Synthesis of Analogues of GABA. III. All Four Stereoisomers of 3-Aminocyclopentanecarboxylic Acid and a Stereochemical Correlation with Amidinomycin

Abstract

All four stereoisomers of 3-aminocyclopentanecarboxylic acid have been prepared as analogues of the inhibitory neurotransmitter GABA. The amino acid degradation product from the antibiotic amidinomycin corresponds to cis-(1R,3S)-3-aminocyclopentanecarboxylic acid and thus amidinomycin is (1R,3S)-N-(2'-amidinoethyl)-3-aminocyclopentane-1-carboxamide (10). A key reaction was the stereoselective reduction of 3-hydroxyiminocyclopentanecarboxylic acid (8) to the corresponding cis amino acid (2).

Predicting the Diastereoselectivity of Rh-Mediated Intramolecular C−H Insertion

“…Preparation and Cyclization of α-Diazo Ester 3. The preparation of 3 started with the enantiomerically pure β-hydroxy ester 16 (Scheme ), which we had prepared previously 1c gave the anti ester, which on reduction and protection gave the acetonide 17 .…”

“…The development of new methods for the stereocontrolled construction of carbocycles is fundamental to the development of target-directed organic synthesis. While many approaches for the preparation of enantiomerically-pure cyclopentanes have been put forward, there is still a need for general strategies for the construction of highly- alkylated cyclopentanes with control of both relative and absolute configuration. As enantiomerically pure acyclic fragments of high enantiomeric purity are readily available, one way to fill this gap would be to develop methods for cyclization that proceed with high diastereoselectivity relative to existing stereogenic centers that are then included in the ring.…”

Stereoselective synthesis of γ-amino acids

“…355 On the other hand, Dieckmann cyclization of 944, obtained in 11 steps from aspartic acid, in the presence of KHMDS gave ketoester derivative 945 in excellent yield as a 3:2 mixture of diastereoisomers, which under sequential reduction with NaBH 4 , mesylation, and treatment with KOt-Bu produced cyclopentene derivative 946 in 79% overall yield. Catalytic hydrogenation of 946 in the presence of Pt/C afforded 947 as a 1:3 mixture of cis/trans, which after treatment with LiOH, followed by acetylation with Ac 2 O in the presence of NaOAc gave lactam (1R,4S)-948 as the only product in 97% yield.…”

Synthesis of γ‐Aminobutyric Acid Analogs

“…Reduction using sodium/ammonia/methanol yielded a separable mixture (cis : trans 55 : 45) of the desired amino acids. However, reduction using zinc in HCl proceeded stereoselectively to the cis amino acids in low yield to afford after crystallization (R,S)-cis-(518) and (S,R)-cis-(518) [369].…”