Enantioselective Total Synthesis of Hyperforin and Pyrohyperforin

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 HfCl4‐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. A 9‐step enantioselective total synthesis of both (+)‐hyperforin and its pyran congener (+)‐pyrohyperforin is described herein. The synthesis highlights a late‐stage 1,3‐diene diversification, including an abiotic cyclization cascade for pyran formation, and a selective 1,4‐semihydrogenation of polyenes.