Proline-Catalyzed Asymmetric Aldol Reaction

As shown in Scheme 53, L-proline-catalyzed asymmetric aldol reaction between 3-methylbutanal and acetone was used by List for the synthesis of (S)-34 [79]. 

The first asymmetric enamine-catalyzed Mannich reactions were described by List in 2000 [208]. Paralleling the development of the enamine-catalyzed aldol reactions, the first asymmetric Mannich reactions were catalyzed by proline, and a range of cyclic and acyclic aliphatic ketones were used as donors (Schemes 24 and 25). In contrast to the aldol reaction, however, most Mannich reactions are syn selective. This is presumably due to the larger size of the imine acceptor, forcing the imine and the enamine to approach each other in a different manner than is possible with aldehyde acceptors (Scheme 23). 

Desymmetrization via proline-catalyzed asymmetric intramolecular aldol reaction can, however, also be performed with acydic diketones of type 109 as has been reported by the Agami group [106], In the first step a prochiral acyclic diketone reacts in the presence of L-proline as catalyst (22-112 mol%) with formation of the aldol adduct 111 (Scheme 6.49). In this step reaction products with two stereogenic centers, 110, are formed. These chiral hydroxyketones 110 are subsequently converted, via dehydration, into the enones 111, by treatment with p-toluenesulfonic acid. 

The Proline-Catalyzed Asymmetric Aldol Reaction Scope, Mechanism and Consequences... 

Scheme 3. Proline-catalyzed asymmetric aldol reactions...

Agami C (1988) Mechanism of the proline-catalyzed enantioselective aldol reaction. Recent advances. Bull Soc Chim Fr 3 499-507 Agami C, Meynier F, Puchot C, Guilhem J, Pascard C (1984) New insights into the mechanism of the proline-catalyzed asymmetric Robinson cycliza-tion structure of two intermediates. Asymmetric dehydration. Tetrahedron 40 1031-1038... 

Bahmanyar S, Houk KN (2001a) The origin of stereoselectivity in proline-catalyzed intramolecular aldol reactions. J Am Chem Soc 123 12911-12912 Bahmanyar S, Houk KN (2001b) Transition states of amine-catalyzed aldol reactions involving enamine intermediates theoretical studies of mechanism, reactivity, and stereoselectivity. J Am Chem Soc 123 11273-11283 Bahmanyar S, HoukKN, Martin HJ, ListB (2003) Quantum mechanical predictions of the stereoselectivities of proline-catalyzed asymmetric intermolec-ular aldol reactions. J Am Chem Soc 125 2475-2479 Barbas CF 3rd, Heine A, Zhong G, Hoffmann T, Gramatikova S, Bjoernstedt R, List B, Anderson J, Stura EA, Wilson I, Lemer RA (1997) Immune versus natural selection antibody aldolases with enzymic rates but broader scope. Science 278 2085-2092... 

Houk s involvement in proline-catalyzed asymmetric induction began in a similar way. Occasionally something very interesting appears in the literature, especially so if it is amendable to elucidation by computational methods, Houk recalls. We are especially interested in synthetic methods where the experimentalist is unclear of just how things work. This was Ihe case with the proline work. We saw the work of Barbas and List on the aldol reaction, and we were aware of the Hajos-Parrish reaction. So we started computations on simple models, and then looked at the Hajos-Parrish reaction, and we came upon an explanation for its stereoselectivity. This was all done without communicating with any of the experimentalists. ... 

List, B. Pojarliev, P Gastello, C. Proline-catalyzed asymmetric aldol reactions between ketones and a-unsubstituted aldehydes, Org. Lett. 2001, 3, 573-575. 

Sharma, A. Sunoj, R. Enamine versus oxazolidinone What controls stereoselectivity in proline-catalyzed asymmetric aldol reactions , Angew. Chem. Int. Ed. 2010, 49, 6373-6377. 

Bahmanyar, S., Houk, K. N., Martin, H. J., List, B. Quantum Mechanical Predictions of the Stereoselectivities of Proline-Catalyzed Asymmetric Intermolecular Aldol Reactions. J. Am. Chem. Soc. 2003,125, 2475-2479. 

SHpsenol /UUU Bark beetles (//J.v) A Organoborane chemistry, L-proline-catalyzed asymmetric aldol reaction [I48r [166J"... 

R.6S) 6 acetoxyhexadeca n-5-olidc Natural mosquito attractant pheromone Atr Proline catalyzed asymmetric aldol reaction 186 ... 

Figure 1. Model proline-catalyzed asymmetric cross aldol reaction.

