Enantioselective synthesis of silanol

Article abstract of DOI:10.1021/ja805848z

An enantioselective nucleophilic substitution reaction of achiral dialkoxysilane has been developed. The reaction proceeds with efficient stereocontrol on the silicon chirality center to give the enantioenriched silyl ether, which can be converted to the

Full text of DOI:10.1021/ja805848z

Published on Web 11/11/2008
Enantioselective Synthesis of Silanol
Kazunobu Igawa,† Junko Takada,‡ Tomohiro Shimono,‡ and Katsuhiko Tomooka*,†,‡
Institute for Materials Chemistry and Engineering, Kyushu UniVersity, Kasuga, Fukuoka 816-8580, Japan, and
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology,
Meguro-ku, Tokyo 152-8552, Japan
Received July 25, 2008; E-mail: ktomooka@cm.kyushu-u.ac.jp
Nonracemic organosilicon compounds that possess the central
chirality on silicon are attractive and potentially useful unnatural chiral
molecules.1-5 Among the variety of organosilanes, silanol A is one
of the most promising compounds as a sila-chiral building block,
similar to carbinol in chiral carbon chemistry, but so far its asymmetric
synthesis had been almost unexplored.6 The lack of their efficient
stereoselective synthesis can be attributed to the unavailability of
silaketone B, which could be envisioned as a prochiral precursor in
analogy with the asymmetric synthesis of carbinols using ketones. The
development of a useful desymmetrization reaction of the readily
available symmetrical tetragonal silicon compounds seems a promising
approach to synthesis of the desired silanols. Our recent contribution
to this area has been the development of a chiral auxiliary-induced
aryl migration reaction of symmetrical diarylsilyl compound C wherein
one of the two aryl groups can be asymmetrically substituted by
suitable alkoxy groups in a highly diastereoselective manner, leading
to enantioenriched silanols A.7 To develop a more versatile stereose-
lective approach, we then focused on the desymmetrization of
dialkoxysilane D. Herein, we wish to report the asymmetric nucleo-
philic substitution reaction of symmetrical dialkoxysilane D that
proceeds with efficient stereocontrol of the chirality center on silicon
in the presence of a chiral coordinating agent to give the enantioen-
riched silyl ether, which could be converted to silanol A without loss
of enantiopurity.
almost quantitative yield (Table 1, entry 1).10,11 Moreover, (R)-2a was
successfully converted to silanol (R)-5a via Birch reduction without
loss of enantiopurity.12 This represents the first example of the
enantioselective synthesis of a silanol, albeit the enantiopurity is
moderate.
Table 1. Enantioselective Substitution Reaction of Dialkoxysilane 1a
2 yield
(%)c
5 yield
(%)c
entry
1
R1
R2
R3
ee (%)d, e
1f 1a Ph t-Bu
n-Bu 2a
n-Bu 2a
n-Bu 2a
99
96
86
99
86
94
92
48 (R) (-)-(R)-5a
55 (R) (-)-(R)-5a
53 (R) (-)-(R)-5a
21 (R) (+)-(R)-5b
66 (R) (+)-(R)-5b
76 (S) (+)-(S)-5c
84 (S) (+)-(S)-5c
93
93
93
99
99
83
83
2
1a Ph t-Bu
3g 1a Ph t-Bu
4f 1a Ph t-Bu
Me
t-Bu 2b
1c Me c-Hex t-Bu 2c
2b
6
7
1b Me Ph
8h 1c Me c-Hex t-Bu 2c
a Unless otherwise specified, the reactions were performed using 3.0
equiv of R3Li/(S,S)-6 in hexane at -78 °C. b Reactions were performed
in NH3-THF at -78 °C. c Isolated yield. d Determined via chiral HPLC
analysis. e Absolute configurations were determined by derivatization to
known compounds. f Reactions were performed in Et2O at -78 °C.
g Reaction was performed with 3.0 equiv of n-BuLi and 10 mol% of
(S,S)-6 in hexane at -40 °C. h Reaction was performed in hexane at
-90 °C.
