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Catalytic enantioselective Mannich-type reactions of silyl enol ethers with aldimines have been successfully performed using a novel chiral zirconium catalyst prepared from zirconium(IV) tert-butoxide (Zr(O t Bu)4), 2 equiv of (R)-6,6‘-dibromo-1,1‘-bi-2-naphthol ((R)-6,6‘-Br2BINOL), and N-methylimidazole. The use of aldimines having N-substituted hydroxyphenyl moieties is essential for obtaining high selectivities, and the N-substituted groups were converted to free amines using oxidative cleavage. Aldimines derived from aromatic aldehydes as well as heterocyclic and aliphatic aldehydes reacted with silyl enol ethers smoothly to afford the corresponding β-amino acid derivatives in high yields and high enantioselectivities. Several NMR experiments have been conducted to clarify the structure of the chiral Zr catalyst and also the catalytic cycle of this asymmetric reaction. Finally, a new BINOL derivative, (R)-6,6‘-bis(trifluoromethyl)-1,1‘-bi-2-naphthol ((R)-6,6‘-(CF3)2BINOL), has been prepared. It was shown that the turnover of the catalyst using this novel ligand was improved, and high levels of yields and selectivities were obtained in the presence of a small amount of the zirconium catalyst.

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Ceramide produced at the endoplasmic reticulum (ER) is transported to the lumen of the Golgi apparatus for conversion to sphingomyelin (SM). N-(3-HydroxySphingolipids are ubiquitous constituents of membrane lipids in mammalian cells and play important roles in cell growth, differentiation, and apoptosis (1-3). Moreover, together with cholesterol, sphingolipids in plasma membrane constitute detergent-resistant microdomains termed lipids rafts, which are involved in membrane trafficking and cell signaling (4,5).De novo biosynthesis of sphingolipids in mammalian cells proceeds as follows (6). The first step is the condensation of L-serine and palmitoyl-CoA, a reaction catalyzed by serine palmitoyl transferase, to generate 3-ketodihydrosphingosine, which is reduced to dihydrosphingosine. Dihydrosphingosine undergoes N-acylation followed by desaturation to generate ceramide (Cer).1 These reactions to produce Cer occur at the cytosolic surface of the endoplasmic reticulum (ER) (7-9). Then, Cer is delivered to the luminal side of the Golgi apparatus and converted to sphingomyelin (SM) by SM synthase catalyzing the transfer of phosphocholine from phosphatidylcholine to Cer (10,11). Cer is also converted to glucosylceramide (GlcCer) by GlcCer synthase catalyzing the transfer of glucose from UDP-glucose to Cer. Although the catalytic site of GlcCer synthase appears to be oriented to the cytoplasm (12, 13), it is controversial whether GlcCer synthase is localized to the Golgi apparatus or more broadly distributed to microsomes. After translocation to the luminal side of the Golgi apparatus, GlcCer is further converted to more complex glycosphingolipids (14).We have previously showed that there are two pathways for transport of de novo synthesized Cer from the ER to the site of SM synthesis in various types of cultured cells, including Chinese hamster ovary (CHO) cells, HeLa cells, and human skin fibroblasts (15). The main pathway of the two is ATP-dependent, and the minor pathway is ATP-independent (or less dependent). In contrast to the synthesis of SM, the access of Cer to the site of GlcCer synthesis is largely independent of ATP. Analysis by in vitro assay of Cer transport in semi-intact CHO cells further revealed that the ATP-dependent transport of Cer, from the ER to the site of SM synthesis, requires cytosol but that cytosol is not required for transport of Cer to the site of GlcCer synthesis (16). In addition, that a CHO cell mutant defective in the ATP-dependent pathway of Cer transport exhibits no defect in transport of proteins from the ER to the Golgi apparatus has suggested that the mechanism of Cer transport differs from that of ER-to-Golgi trafficking of proteins (15).Inhibitors of de novo sphingolipid biosynthesis are useful tools to investigate the metabolism and functions of sphingolipids in cultured cells and in living animals. Various natural and chemically synthesized compounds have been found to be * The costs of publication of this article were defrayed in part by the payment of page charges. This ar...

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