Spirotryprostatin B

Cyclodipeptide 2,5-diketopiperazines (DKP) are privileged structural units present in drugs and natural alkaloids. This work reports a new method for the synthesis of biologically important DKP scaffolds based on an intramolecular nucleophilic α-addition of general amides towards an alkynamide system. The utility of this umpolung cyclization mediated by trimethyl phosphine and l-glutamic acid is highlighted by its application to the concise total syntheses of 6-methoxyspirotryprostatin B (the first total synthesis), spirotryprostatin A, and spirotryprostatin B.

Spirotryprostatins, an indole alkaloid class of nonribosomal peptides isolated from Aspergillus fumigatus, are known for their antimitotic activity in tumor cells. Because spirotryprostatins and many other chemically complex spiro-carbon-bearing natural products exhibit useful biological activities, identifying and understanding the mechanism of spiro-carbon biosynthesis is of great interest. Here we report a detailed study of spiro-ring formation in spirotryprostatins from tryprostatins derived from the fumitremorgin biosynthetic pathway, using reactants and products prepared with engineered yeast and fungal strains. Unexpectedly, FqzB, an FAD-dependent monooxygenase from the unrelated fumiquinazoline biosynthetic pathway, catalyzed spiro-carbon formation in spirotryprostatin A via an epoxidation route. Furthermore, FtmG, a cytochrome P450 from the fumitremorgin biosynthetic pathway, was determined to catalyze the spiro-ring formation in spirotryprostatin B. Our results highlight the versatile role of oxygenating enzymes in the biosynthesis of structurally complex natural products and indicate that cross-talk of different biosynthetic pathways allows product diversification in natural product biosynthesis.

A catalytic intramolecular Heck reaction, followed by capture of the resulting η(3)-allylpalladium intermediate by a tethered diketopiperazine, is the central step in a concise synthetic route to (-)-spirotryprostatin B and three stereoisomers. This study demonstrates that an acyclic, chiral η(3)-allylpalladium fragment generated in a catalytic asymmetric Heck cyclization can be trapped by even a weakly nucleophilic diketopiperazine more rapidly than it undergoes diastereomeric equilibration.