Tongxiang Lu

Two Rapid Catalyst-Free Click Reactions for In Vivo Protein Labeling of Genetically Encoded Strained Alkene/Alkyne Functionalities

Detailed kinetic analyses of inverse electron-demand Diels–Alder cycloaddition and nitrilimine-alkene/alkyne 1,3-diploar cycloaddition reactions were conducted and the reactions were applied for rapid protein bioconjugation. When reacted with a tetrazine or a diaryl nitrilimine, strained alkene/alkyne entities including norbornene, trans-cyclooctene, and cyclooctyne displayed rapid kinetics. To apply these “click” reactions for site-specific protein labeling, five tyrosine derivatives that contain a norbornene, trans-cyclooctene, or cyclooctyne entity were genetically encoded into proteins in Escherichia coli using an engineered pyrrolysyl-tRNA synthetase-tRNACUAPyl pair. Proteins bearing these noncanonical amino acids were successively labeled with a fluorescein tetrazine dye and a diaryl nitrilimine both in vitro and in living cells.

Origin of the Superior Performance of (Thio)Squaramides over (Thio)Ureas in Organocatalysis

The Diels-Alder cycloaddition of anthracene and nitrostyrene catalyzed by the squaramide-derived aminocatalysts (Sq) recently reported by Jørgensen and co-workers (Angew. Chem. 2012, 124, 10417; Angew. Chem. Int. Ed. 2012, 51, 10271) has been studied by using modern tools of computational quantum chemistry. This catalyst is compared with analogous urea-, thiourea-, and thiosquaramide-derived aminocatalysts. Ultimately, a thiosquar-amide-derived catalyst is predicted to result in the lowest free-energy barrier, while retaining the same high degree of enantioselectivity as Sq. This stems in part from the superior hydrogen-bonding ability of thiosquaramides, compared to squaramides and (thio)ureas. We also examine the hydrogen-bonding ability of (thio)ureas and (thio)-squaramides in model complexes. In contrast to previous work, we show that aromaticity does not contribute significantly to the enhanced hydrogen-bonding interactions of squaramides. Overall, thiosquaramide, which has not been explored in the context of either organocatalysis or molecular recognition, is predicted to lead to strong, co-planar hydrogen bonds, and should serve as a potent hydrogen-bonding element in a myriad of applications.

Enantioselectivity in Catalytic Asymmetric Fischer Indolizations Hinges on the Competition of π-Stacking and CH/π Interactions.

Computational analyses of the first catalytic asymmetric Fischer indolization (J. Am. Chem. Soc. 2011, 133, 18534) reveal that enantioselectivity arises from differences in hydrogen bonding and CH/π interactions between the substrate and catalyst in the operative transition states. This selectivity occurs despite strong π-stacking interactions that reduce the enantioselectivity.

Quantifying the role of anion-π interactions in anion-π catalysis.

Matile et al. introduced the concept of anion-π catalysis [Angew. Chem., Int. Ed. 2013, 52, 9940; J. Am. Chem. Soc. 2014, 136, 2101], reporting naphthalene diimide (NDI)-based organocatalysts for the Kemp elimination reaction. We report computational analyses of the operative noncovalent interactions, revealing that anion-π interactions actually increase the activation barriers for some of these catalyzed reactions. We propose new catalysts that are predicted to achieve significant lowering of the activation energy through anion-π interactions.

Harnessing weak interactions for enantioselective catalysis

The traditional tools of physical organic chemistry benefit from modern data analysis techniques [Also see Research Article by Milo et al.] Elucidating catalytic reaction mechanisms is often a challenge, and these difficulties are compounded in the case of enantioselective catalysts. The ability of a catalyst to preferentially form one enantiomer over the other often hinges on the balance of many attractive and repulsive nonbonded interactions that occur in competing transition states. On page 737 of this issue, Milo et al. (1) combine physical organic and computational quantum chemistry with modern data analysis techniques to identify these interactions. Their predictive mathematical models elucidate the underlying reaction mechanism and the role of nonbonded interactions in these enantioselective reactions, facilitating the rational design of more effective catalysts.

