Proline-thiourea catalysts

The use of chiral diols as co-catalyst in aldol reaction led to an improvanent of the achieved results [41]. Thus, when acetone (3a, 8.18 equiv.) was reacted with benzaldehyde (2 h) in DMSO at 0°C catalyzed by (5)-proline (30 mol%) the expected product 4 was obtained in 72% ee, while a 96% ee was achieved in the presence of (R)-BINOL (0.5 mol%). A hypothetical explanation from the authors for this effect is the possible template effect of the chiral diol which may activate and ordered the aldehyde and enamine nucleophile. The same reason was claimed for the beneficial effect achieved by addition of a 10 mol% of (3,5-bistrifluoromethylphenyl)thiourea in the aldol reaction between cyclohexanone (3b) and several aromatic aldehydes catalyzed by proline (1,10 mol%) in hexane a 25°C [42], In this case, reaction times, yields as well as diastereo- and enantioselectivities were improved (75-98%, 76-88% de, 98-99% ee), with these results being also attributed to the enhancement of the proline solubility by the formation of a host-guest proline-thiourea complex. 

Aldol additions of acetone (1) as a nucleophile to ketones without a-acidic protons are feasible. The proline-catalyzed aldol reaction between acetone (1) and 1-aryl-2,2,2-trifluoroethanone (128) led to tertiary alcohol 129 in good yield but with low stereoselectivity [146]. A proline-derived sulfonamide 130 performs much better (Table 3.10, entry 2). Kokotos prepared a prolinamide-thiourea catalyst 131, which under optimum conditions can be used in 2 mol%, even at 0°C (entry 3) [ 147], With proline, the reaction was completed within hours, while more stereoselective catalysts 130 and 131 required 2 days. So far, these are the catalysts of choice for this tran ormation [146-148]. 

A different approximation was reported by Tang, Li, and co-workers [56] by using Seebach s nitroallylic acetate reagent 85, cyclohexanones, and proline-thiourea derivative XXVI as a catalyst. Nitroallylic acetate reacts with cyclohexanones via a double Michael addition, affording the final fused bicyclic ketones 86 in excellent yields and stereoselectivities (Scheme 10.24). 

More recently, it has been reported that primary amines derived from cinchona alkaloids [75] as well as proline derivatives [76], combined with achiral Brpnsted or Lewis acids, may also efficiently catalyze the enantioselective Biginelli reaction. Alternatively, a carbohydrate-based bifnnctional primary amine-thiourea catalyst was developed for this transformation, with similar enantiocontrol [77]. 

Lactol (134, 2-hydroxy-THF) can a-alkylate pentan-2-one under mild conditions, using a proline derivative and an unsymmetrical (but achiral) thiourea as co-catalysts, to give THF derivatives (135), with some enantioselectivity. However, kinetic studies show that the ee is time-dependent, and typically decreasing. While racemization of (135) explains some of the effect, it also appears that there are two competing mechanisms with opposing enantioselectivities operating." ... 

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