John Limanto

Dynamic Kinetic Resolution: Asymmetric Transfer Hydrogenation of α-Alkyl-Substituted β-Ketoamides

Dynamic kinetic resolution (deracemization) of various alpha-alkyl-substituted beta-ketoamides 1 via asymmetric transfer hydrogenation proceeded efficiently to give the corresponding syn-beta-hydroxy amides 3 in high diastereo- and enantioselectivities. Specifically, subjection of 1 to HCO(2)H and Et(3)N in the presence of 0.5-1 mol % of pentafluorobenzenesulfonyl-DPEN-Ru catalyst 2b at 30-40 degrees C in either PhCH(3) or CH(2)Cl(2) generated the syn-hydroxy product 3 selectively in 15-33:1 dr, 93-97% ee, and 75-88% isolated yields.

A Highly Efficient Asymmetric Synthesis of Vernakalant

A novel synthesis of vernakalant is described. Using inexpensive and readily available reagents, the key transformations involve (1) an efficient zinc-amine-promoted etherification, (2) a highly stereoselective enzyme-catalyzed dynamic asymmetric transamination to set up the two contiguous chiral centers in the cyclohexane ring, and (3) a pyrrolidine ring formation via alkyl-B(OH)2-catalyzed amidation and subsequent imide reduction.

Practical and cost-effective manufacturing route for the synthesis of a β-lactamase inhibitor.

Compound 1, a potent and irreversible inhibitor of β-lactamases, is in clinical trials with β-lactam antibiotics for the treatment of serious and antibiotic-resistant bacterial infections. A short, scalable, and cost-effective route for the production of this densely functionalized polycyclic molecule is described.

A multifunctional catalyst that stereoselectively assembles prodrugs

Getting phosphorus into healthy shape ProTide therapeutics play a trick on the body, getting nucleoside analogs where they need to be by decorating them with unnatural phosphoramidates in place of ordinary phosphates. These compounds pose an unusual synthetic challenge because their configuration must be controlled at phosphorus; most methods have been refined to manipulate the geometry of carbon. DiRocco et al. report a metal-free, small-molecule catalyst that attains high selectivity for nucleoside phosphoramidation by activating both reaction partners. Kinetic studies with an early prototype revealed a double role for the catalyst that inspired the rational design of a more active and selective dimeric structure. Science, this issue p. 426 A doubly activating catalyst efficiently forms key phosphorus-based chiral centers inherent to ProTide therapeutics. The catalytic stereoselective synthesis of compounds with chiral phosphorus centers remains an unsolved problem. State-of-the-art methods rely on resolution or stoichiometric chiral auxiliaries. Phosphoramidate prodrugs are a critical component of pronucleotide (ProTide) therapies used in the treatment of viral disease and cancer. Here we describe the development of a catalytic stereoselective method for the installation of phosphorus-stereogenic phosphoramidates to nucleosides through a dynamic stereoselective process. Detailed mechanistic studies and computational modeling led to the rational design of a multifunctional catalyst that enables stereoselectivity as high as 99:1.