Stereoselective Synthesis of 2,4,6‐Trisubstituted Tetrahydropyrans by the Use of Cyclopropanols as Homoenols

Abstract

Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthdayFunctionalized tetrahydropyrans constitute key structural motifs of a large number of biologically active natural products.[1] The conspicuous prevalence of 2,4,6-trisubstituted tetrahydropyrans in these natural products spurred the development of many elegant methods for the enantio-and stereoselective synthesis of appropriately substituted tetrahydropyrans. Several useful synthetic methods are based on the efficient trapping of an oxocarbenium ion by a pendant nucleophile.[2] The ring opening of a cyclopropanol or its silyl ether and addition to a tethered oxocarbenium ion was recently documented by the Minbiole research group and by us. [3,4] We report herein an expedient synthesis of all-cis 2,4,6-trisubstituted tetrahydropyrans by the intramolecular addition of a cyclopropanol moiety to an oxocarbenium ion, which is generated conveniently by adaptation of the Noyori-Markó protocol (Scheme 1).In connection with the synthetic applications of cyclopropanols as homoenol or homoenolate equivalents, we were attracted to the method developed by the research groups of Noyori and Markó for generating an oxocarbenium ion in situ as an electrophilic reaction partner.[5] We chose the transdialkyl cyclopropanol 1 with a 2-hydroxyalkyl side chain for our initial study (Scheme 2). The syn arrangement of the 1,4-diol relative to the cyclopropane ring in 1 was expected to promote formation of the 7-membered acetal A upon treatment with an aldehyde under the conditions described by Noyori and co-workers, and this intermediate might rearrange to form a tetrahydropyran 4. Compounds of type 1 are readily available through the titanium-mediated hydroxycyclopropanation of homoallylic alcohols. [6,7] The treatment of the bis(trimethylsilyl) ether 2 with isobutyraldehyde (3 a) or octanal (3 b) in the presence of TMSOTf in CH 2 Cl 2 indeed afforded 4 a and 4 b, respectively, as single isomers in good yields. Thin layer chromatographic analysis of the reaction mixture indicated that the acetal A formed rapidly after the addition of TMSOTf to the reactants at À78 8C and was then converted slowly into 4 a or 4 b upon warming.[8] This straightforward procedure was also applicable to a wide range of aldehydes, such as a,b-unsaturated aldehydes, aromatic aldehydes, and alkynals. Thus, 4 c-e were formed in comparable yields and with high selectivities (> 20:1). The observed all-cis relative configuration can be rationalized by the cyclization of an E oxocarbenium ion in a chairlike conformation I.The preformation of bis(trimethylsilyl) ethers was subsequently found to be unnecessary; the direct treatment of 1 with an aldehyde in the presence of TMSOTf (2.5 equiv) also afforded the corresponding tetrahydropyrans. For example, 4 b and 4 c were obtained from 1 and 3 b or 3 c in 68 and 70 % (unoptimized) yield, respectively.As a preliminary study toward natural product synthesis, we next examined the cognate coupling of two oxygenated Scheme 1. Preparation of all-cis 2,4,6...

Modern Developments in the Chemistry of Homoenolates

“…In 2007, Cha reported a TMSOTf-catalyzed coupling of aldehydes and cyclopropanols (Scheme 36), [87] which is akin to the cyclopropanol-aldehyde coupling reaction reported by Minbiole (Scheme 33). [85] Condensation of substrate 138 with the desired aldehyde yields intermediate 140.…”

SN2′ Alkylation of Cyclopropanols via Homoenolates

“…These bifunctional reagents require a delicate balance between stability and reactivity for applications in C À C bond formations. As part of research programs on synthetic applications of the Kulinkovich cyclopropanation, [5,6] we report herein the preparation and in situ S N 2' alkylation of mixed zinc/copper keto homoenolates.Treatment of cyclopropanol with diethylzinc should result in formation of the zinc alkoxide A and ethane (Scheme 1). It is not surprising that known zinc and related metal homoenolates are limited primarily to those bearing weakly electrophilic esters, amides, and nitriles.…”

“…A particularly useful class of homoenolates is zinc homoenolates. As part of research programs on synthetic applications of the Kulinkovich cyclopropanation, [5,6] we report herein the preparation and in situ S N 2' alkylation of mixed zinc/copper keto homoenolates. [1,2] In contrast, little is known about zinc homoenolates of ketones and aldehydes because of the known proclivity of metal homoenolates to cyclize into the corresponding cyclopropoxides.…”

SN2′ Alkylation of Cyclopropanols via Homoenolates

“…(1); M = metal]. As part of research programs on synthetic applications of the Kulinkovich cyclopropanation, [5,6] we report herein the preparation and in situ S N 2' alkylation of mixed zinc/copper keto homoenolates.Treatment of cyclopropanol with diethylzinc should result in formation of the zinc alkoxide A and ethane (Scheme 1). A could be in equilibrium with the homoenolate B, where the former is expected to be strongly favored.…”

“…(1); M = metal]. As part of research programs on synthetic applications of the Kulinkovich cyclopropanation, [5,6] we report herein the preparation and in situ S N 2' alkylation of mixed zinc/copper keto homoenolates.…”