Asymmetrie synthesis of chiral silacarboxylic acids and their ester derivatives

Article abstract of DOI:10.1002/anie.200904922

Sila analogues: The first asymmetric synthesis of silacarboxylic acids with a stereogenic center at the silicon atom has been achieved from chiral nonracemic silanols, without loss of optical purity. Silacarboxylic acids can be converted into their corresponding esters using a Mitsunobu-type reaction.

Full text of DOI:10.1002/anie.200904922

Communications
DOI: 10.1002/anie.200904922
Chiral Organosilanes
Asymmetric Synthesis of Chiral Silacarboxylic Acids and Their Ester
Derivatives**
Kazunobu Igawa, Naoto Kokan, and Katsuhiko Tomooka*
Chiral nonracemic carboxylic acids 1 with a stereogenic
center at the a position are a prolific structural motif in basic
life processes within organisms, and are important chiral
building blocks or asymmetric reagents in the field of organic
synthesis. Therefore, naturally occurring chiral carboxylic
acids, as well as numerous artificial derivatives, have been
synthesized and studied from a variety of viewpoints in
organic chemistry and bioorganic chemistry.[1] Accordingly,
their silyl analogues (2)[2] are highly attractive because of the
potential reactivity as well as the unique physical properties
of functional organosilanes. However, the asymmetric syn-
thesis of chiral organosilanes[3,4] has presented significant
challenges that have limited the development of viable
synthetic methods for 2.
prepared from chiral silanol 3 (Scheme 1). It is known that the
stereoselectivity of the reductive lithiation of chiral chloro-
silanes is significantly influenced by the steric demands of the
Scheme 1. Strategy for the asymmetric synthesis of chiral silacarboxylic
acid.
substituents around the silicon atom.[7,8] Therefore, the judi-
cious choice of substituents on the silicon atom was crucial for
attaining high stereospecificity over the series of transforma-
tions in our synthetic strategy.
Gratifyingly, we found that chiral silyllithium compounds
5a,b, derived from 3a,b, underwent smooth carboxylation
upon treatment with carbon dioxide to furnish 2a,b in a highly
stereospecific manner. We also found that the Mitsunobu-
type reactions of 2a,b with a variety of alcohols efficiently
provided novel silacarboxyesters. Herein, we report the
asymmetric synthesis of chiral silacarboxylic acids and their
derivatives from chiral silanols 3.
Our initial experiments focused on the stereoselective
direct chlorination of silanols (S)-3a (> 99% ee) and (S)-3b
(> 99% ee). Despite testing a variety of reagents for this
transformation, including thionyl chloride,[9] we were unable
to obtain the desired chlorosilanes 4a,b, even under harsh
conditions, which was possibly due to the severe steric
congestion around the silicon center in silanols 3a,b. We
then turned our attention to consider stepwise procedures,
including the radical-mediated chlorination of hydrosilanes
(Scheme 2). First, the methyl etherification and subsequent
LiAlH4 reduction of silanols (S)-3a and (S)-3b led to the
formation of the requisite hydrosilanes 7a (R = Me) and 7b
(R = nBu), respectively, whose enantiomeric excesses were
We recently reported the successful asymmetric synthesis
of chiral silanols 3 from the enantioselective nucleophilic
substitution reaction of cyclic dialkoxysilanes; this synthesis
involved an alkyllithium-mediated desymmetrization reac-
tion in the presence of a chiral coordinating agent.[5] The
remarkable efficiency of this method for enantiomerically
enriched silanols 3 prompted us to develop a synthetic route
to 2, starting from 3. We envisaged that chiral silacarboxylic
acids 2 could be obtained from the carboxylation[6] of chiral
silyllithium compounds 5, themselves generated by the
reductive lithiation of chiral chlorosilanes 4, which could be
[*] Dr. K. Igawa, Prof. Dr. K. Tomooka
Institute for Materials Chemistry and Engineering, Kyushu Univer-
sity
Kasuga, Fukuoka 816-8580 (Japan)
Fax: (+81)92-583-7810
E-mail: ktomooka@cm.kyushu-u.ac.jp
Homepage: http://www.cm.kyushu-u.ac.jp/tomooka
N. Kokan
Department of Applied Chemistry, Tokyo Institute of Technology
(Japan)
[**] 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). We thank Y. Tanaka, K. Ideta, and T.
