An underlying goal of drug discovery is to develop safe and stable substances that specifically target essential elements that cause disease. Molecular chirality adds an additional level of specificity and complexity in achieving this objective, as mirror image molecules are distinct substances and must be treated as such. Classical chiral-center enantiomers ( Figure 1A) have been shown to differ significantly in biological activity, pharmacodynamics, pharmacokinetics, and toxicity. 1 The cases of thalidomide 2 and perhexiline, 3 whose enantiomers differ dramatically with respect to toxicity and metabolic properties, emphasize the importance of addressing stereochemistry in drug development.In this Perspective, we address the pharmaceutical implications of a largely overlooked alternative source of drug chirality, atropisomerism, 4 which has the distinct feature of creating molecular chirality as a result of hindered rotation about a bond axis ( Figure 1B). Figure 1C shows space-filling models where it is evident that rotation about the vertical axis is hindered because of steric clashes between the bulky R1 and R2 groups with R3 and R4.Unlike compounds with classical chiral centers, which are often stable and which racemize via a bond breaking and making process, atropisomers racemize via an intramolecular dynamic process that only involves bond rotation. As bond rotation is time-dependent, racemization half-lives for atropisomers can vary dramatically between minutes to years, depending on the degree of steric hindrance, electronic influences, temperature, solvent, etc. Because of this time-dependent feature, drug discovery campaigns can become more complex, or may even be abandoned, when atropisomeric properties are observed. Atropisomerism frequently results as researchers strive to design more compact and conformationally constrained inhibitors. Even for courageous design and synthetic campaigns that attempt to develop atropisomeric compounds, important differences in properties have been reported for enantiomeric pairs, such as in vitro inhibition, crystallization, in vivo racemization rates, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. There are also examples of compounds that were unknowingly developed as a racemic mixture of atropisomers and required chiral detection experiments to finally reveal their existence. Overall, many view atropisomer chirality as a lurking menace with the potential to increase the cost of pharmaceutical research and development and to derail drug Figure 1. (A) Mirror-image enantiomers S and R arise from a classical chiral center (atom). (B) Other enantiomers S a and R a can arise from hindered rotation that creates a chiral axis. (C) Atropisomeric enantiomers S a and R a are shown as space-filling models. Reproduced with permission from ChemMedChem (LaPlante, S. R.; Edwards, P. J.; Fader, L. D.; Jakalian, A.; Hucke, O. Revealing atropisomer axial chirality in drug discovery. 2011, 6, 505À513,

Catalysis has become increasingly important for the pharmaceutical industry. Catalysis is a critical technology that enables economical and environmentally-sound manufacturing processes. The development of a viable catalytic process for industrial scales is a complex task that requires the collaboration of multiple disciplines. In this article, a number of selected, noteworthy industrial examples are discussed to showcase the catalytic technologies that have been successfully practiced on large scales for active pharmaceutical ingredient (API) synthesis, involving transition metal catalysis, biocatalysis and organocatalysis. In addition, several examples of potential and future catalytic transformations are included which can be utilized in pharmaceutical industry in large-scale operational settings.

The first examples of the use of racemic vinylaziridines in a Pd-catalyzed dynamic kinetic asymmetric transformation have been examined. Optimization studies of the Pd-catalyzed addition of vinylaziridines to isocyanates revealed that the chiral ligand between trans-1,2-diaminocyclohexane and 2-diphenylphosphino-1-naphthoic acid is superior to that involving 2-diphenylphosphino benzoic acid. Surprisingly, high ee's required the use of an acid whose pKa was about 4.7 +/- 0.1 as a cocatalyst. Both acetic acid and hydroxybenzotriazole meet this requirement. Less electrophilic isocyanates (e.g., benzyl, p-methoxyphenyl) gave higher ee's than more electrophilic ones (phenyl or benzoyl). Both N-benzyl and N-arylaziridines react well to give good yields and ee's, whereas N-tosylaziridines gave lower ee's. A 1,1-disubstituted aziridine led to the formation of a tertiary C-N bond with ee's comparable to the formation of the secondary C-N bond. The products were easily reduced almost quantitatively to the sensitive imidazolidines which can be readily hydrolyzed to the vicinal diamines. The reactivity pattern is consistent with a Curtin-Hammett situation wherein the enantiodiscriminating event is the cyclization of a rapidly equilibrating dynamic pi-allyl palladium intermediate.

Alkaloids U 0600 DYKAT of Vinyl Aziridines: Total Synthesis of (+)-Pseudodistomin D. -The synthesis of title compound (VIIb) starts with a dynamic kinetic asymmetric transformation (DYKAT) of aziridine (I). -(TROST*, B. M.; FANDRICK, D. R.; Org. Lett. 7 (2005) 5, 823-826; Dep. Chem., Stanford Univ., Stanford, CA 94305, USA; Eng.) -R. Steudel 30-182

Aryltrimethylammonium triflates and tetrafluoroborates were found to be highly reactive electrophiles in the Pd-catalyzed cross coupling with aryl Grignard reagents. The coupling reactions proceed at ambient temperature with a nearly stoichiometric quantity of Grignard reagent, and diverse functionality is tolerated. Competition experiments established the reactivity of PhNMe(3)OTf relative to PhCl, PhBr, PhI, and PhOTf.