Prolines enamine catalysis

In the proline-based enamine catalysis, proline actually plays a dual role. The amino-group of proline acts as Lewis base, whereas the carboxylic group acts as a Brpnsted acid (Scheme 10). 

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. 

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]. 

Aldehydes bearing a-hetero substituents also typically afford anti products, and the general solution to syn selective a-heteroatom substituted aldehyde-aldehyde aldol processes via enamine catalysis also still remains to be discovered. Nevertheless, the anti process is remarkably useful because a variety of highly substituted aldehydes can be accessed in a single operation using only very inexpensive catalysts, such as proline 6 or the phenylalanine-derived imidazohdinone 46 (Scheme 21) [114, 116, 117, 119-121, 188]. 

Barbas, one of the pioneers of enamine catalysis, has incorporated iminium ion intermediates in complex heterodomino reactions. One particularly revealing example that uses the complementary activity of both iminium ion and enamine intermediates is shown in Fig. 12 [188]. Within this intricate catalytic cycle the catalyst, L-proline (58), is actively involved in accelerating two iminium ion catalysed transformations a Knoevenagel condensation and a retro-Michael/Michael addition sequence, resulting in epimerisation. 

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). 

Enamine catalysis using proline or related catalysts has now been applied to both intermolecular and intramolecular nucleophilic addition reactions with a variety of electrophiles. In addition to carbonyl compounds (C = O), these include imines (C = N) in Mannich reactions (List 2000 List et al. 2002 Hayashi et al. 2003a Cordova et al. 2002c ... 

List B (2004) Enamine catalysis is a powerful strategy for the catalytic generation and use of carbanion equivalents. Acc Chem Res 37 548-557 List B, Hoang L, Martin HJ (2004) New mechanistic studies on the proline-catalyzed aldol reaction. Proc Natl Acad Sci USA 101 5839-5842... 

S.C. PanandB. List s paper spans the whole field of current organocat-alysts discussing Lewis and Brpnsted basic and acidic catalysts. Starting from the development of proline-mediated enamine catalysis— the Hajos-Parrish-Eder-Sauer-Wiechert reaction is an intramolecular transformation involving enamine catalysis—into an intermolecular process with various electrophilic reaction partners as a means to access cY-functionalized aldehydes, they discuss a straightforward classification of organocatalysts and expands on Brpnsted acid-mediated transformations, and describe the development of asymmetric counteranion-directed catalysis (ACDC). 

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

Figure 5.1 Reactivity modes for proline eatalysis. (a) bifunctional acid/base catalysis (b) iminium catalysis (c) metal-complexes and (d) enamine catalysis.

In this reaction, L-proline reacts with a donor component to generate an enamine intermediate, which attacks the acceptor and leads to an iminium adduct. The aldol is released after hydrolysis. Since its discovery, enamine catalysis has been developed into a powerful strategy that complements enzyme and metal catalysis [6, 7]. The attractiveness of this approach is due to the following ... 

Dihydroquinolines are obtained via Cu- or Ag-cata-lyzed A -coupling/cyclization when using 2-alkynylbenz-aldehydes, amines, and ketones, which combines metal and enamine catalysis, as demonstrated by Wu et al. [119]. 2-Alkynylbenzaldehyde derivatives have also been used as the additional nucleophile carrier in the silver-catalyzed synthesis of naphthyridines and thienopyridines recently reported by Verma et al. [120], A variety of naphthyridines and thienopyridines were prepared via dual activation using L-proline as the organocatalyst, whereas for other... 

A plausible mechanism for the reaction is shown in Scheme 11.2. The carbonyl group undergoes two a-amino-methylation reactions on the same a-carbon of the ketone 12, which is catalyzed by L-proline through enamine catalysis. The cyclocondensation of the resulting substituted amines 19 with formaldehyde affords the desired spiro[indoline-3, 5 -pyrimidin]-2-one and spiro[indene-2,5 -pyrimidin]-l (3H)-one (Scheme 11.2). 

