Aldol aldehyde donors

Unlike most enantio- and diastereoselective direct aldol processes, the enamine-catalyzed aldol reactions are also feasible with aldehyde donors. In a milestone paper, Northrup and MacMillan reported in 2002 that aldehyde-aldehyde aldol... 

Scheme 19 Asymmetric aldol reactions with aldehyde donors...

The simplest possible aldehyde donor, acetaldehyde, can also be used as the donor Very recently, Hayashi and coworkers discovered how to use acetaldehyde in crossed-aldol reactions - the trick is to use diarylprohnol as the catalyst and to optimize the reaction conditions carefully to prevent oligomerization of acetaldehyde. However, so far the acetaldehyde aldol reactions appear to be limited to aromatic aldehyde acceptors [205],... 

S)-Proline-catalyzed aldehyde donor reactions were first studied in Michael [21] and Mannich reactions (see below), and later in self-aldol and in cross-aldol reactions. (S)-Proline-catalyzed self-aldol and cross-aldol reactions of aldehydes are listed in Table 2.6 [22-24]. In self-aldol reactions, the reactant aldehyde serves as both the aldol donor and the acceptor whereas in cross-aldol reactions, the donor aldehyde and acceptor aldehyde are different. 

Aldol and Mannich-Type Reactions 27 Table 2.6 (S)-Proline-catalyzed cross-aldol reactions of aldehyde donors.3)... 

Table 2.7 Diamine 8-CF3C02H-catalyzed aldol reactions of a,a-disubstituted aldehyde donors to afford hydroxyaldehydes with a quaternary carbon atom [29].

For the aldol reactions of aldehyde donors using (S)-proline or diamine (S)-8-CF3C02H, the major products and the proposed most suitable transition state that explains the stereochemistries of the products are also shown in Scheme 2.12 [8, 29a]. 

Scheme 2.12 The proposed most suitable transition states of the (S)-proline-catalyzed and diamine 8-CF3C02H-catalyzed aldol reactions of aldehyde donors [29b].

In the case of the 9-catalyzed aldol reactions of ketones and aldehyde donors that have a high affinity for water (e.g., chloral, trifluoroacetaldehyde, aqueous formaldehyde or the corresponding hydrates of the aldehydes), the addition of 100-500 mol% water to the reaction mixture accelerated the reaction rate and afforded the products with higher enantiomeric excess (Scheme 2.13) [16]. The presence of a catalytic amount of water (20 or 50 mol%) or no addition of water... 

General Procedures for (S)-Proline-Catalyzed Cross-Aldol Reactions of Aldehyde Donors (p. 28)... 

The use of enzymes for the aldol reaction complements traditional chemical approaches. In the early twentieth century a class of enzymes was recognized that catalyzes, by an aldol condensation, the reversible formation of hexoses from their three carbon components.3 The lyases that catalyze the aldol reaction, are referred to as aldolases. More than 30 aldolases have been characterized to date. These aldolases are capable of stereospecifically catalyzing the reversible addition of a ketone or aldehyde donor to an aldehyde acceptor. Two distinct mechanistic classes of aldolases have been identified (Scheme 5.1).4... 

The cross-aldol reaction between enolisable aldehydes (donor aldehydes) and nonenolisable aldehydes (acceptor aldehydes) is known to be catalysed by L-proline and the related amine catalysts, giving antz -aldol adducts. For instance, the cross-aldol reaction of propanal with 4-nitrobenzaldehyde gave the corresponding anti-dXdoX adduct with excellent diastereo- and enantioselectivity (Scheme 17.4). ° The reaction catalysed by an amino sulfonamide (5 )-3, on the other hand, gave the unusual q n-aldol product as the major diastereomer. ... 