Because of the limitation of the available atlas of sila-stereochem-
istry, we developed a unique reaction sequence to determine the
absolute configuration of 5. Silanol (+)-5a obtained in the reaction in
Table 1 was converted to 4a, and its sign of optical rotation was
identical to that of (R)-4a; the authentic sample of (R)-4a was prepared
from the previously synthesized silanol (S)-7 via a four-step transfor-
mation including (i) methyl etherification, (ii) retro [1,4]-Brook
rearrangement,13 (iii) Wittig olefination, and (iv) hydrogenation, as
shown in Scheme 1.14
A similar enantioselective substitution reaction performed in hexane
gave (R)-2a with a considerably higher enantiopurity (55% ee) (entry
2). Significantly enough, a reaction in hexane without (S,S)-6 gave no
silane 2a at all, and 1a was recovered quantitatively. These results
indicated the feasibility that the enantioselective substitution reaction
could proceed even in a catalytic fashion in terms of (S,S)-6. As
At the outset, we examined the reaction of a variety of dialkoxysi-
lanes with n-BuLi under achiral conditions and found that seven-
membered cyclic silane 1 is a suitable substrate for this approach. For
example, the reaction of n-BuLi (3 equiv) with silane 1a, prepared
from Pht-BuSiCl2 and 1,2-di(hydroxymethyl)benzene, in THF at -78
to -40 °C provided the desired silane (()-2a as a sole product in
93% yield. In sharp contrast, acyclic silanes 3a and 3b gave poor results
under similar conditions (3af4a: 19%, 3bf4b: trace).8
Scheme 1. Synthesis of an Authentic Sample of (R)-4aa
Based on this result, we examined an enantioselective variant using
bisoxazoline (S,S)-69 (3 equiv) as a chiral coordinating agent in Et2O
and afforded silyl ether 2a in enantioenriched form [48% ee, (R)] in
a Reagents and conditions: (a) MeI, KH, DMF, 0 °C, 94%; (b) t-BuLi,
HMPA, THF, -78 °C, 40%; (c) CH3PPh3Br, n-BuLi, THF, 0 °C, 55%; (d)
H2, Pd-C, EtOH, rt, 82%; (e) MeI, KH, DMF, 0 °C, 93%.
† Kyushu University.
‡ Tokyo Institute of Technology.
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10.1021/ja805848z CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
anticipated, the reaction of 1a with 10 mol% of (S,S)-6 and 3 equiv of
n-BuLi provided silanol (R)-2a with an equal level of enantioselectivity
and chemical yield (53% ee, 86%) (entry 3). The developed approach
has been applied to a variety of silanols. As shown in Table 1, a similar
reaction of dialkoxysilanes 1a-c with various types R3Li provided
corresponding silanols in enantioenriched form.15,16 Especially, the
reaction of 1c with t-BuLi provided 2c with a relatively high
enantioselectivity (84% ee, 92%) (entry 8). In these reactions using
(S,S)-6, the bulkier substituents on silane 1 were positioned at R2 on
the major enantiomer of silyl ether 2.
Supporting Information Available: Experimental procedures and
spectral data. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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To clarify the steric course of the present substitution reaction, we
conducted the computational analysis of the reaction of simplified silane
1d (R1, R2 ) Me) with MeLi by using DFT calculations.17,18 The
result of the DFT calculations revealed that the feasible reaction
pathway is a retention process involving apical attack and apical
departure (Figure 1). In the first step, a complex i, which is composed
of MeLi and 1d, engages in the C-Si bond formation via transition
state ii (+8.5 kcal mol-1) wherein the methyl anion and O2 are in the
apical positions of the trigonal bipyramidal structure; thus, a five-
coordinated silicate iii is formed. In the second step, iii converts to
product v over an energy barrier (transition state iv: +10.7 kcal mol-1
)
accompanied by a pseudorotation and elimination of the lithium
coordinating oxygen (O1) from an apical position.
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Tacke, R. Organometallics 2003, 22, 4343.
Figure 1. Potential energy surface for nucleophilic substitution reaction
of cyclic silane 1d (R1, R2 ) Me) and MeLi. Relative zero-point energies
(∆E0) were calculated at the B3LYP/6-311+G(d) level of theory.
