Hydroxyacetone aldol reactions

FSA makes it possible to use dihydroxyacetone or hydroxyacetone as a donor compound for aldolization reactions this opens up the field for novel carbohydrate compounds such as 1-deoxysugars which otherwise can be obtained by DXS through a different reaction. 

The reactions also led to high regioselectivity (> 20 1). For alkylated aldehydes unbranched in the a-position, however, low diastereoselectivity (d.r. 1.7 1) and yields of 38% were obtained, although enantioselectivity remained excellent (> 97% ee). Use of aromatic substrates resulted in a d.r. of 1 1 to 1.5 1 only, and the enantioselectivity was in the range 67 to 80% ee [93]. Some representative examples of the L-proline-catalyzed aldol reaction with hydroxyacetone are given in Scheme 6.35. 

Mechanism and transition states The basic principles of the proline-catalyzed direct aldol reaction are summarized in Section 6.2.1.1 [93, 94a], The preferred diastereo- and enantioselectivity were explained in terms of the potential transition states for the aldol reaction using hydroxyacetone shown in Scheme 6.38 [93], Thus, re-facial attack of the aldehyde at the si face of hydroxyacetone leads to the... 

The regioselectivities of the aldol reactions of hydroxyacetone were reversed from those of the proline-catalyzed reactions when small peptide catalyst 6 or 7 containing (S)-proline at the N-terminal was used, as shown in Table 2.5 [20]. 

Table 2.3 (S)-Proline-catalyzed aldol reactions of hydroxyacetone [6, 7].

Table 2.5 Peptide 6- and 7-catalyzed aldol reaction of hydroxyacetone [20].

Glyoxal can be formed by oxidation of glycolaldehyde (e.g., in Scheme 2.5), but it can also be formed by autoxidation of unsaturated fats and by enzymic degradation of serine.60 2-Oxopropanal can be obtained by retroaldolisation of 1- and 3-deoxyglucosone or by hydrolysis of diacetylformoin (see Scheme 2.5). Butanedione can also be derived from diacetylformoin, but by reduction, dehydration, and hydrolysis (see Scheme 2.5). 2,3-Pentanedione can be formed from butanedione by aldol reaction with formaldehyde, dehydration, and reduction or by aldol condensation of hydroxyacetone and acetaldehyde, followed by dehydration. 

In addition to broad-scope substrate specificity, 38C2 exhibits high enantioselectivity for the aldol reaction. Although this high degree of enantioselectivity has been observed for antibody-catalyzed ester hydrolysis reactions, it is certainly not a feature common to all such catalysts (Janda et al., 1989 Lo et al., 1997 Pollack et al., 1989 Tanaka et al., 1996 Wade and Scanlan, 1996). Furthermore, the rules for the enantioselectivity for 38C2-catalyzed aldol reactions are both simple and general (Hoffmann et al., 1998). For most ketone donors, attack occurs on the si side of the acceptor. However, when a ketone with an a-hydroxy substituent (such as hydroxyacetone) acts as donor, attack occurs on the reside (Scheme 5). 

Mayoralas et al. [70] reported the aldol reaction of hydroxyacetone with different aldehydes catalyzed by immobilized L-proline on a mesoporous support. Heterogenized L-proline on MCM-41 showed higher enantioselectivity (80% ee) than its homogeneous counterpart (75% ee) in the aldol reaction of benzaldehyde with hydroxyacetone in dimethylsulfoxide (DMSO) solvent with the assistance of microwave heating. 

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. 

There is something different here. The absolute stereochemistry at the OH group (the one that comes from hydroxyacetone) is the same in 99 as it was in 97 but the relative stereochemistry is different anti in 99 but syn in 97. The electrophile (ketone in 97 or imine in 99) must approach the proline enamine in different ways. List s suggestion is that the large A-aryl group prefers to keep away from the rest of the molecule in the transition state 100 leading to 99 but that the side chain on the aldehyde is more important in the transition state 101 leading to 97. The dotted arrows in 100 and 101 show where that clash would come and the black dots mark the atoms that join to form the new bond. There is a review of the catalytic asymmetric aldol reaction that includes material from other chapters.22... 

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. 

The dipeptide-derived 64 is a suitable aldol reaction catalyst for handling haloacetones and a-hydroxyacetone, and the the water-compatibility of the analogous 65 underscores its utility in the reaction involving a,a -dihydiDxyacetone. ... 

The diastereoselectivity of the Baylis-Hillman reaction was investigated by attaching chiral auxiliaries to a,-unsaturated ketones [216]. The use of the 4-isopropyloxazoladinone chiral auxiliary in [EMIM][OTf] gave rise to very low di-astereomer ratios (45 55) (Scheme 5.2-88). The authors also describe a proline -catalyzed aldol reaction of acetone, butanone, hydroxyacetone and chloroacetone with a chiral imine and obtain up to 9 1 diastereomer ratios. 

Based on the observations obtained for i-proline-based dipeptides Gong and coworkers were the first to report an efficient catalytic protocol for the asymmetric direct aldol reaction of aldehydes with hydroxyacetone yielding a series of 1,4-diols as major product (1,2-diols just as minor product) in aqueous media providing good yields and excellent enantioselectivities. " ... 

