Convergent Total Synthesis of (+)-TMC-151C by a Vinylogous Mukaiyama Aldol Reaction and Ring-Closing Metathesis
Convergent Total Synthesis of (+)-TMC-151C by a Vinylogous Mukaiyama Aldol Reaction and Ring-Closing Metathesis
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DOI：
10.1002/anie.201006230
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发表时间：
2011-01-01
影响因子：
16.6
通讯作者：
Kobayashi, Susumu
中科院分区：
文献类型：
--
作者：
Matsui, Ryosuke;Seto, Kentaro;Kobayashi, Susumu
TMC-151家族的抗生素剂最初是由制药公司田边制药（Seiyaku）的研究小组于1999年从真菌链状粘帚霉Gilman & Abbott TC 1280中分离的，作为含有β-甘露糖苷和d-甘露醇基团的新型聚酮化合物。[1]还分离了相关的TMC-171抗生素家族和TMC-154。[2]在这些化合物中，TMC-151 C（1）对广泛的肿瘤细胞系（包括HCT-116、B16和HeLa细胞）显示出最显著的细胞毒性。TMC-151 C显示了几个有趣的结构特征。值得注意的是，1）聚酮化合物部分在C1-C13链段中含有三个连续的反高烯丙醇基序和在C14-C20链段中含有三个甲基取代的不对称碳中心，和2）d-甘露糖作为bd-甘露糖苷连接到C13羟基，这在化学合成方面仍然是有问题的（方案1）。这种显著的生物活性和结构复杂性的结合促使我们尝试全合成（+）-TMC-151 C（1）。我们先前开发了一种高度立体选择性的乙烯基-Mukaiyama羟醛缩合反应（VMAR），该反应通过使用乙烯基烯酮甲硅烷基N，O-缩醛2和3实现了显着的远程不对称诱导（方案1）。[3]从合成的角度来看，该方法可以直接提供存在于许多天然存在的化合物中的反-d-羟基-a，g-二甲基a，b-不饱和羰基单元。事实上，VMAR已经被许多研究小组成功地用于天然产物合成，[4]包括我们自己的。[5]考虑到（+）-1中存在三个反高烯丙醇基序（C2-C5、C6-C9和C10-C13单元），我们推断1的全合成将提供VMAR的代表性实例。本文报道了（+）-TMC-151 C（1）的首次全合成。我们最初尝试了一个简单的线性方法，包括三个迭代的VMAR（方案2）。碳水化合物单元然后将在合成的稍后阶段结合。根据已建立的方案，已知的手性醛4 [6]与乙烯基烯酮甲硅烷基N，O-缩醛3在TiCl 4存在下的第一VMAR得到
Antibiotic agents of the TMC-151 family were originally isolated from the fungus Gliocladium catenulatum Gilman & Abbott TC 1280 by a research group at the pharmaceutical company Tanabe Seiyaku in 1999 as novel polyketides containing bd-mannoside and d-mannitol groups.[1] A related TMC-171 family of antibiotics and TMC-154 were also isolated.[2] Of these compounds, TMC-151C (1) shows the most significant cytotoxicity against a wide range of tumor cell lines, including HCT-116, B16, and HeLa cells. TMC-151C displays several interesting structural features. Notably, 1) the polyketide moiety contains three contiguous anti homoallylic alcohol motifs in the C1–C13 segment and three methyl-substituted asymmetric carbon centers in the C14–C20 segment, and 2) d-mannose is attached to the C13 hydroxy group as bd-mannoside, which is still problematic in terms of chemical synthesis (Scheme 1). This combination of significant biological activity and structural complexity encouraged us to attempt the total synthesis of (+)-TMC-151C (1).We previously developed a highly stereoselective vinylogous Mukaiyama aldol reaction (VMAR) that enabled remarkable remote asymmetric induction by using the vinylketene silyl N, O-acetals 2 and 3 (Scheme 1).[3] From a synthetic point of view, this method can directly afford the anti-d-hydroxy-a, g-dimethyl a, b-unsaturated carbonyl unit which is present in many naturally occurring compounds. Indeed, the VMAR has been utilized successfully in natural product syntheses by many research groups,[4] including our own.[5] Given the presence of three anti homoallylic alcohol motifs (C2–C5, C6–C9, and C10–C13 units) in (+)-1, we reasoned that the total synthesis of 1 would provide a representative example of the VMAR. Herein, we report the first total synthesis of (+)-TMC-151C (1). We initially attempted a straightforward linear approach consisting of three iterative VMARs (Scheme 2). The carbohydrate units would then be combined at a later stage in the synthesis. According to the established protocol, the first VMAR of the known chiral aldehyde 4 [6] with the vinylketene silyl N, O-acetal 3 in the presence of TiCl4 afforded the