Optically pure α-(trimethylsilyl)benzyl alcohol: A practical chiral auxiliary for oxocarbenium ion reactions

Article abstract of DOI:10.1021/ol017063m

(matrix presented) Enantiopure (S)-α-(trimethylsilyl)benzyl alcohol (98% ee) was prepared by Noyori's transfer hydrogenation of benzoyltrimethylsilane. The corresponding trimethylsilyl ether was subjected to Marko's silyl modified Sakurai conditions with

Full text of DOI:10.1021/ol017063m

ORGANIC
LETTERS
2002
Vol. 4, No. 1
147-150
Optically Pure r-(Trimethylsilyl)benzyl
Alcohol: A Practical Chiral Auxiliary for
Oxocarbenium Ion Reactions
Jennifer Cossrow and Scott D. Rychnovsky*
Department of Chemistry, 516 Rowland Hall, UniVersity of California, IrVine,
California 92697-2025
srychnoV@uci.edu
Received November 17, 2001
ABSTRACT
Enantiopure (S)-r-(trimethylsilyl)benzyl alcohol (98% ee) was prepared by Noyori’s transfer hydrogenation of benzoyltrimethylsilane. The
corresponding trimethylsilyl ether was subjected to Marko’s silyl modified Sakurai conditions with a variety of aldehydes to afford homoallylic
ethers in high diastereoselectivity. The practicality of the r-trimethylsilyl benzyl group as an oxocarbenium ion auxiliary was further demonstrated
by its efficient deprotection or conversion to a benzyl protecting group.
The synthetic utility of reactions involving oxocarbenium
ion intermediates has prompted several groups to develop
chiral auxiliaries that exert high diastereofacial selectivity.
Various approaches include additions of nucleophiles to
chiral acetals,1 norpseudoephedrine substituted intermedi-
ates,2 and in situ generated oxocarbenium ions.3,1e A number
of these methods require multistep or harsh deprotection
conditions.1,3 We set out to develop a practical and general
chiral auxiliary for oxocarbenium ion reactions. An ideal
chiral auxiliary would fulfill several requirements: both
enantiomers would be readily accessible, it would be easily
incorporated into oxocarbenium ion intermediates, and it
would promote the addition of various nucleophiles to one
diastereotopic face of the oxocarbenium ion. Additionally,
the auxiliary should be easily removed from the ether
products to afford alcohols of high enantiopurity. We now
report an efficient synthesis of an optically pure R-silyl
alcohol and demonstrate its utility as an oxocarbenium ion
auxiliary.
(1) (a) Johnson, W. S.; Harbert, C. A.; Ratcliffe, B. E.; Stipanovic, R.
D. J. Am. Chem. Soc. 1976, 98, 6188-6193. (b) Johnson, W. S.; Elliot, J.
D.; Hanson, G. J. J. Am. Chem. Soc. 1984, 106, 1138-1139. (c) Bartlett,
P. A.; Johnson, W. S.; Elliot, J. D. J. Am. Chem. Soc. 1983, 105, 2088-
2089. (d) Andrus, M. B.; Lepore, S. D. Tetrahedron Lett. 1995, 36, 9149-
9152. (e) Manju, K.; Trehan, S. Chem. Commun. 1999, 1929-1930. (f)
For a review of chiral acetals, see: Alexakis, A.; Mangeney, P. Tetrahe-
dron: Asymmetry 1990, 1, 477-511.
(2) (a) Tietze, L. F.; Dolle, A.; Schiemann, K. Angew. Chem., Int. Ed.
Engl. 1992, 31, 1372-1373. (b) Tietze, L. F.; Schiemann, K.; Wegner, C.
J. Am. Chem. Soc. 1995, 117, 5851-5852. (c) Tietze, L. F.; Schiemann,
K.; Wegner, C.; Wulff, C. Chem. Eur. J. 1996, 2, 1164-1172. (d) Tietze,
L. F.; Volkel, L.; Wulff, C.; Weigand, B.; Bittner, C.; McGrath, P.; Johnson,
K.; Schafer, M. Chem. Eur. J. 2001, 7, 1304.
Development of this chiral auxiliary finds precedent in
Linderman’s work with R-silyl and R-stannyl mixed acetals.4
Linderman demonstrated that additions of nucleophiles to
mixed acetals such as 1 proceeded with high diastereose-
lectivity (Scheme 1). The selectivity was rationalized by
(3) (a) Imwinkelried, R.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1985,
24, 765-766. (b) Mukaiyama, T.; Ohshima, M.; Miyoshi, N. Chem. Lett.
1987, 1121-1124. (c) Mekhalfia, A.; Marko, I. E. Tetrahedron Lett. 1991,
32, 4779-4782. (d) Molander, G. A.; Haar, J. P. J. Am. Chem. Soc. 1993,
115, 40-49.
(4) (a) Linderman, R. J.; Anklekar, T. V. J. Org. Chem. 1992, 57, 5078-
5080. (b) Linderman, R. J.; Chen, K. J. Org. Chem. 1996, 61, 2441-2453.
(c) Linderman, R. J.; Chen, S. Tetrahedron Lett. 1995, 43, 7799-7802. (d)
Linderman, R. J.; Chen, S. Tetrahedron Lett. 1996, 37, 3819-3822.
10.1021/ol017063m CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/14/2001

