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Stereocontrolled organocatalytic synthesis of prostaglandin PGF_(2α) in seven steps

机译：七步立体控制有机催化合成前列腺素PGF_（2α）

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摘要

Prostaglandins are hormone-like chemical messengers that regulate a broad range of physiological activities, including blood circulation, digestion and reproduction. Their biological activities and their complex molecular architectures have made prostaglandins popular targets for synthetic organic chemists for over 40 years. Prostaglandin analogues are widely used as Pharmaceuticals and some, such as latanoprost, which is used to treat glaucoma, have become billion-dollar drugs. Previously reported syntheses of these compounds are quite lengthy, and every chemical step costs time and energy, generates waste and is accompanied by material losses. Using a new bond disconnection, here we report a concise synthesis of the most complex prostaglandin, PGF_(2α), with high levels of control of relative and absolute stereochemistry, and fewer steps. The key step is an aldol cascade reaction of succinaldehyde using proline organocatalysis to create a bicyclic enal in one step and an enantiomeric excess of 98%. This intermediate bicyclic enal is fully primed with the appropriate functionality for attachment of the remaining groups. Access to this bicyclic enal will not only render existing prostaglandin-based drugs more affordable, but will also facilitate the rapid exploration of related chemical structures around the ubiquitous five-membered ring motif, such as potentially therapeutic prostaglandin analogues.
机译：前列腺素是类激素的化学信使，可调节广泛的生理活动，包括血液循环，消化和生殖。它们的生物活性和复杂的分子结构使前列腺素成为合成有机化学家的热门目标已有40多年了。前列腺素类似物被广泛用作药物，一些药物，例如用于治疗青光眼的拉坦前列素，已成为数十亿美元的药物。先前报道的这些化合物的合成相当长，并且每个化学步骤都要花费时间和精力，会产生浪费并伴有材料损失。使用新的键断开连接，在这里我们报告了最复杂的前列腺素PGF_（2α）的简明合成，具有相对和绝对立体化学的高水平控制，步骤更少。关键步骤是使用脯氨酸有机催化在一个步骤中生成琥珀醛的羟醛级联反应，以生成双环烯醛，对映体过量为98％。该中间的双环烯醛已充分涂有适当的官能团，用于连接其余基团。获得这种双环烯不仅将使现有的基于前列腺素的药物更加负担得起，还将促进围绕无所不在的五元环基序周围的相关化学结构的快速探索，例如潜在的治疗性前列腺素类似物。

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  • 来源
    《Nature》 |2012年第7415期|p.278-281|共4页
  • 作者

    Graeme Coulthard; William Erb; Varinder K. Aggarwal;

  • 作者单位

    School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 ITS, UK;

    School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 ITS, UK;

    School of Chemistry, University of Bristol, Cantock's Close, Bristol BS8 ITS, UK;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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