A Diastereoselective Ring Contraction of 1,3-Dioxepins to 2,3,4-Trisubstituted and Tetrasubstituted Tetrahydrofurans

Abstract

A modular and diastereoselective approach to 2,3,4-trisubstituted and tetrasubstituted tetrahydrofurans is reported. The use of dioxepins containing an embedded vinyl acetal functionality leads to a Lewis acid-mediated [1,3] ring contraction to afford tetrahydrofurans in good yield and excellent diastereoselectivity. The use of TMSOTf in MeCN leads to the 2,3-cis/3,4-trans diastereomer while SnCl4 in CH2Cl2 provides the 2,3-trans/3,4-cis diastereomer. A variety of substituents are tolerated at each position. The presence of Lewis basic functionality under the SnCl4 conditions alters the reaction favoring the diastereomer formed under the TMSOTf conditions. We present conclusive evidence that the products of each of these reactions are formed under kinetic control. We further provide stereochemical models consistent with each of these rearrangement reactions that account for the formation of the major diastereomer in each case.

Recent advances in the synthesis of tetrahydrofurans and applications in total synthesis

“…148 Another strategy developed by Rovis and co-workers involves a cyclic acetal, which is activated by a Lewis acid to perform a ring contraction by Mukaiyama-aldol reaction leading M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT to 2,3,4-trisubstituted THF. 149 Notably, the choice of the Lewis acid can lead to two different diastereoselectivities. A similar approach has also been exploited by Friestad and co-workers, but with an external nucleophile (Scheme 44).…”

Heterocyclic chemistry

“…In another highly adaptable approach Oh and colleagues 50 Ring contraction of 1,3-dioxepines allowed the formation of highly substituted tetrahydrofurans wherein the stereoselectivity was dependent upon the conditions employed (see Scheme 33). 51 This process was adapted to allow access to furofuran lignan natural products such as sylvone. 52 Copper catalysed cyclisation of N1-functionalised bromoarylureas in water by the SanMartin and Domı´nguez group 53 gave a range of useful benzimidazolones (Scheme 34).…”

Highly Diastereoselective, Tandem, Three‐Component Synthesis of Tetrahydrofurans from Ketoaldehydes via Silylated β‐Lactone Intermediates

“…[10] The THF motif is commonly found in natural products, and while several approaches toward these heterocycles exist, many routes rely on CÀO bond formation of relatively complex substrates or proceed through oxocarbenium ions derived from O-glycosides. [11] Herein we describe the development of a tandem, threecomponent synthesis of THFs 9 from g-ketoaldehydes 6, thiopyridyl ketene acetals 2, and silyl nucleophiles in which up to two CÀC bonds, one CÀO bond, and three new stereocenters are generated.…”