Prolines enamine

The catalytic cycles are, however, different in the reaction sequence for formation of the enamines which are key intermediates in these aldol reactions. With the type I aldolase a primary amino function of the enzyme is used for direct formation of a neutral imine (Ha) whereas starting from L-proline enamine synthesis proceeds via a positive iminium system (lib) (Scheme 6.23). In this respect, investigations by List et al. on the dependence of the catalytic potential on the type of amino acid are of particular interest. In these studies it has been shown that for catalytic activity the presence of a pyrrolidine ring (in L-proline (S)-37) and the carboxylic acid group is required [69]. 

With regard to the mechanism of the a-amination step, the stereochemistry has been explained on the basis of a transition state involving a proline-enamine struc-... 

Acetone, the component that must enolise, is present in large excess but the achievement is considerable. The reaction involves formation of the proline enamine of acetone 91 which then attacks the aldehyde through a chair-like transition state 92 held together by the acidic proton of proline s carboxylic acid. This gives the imine salt 93 hydrolysed to the product with regeneration of proline. The intermediates are like those in the Robinson annelation enamines and imines. Organic catalysis with amines relies on equilibria between these intermediates and carbonyl compounds. 

It turns out that one of the best ketones for these asymmetric crossed aldol reactions is hydroxy-acetone 96. Combination with isobutyraldehyde 89 gives an aldol that is also an anti-diol 97 with almost perfect selectivity.21 The proline enamine of hydroxyacetone is evidently formed preferentially on the hydroxy side. You will recall from chapter 25 that asymmetric synthesis of anti-diols is not as easy as that of syn diols. 

Hydroxyacetone 96 is a reagent in an even more remarkable reaction the asymmetric direct three-component Mannich reaction. It is combined with an aromatic amine 98 and the inevitable isobutyraldehyde 89 with proline catalysis to give a very high yield of a compound 99 that might have been made by an asymmetric amino-hydroxylation. The proline enamine of hydroxyacetone, must react with the imine salt formed from the amine and isobutyraldehyde. This is a formidable organisation in the asymmetric step. 

There is something different here. The absolute stereochemistry at the OH group (the one that comes from hydroxyacetone) is the same in 99 as it was in 97 but the relative stereochemistry is different anti in 99 but syn in 97. The electrophile (ketone in 97 or imine in 99) must approach the proline enamine in different ways. List s suggestion is that the large A-aryl group prefers to keep away from the rest of the molecule in the transition state 100 leading to 99 but that the side chain on the aldehyde is more important in the transition state 101 leading to 97. The dotted arrows in 100 and 101 show where that clash would come and the black dots mark the atoms that join to form the new bond. There is a review of the catalytic asymmetric aldol reaction that includes material from other chapters.22... 

Details of the interesting asymmetric synthesis of unnatural (-i- )-mesembrine (33) using an L-proline enamine intermediate (see Vol. 3 of these Reports) have appeared.Details are also available " regarding the photochemical synthesis of ( )-crinan, a compound possessing the basic skeleton of the alkaloid crinine (see Vol. 2 of these Reports). 

Agami s model was subsequently challenged by List, Lerner, and Barbas III in 2000 [8a], when they proposed a one-proline enamine mechanism for the proline-catalyzed intermolecular aldol reaction between ketones and aldehydes. Shortly afterwards, on the basis of DFT calculations, Houk and co-workers proposed a very similar mechanism for the Hajos-Parrish intramolecular aldol [19]. Using the B3LYP/6-31H-G(2df,p) level of DFT theory, Houk and co-workers [20] have seen that the energy difference between the two possible chair Zimmermann-Traxler-like transition states, which differ in the orientation of the enamine with... 

The Houk-List model was also applied to explain the origin of stereoselectivity in proline-catalyzed intermolecular aldol reactions [19c, 24]. Contrary to the Hajos-Parrish reaction, there is no restriction on the approach of the electrophile. Interestingly enough, theoretical calculations strongly favour an anti proline enamine... 

