Utilization of 1-Oxa-2,2-(dimesityl)silacyclopentane acetals in the stereoselective synthesis of polyols

Article abstract of DOI:10.1021/ja027335w

We have developed a route for the stereoselective synthesis of 1-oxa-2,2-(dimesityl)silacyclopentane acetals, intermediates in the synthesis of highly functionalized 1,3-diols. This route involves a diastereoselective conjugate addition reaction of a hydrosilyl anion, a subsequent diastereoselective enolate alkylation, and a fluoride-catalyzed intramolecular hydrosilylation reaction to afford the oxasilacyclopentane acetal. A highly selective nucleophilic substitution reaction, followed by oxidation of the C-Si bond, leads to the desired polyol. Copyright

Full text of DOI:10.1021/ja027335w

Published on Web 10/02/2002
Utilization of 1-Oxa-2,2-(dimesityl)silacyclopentane Acetals in the
Stereoselective Synthesis of Polyols
Sharon A. Powell, Jason M. Tenenbaum, and K. A. Woerpel*
Department of Chemistry, UniVersity of California, IrVine, California 92697-2025
Received June 17, 2002
Scheme 2a
Cyclic silanes have been the targets of recent synthetic methods
because these heterocycles can be readily converted into alcohols
after oxidation of a carbon-silicon bond.1-4 The 1-oxa-2-silacy-
clopentane moiety, in particular, is a useful intermediate for the
stereoselective formation of 1,3-diols.5-11 We have shown that
oxasilacyclopentane acetals undergo substitution reactions with a
range of nucleophiles to provide highly substituted oxasilacyclo-
pentane products.12 In this communication, we report a stereose-
lective and high-yielding synthesis of 1-oxa-2,2-(dimesityl)-
silacyclopentane acetals from readily available starting materials.
Subsequent Lewis acid-mediated nucleophilic substitution further
functionalizes the oxasilacyclopentane, and oxidation of the C-Si
bond reveals the 1,3-diol.
Formation of the oxasilacyclopentane acetal was achieved by
conjugate addition of a hydrosilyl anion to an R,â-unsaturated ester
followed by an intramolecular hydrosilylation reaction.13 While
conjugate addition of a hydrosilyl anion has not been previously
demonstrated, conditions developed by Lipshutz for the conjugate
addition of phenyldimethylsilyllithium enabled the stable silyl-
lithium complex Mes2SiHLi‚(THF)2 (4)14,15 to add in a 1,4-fashion
to chiral R,â-unsaturated ester 1a to provide â-silyl ester 2a in high
yield and 99:1 diastereoselectivity (Scheme 1).16,17 The 1-oxa-2-
silacyclopentane acetal 3a was then formed as an 85:15 mixture of
acetal epimers in good yield by an intramolecular hydrosilylation
of â-silyl ester 2a using conditions similar to those developed by
Davis for the hydrosilylation of â-siloxy esters (Scheme 1).13
a Key: (i) 4, Me2Zn, 5 mol % Me2CuLi‚LiCN. (ii) 10 mol % n-Bu4NF,
0 °C. (a) Diastereoselectivities refer to conjugate addition. Diastereoselec-
tivities of the hydrosilylation ranged between 80:20 and 85:15. (b)
Selectivities determined by GCMS or H NMR spectroscopy. (c) 3 equiv
of (CH3)3SiCl added.
1
Scheme 1a
Conversion of the â-silyl esters to the oxasilacyclopentanes
highlighted the mild conditions and functional group tolerance of
the hydrosilylation reaction. Hydrosilylation of â-silyl esters 2b-e
afforded oxasilacyclopentane acetals 3b-e in high yield (Scheme
2). Even a â-silyl ester bearing a hydroxyl group protected as a
TBDMS ether could be converted to the oxasilacyclopentane acetal
(Scheme 2).
The â-silyl esters can be further functionalized by installing an
alkyl group at the R-position with a high degree of stereocontrol.