Explaining the disparate stereoselectivities of N-oxide catalyzed allylations and propargylations of aldehydes.

A simple electrostatic model explains the enhanced stereoselectivity of N-oxide catalyzed allylations compared to propargylations, which in turn explicates the dearth of stereoselective N-oxide propargylation catalysts. These results suggest that N-oxide catalysts that are effective for both allylations and propargylations can be designed by targeting inherently stereoselective ligand configurations and through the manipulation of distortion effects in the operative transition states.

Revised Role of Selectfluor in Homogeneous Au‐Catalyzed Oxidative CO Bond Formations

The pairing of transition metal catalysis with the reagent Selectfluor (F-TEDA-BF4) has attracted considerable attention due to its utility in myriad C-C and C-heteroatom bond-forming reactions. However, little mechanistic information is available for Selectfluor-mediated transition metal-catalyzed reactions and controversy surrounds the precise role of Selectfluor in these processes. We present herein a systematic investigation of homogeneous Au-catalyzed oxidative C-O bond-forming reactions using density functional theory calculations. Currently, Selectfluor is thought to serve as an external oxidant in Au(I)/Au(III) catalysis. However, our investigations suggest that these reactions follow a newly proposed mechanism in which Selectfluor functions as an electrophilic fluorinating reagent involved in a fluorination/defluorination cycle. We have also explored Selectfluor-mediated gold-catalyzed homocoupling reactions, which, when cyclopropyl propargylbenzoate is used as a substrate, lead to an unexpected byproduct.

Theoretical investigation of gold-catalyzed oxidative Csp3–Csp2 bond formation via aromatic C–H activation

The mechanisms of Selectfluor-mediated Au-catalyzed intramolecular Csp3–Csp2 cross-coupling reaction involving direct aryl Csp2–H functionalization have been investigated theoretically. Several pathways involving the oxidation of alkylgold(I) (Cycle I), phosphine Au(I) precatalyst (Cycle II), gold(I) π–alkene complex (Cycle III) and arylgold(I) (Cycle IV) by Selectfluor, respectively, were examined. Our calculation results suggested the following: (1) Cycles I and II are preferred over Cycles III and IV, and the reaction would undergo the energy favored pathways (Cycles I and II), which is further confirmed by stereochemical analysis; (2) Cycle I is competitive with Cycle II, and the rate-determining steps of these two cycles are oxidation of Au(I) species by Selectfluor; (3) water has been found to participate in the catalytic reaction and decrease the activation energy barrier of the reductive elimination.

Mechanism and Origin of Selectivity in Platinum(II)-Catalyzed Reactions of Acyclic γ,δ-Ynones with Alkenes

The generation of platinum‐containing carbonyl ylides from acyclic γ,δ‐ynones and the cycloaddition of these ylides with electron‐rich alkenes have been explored computationally to explain the experimentally observed regio‐ and stereoselectivity. Three pathways for the reaction of ylides with methyl vinyl ether have been investigated. Two of these involve [3+2] cycloadditions, whereas the third involves a [4+2] cycloaddition. Results indicate that the operative reaction pathway depends on the substitution pattern of the acyclic γ,δ‐ynone. For an acyclic γ,δ‐ynone without a methyl substituent at the propargylic position, we predict that both [3+2] cycloaddition pathways are more favorable than the [4+2] cycloaddition pathway, which leads to two products. On the other hand, for an acyclic γ,δ‐ynone with a methyl substituent at the propargylic position, one of the [3+2] pathways is predicted to dominate, which exclusively affords an exo product. This feature arises from the hyperconjugative stabilization effect of the methyl group. Further analysis indicates that steric interactions between the chlorine atom of the catalyst and the methyl group of the vinyl ether lead to the observed exo selectivity. In all cases, the cycloaddition is the rate determining step, whereas for chiral PtCl2(bisphosphine)‐catalyzed reactions it is also stereodetermining, the high degree of enantioselectivity arises from differences in both noncovalent dispersion interactions and extent of partial bond formation in the key transition states for the [3+2] cycloaddition.