title: Highly trans-selective arylation of Achmatowicz rearrangement products by reductive γ-deoxygenation and Heck-Matsuda reaction: asymmetric total synthesis of (-)-musellarins A-C and their analogues.
abstract: Fully functionalized pyranuloses derived from Achmatowicz rearrangement (AR) are versatile building blocks in organic synthesis. However, access to trans-2,6-dihydropyrans from pyranuloses remains underexplored. Herein, we report a new two-step trans arylation of AR products to access 2,6-trans-dihydropyranones. This new trans-arylation method built on numerous plausible, but unsuccessful, direct arylation reactions, including Ferrier-type and Tsuji-Trost-type reactions, was finally enabled by an unprecedented, highly regioselective γ-deoxygenation of AR products by using Zn/HOAc and a diastereoselective Heck-Matsuda coupling. The synthetic utility of the reaction was demonstrated in the first asymmetric total synthesis of (-)-musellarins A-C and 12 analogues in 11-12 steps. The brevity and efficiency of our synthetic route permitted preparation of enantiomerically pure musellarins and analogues (>20 mg) for preliminary cytotoxicity evaluation, which led us to identify two analogues with three-to-six times greater potency than the musellarins as promising new leads.
authors.affiliation: Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong (P. R. China), Fax: (+852) 2358-1594.
authors.forename: Zhilong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Division of Life Science & State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong (P. R. China).
authors.forename: Fanny C F
authors.initials: FC
authors.lastname: Ip
authors.affiliation: Division of Life Science & State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong (P. R. China).
authors.forename: Nancy Y
authors.initials: NY
authors.lastname: Ip
authors.affiliation: Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong (P. R. China), Fax: (+852) 2358-1594. rtong@ust.hk.
authors.forename: Rongbiao
authors.initials: R
authors.lastname: Tong
mesh_terms: D036381:Diarylheptanoids / Q000138:chemical synthesis* / Q000737:chemistry; D010084:Oxidation-Reduction; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry; D013237:Stereoisomerism; D015032:Zinc / Q000737:chemistry*
chemical_list: D036381:Diarylheptanoids; D011714:Pyrans; C000597877:musellarin A; C000597878:musellarin B; C000597879:musellarin C; C073813:3,4-dihydropyran; D015032:Zinc
keywords: Achmatowicz rearrangement; arylation; musellarins; total synthesis; zinc