A Stereodivergent Strategy to Both Product Enantiomers from the Same Enantiomer of a Stereoinducing Catalyst: Agelastatin A

In this article, we report a full account of our recent development of pyrroles and N ‐alkoxyamides as new classes of nucleophiles for palladium‐catalyzed AAA reactions, along with application of these methodologies in the total synthesis of agelastatin A, a marine natural product with exceptional anticancer activity and other biological properties. Our method allows for access to either regioisomer of the pyrrolopiperazinones ( 6 and 19 ) with high efficiency and enantioselectivity. Note that isomer 19 was obtained via a cascade reaction through a double allylic alkylation pathway. From regioisomer 6 , the total synthesis of (+)‐agelastatin A was completed in a very short fashion (four steps from 6 ), during the course of which we developed a new copper catalyst for aziridination and an In(OTf) 3 /DMSO system to oxidatively open an N ‐tosyl aziridine. Starting with the other pyrrolopiperazinone 19 , a five‐step sequence has been developed to furnish a formal total synthesis of (−)‐agelastatin A. A unique feature of our syntheses is the use of two rather different strategies for the total syntheses of both enantiomers of agelastatin A using the same enantiomer of a chiral palladium catalyst.