Molecular Design of a Chiral Brønsted Acid with Two Different Acidic Sites: Regio-, Diastereo-, and Enantioselective Hetero-Diels–Alder Reaction of Azopyridinecarboxylate with Amidodienes Catalyzed by Chiral Carboxylic Acid–Monophosphoric Acid

Abstract

A chiral Brønsted acid containing two different acidic sites, chiral carboxylic acid-monophosphoric acid 1a, was designed to be a new and effective concept in catalytic asymmetric hetero-Diels-Alder reactions of azopyridinecarboxylate with amidodienes. The multipoint hydrogen-bonding interactions among the carboxylic acid, monophosphoric acid, azopyridinecarboxylate, and amidodiene achieved high catalytic and chiral efficiency, producing substituted 1,2,3,6-tetrahydropyridazines with excellent stereocontrol in a single step. This constitutes the first example of regio-, diastereo-, and enantioselective azo-hetero-Diels-Alder reactions by chiral Brønsted acid catalysis.

Dual Brønsted‐acid Organocatalysis: Cooperative Asymmetric Catalysis with Combined Phosphoric and Carboxylic Acids

“…[33] It was postulated that al arger differ- Scheme9.Calculated transition statesf or the [4+ +2]-cycloadditions using the symmetric catalyst(R)-11 a and the unsymmetric version (R)-12 b.T op:Depiction of the hydrogen-bonding networks, bottom:3D-structuresoft he calculated transition states (computed at the B3LYP-D3/6-31G** level of theory,depictions based on xyz-data, [32] dotted red lines indicate short contacts (e.g. [33] It was postulated that al arger differ- Scheme9.Calculated transition statesf or the [4+ +2]-cycloadditions using the symmetric catalyst(R)-11 a and the unsymmetric version (R)-12 b.T op:Depiction of the hydrogen-bonding networks, bottom:3D-structuresoft he calculated transition states (computed at the B3LYP-D3/6-31G** level of theory,depictions based on xyz-data, [32] dotted red lines indicate short contacts (e.g.…”

“…[33] For the free catalyst, calculation wasi na greement with the X-ray structure, showing preferred internal hydrogen-bonding from the carboxylic-acid to the OH-group of the phosphoric acid in aC OOH···(O)P(OH) motif (see Scheme 7). [33] For the free catalyst, calculation wasi na greement with the X-ray structure, showing preferred internal hydrogen-bonding from the carboxylic-acid to the OH-group of the phosphoric acid in aC OOH···(O)P(OH) motif (see Scheme 7).…”

“…More recently,t he heterofunctional phosphoric acid-carboxylic acid catalyst 13 was developed (see Scheme7). [33][34][35] As envisaged, the acid-acid interactions lead to the exclusive formation of the (S)-atropisomers along the naphthyl-phenyl bonds, giving the overall (S,R,S)-diastereoisomers in the case of 11 b/ 12 a and the (S,R)-isomer in the case of 13 (see Scheme 7).…”

“…Te rada and co-workers furtherm odified their bisphosphoric acid catalysts by replacing one of the phosphoric acid groups with ac arboxylic acid, giving the heterobifunctional catalyst (R)-13 (see Scheme7). [33] It was postulated that al arger differ- 1 [b] H( R)-11 a (2.5) 79 99 2 [b] H( R)-TRIP (5.0)36 À88 3 [c] Cl (R)-11 a (2.5) 61 93 4 [c] Cl (R)-12 a (2.5)38 90 5 [c] Cl (R)-12 b (2.5) 67 98 6 [c] Br (R)-12 b (2.5) 95 97 7 [c] Cl (R)-14 a (2.5)30 5 8 [c] Cl (R)-14 b (2.5) 25 À14 9 [b] Br (R)-15 a (2.5)29 71 10 [b] Br (R)-15 b (5.0) 51 À8…”

“…Once again, the particular role of hydrogen-bondingw as elucidated by DFT-calculations. [33] For the free catalyst, calculation wasi na greement with the X-ray structure, showing preferred internal hydrogen-bonding from the carboxylic-acid to the OH-group of the phosphoric acid in aC OOH···(O)P(OH) motif (see Scheme 7). In the calculated transition states (see Scheme 11), the more acidic phosphoric acid was clearly found to act as cBA.H owever,s ubstrate bindingo ft he substrates occurs in aC OOH···(OH)P(O)m otif, with intermolecular hydrogen-bonds being formed between the P(OH) group and the diazo-ester and betweent he P(O)-fragment and the NH-group of the diene (see Scheme 11).…”