Preparation of a 'Si-centered' chiral auxiliary by resolution

Article abstract of DOI:10.1016/j.tetasy.2004.03.014

(R)- and (S)-[(benzyloxy)methyl](tert-butyl)methylsilane [(-)-(R)-1 and (+)-(S)-1], possessing a stereogenic center at the Si-atom, were prepared in highly enantiomerically enriched form by resolution via diastereomeric silyl ethers. Conversion of the hydrosilanes into different functionalized chiral silanes by direct or stepwise substitution of the (Si)-H-atom was shown to proceed with high stereoselectivity (96-98% stereoselectivity under optimized conditions) thus allowing the preparation of substrates where the chiral silicon moiety can act as a chiral auxiliary for stereoselective transformations.

Full text of DOI:10.1016/j.tetasy.2004.03.014

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1501–1505
Preparation of a ‘Si-centered’ chiral auxiliary by resolution
Michael Trzoss, Jie Shao and Stefan Bienz*
University of Zurich, Organic Chemistry, Winterthurerstr. 190, Zurich CH8057, Switzerland
Received 27 February 2004; accepted 3 March 2004
Available online 9 April 2004
Abstract—(R)- and (S)-[(benzyloxy)methyl](tert-butyl)methylsilane [())-(R)-1 and (+)-(S)-1], possessing a stereogenic center at the
Si-atom, were prepared in highly enantiomerically enriched form by resolution via diastereomeric silyl ethers. Conversion of the
hydrosilanes into different functionalized chiral silanes by direct or stepwise substitution of the (Si)–H-atom was shown to proceed
with high stereoselectivity (96–98% stereoselectivity under optimized conditions) thus allowing the preparation of substrates where
the chiral silicon moiety can act as a chiral auxiliary for stereoselective transformations.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
While the use of racemic material was for the most part
sufficient for our initial studies (concerning primarily of
the investigation of stereochemical efficiency of newly
designed chiral auxiliaries), access to the enantiomeri-
cally pure auxiliaries and starting materials is imperative
for establishing new chemical methods for general
application. For auxiliary A we have shown that enan-
tiomerically highly enriched acylsilanes ())-(R)- and (+)-
(S)-2 are accessible by Si-specific biocatalytic reduction
of the respective racemate, chromatographic separation
of the obtained diastereomeric a-hydroxysilanes, and
re-oxidation of the latter.3;9 The biotransformation was
high yielding and as a result scaled-up to batches of 30 g,
We have previously shown that chiral silicon groups can
efficiently be used as chiral auxiliaries for stereoselective
transformations.1–6 Of particular interest was silicon
group A containing a ‘Si-centered’ stereogenic, which
was used as an auxiliary for the asymmetric nucleophilic
addition of organometallics to the carbonyl groups of
acylsilanes 22–5;7 and, more recently, also of a- and b-
silyloxy carbonyl derivatives 3 and 4 (Fig. 1).8 The ste-
reoselectivities obtained by these reactions were high
with a number of useful transformations being per-
formed with the respective addition products.
BnO
Me
BnO
Me
Me
Me
Si
Me
Me
Me
Si
Me
H
A
1
OBn
Si
O
OBn
Si
O
OBn
Si
O
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
O
Me
Me
Me
Me
Me
2
3
4
Figure 1.
* Corresponding author. Tel.: +41-1-635-4245; fax: +41-1-635-6812; e-mail: sbienz@oci.unizh.ch
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.03.014