(7) (a) Tomooka, K.; Nakazaki, A.; Nakai, T. J. Am. Chem. Soc. 2000, 122,
408. (b) Nakazaki, A.; Usuki, J.; Tomooka, K. Synlett 2008, 2064.
(8) Corriu, R.; Boyer, J.; Perz, R. C. R. Acad. Sci. 1988, 307, 1351.
(9) For representative reports on asymmetric reactions using 6 with organo-
lithium reagent: (a) Denmark, S. E.; Nakajima, N.; Nicaise, O. J.-C. J. Am.
Chem. Soc. 1994, 116, 8797. (b) Hodgson, D. M.; Lee, G. P. Tetrahedron:
Asymmetry 1997, 8, 2303. (c) Tomooka, K.; Komine, N.; Nakai, T.
Tetrahedron Lett. 1998, 39, 5513. (d) Tomooka, K.; Yamamoto, K.; Nakai,
T. Angew. Chem., Int. Ed. 1999, 38, 3741.
To gain the insight into the enantioselectivity, we calculated the
transition structures of the first nucleophilic attack step in the reaction
of dialkoxysilane 1a with the MeLi-(S,S)-6 complex and obtained the
lowest energy geometries vi and vii for (R)-2b and (S)-2b, respec-
tively.18,19 The calculated energy of vi is lower than that of vii (∆E )
2.5 kcal/mol), which is in good agreement with the experimentally
observed enantioselectivity. The disadvantage of transition structure
vii is due to the severe steric repulsion between the i-Pr group of (S,S)-6
and t-Bu group of 1a.
(10) Silyl ether 2a was obtained in racemic form when reaction was performed
in THF.
(11) Similar reactions using (-)-sparteine or other chiral bisoxazolines, which
have Me, i-Bu, or t-Bu substituents at N-R-positions on oxazoline rings,
gave 2a in 2%-39% ee.
(12) Silanol 5 is stereochemically stable under standard operation. In sharp
contrast, Tacke and colleagues have reported a rapid racemization of
enantioenriched silanol having ꢀ-amino functionality. The stereochemical
instability of Tacke’s silanol can be attributed to an intramolecular
coordination of the amino group to the silicon; see ref 6b.
(13) Nakazaki, A.; Nakai, T.; Tomooka, K. Angew. Chem., Int. Ed. 2006, 45,
2235.
(14) Absolute stereochemistries of 7 and 9 were determined by X-ray analysis;
see refs 7 and 13.
(15) Absolute stereochemistry of (+)-5b was determined as the R form by
derivatization of 2b to reported hydrosilane: Jankowski, P.; Schaumann,
E.; Wicha, J.; Zarecki, A.; Adiwidjaja, G. Tetrahedron: Asymmetry 1999,
10, 519; see Supporting Information.
(16) Absolute stereochemistry of (+)-5c was determined as the S form via
preparation of authentic sample of (S)-5c from (R)-5b; see Supporting
Information.
(17) Fundamental theoretical study of nucleophilic substitution at silicon was
reported by Holmes et al. : (a) Deiters, J. A.; Holmes, R. R. J. Am. Chem.
Soc. 1987, 109, 1686. (b) Deiters, J. A.; Holmes, R. R. J. Am. Chem. Soc.
1987, 109, 1692.
(18) All calculations were performed with Gaussian 03 on a TSUBAME system
at Tokyo Institute of Technology; see Supporting Information for details.
(19) The calculations were performed at the B3LYP/6-311+G(d)//HF/3-21G
level of theory.
We have described the first example of an enantioselective synthesis
of silanol. The produced enantioenriched silanols can be used as a
sila-chiral building block for various chiral organosilicon compounds.
Thus, this work opens a new chapter for chiral organosilicon chemistry.
Further work and study for the utilization of enantioenriched silanols
is underway.
Acknowledgment. This research was supported in part by a
Grant-in-Aid for Scientific Research (B) No. 19350019 and Global
COE Program (Kyushu Univ.) from MEXT, Japan.
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