Elsevier

Tetrahedron

Volume 64, Issue 10, 3 March 2008, Pages 2359-2368
Tetrahedron

A simple route to enantiopure bis-lactones: synthesis of both enantiomers of epi-nor-canadensolide, nor-canadensolide, and canadensolide

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Abstract

A simple strategy has been developed for the synthesis of both enantiomers of nor-canadensolide, epi-nor-canadensolide, and an intermediate to canadensolide. An orthoester Claisen rearrangement of an appropriately constructed allyl alcohol derivative prepared from R-(+)-2,3-di-O-cyclohexylidine glyceraldehyde followed by epoxidation of the resulting unsaturated esters produced hydroxy-lactones, which on oxidation gave keto-lactones. Stereoselective reduction of the keto-carbonyl using either a chelation controlled or a non-chelation controlled process led to the natural or the epi-series, respectively. The interplay of the electronic effect between the polar groups and the steric effect of the β-substituent during reduction of the keto-lactones turned out to be the key factors in deciding the stereochemical outcome. Regeneration of the aldehyde functionality latent in the ketal moiety of the hydroxy-lactones provided the lactols, which on oxidation gave the bis-lactones.

Introduction

The bis-lactone represented by the general structure 1 is found in a number of structurally related natural products such as canadensolide 1a,1 sporothriolide 1b,2 and xylobovide 1c.3 They differ only in the length of the side chain. These compounds exhibit important biological activities. For example, canadensolide 1a, a mold metabolite formed by Penicillium canadense, possesses an antigerminative activity against fungi. Sporothriolide is an antibacterial, fungicidal, algicidal, and herbicidal agent while xylobovide is a phytotoxic agent. Due to the novel structure with three contiguous stereocenters and interesting biological activities, considerable attention has been focused on the development of new methodology for their synthesis.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 As part of our interest in the synthesis of natural products containing fused butyro-lactones,22 we initiated a program for developing a general flexible route toward the synthesis of these bis-lactones.

We envisaged the bicyclic lactols 2 with appropriate alkyl chain (R) as the intermediates to the bis-lactones (Scheme 1). In a few earlier approaches to canadensolide, the lactol 2a has served as an intermediate. The lactol 2 would become available from the keto-lactone 3. The ketal moiety in 3 would provide the aldehyde functionality and a stereocontrolled hydride reduction of the carbonyl group would deliver the hydroxyl group required for lactol formation. The keto-lactone 3 in principle should be available from the unsaturated ester 4 through lactonisation initiated by addition of an electrophile to the carbon–carbon double bond. Hydride reduction of the carbonyl group with a heteroatom at the α-chiral center generally proceeds with high diastereoselectivity especially when the reaction proceeds through a metal chelated intermediate. The keto-lactone 3 possesses a heteroatom (ring oxygen) next to the carbonyl group. In addition, it has a bulky substituent at β to the carbonyl group. Presumably, the stereochemical outcome during reduction of the keto-carbonyl in 3 would be determined by the interplay of the electronic effect exerted by the lactone oxygen and the steric hindrance posed by the ketal substituent. During the present synthetic investigation we had the opportunity to explore the stereochemical outcome in the reduction of the keto-lactone 3 along with its other three possible diastereomers. This investigation has allowed access to either the natural series or the epi-series of the bis-lactones. In this paper the approach is illustrated by a total synthesis of both enantiomers of nor-canadensolide, epi-nor-canadensolide and a formal synthesis of (+)-canadensolide and (−)-canadensolide.

Section snippets

Results and discussion

The unsaturated ester required for canadensolide was prepared from the allylic alcohol 5 as delineated in Scheme 2. The allylic alcohol 5 was obtained from R-(+)-2,3-di-O-cyclohexylidine glyceraldehyde according to the known procedure.23 Oxidation of the alcohol 5 with Dess–Martin periodinane (DMP)24 afforded the aldehyde 6 in excellent yield. Addition of n-BuLi to the aldehyde 6 followed by orthoester Claisen rearrangement of the resulting alcohol 7 led to a 1:1 mixture of the two

Conclusion

We have developed a general strategy for synthesis of the bis-lactone 1 in enantiomerically pure form. The strategy has been illustrated by a formal synthesis of both enantiomers of canadensolide starting from R-(+)-2,3-di-O-cyclohexilidine glyceraldehyde. Stereocontrolled reduction of the carbonyl group in an appropriately constructed keto-lactone gave both canadensolide and epi-canadensolide. The stereochemical outcome during reduction of the carbonyl group in the keto-lactones has been

General

Melting points were taken in open capillaries in a sulfuric acid bath. Petroleum ether refers to the fraction having bp 60–80 °C. A usual workup of the reaction mixture consists of extraction with ether, washing with brine, drying over Na2SO4, and removal of the solvent in vacuo. Column chromatography was carried out with silica gel (60–120 mesh). Peak positions in 1H and 13C NMR spectra are indicated in parts per million downfield from internal TMS in δ units. NMR spectra were taken in CDCl3 at

Acknowledgements

S.G. thanks Department of Science and Technology, Government of India for Ramanna Fellowship. S.M. thanks CSIR, New Delhi for Junior Research Fellowship. We are thankful to Professor D. Datta of Inorganic Chemistry Department of this Institute for AM1 calculations.

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