Proline enamines from

When (2S)-1-(1-cyclohexene-l-yl)-2-(methoxymethyl)pyrrolidine (206), enamine from cyclohexanone, and (S)-proline-derived (2S)-(methoxymethyl)pyrrolidine is added to the Knoevenagel condensation products (207), mainly one of the possible four diastereomers is formed. The diastereomeric purity was found to be excellent (d.s. > 90%) 203). The stereochemical course of this highly effective asymmetric synthesis allowed the synthesis of the optically active target molecules (208). A possible mechanism discussed by Blarer and Seebach 203). 

The formation of covalent substrate-catalyst adducts might occur, e.g., by single-step Lewis-acid-Lewis-base interaction or by multi-step reactions such as the formation of enamines from aldehydes and secondary amines. The catalysis of aldol reactions by formation of the donor enamine is a striking example of common mechanisms in enzymatic catalysis and organocatalysis - in class-I aldolases lysine provides the catalytically active amine group whereas typical organocatalysts for this purpose are secondary amines, the most simple being proline (Scheme 2.2). 

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]. 

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... 

You will remember from Chapter 26 that crossed aldol reactions between enoUzable partners, like these, usually need one of the reagents to be converted to an enolate equivalent to ensure selective reaction. Here, the acetone is in excess, but the components are just stirred together at room temperature in DMSO The key to success is that one of the two components must be more able to form a reactive enamine with proline than the other. In the case above, the acetone-derived enamine is favoured because (1) enamine formation is reversible, (2) the acetone is in excess, and (3) the enamine from acetone is less hindered and more reactive than the enamine that would arise from the aldehyde. 

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]. 

Notably, proline was unique for this transformation, as all the other chiral secondary amines tested failed to promote the reaction. Another well-estabhshed organo-catalyst (4), invented by MacMillan [27], and unable to form secondary interactions with electrophiles like proUne, was used in the addition of aldehydes to indolyl and other carbocations derived from alcohols. The formation of stable carbenium ions from alcohols and their compatibility with water, generated by the organocatalytic cycle (formation of enamines from the corresponding carbonyl derivatives), was estabUshed by Cozzi in a SnI nucleophilic substitution of alcohols in the presence of water [28]. The enamine formed in situ by the MacMUlan catalyst approaches the carbocation from the less hindered side and the hindrance of the incipient carboca-tion controls the stereoselectivity of the reaction (Scheme 26.2) [29]. 

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 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... 

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

The product in entry 1 of Scheme 2.10 is commonly known as the Wieland-Miescher ketone and is a useful starting material for the preparation of steroids and terpenes. The Robinson annulation to prepare this ketone can be carried out enantioselectively by using the amino acid L-proline to form an enamine intermediate. The 5-enantiomer of the product is obtained in high enantiomeric excess.89 This compound and the corresponding product obtained from cyclopentane-1,3-dione90 are key intermediates in the enantiose-lective synthesis of steroids.91... 

The Stork reaction between methylvinyl ketone and enamine (130) derived from (S)-proline derivatives (131) is of particular interest since chiral cyclohexenones can be obtained. These are useful in many natural product syntheses. Optical yields of 20-50% have been reported 147>. 

The alkylation of enamines (126a) (Y = OCH3, OC2H5, O-t-QHg) derived from (S)-proline esters was first described by Yamada et al.148). 

Asymmetric allylation.n The chiral enamine 1, derived from the allyl ester of (S)-proline, when treated with this Pd(0) complex at 25° in various solvents provides (S)-( — )-2-allylcyclohexanone (2) in 80-100% ee, the highest enantio-selectivity being observed in CHC13. 

Early investigations have demonstrated that aldehydes and ketones can be enantioselectiveiy a-alkyl-ated via Michael reactions of the corresponding enamines, prepared from proline-derived secondary amines.149-156 However, optical purities of the products were generally low and never exceeded 59% ee.iS1 This kind of asymmetric a-alkylation could later be improved, allowing for example the preparation of compound (141) with high ee (Scheme 51).156-160... 

