Automated stereocontrolled assembly-line synthesis of organic molecules
Automated stereocontrolled assembly-line synthesis of organic molecules
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DOI：
10.1038/s44160-022-00158-6
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发表时间：
2022-11-01
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影响因子：
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通讯作者：
Aggarwal, Varinder K.
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作者：
Fasano, Valerio;Mykura, Rory C.;Aggarwal, Varinder K.
自动化使非专家能够制备、测试和分析复杂的生物分子，包括蛋白质和核酸，从而推动了蛋白质组学和基因组学等领域的巨大进步。然而，自动化有机合成领域远远落后，部分原因是有机分子的复杂性和多样性。因此，只有少数相对简单的有机分子，需要少量的合成步骤，已经以自动化的方式制造出来。在这里，我们报告了一个自动化的装配线合成，允许迭代形成C（sp3）-C（sp3）键，具有高度的立体化学控制和再现性，使复杂的有机分子。这是在能够处理空气敏感反应物并进行低温反应的市售机器人平台上实现的，这使得有机硼底物的六个有序的一碳同源化能够在没有人为干预的情况下迭代进行。由于有机分子的复杂性和多样性，自动化有机合成通常局限于合成简单的分子，需要较少的合成步骤。现在，一个机器人平台已经被指示以立体化学控制和迭代的方式构建复杂的结构，例如（+）-kalkitoxin的核心片段。
Automation has fuelled dramatic advances in fields such as proteomics and genomics by enabling non-experts to prepare, test and analyse complex biological molecules, including proteins and nucleic acids. However, the field of automated organic synthesis lags far behind, partly because of the complexity and variety of organic molecules. As a result, only a handful of relatively simple organic molecules, requiring a small number of synthetic steps, have been made in an automated fashion. Here we report an automated assembly-line synthesis that allows iterative formation of C(sp3)-C(sp3) bonds with high stereochemical control and reproducibility, enabling access to complex organic molecules. This was achieved on a commercially available robotic platform capable of handling air-sensitive reactants and performing low-temperature reactions, which enabled six sequenced one-carbon homologations of organoboron substrates to be performed iteratively without human intervention. Together with other automated functional group manipulations, this methodology has been exploited to rapidly build the core fragment of the natural product (+)-kalkitoxin, thus expanding the field of automated organic synthesis.Automated organic synthesis is often limited to making simple molecules, requiring a small number of synthetic steps, because of the complexity and variety of organic molecules. Now, a robotic platform has been instructed to build complex structures, such as the core fragment of (+)-kalkitoxin, in a stereochemically controlled and iterative manner.