RESUMO
The catalytic kinetic resolution of racemic ß-branched aldehydes offers a straightforward stereoselective entry to aldehydes and addition products. Yet, control over stereoselectivity is difficult due to the conformational flexibility of ß-branched aldehydes. Here, we show that the peptide catalyst H-dPro-αMePro-Glu-NH2 resolves ß-branched aldehydes through reaction with nitroolefins and provides γ-nitroaldehydes with three consecutive stereogenic centers in high yields and stereoselectivities. Kinetic, NMR spectroscopic, and computational studies provided insights into the selectivity-determining step and origins of the kinetic resolution.
RESUMO
The S-alkylation of Cys residues with a maleimide and the Nϵ -acylation of Lys residues with an N-hydroxysuccinimide (NHS) ester are common methods for bioconjugation. Using Cys and Lys derivatives as proxies, we assessed differences in reactivity depending on the position of Cys or Lys in a protein sequence. We find that Cys position is exploitable to improve site-selectivity in maleimide-based modifications. Reactivity decreases substantially in the order N-terminal>in-chain>C-terminal Cys due to modulation of sulfhydryl pKa by the α-ammonium and carboxylate groups at the termini. A lower pKa value yields a larger fraction thiolate, which promotes selectivity while somewhat decreasing thiolate nucleophilicity in accord with ß n u c =0.41. Lowering pH and salt concentration enhances selectivity still further. In contrast, differences in the reactivity of Lys towards an NHS ester were modest due to an appreciable decrease in amino group nucleophilicity with a lower pKa of its conjugate acid. Hence, site-selective Lys modification protocols will require electrophiles other than NHS esters.