Prolines cross-aldol reaction

Other electrophilic aldehydes such as l,3-dithianyl-2-carboxaldehyde [72] or aqueous formaldehyde [17] (Scheme 4.12) have been applied successfully in the proline cross-aldol reaction. 

The aldehyde-aldehyde aldol reactions were first nsed in a natural product synthesis setting by Pihko and Erkkila, who prepared prelactone B in only three operations starting from isobutyraldehyde and propionaldehyde (Scheme 40). Crossed aldol reaction under proline catalysis, followed by TBS protection, afforded protected aldehyde 244 in >99% ee. A highly diastereoselective Mukaiyama aldol reaction and ring closure with aqueous HE completed the synthesis [112]. 

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... 

In 2008 Resmini et al. [76] presented their work on the synthesis of novel molecularly imprinted nanogels with Aldolase type I activity in the cross-aldol reaction between 4-nitrobenzaldehyde and acetone. A polymerisable proline derivative was used as the functional monomer to mimic the enamine-based mechanism of aldolase type I enzymes. A 1,3-diketone template, used to create the cavity, was... 

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. 

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)... 

Highly enantioselective cross aldol reactions of 3-acetylthiazolidine-2-thione with aliphatic aldehydes can be effected by use of the chiral diamine 1, derived from (S)-proline, as a ligand for the tin(II) enolate (equation II). 

McMillan and co-workers [146] have reported the first example of direct enantioselective aldehyde-aldehyde cross-aldol reaction using small molecules as catalysts. Subsequently, they have described the enantioselective dimerization and cross-coupling of a-oxygenated aldehydes to provide eiythrose architecture. A second L-proline-catalyzed aldol reaction generates hexoses (O Scheme 22) [147]. 

ENAMINE-BASED ORGANOCATALYTIC CROSS-ALDOL REACTIONS USING PROLINE DERIVATIVES... 

Figure 1. Model proline-catalyzed asymmetric cross aldol reaction.

A few variants of the proline-catalyzed cross-aldolization reactions have been proposed in ILs, by adopting strategy A. The reaction depicted in Figure 1 has been carried out in [bmim][PF6] or [bmim] [BE J by Loh and... 

The catalyhc efficiency of L-proline in ionic liquid was enhanced by the addition of DMF as cosolvent, which may be largely due to tlie increased mass transfer in the presence of DMF [79c]. Thus, the use of only 5 mol% L-proline was sufficient to accomplish the cross-aldol reactions of aliphatic aldehydes, affording a-alkyl-P-hydroxyaldehydes with extremely high enanhoselectivihes (>99% ee) in moderate to high diastereoselectivities (diastereomeric raho 3 1 >19 1). However, under the same reaction conditions, much lower ee-values and yields were observed in a one-pot synthesis of pyranose derivahves by sequential cross-aldol reachons. The L-proline immobilized in the ionic liquid layer could be recovered and reused without any deterioration in catalytic efficiency, with the diastereoselectivity,... 

By using of a modified proline, L-prolinamide 47 (which is known to be a more reactive catalyst than L-proline in cross-aldol reactions [80]), the enantioselectivity of the direct aldol reactions in ionic liquid [bmim][BF4] was remarkably increased as compared with the reaction carried out in acetone (69% ee) (Scheme 7.26) [81]. However, the reusability of the recovered 47 when immobilized in the ionic liquid layer was somewhat inferior to that of the L-proline catalyst this effect could be ascribed to the increased solubility of the organocatalyst 47 in the extracting organic solvents (not provided in the literature), leading to an increased leaching of the catalyst. 

Beside the cross aldol reaction, the Mannich reaction, too, has been the object of successful efforts using organocatalysis. The use of small organic molecules such as proline, cyclohexane diamine and Cinchona alkaloid-derived catalysts has proven extraordinarily useful for the development of asymmetric Mannich reactions in traditional polar solvents such as DMSO, DMP, DMF, etc. However, very few studies have been conducted so far in non-conventional solvents. 

It turns out that one of the best ketones for these asymmetric crossed aldol reactions is hydroxy-acetone 96. Combination with isobutyraldehyde 89 gives an aldol that is also an anti-diol 97 with almost perfect selectivity.21 The proline enamine of hydroxyacetone is evidently formed preferentially on the hydroxy side. You will recall from chapter 25 that asymmetric synthesis of anti-diols is not as easy as that of syn diols. 

