A synthesis of novel nucleosides as potential antiviral agents

Abstract

4'-페닐과 1'-메틸 더블 측쇄, 1',4'-다이메틸 측쇄, 4'-하이드록시 메틸과 1'-메틸 더블 측쇄, 4', 6'-메틸 더블 측쇄를 가진 카보사이클릭 뉴크레오사이드의 합성은 간단한 2-하이드록시 아세토페논, 아세톨, 1,3-다이하이드록시 아세톤에서 완성되었다. 4'-페닐, 메틸, 하이드록시 메틸 그룹은[3,3]-sigmatropic rearrangement 반응을 경유하여 설치되었고 1'-메틸 그룹을 도입하기 위하여 methylmagnesium bromide의 카보닐 추가를 이용하였으며 6'(α)-위치의 메틸 그룹의 소개는Felkin-Ahn에 의하여 통제된 알킬화에 의해 완성되었다. Divinyls 5, 15, 26, 43, 200의 cyclization은 Grubbs catalyst 2nd를 사용하여 실행되었다. Cyclopentenols 8, 16, 27, 43, 205과 Bases의 연결에 Mitsunobu 반응, Pd(0) catalyst, desilylation을 이용하여 목표의 뉴크레오사이드 11, 21, 22, 34~37, 49~51, 206을 합성하였다. 또한 apiosyl 뉴크레오사이드의 합성은 간단한 material과 1,3-다이하이드록시 아세톤에서 완성되었다. 중간물질 58, 177을 ozonolysis, reductions, acetylation을 이용하여 52과 174에서 얻어 피리미딘, 퓨린 Bases와 연결하여 apiosyl 뉴크레오사이드 66~69, 184~189, 194, 195을 얻었다. 또한 새로운 5'-norcarboacyclic 뉴크레오사이드, acyclic 뉴크레오사이드, phosphonic acid 뉴크레오사이드, cyclopentene phosphonate 뉴크레오사이드, acyclic phosphonate 뉴크레오사이드, fluorocyclopropyl 뉴크레오사이드, acyclic version 6'-methylene and 6'(α)-methylated 뉴크레오사이드를 얻기 위하여 간단한 1,1-사이클로뷰탄 다이칼복실릭산, 다이에틸 말론네트, 2-메틸렌프로판-1,3-다이올, 2-뷰텐-1,4-다이올, 1,3-다이하이드록시 메틸에서 완성되었다. 화합물 209의 6'-위치의 메틸렌 그룹은 Mannich 반응Eshenmoser’s salt을 이용하여 설계하고 화합물 215의 6'(α)-위치의 메틸 그룹은 알킬화반응을 이용하여 설게하였다. 중간물질인 mesylates 73, 87, 98, 109, 120, 127, 141 bromides 156, 157, 211, 217와 Bases는 친핵성 치환반응과 deblocking condition을 통하여 뉴크레오사이드 78~81, 92~95, 103~106, 114~117, 121~124, 132~135, 146~ 149, 166~173, 214, 220을 합성하였다. 그리고 합성한 화합물들을 HIV-1, HSV1, 2, HMCV에 대한 항바이러스를 검색한 결과 화합물 34, 37, 79, 122, 135, 194, 206, 214, 220는 항 HIV-1 약효를 나타내고 화합물 49, 78, 116, 146, 167는 항 HMCV 약효를 나타내었다.|The synthesis of 4'-phenyl and 1'-methyl doubly branched, 1',4'-dimethyl branched, 1'-methyl and 4'-hydroxy methyl doubly branched, 4', 6'-methyl doubly branched carbocyclic nucleosides was accomplished from 2-hydroxy acetophenone, acetol and 1,3-dihydroxy acetone. The 4'-phenyl, methyl, hydr-oxymethyl group was installed via a [3,3]-sigmatropic rearrangement reaction and the carbonyl addition of methylmagnesium bromide was used to introduce the 1'-methyl group. The introduction of a methyl group in the 6'(α)-position was accomplished by Felkin-Ahn controlled alkylation. Cyclization of divinyls 5, 15, 26, 42, 200 was performed using 2nd generation Grubbs catalyst. The coupling of cyclopeantenols 8α, 16α, 27, 43, 201 with bases by Mitsunobu reaction, Pd(0) catalyst and desilylation was used to synthesize the target nucleosides 11, 21, 22, 34~37, 49~51, 206. The synthesis of apiosyl nucleosides was accomplished from material and 1,3-dihydroxy acetone. The key apiosyl intermediates of 58, 177 were constructed by sequential ozonolysis, reductions and acetylation from the 52, 174. Condensation of the acetates of 59, 180 with silylated pyrimidine bases and a purine base under Vorbruggen conditions and deblocking afforded a series of apiosyl nucleosides of 66~69, 184~189, 194, 195. The synthesis of a novel carboacyclic version of 5'-norcarboacyclic nucleosides, acyclic nucleosides, phosphonic acid nucleosides, cyclopentene phosphonate nucleosides, acyclic phosphonate nucleoside, fluorocyclopropyl nucleosides, acyclic version 6'(α)-methylene and 6'(α)-methylated nucleosides was accomplished from 1,1-cyclobutane dicarboxylic acid, diethyl malonate, 2-methylenepropane-1,3-diol, 2-butene-1,4-diol, 1,3-dihydroxy methyl. The introduction of a compound 209 methylene group to the requisite 6'-position was carried out employing a Mannich type reaction using Eshenmoser’s salt. Carbonyl enolate alkylation was used to introduce a compound 215 methyl group to the 6'(α)-position. The condensation of the mesylates 73, 87, 98, 109, 120, 127, 141 and bromides 156, 157, 211, 217 with the natural nucleosidic bases under standard nucleophilic substitution and deblocking conditions, afforded the target nucleosides 78~81, 92~95, 103~106, 114~117, 121~124, 132~135, 146~149, 166~173, 214, 220. The synthesized compounds were evaluated for their antiviral activity against HIV-1, HSV-1, 2 and HCMV. Compounds 34, 37, 79, 122, 135, 194, 206, 214, 220 exhibit toxicity nonrelated to any anti-HIV-1 activity. Compounds 49, 78, 116, 146, 167 exhibited good antiviral activity against the HCMV.