Enamine activation mechanisms

SCHEME 2.21. Enamine activation mechanism for the FeCla-catalyzed a-oxyamination of aldehydes. 

Scheme 15 Double activation of reaction components by an enamine/iminium mechanism [81]...

Hong and co-workers have described a formal [3-t-3] cycloaddition of a,P-unsaturated aldehydes using L-proline as the catalyst (Scheme 72) [225], Although the precise mechanism of this reaction is unclear a plausible explanation involves both iminium ion and enamine activation of the substrates and was exploited in the asymmetric synthesis of (-)-isopulegol hydrate 180 and (-)-cubebaol 181. This strategy has also been extended to the trimerisation of acrolein in the synthesis of montiporyne F [226],... 

In 2008 Resmini et al. [76] presented their work on the synthesis of novel molecularly imprinted nanogels with Aldolase type I activity in the cross-aldol reaction between 4-nitrobenzaldehyde and acetone. A polymerisable proline derivative was used as the functional monomer to mimic the enamine-based mechanism of aldolase type I enzymes. A 1,3-diketone template, used to create the cavity, was... 

The process mechanism as shown in Figure 2.23 consists of an initial activation of the aldehyde (66) by the catalyst [(5)-67] with the formation of the corresponding chiral enamine, which then, selectively, adds to nitroalkene (65) in a Michael-type reaction. The following hydrolysis liberates the catalyst, which forms the iminium ion of the a,(3-unsaturated aldehyde (62) to accomplish the conjugate addition with the nitroalkane A. In the third step, another enamine activation of the intermediate B leads to an intramolecular aldol condensation via C. Finally, the hydrolysis of it returns the catalyst and releases the desired chiral tetra-substituted cyclohexene carbaldehyde (68). 

Biological as weU as organic syntheses apply various activation mechanisms in order to force the two educts along a single reaction pathway. Carbon-carbon formation between enols and acceptor carbonyl carbon atoms can, however, be accelerated, if at a neutral pH one simply applies an enamine as donor. Enamines are... 

Later on, Christmann, et al. developed an organocatalytic intramolecular Diels-Alder reaction of a,P-unsaturated dialdehydes, providing the bicyclic systems (such as decalins 13), [8] (Scheme 3.3). The mechanism was assumed to undergo the vinylogous enamine activation [9], followed by a rapid IMDA reaction and subsequent 6-hydride elimination. On the other hand, the synthesis of the cytotoxic marine natural product amaminol B (16) was achieved by Christmann and his co-workers with the key step of the organocatalytic IMDA reaction of 14, Scheme 3.4 [10]. 

As mentioned, the applications of chiral secondary amines in domino processes have been numerous, mainly because of the dual mechanism of activation allowing easy incorporation of other reactions [7, 8]. The first of these processes involves an iminium-enarnine (Scheme 7.1a), and the second an enamine-iminium activation (Scheme 7.1b), both of which can be in operation in domino reactions involving Michael reactions. These modes of action rely on the lower energy lowest unoccupied molecular orbital (LUMO) for the iminium ion and a rise in the highest occupied molecular orbital (HOMO) energy for enamine activation, which are discussed in further detail in Chapter 10 of this book [9, 10]. In the... 

Early work by Tomioka and coworkers [39] described a two-component Michael/ aldol process to cyclopentenes. Furthermore, rhodium-assisted Michael/aldol processes to cyclopentanes and cyclohexanes have also been reported [40]. Later, a Michael addition reaction in combination with an adehyde a-alkylation reaction was reported for the highly stereoselective formation of y-nitroaldehydes 50 [41]. In this publication, a series of aliphatic aldehydes 49 (at Rj) and ( )-5-iodo-l-nitropent-1-ene 48 were reacted in the presence of the organocatalyst 1 and benzoic acid in dimethyl sulfoxide (DMSO) to afford the resulting cyclopentene ring system 50 (Scheme 7.9). The diastereo- and enantioselective process follows the proposed mechanism beginning with enamine activation of the aldehyde to 51 by the catalyst 1 (blocking the re face), and Michael addition of 48 occurs at its more accessible si face. The full enamine-enamine mechanism, illustrated in Scheme 7.9, provided... 

Scheme 10.1 Mechanism of iminium-enamine activation mode.

In terms of modem organocatalysis, the publications of MacMillan et al. and List et al. in 2000 set the stage for two of the most important activation mechanisms employed in organocatalysis today iminium catalysis (27) and enamine catalysis (28). While MacMillan and co-workers used the chiral imidazolium salt 8 to... 

This contribution will be divided according to activation mechanisms used to achieve the targeted transformation and the reaction type itself. However, some caution is necessary. As already shown in the case of the proline-catalyzed inter-molecular aldol reaction (Scheme 4), 12 can be considered to act as a bifunctional catalyst. Therefore, a strict classification according to just one single activation mechanism will not always be possible and very often activation modes like e.g. enamine formation are accompanied with additional interactions, such as e.g. hydrogen bonding. 

