Solvent-free Asymmetric Aldol Reactions Research Articles

New small γ-turn type N-primary amino terminal tripeptide organocatalyst for solvent-free asymmetric aldol reaction of various ketones with aldehydes.

New small γ-turn type N-primary amino terminal tripeptides were synthesized and their functionality as an organocatalyst was examined in the asymmetric aldol reaction of various ketones with different aromatic aldehydes under solvent-free neat conditions to afford the desired chiral anti-aldol products in good to excellent chemical yields, diastereoselectivities and enantioselectivities (up to 99%, up to syn : anti/13 : 87 dr, up to 99% ee).

Design and preparation of a novel prolinamide-based organocatalyst for the solvent-free asymmetric aldol reaction

The preparation of four novel organocatalysts as highly diastereo and enantioselective catalysts for the solvent-free asymmetric aldol reaction was described. These organocatalysts were synthesized in eight steps applying simple and commercially available starting materials. The best results were obtained for the proline-derived catalyst, providing access to the desired adducts in up to 95% yield, 1:19 syn/anti and 98% e.e. Moreover, even sterically bulky aldehydes and substituted cyclohexanones were well tolerated. DFT calculations and control experiments indicated that several hydrogen bonding interactions between the aldehyde and the enamine intermediate are responsible for the stereoselective chiral induction process and that the trifluoroacetate counter-anion is crucial for the attainment of higher stereoselectivities.

ChemInform Abstract: Synthesis and Evaluation of (S)‐Proline‐Containing α,β‐Dipeptides as Organocatalysts in Solvent‐Free Asymmetric Aldol Reactions under Ball‐Milling Conditions.

With the aim of developing sustainable enantioselective reactions, the organocatalytic activity of three proline-based α,β-dipeptides was evaluated in the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde according to three contrasting experimental protocols: (1) solvent-free, under high-speed ball milling (HSBM) activation, (2) neat conditions with conventional stirring, and (3) in solution with conventional stirring. The HSBM technique, providing “green” solvent-free reaction conditions, proved to be the synthetic strategy of choice, proceeding in shorter reaction times and affording the aldol products with higher stereoselectivity. The organocatalytic activity of two of the α,β-dipeptides was then compared in the solvent-free asymmetric aldol reaction under ball-milling activation in order to establish the influence of a stereogenic center in the β-amino acid residue on the stereoinducing ability of the organocatalyst. The organocatalyst with one stereogenic center and the organocatalyst with two stereogenic centers exhibit similar efficiency in the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde, affording the aldol product in excellent yield, and with high anti diastereoselectivity and good enantioselectivity. Thus, the presence of a second stereogenic center in the α,β-dipeptide organocatalysts does not result in a more stereoselective reaction relative to that induced by the α,β-dipeptide organocatalyst with one stereogenic center.

Asymmetric direct aldol reactions catalyzed by chiral amine macrocycle–metal(ii) complexes under solvent-free conditions

Solvent-free asymmetric aldol reactions between cyclohexanone and 4-nitrobenzaldehyde using chiral amine macrocycle–metal(II) complexes as catalysts in a ball mill afforded the anti-aldol product as the major isomer with up to 93% ee.

Solvent-free asymmetric aldol reaction organocatalyzed by (S)-proline-containing thiodipeptides under ball-milling conditions

An efficient, solvent-free ball-milling protocol for the asymmetric aldol reaction between cyclohexanone and cyclopentanone with various aromatic aldehydes using a novel series of (S)-proline-containing dipeptides and thiodipeptides 1a–f as organocatalysts is reported. In general, (S)-proline-containing thiodipeptides proved to be better organocatalysts relative to their analogous amides. In particular, thiodipeptide (S,S)-1d catalyzed the stereoselective formation of the expected aldol products with excellent diastereo- and enantioselectivity (up to 98:2 anti/syn dr and up to 96% ee). This observation may be ascribed to the increased N–H acidity of the thioamide segment that leads to stronger H-bonding interaction with the aldehyde carbonyl at the transition state and thus higher stereoinduction. Furthermore, thiodipeptide 1f proved to be an efficient organocatalyst for the aldol reaction of acetone with isatin and isatin derivatives (ee 56–86%).

Use of Prolyl Sulfonimidamides in Solvent-Free Organocatalytic Asymmetric Aldol Reactions

Prolyl-substituted sulfonimidamides have been synthesized and applied as organocatalysts in solvent-free asymmetric aldol reactions.