Preparation of 4‘-Substituted Thymidines by Substitution of the Thymidine 5‘-Esters

• Published in: Journal of organic chemistry Vol. 66; no. 8; pp. 2624 - 2635
• Main Authors: Jung, Michael E, Toyota, Akemi
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.04.2001; Amer Chemical Soc
• Subjects: Anti-HIV Agents - chemical synthesis; Antineoplastic Agents - chemical synthesis; Antiviral Agents - chemical synthesis; Chemistry; Chemistry, Organic; Humans; Physical Sciences; Pyrimidine Nucleosides - chemical synthesis; Science & Technology; Stereoisomerism; Thermodynamics; Thymidine - analogs & derivatives; Thymidine - chemical synthesis; ACID; ANTI-HIV ACTIVITY; ANALOGS; NUCLEOSIDES; NUCLEOCIDIN; INHIBITORS; CLEAVAGE; DERIVATIVES; OLIGONUCLEOTIDES
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo001223a

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 electrophiles, trapping occurs stereoselectively from either the α- or β-face depending on the electrophile (Scheme ). Deuterioacetic acid in deuteriomethanol affords mainly the α-deuterated product (4a/4b = 2.4:1) while all other electrophiles, e.g., phenylselenenyl chloride, 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 products were determined by coupling constant analysis of both the initial compounds and the diols 6bcd prepared 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% overall yield. When the lithium trianion of 9 (prepared by treatment of 9 with excess LDA and then excess tert-butyllithum) is reacted with electrophiles, trapping also occurs stereoselectively with attack on either the α- or β-face depending on the electrophile (Scheme ). Again, deuterioacetic acid in deuteriomethanol affords mainly the β-deuterated product (11a/10a = 1.6:1) while all other electrophiles, e.g., phenylselenenyl chloride, methyl iodide, allyl bromide, and NFSI, gave predominately (or completely) the product of attack from the α-face (8.7:1 to 100: 0). Again, the structures of the products were determined by coupling constant analysis of both the initial compounds, and the diols 12b−e were prepared by reduction of the ester and by formation of the acetonides 13bcd. A rationale has been developed using molecular mechanics calculations to explain the diastereoselectivity that involves staggered axial attack on the sp2 carbon opposite to the pseudoaxial alkoxy group in the most stable half-chair conformation of the enolates, as shown in Schemes −5.