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Synthesis 2006(15): 2447-2474  
DOI: 10.1055/s-2006-942475
REVIEW
© Georg Thieme Verlag Stuttgart · New York

Stereoselective Total Synthesis of Serine Palmitoyl-CoA Transferase Inhibitors

Hoe-Sup Byun, Xuequan Lu, Robert Bittman*
Department of Chemistry and Biochemistry, Queens College, The City University of New York, Flushing, New York 11367-1597, USA
Fax: +1(718)9973349; e-Mail: robert.bittman@qc.cuny.edu;
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Publikationsverlauf

Received 21 February 2006
Publikationsdatum:
04. Juli 2006 (online)

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Abstract

This review summarizes the total syntheses of the fungal metabolites mycestericin, myriocin, viridiofungin, sulfamisterin, and sphingofungin. The syntheses are organized into three sections: the preparation of (a) the long chain and (b) the polar head group, and (c) the coupling of the two parts of the molecule. The mechanism of action of these potent inhibitors of serine palmitoyl-CoA transferase, the rate-limiting enzyme in the biosynthesis of sphingolipids, is also briefly described.

1 Introduction

2 Synthesis of the Lipid Chain

2.1 The Keto Nonpolar Tail

2.2 The 14(R)-Hydroxy Nonpolar Tail

3 Synthesis of the Polar Head Group

3.1 From Carbohydrate Derivatives

3.2 From a Threitol Derivative

3.3 From an Allylic Alcohol

3.4 From an Oxazolidine

4 Formation of the E Double Bond and Completion of the Tota­l Synthesis

4.1 By Coupling Reactions with Alkenyl Iodides

4.2 By Stereoselective Acylation

4.3 By Wittig or Julia Olefination

4.4 By Aldol Reaction

4.5 By Baylis-Hillman Reaction

4.6 By Palladium-Catalyzed Cross-Coupling Reaction

4.7 By Cross-Metathesis

5 Biochemical and Biological Activities of Sphingofungin B, Sulfamisterin, and Myriocin

5.1 SPT Inhibition by Sphingofungin B and Sulfamisterin

5.2 Immunosuppressive Activities of Mycestericin and Myriocin­

5.3 Proposed Mechanism of Inhibition of SPT by Myriocin

6 Conclusion

Key words

sphingolipids - natural products - inhibitors - antifungal agents - stereoselective synthesis