Stereoselective total synthesis of mucocin, an antitumor agent.
Stereoselective total synthesis of mucocin, an antitumor agent.
复制标题
DOI：
10.1002/anie.200290038
复制
发表时间：
2002-12
影响因子：
--
通讯作者：
Shunya Takahashi;Akemi Kubota;T. Nakata
中科院分区：
文献类型：
--
作者：
Shunya Takahashi;Akemi Kubota;T. Nakata
Mucocin(1)是一种具有代表性的番荔枝内酯[1]，具有四氢吡喃(THP)和四氢呋喃(THF)环。[2]这种新型的乙酰生长素对A-549(肺癌)和Paca-2(胰腺癌)实体瘤具有显著的抑制活性，其效力是阿霉素的10000倍以上。1的强大的抗肿瘤活性和独特的结构激发了人们的合成努力，[3]最近三个研究小组(包括我们)已经成功地完成了它的全合成。[4]最近，我们开发了一种基于SmI2诱导的含有甲酰基的b-烷氧基丙烯酸酯的[5]还原环化反应合成四氢吡喃和环氧丙烷的高效方法。[6]因此我们计划了1的全合成以证明该方法的实用性，现在描述了基于SmI2诱导的还原环化作为关键步骤的1的高效全合成。我们针对1的合成策略是基于一个聚合过程，该过程包括Pd催化的THP/THF链段2和乙烯基碘3的交叉偶联反应，如方案1所示。中心核2中的THP环可以通过SmI2诱导的还原环化而构建，而反式-THF环应该通过高烯丙醇的氧化环化来合成[7]。这种逆合成方法可以将2还原为具有两个甲酰基的b-烷氧基丙烯酸酯4，然后再还原为四醇5。因此，选择具有所需碳链的二醛6作为起始原料。在这种情况下，能否保留4的还原环化反应中的C-12甲酰基，以及开发一种有效的C2对称5的去对称化方法是需要解决的问题。另一方面，g-内酯3应由手性酯7和醛8的羟醛缩合而成。[8]合成始于双醛6[4a]的缩醛反应，以99%的产率得到双二甲缩醛9(方案2)。9的夏普莱斯不对称二羟基化[9]以几乎定量的产率得到C2对称的四醇5[10]。为了实现有效的去对称化，在±58℃下用CsA在甲醇中处理将5转化为双四氢呋喃衍生物10。在RT条件下进行缩醛反应时，观察到THP衍生物的生成。10经苄化后用二异丁基苯还原得单苄基醚
Mucocin (1) is a representative annonaceous acetogenin [1] having a tetrahydropyran (THP) and a tetrahydrofuran (THF) ring.[2] This novel type of acetogenin is known to show remarkable inhibitory activities against A-549 (lung cancer) and PACA-2 (pancreatic cancer) solid tumor lines with a potency of more than 10000 times that of adriamycin. The powerful antitumor activity and the unique structure of 1 have consequently stimulated synthetic efforts,[3] and quite recently three research groups (including ours) have succeeded in its total synthesis.[4] Recently, we developed a highly efficient method for the synthesis of tetrahydropyrans and oxepanes based on a SmI2-induced [5] reductive cyclization of b-alkoxy acrylate containing a formyl group.[6] We thus planned the total synthesis of 1 to demonstrate the utility of the method and now describe here an efficient total synthesis of 1 based on the SmI2-induced reductive cyclization as a key step. Our synthetic strategy directed toward 1 was based on a convergent process which involves a Pd-catalyzed crosscoupling reaction of the THP/THF segment 2 and a vinyl iodide 3 as illustrated in Scheme 1. The THP ring in the central core 2 could be constructed by the SmI2-induced reductive cyclization, whereas the trans-THF ring should be synthesized by oxidative cyclization [7] of a homoallyl alcohol. This retrosynthetic approach can revert 2 back to the b-alkoxy acrylate 4 having two formyl groups, and then to a tetraol 5. Therefore, dialdehyde 6 with the requisite carbon backbone was selected as the starting material. In this scenario, whether the C-12 formyl group in the reductive cyclization of 4 could be retained or not and the development of an efficient method for desymmetrization of C2-symmetric 5 were problems to be solved. On the other hand, the g-lactone 3 should be synthesized by aldol condensation of chiral ester 7 and aldehyde 8.[8]Synthesis began with acetalization of the dialdehyde 6 [4a] to afford the bis (dimethyl acetal) 9 in 99% yield (Scheme 2). The Sharpless asymmetric dihydroxylation [9] of 9 gave the C2-symmetric tetraol 5 [10] in almost quantitative yield. To achieve efficient desymmetrization 5 was transformed into a bisTHF derivative 10 by treatment with CSA in methanol at À58C. Formation of THP derivatives was observed when the acetalization was conducted at RT. Benzylidenation of 10 followed by reduction with DIBAH gave a monobenzyl ether