reduce a number of acylsilanes with high enantioselectivity,8
reduction of 7 with (+)-DIP-Cl afforded the corresponding
alcohol in only 23% ee. Reduction with CBS catalyst
provided the alcohol of only 9% ee, but stoichiometric CBS
reduction was much more selective and gave 9 with 80%
ee.9 As shown in Table 1, a practical enantioselective
Scheme 1. Diastereoselectivity in Linderman’s Addition of
Nucleophiles to R-Silyl Mixed Acetals
Table 1. Noyori’s Transfer Hydrogenation of
Benzoyltrimethylsilane 7
invoking an (E)-oxocarbenium ion intermediate 4, which
adopts a well-defined conformation as the result of a
stereoelectronic preference analogous to the â-silyl effect.5
Linderman proposed that the R-silyl oxocarbenium ion adopts
a conformation that provides maximum overlap of σ C-Si
and π* CdO of the oxocarbenium ion.4 The nucleophile then
adds to the face opposite to the bulky silyl group, resulting
in the observed diastereoselectivity. Linderman’s mixed
acetals were prepared by alkylation of the racemic R-silyl
alcohols with R-chloro ethers, providing a narrow range of
ether products. Optically pure substrates were not investi-
gated. Linderman’s diastereoselective oxocarbenium ion
additions laid the groundwork for our investigation.
reaction
time (h)
yield
(%)
eea
entry
mol % 8
(%)
1
2
3
4
5
6
4
2
1
0.5
0.5
0.2
0.75
1.3
2.4
4.3
3.4
22
94
80
76
82
91
45b
95
96.5
96
95
98
95.6
a The ee’s were determined by HPLC analysis on a Chiracel OD-H
column. b The starting ketone 7 was recovered in 29% yield.
We hoped to access the optically active R-trimethylsilyl
benzyl alcohol6 by an enantioselective reduction of the
corresponding acyl silane. Following Olah’s procedure, free
radical bromination of commercially available benzyltrim-
ethylsilane 5, followed by treatment of the unpurified
dibromide 6 with silver acetate afforded the desired ben-
zoyltrimethylsilane 7 in multigram quantities (Scheme 2).7
reduction of 7 was achieved using Noyori’s asymmetric
transfer hydrogenation conditions with chiral Ru catalyst 8.10
The enantioselective reductions were carried out with 1
M solutions of benzoyltrimethylsilane in 2-propanol, and the
details are recorded in Table 1. Variation of the catalyst
loading provided the alcohol in good yields and high optical
purity (95-98% ee, entries 1-5). Optimal conditions utilized
0.5 mol % of the catalyst and provided the alcohol in 91%
yield and 98% ee (entry 5).11 A lower catalyst loading and
longer reaction time afforded the alcohol in good enanti-
oselectivity but poor yield, with significant recovery of the
starting ketone (entry 6). The absolute configuration was
Scheme 2. Synthesis of Benzoyltrimethylsilane 7
(8) (a) Buynak, J. D.; Strickland, J. B.; Lamb, G. W.; Khasnis, D.; Modi,
S.; Williams, D.; Zhang, H. M. J. Org. Chem. 1991, 56, 7076-7083. (b)
Soderquist, J. A.; Anderson, C. L.; Miranda, E. I.; Rivera, I. Tetrahedron
Lett. 1990, 31, 4677-4680.
(9) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J.
Am. Chem. Soc. 1987, 109, 7925-7926.
(10) (a) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738-8739. (b) Haack, K.-J.; Hashiguchi, S.; Fujii,
A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285-
288. (c) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97-102.
(11) Alcohol 9. To a 21 °C solution of benzoyltrimethylsilane (8.84 g,
49.6 mmol, 1.0 equiv) in 49.6 mL 2-propanol was added catalyst (S,S)-8
(149 mg, 0.25 mmol, 0.005 equiv). After stirring for 3.4 h at 21 °C, the
reaction mixture was filtered through a short plug of silica gel, which was
washed with Et2O (80 mL). Concentration in vacuo provided a crude oil
that was purified by flash column chromatography (2-5-10% diethyl ether/
With the requisite acyl silane in hand, several enantioselective
reductions were screened. While DIP-Cl was reported to
(5) For a review of the â-silyl effect, see: Lambert, J. B. Tetrahedron
1990, 46, 2677-2689.
(6) (a) Mosher, H. S.; Biernbaum, M. S. J. Org. Chem. 1971, 36, 3168-
3177. (b) Tsai, D. J. S.; Matteson, D. S. Organometallics 1983, 2, 236-
241. (c) Linderman, R. J.; Ghannam, A.; Badejo, I. J. Org. Chem. 1991,
56, 5213-5216. (d) Yamazaki, Y.; Kobayashi, H. Chem. Express 1993, 8,
97-100. (e) Takeda, K.; Ohnishi, Y.; Koizumi, T. Org. Lett. 1999, 1, 237-
239. (f) Patrocinio, A. F.; Correa, I. R., Jr.; Moran, P. J. S. J. Chem. Soc.,
Perkin Trans. 1 1999, 3133-3137. (g) Zani, P. J. Mol. Catal. B: Enzym.
2001, 11, 279-285.
hexanes) to afford the title alcohol (8.12 g, 91%) as a white solid: [R]23
D
-109.2 (c 1.00, CHCl3); mp 28-30 °C; IR (KBr) 3423, 2957, 1248, 998,
841 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.32-7.29 (m, 2 H), 7.20-7.17
(m, 3 H), 4.53 (s, 1 H), 1.67 (d, J ) 2.4 Hz, 1 H), 0.01 (s, 9 H); 13C NMR
(125 MHz, CDCl3) δ 144.2, 128.1, 125.8, 124.9, 70.6, -4.1; HRMS (EI)
m/z calcd for C10H15OSi (M - H)+ 179.0892, found 179.0888. Anal. Calcd
for C10H16OSi: C, 66.61; H, 8.94. Found: C, 66.89; H, 8.93.
(7) Olah, G. A.; Berrier, A. L.; Field, L. D.; Prakash, G. K. S. J. Am.
Chem. Soc. 1982, 104, 1349-1355.
148
Org. Lett., Vol. 4, No. 1, 2002