Matsumoto (IMCE, Kyushu Univ.) for HRMS measurements, 29Si
NMR measurements, and single crystal X-ray diffraction analysis,
respectively.
Scheme 2. Preparation of nonracemic chiral chlorosilanes 4: a) MeI,
KH, DMF, RT; b) LiAlH4, Et2O, reflux; c) (PhCO2)2 (10 mol%), CCl4,
reflux. DMF=N,N-dimethylformamide.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904922.
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unambiguously determined to be > 99% using chiral HPLC
analysis. Although their absolute configurations are still to be
confirmed, we believe that these two-step reactions both
proceeded in a highly retentive fashion to give (R)-hydro-
silane products, as previously demonstrated in the reaction of
chiral methoxysilanes with LiAlH4 in acyclic ether.[10] Second,
optically pure 7a and 7b were chlorinated using modified
literature conditions[11] to afford chiral chlorosilanes 4a and
4b, respectively, which were reduced directly without iso-
lation to generate silyllithium compounds 5a,b.
which the carboxylic acid carbonyl moiety is electrophilically
activated, were unsuitable for the comparable condensation
of silacarboxylic acid 2c with a variety of alcohols.[20] For
example, Fischer esterification of achiral silacarboxylic acid
2c in methanol, in the presence of a catalytic amount of
sulfuric acid, gave a substantial amount of methyl ether 6c
(48%) in addition to the desired methyl ester 8b (38%;
Scheme 4). Moreover, DCC-mediated condensation of 2c
Reduction of crude 4a,b was performed by treatment
with excess lithium 1-(dimethylamino)naphthalenide
(LDMAN)[12,13] in tetrahydrofuran. After stirring at À788C
for 1 h, the mixture was bubbled with dried carbon dioxide
followed by acidification to afford silacarboxylic acids 2a and
2b, both of which gave negative values for their optical
rotation [Eq. (1)]. The enantiomeric excesses of 2a and 2b
Scheme 4. Methyl esterification of silacarboxylic acid 2c: a) cat.
=
H2SO4, MeOH, reflux; b) MeOH, DCC, cat. DMAP, CH2Cl2, RT. DCC
N,N’-dicyclohexylcarbodiimide, DMAP=4-(dimethylamino)pyridine.
with methanol afforded unexpected silacarboxylic acid silyl
ester 9 (56%)[21] in addition to 8b (6%) and 6c (15%).
Therefore, we tentatively conclude that an electrophilically
activated silacarbonyl intermediate bearing an electron-with-
drawing group (EWG) prefers decarbonylation to nucleo-
philic attack at the carbonyl carbon [Eq. (2); Nu = nucleo-
phile].
were successfully determined by chiral HPLC analysis to be
96% and > 98% ee, respectively.[14] These results demon-
strate that the sterically bulky substituents around the silicon
atom contribute to the high stereospecificity.
Novel chiral silacarboxylic acids 2a and 2b have com-
parable stereochemical stability to chiral carboxylic acids 1;
that is, nonracemic samples 2a and 2b showed no deterio-
ration of their optical purity after refrigeration for one year
(08C) under an argon atmosphere.[15] Moreover, the Mitsu-
nobu-type reaction of (S)-2a with 9-anthracene methanol
smoothly afforded crystalline ester 8a. Crystals suitable for
X-ray diffraction were obtained, which revealed the absolute
stereochemistry of 8a;[16,17] this result is significant consider-
ing the limited understanding of sila-stereochemistry
(Scheme 3).[18] Considering that the chlorination of chiral
hydrosilanes is known to be a retentive process,[11c] we
concluded that the reduction of 4 and subsequent carbox-
ylation may have overall retention of configuration.
Intrigued by the distinctive reactivity of these silacarbox-
ylic acids, we performed density functional theory (DFT)
calculations and natural bond orbital (NBO) analysis on
pivalic acid (1a) and trimethylsilylcarboxylic acid (2d), to
make a comparison of the reactivity between structurally
simple carboxylic acids and silacarboxylic acids;[22,23] their
representative atomic charges and unoccupied orbitals are
shown in Figure 1. Notably, the atomic charge at the silicon
atom (+ 1.623) of 2d is more positive than that at the carbonyl
carbon (+ 0.431), in sharp contrast to 1a, which has an a
carbon that is less-positive (À0.189) than the carbonyl carbon
It is worth noting that the preparation of silacarboxyesters
from silacarboxylic acids, by routes other than the described
Mitsunobu-type reaction,[19] is particularly challenging.
