Stereo- and Regiochemical Transannular Cyclization of a Common Hexahydro-1H-azonine to Afford Three Different Indolizidinone Dipeptide Mimetics.,The Journal of Organic Chemistry

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Stereo- and Regiochemical Transannular Cyclization of a Common Hexahydro-1H-azonine to Afford Three Different Indolizidinone Dipeptide Mimetics.
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2019-11-15 , DOI: 10.1021/acs.joc.9b01861
N D Prasad Atmuri ₁ , William D Lubell ₁

Affiliation

Sets of azabicyclo[X.Y.0]alkanone amino acids have been effectively used to identify active conformers in peptide-based drug discovery, but they usually require multiple routes to synthesize. Employing a common method from the same nine-membered unsaturated lactam precursor, we developed conditions for stereo- and regiochemical transannular cyclizations to synthesize three different indolizidin-2- and 9-one amino acid (I2aa and I9aa) analogues. For example, (3S,5R,6R,9S)- and (3S,5S,6S,9S)-I2aa diastereomers were prepared from hexahydro-1H-azonines by using iodine in THF and in MeCN with DIB as an additive. The regioselectivity of the transannular cyclization was influenced by amine protection to favor the synthesis of the I9aa isomer. Moreover, side chains were added onto the I2aa and I9aa ring systems by way of olefin intermediates that underwent Pd-catalyzed C-H bond activation and allylic oxidation.

中文翻译：

常见的六氢-1H-氮丙氨酸的立体和区域化学环过环化，以提供三种不同的吲哚并二酮二肽模拟物。

在基于肽的药物发现中，氮杂双环[XY0]烷酮氨基酸组已被有效地用于识别活性构象异构体，但它们通常需要多种合成途径。我们采用来自相同的九元不饱和内酰胺前体的通用方法，开发了立体化学和区域化学跨环环化的条件，以合成三种不同的吲哚izidin-2-和9-one氨基酸（I2aa和I9aa）类似物。例如，通过在THF中和在MeCN中使用碘，用DIB作为添加剂，由六氢-1H-氮丙氨酸制备（3S，5R，6R，9S）-和（3S，5S，6S，9S）-I2aa非对映异构体。跨环环化的区域选择性受到胺保护的影响，以利于I9aa异构体的合成。而且，

更新日期：2019-11-17

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