|Budget Amount *help
¥2,700,000 (Direct Cost : ¥2,700,000)
Fiscal Year 2000 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1999 : ¥700,000 (Direct Cost : ¥700,000)
Fiscal Year 1998 : ¥1,500,000 (Direct Cost : ¥1,500,000)
Development of the synthetic procedures for chiral α, α-disubstituted α-amino acids are of continuing interest, since these compounds are needed for the synthesis of enzyme inhibitors and peptidomimetics. Among these amino acids, an α-substituted serine structure is often observed as a subunit of many biologically active natural products, such as conagenin, lactacystin, myriocins, and mycestericins.
Recently we have been involved in the chiral synthesis of biologically active natural products by utilization of PLE-catalyzed asymmetric hydrolysis of the pro-chiral malonate derivatives, and reported the preparation of the key intermediates for aphanorphine and furanosesquiterpenes. As an extension of this work, we are interested in the synthesis of an α-substituted serine derivative for the preparation of myriocin and its congeners. As a means to investigate the scope and limitation of the PLE-catalyzed asymmetric hydrolysis of pro-chiral malonates, we chose the structurally simple cycloh
exene derivatives as the starting materials, in which the discriminative sites for the enzyme lay between the sp2 and sp3 carbons. To the best of our knowledge for PLE-catalyzed asymmetric hydrolysis of malonate derivatives, none of the application to the compounds having such a small functional difference has been appeared.
Thus, incubation of 1, 1-di-ethoxycarbony-2-cyclohexene in a phosphate buffer solution restulted in the desired half-ester. The obtained half-ester was then converted to an α-substituted serine derivative by introduction of an amino group using Curtius rearrangement, followed by oxidative cleavage reaction of cyclohexene ring, as the key reactions.
In summary, we have disclosed an alternative procedure for the preparation of an α-substituted serine derivative in relatively short steps via asymmetric enzymatic hydrolysis of the malonate derivative, in which the difference between the sp2 and sp3 carbons was discriminated by the enzyme. The enantiomeric excess of the hydrolyzed product obtained here was not high enough for the synthesis of natural compounds, however, the skeletal modification, such as the functionalization of the starting material at the 2 and 6 positions of cyclohexene ring, would be able to increase the enantioselectivity. Moreover, the synthesis of chiral compounds having either R- or S-configuration at the quaternary chiral center might also be possible by employing the functional exchange reaction. Less