Recently, some extensive research has been devoted to exploring a diastereo-selective and enantioselective route for the synthesis of a-hydroxyaldehydes or a-hydroxyketones because they are important building blocks for the construction of complex natural products and biologically active molecules [91]. In parallel with the transition-metal-catalyzed asymmetric nitroso-aldol reaction [92], much interest has also been expressed towards the proline-catalyzed direct asymmetric a-aminoxylation of aldehydes or ketones for the synthesis of optically active a-hydroxyladehydes and a-hydroxyketones [93]. Wang [94] and Huang [95] independently reported an L-proline-catalyzed asymmetric a-aminoxylation reaction in ionic liquids, whereby it was found tliat aldehydes and ketones could undergo... 

This is especially important in those cases where the catalyst has to be used in quite substantial amounts, as in the above-discussed (5)-proline-catalyzed asymmetric aldol reactions, where the catalyst is usually used at 30 mol.%. ... 

Progress in the study on the reaction mechanisms of proline-catalyzed asymmetric direct aldol reactions 06CJO1463. 

Chiral amines can react with so-called Mannich donors such as ketones or aldehydes. The resulting chiral enamines wiU then attack a Mannich acceptor, usually a prochiral aldimine, thereby introducing one or two chiral centers in the Mannich product. This usually is a P-aminoaldehyde or P-aminoketone, optionally substituted at the a-position. Inspired by their work on proline-catalyzed asymmetric aldol reactions [1], the List group envisioned that the related Mannich reactions might also be carried out with a catalytic amount of an enantiomerically pure chiral amine. This led in 2000 to the first direct catalytic asymmetric organocatalyzed Mannich reaction, catalyzed by L-proline (1, Scheme 5.1) [2],... 

The Hajos-Parrish-Eder-Sauer-Wiechert synthesis (Scheme 5) was the first example of an intramolecular proline-catalyzed asymmetric aldol reaction. Systematically, this reaction can be described as a 6-enolendo cyclization. In 2003, List et al. described the first example of an intramolecular enolexo aldolization 85). This approach was then used by Pearson and Mans for the synthesis of (-i-)-cocaine 92, starting from the weso-dialdehyde 90 on treatment with (S)-12 86). This desymmetrization process gave 91 as a mixture of epimers with good enantio-selectivity. The tropane skeleton 91 could be further transformed into +)-92 by conventional means (Scheme 21). 

List B, Pojarliev P, Castello C (2001) Proline-Catalyzed Asymmetric Aldol Reactions Between Ketones and a-Unsuhstituted Aldehydes. Org Lett 3 573... 

Ikishima H, Sekiguchi Y, Ichikawa Y, Kotsuki H (2006) Synthesis of (-)-(5J ,6S)-6-Acetoxyhexadecanolide Based on L-Proline-Catalyzed Asymmetric Aldol Reactions. Tetrahedron 62 311... 

In 1986, we discovered the first three cases of nonlinear effects in asymmetric synthesis the Shaipless epoxidation of geraniol ((+)-NLE), the asymmetric oxidation of p-tolyl methyl sulfide by our titanium reagent ((-)-NLE), and the proline catalyzed asymmetric aldolization of a triketone ( (-)-NLE). The mechanism of the last reaction was studied by Agami et al and found to be second-order with respect to proline. ... 

Since the early example of a proline-catalyzed asymmetric domino Michael-aldol reaction reported by Bui and Barbas in 2000 [57], a number of these reactions have been successfully developed by several groups. For example, Wang et al. have reported the synthesis of chiral densely functionalized cyclopentenes on the basis of a domino Michael-aldol reaction followed by dehydration between aromatic enals and dimethyl 2-oxoethylmalonate [67]. High yields (63-89%) and enanhose-lectivities (91-97% ee) were obtained by using (S)-diphenylprolinol sUyl ethers as catalysts. On the other hand, the condensation of P-nitroketones 36 onto enals in the presence of 8 was shown by Hong et al. to afford the corresponding domino Michael-aldol products 37 through the iminium-enamine activation mode [68]. 

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. 

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

It is true that highly enantioselective reactions are possible with proline in the asymmetric a-amination of aldehydes by azodicarboxylates and in a-oxidation with nitrosobenzene. However, good rather than excellent yields and enantioselectivities are more common in intermolecular Michael and aldol reactions. Moreover, the high catalyst loadings required for proline-catalyzed aldol reactions (up to 30%), and low TOFs (from hours to days to achieve a good conversion, even at a high catalyst... 

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