Journal Article
The synthesis of isotopically labeled (+)-2-amino-bicyclo[3.1.0]hexane-2,6-carboxylic acid and its 2-oxa-and 2-thia-analogs
Wheeler, WJ; O'Bannon, DD; Kennedy, JH; Monn, JA; Tharp-Taylor, RW; Valli, MJ; Kuo, FJ
Journal of Labelled Compounds and Radiopharmaceuticals
ISSN: 0362-4803
EISSN: 1099-1344
JOHN WILEY & SONS LTD
As part of a program aimed at the design of conformationally constrained analogs of glutamic acid, (+)-2-aminobicyclo[3.1.0]hexane-2,6-carboxylic acid (1), identified as a highly potent, selective, group II metabotropic glutamate receptor agonist has been synthesized and studied clinically. Heterocyclic analogs of 1 were subsequently synthesized in which the C-2 methylene has been replaced by an oxygen atom (2) or a sulfur atom (3). C-14 labeled isotopomers of 1, 2 and 3 have been synthesized to facilitate pre-clinical ADME studies. A tritium labeled isotopomer of 1 was also synthesized for use in in vitro experiments. A stable labeled isotopomer of rac-1 was prepared for use as an internal standard for bioanalytical assays. The key step in each of these syntheses was the reaction of chiral ketone 4, 5 or 6 with K14CN/ (NH4)2CO3 using the Bucherer-Berg protocol. In the preparation of the stable labeled isotopomer, rac-4-[13C 2] was prepared in two steps from ethyl bromoacetate-[UL- 13C2]; subsequent reaction of rac-4-[13C 2] with K13CN/15NH4Cl/Na 2CO3, followed by hydrolysis of the hydantoin yielded rac-1-[13C3, 15N]. Copyright © 2005 John Wiley & Sons, Ltd.
mGlu agonist; carbon 14; tritium; Bucherer-Berg reaction