To rationalize the cooperative intervention of the co-catalytic system (Pmh-containing peptide and proline), two possible transition states were proposed. The first contains a proline-enamine intermediate (Figure 5.8a) with the histidine... 

Figure 5.8 Possible transition state assemblies involving (a) proline-enamine intermediates and (b) peptide-proline-MVK conjugate addition product intermediates.

Scheme 17.1 Formation of (a) proline-enamine (b) dimethylamine-enamine.

The most convincing evidence on the existence of a proline enamine came in late 2010 from List s group, who elucidated the structure of both aldehyde and ketone-derived proline enaminones (7 and 8 in Figure 17.3) using X-ray crystallography. The enamines were found to remain in an ( )-configuration around the double bond, which maintains an exclusive anti-conformation with respect to the carboxylic acid group [15]. 

In addition to traditional aldol, Mannich, and Michael reactions, enamines can also be used to enable a-amination, chlorination, and fluorination of carhonyl groups. a-Amination can be achieved by reaction of proline enamines with allq l diazodicarboxylates 280, which can be subsequently converted to amino acid derivatives as demonstrated by List (Scheme 14.90). 

Scheme 14.90 a-Amination of proline enamines with alkyl diazodicarbojgrlates. ... 

Enamines derived from ketones are allylated[79]. The intramolecular asymmetric allylation (chirality transfer) of cyclohexanone via its 5-proline ally ester enamine 120 proceeds to give o-allylcyclohexanone (121) with 98% ee[80,8l]. Low ee was observed in intermolecular allylation. Similarly, the asymmetric allylation of imines and hydrazones of aldehydes and ketones has been carried out[82]. 

This group was developed for the protection of amino acids. It is formed from 4-ethoxy-l,l,l-trifluoro-3-buten-2-one in aqueous sodium hydroxide (70-94% yield). Primary amino acids form the Z-enamines, whereas secondary amines such as proline form the -enamines. Deprotection is achieved with 1-6 N aqueous HCl in dioxane at rt. ... 

An interesting case in the perspective of artificial enzymes for enantioselective synthesis is the recently described peptide dendrimer aldolases [36]. These dendrimers utilize the enamine type I aldolase mechanism, which is found in natural aldolases [37] and antibodies [21].These aldolase dendrimers, for example, L2Dl,have multiple N-terminal proline residues as found in catalytic aldolase peptides [38], and display catalytic activity in aqueous medium under conditions where the small molecule catalysts are inactive (Figure 3.8). As most enzyme models, these dendrimers remain very far from natural enzymes in terms ofboth activity and selectivity, and at present should only be considered in the perspective of fundamental studies. 

The values of x = 0.5 and = 1 for the kinetic orders in acetone [1] and aldehyde [2] are not trae kinetic orders for this reaction. Rather, these values represent the power-law compromise for a catalytic reaction with a more complex catalytic rate law that corresponds to the proposed steady-state catalytic cycle shown in Scheme 50.3. In the generally accepted mechanism for the intermolecular direct aldol reaction, proline reacts with the ketone substrate to form an enamine, which then attacks the aldehyde substrate." A reaction exhibiting saturation kinetics in [1] and rate-limiting addition of [2] can show apparent power law kinetics with both x and y exhibiting orders between zero and one. 

A different type of catalysis is observed using proline as a catalyst.166 Proline promotes addition of acetone to aromatic aldehydes with 65-77% enantioselectivity. It has been suggested that the carboxylic acid functions as an intramolecular proton donor and promotes reaction through an enamine intermediate. 

A similar reaction occurs with 2-methylcyclopentane-l,3-dione,176 and can be done enantioselectively by using the amino acid L-proline to form an enamine intermediate. The (S)-enantiomer of the product is obtained in high enantiomeric excess.177... 

The detailed mechanism of this enantioselective transformation remains under investigation.178 It is known that the acidic carboxylic group is crucial, and the cyclization is believed to occur via the enamine derived from the catalyst and the exocyclic ketone. A computational study suggested that the proton transfer occurs through a TS very similar to that described for the proline-catalyzed aldol reaction (see page 132).179... 