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M. Trzoss et al. / Tetrahedron: Asymmetry 15 (2004) 1501–1505
allowing the preparation of reasonable amounts of
material with this process in one cycle. However, the
procedure itself is not open to the general chemical
community since it requires access to rather large reac-
tors along with a knowledge of handling microorgan-
isms. We thus searched for an alternative method for the
preparation of enantiomerically pure silicon compounds
A and considered hydrosilane 1 as a suitable target.
Hydrosilane 1 is largely configurationally stable10 and is
suitable as a starting material for the preparation of
silanes with different functionalities.
in the presence of Et3N and DMAP, which gave an 87%
yield of the two optically active ethers (R,S)-6 and (S,S)-7.
Additional products that can be silylated at the sec-
ondary alcohol group of the diol were not obtained in
this reaction. After separation of the diastereomeric
products, the reduction of (R,S)-7 and (S,S)-8 with
LiAlH4 in Et2O at low temperatures afforded stereo-
selectively, the respective hydrosilanes (+)-(S)-1 and ())-
(R)-1 with enantiomeric ratios (er) of 97:3 (together with
diol (S)-9, which could be recovered). The enantiomeric
purities of the two hydrosilanes were determined by
means of 1H NMR spectroscopy, performed in the
presence of the Pirkle reagent.11 Since the conversion of
silyl ethers into hydrosilanes is known to proceed with
retention of configuration, the relative configurations of
(R,S)-7 and (S,S)-8 were deduced on the basis of the
already known reduction products (+)-(S)- and ())-(R)-
1,5 respectively.
Herein we report a novel and convenient route to the
enantiomerically highly enriched hydrosilanes ())-(R)-
and (+)-(S)-1, and show that these hydrosilanes can in
fact be converted stereospecifically into several func-
tionalized compounds such as acylsilanes, halogenosil-
anes, and silyl ethers.
To prove the viability of compounds 1 to be used as
starting materials for the preparation of differently
functionalized enantiomerically enriched chiral silanes,
hydrosilane (R)-1 was treated with freshly prepared
1-ethoxyvinyllithium at )100 ꢁC in THF to deliver vinyl
ether (S)-10, which was directly hydrolyzed by treatment
with diluted aqueous HCl to afford the (S)-configured
acylsilane (+)-2 (Scheme 2). Starting from ())-(R)-1 of
97% enantiomeric ratio (er), (S)-2 of 95% er was
obtained, showing that the substitution reaction pro-
ceeded to 98% with retention of configuration. The
enantiomeric ratio of acylsilane 2 was determined, as
2. Results
During earlier investigations we noticed that diastereo-
meric silyl ethers 7 and 8 (obtained as racemates by the
addition of phenylmagnesium bromide to a racemic
aldehyde precursor) could be readily separated by flash
chromatography,8 which would thus allow the resolu-
tion of the silicon auxiliary when the respective
mono-silyl ethers of racemic chlorosilane ( )-5 with
enantiomerically pure diols (R)- or (S)-9 were prepared
(Scheme 1).
1
previously described, by H NMR of the Mosher ester
derivatives of the separated corresponding diastereo-
meric alcohols that were obtained by reduction of a
sample of the ketone with LiAlH4.4
Hence, enantiomerically pure diol (S)-6, which is com-
mercially available, was treated with chlorosilane ( )-5
OH
HO
Ph
OBn
OBn
Si
OH
Ph
OBn
Si
OH
Ph
(S)-6
Cl
O
O
Si
+
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et3N, DMAP
CH2Cl2, 20°C
Me
Me
Me
( )-5
(R,S)-7
(S,S)-8
(>99:1 dr)
(>99:1 dr)
1. separation
by chromatography
2. LiAlH4, Et2O
_
_
60°C to 30°C
OBn
Si
OBn
H
H
Si
Me
Me
Me
Me
Me
Me
Me
Me
_
(+)-(S)-1
( )-(R)-1
(97:3 er)
(97:3 er)
Scheme 1.

