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

Abstract

Enantioselective catalytic formation of polyfunctional molecules, such as non‐natural amino acids, is important for the efficient production of many chiral compounds. To this end, we present here the synthesis and evaluation of the catalytic activity of bifunctional peptide–thiourea organocatalysts. These hybrid organocatalysts consist of Pro‐Pro dipeptide and thiourea moiety connected via a 1,2‐diaminocyclohexane unit. These catalysts promoted challenging Mannich reaction between α‐imino esters and pyruvates, providing orthogonally protected oxo‐glutamate derivatives. The N‐tosyl‐protected imino ester, as the most active imine, was required to compensate for the poor reactivity of pyruvates. DFT calculations, NMR, and CD spectroscopy help elucidate the mode of action of these catalysts. Configuration of the dipeptide Pro‐Pro moiety is responsible for the sense of the stereoinduction of the Mannich reaction.

Organocatalytic Activation of Pyruvates Toward Michael Addition to Nitroalkenes: Synthesis of γ‐Aminobutyric Acid (GABA) Derivatives

“…The use of proline supported by additional amine ( VIII ), peptide ( IX ) or thiourea ( X ) elements was not progressive, although it is worth noting the high efficiency observed for the use of tripeptide IX (Table 1, entry 10). This observation confirms the possibility of using proline peptides in similar addition reactions [13] . Our experiments also confirmed that the Takemoto catalyst ( XI ) cannot be used in this reaction, but the application of its derivative with a free primary amino group ( XII ) could be an interesting direction for future research due to observed high stereoselectivity of the addition reaction (Table 1, entry 13).…”

“…This observation confirms the possibility of using proline peptides in similar addition reactions. [13] Our experiments also confirmed that the Takemoto catalyst (XI) cannot be used in this reaction, but the application of its derivative with a free primary amino group (XII) could be an interesting direction for future research due to observed high stereoselectivity of the addition reaction (Table 1, entry 13). In the case of these catalysts, however, the self-condensation product of pyruvate was dominant in the reaction mixture.…”

“…The reactions of pyruvates and cyclic sulfonylimines afforded the desired Mannich products by using primary cinchonabased amine [12] while addition to tosyl-protected glyoxylate have been achieved by using bifunctional peptide-thiourea organocatalysts most likely through an enamine mechanism with moderate yield and ees. [13] However, we assumed that the enamine intermediate obtained from pyruvates could be captured by nitroalkenes being particularly attractive acceptors capable of reacting with keto acids in the Michael reaction [14] because of the presence of nitro group, which in turn can be easily transformed into various functionalities. [15] The challenging reactivity of α-keto esters as prenucleophiles in organocatalyzed Michael reactions has been initially reported by Bonne and Rodriguez.…”

“…However, this example is a precedent and despite intensive work in this area, no other examples of reactions of simple pyruvic acid esters with aldehydes have been found. Two examples of amine‐catalyzed reactions of pyruvates with more reactive electrophiles was described independently by Tanaka [12] and Šebesta [13] in 2022. The reactions of pyruvates and cyclic sulfonylimines afforded the desired Mannich products by using primary cinchona‐based amine [12] while addition to tosyl‐protected glyoxylate have been achieved by using bifunctional peptide‐thiourea organocatalysts most likely through an enamine mechanism with moderate yield and ee s [13] …”