Brpnsted Acid Catalysis Hydrogen-Bonding Activation

To date, hydrogen bond catalysis has been successfully utilized to facilitate enantioselective Michael additions, Baylis-Hillman reactions, Diels-Alder cycloadditions, and additions of 7i-nucleophiles to imines. 

Meanwhile, chiral (thio)urea catalysts have been employed for a variety of imine addition reactions consisting of Mannich, aza-Henry, Pictet-Spengler, and hydrophosphonylation reactions.  

Conjugate Additions and Baylis-Hillman Reactions Peptide catalysts have reemerged as a viable approach to asymmetric catalysis. In particular, Miller 

Interestingly, this catalyst and related systems typically function as chiral DMAP-type catalysts.However, in this case, mechanistic studies suggest that the role of 36 is to serve as a conjugate base for the protic catalyst derivative. 

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Figure 11.4. Hydrogen-bonding and Br0nsted acid complexation modes for the LUMO-lowering activation of substrates inherent to the field of Brpnsted acid catalysis.

Hydrogen would be the simplest center element. Indeed, chiral Brpnsted acids have emerged as a new class of organocatalysis over the last few years [3-13]. The field of asymmetric Brpnsted acid catalysis can be divided into general acid catalysis and specific acid catalysis. A general acid activates its substrate (1) via hydrogen bonding (Scheme 2, a), whereas the substrate (1) of a specific acid is activated via protonation (Scheme 2, b). 

The use of chiral Brpnsted acid catalysis as a mode of asymmetric activation burgeoned dramatically in the early part of the twenty first century [35]. The role of hydrogen in this process is, in essence, similar to that of Lewis acid catalysts - i.e. activation of the C=X bond (X=0, NR, CR ) by decreasing the LUMO energy and ultimately leading to promotion of nucleophilic addition to the C=X bond (Fig. 1.5). 

Taking imine activation as an example, the relative roles of proton transfer/ ion-pairing versus hydrogen bonding have been probed for Brpnsted acid catalysis. Taking simple diaryl ketimines and aldimines as model substrates and... 

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