Preparation of 4 '-substituted thymidines by substitution of the thymidine5 '-esters

tert-Butyl thymidylate 3 was prepared from thymidine 1 in six steps and 67% overall yield. When the lithium trianion of 3 (prepared by treatment of 3 with excess LDA and then excess tert-butyllithum) is reacted with electroph iles, trapping occurs stereoselectively from either the alpha -or beta -fac e depending on the electrophile (Scheme 1). Deuterioacetic acid in deuterio methanol affords mainly the alpha -deuterated product (4a/4b = 2.4:1) while all other electrophiles, e.g., phenylselenenyl chloride, allyl bromide, an d N-fluorobenzenesulfonimide (NFSI), give predominately (or completely) the products of attack from the beta -face (5bcd/4bcd = 3.7:1 to 100:0). The s tructures of the products were determined by coupling constant analysis of both the initial compounds and the diols 6bcd prepared by ester reduction a nd by formation of the acetonides 7bc. The methyl ester of the 3 ' -epimer of thymidylic acid 9 was also prepared from thymidine 1 in nine steps and 7 4% overall yield. When the lithium trianion of 9 (prepared by treatment of 9 with excess LDA and then excess tert-butyllithum) is reacted with electro philes, trapping also occurs stereoselectively with attack on either the al pha- or beta -face depending on the electrophile (Scheme 2). Again, deuteri oacetic acid in deuteriomethanol affords mainly the beta -deuterated produc t (11a/10a = 1.6:1) while all other electrophiles, e.g., phenylselenenyl ch loride, methyl iodide, allyl bromide, and NFSI, gave predominately (or comp letely) the product of attack from the alpha -face (8.7:1 to 100: 0). Again , the structures of the products were determined by coupling constant analy sis of both the initial compounds, and the diols 12b-e were prepared by red uction of the ester and by formation of the acetonides 13bcd. A rationale h as been developed using molecular mechanics calculations to explain the dia stereoselectivity that involves staggered axial attack on the sp(2) carbon opposite to the pseudoaxial alkoxy group in the most stable half-chair conf ormation of the enolates, as shown in Schemes 3-5.