Rhodium-Catalyzed C-H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles.
Rhodium-Catalyzed C-H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles.
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DOI：
10.1021/acs.accounts.1c00027
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发表时间：
2021-04-06
影响因子：
18.3
通讯作者：
Ellman JA
中科院分区：
文献类型：
--
作者：
Dongbang S;Confair DN;Ellman JA
氮杂环存在于约60%的药物中，其中并入立体中心的非平面杂环对药物化学、化学生物学和合成方法开发领域具有相当大的兴趣。在过去的几年里，我们的实验室已经开发出合成策略，以获得具有多个立体中心的高度官能化的氮杂环。这种方法的核心是通过Rh催化的C-H键烯基化/电环化级联反应从容易获得的α，β-不饱和亚胺和炔有效制备不同的1，2-二氢吡啶。通常密集取代的1，2-二氢吡啶产物已被证明是极其通用的中间体，其可以以高区域选择性和立体选择性进行加工，通常无需纯化或甚至分离。质子化或烷基化后加入氢化物或碳亲核试剂可得到具有不同区域选择性和立体选择性的四氢吡啶，这取决于反应条件。与DFT计算相结合的机制实验提供了观察到的高水平的区域控制和立体控制的理由。通过非对映选择性环氧化和区域选择性开环进一步精制四氢吡啶，得到羟基取代的哌啶。或者，哌啶可以直接由二氢吡啶通过催化氢化以良好的产率和高的面选择性获得。当使用三甲基甲硅烷基炔或N-三甲基甲硅烷基甲基亚胺作为起始输入时，Rh催化的C-H键烯基化/电环化级联提供甲硅烷基取代的二氢吡啶，其使得能够进行许多新的和有用的转化为不同的杂环类。这些产物在酸性条件下的质子化引发甲硅烷基的损失，形成不稳定的甲亚胺叶立德，这将难以通过其他手段获得。根据甲硅烷基的位置，[3+2]环加成的偶氮甲碱叶立德与dipolophiles提供tropane或indolizidine特权框架，其分子内环加成产生复杂的多环产物与多达五个连续的立体异构中心。通过使用不同类型的条件，甲硅烷基的损失可导致重排成环丙基稠合的吡咯烷或氨基环戊二烯。由DFT计算支持的机理实验为这些不寻常的重排提供了反应途径。在这个帐户中描述的转换是服从于天然产物合成和药物发现的应用程序，由于所制备的结构基序的生物相关性，短的反应序列，依赖于容易获得的起始输入，高regiocontraction和stereocontraction，和优良的官能团相容性。例如，该方法已被应用于吗啡喃药物的有效不对称合成，包括阿片样物质拮抗剂（-）-纳洛酮，其广泛用于治疗药物滥用。
Nitrogen heterocycles are present in approximately 60% of drugs, with non-planar heterocycles incorporating stereogenic centers being of considerable interest to the fields of medicinal chemistry, chemical biology, and synthetic methods development. Over the past several years, our laboratory has developed synthetic strategies to access highly functionalized nitrogen heterocycles with multiple stereogenic centers. This approach centers on the efficient preparation of diverse 1,2-dihydropyridines by a Rh-catalyzed C−H bond alkenylation/electrocyclization cascade from readily available α,β-unsaturated imines and alkynes. The often densely substituted 1,2-dihydropyridine products have proven to be extremely versatile intermediates that can be elaborated with high regioselectivity and stereoselectivity, often without purification or even isolation. Protonation or alkylation followed by addition of hydride or carbon nucleophiles affords tetrahydropyridines with divergent regioselectivity and stereoselectivity depending on the reaction conditions. Mechanistic experiments in combination with DFT calculations provide a rationale for the high level of regiocontrol and stereocontrol that is observed. Further elaboration of the tetrahydropyridines by diastereoselective epoxidation and regioselective opening furnishes hydroxy-substituted piperidines. Alternatively, piperidines can be obtained directly from dihydropyridines by catalytic hydrogenation in good yield and with high face selectivity. When trimethylsilyl alkynes or N-trimethylsilylmethyl imines are employed as starting inputs, the Rh-catalyzed C−H bond alkenylation/electrocyclization cascade provides silyl-substituted dihydropyridines that enable a host of new and useful transformations to different heterocycle classes. Protonation of these products under acidic conditions triggers the loss of the silyl group with formation of unstabilized azomethine ylides that would be difficult to access by other means. Depending on the location of the silyl group, [3+2] cycloaddition of the azomethine ylides with dipolarophiles provides tropane or indolizidine privileged frameworks, which for intramolecular cycloadditions yield complex polycyclic products with up to five contiguous stereogenic centers. By employing different types of conditions, loss of the silyl group can result in either rearrangement to cyclopropyl fused pyrrolidines or to aminocyclopentadienes. Mechanistic experiments supported by DFT calculations provide reaction pathways for these unusual rearrangements. The transformations described in this Account are amenable to natural product synthesis and drug discovery applications due to the biological relevance of the structural motifs that are prepared, short reaction sequences that rely on readily available starting inputs, high regiocontrol and stereocontrol, and excellent functional group compatibility. For example, the methods have been applied to efficient asymmetric syntheses of morphinan drugs, including the opioid antagonist (−)-naltrexone, which is extensively used for the treatment of drug abuse.
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影响因子：
15
作者：
Ischay, Michael A.;Takase, Michael K.;Bergman, Robert G.;Ellman, Jonathan A.
通讯作者：
Ellman, Jonathan A.
影响因子：
15
作者：
Chen S;Bacauanu V;Knecht T;Mercado BQ;Bergman RG;Ellman JA
通讯作者：
Ellman JA
DOI：
10.1021/jo202280e
发表时间：
2012-03-02
期刊：
The Journal of organic chemistry
影响因子：
--
作者：
Martin RM;Bergman RG;Ellman JA
通讯作者：
Ellman JA
影响因子：
16.6
作者：
Duttwyler, Simon;Chen, Shuming;Lu, Colin;Mercado, Brandon Q.;Bergman, Robert G.;Ellman, Jonathan A.
通讯作者：
Ellman, Jonathan A.
影响因子：
15
作者：
McManus, Joshua B.;Onuska, Nicholas P. R.;Nicewicz, David A.
通讯作者：
Nicewicz, David A.