Gin, Arnold, Day, and DurÃ³n. JACS, 2006, ASAP. DOI: 10.1021/ja063860+.
Yet another top synthesis by David Gin, who really must be one of the most prolific total synthesisers this year! I really appreciate the fact that each molecule completed this year is completely different to the others, and they often contain hugely varying functionality. This time he has turned his attention on the batzelladines, working on structures A & D using some top new methodology. Focusing on batzelladine A, he uses their new methodology quite early-on, setting up the stereochemistry about both of the guanidine centers using a new [4 + 2]-annulation approach, combining a carbodiimide (made via a with a Staudinger-aza-Wittig condensation) with a chiral imine to produce the product in good yield.
He gives a few examples of this cyclisation, one as a lone test case and another in the synthesis of the batzelladine core, and discusses the possible mechanism for the reaction (with four different proposals). My money’s on the inverse electron demand hetero-Diels-Alder, generally cause it’s got a better name . Also, they completed the cyclisation with both geometries of olefin in the carbodiimide, to the same result.
For the left-handside, the five-member ring is opened to a terminal olefin, and the sidechain bolted-on with a bit of Grubbs II action, and transesterification attaches the guanidine sidechain. With this component prepared, they took the other side, a common feature in all batzelladines, and prepared the cesium carboxylate to O-alkylate with the alkyl methanesulfonate of the left-handside. Coupling gave the ester, in a fashion I hadn’t seen used much. Completion of the final ring, salt formation, and deprotection then gave the product, in a rather quick twenty steps!