Double activation catalysis for α'-Alkylidene cyclic enones with chiral amines and thiols

Cooperative catalysis has contributed greatly to the progress of asymmetric synthesis. However, double-activation catalysis has been less explored, especially for covalently tethered species. Here, we present a double-activation strategy for α’-alkylidene cyclic enone substrates that uses a chiral primary amine and 2-mercaptobenzoic acid to promote regio- and chemoselective addition to generate the complex interrupted iminium ion species. Significantly enhanced reactivity and enantioselectivity were observed for β-regioselective Michael addition and Friedel-Crafts alkylation with malononitriles and indoles, respectively, which produced a spectrum of chiral cyclic adducts with an exo-alkylidene group. Moreover, a HRMS study detected a few key covalently tethered intermediates among the substrates and catalysts, which helped elucidate the catalytic mechanism.

Wang ZX et al. Chemistry. 2017 May 18
Doi: 10.1002/chem.201702183

Electric fields and enzyme catalysis

What happens inside an enzyme’s active site to allow slow and difficult chemical reactions to occur so rapidly? This question has occupied biochemists’ attention for a long time. Computer models of increasing sophistication have predicted an important role for electrostatic interactions in enzymatic reactions, yet this hypothesis has proved vexingly difficult to test experimentally. Recent experiments utilizing the vibrational Stark effect make it possible to measure the electric field a substrate molecule experiences when bound inside its enzyme’s active site. These experiments have provided compelling evidence supporting a major electrostatic contribution to enzymatic catalysis. Here, we review these results and develop a simple model for electrostatic catalysis that enables us to incorporate disparate concepts introduced by many investigators to describe how enzymes work into a more unified framework stressing the importance of electric fields at the active site.

Fried SD et al. Annu Rev Biochem. 2017 Jun 20;86:387-415.
Doi: 10.1146/annurev-biochem-061516-044432.

Switching between anion-binding catalysis and aminocatalysis with a rotaxane dual-function catalyst

The “off” state for aminocatalysis by a switchable [2]rotaxane is shown to correspond to an “on” state for anion-binding catalysis. Conversely, the aminocatalysis “on” state of the dual-function rotaxane is inactive in anion-binding catalysis. Switching between the different states is achieved through the stimuli-induced change of position of the macrocycle on the rotaxane thread. The anion-binding catalysis results from a pair of triazolium groups that act together to CH-hydrogen-bond to halide anions when the macrocycle is located on an alternative (ammonium) binding site, stabilizing the in situ generation of benzhydryl cation and oxonium ion intermediates from activated alkyl halides. The aminocatalysis and anion-binding catalysis sites of the dual-function rotaxane catalyst can be sequentially concealed or revealed, enabling catalysis of both steps of a tandem reaction process.

Eichstaedt K et al. J Am Chem Soc. 2017 Jul 12;139(27):9376-9381.
Doi: 10.1021/jacs.7b04955. Epub 2017 Jul 3.