A representative alkylation of â-silyl ester 2a was carried out with
MeI. Under optimized conditions, the desired R-methyl-â-silyl ester
5a was obtained with 97:3 diastereoselectivity (eq 1). As expected,
alkylation occurs trans to the large â-silyl substituent,24-26 providing
the framework for the synthetically challenging anti,anti dipropi-
onate stereotriad.27-29 Ester 5a undergoes hydrosilylation to afford
oxasilacyclopentane 6a in a similar manner as â-silyl ester 2a.
The efficiency of this route can be greatly increased because
conjugate addition, enolate alkylation, and hydrosilylation can be
conducted in one flask without isolation of intermediates. For
example, after conjugate addition of silyllithium 4 to 1f, the resulting
enolate was alkylated stereoselectively with MeI. After being stirred
a Key: (i) 4, Me2Zn, 5 mol % Me2CuLi‚LiCN, 3 equiv of (CH3)3SiCl,
-78 °C. (ii) 10 mol % n-Bu4NF, 0 °C.
The conjugate addition of silyl anion 4 to R,â-unsaturated esters
containing stereogenic centers proceeded with high selectivity for
a variety of substrates. Conjugate addition to enoates possessing
an alkoxy group at the γ-position afforded products with high
selectivity.7,18,19 Addition to enoate 1b resulted in 96:4 selectivity;
selectivity increased to 98:2 for conjugate addition to enoate 1c,
derived from D-mannitol (Scheme 2).20 Conjugate additions to esters
containing the γ-methyl-δ-alkoxy substitution pattern resulted in
even higher selectivities.7 The choice of hydroxyl protecting group
had little effect on the outcome of the conjugate addition (cf., 1a
and 1d, Schemes 1 and 2).21 Addition to enoate 1e22 demonstrated
that the selectivity of the addition is unaffected by the orientation
of the δ-stereocenter (Scheme 2).7,23
* To whom correspondence should be addressed. E-mail: kwoerpel@uci.edu.
9
12648
J. AM. CHEM. SOC. 2002, 124, 12648-12649
10.1021/ja027335w CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
the desired polyol. This method provides a general approach to
acyclic polyols because substitution can be independently installed
in a modular manner at each step in the synthetic pathway with
high selectivity.
Acknowledgment. This research was supported by the National
Institutes of Health (General Medical Sciences, GM54909). 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. J.M.T. thanks Pfizer, Inc., for providing
a Graduate Research Fellowship. We would like to thank Dr. L.
Pfeifer for valuable discussions. We also thank Dr. J. Greaves and
Dr. J. Mudd for mass spectrometric data and Dr. J. Ziller for X-ray
analyses.
overnight, the reaction mixture was treated with n-Bu4NF (eq 2),
leading directly to the oxasilacyclopentane acetal 6f.
Supporting Information Available: Full experimental and char-
acterization data (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
Lewis acid-mediated nucleophilic substitution followed by oxida-
tion of the carbon-silicon bond1,2 revealed the 1,3-diol moiety
(Scheme 3). Allyltrimethylsilane was employed as the representative
nucleophile.30 In accordance with our studies of five-membered ring
oxocarbenium ions,30,31 nucleophilic substitution provided the 1,3-
trans products with high stereoselectivity (Scheme 3). Oxidation
of the resulting oxasilacyclopentanes with alkyl hydroperoxides32
provided 1,3-diols, including polyol 8a containing the desired
anti,anti stereotriad (Scheme 3).
References
(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.
(3) Liu, D.; Kozmin, S. A. Angew. Chem., Int. Ed. 2001, 40, 4757-4759.
(4) Bols, M.; Skrydstrup, T. Chem. ReV. 1995, 95, 1253-1277.
(5) Murakami, M.; Suginome, M.; Fujimoto, K.; Nakamura, H.; Andersson,
P. G.; Ito, Y. J. Am. Chem. Soc. 1993, 115, 6487-6498.
(6) Young, D. G. J.; Hale, M. R.; Hoveyda, A. H. Tetrahedron Lett. 1996,
37, 827-830.
Scheme 3a
(7) Hale, M. R.; Hoveyda, A. H. J. Org. Chem. 1994, 59, 4370-4374.
