A concise, stereocontrolled synthesis of (-)-saframycin A by the directed condensation of α-amino aldehyde precursors
A concise, stereocontrolled synthesis of (-)-saframycin A by the directed condensation of α-amino aldehyde precursors
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DOI：
10.1021/ja993079k
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发表时间：
1999-11-24
影响因子：
15
通讯作者：
Kung, DW
中科院分区：
文献类型：
--
作者：
Myers, AG;Kung, DW
在这项工作中，我们描述了一个短的和对映选择性的合成路线，有效的抗肿瘤剂（-）-saframycin A（1），一个双醌生物碱的微生物来源。1，2该路线采用了一种新的和强大的合成策略，涉及光学活性R-氨基醛的直接缩合。如图所示，该策略是从1的逆合成分析发展而来的，其中由醛与胺的缩合引发的一系列转化（例如，还原胺化、Pictet-Spengler和Strecker反应）被设想为从五个简单组分组装靶1：氰化氢、甲醛和三种R-氨基醛[其中两种（结构3）相同，因此1具有潜在对称性]。分析的复杂性出现在确定的精确顺序和立体化学的键合事件，将链接的前体（七个键必须形成），并考虑的基本问题的稳定性，反应性，和保护策略周围的建议使用的光学活性R-氨基醛作为合成中间体。最近，我们报道了一系列的“C-保护的”光学活性R-氨基醛，其中包括一个氨基腈基团作为掩蔽醛的发展。发现由结构5例示的吗啉代腈衍生物是特别有用的合成中间体，其与光学活性的N-保护的R-氨基醛进行缩合反应，其中任一组分几乎没有差向异构化，从而建立了本文详述的（-）-沙夫霉素A的定向组装的基础。如前所述，从（-）-伪麻黄碱甘氨酰胺的不对称烷基化的相同产物制备高对映体过量的相同手性R-氨基醛（3）的N-和C-保护形式。在硫酸钠存在下，在二氯甲烷中，在23 ℃下，将N-保护的R-氨基醛4（96%ee，1.05当量）加入到C-保护的R-氨基醛5（92%ee，1当量）中，干净地得到亚胺6（假定为反式），没有可检测到的任一R-立构中心的差向异构化（1H NMR分析，> 90%产率）。将无水溴化锂在二甲氧基乙烷中的饱和溶液加入到亚胺中间体中，并加热至35 ℃，引起Pictet-Spengler环化，以提供1：5：1的环化产物。
In this work we describe a short and enantioselective synthetic route to the potent antitumor agent (-)-saframycin A (1), a bisquinone alkaloid of microbial origin. 1, 2 The route employs a new and powerful synthetic strategy involving the directed condensation of optically active R-amino aldehydes. This strategy evolved from retrosynthetic analysis of 1, as shown, where a series of transformations initiated by the condensation of an aldehyde with an amine (eg, reductive amination, Pictet-Spengler, and Strecker reactions) was envisioned to assemble the target 1 from five simple components: hydrogen cyanide, formaldehyde, and three R-amino aldehydes [two of which (structure 3) are the same, hence the latent symmetry of 1]. The complexity of the analysis arises in the determination of the precise order and stereochemistry of bonding events that will link the precursors (seven bonds must be formed), and upon consideration of the fundamental issues of stability, reactivity, and protection strategies surrounding the proposed use of optically active R-amino aldehydes as synthetic intermediates. Recently, we reported the development of a series of “C-protected” optically active R-amino aldehydes that incorporates an amino nitrile group as a masked aldehyde. 3 Morpholino nitrile derivatives, exemplified by structure 5, were found to be particularly useful synthetic intermediates, undergoing condensation reactions with optically active N-protected R-amino aldehydes with little to no epimerization of either component, thus establishing the basis for the directed assembly of (-)-saframycin A detailed herein.Compounds 4 and 5, N-and C-protected versions of the same chiral R-amino aldehyde (3), were prepared in high enantiomeric excess from the same product of asymmetric alkylation of (-)-pseudoephedrine glycinamide, as previously described. 3, 4 Addition of N-protected R-amino aldehyde 4 (96% ee, 1.05 equiv) to C-protected R-amino aldehyde 5 (92% ee, 1 equiv) 5 in dichloromethane at 23 C in the presence of sodium sulfate cleanly provided the imine 6 (presumed trans) without detectable epimerization of either R-stereocenter (1H NMR analysis,> 90% yield. Addition of a saturated solution of anhydrous lithium bromide in dimethoxyethane to the imine intermediate and warming to 35 C brought about Pictet-Spengler cyclization to provide a∼ 5: 1