Indeed, various conventional procedures for the dehydrative
condensation reaction of carboxylic acids and alcohols, in
À
(+ 0.831). Furthermore, both the LUMO + 1 (Si C s*
Scheme 3. Esterification of (S)-2a and the molecular structure of ester
(S)-8a (ellipsoids set at 40% probability level). DEAD=diethyl azodi-
carboxylate.
Figure 1. DFT calculation and NBO analysis of carboxylic acids 1a and
2d. LUMO=lowest unoccupied molecular orbital.
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Communications
[2] Several achiral silacarboxylic acids have been synthesized; for
selected pioneering works, see: a) R. A. Benkeser, R. G. Sev-
erson, J. Am. Chem. Soc. 1951, 73, 1424 – 1427; b) A. G. Brook,
H. Gilman, L. S. Miller, J. Am. Chem. Soc. 1953, 75, 4759 – 4765;
c) A. G. Brook, J. Am. Chem. Soc. 1955, 77, 4827 – 4829.
[3] For leading reviews of chiral silicon compounds, see: a) L. H.
Sommer, Stereochemistry, Mechanism and Silicon, McGraw-
Hill, New York, 1965; b) R. J. P. Corriu, C. Guꢀrin, J. J. Moreau
in Topics in Stereochemistry, Vol. 15 (Ed.: E. L. Eliel), Wiley,
New York, 1984, pp. 43 – 198; c) M. A. Brook, Silicon in Organic,
Organometallic, and Polymer Chemistry, Wiley, New York, 2000,
pp. 115 – 137; d) T. Murafuji, K. Kurotobi, N. Nakamura, Y.
Sugihara, Curr. Org. Chem. 2002, 6, 1469 – 1494.
[4] For representative reports on the asymmetric synthesis of chiral
silicon compounds, see: a) L. H. Sommer, C. L. Frye, J. Am.
Chem. Soc. 1959, 81, 1013; b) R. J. P. Corriu, J. J. E. Moreau,
Tetrahedron Lett. 1973, 14, 4469 – 4472; c) R. Tacke, S. Brak-
mann, F. Wuttke, J. Fooladi, C. Syldatk, D. Schomburg, J.
Organomet. Chem. 1991, 403, 29 – 41; d) T. Ohta, M. Ito, A.
Tsuneto, H. Takaya, J. Chem. Soc. Chem. Commun. 1994, 2525 –
2526; e) K. Kobayashi, T. Kato, M. Unno, S. Masuda, Bull.
Chem. Soc. Jpn. 1997, 70, 1393 – 1401; f) A. Kawachi, H. Maeda,
K. Mitsudo, K. Tamao, Organometallics 1999, 18, 4530 – 4533;
g) K. Tomooka, A. Nakazaki, T. Nakai, J. Am. Chem. Soc. 2000,
122, 408 – 409; h) S. Rendler, G. Auer, M. Keller, M. Oestreich,
Adv. Synth. Catal. 2006, 348, 1171 – 1182; i) A. Nakazaki, J.
Usuki, K. Tomooka, Synlett 2008, 2064 – 2068.
orbital) and the LUMO (carbonyl group p* orbital) of 2d
have negative energy values (À0.348 and À0.711 eV, respec-
tively). Therefore, the electrostatic effect of the silicon atom,
À
as well as the low energy-level of the Si C s* orbital, should
greatly contribute to the increased electrophilicity at the
silicon center in silacarboxylic acids, thereby facilitating the
nucleophilic substitution.[24] These results are consistent with
our hypothesis.
Accordingly, the Mitsunobu-type reaction of silacarbox-
ylic acids with alcohols, in which the alcohol is activated in
preference to silacarboxylic acids, is a judicious choice for the
preparation of a variety of silacarboxyesters; achiral 2c also
undergoes smooth condensation with various alcohols
(2 equiv) including methanol, ethanol and isopropanol, in
the presence of DEAD (2 equiv) and PPh3 (2 equiv),[25] to
furnish silacarboxyesters tBuPhR1SiCO2R2 (8) in moderate to
good yields (Table 1, entries 1–3). Furthermore, the corre-
sponding reaction of silacarboxylic acid (S)-2b with ethanol
proceeds without any loss of enantiopurity to afford (S)-8e in
high yield (90%; Table 1, entry 4).
