title: Diastereoselective one-pot Wittig olefination-Michael addition and olefin cross metathesis strategy for total synthesis of cytotoxic natural product (+)-varitriol and its higher analogues.
abstract: A stereoselective route for the total synthesis of anticancer marine natural product (+)-varitriol (1) is detailed herein. The impressive biological activity and interesting structural features of natural (+)-varitriol fuelled us to undertake the synthesis of some higher analogues (1a-j) of this molecule. The key features of the synthetic strategy include one-pot Wittig olefination followed by a highly diastereoselective oxa-Michael addition to assemble stereochemically pure tetrasubstituted THF moiety of the natural varitriol and olefin cross metathesis to couple the aromatic part with tetrasubstituted THF moiety. The total synthesis of title natural product is efficient with 21.8% overall yield for 9 linear steps from D-ribose and thus facilitates the more scaled-up practical route for the synthesis of 1 and its analogues as well. The synthetic (+)-varitriol (1) and its analogues were screened for their cytotoxicity. The present synthetic approach paves the way for preparation of numerous analogues of the title natural product for drug development.
authors: Division of Medicinal and Process Chemistry, Central Drug Research Institute (CDRI), CSIR, Lucknow, 226 001, India.
authors: Partha
authors: P
authors: Ghosal
authors: Deepty
authors: D
authors: Sharma
authors: Brijesh
authors: B
authors: Kumar
authors: Sanjeev
authors: S
authors: Meena
authors: Sudhir
authors: S
authors: Sinha
authors: Arun K
authors: AK
authors: Shaw
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001592:Benzyl Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D051379:Mice; D008968:Molecular Conformation; D041681:NIH 3T3 Cells; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000475:Alkenes; D000970:Antineoplastic Agents; D001592:Benzyl Alcohols; D001688:Biological Products; D005663:Furans; C456047:varitriol