Table 2. Diastereoselective Additions of Allyltrimethylsilane to Oxocarbenium Ions Generated in Situ
entry
R
solvent
yielda (%)
diastereo ratio
abs configb
1
2
3
4
5
6
7
8
9
C6H11
(CH2)2-C6H5
(CH2)4CH3
(a )
(b)
(c)
(d )
(e)
(e)
(f)
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
CH2Cl2
PhCH3
PhCH3
CH2Cl2
87
75
86
83
69
72
96
69
75
97:3c
95:5d
97:3c
97:3c
95:5d
95:5d
91:9c
86:14c
86:14c
Se
Re
Re
CH(CH3)2
(CH2)2OTBDPS
(CH2)2OTBDPS
C6H5
CHdCH-C6H5
CHdCH-C6H5
Sf
(g)
(g)
a Yield of purified product. b Absolute configuration of newly formed stereocenter. c Based on GC analysis of unpurified product. d Based on H NMR
analysis of purified product. e Determined by deprotection (Na/NH3) and comparison to literature rotation of the known alcohol (details in Supporting
Information.) f Determined by comparison of the rotation of the corresponding benzyl ether to an authentic sample (details in Supporting Information.)
1
determined to be S on the basis of advanced Mosher’s ester
analysis12 and by comparison of the sign of the rotation to
literature values.6 The R enantiomer would be available using
the enantiomeric catalyst. Thus, gram quantities of crystal-
line,13 enantiopure alcohol 9 were accessed by an efficient
synthesis in three steps from commercially available material.
Marko’s in situ allylation reaction was used to evaluate
the utility of the chiral auxiliary.3c Silyl ether 10 was prepared
in 81-91% yield by treatment of alcohol 9 (98% ee) with
catalytic saccharin and HMDS.14 Marko’s conditions in-
volved the treatment of a silyl ether, in our case compound
10, with an aldehyde and catalytic TMSOTf to generate an
oxocarbenium ion intermediate in situ. The allylsilane adds
to the oxocarbenium ion to afford homoallylic ether 12 (Table
2). Homoallylic ethers 12a-e, derived from aliphatic alde-
hydes, were obtained in good yields with diastereoselectivi-
ties ranging from 95:5 to 97:3 (entries 1-6). Ether 12f,
derived from benzaldehyde, was accessed in excellent yield
but slightly lower diastereoselectivity (entry 7). The lowest
diastereoselectivity was observed from allylation of the
oxocarbenium ion derived from trans-cinnamaldehyde (en-
tries 8 and 9). In both toluene and dichloromethane, ether
12g was obtained in good yield but only 6:1 diastereoselec-
tivity. In four cases, the configurations of the newly formed
stereogenic centers were assigned by deprotection and
comparison of the optical rotations with known compounds.15
In each case the configuration of the product was that
predicted by Linderman’s model.4 These results demonstrate
that the R-(trimethylsilyl)benzyl alcohol auxiliary leads to
high levels of diastereoselectivity, particularly when used
with alkyl oxocarbenium ions.
With an efficient synthesis and the demonstration of the
auxiliary’s utility in a sample reaction, we turned to the
investigation of deprotection strategies. Conversion of the
auxiliary to the widely used benzyl protecting group was
achieved by treatment of ethers 12 with TBAF at room
temperature. For example, ether 12a was converted to the
corresponding benzyl ether 13a in 97% yield (Scheme 3).
Scheme 3. Deprotection Strategies
The other aliphatic ethers 12b-e were also transformed to
the corresponding benzyl ethers in good to excellent yields.15
However, lower yields were observed for the unsaturated
derivatives 12f and 12g (vide infra). A one-step deprotection
was also realized by treatment of 12b with sodium in
ammonia; the corresponding homoallylic alcohol 14b was
obtained in 80% yield.16 Both direct deprotection and
conversion of the auxiliary-derived ethers 12 to benzyl
protected ethers were achieved.
(12) (a) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543-2549. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092-4096.
(13) Optically pure 9 is a low melting, crystalline solid, whereas the
racemate is an oil. Alcohol 9 apparently crystallizes as a conglomerate,
which will facilitate the preparation of optically pure samples.
(14) Bruynes, C. A.; Jurriens, T. K. J. Org. Chem. 1982, 47, 3966-
3969.
(16) The Na/NH3 deprotection was less reliable than the TBAF depro-
tection, and the yields varied from substrate to substrate.
(15) See Supporting Information for details.
Org. Lett., Vol. 4, No. 1, 2002
149

