(1S,2R)-[(benzyloxy)methyl]cyclopent-3-enol. A versatile synthon for the preparation of 4',1'a-methano- and 1',1'a-methanocarbocyclic nucleosides
(1S,2R)-[(benzyloxy)methyl]cyclopent-3-enol. A versatile synthon for the preparation of 4',1'a-methano- and 1',1'a-methanocarbocyclic nucleosides
复制标题
DOI：
10.1021/jo962124t
复制
发表时间：
1997-07-11
影响因子：
3.6
通讯作者：
Marquez, VE
中科院分区：
文献类型：
--
作者：
Ezzitouni, A;Russ, P;Marquez, VE
简介4', 1'a-甲基碳环胸苷（1，方案1）是最近发现的一种有效的抗疱疹病毒药物，其体外抗HSV-1和HSV-2活性优于阿昔洛韦。 1 然而，结构相关且构象不同的 1', 1' a-亚甲基碳环胸苷 (2) 完全没有抗病毒活性。 1, 2 我们最近提出，1 和 2 之间的差异可能与刚性双环所施加的对映假糖构象有关[3.1。 0]己烷体系。 1 在 1 的情况下，假糖的构象模仿锁定在假旋转周期北半球的 2'-脱氧糖，而在 2 中，假糖模仿锁定在南半球的 2'-脱氧糖。 3 为了准备额外数量的 1 进行进一步的生物测试，我们决定研究一种已发表方法的替代方法。 1, 4, 5 这些方法从首次用于合成奈普拉诺星 A (4) 的相同手性环戊烯酮前体 3（方案 1）开始。 6 在这些方法中，需要采用两步脱氧方案来去除多余的羟基，因此，需要开发一种绕过这些步骤的方法。因此，我们考虑了使用易于获得的环戊烯醇合成子 (1S, 2R)-2-[(苄氧基)甲基]环戊-3-烯醇 (5) 作为制备 1 和其他 4', 1' a-亚甲基碳核苷的起始材料的可能性。化合物 5 由 Roberts 等人开发。 7, 8 用于合成 2'-脱氧碳核苷，最近，我们利用它来合成 1', 1' a-亚甲基碳环核苷，包括 2. 2 如果成功，相同的纯手性化合物可以作为这两个系列构象锁定核苷的共同前体。如方案 2 所示，从 5 生成的中间体硒氧化物 7a, b 的顺式消除在理论上可以沿两个方向进行，分别得到烯丙基叠氮化物（路径A）或乙烯基叠氮化物（路径B）。逆合成上，在对每个烯烃进行羟基定向环丙烷化后，路径A应该提供4', 1' a-亚甲基碳核苷系列，而路径B将导致1', 1' a-亚甲基碳核苷系列。顺式消除的首选途径将取决于氢的提取难易程度（Ha 与 Hb）、五元 Ei 过渡态的稳定性以及所得产物的稳定性。
Introduction4′, 1′ a-Methanocarbocyclic thymidine (1, Scheme 1) is a recently discovered potent anti-herpes virus agent that showed better in vitro activity against HSV-1 and HSV-2 than acyclovir. 1 The structurally related and conformationally distinct 1′, 1′ a-methanocarbocyclic thymidine (2), however, was totally devoid of antiviral activity. 1, 2 We have recently suggested that the difference between 1 and 2 might be related to their antipodal pseudosugar conformation imposed by the rigid bicyclo [3.1. 0] hexane system. 1 In the case of 1, the conformation of the pseudosugar mimics that of a 2′-deoxysugar locked in the northern hemisphere of the pseudorotational cycle, whereas in 2 the pseudosugar mimics a 2′-deoxysugar locked in the southern hemisphere. 3 In an effort to prepare additional quantities of 1 for further biological testing, we decided to investigate an alternative approach to the already published methods. 1, 4, 5 These methods begin with the same chiral cyclopentenone precursor 3 (Scheme 1) that was first employed for the synthesis of neplanocin A (4). 6 In these methodologies, a two-step deoxygenation protocol to remove the extra hydroxyl group was necessary, and thus, the development of a method that circumvented these steps was desirable. For that reason, we considered the possibility of using the readily accessible cyclopentenol synthon,(1S, 2R)-2-[(benzyloxy) methyl] cyclopent-3-enol (5), as a starting material for the preparation of 1 and other 4′, 1′ a-methanocarbanucleosides. Compound 5 was developed by Roberts et al. 7, 8 for the synthesis of 2′-deoxycarbanucleosides, and recently, we have utilized it for the synthesis of 1′, 1′ a-methano carbocyclic nucleosides, including 2. 2 If successful, the same homochiral compound could then serve as a common precursor to both series of conformationally locked nucleosides.As illustrated in Scheme 2, syn-elimination of the intermediate selenoxides 7a, b generated from 5 could in theory proceed in two directions, giving the allylic azide (path A) or the vinyl azide (path B), respectively. Retrosynthetically, path A should provide access to the 4′, 1′ amethanocarbanucleoside series, whereas path B would lead to the 1′, 1′ a-methanocarbanucleoside series, after performing hydroxyl-directed cyclopropanations on each olefin. The preferred pathway for the syn-elimination would be determined by the ease of abstraction of the hydrogens (Ha vs Hb), the stability of the five-membered Ei transition state, and the stability of the resulting