Synthesis of a C1-C21 subunit of the protein phosphatase inhibitor tautomycin: a formal total synthesis.
The synthesis of a C1-C21 subunit of tautomycin is described. The convergent route employs enantioenriched allenylstannane and zinc reagents derived from (S)-3-butyn-2-ol methanesulfonate. These reagents react with appropriate aldehyde segments to yield syn and anti adducts with high diastereoselectivity. The derived lithioalkynes are joined stepwise to a CO equivalent, (MeONMe)2C=O, to afford an intermediate ketone which is converted to the core spiroketal moiety of tautomycin upon acid treatment. Chain elongation by another addition of the aforementioned allenylzinc reagent to a spiroketal aldehyde proceeds with high diastereoselectivity to install the remaining stereocenters. The resulting homopropargylic alcohol adduct is converted to a methyl ketone through intramolecular hydrosilylation of the alkyne and Tamao oxidation of the derived five-membered siloxane. This ketone proved identical to an intermediate employed by Chamberlin in a prior total synthesis of tautomycin.
Marshall
J A
JA
Department of Chemistry, McCormick Road, P.O. Box 400319, University of Virginia, Charlottesville, Virginia 22904, USA. jam5x@virginia.edu
Yanik
M M
MM
D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011714:Pyrans; D013056:Spectrophotometry, Ultraviolet; D013141:Spiro Compounds; D013237:Stereoisomerism
D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D011714:Pyrans; D013141:Spiro Compounds; C053079:tautomycin; D010749:Phosphoprotein Phosphatases