Methicillin-resistant Staphylococcus aureus infection can be treated effectively by combining a β-lactam antibiotic with a drug that targets FtsZ.

The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.

Oxidative cyclizations of a variety of heteroatom nucleophiles onto unactivated olefins are catalyzed by palladium(II) and pyridine in the presence of molecular oxygen as the sole stoichiometric oxidant in a nonpolar solvent (toluene). Reactivity studies of a number of N-ligated palladium complexes show that chelating ligands slow the reaction. Nearly identical conditions are applicable to five different types of nucleophiles: phenols, primary alcohols, carboxylic acids, a vinylogous acid, and amides. Electron-rich phenols are excellent substrates, and multiple olefin substitution patterns are tolerated. Primary alcohols undergo oxidative cyclization without significant oxidation to the aldehyde, a fact that illustrates the range of reactivity available from various Pd(II) salts under differing conditions. Alcohols can form both fused and spirocyclic ring systems, depending on the position of the olefin relative to the tethered alcohol; the same is true of the acid derivatives. The racemic conditions served as a platform for the development of an enantioselective reaction. Experiments with stereospecifically deuterated primary alcohol substrates rule out a "Wacker-type" mechanism involving anti oxypalladation and suggest that the reaction proceeds by syn oxypalladation for both mono-and bidentate ligands. In contrast, cyclizations of deuterium-labeled carboxylic acid substrates undergo anti oxypalladation.

Catalytic asymmetric oxidation-chemistry involving heteroatom transfer from a reagent to a substrate is perhaps unparalleled in synthetic utility for the construction of enantioenriched materials.[1] Conversely, there is a significant deficiency of asymmetric two-electron oxidations that do not involve heteroatom transfer. Some potentially valuable reactions of this type include the oxidation of secondary alcohols and oxidative heterocyclizations (Scheme 1). The design of efficient processes of this nature requires an abundant, inexpensive, and effective stoichiometric oxidant, and a solvent that is amenable to asymmetric catalysis. To begin to address this general synthetic problem, we recently developed a Pd-catalyzed oxidative kinetic resolution of secondary alcohols in toluene that uses molecular oxygen as the terminal oxidant (Scheme 1). [2,3] Herein we demonstrate the utility of this simple system (Pd catalyst, ligand, PhCH 3 , O 2 ) for the construction of a range of heterocycles by catalytic oxidative cyclization. We also demonstrate for the first time that aerobic cyclizations of this type are amenable to asymmetric catalysis, and thereby establish a critical proof of concept for the further development of catalytic asymmetric oxidative cyclizations that use molecular oxygen as the sole stoichiometric oxidant.Palladium-catalyzed bond-forming constructions have become indispensable in organic chemistry.[4] A favorable property of palladium is that it can serve as both a nucleophile (i.e., Pd 0 ) and an electrophile (i.e., Pd II ), which produces many opportunities for catalysis. Although both modes are prevalent, electrophilic oxidative catalysis by Pd II has garnered less attention in the asymmetric arena. Adding to the disparity is the fact that until recently, cocatalysts (e.g., copper salts) or organic oxidants (e.g., benzoquinone) were necessary for the reoxidation of Pd 0 to Pd II , thus creating a nearly intractable situation for asymmetric catalysis. For example, the use of the traditional copper/O 2 reoxidation system introduces a secondary catalytic cycle, while the benzoquinone system requires the removal of stoichiometric quantities of organic compounds at the end of the reaction. In contrast, reactions that proceed under direct dioxygen coupled catalysis produce H 2 O as the sole byproduct. Despite the difficulties of the traditional systems, seminal works by Hosokawa and Murahashi, [5] Hayashi, [6] Sasai, [7] and Bäckvall [8] have established the potential for enantioselective Pd II -catalyzed oxidative cyclizations and dialkoxylations. [9] To the best of our knowledge, however, there were no examples of direct dioxygen-coupled enantioselective Pd II

Hepatitis A virus (HAV) 3C enzyme is a cysteine proteinase essential for viral replication and infectivity and represents a target for the development of antiviral drugs. A number of serine and threonine beta-lactones were synthesized and tested against HAV 3C proteinase. The D-N-Cbz-serine beta-lactone 5a displays competitive reversible inhibition with a K(i) value of 1.50 x 10(-6) M. Its enantiomer, L-N-Cbz-serine beta-lactone 5b is an irreversible inactivator with k(inact) = 0.70 min(-1), K(Iota) = 1.84 x 10(-4) M and k(inact)/K(Iota) = 3800 M(-1) min(-1). Mass spectrometry and HMQC NMR studies using (13)C-labeled 5b show that inactivation of the enzyme occurs by nucleophilic attack of the cysteine thiol (Cys-172) at the beta-position of the oxetanone ring. Although the N-Cbz-serine beta-lactones 5a and 5b display potent inhibition, other related analogues with an N-Cbz side chain, such as the five-membered ring homoserine gamma-lactones 14a and 14b, the four-membered ring beta-lactam 33, 2-methylene oxetane 34, cyclobutanone 36, and 3-azetidinone 39, fail to give significant inhibition of HAV 3C proteinase, thus demonstrating the importance of the beta-lactone ring for binding.