Design and synthesis of N-nonpolar nucleobasedipeptides: application of the Ugi reaction for the preparation of dipeptides having fluoroarylalkyl groups appended to the nitrogen atom

Abstract

A single-step one-pot synthesis based on the Ugi four-component condensation of previously unknown dipeptides, 2, 3, 4 and 5, having a fluoroaromatic group appended to the nitrogen atom, is described. The series of dipeptides produced here can be viewed as nonpolar nucleobase dipeptides since the difluorotoluene nucleoside 1 is a well known nonpolar analogue of natural thymidine. A mixture of N-protected amino acids 7, fluorophenethylamines 6, isocyanides 8, and acetone or paraformaldehyde are stirred in methanol in the presence of 3 Å molecular sieves to furnish the N-fluoroarylethyl-Aib- or -Gly-containing dipeptides 2 or 3, in moderate yields. The dipeptides 2d and 3b, having a cyclohex-1-enamide moiety, are deprotected readily with 3 M HCl in THF to afford the free dipeptides in high yields. The N-fluoroarylmethyl-Aib- or -Gly-containing β-alanyl dipeptides 4 or 5, designed based on the structure of 2′,5′-linked isoDNA, are also synthesized in a similar fashion to the preparation of 2, in moderate to good yields as both protected and free dipeptides.