171889-06-8Relevant academic research and scientific papers
The bisected s-trans conformation-controlled highly stereoselective addition of Grignard reagents to C-cyclopropylaldonitrone. An efficient synthesis of 1-phenyl-2-[(S)-1-aminoalkyl]-N,Ndiethylcyclopropanecarboxamides, a new class of potent NMDA receptor antagonists
Kazuta, Yuji,Shuto, Satoshi,Abe, Hiroshi,Matsuda, Akira
, p. 599 - 604 (2007/10/03)
An efficient synthesis of 1-phenyl-2-[(S)-1-aminoethyl]- and 1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamides [1a (PEDC) and 1b (PPDC), respectively], potent NMDA receptor antagonists having a cyclopropane structure, was achieved. We have shown for the first time that C-cyclopropylaldonitrone preferentially exists in the bisected s-trans conformation, due to the characteristic stereoelectronic effects of the cyclopropane ring, by X-ray crystallographic analysis, NMR studies, and theoretical calculations. Based on these findings, the highly stereoselective addition reaction of Grignard reagents to C-cyclopropylaldonitrone 6 was developed, and the reaction was successfully used as the key step for the preparation of the NMDA receptor antagonists la and lb as well as for a newly designed isopropyl-type congener 1c. The facial selectivity of the addition of Grignard reagents can be explained by the attack of the reagents from the less hindered side of the substrate in the predicted bisected s-trans conformation. This Grignard reaction is the first example of a highly stereoselective addition to a nitrone via a non-chelation controlled pathway.
Highly stereoselective addition of Grignard reagents to C- cyclopropylnitrone via the bisected s-trans conformation. An efficient synthesis of PEDC, a potent NMDA receptor antagonist having a cyclopropane structure
Kazuta, Yuji,Shuto, Satoshi,Matsuda, Akira
, p. 5373 - 5377 (2007/10/03)
An efficient synthesis of PEDC (1), a potent NMDA receptor antagonist of a cyclopropane structure, was achieved. The highly stereoselective addition reaction of MeMgBr to C-cyclopropylnitrone 2, via its bisected s-trans conformation which can be predicted from the stereo-electronic effects, was developed as the key step. The s-trans conformation predominant in C- cyclopropynitrone 2 was suggested by NOE experiments. (C) 2000 Elsevier Science Ltd.
Conformational restriction by repulsion between adjacent substituents on a cyclopropane ring: Design and enantioselective synthesis of 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides as potent NMDA receptor antagonists
Shuto, Satoshi,Ono, Shizuka,Hase, Yukako,Kamiyama, Noriko,Takada, Hironao,Yamasihita, Kanako,Matsuda, Akira
, p. 915 - 923 (2007/10/03)
Adjacent substituents on a cyclopropane ring mutually exert steric repulsion quite significantly, because they are fixed in eclipsed conformation to each other. Based on this structural feature of the cyclopropane ring, conformationally restricted analogs of milnacipran (1), namely 1-phenyl-2-(1-aminoalkyl)-N,N-diethylcyclopropanecarboxamides (2, 3, ent-2, and ent-3) were designed as potent NMDA receptor antagonists and were synthesized highly enantioselectively. Reaction of (R)-epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH2 in benzene gave a chiral cyclopropane derivative that was isolated as lactone 4 with 96% ee in 67% yield, after alkaline hydrolysis of the cyano group. The nucleophilic addition reaction of Grignard reagents to aldehyde 10, which was readily prepared from 4, proceeded highly selectively from the si-face to afford addition products 11 in high yields. Although hydride reduction of the corresponding ketone 15b, prepared from 11b, with L-Selectride also proceeded highly diastereoselectively, the facial selectivity was reversed to give the re-face addition product lib. On the other hand, reduction of 15 with DIBAL-H afforded the si-face addition product 12 in high yields. These results suggested that these nucleophilic addition reactions proceeded via either the bisected s-trans or s-cis conformation of the cyclopropylcarbonyl derivatives. From 11 and 12, the target conformationally resticted analogs, 2 and 3, were synthesized, respectively. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, ent-2 and ent-3, were also synthesized. The structures of the conformationally restricted analogs detected by the X-ray crystallographic analysis suggested that their conformations can be restricted as we hypothesized. Thus, a new method for restricting the conformation of cyclopropane derivatives has been developed.
Synthesis of (+)- and (-)-milnaciprans and their conformationally restricted analogs
Shuto, Satoshi,Ono, Shizuka,Hase, Yukako,Kamiyama, Noriko,Matsuda, Akira
, p. 641 - 644 (2007/10/02)
Reaction of (R)-epichlorohydrin [(R)-5] and phenylacetonitrile (6) in the presence of NaNH2 in benzene gave a cyclopropane derivative which was isolated as lactone 4 [(1S,2R)-2-oxo-1-phenyl-3-oxabicyclo[3,1,0]hexane] of 96% e.e. in 67% yield, after alkaline hydrolysis of the cyano group. Compound 4 was readily converted to (+)-milnacipran [(+)-1], by which the absolute stereochemistry of (+)-1 was confirmed. (1S,2R)-1-phenyl-2-[(S)-1-aminoethyl]-cyclopropane-N,N-diethylcarboxam ides (2), a conformationally restricted analog of 1, was also synthesized in high enantiomeric purity from 4. Starting from (S)-epichlorohydrin [(S)-5], their corresponding enantiomers, namely (-)-milnacipran [(-)-1] and ent-2, were also synthesized.
