Enantioselective synthesis of 5-methylidenedihydrouracils as potential anticancer agents

Abstract

An efficient, versatile, enantioselective synthesis of 1,3-disubstituted and 1,3,6-trisubstituted 5-methylidenedihydrouracils applying Horner-Wadsworth Emmons methodology was developed. Starting 1,3-disubstituted 5-diethoxyphosphoryluracils were subjected to reduction of the double bond or addition of various Grignard reagents and obtained Horner-Wadsworth Emmons reagents were used for the olefination of formaldehyde. Enantioselective synthesis of 1,3,6-trisubstituted 5-methylidenedihydrouracils was accomplished by introducing (R,R)- or (S,S)-di(1-phenylethylamino)phosphoryl groups as chiral auxiliary. Additions of Grignard reagents in the presence of these groups were highly and complimentary diastereoselective (de ∼ 80%). Further separation of the diastereomeric mixtures by column chromatography enabled synthesis of (R)- and (S)-1,3,6-trisubstituted-5-methylidenedihydrouracils with ee ≥ 98%. Furthermore, absolute configuration of the adducts and final products was established using single crystal X-ray analysis. Stereochemical course of the addition reactions is also discussed.