Enantioselectivity enamine reactions

This catalytic enamine formation is limited to aldehydes and ketones as starting materials - it does not appear to be possible to prepare corresponding enamines , i.e. A,0-ketene acetals, from esters in this fashion. Nevertheless, the preparation of simple, reactive nucleophiles from normally electrophilic species, aldehydes and ketones, in a catalytic fashion sounds highly attfactive. Furthermore, the catalytic nature of these reactions allows the use of chiral amines, and the further possibility that these reactions can be rendered enantioselective. Enamines react readily with a wide variety of electrophiles, and the range of reactions that can be catalyzed by enamine catalysis is summarized in Scheme 2. 

Over the past eight years, enantioselective enamine catalysis has expanded in scope more rapidly than perhaps any other field of asymmetric catalysis. From a handful of examples within the realm of aldol catalysis known in the beginning of 2000, the field enamine catalysis now comprises more than 50 different reactions, nearly 1000 different catalysts, and more than 1000 examples Still, major challenges remain to be solved. 

Enamines, reaction with quinones, 20, 3 Enantioselective aldol reactions, 67, 1 allylation and crotylation, 73, 1 Ene reaction, in photosensitized oxygenation, 20, 2 Enolates ... 

In order to form the anti-products enantioselectively, the reaction face of either the enamine or the imine must be opposite that utilized in the proline-catalyzed reactions. In the reactions catalyzed by 13 (Scheme 2.15b), the methyl group at 5-position of the pyrrolidine ring acts to fix the conformation of the enamine and the acid functionality at the 3-position controls the enamine and imine face selection in the transition state (Scheme 2.15b). In order to avoid steric interactions between the substituent at the 5-position of this catalyst and the imine in the transition state, catalyst 13 has a trans configuration for substituents at the... 

The enamine geometry 32 is cmcial for the stereocontrol in organocatalytic aldehyde-aldehyde couplings amines of type 31 are convenient catalysts for enantioselective enamine-aldol reactions. Examples are shown in Scheme 24 [126,131,132,133,134,135]. 

Sevin, A., Masure, D., Giessner-Prettre, C., Pfau, M. A theoretical investigation of enantioselectivity Michael reaction of secondary enamines with enones. Helv. Chim. Acta 1990, 73, 552-573. 

Enamine-mediated aldolizations offer much better prospects for a stereo-controlled process. The famous enantioselective proline-catalyzed triketone cyclization to the Wieland-Miescher ketone 43 [56], as well as the chemistry of type I aldolase enzymes [57],provide ample precedents for stereo- and enantioselective enamine-mediated reactions. 

A new catalyst incorporating chiral thiourea and nucleophilic Lewis base showed efficiency in the asymmetric BH reactions. The use of a binaphthyl-based amino-thiourea catalyst 63 synthesized by Wang et al. [ 114] resulted in good yields and enantioselectivities in the reaction of cyclohexenone and aldehydes. Another amino-thiourea 12 was demonstrated as an efficient bifunctional catalyst for the enantio-selective aza-BH reaction of (3-methyl-nitrostyrene and iV-tosyl-aldimines, affording P-nitro-y-enamines in modest to excellent enantioselectivities and diastereoselec-tivities (Scheme 9.32). It was found that no reaction occurred in the absence of the methyl group of nitroalkene [115]. A similar phophine-thiourea catalyst 64 was reported in 2008 by Wu and co-workers [116] and turned out to be efficient in the asymmetric BH reaction of MVK and aldehydes, providing fast reaction rate, good yields, and excellent enantioselectivities (87-94% ee). More recently, aL-threonine-derived phosphine-thiourea catalyst 65 was readily synthesized by Lu and coworkers [117] and applied in the enantioselective BH reaction of aryl aldehyde with methyl acrylate. 

In 2010, Shibata and co-workers developed an enantioselective enamine-trifluoropyruvate domino aldol-cyclisation reaction to yield chiral pyrroli-dones. Several commercially available derivatives of cinchona alkaloids were screened in combination with Ti(Oi-Pr)4. Hydroquinine diether ((DHQD)2AQN) was found to be the best ligand and afforded the products in high yields and enantioselectivities of up to 92% ee, as shown in Scheme 7.19. Using this system, five cyclic enamines with different protecting groups were screened with remarkable results. The enantiomers of the products were also accessible by applying the pseudoenantiomeric cinchona alkaloid. 

In addition to the studies mentioned above, chiral alcohols have been used as H-bonding catalysts in a vinylogous aldol reaction of Chan s diene with aldehydes [73], in an enantioselective Strecker reaction [74], and in the enantioselective addition of aza-enamines to imines [75]. Taddol has also found use as a memory of chirality enhancer in the stereoselective synthesis of (i-lactams from amino acid derivatives [76, 77]. 

Enamine catalysis provided the synthetic platform for a second example of asymmetric MCR. In 2001, Barbas and colleagues described a Knoevenagel/Michael reaction sequence between acetone, benzaldehyde (14), and diethyl malonate (15) catalyzed by the chiral secondary amine 16 (Scheme 42.4). Despite the moderate level of enantioselectivity, this reaction was engineered upon rather sophisticated catalytic machinery [21]. The catalyst promoted both individual steps of the MCR, although only the second enamine-catalyzed process was stereo-determining. The... 

In the early 1970s, i-proline (222) was shown to function as a chiral catalyst for enantioselective aldol addition reactions (Chapter 4) [156]. With the aim of expanding the scope of proline-catalyzed asymmetric aldol additions [157], List reported that proline also catalyzes enantioselective Mannich reactions (Equation 19) [158]. Whereas most catalytic enantioselective Mannich reactions with aldehydes typically afford the corresponding syn products, Barbas, Tanaka, and Houk demonstrated that the complementary anti products such as 232 could be obtained highly selectively in the presence of the methyl-substituted proline catalyst 229 (99% ee, 98 2 dr. Scheme 11.33) [159]. It was proposed that these transformations proceeded through the energetically favored enamine 230 and transition state structure 231. 

Diastereoselective and enantioselective [3C+2S] carbocyclisations have been recently developed by Barluenga et al. by the reaction of tungsten alkenylcarbene complexes and enamines derived from chiral amines. Interestingly, the regio-chemistry of the final products is different for enamines derived from aldehydes and those derived from ketones. The use of chiral non-racemic enamines allows the asymmetric synthesis of substituted cyclopentenone derivatives [77] (Scheme 30). 

The potential of Fischer carbene complexes in the construction of complex structures from simple starting materials is nicely reflected in the next example. Thus, the reaction of alkenylcarbene complexes of chromium and tungsten with cyclopentanone and cyclohexanone enamines allows the di-astereo- and enantioselective synthesis of functionalised bicyclo[3.2.1]octane and bicyclo[3.3.1]nonane derivatives [12] (Scheme 44). The mechanism of this transformation is initiated by a 1,4-addition of the C -enamine to the alkenylcarbene complex. Further 1,2-addition of the of the newly formed enamine to the carbene carbon leads to a metalate intermediate which can... 

When either or both of the reaction components has a chiral substituent, the reaction can be enantioselective (only one of the four diastereomers formed predominantly), and this has been accomplished a number of times. Enantioselective addition has also been achieved by the use of a chiral catalyst and by using optically active enamines instead of enolates. Chiral imines have also been used. ... 

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