carried out on 1,1-dimethylethyl ester-N-(3-
OC(O)NM62

101 chloro-4-hydroxyphenyl)-carbamic acid (2.0 mg, 8.2 mmol) as

 

 

described in the preparation of 3-((tert-butoxycarbonyl)amino)phenyl dimethyl-
carbamate except that the reaction mixture was stirred for 25 h at 70 °C. This

modified protocol afforded 1.9 g of the desired product as a white crystal but it

126

 

contained impurity (74%). mp = 162 °C; 1H NMR (500 MHZ, DMSO) 5 7.55 (br s,
1 H), 7.15-7.05 (m, 2 H), 6.58—6.45 (m, 1 H), 3.11 (s, 3 H), 3.00 (s, 3 H), 1.49 (s,
9 H); ”C NMR (125 MHZ, DMSO) 8 154.2, 152.5, 142.5, 135.7, 127.0, 123.7,
119.8, 117.5, 80.5, 35.8, 35.4, 28.2; IR (neat) 3429, 3321,1718,1518 cm";

HRMS (ESI+) (m/z) calcd for C14H19N2O4Cl [M+H]“ 315.1112, found 315.1118.

 

1 ,1-Dimethylethyl ester-[4-(dimethylamino)phenyI]-carbamic

 

 

NHBoc
acidg5
NM To a solution of N-Boc-p-phenylene diamine (2.0 g, 9.6 mmol) in
e2
_1°2_. EtOAc (40 mL) was added formaldehyde (1.5 mL of 37% solution in

water, 21.1 mmol) and 10% Pd/C (192 mg). The reaction mixture was
hydrogenated at atmospheric pressure for 63 h. The reaction mixture was filtered
and the solvent was evaporated. The residue was purified by silica gel column
chromatography using EtOAc/hexane (3:7) to afford 513 mg of the desired
product as a white solid (22%). mp = 98 °C; 1H NMR (500 MHZ, CDCI3) 8 7.18 (br
d, J = 7.7 Hz, 2 H), 6.67 (d, J = 8.9 Hz, 2 H), 6.23 (br s, 1 H), 2.87 (s, 6 H), 1.48
(s, 9 H); 130 NMR (125 MHz, CDCI3) 8 153.3, 147.4, 128.3, 120.7, 113.4, 79.8,

41.1, 28.3. The spectral data were consistent with literature values.96

127

 

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133

        

 

   

   

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