The self-assembly of cinchona alkaloid-derived thioureas and proline, which enables the inverse-electron-demand hetero-Diels-Alder reactions between aldehydes R R CHCH=0 and electron-deficient enones R CH=CHCOR", affording (260), has been discussed in the paragraph covering enamine catalysis. ... 

These findings were extended to a set of very useful cascade reactions by the MacMiUan group [111]. In a first series 1,4-hydride additions were combined with aminations, oxidations, or Mannich reactions (Scheme 4.30). The hydride transfer was catalyzed by imidazoHdinone 9, whereas subsequent functionalization was realized by enamine catalysis through the deployment of proline. Depending on the chirality of proline used, optically pure anti- or syu-configured products 84-86 were isolated. 

Based on these results the following reaction pathway can be assumed. Iminium catalysis is reahzed by the use of chiral imidazolidinones. The subsequent enamine catalysis (HOMO achvation) is realized by deployment of proline. The anti-configured products were detected by application of L-proline, whereas the use of D-proline determines the syn[Pg.90]

A wide range of small organic molecules, mainly secondary amines such as proline derivatives, promote asymmetric aldol reactions through enamine catalysis [6]. List, Reymond, Gong, and others reported the first examples of peptidic catalysts for aldol reactions [7]. In their report, Reymond and coworkers [7a] developed two classes of peptides, following two different designs. In the first peptide class a primary amine is present as a side chain residue (similar to the natural type I aldolase) or as free N-terminus in the second a secondary amine or a proHne residue is present at the N-terminus of the peptide, which incorporated at least one free carboxyhc function (Figure 5.3). 

In contrast to the early report of intramolecular desymmetrization reactions [6], the intramolecular ring-closing reactions of achiral substrates via enamine catalysis were not disclosed until the beginning of the twenty-first century. In 2003, list reported the first highly stereoselective intramolecular aldol reaction of achiral dicarbonyl compounds. Cyclic aldol products 6a-< were delivered from heptanedials 5 with excellent diastereo- and enantioselectivity by the catalysis of L-proline (Scheme 36.2). The cyclization of ketoaldehyde 7 afforded alcohol 8 as a 2 1 diastereomeric mixture but with 99% ee. This strategy could provide P hydroxyl carbonyl derivatives that are of potential applications in organic synthesis [7aj. 

In 2003, a proline-catalyzed enamine-enamine activation sequence was used to develop a three-component reaction leading to functionalized P-amino alcohols 35 [29, 30]. The reaction used both ketones (specifically, acetone) and aldehydes 33 as donors, together with azodicarboxylate 34 (Scheme 42.9) [30]. The first step is the pro line-catalyzed amination of aldehydes [31], leading to intermediate 36, which represents the electrophiUc substrate for the subsequent aldol reaction with acetone. Both intermolecular steps proceed under enamine catalysis by proline 1. A key factor in the high level of chemoselectivity observed was the much higher reactivity of aldehyde over ketone in the proline-catalyzed a-amination reaction, which selectively forms 36. 

It is believed that monofunctional imidazolidinones are optimal for iminium catalysis but without the necessary structural features to participate in bifunctional enamine catalysis (e.g., activation of electrophiles via electrostatic interaction). Conversely, proline has proved to be an enamine catalyst for which bifunctional activation is a standard mode of operation aCTOss a variety of transformation types, yet it is generally ineffective as an iminium catalyst with enals or enones. Therefore, a combination of imidazoUdinone and proline may provide a dual-catalyst system that could fully satisfy the chemoselectivify requirements for cycle-specific catalysis [136]. 

In addition to imininm-initiated cascade reactions, two of the steps in enamine-activated cascade reactions can also be enforced by cycle-specific catalysis. It is well known that diphenylprolinol silyl ether catalyst 34 is optimal for diverse enamine-mediated transformations to fnmish prodncts with high enantioselectivities. However, similar to imidazolidinone catalysts, it proved to be less effective or ineffective for bifunctional enamine catalysis. Cycle-specific catalysis via an aza-Michael/Mannich sequence by combining 34 and either enantiomer of proline was thus developed to generate 206 in about 60% yields with excellent diastereo- and enantioselectivities (Scheme 1.89) [139]. 

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