Asymmetric Allenic Pauson−Khand Reaction to Access Thapsigargin: Influence of aRemote Stereocenter on Stereodifferentiation

Thapsigargin is a potent histamine liberator, a subnanomolar inhibitor of sarco/endoplasmic reticulum calcium ATPase, and a potent inhibitor of major human respiratory viruses including RSV, OC43, SARS-COV-2, and influenza A virus. G202, G115, MAD, and JQ- FT are prodrugs of thapsigargin with anticancer and antileukemic properties. Among more than a hundred synthesized thapsigargin analogs, there are only two reports on a stereochemical change which puts a limit on the SAR studies. To fill this gap, herein we report an asymmetric synthesis of thapsigarin analogs with the potential of accessing different stereoisomers. We initiated the synthesis of thapsigargin using an achiral starting material, 3-furaldehyde, which is a key feature of our approach compared to the three previous total synthesis reports. We synthesized the 5,7,5- ring system of thapsigargin through an asymmetric catalysis approach giving access to a stereochemical array of thapsigargin analogs. The C8 stereocenter was set via an organocatalyzed asymmetric aldol reaction of a heteroarenyl aldehyde and acetone. The C2 stereocenter was set via an asymmetric allenic Pauson–Khand reaction through a catalyst-controlled stereodifferentiative dynamic kinetic asymmetric transformation process. The molecular configuration for all stereoisomers was assigned using VCD and 13C NMR. DFT computed transition state structures were predictive of enantioselectivity and aligned with the stereochemical assignments.