Use of an Aminosilyllithium for the Diastereoselective Synthesis of Diphenyl Oxasilacyclopentane Acetals and Polyols

Article abstract of DOI:10.1021/ol035577a

(Equation presented) The conjugate addition reaction of a stable, in situ generated silyllithium gives a β-hydroxysilyl ester with high diastereoselectivity. Conversion of the β-hydroxysilyl ester to a β-fluorosilyl ester affords the precursor to the oxasilacyclopentane acetal in high yields under mild conditions. A hydride reduction and subsequent intramolecular silylation lead to the acetal in excellent yields. Finally, highly selective nucleophilic substitution affords oxasilacyclopentanes, which undergo a mild oxidation to afford 1,3-trans diols with high selectivity.

Full text of DOI:10.1021/ol035577a

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4325-4327
Use of an Aminosilyllithium for the
Diastereoselective Synthesis of Diphenyl
Oxasilacyclopentane Acetals and
Polyols
Jason M. Tenenbaum and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
kwoerpel@uci.edu
Received August 21, 2003
ABSTRACT
The conjugate addition reaction of a stable, in situ generated silyllithium gives a â-hydroxysilyl ester with high diastereoselectivity. Conversion
of the â-hydroxysilyl ester to a â-fluorosilyl ester affords the precursor to the oxasilacyclopentane acetal in high yields under mild conditions.
A hydride reduction and subsequent intramolecular silylation lead to the acetal in excellent yields. Finally, highly selective nucleophilic substitution
affords oxasilacyclopentanes, which undergo a mild oxidation to afford 1,3-trans diols with high selectivity.
Oxasilacyclopentanes are powerful intermediates in organic
synthesis, since they can be readily converted into diols after
oxidation of the carbon-silicon bond.1-13 Recently, we
showed that a variety of highly functionalized 1,3-diols can
be obtained diastereoselectively from R,â-unsaturated esters
through the intermediacy of a dimesityl silacyclopentane
acetal (Scheme 1).14 Conjugate addition of Mes2HSiLi‚
drosilylation15 of the carbonyl to afford acetal 3a. Subsequent
Lewis acid mediated nucleophilic substitution and oxidation
of the carbon-silicon bond gave the 1,3-trans diol 4.
Although high selectivities and yields were observed for
this reaction sequence, we wanted to increase its efficiency
and substrate compatibility. Hydrosilyllithium 1 is unstable
in solution, so isolation of this anion as its stable THF solvate
in a glovebox or using Schlenk techniques were required to
obtain reliable yields.16 The dimesitylsilyl anion would not
add to (Z)-R,â-unsaturated esters. The steric bulk of the
mesityl substituents on the silicon atom also required the
Scheme 1. Formation of Polyols from â-Silyl Esters
(7) Young, D. G. J.; Hale, M. R.; Hoveyda, A. H. Tetrahedron Lett.
1996, 37, 827-830.
(8) Hale, M. R.; Hoveyda, A. H. J. Org. Chem. 1994, 59, 4370-4374.
(9) Zacuto, M. J.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 8587-
8588.
(10) Zacuto, M. J.; O’Malley, S. J.; Leighton, J. L. J. Am. Chem. Soc.
2002, 124, 7890-7891.
(THF)2 (1) to an R,â-unsaturated ester provided â-silyl ester
2a, which underwent fluoride-catalyzed intramolecular hy-
(11) Tamao, K.; Nakajima, T.; Sumiya, R.; Arai, H.; Higuchi, N.; Ito,
Y. J. Am. Chem. Soc. 1986, 108, 6090-6093.
(12) Kablean, S. N.; Marsden, S. P.; Craig, A. M. Tetrahedron Lett. 1998,
39, 5109-5112.
(1) Tamao, K.; Akita, M.; Kumada, M. J. Organomet. Chem. 1983, 254,
13-22.
(2) Jones, G. R.; Landais, Y. Tetrahedron 1996, 52, 7599-7662.