(8) Zacuto, M. J.; Leighton, J. L. J. Am. Chem. Soc. 2000, 122, 8587-8588.
(9) Tamao, K.; Nakajima, T.; Sumiya, R.; Arai, H.; Higuchi, N.; Ito, Y. J.
Am. Chem. Soc. 1986, 108, 6090-6093.
(10) Kablean, S. N.; Marsden, S. P.; Craig, A. M. Tetrahedron Lett. 1998, 39,
5109-5112.
(11) Tanino, K.; Yoshitani, N.; Moriyama, F.; Kuwajima, I. J. Org. Chem.
1997, 62, 4206-4207.
(12) Bear, T. J.; Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 2002, 67, 2056-
2064 and references therein.
(13) Davis, A. P.; Hegarty, S. C. J. Am. Chem. Soc. 1992, 114, 2745-2746.
(14) The yields were significantly reduced when silyllithium 4 was generated
in situ.
(15) Roddick, D. M.; Heyn, R. H.; Tilley, T. D. Organometallics 1989, 8,
324-330.
(16) Lipshutz, B. H.; Sclafani, J. A.; Takanami, T. J. Am. Chem. Soc. 1998,
120, 4021-4022.
(17) Depending on the substrate, stereochemistries were proven by either X-ray
crystallography, spectroscopy, or chemical correlation.
(18) Krief, A.; Provins, L.; Dumont, W. Angew. Chem., Int. Ed. 1999, 38,
1946-1948.
(19) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.; Kitahara, H. J. Am.
Chem. Soc. 1992, 114, 7652-7660.
(20) The dimethyl acetonide protected enoate derived from D-mannitol
underwent conjugate addition in a similar fashion.
(21) Similar results were observed when the hydroxyl group was protected as
the pivaloate ester.
(22) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem.
Soc. 2002, 124, 392-393.
(23) The optical activity of enoates 1c and 1e was preserved.
(24) McGarvey, G. J.; Williams, J. M. J. Am. Chem. Soc. 1985, 107, 1435-
1437.
a Key: (i) CH2CHCH2Si(CH3)3, BF3‚OEt2, -78 °C to 0 °C. (ii) 10 equiv
of CsOH‚H2O, 5.5 equiv of CsF, 8 equiv of t-BuOOH, NMP. (a)
Diastereoselectivity determined by GCMS or 1H NMR spectroscopy. (b) 8
equiv of cumene hydroperoxide was used.
(25) Panek, J. S.; Beresis, R.; Xu, F.; Yang, M. J. Org. Chem. 1991, 56, 7341-
7344.
(26) Crump, R. A. N. C.; Fleming, I.; Hill, J. H. M.; Parker, D.; Reddy, N. L.;
Waterson, D. J. Chem. Soc., Perkin Trans. 1 1992, 3277-3294.
(27) Hoffmann, R. W.; Dahmann, G.; Andersen, M. W. Synthesis 1994, 629-
638.
In conclusion, we have developed a route for the stereoselective
synthesis of 1-oxa-2,2-(dimesityl)silacyclopentane acetals, inter-
mediates for the formation of highly functionalized 1,3-diols. This
route involves a diastereoselective conjugate addition reaction of a
silyllithium reagent, subsequent diastereoselective enolate alkylation,
and a fluoride-catalyzed hydrosilylation reaction to afford the
oxasilacyclopentane acetal. A highly selective nucleophilic substitu-
tion reaction, followed by oxidation of the C-Si bond, leads to
(28) Marshall, J. A.; Perkins, J. F.; Wolf, M. A. J. Org. Chem. 1995, 60, 5556-
5559.
(29) Roush, W. R.; Chemler, S. R. J. Org. Chem. 1998, 63, 3800-3801.
(30) Shaw, J. T.; Woerpel, K. A. J. Org. Chem. 1997, 62, 6706-6707.
(31) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem.
Soc. 1999, 121, 12209-12210.
(32) Smitrovich, J. H.; Woerpel, K. A. J. Org. Chem. 1996, 61, 6044-6046.
JA027335W
9
J. AM. CHEM. SOC. VOL. 124, NO. 43, 2002 12649