An efficient synthetic strategy for cis-clerodane diterpenoids has been developed. The key ingredient is the face selective Diels-Alder reaction of dienophile 8. The successful application of this strategy has culminated in the total synthesis of the naturally occurring compound 6b-acetoxy-2-oxokolavenool in racemic form.Clerodane diterpenoids form a very large family of secondary metabolites; over one thousand members have so far been identified. 1 From a biological point of view, clerodanoids are rather interesting. A broad spectrum of significant biological activities has been found for the major portion of the relative few compounds screened. 2 According to the stereochemistry around the ring junction of the decalin nucleus, clerodanes are subdivided into the transand cis-series in roughly 2:1 ratio. During the past twenty years, extensive efforts have been devoted towards the total synthesis of this family of the diterpenoids. 3 Most of the synthetic approaches, however, are designed to tackle a specific target molecule. The natural abundance of a series of structurally closely related clerodanes dictates the development of a common strategy for their synthesis. Recently, a general approach to the cis-series of compounds has been developed in our laboratories. 4 As demonstrated in Scheme 1 with (+/-)-6b-acetoxy-2-oxokolavenool (1) as a specific example, 4c the key operation involves the face selective Diels-Alder addition of dienone ester 2 to trans-piperylene allowing the rapid construction, in a highly stereoselective manner, of the required decalin core with concomitant placement of several functional groups into the strategic positions. This approach proved to be highly versatile. Its application has resulted in the successful synthesis of several other cisclerodanes. 4b,c,5 However, there are a couple of drawbacks which reduce the overall efficiency of the synthetic approach. Both the installation of the angular methyl group (3®4) and the modification of the benzyl side chain to the butanone moiety (5®6) require lengthy operations (four steps each). We have since developed a considerably more efficient general strategy in which these problems have been successfully addressed. In this communication we wish to illustrate this newly developed synthetic strategy for cis-clerodanes using compound 1 as a specific example.
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