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4759.
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sson, P. G.; Ito, Y. J. Am. Chem. Soc. 1993, 115, 6487-6498.
(13) Tanino, K.; Yoshitani, N.; Moriyama, F.; Kuwajima, I. J. Org. Chem.
1997, 62, 4206-4207.
(14) Powell, S. A.; Tenenbaum, J. M.; Woerpel, K. A. J. Am. Chem.
Soc. 2002, 124, 12648-12649.
(15) Davis, A. P.; Hegarty, S. C. J. Am. Chem. Soc. 1992, 114, 2745-
2746.
(16) Roddick, D. M.; Heyn, R. H.; Tilley, T. D. Organometallics 1989,
8, 324-330.
10.1021/ol035577a CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/22/2003

Scheme 2. Conjugate Addition to Ester 7a
Scheme 3. Conjugate Addition to Esters 10 and 11
a Reaction conditions: (a) (i) 6, Li0; then Me2Zn, 5 mol %
Me2CuLi‚LiCN; (ii) aqueous NH4Cl, 68%. (b) BF3‚OEt2, CH2Cl2,
-78 °C, 78%. (c) Conditions as in (a) and (b), but without isolation
of silanol 8; 68% over two steps.
use of strongly basic conditions to oxidize the oxasilacyclo-
pentane.
This communication reports the development of methodol-
ogy that greatly improves the sequence shown in Scheme 1.
The aminosilyllithium Ph2Si(NEt2)Li (5) developed by
Tamao and Kawachi was used to introduce the carbon-
silicon bond, obviating the isolation of an unstable silyl-
lithium.17-19 Because metal-mediated conjugate addition of
silyl anion 5 led to a â-silyl ester lacking a hydride
functionality20 (as compared to the original protocol),
conversion of ester 2 to acetal 3 was re-engineered. The
resulting oxasilacyclopentane was oxidized easily under mild
Tamao conditions.21 This new procedure allows for the
diastereoselective synthesis of polyols from both (E)- and
(Z)-enoates.
The conversion of the R,â-unsaturated ester to the ap-
propriately functionalized â-silyl ester was accomplished in
two steps. The metal-mediated conjugate addition22,23 of
aminosilyllithium 5, generated in situ from Ph2Si(NEt2)Cl
(6),24 to R,â-unsaturated ester 7 followed by aqueous workup
afforded â-hydroxysilyl ester 8 in 68% yield (Scheme 2).17
Treatment of hydroxysilyl 8 with BF3‚OEt2 in CH2Cl2 at -78
°C gave â-fluorosilyl ester 9 in 78% yield.25 Harsh condi-
tions, such as HF or Ph2S(O)F2, were previously required to
convert silanols to fluorosilanes.26-30 Further optimization
was achieved, because conversion of enoate 7 to ester 9 could
be carried out with only a single purification, resulting in a
68% overall yield.
These conditions were applied to a variety of other
substrates. Metal-mediated conjugate addition to (Z)-enoates,
which were unreactive with silyllithium 1,14 could now be
performed with Ph2Si(NEt2)Li (5). Metal-mediated conjugate
addition of aminosilyllithium 5 to enoate 10 and subsequent
treatment of the silanol with BF3‚Et2O afforded a 63% overall
yield of â-fluorosilyl ester 9 (Scheme 3). The metal-mediated
conjugate addition of aminosilyllithium 5 to enoates contain-
ing stereogenic centers proceeded with high selectivity.8,31,32
Addition of Ph2Si(NEt2)Li (5) to enoate 11 followed by
conversion to the fluoride afforded ester 12 with a 99:1
diastereoselectivity in 76% overall yield (Scheme 3).
