Scaling Up The Axinellamines

A quicker, more efficient, and stereocontrolled route to a key intermediate in the total syntheses of axinellamines, massadines, and palau’amine has been developed. The route provides access to gram quantities of the natural products—amounts needed to conduct follow-up studies on their biological properties. Scripps Research Institute’s Phil S. Baran recognized a central inefficiency in his group’s syntheses of the aforementioned compounds: All went through a common spiroaminoketone intermediate, which was synthesized in 1% overall yield via a 20-step sequence that proceeded without stereocontrol at the spiro carbon. Along with coworkersShun Su and Rodrigo A. Rodriguez, Baran was able to shorten this route to just eight steps with 13% overall yield and stereocontrol at the spiro carbon (J. Am. Chem. Soc., DOI: 10.1021/ja206191g). Synthetic highlights include an ethylene glycol-assisted Pauson-Khand cycloaddition reaction, an indium/zinc-mediated Barbier-type reaction, and a chlorination-spirocyclization. With gram batches of the spiroaminoketone in hand, Baran’s team went on to synthesize 0.89 g and 0.22 g of axinellamine A and B, respectively, “dramatically surpassing both the efficiency of our previous synthesis and isolation from natural sources,” they note.