The TS proposed for these proline-catalyzed reactions is very similar to that for the proline-catalyzed aldol addition (see p. 132). In the case of imines, however, the aldehyde substituent is directed toward the enamine double bond because of the dominant steric effect of the (V-aryl substituent. This leads to formation of syn isomers, whereas the aldol reaction leads to anti isomers. This is the TS found to be the most stable by B3LYP/6-31G computations.199 The proton transfer is essentially complete at the TS. As with the aldol addition TS, the enamine is oriented anti to the proline carboxy group in the most stable TS. 

At present, one of the most successful catalysts for enamine activation has been proline (2). Proline is a cheap, widely and commercially available amino acid that can be found in both enantiomeric forms and, as such, represents a remarkable synthetic alternative to many established asymmetric catalysts. Given such attractive features, it has become the catalyst of choice for many enamine-catalyzed processes. However, various more recent studies have demonstrated that proline is not a universal catalyst for transformations that involve the a-functionalization of ketone or aldehyde carbonyls. Indeed, these studies have demonstrated that the iminium catalysts developed by MacMillan (imidazolidinones) and Jprgensen (pyrrolidines) are also highly effective for enamine activation with respect to... 

Michael additions using proline (2) as the organocatalyst have proven disappointing in terms of enantiocontrol, ° ° ° stimulating the search for a more selective enamine catalyst system. In this context, imidazolidinones (initially... 

The development of enamine catalysis parallels that of iminium catalysis (Scheme 3) [24], Like iminium catalysis, the concept took a long time to mature, and also required a key discovery - the discovery of intermolecular proline-catalyzed aldol reactions by List and coworkers in 2000 [23] - to set the field in motion. The timeline of historical developments of enamine catalysis is outlined in Scheme 4. 

Type A enamine catalysts include simple amino acids, such as proline 6, and most of their derivatives (such as the tetrazole 44 and various sulfonamides, e.g. 45). They are typically used for aldol, Mannich, a-amination and a-oxygenation reactions - these are all reactions where the electrophile can readily be activated by hydrogen bonding (Scheme 12) [8, 9, 12, 46],... 

The delicateness of the aldol protocol has perhaps been one of the factors why enamine catalysis of the aldol reaction did not emerge nntil the 1970s. The Hajos-Parrish-Eder-Sauer-Wiechert reaction [30] (Scheme 16) was an important early example of an intramolecular enamine-catalyzed aldol reaction. However, it was not nntil 2000 when List, Barbas and Lemer demonstrated that the same reaction can also be performed in an intermolecular fashion, using proline as a simple enamine catalyst [26]. 

Typical starting materials, catalysts, and products of the enamine-catalyzed aldol reaction are summarized in Scheme 17. In proline-catalyzed aldol reactions, enantioselectivities are good to excellent with selected cyclic ketones, such as cyclohexanone and 4-thianone, but generally lower with acetone. Hindered aldehyde acceptors, such as isobutyraldehyde and pivalaldehyde, afford high enantioselectivities even with acetone. In general, the reactions are anti selective, but there are aheady a number of examples of syn selective enamine aldol processes [200, 201] (Schemes 17 and 18, see below). However, syn selective aldol reactions are still rare, especially with cychc ketones. 

Ketone donors bearing a-heteroatoms are particularly useful donors for the enamine-catalyzed aldol reactions (Scheme 18). Both anti and syn aldol products can be accessed in remarkably high enantioselectivities using either proline or proline-derived amide, sulfonamide, or peptide catalysts. The syn selective variant of this reaction was discovered by Barbas [179]. Very recently, Luo and Cheng have also described a syn selective variant with dihydroxyacetone donors [201], and the Barbas group has developed improved threonine-derived catalysts 71 (Scheme 18) for syn selective reactions with both protected and unprotected dihydroxyacetone [202]. 

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