Enantioselective Total Synthesis of Hyperforin and Pyrohyperforin

Abstract

Capitalizing on the late-stage diversification of an essential 1,3-diene intermediate, we describe herein a 9-step enantioselective total synthesis of (+)-hyperforin and (+)-pyrohyperforin, starting from commercially available allylacetone. Our convergent synthesis features a series of critical reactions: 1) an enantioselective deconjugative α-alkylation of α,β-unsaturated acid using chiral lithium amides as noncovalent stereodirecting auxiliaries; 2) a HfCl 4 -mediated carbonyl α-tert-alkylation to forge the intricate bicyclo[3.3.1]nonane framework; 3) an abiotic cascade pyran formation; and 4) a selective 1,4-semihydrogenation of polyenes. During the course of our synthesis, we also identified a 1,2-cyclopropanediol overbred intermediate which was responsible for the 1,3-diene precursor formation through a controlled fragmentation.

The Total Synthesis of Hyperfirin via a Cyclooctadiene Strategy

“…Along with their structural variety, PPAPs exhibit a multitude of intriguing biological activities . As a result, numerous synthetic efforts have been undertaken in the past few decades dedicated to the total synthesis of PPAPs (Figure , 2 , − 3 , − 4 , − 5 , − 6 ). Surprisingly, the bicyclic core structure is mostly derived from six-membered ring structures.…”