Total synthesis of thapsigargin, a potent SERCA pump inhibitor.
The enantioselective total synthesis of thapsigargin, a potent, selective inhibitor of the Ca2+ pump SERCA, is described. Starting from ketoalcohol 8, key steps involve regioselective introduction of the internal olefin at C4-C5, judicious protecting group choice to allow chelation-controlled reduction at C3, and chemoselective introduction of the angelate ester function at C3-O. A selective esterification approach completes the total synthesis in a total of 42 steps and 0.61% overall yield (88.6% average yield per step). [reaction: see text].
Ball
Matthew
M
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
Andrews
Stephen P
SP
Wierschem
Frank
F
Cleator
Ed
E
Smith
Martin D
MD
Ley
Steven V
SV
D000438:Alcohols / Q000737:chemistry; D000475:Alkenes / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D010084:Oxidation-Reduction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D019284:Thapsigargin / Q000138:chemical synthesis*
D000438:Alcohols; D000475:Alkenes; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases