Aldol reaction, intermolecular

1 Intermolecular Aldol Reaction With Formation of One Stereogenic Center 

The asymmetric aldol reaction is one of the most important topics in modern catalytic synthesis [54]. The products, namely / -hydroxy carbonyl compounds, have a broad range of applications and play a key role in the production of pharmaceuticals [55], Since the discovery of the catalytic asymmetric aldol reaction with enolsi-lanes by Mukaiyama et al. [56], steady improvements of the metal-catalyzed asymmetric aldol reaction have been made by many groups [57]. For this type of aldol reaction a series of chiral metal catalysts which act as Lewis acids activating the aldol acceptor have been shown to be quite efficient. It was recently shown by the Shibasaki group that the asymmetric metal-catalyzed aldol reaction can be also performed with unmodified ketones [57a], During the last few years, several new concepts have been developed which are based on use of organocatalysts [58], Enolates and unmodified ketones can be used as aldol donors. 

The concept In the first example of an organic base-catalyzed asymmetric intermolecular aldol reaction, Denmark et al. impressively demonstrated that the pres- 

Trichlorosilylenolates of type 13 were used as nucleophiles. Such enolates are highly activated ketone derivatives and react spontaneously with several aldehydes at room temperature. At —78 °C, however, the uncatalyzed reaction can be suppressed almost completely (formation of the undesired racemic aldol adduct is only 4%). Thus, at —78 °C and in the presence of the chiral organocatalyst 14 the acetone-derived enolate and benzaldehyde gave the desired adduct in high yield 

Process development and optimization Detailed process development was conducted using synthesis of (S)-16 as model reaction [60]. The preferred reaction temperature was —78 °C lower temperatures, e.g. —90 °C, resulted in no improvement. With regard to the amount of catalyst, at least 5 mol% is required to obtain high enantioselectivity. Further increasing the amount of catalyst did not, however, result in sufficient improvement to justify use of an increased amount. From a practical standpoint the short reaction time (2 h for aromatic and a,/ -unsaturated aldehydes) in combination with a high concentration of substrate (up to 0.5 mol L ) is attractive, and results in an excellent space-time yield of up to 856 g L 1 day-1. 

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It is worth pointing out that the stereochemistry of intermediate 147 at C-9 and C-10 is inconsequential since both positions will eventually bear trigonal carbonyl groups in the final product. The synthetic problem is thus significantly simplified by virtue of the fact that any or all C9-C10 diol stereoisomers could be utilized. A particularly attractive means for the construction of the C9-C10 bond and the requisite C8-C10 functionality in 147 is revealed by the disconnection shown in Scheme 41. It was anticipated that the venerable intermolecular aldol reaction could be relied upon to accomplish the union of aldehyde 150 and methyl glycolate (151) through a bond between carbons 9 and 10. 

Proline (l)-catalyzed intermolecular aldol reaction, Ustetal. (refs. 14,15) ... 

Surprisingly, the catalytic potential of proline (1) in asymmetric aldol reactions was not explored further until recently. List et al. reported pioneering studies in 2000 on intermolecular aldol reactions [14, 15]. For example, acetone can be added to a variety of aldehydes, affording the corresponding aldols in excellent yields and enantiomeric purity. The example of iso-butyraldehyde as acceptor is shown in Scheme 1.4. In this example, the product aldol 13 was obtained in 97% isolated yield and with 96% ee [14, 15]. The remarkable chemo- and enantioselectivity observed by List et al. triggered massive further research activity in proline-catalyzed aldol, Mannich, Michael, and related reactions. In the same year, MacMillan et al. reported that the phenylalanine-derived secondary amine 5 catalyzes the Diels-Alder reaction of a,/>-un saturated aldehydes with enantioselectivity up to 94% (Scheme 1.4) [16]. This initial report by MacMillan et al. was followed by numerous further applications of the catalyst 5 and related secondary amines. 

