Enantioselective desymmetrization of 2-substituted serinols and its synthetic application to sphingofungin E

Abstract

The chiral quaternary carbon with nitrogen atom is considered as valuable building blocks, which are found in various physiologically potent natural products, such as myriocin , manzacidin, lactacystinm sphingofungin, etc. To the best of our knowledge, desymmetrization has not yet been documented to synthesize chiral t-alkylamine building blocks. Herein, we report highly effective enantioselective monobenzoylation of 2-substituted 2-benzamido-1,3-propanediols by catalytic desymmetrization to install chiral quaternary carbon centers and its synthetic application to manzacidin A. Enantioselective as well as chemical conversion proved to be greatly dependent on protecting group of the amino group in the substrate, desymmetrizing reagent, base, solvent, and naturally, catalyst. The highly effective desymmetrization has been implemented using N-benzoylated substrates with benzoyl chloride and triethylamine in the presence of the tetraphenylbisoxazoline $(86)-CuCl_2$ complex in THF at ambient temperature. Extensive survey of catalysts revealed that dimethylmalonate-bridged $bisoxazoline-CuCl_2$ complexs were superior. Among them, the tetraphenylbisoxazoline $(96)-CuCl_2$ complex turned out to work most efficiently with a wide array of the substrates. All the examined substrates except for the 2-phenylserinol 141 have been desymmetrized in the presence of $(96)-CuCl_2$ complex to attain high enantioselectivity ranging from 85 to 95% ee. Complementary use of the diisopropylbisoxazoline $(94)-CuCl_2$ complex has remedied the mediocre desymmetrization of 141 to gain a significantly improved enantioselectivity from 63 to 83% ee. In addition, we have shown the possibility that the chiral t-alkylamine building block prepared by asymmetric desymmetrization can be utilized in a total synthesis of shpingofungin E. To achieve our total synthesis of sphingofunfin E, it is necessary to develop on efficient method for installation of the two hydroxyl groups at the α,β-unsa...