Hybrid Peptide–Thiourea Catalyst for Asymmetric Michael Additions of Aldehydes to Heterocyclic Nitroalkenes

Abstract

Bifunctional organocatalysis combining covalent and noncovalent activation is presented. The hybrid peptide− thiourea catalyst features a N-terminal proline moiety for aldehyde activation and a thiourea unit for electrophile activation. This catalyst effectively promotes asymmetric Michael additions of aldehydes to challenging but biologically relevant heterocyclecontaining nitroalkenes. The catalyst can be used under solvent-free conditions. Spectroscopic and density functional theory studies elucidate the catalyst structure and mode of action.

Pro‐Pro Dipeptide‐Thiourea Organocatalyst in the Mannich Reaction between α‐Imino Esters and Pyruvates

“…Hybrid peptide‐thiourea catalyst C1 was synthesized using our group‘s previously developed protocol [16] . Stereoisomeric catalysts C2 ‐ 5 were synthesized similarly using corresponding building blocks.…”

“…82 : 18 (Scheme 3). Initial conditions (10 mol% catalyst loading, N‐ methylmorpholine (NMM) as a base and dichloromethane as a solvent) were inspired by our previous work with peptide‐thiourea catalyst [16] . The reaction was very slow (less than 5 % conversion after 4 days) without the base.…”

“…We have recently described a hybrid peptide-thiourea organocatalyst, which proved instrumental in the Michael addition of aldehydes to heterocycle-containing nitroalkenes. [16] To gain more insight into catalytic properties of these promising catalysts, we have decided to synthesize complementary diastereoisomeric organocatalysts. In these catalysts, Pro-Pro moiety is connected with thiourea moiety via a cyclohexane diamine unit, which provides the catalyst with a hair-pin arrangement potentially beneficial for bifunctional activation.…”

Mechanochemical Organocatalysis: Do High Enantioselectivities Contradict What We Might Expect?

“…The data presented does not lead to a strong answer to this question. Certainly, examples of high enantioselectivities are achievable by milling, but so too are selectivities that are not as high as solvent comparators [161] . There are many factors to consider, and some of our thoughts are summarised here.…”

“…Certainly, examples of high enantioselectivities are achievable by milling, but so too are selectivities that are not as high as solvent comparators. [161] There are many factors to consider, and some of our thoughts are summarised here. Reporting of low enantiomeric excesses ( ee values) as part of an optimised process is likely to be underrepresented in the literature, meaning that the data presented is inherently biased.…”