Cross-aldol reaction, aldehyde donors

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. 

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],... 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

Significant for cross-aldol reactions, when an aldehyde was mixed with (S)-proline in a reaction solvent, the dimer (the self-aldol product) was the predominant initial product. Formation of the trimer typically requires extended reaction time (as described above). Thus, it is possible to perform controlled cross-aldol reactions, wherein the donor aldehyde and the acceptor aldehyde are different. In order to obtain a cross-aldol product in good yield, it was often required that the donor aldehyde be slowly added into the mixture of the acceptor aldehyde and (S)-proline in a solvent to prevent the formation of the self-aldol product of the donor aldehyde. The outcome of these reactions depends on the aldehydes used for the reactions. Slow addition conditions can sometimes be avoided through the use of excess equivalents of donor or acceptor aldehyde - that is, the use of 5-10 equiv. of acceptor aldehyde or donor aldehyde. In general, aldehydes that easily form self-aldol products cannot be used as the acceptor aldehydes in... 

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

S)-Proline-catalyzed cross-aldol reaction of aldehydes followed by Mukaiyama aldol reaction sequence was used for the synthesis of prelactone B [27]. The products of the aldol reactions of O-protected a-oxyaldehydes are protected carbohydrates, and were also transformed to highly enantiomerically enriched hexose derivatives, again through a second Mukaiyama aldol reaction (Scheme 2.5) [28]. The products of the aldol reactions of N-protected a-aminoaldehyde donor were easily converted to the corresponding highly enantiomerically enriched /Miydroxy-a-amino acids and their derivatives (Scheme 2.6) [24]. (For experimental details see Chapter 14.1.1). 

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

General Procedure for O-tert-Butyl-L-Threonine Catalyzed Cross-Aldol Reactions of Ketone Donors and Aldehyde Acceptors [2] (p. 23)... 

One normally expects antibodies to have a low tolerance to substrate modifications, however an ongoing feature of these aldolase antibodies is their wide scope. They accept a remarkable range of aldol donors and acceptors and perform crossed-, intramolecular- and retro-variants of this reaction, with high yields, rates, and stereospecificities [81,82,83]. Substrate modification experiments have revealed that when acetone is the aldol donor in a ketone-aldehyde crossed aldol reaction, stereoinduction is linked to attack of the sz-face of a prochiral aldehyde with typically >95% ee and when hydroxyacetone is the donor substrate, attack occurs preferentially at the re-face of the aldehyde leading to a diastereomeric a,P-dihydroxy ketones with the two stereogenic centers having an a-syn configuration. This reaction leads to stereospecificities of typically 70 to >99% ee. 

Almost inevitably, a method to eany out a proline-eatalysed, asymmetric cross-aldol reaction was shortly after described by Tanaka and Barbas et al. The reaction of the protected a-amino aldehyde 8 with branched aldehyde 9 gave access to y-branched p-hydro gr-a-amino aldehyde 10, which was further used to generate the respective amino acid derivative 11 (Scheme 5.7). The surrounding study showed that the roles of the individual aldehydes as donor or acceptor were invertible, depending on whether branched or nonbranched aldehydes were applied. When a-nonbranched aldehydes were... 

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. ... 

In this cross-aldol reaction, formation of the enamine intermediate of an a-chloroaldehyde would be inhibited or significantly slowed down due to steric repulsion, and the formed enamine intermediate of a donor aldehyde reacts predominantly with the electronically activated a-chloroaldehyde (Scheme 17.7). The homo-aldol reaction of the donor aldehyde is suppressed probably due to the moderate nucleophilicity of (S)-4. 

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). 

Most enzymes used by Nature for carbon-carbon bond formation and cleavage ( lyases ) catalyze a crossed aldol reaction in the form of a reversible, stereocontrolled addition of a nucleophilic ketone donor to an electrophilic aldehyde acceptor. Synthetically the most useful and most extensively studied enzymes use aldol donors comprising 2-carbon or 3-carbon fragments and can be grouped into fom categories depending on the structure of their nucleophilic component (Figme 5.2) (i) pyruvate-... 

Aldolase antibodies 38C2 and 33F12 generated by immunization with diketone 1 are capable of accelerating more than 100 different aldol reactions [4, 8, 11, 15, 16]. Some examples of cross-aldol reactions are shown in Table 6.1. For cross-aldol reactions, a variety of ketones are accepted as donors, including aliphatic open-chain ketones (for example acetone to pentanone), aliphatic cyclic ketones (cyclopentanone to cycloheptanone), functionalized open-chain ketones (hydroxyacetone, dihydroxyacetone, fluoroacetone), and functionalized cyclic ketones (2-hydroxycyclohexanone). As with the donors, the antibodies also accept different kinds of aldehyde substrate, for example benzaldehyde derivatives 8-10, a,j5-unsaturated aldehyde 11, and aliphatic aldehydes 12 and 13 with products as indicated in Table 6.1. 

Cyclohexyl carbaldehyde is also a good substrate [70a, 71]. Tertiary aldehydes, e.g. pivaldehyde, are excellent substrates, furnishing the aldol products, e.g. (R)-38f, with >99% ee and in high yield [70a], Aliphatic a-unsubstituted aldehydes, e.g. pentanal, which usually undergo self-aldolization, can also yield optically active cross-aldol products [71, 73]. A prerequisite for efficient reaction is, however, that the reaction is conducted in neat acetone. Thus, a yield of 75% with 73% ee was achieved in the reaction of pentanal as acceptor and acetone as donor [71]. 

A direct enantioselective cross-aldol-type reaction of acetonitrile with an aldehyde (RCHO) has been reported, giving /3-cyano alcohol product, R-CH (OH)-CH2-CN, (7e) in up to 77% ee.148 CH3CN, acting as an acetate surrogate, is chemoselectively activated and deprotonated using a soft metal alkoxide (CuO-Bu1) in a strong donor solvent (HMPA), with a bulky chiral diphosphine as auxiliary. 

For satisfactory diemo- and stereoselectivity, most catalytic, direct cross-aldol methods are limited to the use of non enolizable (aromatic, a-tert-alkyl) or kineti-cally non enolizable (highly branched, ,/funsaturated) aldehydes as acceptor carbonyls. With aromatic aldehydes, however, enantioselectivity is sometimes moderate, and the dehydration side-product may be important. With regard to the donor counterpart, the best suited pronucleophile substrates for these reactions are symmetric ketones (acetone) and ketones with only one site amenable for enolization (acetophenones). With symmetric cyclic or acyclic ketones superior to acetone, syn/anti mixtures of variable composition are obtained [8b, 11, 19a]. Of particularly broad scope is the reaction of N-propionylthiazolidinethiones with aldehydes, which regularly gives high enantioselectivity of the syn aldol adduct of aromatic, a,fi-unsaturated, branched, and unbranched aldehydes [13]. 

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]. 

In addition to ketones, aldehydes can also be used as aldol donors in pro-line-catalyzed reactions [144]. Barbas et al. found that treating acetaldehyde solutions tvith proline provided aldehyde 185, an aldol trimer of acetaldehyde, in 84% ee and 4% yield (Scheme 4.42, Eq. (1)) [145, 146]. As shotvn by Jorgensen et al., other simple a-unbranched aldehydes can also be used as donors in proline-catalyzed cross aldolization tvith activated non-enolizable ketone acceptors to give aldols 188 in high enantioselectivity and yield (Scheme 4.42, Eq. (2)) [147]. 

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