Table 1: Mitsunobu-type reaction of silacarboxylic acids 2.[a]
Entry
2
R1
R2OH
8
Yield [%][b]
[5] K. Igawa, J. Takada, T. Shimono, K. Tomooka, J. Am. Chem. Soc.
2008, 130, 16132 – 16133.
1
2
3
4
2c
2c
2c
Ph
Ph
Ph
MeOH
EtOH
iPrOH
EtOH
8b
8c
8d
95
95
72[c]
90
[6] For the synthesis of triphenylsilylcarboxylic acid and dimethyl-
phenylsilylcarboxylic acid from reaction of their corresponding
silyllithium compounds with carbon dioxide; see: a) M. V.
George, H. Gilman, J. Am. Chem. Soc. 1959, 81, 3288 – 3291;
b) H. Gilman, W. J. Trepka, J. Org. Chem. 1960, 25, 2201 – 2203.
[7] The substituent effect on stereochemical stability of chiral
silyllithium compounds has been studied by Oestreich and co-
workers: M. Oestreich, G. Auer, M. Keller, Eur. J. Org. Chem.
2005, 184 – 195.
[8] There have been several precedents for the preparation of
enantomerically enriched chiral silyllithium compounds, fol-
lowed by stereospecific electrophilic substitution reactions, see:
a) M. Omote, T. Tokita, Y. Shimizu, I. Imae, E. Shirakawa, Y.
Kawakami, J. Organomet. Chem. 2000, 611, 20 – 25; b) C.
Strohmann, J. Hꢁrnig, D. Auer, Chem. Commun. 2002, 766 –
767; c) C. Strohmann, C. Dꢂschlein, M. Kellert, D. Auer, Angew.
Chem. 2007, 119, 4864 – 4866; Angew. Chem. Int. Ed. 2007, 46,
4780 – 4782.
(S)-2b
nBu
(S)-8e
[a] Reaction conditions: R2OH (2 equiv), DEAD (2 equiv), PPh3 (2 equiv),
THF, 08C. [b] Yield of isolated products. [c] Silyl ester 9 was isolated in
7% yield.
In conclusion, we have described the first asymmetric
synthesis of chiral silacarboxylic acids by the stereospecific
carboxylation of silyllithium compounds that are derived
from chiral chlorosilanes as the key step. We have also found
that the silacarboxylic acids can be converted into their ester
derivatives using Mitsunobu-type conditions. These results
should open up the possibility for the preparation of
enantiomerically enriched functional silicon compounds that
may have potential utility as bioactive compounds, chiral
reagents, or functional materials. Further studies on chiral
silacarboxylic acids and their esters are underway.[26]
[9] P. D. Lickiss, K. M. Stubbs, J. Organomet. Chem. 1991, 421, 171 –
174.
[10] a) L. H. Sommer, C. L. Frye, G. A. Parker, K. W. Michael, J. Am.
Chem. Soc. 1964, 86, 3271 – 3276; b) L. H. Sommer, K. W.
Michael, W. D. Korte, J. Am. Chem. Soc. 1967, 89, 868 – 875;
c) F. Meganem, A. Jean, M. Lequan, J. Organomet. Chem. 1974,
74, 43 – 48; d) R. J. P. Corriu, C. Guꢀrin, Tetrahedron 1981, 37,
2467 – 2472.
[11] a) Y. Nagai, K. Yamazaki, I. Shiojima, N. Kobori, M. Hayashi, J.
Organomet. Chem. 1967, 9, P21 – P24; b) H. Sakurai, M.
Murakami, M. Kumada, J. Am. Chem. Soc. 1969, 91, 519 – 520;
c) L. H. Sommer, L. A. Ulland, J. Org. Chem. 1972, 37, 3878 –
3881.
[12] K. Tamao, A. Kawachi, Organometallics 1995, 14, 3108 – 3111.
[13] Mochida and co-workers isolated a complex of (R)-5a with (À)-
sparteine using fractional crystallization from a mixture of
racemic 5a and (À)-sparteine: M. Nanjo, M. Maehara, Y.
