A conformationally restricted GABA analogue based on octahydro-1H-cyclopenta[b]pyridine scaffold
- 165 Downloads
An approach to rel-(4aS,6R,7aR)-octahydro-1H-cyclopenta[b]pyridine-6-carboxylic acid—a bicyclic conformationally restricted γ-aminobutyric acid (GABA) analogue was developed. The eight-step sequence relied on the reaction of 2,3-bis(chloromethyl)pyridine and a C1-binucleophile and the catalytic reduction of the pyridine ring as the key steps and allowed for the preparation of the title compound in 9.0% overall yield. Assessment of the octahydro-1H-cyclopenta[b]pyridine scaffold geometry showed that this template can be considered truly three-dimensional.
KeywordsConformational restriction Amino acids Bicyclic compounds Pyridine Hydrogenation GABA analogues
The authors thank Prof. Andrey A. Tolmachev for his encouragement and support and Ms. Yuliya Kuchkovska for her help with preparation of Fig. 3.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interests.
The work was funded by Enamine Ltd.
This article does not contain any studies with human participants or animals performed by any of the authors.
- Aceña JL, Sorochinsky AE, Soloshonok V (2014) Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 3: Michael addition reactions and miscellaneous transformations. Amino Acids 46:2047–2073. https://doi.org/10.1007/s00726-014-1764-5 CrossRefPubMedGoogle Scholar
- Crittenden DL, Jordan MJT, Chebib M, Crittenden DL, Park A, Qiu J, Silverman RB, Duke RK, Johnston GAR (2006) Enantiomers of cis-constrained and flexible 2-substituted GABA analogues exert opposite effects at recombinant GABA(C) receptors. Bioorg Med Chem 14:447–455. https://doi.org/10.1016/j.bmc.2005.08.037 CrossRefPubMedGoogle Scholar
- Grimm JS, Maryanoff CA, Patel M, Palmer DC, Sorgi KL, Stefanick S, Webster RRH, Zhang X (2002) Reaction safety: a critical parameter in the development of a scalable synthesis of 2,3-bis-chloromethylpyridine hydrochloride. Org Proc Res Dev 6:938–942. https://doi.org/10.1021/op025545n CrossRefGoogle Scholar
- Grygorenko OO, Babenko P, Volochnyuk DM, Raievskyi O, Komarov IV (2016) Following Ramachandran: exit vector plots (EVP) as a tool to navigate chemical space covered by 3D bifunctional scaffolds. The case of cycloalkanes. RSC Adv 6:17595–17605. https://doi.org/10.1039/C5RA19958A CrossRefGoogle Scholar
- Guthikonda RN, Shah SK, Pacholok SG, Humes JL, Mumford RA, Grant SK, Chabin RM, Green BG, Tsou N, Ball R, Fletcher DS, Luell S, Euan MacIntyre D, Maccoss M (2005) Bicyclic amidine inhibitors of nitric oxide synthase: discovery of perhydro-iminopyrindine and perhydro-iminoquinoline as potent, orally active inhibitors of inducible nitric oxide synthase. Bioorg Med Chem Lett 15:1997–2001. https://doi.org/10.1016/j.bmcl.2005.02.067 CrossRefPubMedGoogle Scholar
- Kobayashi T, Suemasa A, Igawa A, Ide S, Fukuda H, Abe H, Arisawa M, Minami M, Shuto S (2014) Conformationally restricted gaba with bicyclo[3.1.0]hexane backbone as the first highly selective BGT-1 inhibitor. ACS Med Chem Lett 5:889–893. https://doi.org/10.1021/ml500134k CrossRefPubMedPubMedCentralGoogle Scholar
- Soloshonok VA (2002) Highly diastereoselective Michael addition reactions between nucleophilic glycine equivalents and β-substituted-α, β-unsaturated carboxylic acid derivatives a general approach to the stereochemically defined and sterically χ-constrained α-amino acids. Curr Org Chem 6:341–364. https://doi.org/10.2174/1385272024605014 CrossRefGoogle Scholar
- Sorochinsky A, Aceña J, Moriwaki H, Sato T, Soloshonok V (2013b) Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 2: Aldol, Mannich addition reactions, deracemization and (S) to (R) interconversion of α-amino acids. Amino Acids 45:1017–1033. https://doi.org/10.1007/s00726-013-1580-3 CrossRefPubMedGoogle Scholar
- Van Bever WFM, Knaeps AG, Willems JJM, Hermans BKF, Janssen PAJ (1973) Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-[3-methyl-1-(2-phenylethyl)-4-piperidyl]-N-phenylpropanamide and N-[3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl]-N-phenylpropanamide. J Med Chem 16:394–397. https://doi.org/10.1021/jm00256a003 CrossRefPubMedGoogle Scholar
- Witiak DT, Patch RJ, Enna SJ, Fung YK (1986) Stereoselective syntheses of the trans-decahydroquinoline-5-carboxylic acid epimers. Diastereomeric zwitterionic probes of γ-aminobutyric acid-related biological properties in vitro and in vivo. J Med Chem 29:1–8. https://doi.org/10.1021/jm00151a001 CrossRefPubMedGoogle Scholar