The in situ allylation reaction provides a facile route to the
2,3-Wittig rearrangement precursor 12g.
Scheme 4. A 2,3-Wittig Rearrangement Product
In summary, optically pure R-trimethylsilyl benzyl alcohol
has been developed as a practical chiral auxiliary for
oxocarbenium ion reactions. The optically pure auxiliary was
prepared in three steps from commercially available ben-
zyltrimethylsilane in 75% overall yield. A key step was
Noyori’s transfer hydrogenation of benzoyltrimethylsilane
7 using Ru catalyst (S,S)-8. Further investigation to determine
the scope of this asymmetric reduction for generating
optically active R-silyl alcohols is underway. The auxiliary
was effective in directing allyltrimethylsilane to one dias-
tereotopic face of an oxocarbenium ion, generated in situ
according to Marko’s protocol. The absolute configuration
of the newly formed stereocenter was in accordance with
the predicted configuration based on Linderman’s model. The
TBAF-mediated conversion of the auxiliary to the syntheti-
cally useful benzyl protecting group was efficient for all alkyl
derivatives. Alcohol 9 has many of the features of an ideal
oxocarbenium ion chiral auxiliary. The scope and utility of
auxiliary 9 in other oxocarbenium ion reactions is under
investigation and will be reported in due course.
The TBAF reaction of the trans-cinnamyl product 12g was
anomalous. As shown in Scheme 4, treatment of 12g with
TBAF afforded only 35% of the desired benzyl alcohol 13g.
It was accompanied by alcohol 15, which was isolated in
47% yield as a 3:1 mixture of diastereomers. Compound 15
presumably arose from a 2,3-Wittig rearrangement that
occurs upon generation of the benzylic anion equivalent.
Maleczka recently reported a 2,3-Wittig rearrangement
product resulting from treatment of an R-trimethylsilyl benzyl
ether with cesium fluoride.17 Rearrangement product 15 was
also isolated in 41% yield as a >20:1 mixture of diastere-
omers when ether 12g was treated with sodium in ammonia.
The difference in diastereoselectivities with TBAF and Na/
NH3 conditions might arise from a deprotonation, 2,3-Wittig
rearrangement, and Brook rearrangement in the latter case,
but we have no direct evidence supporting this hypothesis.
Acknowledgment. The Petroleum Research Fund, ad-
ministered by the American Chemical Society, provided
financial support (37325-AC).
Supporting Information Available: Preparation and
characterization of the compounds described in the paper.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Maleczka, R. E.; Geng, F. Org. Lett. 1999, 1, 1111-1113.
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