Asymmetric Direct Aldol Reaction Assisted by Water and a Proline‐Derived Tetrazole Catalyst

Abstract

Mit Wasser geht's besser! Das gilt für direkte Aldolreaktionen wie die gezeigte. Bisher erachtete man Aldehyde mit hoher Wasseraffinität oder Wasserlöslichkeit als für die asymmetrische Synthese nicht zugänglich.

Asymmetric Catalysis by Chiral Hydrogen‐Bond Donors

“…The replacement of prolines carboxylic acid group with tetrazole, a frequently employed carboxylic acid mimic in medicinal chemistry, has also afforded promising results. [90] The improved activity of catalyst 19 d in O-nitroso aldol reactions of ketones, Mannich reactions of imino esters, and aldol reactions of chloral may be ascribed to its altered pK a or increased solubility in comparison to proline.…”

Proline‐Derived N‐Sulfonylcarboxamides: Readily Available, Highly Enantioselective and Versatile Catalysts for Direct Aldol Reactions

“…[8] We assume that in the sulfonamide-catalyzed reaction, the acidic NH-proton replaces the carboxylic proton (transition state IIIb, Scheme 5), and the same probably holds for the tetrazole-derivatized proline catalysts. [15,17] The origin of the improved enantioselectivity observed with the acylsulfonamide catalysts 6a -c may be explained by a better shielding of one of the enantiotopic faces of the aldehyde by the aryl ring (Scheme 5). It may also be speculated that "tighter" hydrogen bonding in the transition state IIIb accounts for the better stereoselection observed.…”

“…[16] The pyrrolidinyltetrazole 5 (Scheme 3) thus obtained was employed in asymmetric Mannich and aldol reactions quite successfully, with enantiomeric excesses ranging up to 99% ee. [15] However, in the aldol reaction shown in Scheme 2, Arvidsson and Hartikka observed only a minor increase in activity, but no improvement in enantioselectivity for the tetrazole 5 compared to l-proline (3). [17] Unfortunately, the nature of the tetrazole group prevents further optimization of the catalytic properties of 5, e.g., by attaching substituents of varying electronic and steric properties.…”

Quinidine Thiourea‐Catalyzed Aldol Reaction of Unactivated Ketones: Highly Enantioselective Synthesis of 3‐Alkyl‐3‐hydroxyindolin‐2‐ones

“…For example, the ee value of 4-bromoisatin 12 c ( Table 2, entry 3) is much higher than that of 6-bromoisatin 12 e (Table 2, entry 5). Acetophenone (11 b) is a tough substrate for the enamine mechanism because of its low electrophilicity [14] and it has never been used in the asymmetric aldol reaction with isatin. However, as is evident from the results in Table 2, 11 b is even more reactive than acetone under our conditions (only 10 equiv ketone is necessary), and [a] Unless otherwise indicated, all reactions were carried out with isatin (0.10 mmol), acetone, and the catalyst (0.01 mmol, 10 mol %) in the specified solvent (1.0 mL for acetone; 2.0 mL for THF and other solvents) at room temperature.…”