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Totally Synthetic by Paul H. Docherty, 17 August 2007

Total Synthesis of Aplysiallene


J. Wang, B. L. Pagenkopf, Org. Lett. 2007, 9, 3703-3706.

DOI: 10.1021/ol701797e

The target is certainly appealing; quite an interesting array of functionality there. It does have some biological activity, as a Na/K ATPase inhibitor, but isn’t particularly potent. The chemistry gets interesting with a desymmetrization of a diol using an orthoester to provide the acetate. Then they form the first tetrahydrofuran (THF) using an interesting Mukaiyama cobalt-catalyzed aerobic oxidative cyclisation, a method popular with the group. They state that the hydroperoxide is there to oxidise the cobalt up to Co(III), but maybe the atmospheric oxygen will do that alone…

Either way, a smart result. They repeat this technique shortly, after a bit of protecting group modifications, generating the fused bis-THF required. The diene is appended by doing an oxidation followed by a pair of Wittig olefinations. On the other end of the molecule, an oxidation and alkylation provided the propargyl alcohol (interestingly using a titanium acetylide, used by Overman in similar work…). Treatment of this with LiCuBr2 gave the allene, with a strong bias towards the desired diastereoisomer (which, in the event, wasn’t the natural product). Nice chemistry!