Published on Web 11/27/2002
Substituent Effects on Regioselective Intramolecular
Oxidation of Unactivated C-H Bonds: Stereoselective
Synthesis of Substituted Tetrahydropyrans
Man-Kin Wong, Nga-Wai Chung, Lan He, and Dan Yang*
Contribution from the Department of Chemistry, The UniVersity of Hong Kong,
Pokfulam Road, Hong Kong
Received August 31, 2002; E-mail: yangdan@hku.hk
Abstract: Our previously reported intramolecular δ-selective C-H bond oxidation by dioxiranes, generated
in situ from activated ketones, offers a novel approach to the synthesis of tetrahydropyrans. To synthesize
substituted tetrahydropyrans in a stereoselective manner, we examined the effects of alkyl, nitrogen, and
oxygen substituents at the R-, â-, and γ-sites of ketones on the stereoselectivities of intramolecular C-H
bond oxidation reactions. Ketones 1-4 with a methyl group at the R-, â-, or γ-site showed the diastereo-
selectivities that agreed with the trans/cis ratio predicted by considering steric interactions in the transition
states. Furthermore, ketones 5 and 6 carrying a bulky phthalimido group at the R- and the â-sites,
respectively, exhibited excellent stereoselectivity, each affording only one diastereomer. However, ketones
9 and 10 bearing â-oxygen substituents gave reversed stereoselectivity as compared to those with â-alkyl
or nitrogen substituents, possibly because of the hydrogen bonding interaction in the transition state. For
ketones 12 and 13, both bearing methyl and silyloxy groups, the hydrogen bonding interaction was probably
more important than the steric effect on the diastereoselectivity of intramolecular oxidation of C-H bonds.
Introduction
substituents in the transition states of cyclizations. Despite the
success of those methods, the search for a novel strategy for
Substituted tetrahydropyrans are important building blocks
of many biologically active natural products such as marine
toxins and polyether antibiotics.1 Thus, the development of
efficient methods for the construction of functionalized tetrahy-
dropyrans has received considerable attention.2
Intramolecular cyclizations through the formation of C-O
and C-C bonds represent the two main approaches for the
synthesis of multisubstituted tetrahydropyrans.3,4 These cycliza-
tions usually proceeded with good to excellent stereoselectivities,
generally governed by the steric interactions developed between
the efficient assembly of multifunctionalized tetrahydropyrans
continues to be a significant goal in organic synthesis.
Recently we developed a novel method for the synthesis of
tetrahydropyrans via dioxirane mediated regioselective intramo-
lecular hydroxylation.5-7 Unlike the currently employed methods
involving formations of C-O and C-C bonds, our approach
involved a concerted intramolecular oxidation of unactivated δ
C-H bonds of ketones to give δ-hydroxy ketones, which then
cyclized to afford tetrahydropyrans (Scheme 1).8
In this work, we investigated the substituent effects on the
stereoselective oxidation of unactivated C-H bonds of ketones.
We found that substituents (such as methyl, nitrogen, and
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10.1021/ja028357l CCC: $25.00 © 2003 American Chemical Society