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Totally Synthetic by Paul H. Docherty, 26 September 2009

Total Synthesis of Biyouyanagin A


C. Du, L. Li, Y. Li, Z. Xie, Angew. Chem. Int. Ed. 2009, 48, 7853-7856.

DOI: 10.1002/anie.200902908

In the total synthesis of Biyouyanagin A, Zhixiang Xie’s route uses the same end-game as that developed by Nicolaou two years ago. However, he uses some quite powerful chemistry for getting to that point. The right part of the molecule is a distinct natural product - hyperolactone C, with the left hand also natural - zingiberene. The latter was produced as in Nicolaou’s paper, but hyperolactone - the more challenging portion - was produced in a rather different manner.

First up is the synthesis of the actual lactone. The starting material for this chemistry is a rather sensitive tricarbonyl compound, with unusual diazo group. Selective diazotisation of the β-keto ester postion was achieved by working with the benzyl alcohol and oxidising the product with DMP. A rhodium catalyst extruded nitrogen to form a carbonyl ylide, which cyclised to give a furanone.

It was then time for the center-piece - a palladium-catalyzed asymmetric allylic alkylation, pioneered by Barry Trost (Pd-AAA). See also Trost's total syntheses of Tamiflu, Terpestacin or a recent review. However, one case left untouched by Trost is the creation of two adjacent stereocenters in this reaction - a case Xie intended to tackle. In this case, he was using a racemic isoprene monoepoxide along with a Pd catalyst and a that β-keto ester to achieve a respectable yield, a good d.r. and a very high enantiomeric excess. Using a para-chloro substituent on the phenyl ring changes reaction electronics tremendously, so both the yield (68%) as well as the d.r. are improved. However, the removal of such substituents is difficult…

Addition of PTSA resulted in ring formation of the hyperolactone and Xie's part is done. I will now reiterate the synthesis of biyouyanagin A, which is based on Nicolaou’s chemistry. What we need is a photochemical [2+2] cycloaddition. The interesting fact is: this reaction is biomimetic - I wasn’t aware of [2+2]s in nature. Well done! Seven steps in all.