M. Trzoss et al. / Tetrahedron: Asymmetry 15 (2004) 1501–1505
1503
OEt
OBn OEt
OBn
Si
O
Li
HCl
Si
Me
Me
Me
Me
Me
Me
Me
H2O /THF
23°C
Me
THF
_
_
Me
100°C to 80°C
OBn
Si
(S)-10
(+)-(S)-2
H
(95:5 er)
Me
Me
Me
Me
_
( )-(R)-1
OBn
Si
OH
Ph
OBn
OH
Ph
(97:3 er)
1. Br2 / Pyridine
_
Et2O, 100°C
O
O
Si
+
Me
Me
Me
Me
OH
2.
Me
Me
HO
Ph
Me
Me
(R,S)-7
(S,S)-8
(S)-6
_
100°C to 0°C
93 : 7
Scheme 2.
Lower selectivity was observed for the conversion of
enantiomerically enriched hydrosilanes 1 into silyl
ethers. Treatment of ())-(R)-1 (er 97:3) with Br2 at
)100 ꢁC in the presence of pyridine followed by the
addition of enantiomerically pure diol (S)-6 gave, after
gradual warm-up of the mixture to 0 ꢁC and aqueous
work-up, silyl ethers (R,S)-7 and (S,S)-8 in diastereo-
meric ratios (dr) of 80:20 to 93:7, depending on the
solvent used. In CH2Cl2, the formation of the silylether
from the intermediary bromosilane proceeded rather
rapidly even at )60 ꢁC, while the same transformation
proceeded more slowly, but with higher selectivity, even
when it was warmed to 0 ꢁC, when Et2O was used as the
solvent. The overall reaction, with retention of the
configuration in the first and inversion of configuration
in the second step, proceeded with 82–96% overall ste-
reoselectivity. The loss of stereochemical information
during the process was probably due to partial racemi-
zation of the bromosilane in the presence of Brꢀ that is
formed during the bromination and subsequent substi-
tution steps rather than to a nonselective substitution
reaction itself.
4. Experimental
4.1. General
Unless otherwise stated: manipulations were carried out
under Ar in oven-dried glass equipment. For reactions,
Et2O was freshly distilled from Na with benzophenone
ketyl as indicator; CH2Cl2 was freshly distilled from
CaH2; benzene (Anal. Grade) was stored over Na. All
organic solvents were distilled prior to use. Extracts
were washed with satd aq NH4Cl solution and brine and
dried over MgSO4. Solutions for work-up procedures
were prepared in deionized H2O. Chromatography:
Merck silica gel 60 (40–63 lm). Mp: Mettler FP5/FP52.
IR spectra: neat liquid films between NaCl plates; Per-
kin–Elmer 297 or 781; in cmꢀ1, strong bands only. H
1
NMR spectra in CDCl3; Bruker ARX-300 (300 MHz); d
in ppm relative to CHCl3 (d 7.26), J in Hz. 13C NMR
spectra in CDCl3; Bruker ARX-300 (75.5 MHz); d in
ppm relative to CDCl3 (d 77.0); multiplicities from
DEPT-135 and DEPT-90 experiments. Mass spectro-
metry (MS): Finnigan SSQ 700; chemical ionization (CI)
with NH3 as the reactant gas; quasi-molecular ions and
characteristic fragments; in m=z (rel.%).
3. Conclusion
4.2. (SiR,1S)- and (SiS,1S)-2-{[[(Benzyloxy)methyl](tert-
butyl)methylsilyl]oxy}-1-phenylethanol (R,S)-7 and (S,S)-
8 and resolution
We have shown herein that ‘Si-centered’ chiral silicon
group A can be prepared in the form of hydrosilanes
())-(R)- and (+)-(S)-1 in highly enantiomerically
enriched forms. Transformation into differently func-
tionalized silanes can be effected with moderate to high
stereoselectivity, too, depending on the reaction condi-
tions used. Direct substitution of the hydrosilane by
treatment with a nucleophile seems to be advantageous
over a stepwise procedure, where racemization of the
intermediary species is possible.
Et3N (1.27 mL, 9.1 mmol), DMAP (0.1 g, 0.8 mmol),
and (S)-1-phenylethane-1,2-diol (S)-6 (1.08 g, 7.8 mmol)
were added at 0 ꢁC successively to a stirred solution of
rac-[(benzyloxy)methyl](tert-butyl)chloro(methyl)silane
( )-5 (2.00 g, 7.8 mmol) in CH2Cl2 (30 mL). The mixture
was warmed to 23 ꢁC and stirred for an additional 3 h. It
was quenched with satd aq NH4Cl solution, extracted
with Et2O, and chromatographed (hexane/Et2O 3:1) to

