A Maitland-Japp inspired synthesis of dihydropyran-4-ones and their stereoselective conversion to functionalised tetrahydropyran-4-ones.

Paul A Clarke,Nadiah Mad Nasir,Philip B Sellars

doi:10.1039/c5ob00292c

Abstract

The Maitland-Japp reaction has been extended to the synthesis of highly functionalised dihydropyran-4-ones. These dihydropyran-4-ones can in turn be converted stereoselectively into tetrahydropyran-4-ones with tertiary and quaternary stereocentres via the one-pot addition of hydride or carbon nucleophiles and trapping with carbon electrophiles. The utility of this method is demonstrated by providing access to the functionalised tetrahydropyran units present in a component of the Civet fragrance and the anticancer polyketide lasonolide A.

Highlights

Tetrahydropyran (THP) containing natural products, such as (−)-centrolobine, (+)-phorboxazole A and B, (−)-lasonolide A, and Civet cat secretion (Fig. 1), are an important class of synthetic targets because of their challenging architectural features, their biological activities and their limited availability from natural sources
There have been significant developments in the formation of tetrahydropyrans by the Prins reaction[5] and the hetero-Diels–Alder reaction,[6] and these strategies have been applied with varying degrees of success to the synthesis of tetrahydropyran-containing natural products including (−)-centrolobine, (+)-phorboxazole A and B, and (−)-lasonolide A.4
Formation of dihydropyran-4-ones Our initial investigations focused on modifying the Maitland– Japp cyclisation to produce dihydropyran-4-ones 10

Summary

Introduction

Tetrahydropyran (THP) containing natural products, such as (−)-centrolobine, (+)-phorboxazole A and B, (−)-lasonolide A, and Civet cat secretion (Fig. 1), are an important class of synthetic targets because of their challenging architectural features, their biological activities and their limited availability from natural sources. Ducts such as (−)-centrolobine[8] and (+)-phorboxazole B.9,10 Our work in this area focused on updating the venerable Maitland–Japp reaction,[11] initially as a two-pot process involving the addition of the Weiler dianion to an aldehyde in the first step, to be followed by the Lewis acid catalysed Knoevenagel reaction and oxy-Michael cyclisation in the second step.[12] This in turn led to the development of a onepot procedure. When Chan’s diene was used as the nucleophile, we found that we could effect a Lewis acid catalysed Mukaiyama aldol reaction and follow it with the Knoevenagel reaction and oxy-Michael cyclisation, without the need for isolation of the intermediate δ-hydroxy-β-ketoester adduct This generated mixtures of 2,6-cis and 2,6-trans-tetrahydropyran4-ones in good yields.[13] Later we replaced Chan’s diene with diketene and made the reaction pot, atom and step economic (PASE),[14] as well as asymmetric.[14,15].

Results and discussion

Conclusions

For lasonolide A see