Biginelli synthesis of 3,4-dihydropyrimidin-2( 1 //)-oncs (99) from an aldehyde, a /3-diketone, and urea is catalysed by L-proline methyl ester hydrochloride.276 Although evidence strongly supports an enamine mechanism, the products were essentially racemic. 

In this transformation two new C-C-rr-bonds are formed from three different components. The enantioselectivity of this reaction is generally low (< 5%). With cyclic ketones the corresponding products were obtained as single diastereomers. It is proposed that this reaction involves a Knoevenagel-hetero-Diels-Alder sequence where proline utilizes both iminium and enamine catalysis (Scheme 9.20). 

Mechanistically it seems that the reactions follow an enamine mechanism, in which the enamine derived from the ketone and proline reacts with the imine formed in situ from the aldehyde and p-anisidine. 

Zhong rationalized the enantioselectivity by proposing an enamine mechanism which proceeds via the chair transition state shown in Figure 7.1 [11]. In this transition state, the Si face of an E enamine formed from the aldehyde and the catalyst L-proline approaches the less-hindered oxygen atom of nitrosobenzene leading to the chiral product with (R) configuration. This mechanism is in accordance with the proposed reaction mechanism for the aldol reaction (see chapter 6.2). 

In principle, L-proline acts as an enzyme mimic of the metal-free aldolase of type I. Similar to this enzyme L-proline catalyzes the direct aldol reaction according to an enamine mechanism. Thus, for the first time a mimic of the aldolase of type I was found. The close relation of the reaction mechanisms of the aldolase of type 1 [5b] and L-proline [4] is shown in a graphical comparison of both reaction cycles in Scheme 3. In both cases the formation of the enamines Ila and lib, respectively, represents the initial step. These reactions are carried out starting from the corresponding ketone and the amino functionality of the enzyme or L-proline. The conversion of the enamine intermediates Ha and lib, respectively, with an aldehyde, and the subsequent release of the catalytic system (aldolase of type I or L-proline) furnishes the aldol product. 

Of the several studies made of enolates derived from such a-aminoke-tones,37 the most interesting one from the point of view of this work came from Holladay and co-workers who studied alkylation reactions of pyrrolidine enamine 40 derived from protected 4-keto-L-proline 41 with allyl bromide (Scheme 10).38 A 44% yield of two diastereoisomers of allylated material 42 was obtained with a quoted isomer ratio of trans cis of 2 1. 

The existence of the enamine intermediate of proline-catalyzed reaction with acetone as a donor was detected by mass analysis [54], but not by aH NMR. The formation of the presumed enamine intermediate generated from pyrrolidine-acetic acid and isobutyraldehyde was confirmed by 1H NMR [29a]. In this study, the enamine formation in the presence of pyrrolidine-acetic acid was observed within 5 min, but the enamine was shown to form only very slowly in the absence of acid. In these pyrrolidine derivative-acid combination catalysts, the acid component was shown to be important both for faster enamine formation and for the stereocontrol in the C-C bond-forming step. These catalyst systems are essentially split-proline systems that allow for the contributions of the pyrrolidine and carboxylate functionalities of proline to be probed independently. 

The partial steps of the conjugate addition in aminocatalytic reactions are in dynamic equilibrium, and thus products are formed under thermodynamic control. This fact is translated also in the geometry of the enamine intermediates, leading to the product, which can be either E or Z (Fig. 2.9). The geometry of the enamine depends on the catalyst structure and also on the substrate. Whilst proline-catalyzed reactions form preferentially, with a-alkyl substituted ketones, the. E-isomer, enamines derived from pipecolic acid afford an approximate 1 1 mixture of the E and Z isomers [6], In turn, small- and medium-sized cyclic ketones afford the E isomer. 

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