Agariblazeispirol C is a structurally intriguing natural product that has been extracted from <i>Agaricus blazei</i>, a precious fungus that contains a rich source of bioactive natural products. To date, there has been no reported total synthesis of this compound, presenting the opportunity to confirm the structure of this novel target, and to explore any potential biological and pharmacological activity. From a synthetic perspective, the four contiguous, and inherently distinct, stereocentres present within the unconventional steroidal framework makes this molecule a preparatively challenging target. Thus far, we have established the key core skeleton of the natural product (in a racemic sense) through two effective metal-mediated cyclisation processes; an intramolecular Heck reaction and a Pauson-Khand cyclisation.<br/><br/>Furthermore, we have established an approach which lays the foundations for the first asymmetric synthesis of this natural target. The use of an asymmetric intramolecular Heck reaction constructs and establishes the key quaternary carbon centre of the B,C-ring system. This is crucial, and will serve to control the diastereoselectivity of the downstream Pauson-Khand reaction (PKR). An extensive optimisation of the asymmetric Heck reaction was performed, including the study of varying Heck precursors, solvents, additives, and a screen of chiral ligands. Pleasingly, this challenging investigation resulted in an impressive 86% ee with an excellent isolated yield of 85% for the desired system. Efforts are now underway to advance this intermediate towards the completion of the first total synthesis of agariblazeispirol C.

Towards the total synthesis of agariblazeispirol C

2019 Fall National Meeting

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