Rigid dipeptide surrogates: Syntheses of enantiopure quinolizidinone and pyrroloazepinone amino acids from a common diaminodicarboxylate precursor
Rigid dipeptide surrogates: Syntheses of enantiopure quinolizidinone and pyrroloazepinone amino acids from a common diaminodicarboxylate precursor
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DOI：
10.1021/jo991766o
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发表时间：
2000-04-07
影响因子：
3.6
通讯作者：
Lubell, WD
中科院分区：
文献类型：
--
作者：
Gosselin, F;Lubell, WD
一种通用的和实用的方法，从一个共同的二氨基二羧酸前体合成不同的环大小的氮杂双环[X.Y.0]烷烃氨基酸已被开发作为一种手段，用于模拟不同的肽构象。(2S首先通过N-（PhF）天冬氨酸β-醛8与焦谷氨酸衍生的β-酮基膦酸酯12（PhF = 9-苯基芴-9-基）的Horner-Wadsworth-Emmons烯化反应以83%的产率制备5-氧代-2-[N-（PhF）氨基] 9-[N-（BOC）氨基]癸-4-烯二酸10-苄基1-叔丁酯（18）。然后通过从L-焦谷氨酸经七步合成对映体纯的喹嗪-2-酮氨基酸6和40%的总收率来说明这种制备氮杂双环[X.Y.0]烷烃氨基酸的方法的实用性。氢化δ-酮α，ω-二氨基癸二酸酯18，然后进行内酰胺环化和保护，得到喹嗪-2-酮氨基酸6，为单一非对映异构体。该方法的通用性接下来通过在11个步骤中以13%的总产率从焦谷氨酸合成吡咯并氮杂卓-2-酮氨基酸6的两种环融合异构体来证明。氢化物还原18，然后甲磺酸酯置换，得到5-烷基脯氨酸22。保护基操作、内酰胺环化和酯基的去除以1：2的非对映体比例容易地得到可分离的吡咯并氮杂卓酮氨基酸（7S）-和（7 R）-7。通过引入两个新的氮杂双环烷氨基酸，使用我们的烯烃化方法，我们已经扩大了这些重要的杂环的多样性，研究肽的生物活性的构象要求。
A versatile and practical approach for synthesizing azabicyclo[X.Y.0]alkane amino acids of different ring sizes from a common diaminodicarboxylate precursor has been developed as a means for mimicking different peptide conformations. (2S,SS)-1-tert-Butyl 10-benzyl 5-oxo-2-[N-(PhF)amino] 9-[N-(BOC)amino]dec-4-enedioate (18) was first prepared in 83% yield by the Horner-Wadsworth-Emmons olefination of N-(PhF)aspartate beta-aldehyde 8 with pyroglutamate-derived beta-keto phosphonate 12 (PhF = 9-phenylfluoren-9-yl). The practicality of this approach for making azabicyclo[X.Y.0]alkane amino acids was then illustrated by the first synthesis of enantiopure quinolizidin-2-one amino acid 6 in seven steps and 40% overall yield from L-pyroglutamic acid. Hydrogenation of delta-keto alpha,omega-diaminosebacate 18, followed by lactam cyclization and protection, gave quinolizidin-2-one amino acid 6 as a single diastereomer. The versatility of this approach was next demonstrated by the synthesis of both ring-fusion isomers of pyrroloazepin-2-one amino acid 6 in 11 steps and 13% overall yield from pyroglutamic acid. Hydride reduction of 18, followed by methanesulfonate displacement, gave 5-alkylproline 22. Protective group manipulations, lactam cyclization, and removal of the ester group afforded readily separable pyrroloazepinone amino acids (7S)- and (7R)-7 in a 1:2 diastereomeric ratio. By introducing two new azabicycloalkane amino acids using our olefination approach, we have expanded the diversity of these important heterocycles for studying the conformational requirements for peptide biological activity.