A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.

The development of a scalable asymmetric route to a new calcitonin gene-related peptide (CGRP) receptor antagonist is described. The synthesis of the two key fragments was redefined, and the intermediates were accessed through novel chemistry. Chiral lactam 2 was prepared by an enzyme mediated dynamic kinetic transamination which simultaneously set two stereocenters. Enzyme evolution resulted in an optimized transaminase providing the desired configuration in >60:1 syn/anti. The final chiral center was set via a crystallization induced diastereomeric transformation. The asymmetric spirocyclization to form the second fragment, chiral spiro acid intermediate 3, was catalyzed by a novel doubly quaternized phase transfer catalyst and provided optically pure material on isolation. With the two fragments in hand, development of their final union by amide bond formation and subsequent direct isolation is described. The described chemistry has been used to deliver over 100 kg of our desired target, ubrogepant.

Developing new antiretroviral therapies for HIV-1 infection with potential for less frequent dosing represents an important goal within drug discovery. Herein, we present the discovery of ethyl (1-((4-((4-fluorobenzyl)carbamoyl)-1-methyl-2-(2-(5-methyl- 1,3,4-oxadiazole-2-carboxamido)propan-2-yl)-6-oxo-1,6-dihydropyrimidin-5-yl)oxy)ethyl) carbonate (MK-8970), a highly optimized prodrug of raltegravir (Isentress). Raltegravir is a small molecule HIV integrase strand-transfer inhibitor approved for the treatment of HIV infection with twice-daily administration. Two classes of prodrugs were designed to have enhanced colonic absorption, and derivatives were evaluated in pharmacokinetic studies, both in vitro and in vivo in different species, ultimately leading to the identification of MK-8970 as a suitable candidate for development as an HIV therapeutic with the potential to require less frequent administration while maintaining the favorable efficacy, tolerability, and minimal drug-drug interaction profile of raltegravir.

We describe a convergent synthesis of the MRSA β-methyl carbapenem 1, wherein the molecule is assembled from the naphthosultam side chain 2 and the allylic carbonate of the β-Me carbapenem piece 6. The β-Me stereochemistry of 6 is set up in a novel titanium enolate addition into the TBDMS acetoxy azetidinone 5. The benzenesulfonate salt of 1 is endowed with exceptional stability.The ability of pathogenic bacteria to rapidly develop resistance to the existing repertoire of antibacterial agents poses a constant challenge for medicinal chemistry and the pharmaceutical industry. Consequently, an urgent need exists to expand the quality of the arsenal of compounds at the disposal of the medical community in order to prevent an upsurge of oftenfatal bacterial infections. Prominent among the many antibacterial agents are the β-lactams, and especially the carbapenems, such as imipenem. 1 Carbapenems are endowed with broadspectrum antibacterial properties combined with good tolerability and are consequently one of the most potent weapons in the fight against bacterial infections. Work from numerous laboratories has revealed some important structure-activity relationships: addition of a β-Me group in the 1-position increases the metabolic and chemical stability, while attachment of aryl groups either directly or through a heteroatom linker to the 2-position of the carbapenem results in exquisitely potent antibacterial agents. 2 A recent, very promising carbapenem development candidate with anti-MRSA (Methicillin-resistant Staphylococcus aureus) activity is 1, which attaches a naphthosultam side chain

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