The GPCR participates in several physiological processes, and its dysfunction is related to many pathologic disorders [1]. In this way, the discovery of ligands that can bind to such receptors selectively is of considerable importance in developing new drugs. The Molispiration software calculated excellent bioactivity scores for three new molecules as GPCR ligands 4-6. As part of our goal to use the diversity-oriented synthesis (DOS) as a strategy to create a structurally complex organic molecules database [2] from the Diels-Alder adduct tricyclo[6.2.1.02,7]-undeca-4,9-diene-3,6-dione (1), we have synthesized the advanced intermediate 3 from a key step 1,3-dipolar cycloaddition [3] between the nitrone 2 and the dipolarophile obtained from 1 after treatment with Zn/HCl (Scheme 1). The potential ligands 4-6 will be prepared after some chemical modifications in cyclohexanedione moiety present in 3. The isoxazolidine 3 was characterized by 1H and 13C NMR spectroscopy.

Scheme 1. Synthesis of new GPCR ligands

References:
[1] Hauser, A. S.; Chavali, S.; Masuho, I.; et al. Cell 2018, 172, 41. [Crossref]
[2] Schreiber, S. L. Science 2000, 287, 1964. [Crossref]
[3] Reddy, D. S.; Reddy, G. G.; Beatriz, A.; Corey, E. J. Org. Lett. 2021, 23, 5445. [Crossref]