ABSTRACT
The development of a convergent route to the NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) agonist BMS-986299 is reported. The synthesis relies on a key Miyaura borylation and a tandem Suzuki-Miyaura coupling between an iodoimidazole and an o-aminochloroarene, followed by acid-mediated cyclization to afford the aminoquinoline core. The subsequent Boc cleavage and regioselective acylation afford the target compound. Two routes to the iodoimidazole intermediate are presented, along with the synthesis of the o-aminochloroarene via Negishi coupling. The convergent six-step route leads to an 80% reduction in process mass intensity compared to the linear enabling synthesis.
Subject(s)
Imidazoles , NLR Family, Pyrin Domain-Containing 3 Protein , Cyclization , AcylationABSTRACT
A highly stereoselective synthesis of a cyclic dinucleotide (CDN) STING agonist containing two chiral thiophosphoramidate linkages is described. These rare yet key functional groups were, for the first time, installed efficiently and with high diastereoselectivity using a specially designed P(V) reagent. By utilizing this strategy, the CDN was prepared in greater than 16-fold higher yield than the prior P(III) approach, with fewer hazardous reagents and chromatographic purifications.
Subject(s)
Membrane Proteins , Indicators and Reagents , Membrane Proteins/chemistryABSTRACT
Here we present a novel strategy for the synthesis of enantiomerically enriched tetrahydronaphthalen-1-ols. The reaction proceeds via an alkylation (via hydrogen borrowing) and ammonium formate-mediated asymmetric transfer hydrogenation (via dynamic kinetic resolution), giving alkylated tetralols in high yields and good enantio- and diastereoselectivity across a diverse range of both alcohol and tetralone substrates. Additionally, these products were successfully derivatized to several complex molecules, demonstrating the utility of the tetrahydronaphthalen-1-ol.