Stereoselective preparation of ceramide and its skeleton backbone modified analogues via cyclic thionocarbonate intermediates derived by catalytic asymmetric dihydroxylation of alpha,beta-unsaturated ester precursors.
A novel and efficient synthetic route to ceramide 1a and skeleton backbone modified ceramide analogues 1b,c is reported. The syntheses utilize osmium-catalyzed asymmetric dihydroxylation of (E)-alpha, beta-unsaturated ester 5a-c as the chiral induction step, with the desired configurations in the products 1a-c, 2a, and 13 being generated by regioselective azide substitution at the alpha position of alpha,beta-dihydroxyesters 6a-c via a cyclic thionocarbonate intermediate. Azido esters 10a-c are converted to the corresponding ceramides 1a-c by a sequence of azide reduction, N-acylation, ester reduction (NaBH(4)/LiBr), and Birch reduction of the triple bond (Li, EtNH(2)). These seven- to eight-step syntheses afford the target compounds 1a-c with excellent stereocontrol and in 30-42% overall yields. Furthermore, propargylic alpha-azido-beta-hydroxyester 10a is converted to D-erythro-sphingosine 2a via simultaneous reduction of the triple bond, azido, and ester functional groups with LiAlH(4), providing a highly concise and practical four-step synthesis of this key naturally occurring sphingolipid. The L-erythro stereoisomers are also available in high enantiomeric purity by the method described herein.
He
L
L
Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, New York 11367-1597, USA.
Byun
H S
HS
Bittman
R
R
D002384:Catalysis; D002518:Ceramides / Q000138:chemical synthesis*; D004952:Esters / Q000138:chemical synthesis; D006900:Hydroxylation; D007202:Indicators and Reagents; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013440:Sulfides / Q000138:chemical synthesis*
D002518:Ceramides; D004952:Esters; D007202:Indicators and Reagents; D013440:Sulfides; D013110:Sphingosine