Total Synthesis of Nominal Diazonamides-Part 2: On the True Structure and Origin of Natural Isolates

Abstract

Unable to bear the weight of scrutiny, the original structure proposed for (−)-diazonamide A (1) must be revised. A convergent, stereocontrolled total synthesis provided 1, which shows altered physical and spectroscopic characteristics relative to those of a sample of the natural product. Reinterpretation of reported data and new insight indicate that the actual structure of diazonamide A is the aminal-containing (S)-α-hydroxy isovaleric acid conjugate 2. Gratifyingly, a synthetic C11 acetal congener of 2 is, by all biological measures examined, similarly potent and functionally equivalent to the antimitotic natural product.