Asymmetric synthesis of cis-(-)-(2R4S)-4-(phosphonomethyl)-2-piperidinecarboxylic acid, a potent NMDA receptor antagonist

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 8, 1996, Pages 963-966

  Skiles, Jerry W ^a   Giannousis, Peter P ^a   Fales, Kevin R ^a,b  

^a NOVARTIS PHARMA AG   (Switzerland)

^b WAYNE STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 PHOSPHONOMETHYLPIPECOLIC ACID; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR BLOCKING AGENT;

ANIMAL TISSUE; ARTICLE; BRAIN; CONTROLLED STUDY; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG SYNTHESIS; ENANTIOMER; NONHUMAN; STEREOCHEMISTRY;

EID: 0029962102     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00150-3     Document Type: Article

References (22)

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19. 13C NMR which are consistent with the assigned structures.
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21. As an additional proof of the absolute stereochemical assignments, the carboxamide diethyl ester of cis-(±)-1 could also be resolved into the respective enantiomers via its di-p-toluoyl-L-tartarate salts (see 15 below). Hydrolysis of each enantiomer with 6 N HCl afforded both cis-(+)-1 and cis-(-)-1. Optical rotaions as well as NMR, MS, and IR of these resolved materials were identical to those prepared by synthetic means. In addition to correlation with the known natural product (2S4A)-14b the single crystal X-ray structure of the cis-(+)-carboxamide diethyl ester di-p-toluoyl-L-tartaric acid salt of 1, i.e. 15 below, confirmed our absolute stereochemical assignments. Complete listings of atomic coordinates, bond lengths, bond angles, thermal parameters and structure factors for compound 15 have been deposited at the Cambridge Crystallographic Data Centre, University Chemical Laboratory, Lensfield Road, Cambridge, CB2 1EW England. (Equation Presented)
22. For details of the NMDA receptor binding assay see references 3 and 4.