Computational Studies on Cinchona Alkaloid-Catalyzed Asymmetric Organic Reactions

Abstract

Remarkable progress in the area of asymmetric organocatalysis has been achieved in the last decades. Cinchona alkaloids and their derivatives have emerged as powerful organocatalysts owing to their reactivities leading to high enantioselectivities. The widespread usage of cinchona alkaloids has been attributed to their nontoxicity, ease of use, stability, cost effectiveness, recyclability, and practical utilization in industry. The presence of tunable functional groups enables cinchona alkaloids to catalyze a broad range of reactions. Excellent experimental studies have extensively contributed to this field, and highly selective reactions were catalyzed by cinchona alkaloids and their derivatives. Computational modeling has helped elucidate the mechanistic aspects of cinchona alkaloid catalyzed reactions as well as the origins of the selectivity they induce. These studies have complemented experimental work for the design of more efficient catalysts. This Account presents recent computational studies on cinchona alkaloid catalyzed organic reactions and the theoretical rationalizations behind their effectiveness and ability to induce selectivity. Valuable efforts to investigate the mechanisms of reactions catalyzed by cinchona alkaloids and the key aspects of the catalytic activity of cinchona alkaloids in reactions ranging from pharmaceutical to industrial applications are summarized. Quantum mechanics, particularly density functional theory (DFT), and molecular mechanics, including ONIOM, were used to rationalize experimental findings by providing mechanistic insights into reaction mechanisms. B3LYP with modest basis sets has been used in most of the studies; nonetheless, the energetics have been corrected with higher basis sets as well as functionals parametrized to include dispersion M05-2X, M06-2X, and M06-L and functionals with dispersion corrections. Since cinchona alkaloids catalyze reactions by forming complexes with substrates via hydrogen bonds and long-range interactions, the use of split valence triple-ζ basis sets including diffuse and polarization functions on heavy atoms and polarization functions on hydrogens are recommended. Most of the studies have used the continuum-based models to mimic the condensed phase in which organocatalysts function; in some cases, explicit solvation was shown to yield better quantitative agreement with experimental findings. The conformational behavior of cinchona alkaloids is also highlighted as it is expected to shed light on the origin of selectivity and pave the way to a comprehensive understanding of the catalytic mechanism. The ultimate goal of this Account is to provide an up-to-date overlook on cinchona alkaloid catalyzed chemistry and provide insight for future studies in both experimental and theoretical fields.

Stereo‐ and Regioselective Construction of Spirooxindoles Having Continuous Spiral Rings via Asymmetric [3+2] Cyclization of 3‐Isothiocyanato Oxindoles with Thioaurone Derivatives

“…Based on the experimental results and the previous literature, [ 11f,15 ] a plausible mechanism relating to a stepwise manner for this asymmetric Michael/cyclization cascade reaction was proposed. In line with the well‐established mode of action of cinchona alkaloid derived bifunctional catalysts, the tertiary amine unit of the quinine deprotonates and orients the 3‐isothiocyanato oxindole 1a by forming hydrogen bond.…”

Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis

“…Considering the conformational flexibility of reactants is clearly important and we may refer to Refs. for further discussion.…”

Synthesis of Quinoline‐4‐carboxamides and Quinoline‐4‐carboxylates via a Modified Pfitzinger Reaction of N‐Vinylisatins

“…For example, quinine 1 and quinidine 2 are two quinoline natural Cinchona-alkaloids which display antimalarial [1] and antiarrhythmic [2] properties, respectively. Besides, some derivatives of these latter 4-substituted alkaloids are used as asymmetric catalysts for a variety of applications [3] (Figure 1). Among the synthetic derivatives with important biological activities are several quinoline-4-carboxamide scaffolds.…”