Catalysis of Hydrogen–Deuterium Exchange Reactions by 4-Substituted Proline Derivatives

Abstract

The identification and understanding of structure–activity relationships is vital for rational catalyst design. A kinetic study of the hydrogen–deuterium exchange reaction of cyclohexanone in aqueous solution, as catalyzed by proline derivatives, has revealed valuable structure–activity relationships. In phosphate-buffered solution, cis-4-fluoroproline is more active than the trans isomer, a distinction that appears to originate from a destabilizing interaction between the fluorine atom and phosphate anion during general acid catalyzed dehydration of the carbinolamine intermediate. Trans-4-ammoniumprolines are exceptionally active catalysts owing to favourable Coulombic interactions involving the ammonium group and the alkoxide moiety formed upon 1,2-addition of the proline derivative to the ketone. These results could be used for the optimisation of proline catalysts, especially in transformations where the formation of the putative iminium ion is rate-limiting.

Benzoxazine Formation Mechanism Evaluation by Direct Observation of Reaction Intermediates

“…Due to the prime relevance of benzoxazine and the far-reaching implications of iminium-based mechanisms in organic chemistry, a detailed investigation of their formation mechanism is not only necessary for gaining a better understanding of this specific reaction, but it can also provide a model for the study of a more comprehensive class of iminium activated mechanisms . The iminium chemistry has been evaluated by diverse experimental − and theoretical − approaches and has become a basis for the numerous reports on diverse synthetic and catalytical pathways, including recent strategies based on these species, − despite the difficulties in characterizing the iminium intermediates in the reaction media. ,, …”

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

“…These findings will be helpful for the design and the use of proline analogues in complex biological systems such as peptides and proteins, especially in 19 F NMR labelling, where fluorinated prolines can serve as spectroscopic probes. Potential areas for the application of fluorinated prolines are numerous, and include the design of molecular recognition systems [101], organocatalysis [102], drug discovery [103] and more.…”

Application of (4R)-aminoproline in peptide engineering: conformational bias and pH-responsiveness revisited

“…According to the report, alkylated aminoproline displayed two transitions at around pD 7.4 and 10.3, while the second number can be attributed to the side-chain ammonium group. 12 To add clarity to where the transition in peptides may occur, we set out to examine the experimental acidity for peptides containing Amp as a residue. We were particularly interested in understanding how the pK a of the side-chain depends on the presence of neighboring charges.…”

“…1A). [5][6][7][8][9][10][11][12] Among others, (4R)-aminoproline (Amp) is a structurally very simple proline analogue. Its chemical synthesis is relatively straightforward and typically starts from natural (4R)-hydroxyproline (Hyp) and proceeding either via an azide or through reductive amination (Fig.…”