The use of L-proline as an aldolase mimic has produced extraordinary results in cross-aldol reactions of acetone and aldehydes and of dissimilar aldehydes, giving p-hydroxyketones with ee s > 80%. From limited results it appears that L-proline is as active or more active than the catalysts mentioned above (below ambient temperatures, with good yields in <24 h), and exhibits consider-... 

You will remember from Chapter 26 that crossed aldol reactions between enoUzable partners, like these, usually need one of the reagents to be converted to an enolate equivalent to ensure selective reaction. Here, the acetone is in excess, but the components are just stirred together at room temperature in DMSO The key to success is that one of the two components must be more able to form a reactive enamine with proline than the other. In the case above, the acetone-derived enamine is favoured because (1) enamine formation is reversible, (2) the acetone is in excess, and (3) the enamine from acetone is less hindered and more reactive than the enamine that would arise from the aldehyde. 

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... 

Scheme 5.8 Proline-catalysed direct aldehyde cross-aldol reaction.

Catalyst 15n is able to promote asymmetric cross-aldol reactions of acetone with activated ketones, to generate a quaternary carbon stereogenic centre bearing an OH function, whereas catalysts 15b-d are very active in the reaction of acetone and p-nitrobenzaldehyde in a series of solvents and catalyst loadings. Ley and coworkers reported the synthesis of the parent members of the sulfonamide family - proline methyl sulfonamide... 

For aldol reactions, typically proline-type catalysts were used. However, Palomo and coworkers reported cross-aldol reactions between unmodified aldehydes and ynals. This transformation was enabled by the cooperative action of newly designed catalyst C7, copper iodide and a Bronsted acid. In this way, remarkably high levels of diastereo- and enantioselectivily were achieved (Scheme 8.32). 

Proline (1) has showed to be a effective catalyst for both the homo-aldol and the cross-aldol reactions (Schane 4.12). Thus, the homo-aldol process using propi-onaldehyde (R =Me in 5a and R =Et in 2) afforded the expected a-hydroxyaldehyde in an excellent enantioselectivity for the major anti-29. Under similar reaction conditions, the cross-aldol reaction between propionaldehyde as source of nucleophile (5, R =Me) and other different aliphatic and aromatic aldehydes has been performed, giving the anti-29 isomer as the main diastereoisomer [71], This reaction course has been explained due to the steric hindrance as well as the kinetic inaccessibility of the hydrogen for some a,a-disubstimted aldehydes which leads, in both cases, to a very thermodynamic unstable corresponding nucleophilic enamine intermediate. 

The cross-aldol reaction between propionaldehyde (5a, R =Me in Scheme 4.12) and p-nitrobenzaldehyde gave the corresponding compound anti-29 (> 88% yield, 88% de and 99% ee), which has been used as the asymmetric key step in the synthesis of trichostatin A [76], In a similar way, using propionaldehyde (Sa, R =Me in Scheme 4.12) and an excess isobutyraldehyde (4 equiv, R =j-Pr) catalyzed by proline (10 mol%), product anti-29 (98% de and 99% ee) was obtained. Subsequent diastereoselective Mukaiyama aldol reaction followed by lactonization gave prelactone B [77]. The synthesis of (-)-enterolactone has been achieved by a cross-aldol reaction between methyl 4-oxobutyrate and 3-methoxybenzaldehyde catalyzed by proline (20 mol%) as a key step [78],... 

Lewis acid for this last Mukaiyama-aldol reaction afforded the diastereomeric mannose derivative with similarresults. Thehomo-aldolreaction depicted in Schetne4.13 showed a positive non-linear effect [83], which was attributed to the formation of the inactive imidazolidinone derivative of both enantiomers of proline with anti-21 (R=Bn) in the different reaction rates, resulting in a kinetic resolution of proline by the final product. The cross-aldol reaction between a-silyloxyacetaldehydes of type 30 with propanal has been used in the synthesis of one key fragment for the preparation of (H-)-spongistatin 1 [84]. 

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 introduction of a halogen at the a-position in an acceptor aldehyde influences the course of the cross-aldol reaction by imposing steric constraints and by activating the carbonyl group towards electrophilic attack [144]. As a result, a-haloaldehyde preferentially reacts as an acceptor in L-proline-catalyzed reactions, affording aldols with rzwft-stereoselectivity. 

Syn-Aldols. The synthesis of sy/j-aldols via the cross-aldol reaction is not an easy task since the sy -selectivity requires the reaction to proceed through the (Z)-enamine (Scheme 3.24). All proline-based catalysts tend to give ( )-enamines as... 

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