A variety of medium-ring heterocycles, prepared efficiently by the Ru-catalyzed diene metathesis method, undergo asymmetric catalytic ethylmagnesation to afford nonracemic unsaturated alcohols and amides in excellent enantiomeric purity (>98% ee). Noteworthy features of these studies are as follows:  (i) Eight-membered unsaturated tosyl amides are readily prepared by transition-metal-catalyzed metathesis. (ii) With six-, seven-, and eight-membered N-containing substrates the presence of an electron-withdrawing Ts unit is required for efficient carbomagnesation (corresponding alkylamines are inert). Chiral medium-ring heterocycles are resolved by the Zr-catalyzed C−C bond-forming reaction to afford recovered starting materials in up to >99% ee. The kinetic resolution data indicate that simple steric models can reliably predict the sense of the asymmetric induction in the asymmetric carbomagnesation or kinetic resolution. However, experimental results presented herein also illustrate that the observed levels of enantioselectivity cannot be predicted on the basis of such paradigms.

The development and optimization of a scalable synthesis of sodium-dependent glucose cotransporter 2 inhibitor, ertugliflozin, for the treatment of type-2 diabetes is described. Highlights of the chemistry are a concise, four-step synthesis of a structurally complex API from known intermediate 4 via persilylation–selective monodesilylation, primary alcohol oxidation, aldol-crossed-Cannizzaro reaction, and solid-phase acid-catalyzed bicyclic ketal formation. The final API was isolated as the l-pyroglutamic acid cocrystal.

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Pyrido[4,3-d]pyrimidin-4(3H)-one (1) was prepared by reacting 2-trifluoromethyl-4-iodo-nicotinic acid (2) with amidine 9a catalyzed by Pd(2)(dba)(3) and Xantphos, followed by cyclization effected with HBTU and subsequent demethylation using PhBCl(2). The amidine arylation method was found applicable for the syntheses of quinazolin-4(3H)-ones. Thus, reaction of 2-bromo or 2-iodo benzoate esters with amdidines afforded substituted quinazolin-4(3H)-ones in 44-89% yields.

As part of a strategy to deliver short-acting calcium-sensing receptor (CaSR) antagonists, the metabolically labile thiomethyl functionality was incorporated into the zwitterionic amino alcohol derivative 3 with the hope of increasing human clearance through oxidative metabolism, while delivering a pharmacologically inactive sulfoxide metabolite. The effort led to the identification of thioanisoles 22 and 23 as potent and orally active CaSR antagonists with a rapid onset of action and short pharmacokinetic half-lives, which led to a rapid and transient stimulation of parathyroid hormone in a dose-dependent fashion following oral administration to rats. On the basis of the balance between target pharmacology, safety, and human disposition profiles, 22 and 23 were advanced as clinical candidates for the treatment of osteoporosis.