Insight into Substrate Recognition by Urea-Based Helical Foldamer Catalysts Using a DFT Global Optimization Approach.

Peptides and foldamers have recently gained increasing attention as chiral catalysts to achieve challenging (asymmetric) transformations. We previously reported that short helically folded aliphatic oligoureas in combination with achiral Brønsted bases are effective H-bonding catalysts for C-C bond-forming reactions─i.e., the conjugate addition of 1,3-dicarbonyl pronucleophiles to nitroalkenes─with high reactivity and selectivity and at remarkably low chiral catalyst/substrate molar ratios. This theoretical investigation at the density functional theory level of theory, aims to both analyze how the substrates of the reaction interact with the foldamer catalyst and rationalize a chain-length dependence effect on the catalytic properties. We confirm that the first two ureas are the only H-bond donors available to interact with external molecules. Moreover, each urea site interacts with one of the two reactants allowing a short distance between the two reacting carbons, thus facilitating the conjugated addition. Additionally, it was observed that the molecular recognition and catalyst-substrate interactions are mainly governed by electrostatic interactions but not orbital interactions (see from NBO if this is finally true). On these grounds, an electrostatic potential (ESP) analysis showed an important internal charge separation in the catalyst, the positive ESP region being concentrated around the first two ureas, with its area extending as the number of residues increases.

The Silicon-Hydrogen Exchange Reaction: A Catalytic σ-Bond Metathesis Approach to the Enantioselective Synthesis of Enol Silanes.

The use of chiral enol silanes in fundamental transformations such as Mukaiyama aldol, Michael, and Mannich reactions as well as Saegusa-Ito dehydrogenations has enabled the chemical synthesis of enantiopure natural products and valuable pharmaceuticals. However, accessing these intermediates in high enantiopurity has generally required the use of either stoichiometric chiral precursors or stoichiometric chiral reagents. We now describe a catalytic approach in which strongly acidic and confined imidodiphosphorimidates (IDPi) catalyze highly enantioselective interconversions of ketones and enol silanes. These "silicon-hydrogen exchange reactions" enable access to enantiopure enol silanes via tautomerizing σ-bond metatheses, either in a deprotosilylative desymmetrization of ketones with allyl silanes as the silicon source or in a protodesilylative kinetic resolution of racemic enol silanes with a carboxylic acid as the silyl acceptor.

Helical Oligourea Foldamers as Powerful Hydrogen Bonding Catalysts for Enantioselective C-C Bond-Forming Reactions.

Substantial progress has been made toward the development of metal-free catalysts of enantioselective transformations, yet the discovery of organic catalysts effective at low catalyst loadings remains a major challenge. Here we report a novel synergistic catalyst combination system consisting of a peptide-inspired chiral helical (thio)urea oligomer and a simple tertiary amine that is able to promote the Michael reaction between enolizable carbonyl compounds and nitroolefins with excellent enantioselectivities at exceptionally low (1/10 000) chiral catalyst/substrate molar ratios. In addition to high selectivity, which correlates strongly with helix folding, the system we report here is also highly amenable to optimization, as each of its components can be fine-tuned separately to increase reaction rates and/or selectivities. The predictability of the foldamer secondary structure coupled to the high level of control over the primary sequence results in a system with significant potential for future catalyst design.