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在形式上的[4 + 2]环加成反应中，6-羧基取代吡喃酮作为双碳单元的区域选择性环化反应。

Regioselective Annulation of 6-Carboxy-Substituted Pyrones as a Two-Carbon Unit in Formal [4 + 2] Cycloaddition Reactions.

作者信息

Kohanov Zachary A, Shuvo Suzzudul Islam, Lowell Andrew N

机构信息

Department of Chemistry, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, Virginia 24061, United States.

Center for Emerging, Zoonotic, and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, Virginia 24061, United States.

出版信息

J Org Chem. 2024 Jul 5;89(13):9557-9568. doi: 10.1021/acs.joc.4c01044. Epub 2024 Jun 13.

DOI:10.1021/acs.joc.4c01044
PMID:38869104
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11232011/
Abstract

Heterocycles serve as a critical motif in chemistry, but despite being present in more than 85% of pharmaceuticals, there are limited methods for their construction. Here, we describe the incorporation of intact pyrone (2-pyran-2-one) into larger ring systems via annulation. In a formal [4 + 2] cycloaddition, the pyrone regioselectively accepts a benzylic anion as a nucleophile in a conjugate addition fashion, with the subsequent pyrone-derived enolate attaching to a pendant ester on the initial nucleophile. Subsequent base-driven enolate formation and elimination establish aromaticity of the newly formed ring. After optimization of this process using an NMR-based assessment to overcome solubility and separation challenges, the reaction was successfully applied to a library of 6-ester and -amide-substituted pyrones and using a phenyl ester and other substituted sulfoxides. This technology enables the incorporation of intact pyrone rings into more complex systems, such as for the total synthesis of the natural product thermorubin.

摘要

杂环是化学中的关键结构单元，尽管超过85%的药物中都含有杂环，但构建杂环的方法却很有限。在此，我们描述了通过环化反应将完整的吡喃酮（2-吡喃-2-酮）并入更大的环系。在形式上的[4 + 2]环加成反应中，吡喃酮以共轭加成的方式区域选择性地接受苄基阴离子作为亲核试剂，随后由吡喃酮衍生的烯醇盐连接到初始亲核试剂上的侧链酯上。随后碱驱动的烯醇盐形成和消除反应确立了新形成环的芳香性。在用基于核磁共振的评估方法优化该过程以克服溶解性和分离挑战后，该反应成功应用于一系列6-酯基和酰胺基取代的吡喃酮，并使用了苯基酯和其他取代的亚砜。这项技术能够将完整的吡喃酮环并入更复杂的体系中，例如用于天然产物嗜热菌素的全合成。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/b91c38e59104/jo4c01044_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/3b65133d3a42/jo4c01044_0001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/68d5dc45dd0d/jo4c01044_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/749a71b3cc58/jo4c01044_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/f039abd06fb3/jo4c01044_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/65a13ba08ad4/jo4c01044_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/f1407e1822d7/jo4c01044_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/c002e7068250/jo4c01044_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/b91c38e59104/jo4c01044_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/3b65133d3a42/jo4c01044_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/c9c54015a212/jo4c01044_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/68d5dc45dd0d/jo4c01044_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/749a71b3cc58/jo4c01044_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/f039abd06fb3/jo4c01044_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/65a13ba08ad4/jo4c01044_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/f1407e1822d7/jo4c01044_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/c002e7068250/jo4c01044_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6758/11232011/b91c38e59104/jo4c01044_0009.jpg

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