A stereocontrolled, efficient synthetic route to bioactive sphingolipids: synthesis of phytosphingosine and phytoceramides from unsaturated ester precursors via cyclic sulfate intermediates.
An efficient and highly enantioselective method for the preparation of D-ribo- and L-lyxo-phytosphingosines (1a,b, respectively) and phytoceramides (2a,b) has been developed. The key steps in the syntheses are as follows: (i) osmium-catalyzed asymmetric dihydroxylation of 4-O-protected (E)-alpha,beta-unsaturated ester 5 (generated by dihydroxylation of 1-hexadecene, followed by oxidation to the aldehyde and Horner-Wadsworth-Emmons olefination), (ii) conversion to cyclic sulfate intermediate 7, and (iii) regioselective alpha-azidation of 7. Reduction of 4-O-protected 2-azido ester 8 via alpha-azidolactone 9 afforded phytosphingosine 1a. Staudinger reduction of the azido group of 8, followed by in situ N-acylation in aqueous media and reduction of the ester functionality with NaBH(4)/LiBr, provided phytoceramide 2a. By using a similar approach, phytosphingosine 1b was synthesized. D-erythro-4, 5-Dihydrosphingosine 1c and D-erythro-4,5-dihydroceramide 2c were synthesized in high yield from 1-hexadecanol via cyclic sulfate intermediate 15. The desired configurations at C-2, C-3, and C-4 of the sphingoid chain can be accessed readily by the route described here.
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Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing, New York 11367-1597, USA.
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Bittman
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D002518:Ceramides / Q000138:chemical synthesis*; D004952:Esters / Q000737:chemistry; D007202:Indicators and Reagents; D013107:Sphingolipids / Q000138:chemical synthesis*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D013237:Stereoisomerism; D013431:Sulfates / Q000737:chemistry
D002518:Ceramides; D004952:Esters; D007202:Indicators and Reagents; D013107:Sphingolipids; D013431:Sulfates; C012491:phytosphingosine; D013110:Sphingosine