Non‐iterative Asymmetric Synthesis of C15 Polyketide Spiroketals

Abstract

AbstractThe 2,2′‐methylenebis[furan] (1) was converted to 1‐{(4R,6S))‐6‐[(2R)‐2,4‐dihydroxybutyl]‐2,2‐dimethyl‐1,3‐dioxan‐4‐yl}‐3‐[(2R,4R)‐tetrahydro‐4,6‐dihydroxy‐2H‐pyran‐2‐yl)propan‐2‐one ((+)‐18) and its (4S)‐epimer (−)‐19 with high stereo‐ and enantioselectivity (Schemes 1–3). Under acidic methanolysis, (+)‐18 yielded a single spiroketal, (3R)‐4‐{(1R,3S,4′R,5R,6′S,7R)‐3′,4′,5′,6′‐tetrahydro‐4′‐hydroxy‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐6′‐yl}butane‐1,3‐diol ((−)‐20), in which both O‐atoms at the spiro center reside in equatorial positions, this being due to the tricyclic nature of (−)‐20 (methyl pyranoside formation). Compound (−)‐19 was converted similarly into the (4′S)‐epimeric tricyclic spiroketal (−)‐21 that also adopts a similar (3S)‐configuration and conformation. Spiroketals (−)‐20, (−)‐21 and analog (−)‐23, i.e., (1R,3S,4′R,5R,6′R)‐3′,4′,5′,6′‐tetrahydro‐6′‐[(2S)‐2‐hydroxybut‐3‐enyl]‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2H]pyran]‐4′‐ol, derived from (−)‐20, were assayed for their cytotoxicity toward murine P388 lymphocytic leukemia and six human cancer cell lines. Only racemic (±)‐21 showed evidence of cancer‐cell‐growth inhibition (P388, ED50: 6.9 μg/ml).