Catalytic asymmetric aldol equivalents in the enantioselective synthesis of the apoptolidin C aglycone.
Catalytic asymmetric aldol equivalents in the enantioselective synthesis of the apoptolidin C aglycone.
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DOI：
10.1002/anie.201004925
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发表时间：
2010-11
影响因子：
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通讯作者：
Thomas R. Vargo;J. Hale;S. G. Nelson
中科院分区：
文献类型：
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作者：
Thomas R. Vargo;J. Hale;S. G. Nelson
Apoptolidins A-E是一类大环内酯类天然产物，作为高选择性的细胞凋亡调节剂而受到广泛关注。在癌症化疗中实现更大选择性的迫切需要刺激了阐明雷公藤甲素独特药理学特征的机制和结构基础的努力。这些努力包括几个总合成的雷公藤甲素，其中每一个都提供了宝贵的见解的战略，化学修饰的天然产品，扩大药理学分析。类似的考虑激发了我们的兴趣，在开发一个对映选择性合成的雷公藤甲素探索能力的催化不对称羟醛反应替代品，以促进这些天然产物的合成。为了实现这一目标，我们在本文中描述了apoptolidinone C（1）（apoptolidin C苷配基）的对映选择性合成，其中催化不对称C C键结构提供了通往所有十个必需立体中心的管道。它们在组装乙酸酯或丙酸酯衍生的聚酮结构中的效用是现代基于醛醇的反应技术的定义特征之一。存在一系列利用化学计量手性控制剂的羟醛或羟醛等价物，其提供用于构建复杂的聚乙酸酯和聚丙酸酯阵列的非常可靠和可预测的方法。为了我们的目的，雷公藤甲素C糖苷配基提供了一个平台，用于评估在类似的合成努力中是否可以实现类似水平的操作效率和便利性，其中立体控制将完全来自基于催化剂的亚化学计量手性控制剂。具体地，催化不对称酰基卤-醛环化缩合（AAC）反应分别使用基于Al的刘易斯酸或金鸡纳生物碱刘易斯碱催化剂提供高度立体选择性的乙酸酯或丙酸酯羟醛当量。复杂的聚酮组合预测的AAC方法遵循催化剂控制的C-C键结构的迭代模式，然后由b-内酯refunctionalization的b-烷氧基醛所需的连续链同系物的序列让人想起的迭代同系物refunctionalization序列中观察到的生物合成聚酮组装。通过在C10和C11-C12键上断开1以显示混合的乙酸酯/丙酸酯衍生的C12-C28片段2和广泛脱水的聚丙酸酯C1-C11片段3，从前述分析中出现了雷公藤甲素酮C（1）的合成（方案1）。这个合成词
Apoptolidins A–E are a family of macrolide natural products that have attracted considerable attention as highly selective apoptosis regulators. The critical need for achieving greater selectivity in cancer chemotherapeutics has stimulated efforts to elucidate the mechanistic and structural basis for the apoptolidin s unique pharmacological profile. These efforts include several total syntheses of apoptolidin A, each of which has provided invaluable insights into strategies for chemically modifying the natural product for expanded pharmacological profiling. Similar considerations inspired our interest in developing an enantioselective synthesis of the apoptolidins exploring the capacity of catalytic asymmetric aldol reaction surrogates to facilitate the synthesis of these natural products. Toward this goal, we describe herein an enantioselective synthesis of apoptolidinone C (1), the apoptolidin C aglycone, wherein catalytic asymmetric C C bond constructions provide the conduit to all ten of the requisite stereogenic centers. Their utility in assembling acetateor propionate-derived polyketide architecture is among the defining characteristics of modern aldol-based reaction technologies. There exists an array of aldol or aldol equivalents utilizing stoichiometric chiral controllers that provide exceptionally reliable and predictable methods for constructing complex polyacetate and polypropionate arrays. For our purposes, the apoptolidin C aglycone provided a platform for evaluating whether similar levels of operational efficiency and expediency could be achieved in similar synthesis endeavors wherein stereocontrol would derive exclusively from catalyst-based substoichiometric chiral controllers. Specifically, catalytic asymmetric acyl halide–aldehyde cyclocondensation (AAC) reactions provide highly stereoselective acetate or propionate aldol equivalents using Al-based Lewis acid or cinchona alkaloid Lewis base catalysts, respectively. Complex polyketide assemblage predicated on the AAC methodology follows a reiterative pattern of catalyst controlled C C bond construction followed by b-lactone refunctionalization to the b-alkoxy aldehyde required for continued chain homologation in a sequence reminiscent of the iterative homologation–refunctionalization sequence observed in biosynthetic polyketide assembly. A synthesis of apoptolidinone C (1) emerges from the preceding analysis by disconnecting 1 across the C1 O and C11 C12 bonds to reveal the mixed acetate/propionatederived C12–C28 fragment 2 and the extensively dehydrated polypropionate C1–C11 fragment 3 (Scheme 1). The syn-