N-primary-amine-terminal p-turn tetrapeptides were designed and applied by Da and coworkers for the asymmetric aldol reaction. The con-formationally restricted p-turn, due to the u-Pro-Gly-unit, was indicated by CD and NOESY spectra, contributes to the high enantioselectivity in the aldol reaction of aldehydes with acetone in methanol, assisted by benzoic acid as additive. When employing hydroxyacetone instead of acetone, (5 )-BINOL was used as additive. In every case, tetrapeptide 48 was the best performing catalyst, giving the desired products in enantiomeric excesses of more than 99% (Scheme 13.28a). ... 

The aldol reaction between functionalized ketones, such as hydroxyacetone (8a, 29.2 equiv.) with high electrophilic aldehydes, was possible using different A -terminal proline peptide derivatives (10-20 mol%) in mixtures of THF water at 0°C. Among ten screened different di-, tri-, tetra-, penta- and hexapeptides, catalysts 120a, b (Fig. 4.20) with lipophilic phenylalanine residues gave the best performance, providing mainly regioisomers /xo-10 (Scheme 4.3, R =H) in 82 and 76% yield, and 82 and 87% ee, respectively [207]. 

The direct aldol reaction of hydroxyacetone (HA, 39) with an aldehyde leads to either a 1,2-diol (branched) or a 1,4-diol (linear), with the latter being the disfavored... 

List demonstrated that the L-proline-catalyzed aldol reaction of hydroxyacetone (39) with aldehydes furnished a t/-aldols in a regio- and stereoselective manner but with modest yields [65]. Diastereoselectivity was high for aliphatic, branched aldehydes and low for aromatic ones [14]. The use of TBDMS-protected hydroxyacetone as a donor led to an increase in yield and diastereoselectivity and a decrease in enantioselectivity [66]. Under solvent-free conditions, (5)-BINAM 13a generates aldols with high regio- and diastereocontrol but with hardly any enantiomeric excess [34c]. The enantioselectivity increased to a satisfactory level after... 

SCHEME 3.13. The aldol reaction of 0-Bn-hydroxyacetone (51) with 4-nitrobenzaldehyde (2a) [10a],... 

Given the number of reports describing aldol reactions with hydroxyacetone (39) as a donor, little work has been done with other a-heterosubstituted acetones. Chloroacetone seems to be a problematic nucleophile While the regio- and stereoselectivity of its reactions are satisfactory, the yields of a ti-aldols are low or moderate, regardless of the aldehyde used [68] a-Fluoroaldols such as anti-46 can be effectively synthesized using prolinol as a catalyst [69]. 

The first iyn-selective organocatalytic aldol reaction was disclosed by Barbas III et al. [98]. Based on previous studies on antibody-mediated aldol reactions, they envisaged that the aldol reaction of unmodified hydroxyacetone with an aldehyde should proceed through the (Z)-enamine intermediate in the transition state and thus produce a yn-aldol. Indeed, the reaction catalyzed by O-tBu-L-thyrosine proceeds with high yn-stereoselectivity. Subsequently, the catalyst loading was decreased to 5 mol% by replacing the tyrosine derivative with the O-acylated cysteine (80) [99,90e]. Importantly, donors and acceptors can be used in stoichiometric amounts (Chart 3.10). 

It is believed that the hydroxyl group present in hydroxyacetone (39) stabilizes the (Z)-enamine via hydrogen bond formation, and thus the use of O-protected derivatives as donors in the direct aldol reaction required, at best, tuning the reaction conditions. Only a few catalysts were applied to the reaction of O-Bn-hydroxya-cetone (51) with various aldehydes [103, 58]. Luo and Cheng s catalyst 38 also... 

SCHEME 3.18. Aldol reaction of hydroxyacetone (39) with aliphatic aldehydes. 

The mechanism of enamine catalysis has been established the enamine is the active form of nucleophile. Other modes of activation are less developed and are limited to a certain group of donors and acceptors. Quinidine was found to catalyze the reaction of hydroxyacetone with aldehydes to yield the desired 5y -aldols with moderate diastereoselectivity and low enantioselectivity [169]. This represents the first example of a tertiary amine catalyzing the direct aldol reaction. Even (3, y-unsaturated a-keto ester 154 was successfidly coupled with protected hydroxyacetone 51 in the presence of 20 mol% of 9-amino-9-deoxy-cpi-cinchonine 155 and a small amount of TEA (Scheme 3.27). 

Dibenz[c,e]azepine salt (57) - derived fromfranj-l,2-diaminocyclohexane -promotes highly diastereo- and enantio-selective crossed-aldols of cyclohexanone and aromatic aldehydes. Chiral l-amino-2-sulfonamidocyclohexanes catalyse syn-aldols of benzaldehydes and hydroxyacetone. A chiral l°-3° diamine promotes 0 aldol reactions of acetone and -unsaturated a-ketoesters in yields up to 99% and (g) ees up to 96%. ... 

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