The mechanism of the amino acid-catalyzed Mannich reactions is depicted in Scheme 4.14. Accordingly, the ketone or aldehyde donor reacts with the amino acid to give an enamine. Next, the preformed or in situ- generated imine reacts with the enamine to give after hydrolysis the enantiomerically enriched Mannich product, and the catalytic cycle can be repeated. It is important to bear in mind that N-Chz-, N- Boc-, or A-benzoyl-protected imines are water-sensitive. Thus, they can hydrolyze and thereby decrease the yield of the transformation. Moreover, in the case of cross-Mannich-type addition with aldehydes as nucleophiles the catalytic self-aldolization pathway can compete with the desired pathway and lead to nonlinear effects [63]. 

Aldehyde donors were also employed successfully in the syntheses of convolutamydines E (77) and B (78) (80-82). The strategy was the same as depicted for the synthesis of (/ )- and (5)-convolutamydine A (32) (Scheme 9), but using acetaldehyde (79) instead of acetone (13) as the nucleophile in the cross-aldol reaction with dibromo-isatm 33 (Scheme 19). Nakamura et al. utilized catalyst 37, followed by a NaBH3CN-mediated reduction to obtain (/ )-convolutamydine E (77) in excellent yield and enantioselectivity. Chlorination of 77 then gave (l )-convolutamydine B (78) (Scheme 19) (80, 81). 

Preparative amine-catalyzed intermolecular aldolizations /ith aldehyde donors. 

The (Z)-enamine transition state 31 was proposed as the intermediate in the syn-selective reaction of an acyclic ketone donor with an aldehyde acceptor catalyzed by 22. In this type of reaction, formation of the ( )-enamine of the acyclic ketone is disfavored due to steric repulsion between R and substituents (Figure 28.3) [18]. The (F)-enamine formed by an aldehyde donor with the axially chiral catalyst 23 can react with an aldehyde acceptor that is activated by the proximal acidic proton of 23 via transition model 33, thus affording the syn-aldol product [19],... 

I If one of the carbonyl partners contains no or hydrogens, and thus can t form an enolate ion to become a donor, but does contain an unhindered carbonyl group and so is a good acceptor of nucleophiles, then a mixed aldol reaction is likely to be successful. This is the case, for instance, when either benz-aldehyde or formaldehyde is used as one of the carbonyl partners. 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

The aldol reaction is a carbonyl condensation that occurs between two aldehyde or ketone molecules. Aldol reactions are reversible, leading first to a /3-hydroxy aldehyde or ketone and then to an cr,/6-unsaturated product. Mixed aldol condensations between two different aldehydes or ketones generally give a mixture of all four possible products. A mixed reaction can be successful, however, if one of the two partners is an unusually good donor (ethyl aceto-acetate, for instance) or if it can act only as an acceptor (formaldehyde and benzaldehyde, for instance). Intramolecular aldol condensations of 1,4- and 1,5-diketones are also successful and provide a good way to make five-and six-inembered rings. 

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. 

The charged group introduced into products by the aldol donors (phosphate, carboxylate) facilitates product isolation and purification by salt precipitation and ion exchange techniques. Although many aldehydic substrates of interest for organic synthesis have low water solubility, at present only limited data is available on the stability of aldolases in organic cosolvents, thus in individual cases the optimal conditions must be chosen carefully. 

Similar to DHAP aldolases, the 3-hexulose 6-phosphate aldolase found in Methylomonas Ml 5 is highly specific for the aldol donor component D-ribulose 5-phosphate, but accepts a wide variety of aldehydes as replacement for formaldehyde as the acceptor. With propanal,... 

Typically, lyases are quite specific for the nucleophilic donor component owing to mechanistic requirements. Usually, approach of the aldol acceptor to the enzyme-bound nucleophile occurs stereospedfically following an overall retention mechanism, while the facial differentiation of the aldehyde carbonyl is responsible for the relative stereoselectivity. In this manner, the stereochemistry of the C—C bond formation is completely controlled by the enzymes, in general irrespective of the constitution or configuration of the substrate, which renders the enzymes highly predictable. On the other hand, most of the lyases allow a reasonably broad variation of the electrophilic acceptor component that is usually an aldehyde. This feature... 

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