Natural Product Synthesis & Chemical Biology

3. Enantioselective Total Synthesis of Hyperforin and Pyrohyperforin

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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 1,2cyclopropanediol overbred intermediate which was responsible for the 1,3-diene precursor formation through a controlled fragmentation.

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