Synthesis of (+)-manoalide via a copper(I)-mediated 1,2-metalate rearrangement.
An enantiospecific synthesis of the phospholipase A(2) inhibitor (+)-(4R)-manoalide is reported in which all 25 carbons of the sesterterpenoid skeleton are constructed from 3-furaldehyde, trimethylalane, oxirane, CO, beta-ionone, and propargyl bromide. The overall yield for the longest linear sequence (12 steps) is 12%. Key steps include (a) a zirconium-catalyzed carboalumination reaction to construct the C10-C11 trisubstituted alkene, (b) a Cu(I)-mediated 1,2-metalate rearrangement to construct the C6-C7 trisubstituted alkene, (c) a Sharpless kinetic resolution to secure the (4R)-stereochemistry, (d) generation of a 5-stannyl-2,3-dihydrofuran by Mo-catalyzed cycloisomerization of a homopropargylic alcohol, and (e) construction of the hydroxyfuranone ring by photooxidation of a silylfuran.
Pommier
Agnès
A
Department of Chemistry, Glasgow University, Scotland.
Stepanenko
Viatcheslav
V
Jarowicki
Krzysztof
K
Kocienski
Philip J
PJ
D000475:Alkenes / Q000032:analysis / Q000138:chemical synthesis*; D000818:Animals; D002384:Catalysis; D003300:Copper / Q000737:chemistry*; D003500:Cyclization; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011161:Porifera / Q000737:chemistry; D013237:Stereoisomerism; D013729:Terpenes / Q000032:analysis / Q000138:chemical synthesis*; D015040:Zirconium / Q000737:chemistry
D000475:Alkenes; D013729:Terpenes; D003300:Copper; D015040:Zirconium; C045673:manoalide