Application of Proline-Derived (Thio)squaramide Organocatalysts in Asymmetric Diels–Alder and Conjugate Addition Reactions

Abstract

The synthesis of chiral proline-derived squaramide and thiosquaramide organocatalysts, which are capable of the dual activation in asymmetric reactions is reported. The (thio)squaramide moiety can form hydrogen bonds to activate the substrates and to stereocontrol the reaction, while the pyrrolidine unit can form enamines to activate carbonyl compounds via aminocatalysis. Comparing the performance of thiosquaramide to squaramide, the Diels–Alder reaction of (anthracen-9-yl)acetaldehyde and trans-β-nitrostyrene was examined, which has been investigated in the literature using quantum chemical calculations. Both squaramide and thiosquaramide gave excellent yields (up to 99%) and enantiomeric excess values (up to 98%). Moreover, their catalytic performance was compared in conjugate addition of lawsone to β,γ-unsaturated α-keto ester.

Recent Advances in Asymmetric Synthesis of Pyrrolidine-Based Organocatalysts and Their Application: A 15-Year Update

“…Their catalytic performances were tested in the asymmetric Diels-Alder reaction of (anthracen-9-yl)acetaldehyde and trans-β-nitrostyrene with good results, and were also tested in the asymmetric conjugate addition of 2-hydroxy-1,4-naphthoquinone to ethyl (E)-2-oxo-4-phenylbut-3-enoate (Scheme 58), which provided high yields but low enantiocontrol. Very recently (2022), Kupai and co-workers synthesized the squaramide 77c and thiosquaramide 93a organocatalysts (Scheme 58) [142], which were structurally very similar to those already proposed by Jørgensen [122] and Šebesta [140]. Their catalytic performances were tested in the asymmetric Diels-Alder reaction of (anthracen-9-yl)acetaldehyde and trans-β-nitrostyrene with good results, and were also tested in the asymmetric conjugate addition of 2-hydroxy-1,4-naphthoquinone to ethyl (E)-2-oxo-4-phenylbut-3-enoate (Scheme 58), which provided high yields but low enantiocontrol.…”

A novel recyclable organocatalyst for the gram-scale enantioselective synthesis of (S)-baclofen

“…To prove that the previously applied catalytic unit kept its activity, the lipophilic organocatalyst 2 was applied in the stereoselective Michael addition of trans-β-nitrostyrene (12) and acetylacetone (13). Choosing the best solvent for the reaction is crucial, thus, solubility tests were carried out (Table 1).…”

“…To investigate the solvent effect, the stereoselective Michael addition reaction was carried out in those solvents that dissolved the catalyst and from which the catalyst was successfully precipitated by adding methanol. Furthermore, a reaction in which acetylacetone (13) did not only act as a reactant but also as a solvent was examined (Table 2).…”

“…The application of organocatalysts is well-established in several organic reactions, including but not limited to aldol reactions [ 6 ], Michael additions [ 9 ], Mannich reactions [ 10 ], aza-Henry reactions [ 11 ], and Diels–Alder cycloadditions [ 12 – 13 ]. Although the benefits of organocatalysts are undoubted, their synthesis is often a long and expensive process.…”

Cinchona‐Based Hydrogen‐Bond Donor Organocatalyst Metal Complexes: Asymmetric Catalysis and Structure Determination

“…Thiosquaramides, [28] sulfur analogs of squaramides were first predicted computationally as potentially more effective hydrogen‐bond donating organocatalysts. [29] Recently, Rawal and co‐workers, and other research groups synthesized thiosquaramide catalysts and applied them in Michael addition, conjugate, [30] and aza‐Diels–Alder reactions. [ 31 , 32 , 33 , 34 , 35 ] These bifunctional thiosquaramides are a promising new class of catalysts, which possess increased aromaticity, higher acidity, and greater solubility in non‐polar solvents compared to those of squaramides and thioureas.…”