Sphingosine, aldol reaction

This method has been applied in the enantioselective synthesis of d-erythro-sphingosine and phytosphingosine. Sphingosine became an important substance for studying signal transduction since the discovery of protein kinase C inhibition by this compound.48 Many efforts have been made to synthesize sphingosine and its derivatives.49 Kobayashi et al. reported another route to this type of compound in which a Lewis acid-catalyzed asymmetric aldol reaction was a key step. 

In the synthesis of D-eryt/zro-sphingosine (78 without BOC protection), the key step is the asymmetric aldol reaction of trimethylsilylpropynal 75 with ke-tene silyl acetal 76 derived from a-benzyloxy acetate. The reaction was carried out with 20 mol% of tin(II) triflate chiral diamine and tin(II) oxide. Slow addition of substrates to the catalyst in propionitrile furnishes the desired aldol adduct 77 with high diastereo- and enantioselectivity (syn/anti = 97 3, 91% ee for syn). In the synthesis of protected phytosphingosine (80, OH and NH2 protected as OAc and NHAc, respectively), the asymmetric aldol reaction is again employed as the key step. As depicted in Scheme 3-27, the reaction between acrolein and ketene silyl aectal 76 proceeds smoothly, affording the desired product 80 with 96% diastereoselectivity [syn/anti = 98 2) and 96% ee for syn (Scheme 3-27).50... 

The usefulness of the gold-catalyzed aldol reaction was demonstrated by application of the method to the asymmetric synthesis of the important membrane components D-erythro and ffereo-sphingosines, and their stereoisomers (Scheme 8B1.2) [13], and MeBmt, an unusual amino acid in the immunosuppressive undecapeptide cyclosporine (Scheme 8B1.3) [14]. 

The gold(I)-catalyzed asymmetric aldol reaction with the chiral ligand R)- S)-(1) has been applied in the synthesis of o-erythro-and /lireo-sphingosines (eq 11). The D-eo lIiw-sphingosine can be prepared from the three isomer by inversion of the C-3 hydroxyl group. 

The frans-oxazolines with high enantiomeric excess can readily be converted to optically active fhreo-P-hydroxy-a-amino acids without epimerization by acid hydrolysis. Moreover, the aldol reaction was applied to the total synthesis of Cyclosporin s unusual amino acid MeBmt [ 16], and to the asymmetric synthesis of D-threo- and D-eryfhro-sphingosine, important membrane components [ 17]. The [substrate]/[catalyst] ratio can be raised to 10,000/1 without significant loss of the stereoselectivity in the reaction of 3 with 3,4-methylenedioxybenzalde-hyde (91% ee, translcis=9 l9), indicating that the gold-catalyzed aldol reaction may provide a practical process to produce optically active fhreo-P-hydroxy-a-amino acids [6]. 

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