Highly Stereoselective, Organocatalytic Mannich-type Addition of Glyoxylate Cyanohydrin: A Versatile Building Block for the Asymmetric Synthesis of β-Amino-α-ketoacids
Highly Stereoselective, Organocatalytic Mannich-type Addition of Glyoxylate Cyanohydrin: A Versatile Building Block for the Asymmetric Synthesis of β-Amino-α-ketoacids
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DOI：
10.1021/acscatal.2c00950
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发表时间：
2022-05-06
期刊：
影响因子：
12.9
通讯作者：
Takemoto，Yoshiji
中科院分区：
文献类型：
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作者：
Tokuhiro，Yusuke;Yoshikawa，Kosuke;Takemoto，Yoshiji
β-氨基-α-酮酸是一类重要的非天然氨基酸，它具有独特的生物活性和反应活性，来源于α-位上高度亲电的羰基。尽管该基序具有广泛的用途，但可靠的β-氨基-α-酮酸的合成方法仅限于基于手性池方法的α-氨基酸的氧化同源。在这篇文章中，我们报道了一种替代的实用方法来不对称合成β-氨基-α-酮酸类化合物，该方法是基于乙氧基氰醇的高立体选择性的有机催化Mannich类型加成反应。优化的氨基硫脲催化剂以良好的产率和立体选择性(高达100%的产率，99%的ee，94：1的dR)提供了多种来自α-Boc亚胺的加合物，并且该反应可用于直接使用Mon-Boc亚胺类化合物作为亚胺前体，大大扩展了底物的范围。实验构效关系和计算研究表明，双(三氟甲基)苯基与取代基的空间斥力和吸引作用可能是导致高非对映选择性的原因，而硫脲支架由于分子内氢键长度的不同，提供了比苯并噻二嗪更窄的催化口袋，从而导致了良好的对映选择性。不对称加合物可以很容易地转化为保持其光学纯度的β-氨基-α-酮酸，这些加合物可以用于酰胺的脱羧基形成，而不需要通过柱层析进行纯化。以分子内酰基迁移为关键步骤制备了多肽-α-酮酸，并将其应用于脱羧肽与含有各种非保护官能团的二肽的偶联和[2+2+2]序列多肽的偶联。此外，通过在高活性α-羰基上使用氰醇基序，实现了保留立体信息的多肽-α-酮酰胺的高效合成，并在没有任何异构化的情况下合成了含有α-酮酰胺的药物替拉维韦。
β-Amino-α-ketoacids are important unnatural amino acids that exhibit unique bioactivity and reactivity derived from the highly electrophilic carbonyl group at the α-position. Despite the broad utility of the motif, reliable synthetic methods for β-amino-α-ketoacids have been limited to the oxidative homologation of α-amino acids based on a chiral-pool approach. In this article, we report an alternative practical method for the asymmetric synthesis of β-amino-α-ketoacid equivalents based on a highly stereoselective organocatalyzed Mannich-type addition using glyoxylate cyanohydrin. The optimal aminothiourea catalyst provides a wide variety of adducts fromN-Boc imines in excellent yield and stereoselectivity (up to 100% yield, 99% ee, 94:1 dr), and the reaction can be applied to the direct use of α-amido sulfones as imine precursors, which significantly expands the substrate scope. The experimental structure–activity relationships and computational studies indicated that steric repulsion with the substituent on the amine moiety and the attractive interaction with the bis(trifluoromethyl)phenyl group might contribute to the high diastereoselectivity and that the thiourea scaffold provides a narrower catalytic pocket compared to benzothiadiazine due to the difference in the length of the intramolecular hydrogen bonding, which results in excellent enantioselectivity. The asymmetric adducts can be readily converted into β-amino-α-ketoacids that maintain their optical purity, and these can be used for the decarboxylative formation of amides without purification by column chromatography. Peptide-α-ketoacids were also prepared via intramolecular acyl migration as a key step and applied to decarboxylative peptide coupling with dipeptides that bear various unprotected functional groups and to [2 + 2 + 2] sequential peptide coupling. Furthermore, the efficient synthesis of peptide-α-ketoamides with retention of the stereo-information was achieved by using the cyanohydrin motif at the highly reactive α-carbonyl group, and the synthesis of an α-ketoamide-containing medicine, Telaprevir, was accomplished without any epimerization.