The postulated mechanism starts with the diastereo- and enantioselective domino iminium-enamine activation of enals 95 in the presence of malonate 160 to form the... 

SCHEME 11.2 Mannich-type mechanism through enamine activation. 

Intramolecular Michael Reaction of Aldehydes. Imidazolidinone catalyst 1 mediates the asymmetric intramolecular Michael addition of simple aldehydes to enones at rt (eq 15). The reaction is thought to proceed via an enamine mechanism but a dual-activation mechanism involving both enamine and iminium catalysis can also be considered. When a catalytic amount of 1 was used, products were obtained in excellent yield although in low enantioselectivity (eq 15). Better selectivity was observed, however, when catalyst 2 was used (eq 15). 

Although the emphasis in this chapter has been on tbe synthesis and mechanism of formation of simple enamines, brief mention will be made of the addition of amines to activated acetylenes to indicate the interest and activity in this area of substituted enamines. Since such additions tend to be stereospecific, inclusion in this section seems apropos. The addition of amines to acetylenes has been much studied 130), but the assigning of the stereochemistry about the newly formed double bond could not be done unequivocally until the techniques of NMR spectroscopy were well developed. In the research efforts described below, NMR spectroscopy was used to determine isomer content and to follow the progress of some of the reactions. 

The mechanism of the cycloaddition of phenyl azide to norbornene has been shown to involve a concerted mechanism with a charge imbalance in the transition state (199). In a similar manner the cycloaddition of phenyl azide to enamines apparently proceeds by a concerted mechanism (194, 194a). This is shown by a rather large negative entropy of activation (—36 entropy units for l-(N-morpholino)cyclopentene in benzene solvent at 25°C), indicative of a highly ordered transition state. Varying solvents from those of small dielectric constants to those of large dielectric constants has... 

A unique method to generate the pyridine ring employed a transition metal-mediated 6-endo-dig cyclization of A-propargylamine derivative 120. The reaction proceeds in 5-12 h with yields of 22-74%. Gold (HI) salts are required to catalyze the reaction, but copper salts are sufficient with reactive ketones. A proposed reaction mechanism involves activation of the alkyne by transition metal complexation. This lowers the activation energy for the enamine addition to the alkyne that generates 121. The transition metal also behaves as a Lewis acid and facilitates formation of 120 from 118 and 119. Subsequent aromatization of 121 affords pyridine 122. 

Due to mechanistic requirements, most of these enzymes are quite specific for the nucleophilic component, which most often is dihydroxyacetone phosphate (DHAP, 3-hydroxy-2-ox-opropyl phosphate) or pyruvate (2-oxopropanoate), while they allow a reasonable variation of the electrophile, which usually is an aldehyde. Activation of the donor substrate by stereospecific deprotonation is either achieved via imine/enamine formation (type 1 aldolases) or via transition metal ion induced enolization (type 2 aldolases mostly Zn2 )2. The approach of the aldol acceptor occurs stereospecifically following an overall retention mechanism, while facial differentiation of the aldehyde is responsible for the relative stereoselectivity. 

Like many other antibodies, the activity of antibody 14D9 is sufficient for preparative application, yet it remains modest when compared to that of enzymes. The protein is relatively difficult to produce, although a recombinant format as a fusion vdth the NusA protein was found to provide the antibody in soluble form with good activity [20]. It should be mentioned that aldolase catalytic antibodies operating by an enamine mechanism, obtained by the principle of reactive immunization mentioned above [15], represent another example of enantioselective antibodies, which have proven to be preparatively useful in organic synthesis [21]. One such aldolase antibody, antibody 38C2, is commercially available and provides a useful alternative to natural aldolases to prepare a variety of enantiomerically pure aldol products, which are otherwise difficult to prepare, allovdng applications in natural product synthesis [22]. 

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. 

Since activation of the N-H bond of PhNHj by Ru3(CO)i2 has been reported to take place under similar conditions [306], it has been proposed that the reaction mechanism involves (i) generation of an anUido ruthenium hydride, (ii) coordination of the alkyne, (iii) intramolecular nucleophilic attack of the nitrogen lone pair on the coordinated triple bond, and (iv) reductive ehmination of the enamine with regeneration of the active Ru(0) center [305]. 

The detailed mechanism of inhibition of TEM-2 (class A) enzyme with clavulanate has been established (Scheme 1) [23,24], The inhibition is a consequence of the instability of the acyl enzyme formed between the /1-lactam of clavulanate and the active site Ser-70 of the enzyme. In competition with deacylation, the clavulanate acyl-enzyme complex A undergoes an intramolecular fragmentation. This fragmentation initially provides the new acyl enzyme species B, which is at once capable of further reaction, including tautomeriza-tion to an entity C that is much less chemically reactive to deacylation. This species C then undergoes decarboxylation to give another key intermediate enamine D, which is in equilibrium with imine E. The imine E either forms stable cross-linked vinyl ether F, by interacting with Ser-130 or is converted to the hydrated aldehyde G to complete the inactivation. 

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