Diastereoseletive Transannular Oxa-Conjugate Addition Generates the 2,6-cis-Disubstituted Tetrahydropyran of Neopeltolide

Abstract

Transannular 2,6-disubstituted pyrans, like the one found in the cytotoxic marine natural product neopeltolide, are a key functional group in many polyketides. While oxa-conjugate additions have been shown to provide direct and rapid access to tetrahydropyrans in acyclic neopeltolide intermediates, a transannular strategy for construction of this ring system in a macrocyclic core has not been investigated. In this study, we demonstrate that a transannular oxa-conjugate addition strategy is a viable approach to the construction of the bicyclic core of neopeltolide. We show that transannular addition occurs readily with an α,β-unsaturated ketone as the Michael acceptor and does not occur when an α,β-unsaturated ester is the Michael acceptor. Our data indicates that oxa-conjugate addition is reversible and that the stereochemical outcome can be under thermodynamic control. Using computational chemistry, we show that the lowest energy diastereomer is the desired cis-pyran found in neopeltolide, and we experimentally demonstrate that the trans and cis diastereomers are interconvertible under reaction conditions with the cis-pyran product predominating. This oxa-conjugate addition strategy should provide a viable route to accessing the fully elaborated macrocyclic core of neopeltolide.

Contemporary Strategies for the Synthesis of Tetrahydropyran Derivatives: Application to Total Synthesis of Neopeltolide, a Marine Macrolide Natural Product

“…Florence and Cadou reported their synthetic studies on neopeltolide, in which a transannular oxa-Michael reaction was planned as a key transformation [ 157 ]. Very recently, Boddy et al reported the synthesis of a neopeltolide model compound by using a transannular oxa-Michael addition [ 158 ].…”

Six-Membered Ring Systems

“…Ring-closing metathesis was applied to the synthesis of 3,6-dihydro-2H-pyrans starting from diene and enyne skeletons using Grubbs catalysts (16TA954,16EJO3900) and also to construct the 5,6-dihydropyran-2-one ring in many natural compounds including cryptocaryol (16AGE5049), cryptomoscatone D1 and (5R,7S)-kurzilactone (16TL1087), the C1-C27 subunit of hemicalide (16JOC11275), 12 withanolide analogs (16S48), and in the synthesis of eight pure stereoisomers of pironetin-dumetorine hybrids, a new scaffold for tubulin binders (16EJO2029). Prins cyclization was used to build the tetrahydropyran core of four diarylheptanoids from Dioscorea villosa (16TL3505), while oxa-Michael cyclization reactions were used to prepare the tetrahydropyran rings of (−)-gilbertine (16JOC4566), neopeltolide (16JOC415), rhopaloic acid A (16AGE3455), and fragments of various polyketides (16AGE6280).…”