Ushida, Y. Awamura, K. Mochida, Tetrahedron Lett. 2005, 46,
8945 – 8947.
Received: September 2, 2009
Revised: October 21, 2009
Published online: December 22, 2009
Keywords: asymmetric synthesis · carboxylation · esterification ·
.
silacarboxylic acids · silanes
[1] For representative reviews of carboxylic acids and their deriv-
atives, see: a) The Chemistry of Acid Derivatives, part1 and part 2
(Ed.: S. Patai), Wiley, Chichester, 1992; b) M. A. Ogliaruso, J. F.
Wolfe in Synthesis of Carboxylic Acids, Esters, and Their
Derivatives (Eds.: S. Patai and Z. Rappoport), Wiley, Chichester,
1992; c) A. S. Franklin, J. Chem. Soc. Perkin Trans. 1 1999, 3537 –
3554.
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[14] Neither the reductive lithiation of 4a nor that of 4b led to the
formation of any trace of disilanes (tBuPhRSi)2 (R = Me, nBu)
under conditions similar to those given in Ref. [12].
[15] In contrast, heating of 2a and 2b or treatment with base caused
decarbonylation to afford the corresponding silanols. A similar
observation with triphenylsilyl carboxylic acid has been
reported, see: A. G. Brook, H. Gilman, J. Am. Chem. Soc.
1955, 77, 2322 – 2325.
[16] The absolute stereochemistry of (S)-8a was determined by the
Flack parameter of this crystallographic data: H. D. Flack, Acta
Crystallogr. Sect. A 1983, 39, 876 – 881. Selected crystallographic
data of ( S)-8a is provided in the Supporting Information.
CCDC 745046 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
yield). In contrast, the similar reaction of 5c with carbon dioxide
provided 2c in higher yield (61%). The reason for the difference
in the efficiency of these reactions is now under investigation;
see the Supporting Information for details.
[20] In good agreement with our observations; to the best of our
knowledge the preparative methods for silacarboxyesters have
been largely limited to using diazoalkane, see Ref. [15].
[21] X-ray diffraction study of silyl ester 9 was reported by Rettig and
Trotter: S. J. Rettig, J. Trotter, Acta Crystallogr. Sect. A Acta
Crystallogr. Sect. C 1988, 44, 1850 – 1851.
[22] All calculations were performed at B3LYP/6-31 + G(d,p) level
of theory with Gaussian 03 on TSUBAME system at Tokyo
Institute of Technology; see the Supporting Information for
details.
[23] Gaussian03 (RevisionD.02): M. J. Frisch et al., see the Support-
ing Information.
[17] The absolute stereochemistry of (À)-2b was also determined to
be the (S)-form by X-ray diffraction study of its crystalline ester
derivative; see the Supporting Information.
[18] In contrast to chiral silicon compounds, the absolute config-
uration in chiral carbon compounds has been well documented;
see: a) W. Klyne, J. Buckingham, Atlas of Stereochemistry,
Chapman and Hall, London, 1974; b) W. Klyne, J. Buckingham,
Atlas of Stereochemistry, Vol. 2, Chapman and Hall, London,
1978.
[19] A variety of silacarboxyesters can be obtained by the reaction of
silyllithium compounds with alkyl haloformates, albeit in
moderate chemical yield (e.g., reaction of tBuPh2SiLi (5c) with
ethyl chloroformate in THF at À788C provided 8c in 49%
[24] Remarkable differences between silacarboxylic acids and
common carboxylic acids in the acidity and UV absorption of
the carbonyl groups have been reported: a) G. J. D. Peddle,
R. W. Walsingham, J. Am. Chem. Soc. 1969, 91, 2154 – 2155;
b) O. W. Steward, J. E. Dziedzic, J. S. Johnson, J. Org. Chem.
1971, 36, 3475 – 3480; c) O. W. Steward, J. E. Dziedzic, J. S.
Johnson, J. O. Frohliger, J. Org. Chem. 1971, 36, 3480 – 3484.
[25] O. Mitsunobu, Synthesis 1981, 1 – 28.
[26] We have also found that the reaction of silyllithium compound
5c with N, N- dimethyl chloroformamide in tetrahydrofuran at
À788C
provides
the
corresponding
silacarboxamide,
tBuPh2SiCONMe2 (10), albeit in low yield (20%); see the
Supporting Information for details.
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