Synthesis of a thromboxane A2 receptor antagonist possessing the dioxabicycloheptane nucleus of TXA2

Autor:	Josef Fried, Ramiya H. Premchandran, M. L. Ogletree
Rok vydání:	1993
Předmět:	Agonist Bicyclic molecule medicine.drug_class Stereochemistry Organic Chemistry Antagonist Receptor antagonist Thromboxane A2 chemistry.chemical_compound Nucleophile chemistry medicine Reformatsky reaction Receptor
Zdroj:	The Journal of Organic Chemistry. 58:5724-5731
ISSN:	1520-6904 0022-3263
DOI:	10.1021/jo00073a035
Popis:	The synthesis of the TXA 2 /PGH 2 receptor antagonist 6 ([7,7-difluoro-3-[(N-heptanoylglycyl)aminomethyl-2,6-dioxabicyclo[3.1.1]hept-4-yl]-5-heptenoic acid )from the known chiral intermediate (-)-8 is described. The critical reaction is the inversion of C-S in 11a and 11b by an intramolecular cyclization reaction induced by nucleophilic reagents as shown in structure 13a. The key intermediate 22 was prepared in 26.5% yield in five steps. Diastereoselectivity is high in all but one of the steps, the Reformatsky reaction, which leads to equal amounts of 11a and 11b. The design of 6 is based on the dioxabicycloheptane nucleus characteristic of TXA 2 (1), which has been stabilized by fluorination. To this nucleus the two side chains are attached in cis orientation, and the ω-chain is modified as reported for the receptor antagonist (-) 5, which in turn is an analogue of PGH 2 (3). These changes inthe side chains have the effect of converting the powerful agonist 2 (DFTXA 2 ) into a receptor antagonist devoid of agonist activity, which binds to the receptor with nanomolar affinity. These findings lend support to the view of a single TXA 2 /PGH 2 receptor
Databáze:	OpenAIRE
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