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Non‐iterative Asymmetric Synthesis of C 15 Polyketide Spiroketals
Author(s) -
Meilert Kai,
Pettit George R.,
Vogel Pierre
Publication year - 2004
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200490136
Subject(s) - chemistry , stereochemistry , pyran , nonane , polyketide , cytotoxicity , furan , diol , cancer cell lines , cancer cell , biosynthesis , cancer , in vitro , organic chemistry , biochemistry , medicine , enzyme
The 2,2′‐methylenebis[furan] ( 1 ) was converted to 1‐{(4 R ,6 S ))‐6‐[(2 R )‐2,4‐dihydroxybutyl]‐2,2‐dimethyl‐1,3‐dioxan‐4‐yl}‐3‐[(2 R ,4 R )‐tetrahydro‐4,6‐dihydroxy‐2 H ‐pyran‐2‐yl)propan‐2‐one ((+)‐ 18 ) and its (4 S )‐epimer (−)‐ 19 with high stereo‐ and enantioselectivity ( Schemes 1 – 3 ). Under acidic methanolysis, (+)‐ 18 yielded a single spiroketal, (3 R )‐4‐{(1 R ,3 S ,4′ R ,5 R ,6′ S ,7 R )‐3′,4′,5′,6′‐tetrahydro‐4′‐hydroxy‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2 H ]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 (3 S )‐configuration and conformation. Spiroketals (−)‐ 20 , (−)‐ 21 and analog (−)‐ 23 , i.e. , (1 R ,3 S ,4′ R ,5 R ,6′ R )‐3′,4′,5′,6′‐tetrahydro‐6′‐[(2 S )‐2‐hydroxybut‐3‐enyl]‐7‐methoxyspiro[2,6‐dioxabicyclo[3.3.1]nonane‐3,2′‐[2 H ]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, ED 50 : 6.9 μg/ml).