Synthesis and Antiviral Evaluation of Novel 6′(α)‐Methyl‐Branched Carbovir Analogues

Abstract

A new stereoselective synthesis of 6'-branched Carbovir analogues was accomplished in this study. The introduction of a methyl group in the requisite 6'(alpha)-position was carried out using an ester enolate alkylation (LHMDS, CH3I). The desired cyclopentenol 7 was synthesized via a Felkin-Anh-controlled Grignard addition and ring-closing metathesis using second-generation Grubbs' catalyst. The natural bases (adenine, cytosine) were efficiently coupled using a Pd(0) catalyst. When the synthesized compounds were examined for their activity against several viruses such as the HIV-1, HSV-1, HSV-2, and HCMV, the adenine analogue 12 exhibited moderate antiviral activity against the HCMV.

Synthesis and Antiviral Activity of 2'(β)-Hydroxymethylated Carbodine Analogues Against Hepatitis C Virus

“…The γ,δ-unsaturated ethyl ester 5 was readily synthesized from the commercially available 2-butene-1,4-diol (4) using the reported procedure. 12 The ester 5 was reduced to the corresponding aldehyde 6 using DIBAL-H in toluene at -78 o C. The condensation of 6 with the lithium reagent prepared from 3 equivalents of 2-bromo-allyloxy-tert-butyldimethylsilane 7 and 2.5 equivalents of butyllithium in THF at -110 o C yielded diene analogue 8 13 (Scheme 1). The diene analogue 8 diastereomeric mixture was subjected to ring-closing metathesis (RCM) conditions [14][15][16][17][18] to yield cyclo- 2'-C-Me-C: 2'-C-Methylcytidine.…”

Synthesis and anti-HIV Study of Novel Acyclic Guanine Derivatives

“…[9] The addition of one equivalent of DIBALH to a solution of the ester 4 in anhydrous toluene at −78 • C gave the reduced aldehyde derivative 5. The treatment of carbonyl 5 with the Eschenmoser salt (methylene-N ,N -dimethylammonium iodide) [10,11] gave α-methylenated aldehyde derivative 6, which was subjected to the Luche reduction procedure (NaBH 4 /CeCl 3 ·7H 2 O) [12,13] using sodium borohydride in the presence of cerium chloride to provide the allylic alcohol 7.…”

“…First, an attempt was made to methylate the carbonyl derivative 5 using the well-known alkylation procedure (LiHMDS/CH 3 I), which was previously developed in our laboratory obtaining 12. [9] The carbonyl functional group of compound 12 was reduced using the Luche procedure to give the alcohol 13. Compound 13 was subjected to similar reaction conditions as described above for compound 11 (bromination, purine base condensation, and deprotection) to provide the target nucleoside 17 (Scheme 2).…”

Synthesis of Cyclopentitols by Ring-Closing Approaches

“…A stereoselective synthesis of 6′-branched carbovir analogues 75 has been accomplished starting from dihydroxy butene 72 (Scheme 24). 168 The cyclopentenol 74 has been obtained in good yield by RCM of diene 73 as an easily separable isomeric mixture.…”