The concept The possibility of using a simple organic molecule from the chiral pool to act like an enzyme for the catalytic intermolecular aldol reaction has recently been reported by the List and Barbas groups [69-71]. L-proline, (S)-37, was chosen as the simple unmodified catalytic molecule from the chiral pool . The proline-catalyzed reaction of acetone with an aldehyde, 36, at room temperature resulted in the formation of the desired aldol products 38 in satisfactory to very good yields and with enantioselectivity up to >99% ee (Scheme 6.18) [69, 70a],... 

Intermolecular Aldol Reaction with Formation of Two Stereogenic Centers... 

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... 

Intermolecular aldol reaction [6.2.1] Intramolecular aldol reaction [6.2.2]... 

Intermolecular Michael addition [4.1] Intermolecular aldol reaction [6.2.1] Intramolecular aldol reaction [6.2.2] Aldol-related reactions (e.g. vinylogous Mukaiyama-type aldol) [6.2.3]... 

Direct intermolecular aldol reactions, catalysed by proline, between tetrahydro-4H-thiopyranone (25) and racemic aldehydes exhibit enantiotopic group selectivity and dynamic kinetic resolution, with ee% of >98% in some cases.109... 

Enholm reported radical-anionic sequences involving ketyl radical cyclisa-tions that culminate in intermolecular aldol reactions treatment of aldehyde 24 and cyclohexane carboxaldehyde with Sml2 triggers a radical cyclisation-intermolecular aldol sequence to give 25 in good yield (Scheme 6.10).15... 

The first highly enantioselective examples of this catalysis strategy were reported by MacMillan et al. in 2000 (Ahrendt et al. 2000 also see Wilson et al. 2005 Northrup and MacMillan 2002b), shortly after our first report on the proline-catalyzed intermolecular aldol reaction had appeared. The MacMillan group has quickly established that Diels-... 

Hoang L, Bahmanyar S, Houk KN, List B (2003) Kinetic and stereochemical evidence for the involvement of only one proline molecule in the transition states of proline-catalyzed intra- and intermolecular aldol reactions. J Am Chem Soc 125 16-17... 

Mechanism of Amine-Catalyzed Intermolecular Aldol Reactions... 

Houk and Bahmanyar began a series of computational studies of organocat-alyzed aldol reactions with an examination of simple intermolecular aldol reactions catalyzed by small amines. They first looked at the methylamine-catalyzed aldol... 

Bahmanyar, S. Honk, K. N. Martin, H. J. List, B. Quantum mechanical predictions of the stereoselectivities of proUne-catalyzed asymmetric intermolecular aldol reactions, J. Am. Chem. Soc. 2003,125, 2475-2479. 

The second case must start with an intermolecular aldol reaction. Only one ketone can and the 1,2-diketone is more electrophilic because each carbonyl group makes the other electrophilic. The first reaction is unambiguous. 

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]. 

Computational studies suggest that the mechanism of the proline catalyzed aldol cyclization is best described by the nucleophilic addition of the neutral enamine to the carbonyl group together with hydrogen transfer from the proline carboxylic acid moiety to the developing alkoxide. A metal-free partial Zimmerman-Traxler-type transition state involving a chair-like arrangement of enamine and carbonyl atoms and the participation of only one proline molecule has been established [118,119]. On the basis of density functional theory (DFT) calculations Cordova and co-workers [120,121] have studied the primary amino acid intermolecular aldol reaction mechanism. They demonstrated that only one amino acid molecule is involved in the... 

The L-alanine catalyzed reaction of 25 and BnOCH2CHO gives 5-0-benzyl-1,3-di-O-isopro-pylidene-L-ribulose [121]. The direct asymmetric intermolecular aldol reactions are also catalyzed by small peptides. For instance, in the presence of 30mol% of L-Ala-L-Ala in DMSO containing 10 equivalents of H2O, 25 reacted with 4-cyanobenzaldehyde giving the corresponding aldols with an antilsyn ratio of 13 1 and ee of 99% for the anti aldol (65% yield) [145]. 

Arno, M., Domingo, L. R. Density functional theory study of the mechanism of the proline-catalyzed intermolecular aldol reaction. Theoretical Chemistry Accounts 2002,108, 232-239. 

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