Synthesis of bioactive marine natural products using intramolecular ene reaction of acylnitroso compounds

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Halichlorine and pinnaic acid are structurally related marine alkaloids isolated by Uemura and co-workers in 1996. The unusual structures of these alkaloids, coupled with the valuable biological activities, have inspired numerous synthetic investigations, culminating in several routes to the core azaspirodecane system. We have developed the synthesis of the Danishefsky key intermediates starting with the azaspirobicyclic ketone as a common precursor, which was obtained using intramolecular ene reaction of acylnitroso compounds and achieved. Upon oxidation of the hydroxamic acid with Pr_4NIO_4, intramolecular ene reaction of the in situ generated acylnitroso compound proceeded smoothly to yield the spirocyclic lactam as a single diastereomer. Subsequent hydrogenation and highly stereoselective ethynylation led to the azaspirocyclic ketone, which was converted to the 1,7-disubstituted 6-azaspiro[4.5]decane key intemediate with the proper stereochemistry established by olefin hydrogenation followed by C-methylation of the tricyclic lactam and the subsequent processes involving lactam ring-opening using methyl triflate. The spirobicyclic compound thus obtained was converted to the TBDPS-protected Danishefsky intermediate in the total synthesis of pinnaic acid via five steps involving Horner-Wadsworth-Emmons homologation. Furthermore, the ethyl ester analog of the Danishefsky key intermediate in the total synthesis of halichlorine was achieved from the azaspirobicyclic aldehyde via ring-closing metathesis of the diene with the second-generation Grubbs'catalyst.