Sphingolipid synthesis, scheme

Kobayashi has reported a remarkable series of chiral Zr(IV) complexes as catalysts for enantioselective aldol addition reactions [136, 137]. These are readily prepared from 3,3 -dihalo-BINOL derivatives and Zr(OtBu)4. The putative zirconium complex 266 is reported to mediate the formation of anti aldol adducts with excellent diastereo- and enantioselectivity (Scheme 4.33). It is noteworthy that under optimal conditions, the reactions are carried out in aqueous propanol/toluene solvent mixtures. As such, the process is tolerant of and indeed thrives in, the presence of water. A demonstration of its use was reported in the synthesis of khafrefungin (269), an inhibitor of fungal sphingolipid synthesis [137]. 

Sphingosine, the essential component of sphingolipids (10.44c) requires phosphate energy carriers and pyridoxal phosphate for its enzymatic synthesis. This is then converted into sphingomyelin according to scheme (11.104). 

This asymmetric Mannich-type reaction was successfully applied to the synthesis of (1 J ,31 )-N-(3-hydroxy-l-hydroxymethyl-3-phenylpropyl) dodecanamide (HPA-12), which is the first compound that specifically inhibits sphingomyelin synthesis in mammalian cells, and is also expected to act as a drug that inhibits intracellular trafficking of sphingolipids (Scheme 3.27). ... 

---