The enolate of the â-fluorosilyl ester could be alkylated
without O-silylation of the fluorosilane. Treatment of ester
9 with LiN(i-Pr)2, 5 equiv of DMPU, and 2 equiv of MeI at
-78 °C gave â-fluorosilyl ester 13 with 90:10 diastereose-
lectivity in 65% yield (Scheme 4).33 Upon warming the
Scheme 4. Diastereoselective Addition to Ester 9
(17) Tamao, K.; Kawachi, A.; Ito, Y. J. Am. Chem. Soc. 1992, 114,
3989-3990.
(18) Usuda, H.; Kanai, M.; Shibasaki, M. Tetrahedron Lett. 2002, 43,
3621-3624.
(19) Barrett, A. G. M.; Head, J.; Smith, M. L.; Stock, N. S.; White, A.
J. P.; Williams, D. J. J. Org. Chem. 1999, 64, 6005-6018.
(20) Diphenylhydrosilyllithium is unstable and gave irreproducible results.
(21) Tamao, K.; Ishida, N.; Tanaka, T.; Kumada, M. Organometallics
1983, 2, 1694-1696.
(22) Lipshutz, B. H.; Sclafani, J. A.; Takanami, T. J. Am. Chem. Soc.
1998, 120, 4021-4022.
(23) Ager, D. J.; Fleming, I.; Patel, S. K. J. Chem. Soc., Perkin Trans.
1 1981, 2520-2526.
(24) Chlorosilane 6 can be easily synthesized on a multigram scale.
Tamao, K.; Nakajo, E.; Ito, Y. Tetrahedron 1988, 44, 3997-4007.
(25) Despite the additional steps, the formation of the â-fluorosilyl ester
was necessary as hydride reduction of the â-aminosilyl or â-silanol esters
led only to â-silyl aldehydes.
enolate above -78 °C, significant amounts of O-silylation
were observed.
With the â-fluorosilyl esters in hand, a variety of hydride
reducing agents were screened for the hydride reduction and
subsequent intramolecular silylation reaction. The use of mild
reducing agents resulted in no reaction with ester 9, and
strong reducing agents led to hydrolysis of the fluorosilane.
Treatment with i-Bu2AlH in CH2Cl2 at -78 °C provided a
â-fluorosilyl aldehyde, which afforded a mixture of the
methyl and ethyl oxasilacyclopentane acetals upon addition
(26) Ou, X.; Janzen, A. F. J. Fluorine Chem. 2000, 101, 279-284.
(27) Earborn, C. J. Chem. Soc. 1953, 494-497.
(28) Earborn, C. J. Chem. Soc. 1952, 2846-2848.
(29) Handy, C. J.; Lam, Y.-F.; DeShong, P. J. Org. Chem. 2000, 65,
3542-3543.
(30) Magar, S. S.; Desai, R. C.; Fuchs, P. L. J. Org. Chem. 1992, 57,
5360-5369.
(31) Krief, A.; Provins, L.; Dumont, W. Angew. Chem., Int. Ed. 1999,
38, 1946-1948.
(32) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H. J.
Am. Chem. Soc. 1992, 114, 7652-7660.
(33) McGarvey, G. J.; Williams, J. M. J. Am. Chem. Soc. 1985, 107,
1435-1437.
4326
Org. Lett., Vol. 5, No. 23, 2003

Scheme 5. Hydride Reduction and Intramolecular Silylation
of Ester 9a
Scheme 7. Conversion of Acetals 14-16 to 1,3-Diols 18, 20,
and 22a
a Reaction conditions: (a) (i) i-Bu2AlH, CH2Cl2, -78 °C; (ii)
EtOH, 97%, 68:32 ds. (b) 1:1 LiBH4/MeOH, Et2O, 22 °C, 86%,
56:44 ds.
of MeOH. When the aldehyde was treated with EtOH, the
desired ethyl acetal 14 was obtained as a 62:38 ratio of acetal
epimers in 97% yield (Scheme 5).34 The reduction with i-Bu2-
AlH was sensitive to the reaction conditions, and even small
variations in temperature or concentration led to significant
amounts of overreduction of the ester. Treatment of ester 9
with LiBH4 and MeOH in Et2O at 22 °C resulted in the direct
formation of oxasilacyclopentane acetal 14 as a 56:44
mixture of acetal epimers in 86% yield without formation
of the â-fluorosilyl aldehyde or significant amounts of
overreduction.
