Catalytic asymmetric enamine aldol

Notz W, Tanaka F, Barbas CF (2004) Enamine-based organocatalysis with proline and diamines the development of direct catalytic asymmetric aldol, Mannich, Michael, and Diels-Alder reactions. Acc Chem Res 37(8) 580-591... 

Notz, W., Tanaka, F., Barbas, C. F., III. Enamine-Based Organocatalysis with Proline and Diamines The Development of Direct Catalytic Asymmetric Aldol, Mannich, Michael, and Diels-Alder Reactions. Acc. Chem. Res. 2004, 37, 580-591. 

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... 

Enamine-Based Organocatalysts with Proline and Diamines The Development of Direct Catalytic Asymmetric Aldol ... 

Type I aldolases activate the aldol donor by the formation of enamines with active site amino acids and an alternate approach to the direct catalytic asymmetric aldol reaction centres on mimicking this process using proline-based organocatalysts. In fact, one of the earliest examples of asymmetric catalysis uses (S)-profine (7.66) as a catalyst for the intramolecular aldol reaction (the Hajos-Eder-Saeur-Wiechert reaction).As an example the achiral triketone (7.67) cyclises to give the aldol product (7.68) with good enantioselectivity. 

An alternate approach to the direct asymmetric Mannich reaction uses enan-tiomericaUy pure organocatalysts. L-Proline and derivatives, applied with much success to the catalytic asymmetric aldol reaction (see Section 7.1), also function as effective catalysts in the Mannich reaction. The mechanism of this process is similar to the L-proline-catalysed aldol reaction involving conversion of the donor into an enamine and proceeds via a closed six-membered transition state similar to that depicted in Figure 7.4. However, in contrast to the L-proline-catalysed aldol reaction, the sy -Mannich adduct is the major diastereomer formed and the si rather than the re-face of the acceptor undergoes attack, as depicted in Figure 7.5. 

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],... 

Moving to the use of 9-deo3gr-9-amino-epi Cinchona-, in 2007, shortly after the disclosure of their usefulness in conjugate additions, summarised in Section 14.2, Liu and coworkers demonstrated that these primaiy amines are also efficient in catalytic asymmetric 1,2-additions proceeding through enamine intermediates. The authors reported a highly enantioselective aldol addition of cyclic ketones to aromatic aldehydes catalysed by a primary amine derived from cinchonine (CNA) and proceeding in the absence of... 

Recently, List has described a cascade reaction promoted by phosphoric acid 1 in combination with stoichiometric amounts of achiral amine, which transforms various 2,6-diketones to the corresponding ds-cyclohexylamines (Scheme 5.28) [50]. This three-step process involves initial aldolization via enamine catalysis to give conjugate iminium ion intermediate A. Next, asymmetric conjugate reduction followed by a diastereoselective 1,2 hydride addition completes the catalytic cycle. 

The most interesting and practical asymmetric induction process that involves enamines is the proline-catalyzed conversion of the prochiral triketone in Scheme 15 to the cyclic aldol condensation product" or to the aldol product. The course of the reaction is determined by the presence (or absence) of a strong acid such as hydrochloric acid as a cocatalyst. As a result of both the practical significance of the product(s) as synthetic intermediate(s) and the catalytic nature of this process, there has been a high level of interest directed at establishing the mechanistic pathway for these reactions. 

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. ... 

The catalyst we will use Is the amino acid L-proline—no derivatization or protection required. It was actually back in 1971 that it was first noted that L-proline will catalyse asymmetric aldols, but until the year 2000 examples were limited to this one cyclization. Treatment of a triketone with proline leads to selective cyclization onto one of the two enantiotopic carbonyl groups. A molecule of proline must condense with the least hindered ketone, and in this case an enamine (rather than an iminium ion) can form. The chiral enamine can select to react with only one of the two other carbonyl groups, and it turns out that it chooses with rather high selectivity the one coloured green in the scheme below. Cyclization, in the manner of a Robinson annelation, and hydrolysis of the resulting iminium ion follow on, releasing the molecule of L-proline to start another catalytic cycle. The isolated product is the bicyclic ketone, in 93% ee. 

Barbas and researchers identified that the diamine la TFA salt can catalyse the asymmetric intermolecular direct aldol reactions of a,a-dialkylaldehydes with aromatic aldehydes (Scheme 9.2). The bifunctional catalytic system exhibited excellent reactivity to give products with moderate diastereo- and enantioselectivities. Notably, L-proline is an ineffective catalyst for this class of aldol reactions. The re-face attack of an enamine intermediate on an aryl aldehyde was proposed, causing the observed stereochemistry. 

Chen and co-workers [72] reported an asymmetric quadruple amino catalytic domino reaction catalyzed by secondary amines. The reaction consists of a quadruple iminium-enamine-iminium-enamine cascade reaction initiated by a Michael addition of oxindole 114 to the enal and a subsequent intramolecular Michael reaction between the enamine formed in the previous step and the unsaturated oxindole to yield intermediate 116. Next, this intermediate reacts with another molecule of enal via a Michael addition of the oxindole to the enal. The sequence ends with an intramolecular aldol reaction between the preformed enamine and the aldehyde. This organocascade reaction affords highly complex spirooxindoles 118 bearing six contiguous chiral centers in excellent yields and with excellent diastereo- and enantioselectivities (Scheme 10.31). 

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