Peptide‐Catalyzed Stereoselective Conjugate Addition Reactions of Aldehydes to Maleimide

Abstract

The tripeptide H-dPro-Pro-Asn-NH 2 is presented as ac atalyst for asymmetric conjugate addition reactions of aldehydes to maleimide.T he peptidic catalyst promotes the reaction between various aldehydes and unprotected maleimide with high stereoselectivities and yields.T he obtained products were readily derivatized to the corresponding pyrrolidines,l actams,l actones,a nd peptide-like compounds. 1 HNMR spectroscopic,c rystallographic,a nd computational investigations provided insight into the conformational properties of H-dPro-Pro-Asn-NH 2 and revealed the importance of hydrogen bonding between the peptide and maleimide for catalyzing the stereoselective CÀCbond formation.

Rigorous Conformational Analysis of Pyrrolidine Enamines with Relevance to Organocatalysis

“…The magnitude of Δ E , Δ G gas , and Δ G sol shows that neither the high enantioselectivity nor the reversal of the enantioselectivity can originate from a stability difference in the s‐ cis and s‐ trans enamines alone. This is in agreement with several other theoretical investigations that also reported small electronic energy difference between s‐ cis and s‐ trans conformers (without extensive conformational analysis) . Our results are also in agreement with experimental studies which detected aldehyde‐ and ketone‐derived enamines in s‐ cis as well as s‐ trans conformations .…”

“…The C(2) substituent also adopts the sc‐exo conformation in the reported crystallographic structure and a structure similar to 6e was predominately encountered in this conformation in an in situ NMR study . Our analysis suggests that the conflicting theoretical results reported for the conformation of the C(2) substituent of 6e and structurally similar compounds might be a result of insufficient conformational sampling.…”

“…All four conformers are significantly populated in equilibrium (0.05 < p i < 0.59). Many theoretical studies on the origin of stereoselectivity in Michael additions take these four conformational degrees of freedom into account, but neglect the conformational diversity which quickly emerges for larger C(2) and N(1) substituents. A large number of rotatable bonds in the C(2) and N(1) substituents can give rise to a large number of stable conformers ( e.g ., over 200 for 6e ).…”

“…The preferred chiral secondary amines are substituted pyrrolidines with a myriad of substituents in the 2‐position. A by no means complete or chronological collection is presented in Scheme for illustration purposes.…”

Carboxylate Salt Bridge‐Mediated Enamine Catalysis: Expanded Michael Reaction Substrate Scope and Facile Access to Antidepressant (R)‐Pristiq

“…Those results led us to pursue a higher level challenge: the first Michael reaction in which both the electrophile and the nucleophile contain an acidic moiety . To test this possibility and simultaneously examine stereogenic quaternary carbon formation, we added a phenol‐containing non‐symmetrical α‐branched aldehyde ( 7 ) to 3‐OH‐β‐nitrostyrene and separately to maleimide, (Scheme ). The produced Michael products ( 8 and 9 ) contain vicinal quaternary‐tertiary stereogenic centers and were obtained in high ee and good yield under remarkably practical starting material stoichiometries and reasonable catalyst loadings (Scheme ).…”