a Reaction conditions: (a) CH2CHCH2Si(CH3)3, BF3‚OEt2, CH2Cl2,
85%. (b) 30% H2O2, KF, KHCO3, 1:1 MeOH/THF, 64%. (c)
CH2CHCH2Si(CH3)3, BF3‚OEt2, CH2Cl2, 63%. (d) 30% H2O2, KF,
KHCO3, 1:1 MeOH/THF, 62%. (e) CH2CHCH2Si(CH3)3, SnCl4,
toluene. (f) 30% H2O2, KF, KHCO3, 1:1 MeOH/THF, 56% over
two steps.
With optimized conditions in hand, the procedure was
applied to the other â-fluorosilyl esters to afford oxasilacy-
clopentane acetals 18 and 19 in good yield (Scheme 6). The
functional group tolerance of the overall reaction sequence
(Scheme 7).1,2,21,36
In conclusion, we have developed a method for the
synthesis of oxasilacyclopentane acetals, which serve as
valuable precursors for the diastereoselective synthesis of
1,3-trans diols. The conjugate addition reaction of a stable,
in situ generated silyllithium proceeded with high diaste-
reoselectivity. Conversion of a â-hydroxysilyl ester to a
â-fluorosilyl ester afforded the precursor to the hydride
reduction reaction in high yields under mild conditions. The
reduction and subsequent intramolecular silylation led to the
oxasilacyclopentane acetal in excellent yields using a variety
of mild reducing agents. Finally, highly selective nucleophilic
substitution afforded oxasilacyclopentanes, which underwent
a mild Tamao oxidation21 of the carbon-silicon bond to
provide 1,3-trans diols with high selectivity.
Scheme 6. Hydride Reduction and Intramolecular Silylation
of Esters 12 and 13
Acknowledgment. This research was supported by the
National Institutes of Health (General Medical Sciences,
GM54909). J.M.T. thanks Pfizer, Inc. for a graduate research
fellowship. K.A.W. thanks the Camille and Henry Dreyfus
Foundation, Merck Research Laboratories, Johnson and
Johnson, and the Sloan Foundation for awards to support
research. We thank Dr. Annaliese Franz for her conditions
for the conversion of a silanol to a fluorosilane, and Dr. J.
Greaves and Dr. J. Mudd for mass spectrometric data.
use of LiBH4 and MeOH resulted in direct silylation of esters
15 and 16 with little or no overreduction observed. The direct
formation of the acetal using LiBH4 was employed to avoid
the concern that acetal formation could be incomplete with
the two-step i-Bu2AlH procedure.
As in the case with the mesityl-substituted oxasilacyclo-
pentane acetals,14 Lewis acid mediated nucleophilic substitu-
tion of allyltrimethylsilane followed by oxidation of the
carbon-silicon bond proceeded with excellent selectivities
for acetals 14-16 (Scheme 7). The observed selectivities
are in accordance with our studies of five-membered-ring
oxocarbenium ions.35 Oxidation of the oxasilacyclopentanes
17, 19, and 21 to polyols 18, 20, and 22 was performed with
the more mild Tamao conditions, which illustrated the
Supporting Information Available: Full experimental
procedures and spectroscopic proof of stereochemistry. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL035577A
(35) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am.
Chem. Soc. 1999, 121, 12209-12210.
(36) The nucleophilic substitution and oxidation reactions have not been
optimized, and an erosion in the yields were observed compared to reactions
with the dimesityloxasilacyclopentane acetals.
(34) The reduction could also be carried out in toluene, but the yields
were lower.
Org. Lett., Vol. 5, No. 23, 2003
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