The development of a concise asymmetric synthesis of the antiviral development candidate letermovir is reported, proceeding in >60% yield over a total of seven steps from commercially available materials. Key to the effectiveness of this process is a novel cinchonidine-based PTC-catalyzed aza-Michael reaction to configure the single stereocenter.

A divergent and regioselective synthesis of either 3-substituted benzisoxazoles or 2-substituted benzoxazoles from readily accessible ortho-hydroxyaryl N-H ketimines is described. The reaction proceeds in two distinct pathways through a common N-Cl imine intermediate: (a) N-O bond formation to form benzisoxazole under anhydrous conditions and (b) NaOCl mediated Beckmann-type rearrangement to form benzoxazole, respectively. The reaction path also depends on the electronic nature of the aromatic ring, with the electron-rich aromatic rings favoring the rearrangement and the electron-deficient rings favoring the N-O bond formation. A Beckmann-type rearrangement mechanism via net [1,2]-aryl migration for the formation of 2-substituted benzoxazole is proposed.

The synthesis of the potent anti-HIV investigational treatment islatravir is described. The key step in this synthesis is a highly enantioselective catalytic asymmetric alkynylation of a ketone. This reaction is a rare example of the asymmetric addition of an alkyne nucleophile to a ketone through ligand-accelerated catalysis that was performed on a greater than 100 g scale. By leveraging a multienzyme cascade, a highly diastereoselective aldol-glycosylation was used to complete the target in eight steps.

A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,β-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.

Two new routes to a pyrimidyl tetrazole intermediate are described. The first-generation route featured an iron-catalyzed cross-coupling between 4-butenylmagnesium bromide and a 4-chloropyrimidine derivative to afford an alkene-bearing pyrimidine intermediate. A subsequent intramolecular Heck cyclization afforded the desired bicyclic core, which was subsequently converted to the corresponding carboxylic acid via hydroboration and oxidation. This route was rapidly defined and used to prepare the initial 0.3 kg of the pyrimidyl tetrazole intermediate, which supported early toxicology and clinical studies of a drug candidate. A second-generation, eight-step route to the pyrimidyl tetrazole intermediate was defined and demonstrated on multikilogram scale in a 21% overall yield. The key transformation in this sequence was a copper­(I) mediated cyclization of an iodopyrimidine, affording the bicyclic core of the target in quantitative yield. Due to the larger scale involved for the second-generation approach, significant process safety evaluation was undertaken for a number of steps in this route, and the highlights of these studies are presented.