Scheme 1. Existing Stereoselective Approaches to
Scheme 3. Intramolecular Allylation Approach to
2,4,5-Trisubstituted THPs 8
2,4,5-Trisubstituted THPs
we hypothesized that this structural change might have a
pronounced effect on the 1,4-stereoinduction but would have
minimal impact on the 1,3-stereoinduction because the
electrostatic interactions governing this aspect of the reaction
should effectively remain the same. Furthermore, by using
a more robust methylene bridge to connect the allylsilane to
the aldehyde, we hoped to be able to investigate Brønsted
acid activators, something we had been unable to do in our
previous cyclizations because of the lability of the silyl tether
to these activators.
â-carbinol stereocenter. Treatment of 5 with TMSOTf, in
the presence of a Brønsted acid scavenger, effected intramo-
lecular allylation to provide two out of the four possible
oxasilacycles 6 (Scheme 2).4c Complete 1,3-stereoinduction
Because â-hydroxy esters are readily accessed in enan-
tiomerically enriched form,7 we opted for a route to the
cyclization precursor 7 which would exploit this facile entry
into enantiomerically enriched systems (Table 1). The
lynchpin step in our synthesis of 7 would therefore involve
the formation of the ether linkage between â-hydroxy ester
11 and an allylsilane or a masked synthetic equivalent.
Mindful of the propensity for allylsilanes containing a leaving
group at the γ-terminus to degrade through a vinylogous Si-
mediated elimination sequence,8 we chose to tether a
propargyl silane precursor instead, as we expected this
functionality would be less susceptible to degradation via
this pathway. Significantly, unmasking the double bond at a
later stage in the synthesis through a partial hydrogenation
would also allow access to a (Z)-allylsilane, which has been
shown in related systems to impart higher levels of stereo-
selectivity in intramolecular allylation reactions than its (E)-
stereoisomer.9
Scheme 2. Intramolecular Allylation of Aldehyde 5 Generates
Two Out of the Possible Four Oxasilacycles
The propensity for â-hydroxy esters to undergo dehydra-
tion or a retro-aldol transformation called for a nonbasic
etherification procedure. To this end, propargyl alcohol 910
was first transformed into trichloroacetimidate 10,11 which
reacted with â-hydroxy ester 11, in the presence of TMSOTf,
to provide ether 12 in good yield.12 Partial hydrogenation of
the alkyne functionality in 12 using Ra-Ni/H2 afforded the
is observed in this cyclization. We have rationalized this
observation on electrostatic grounds according to a modified
Evans dipole model in which the dipole moments across the
polar CdO and C-O bonds are opposing one another in
the transition state (TS).6 The more modest 1,4-stereoinduc-
tion arises from minimizing steric interactions between the
allylsilane and the ethyl substituents contained within the
silyl tether, which is best achieved by placing the allylsilane
in a pseudoaxial orientation.
Substituting the diethylsilyl tether in aldehyde 5 for a
methylene group would provide 7 and a route to the
corresponding 2,4,5-trisubstituted THP 8 (Scheme 3).3 On
the basis of our previous observations with 5 (Scheme 2),4c
(7) For aldol approaches, see: (a) Palomo, C.; Oiarbide, M.; Garc´ıa, J.
M. Chem. Soc. ReV. 2004, 33, 65. (b) Machajewski, T. D.; Wong, C.-H.
Angew. Chem., Int. Ed. 2000, 39, 1352. (c) Asymmetric reduction of â-keto
esters provides an alternative strategy: Noyori, R. In Asymmetric Catalysis
in Organic Synthesis; Wiley: New York, 1994. (d) Nakamura, K.; Matsuda,
T. Curr. Org. Chem. 2006, 10, 1217.
(8) (a) Fleming, I.; Morgan, I. T.; Sarkar, A. K. J. Chem. Soc., Perkin
Trans. 1 1998, 2749. (b) Angoh, A. G.; Clive, D. L. J. J. Chem. Soc., Chem.
Commun. 1984, 534.
(4) (a) Ramalho, R.; Beignet, J.; Humphries, A. C.; Cox, L. R. Synthesis
2005, 3389. (b) Beignet, J.; Tiernan, J.; Woo, C. H.; Kariuki, B. M.; Cox,
L. R. J. Org. Chem. 2004, 69, 6341. (c) Beignet, J.; Cox, L. R. Org. Lett.
2003, 5, 4231.
(9) (a) Schlosser, M.; Franzini, L.; Bauer, C.; Leroux, F. Chem.-Eur.
J. 2001, 7, 1909. (b) Keck, G. E.; Dougherty, S. M.; Savin, K. A. J. Am.
Chem. Soc. 1995, 117, 6210.
(10) (a) McGarvey, G. J.; Bajwa, J. S. J. Org. Chem. 1984, 49, 4091.
(b) Slutsky, J.; Kwart, H. J. Am. Chem. Soc. 1973, 95, 8678.
(11) (a) Wessel, H.-P.; Iversen, T.; Bundle, D. R. J. Chem. Soc., Perkin
Trans. 1 1985, 2247. (b) Clark, J. S.; Fessard, T. C.; Wilson, C. Org. Lett.
2004, 6, 1773.
(5) (a) For reviews on the temporary silicon connection: Cox, L. R.;
Ley, S. V. In Templated Organic Synthesis; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: Weinheim, 1999; pp 275-395. (b) Gauthier, D. R., Jr.;
Zandi, K. S.; Shea, K. J. Tetrahedron 1998, 54, 2289. (c) Bols, M.;
Skrydstrup, T. Chem. ReV. 1995, 95, 1253.
(12) Standard etherification conditions using trichloroacetimidates use
TfOH as the activator. In our case, however, this acid effected protodesi-
lylation of ether 12, providing an allene as the major product.
(6) Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem.
Soc. 1996, 118, 4322.
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Org. Lett., Vol. 8, No. 20, 2006