Aldol reactions ketone donors, intermolecular

As in intermolecular aldol reactions, amine-catalyzed 5-enolexo aldolizations can either lead to aldol condensation (Eqs. (l)-(4)) or addition products (Eq. (5)). These reactions usually involve an aldehyde group as the aldol donor the corresponding amine-catalyzed 5-enolexo aldolizations of ketone donors have so far not been realized. The acceptor carbonyl group can either be an aldehyde or a ketone. 

Aldol reactions using phosphoramides as organocatalysts The organic base-catalyzed asymmetric intermolecular aldol reaction with ketone-derived donors can be successfully applied to the construction of aldol products with two stereogenic centers [82-86]. Trichlorosilyl enolates of type 51 have been used as nucleophiles. Such enolates are strongly activated ketone derivatives and react spontaneously with several aldehydes at —80 °C. A first important result was that in the aldol reaction of 51 catalytic amounts of HMPA led to acceleration of the rate of reaction. After screening several optically active phosphoramides as catalysts in a model reaction the aldol product anti-53 was obtained with a diastereomeric... 

The as)rmmetric proline-catalyzed intramolecular aldol cyclization, known as the Hajos-Par-rish-Eder-Sauer-Wiechert reaction [106,107], was discovered in the 1970s [108,109,110,111]. This reaction, together with the discovery of nonproteinogenic metal complex-catalyzed direct asymmetric aldol reactions (see also Sect 5.5.1) [112,113,114], led to the development by List and co-workers [115,116] of the first proline-catalyzed intermolecular aldol reaction. Under these conditions, the reaction between a ketone and an aldehyde is possible if a large excess of the ketone donor is used. For example, acetone reacts with several aldehydes in dimethylsulfoxide (DMSO) to give the corresponding aldol in good yields and enantiomeric excesses (ee) (O Scheme 17) [117]. 

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. 

The reaction is carried out in vapour phase (250°C) using a flow system (see methods section). This procedure turned out to be essential in order to mantain the hydrogen transfer as the main reaction pathway. A batch experiment carried out in an autoclave actually showed a wide range of condensation products besides some saturated ketone [6]. Reactions of ketones over oxide catalysts can lead to a variety of products due inter alia to aldol condensation, intramolecular dehydration and intermolecular disproportionation [16]. However, the presence of a good hydrogen donor such as a secondary alcohol and vapour phase conditions favour the transfer hydrogenation as the major reaction [16,17]. In our reaction conditions, products attributable to crotonic condensations and subsequent 1,4 Michael addition [18] were observed by g.l.c.-m.s. (Table 1). 

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. ... 

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