Highly stereoselective and scalable anti-aldol reactions using N-(p-dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide: scope and origins of stereoselectivities

Abstract

A highly enantio- and diastereoselective anti-aldol process (up to >99% ee, >99:1 dr) catalyzed by a proline mimetic-N-(p-dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide-has been developed. Catalyst loading as low as 2 mol % can be employed. Use of industry-friendly solvents for this transformation as well as neat reaction conditions have been demonstrated. The scope of this transformation on a range of aldehydes and ketones is explored. Density functional theory computations reveal that the origins of enhanced diastereoselectivity are due to the presence of nonclassical hydrogen bonds between the sulfonamide, the electrophile, and the catalyst enamine that favor the major anti-Re aldol TS in the Houk-List model.

Figure 1

N-(p-Dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide.

Figure 2

Solubility Comparison of Organocatalysts in CH₂Cl₂.^{a a} The left image illustrates that 300 mg of sulfonamide 1 is soluble in 1 mL of CH₂Cl₂ and right image demonstrates that 300 mg of proline is not readily soluble in 1 mL of CH₂Cl₂.

Figure 3

The lowest energy transition structures for the aldol reaction between cyclohexanone enamine of proline-sulfonamide and benzaldehyde leading to the formation of each of the diastereomeric products. Anti/syn refers to the arrangement of the enamine with respect to the organic acid moiety while re/si denotes the facial attack of the aldehyde electrophile. Distances are in Ångstroms, energies in kcal/mol. Green lines designate possible stabilizing electrostatic interactions. Structures and thermodynamic corrections computed using B3LYP/6–31G* in the gas phase. Numbers in parenthesis include solvation corrections for DCE. ∞ designates infinite basis set extrapolation from the Dunning cc-pVTZ and cc-pVQZ basis sets.

Figure 4

Three Anti-Re transition structures for the aldol reaction between cyclohexanone enamine of proline-sulfonamide and benzaldehyde, showing three different conformations of the sulfonamide. Distances are in Ångstroms, energies in kcal/mol. Green lines designate possible stabilizing electrostatic interactions. Structures and thermodynamic corrections computed using B3LYP/6–31G* in the gas phase. Numbers in parenthesis include solvation corrections for DCE. ∞ designates infinite basis set extrapolation from the Dunning cc-pVTZ and cc-pVQZ basis sets.

Figure 5

Effect of Carbonyl Motif on Catalyst Performance

Scheme 1

Development of an Organocatalyzed, Intramolecular Michael Addition and Application to Lycopodine.

Scheme 2

Scope of Aldehyde Moiety at 2-Methyltetrahydrofuran as solvent.^{a,b,c a} All reactions were performed at 2 M concentration of 16 in solution and with five equivalents of 5. ^b Enantiomeric excess was determined by chiral HPLC analysis. ^c Diastereomeric ratios (dr) were determined by ¹H NMR analysis.

Scheme 3

Large Scale Example of Aldol Reaction.^{a,b a} Enantiomeric excess was determined by chiral HPLC analysis. ^b Diastereomeric ratios (dr) were determined by ¹H NMR analysis.

Scheme 4

Use of Substituted Cyclohexanones in Aldol Reactions.^{a,b,c a} All reactions were performed at 2 M concentration of 6 in solution and five equivalents of ketone 18. ^b Enantiomeric excess was determined by chiral HPLC analysis. ^c Diastereomeric ratios (dr) were determined by ¹H NMR analysis.

Scheme 5

Use of 4-Thiopyranone in Aldol Reactions.^{a,b,c a} All reactions were performed at 2 M concentration of aldehyde in solution and was five equivalents of 26. ^b Enantiomeric excess was determined by chiral HPLC analysis. ^c Diastereomeric ratios were determined by ¹H NMR analysis.

Scheme 6

Use of Glycolates in Aldol Reactions.^{a,b,c a} All reactions were performed at 2 M concentration of 6 in solution and was five equivalents of 24. ^b Enantiomeric excess was determined by chiral HPLC analysis. ^c Diastereomeric ratios (dr) were determined by ¹H NMR analysis.