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M. Trzoss et al. / Tetrahedron: Asymmetry 15 (2004) 1501–1505
provide silylethers (R,S)-7 (1.21 g, 3.4 mmol) and (S,S)-8
(1.22 g, 3.4 mmol) in 87% overall yield.
NaHCO3 solution, extraction with Et2O, and chroma-
tography (hexane/Et2O 3:1) provided acylsilane (+)-(S)-
2 {202 mg, 0.76 mmol, 85%; ½aꢁ ¼ )8.7 (c 0.57, CHCl3),
23
D
95:5 er}, which was spectroscopically identical with ( )-
23
(R,S)-7: ½aꢁ ¼ 42.4 (c 1.23, CHCl3, 100:0 er). IR: 3440
D
br, 2930, 2860, 1100 br, 1070, 700. H NMR: 7.31–7.18
1
2 reported earlier.1 The er of the product was deter-
1
(m, 10 arom H); 4.75–4.71 (m, CHOH); 4.46 (s, PhCH2);
3.85 (d, J ¼ 1:9, OH); 3.81 (dd, J1 ¼ 10:5, J2 ¼ 3:1,
SiOCHH); 3.56 (dd, J1 ¼ 10:5, J2 ¼ 9:0, SiOCHH); 3.25,
3.15 (AB, J ¼ 13:1, SiCH2); 0.87 (s, t-Bu); 0.10 (s,
SiMe). 13C NMR: 140.4, 138.0 (2s, 2 arom C); 128.3,
128.1, 127.9, 127.6 (4d, 4 · 2 arom C); 127.5, 126.2 (2d, 2
arom C); 77.2 (t, PhC2); 74.5 (d, CHOH); 70.2 (t, SiO-
CH2); 60.2 (t, SiCH2); 25.9 (q, CMe3); 18.1 (s, CMe3);
)8.1 (q, SiMe). CI-MS: 376 (100, [M+NH4]þ); 358 (57,
[M+NH4–H2O]þ).
mined by means of H NMR spectroscopy performed
with the Mosher ester derivatives of the separated dia-
stereomeric reduction products of (+)-(S)-2 as reported
earlier.4
4.5. (SiR,1S)-2-{[[(Benzyloxy)methyl](tert-butyl)methyl-
silyl]oxy}-1-phenylethanol (S,S)-8 from ())-(R)-1
A solution of Br2 (0.74 mmol) in Et2O (1 mL) was added
dropwise at )100 ꢁC to a stirred solution of hydrosilane
())-(R)-1 (150 mg, 0.67 mmol) and pyridine (107 mg,
1.34 mmol) in Et2O (10 mL). After 30 min, (S)-1-phen-
ylethane-1,2-diol (S)-6 (121 mg, 0.88 mmol) was added
at )100 ꢁC and stirring was continued for an additional
2 h while the mixture was allowed to warm to )60 ꢁC.
Over a period of 4 h, the temperature was allowed to
reach 0 ꢁC and stirring continued at this temperature for
an additional 3 h. Addition of satd aq NH4Cl solution,
extraction with Et2O, and chromatography (hexane/
Et2O 3:1) provided silylether (S,S)-8 (180 mg,
0.51 mmol) together with (R,S)-7 and (14 mg,
0.04 mmol) corresponding to 82% overall yield and a dr
23
(S,S)-8: ½aꢁ ¼ +26.3 (c 1.32, CHCl3, 100:0 er). IR: 3440
D
br, 2930, 2860, 1100 br, 1070, 700. H NMR: 7.31–7.17
1
(m, 10 arom H); 4.73–4.68 (m, CHOH); 4.47, 4.43 (AB,
J ¼ 12:1, PhCH2); 3.85 (dd, J1 ¼ 10:4, J2 ¼ 3:2,
SiOCHH); 3.61 (dd, J1 ¼ 10:4, J2 ¼ 8:2, SiOCHH); 3.45
(d, J ¼ 3:0, OH); 3.27, 3.15 (AB, J ¼ 13:4, SiCH2); 0.87
(s, t-Bu); 0.09 (s, SiMe). 13C NMR: 140.6, 138.2 (2s, 2
arom C); 128.3, 128.2, 127.8, 127.6 (4d, 4 · 2 arom C);
127.5, 126.2 (2d, 2 arom C); 77.3 (t, PhC2); 74.4 (d,
CHOH); 69.7 (t, SiOCH2); 60.2 (t, SiCH2); 26.1 (q,
CMe3); 18.2, (s, CMe3); )7.8 (q, SiMe). CI-MS: 376
(100, [M+NH4]þ); 358 (55, [M+NH4)H2O]þ).
1
of 93:7 (determined by H NMR spectroscopy on the
crude product).
4.3. (R)- and (S)-[(Benzyloxy)methyl](tert-butyl)meth-
ylsilane ())-(R)-1 and (+)-(S)-1
A solution of the silylether (S,S)-8 (500 mg, 1.39 mmol)
in Et2O (1 mL) was added at )60 ꢁC to a stirred sus-
pension of LiAlH4 (53 mg, 1.39 mmol) in Et2O (20 mL).
The mixture was warmed to )30 ꢁC and, after stirring
for an additional 2 h, 5% aq H2SO4 solution was added
to neutral pH. This was extracted with Et2O and chro-
Acknowledgements
We would like to thank the Swiss National Science
Foundation for their generous financial support and the
Chinese Scholarship Counsel for the fellowship to S.J.
matographed (hexane/Et2O 3:1) to afford hydrosilane
23
D
CHCl3), 97:3 er} and diol (S)-6 (177 mg, 1.28 mmol,
())-(R)-1 {291 mg, 1.31 mmol, 94%; ½aꢁ ¼ )6.5 (c 1.10,
References and notes
92%). Analogously, (+)-(S)-1 was obtained from (R,S)-7
23
D
in 94% yield {½aꢁ ¼ +6.5 (c 1.10, CHCl3), 97:3 er}. The
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chiroptical properties, were identical to those of ( )-1
1
reported earlier;1 the er were determined by H NMR
spectroscopy in presence of the Pirkle reagent.11
€
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€
4.4. (S)-1-{[(Benzyloxy)methyl](tert-butyl)methyl-
silyl}ethanone (+)-(S)-2 from ())-(R)-1
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A solution of freshly prepared 1-ethoxyvinyllithium
(3.15 mmol) in THF (8 mL) was slowly added at )100 ꢁC
to a stirred solution of hydrosilane ())-(R)-1 (200 mg,
0.90 mmol) in THF (10 mL). The mixture was allowed to
warm to )60 ꢁC and stirred at this temperature for an
additional 5 h before it was quenched by the addition of
satd aq NH4Cl solution. After extraction with Et2O, the
crude product was dissolved in acetone (5 mL), after
which 10% aq HCl solution (0.5 mL) was added and
stirred for 1 h at 23 ꢁC. Neutralization with satd aq

M. Trzoss et al. / Tetrahedron: Asymmetry 15 (2004) 1501–1505
1505
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