| Abstract
| - tert-Butyl thymidylate 3 was prepared from thymidine 1 in six steps and 67% overall yield. Whenthe lithium trianion of 3 (prepared by treatment of 3 with excess LDA and then excesstert-butyllithum) is reacted with electrophiles, trapping occurs stereoselectively from either the α-or β-face depending on the electrophile (Scheme ). Deuterioacetic acid in deuteriomethanol affordsmainly the α-deuterated product (4a/4b = 2.4:1) while all other electrophiles, e.g., phenylselenenylchloride, allyl bromide, and N-fluorobenzenesulfonimide (NFSI), give predominately (or completely)the products of attack from the β-face (5bcd/4bcd = 3.7:1 to 100:0). The structures of the productswere determined by coupling constant analysis of both the initial compounds and the diols 6bcdprepared by ester reduction and 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 74% overallyield. When the lithium trianion of 9 (prepared by treatment of 9 with excess LDA and then excesstert-butyllithum) is reacted with electrophiles, trapping also occurs stereoselectively with attackon either the α- or β-face depending on the electrophile (Scheme ). Again, deuterioacetic acid indeuteriomethanol affords mainly the β-deuterated product (11a/10a = 1.6:1) while all otherelectrophiles, e.g., phenylselenenyl chloride, methyl iodide, allyl bromide, and NFSI, gavepredominately (or completely) the product of attack from the α-face (8.7:1 to 100: 0). Again, thestructures of the products were determined by coupling constant analysis of both the initialcompounds, and the diols 12b−e were prepared by reduction of the ester and by formation of theacetonides 13bcd. A rationale has been developed using molecular mechanics calculations to explainthe diastereoselectivity that involves staggered axial attack on the sp2 carbon opposite to thepseudoaxial alkoxy group in the most stable half-chair conformation of the enolates, as shown inSchemes −5.
|
