Aldol direct asymmetric

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

Direct asymmetric aldol reactions, that is between aldehydes and unmodified ketones has been accomplished using a lanthanum trilithium tri(binaphth-oxide) complex1 281. 

The next task was to form the C2-C3 aldol bond stereoselectively. However, asymmetric coupling of acetate derivatives to aldehydes is often accompanied by poor / -induction [89]. Moreover, the C3-C4 bond is particularly sensitive to retro-aldol reaction, especially under basic conditions. In the natural products, this was observed to be the main decomposition reaction. The first total syntheses of epothilones circumvented this problem by constructing this part of the molecule in an indirect manner, e.g., by using reduced forms at Cl or C5. We decided to employ our chromium-Reformatsky methodology, which avoids these problems and allows the direct use of reagents in the correct oxidation state. The non-basic reaction conditions, the intermediacy of a chromium(III) aldolate that is resistant to retro-aldol reaction, and the potential of a direct asymmetric carboxymethyl ( acetate ) transfer favor the use of this method [90]. 

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

The formation of aldehyde enolates is complicated by the disposition of aldehydes to undergo aldol condensation. Therefore, there are very few examples of direct asymmetric alkylations of aldehydes. 

List gave the first examples of the proline-catalyzed direct asymmetric three-component Mannich reactions of ketones, aldehydes, and amines (Scheme 14) [35], This was the first organocatalytic asymmetric Mannich reaction. These reactions do not require enolate equivalents or preformed imine equivalent. Both a-substituted and a-unsubstituted aldehydes gave the corresponding p-amino ketones 40 in good to excellent yield and with enantiomeric excesses up to 91%. The aldol addition and condensation products were observed as side products in this reaction. The application of their reaction to the highly enantioselective synthesis of 1,2-amino alcohols was also presented [36]. A plausible mechanism of the proline-catalyzed three-component Mannich reaction is shown in Fig. 2. The ketone reacts with proline to give an enamine 41. In a second pre-equilib-... 

Keywords Aldol, Direct, Ketone, Asymmetric catalysis, Enantioselective reaction, Diastereo-selectivity, 1,2-Diol, Aldehyde, Enamine, Lewis acid, Bronsted base, Organocatalysis, Bimetal-... 

The direct asymmetric aldol reaction under phase-transfer conditions is a representative example of this class of phase-transfer reaction, which is known to proceed with a catalytic amount of base and to include an undesired retro-process (Scheme 1.6) [9]. Here, the onium enolate 4 reacts with aldehyde in the organic... 

Direct Asymmetric Aldol Reaction of Glycine Schiff Base... 

Table 5.12 Direct asymmetric aldol reactions of 2 with aldehydes under phase-transfer conditions.

A short review examines the current status and prospects for the direct asymmetric aldol-Tishchenko reaction, a process which allows for stereocontrol of three con- tiguous chiral centres in three-aldehyde or aldehyde-ketone-aldehyde reactant combinations.139... 

It is worth noting that, in a similar manner to enzymatic conversions with type I or II aldolases, a direct asymmetric aldol reaction was achieved when L-proline was used as catalyst. Accordingly, the use of enol derivatives of the ketone component is not necessary, i.e. ketones (acting as donors) can be used directly without previous modification [72]. So far, most asymmetric catalytic aldol reactions with... 

The role of assistance by water in the direct asymmetric aldol catalysed by amino acids has been studied in DMSO and in DMF.110... 

Structure-activity relationships have been probed in (S)-histidine-based dipeptides employed as organocatalysts for direct asymmetric aldol reactions, focusing on intramolecular cooperation between side-chain functions H-Leu-His-OH proved particularly useful.111... 

Simple dipeptides bearing a primary amino N-terminus catalyse direct asymmetric intramolecular aldol reactions in up to 99% ee.115 These simple catalysts such as L-Ala-L-Ala and L-Val-L-Phe can also promote the asymmetric formation of sugars, further suggesting a possible role in prebiotic chemistry. 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

Scheme 6. Proposed catalytic cycle for the direct asymmetric aldol addition reaction of N-propionylthiazolidinethione [13].

Shibasaki and coworkers have conducted extensive research on the use of hetero-bimetallic complexes as catalysts for asymmetric synthesis [11]. The reactions are catalyzed by heterobimetallic complexes that function as both a Lewis acid and a Bronsted base. Among these, LaLi3tris(binaphthoxide) catalyst 1 (LLB) was proven to be an effective catalyst in direct asymmetric aldol reactions (Fig. 1) [12]. On the basis of this research, Shibasaki et al. reported the first report of a direct catalytic asymmetric Mannich reaction [13],... 

Their previous screening of catalysts for of aldol reactions and Robinson annu-lations suggested the possibility that chiral amines might also be able to catalyze the Mannich reaction [30, 31]. Thus, screening of catalysts for Mannich-type reactions between N-OMP-protected aldimines and acetone revealed that chiral diamine salt 10, L-proline 11, and 5,5-dimethylthiazolidine-4-carboxylic acid (DMTC) 12 are catalysts of Mannich-type reactions affording Mannich adducts in moderate yields with 60-88 % ee. To extend the Mannich-type reactions to aliphatic imines, the DMTC 12-catalyzed reactions are performed as one-pot three-component procedures. The o-anisidine component has to be exchanged with p-anisidine for the one-pot reactions to occur. The DMTC 12-catalyzed one-pot three-component direct asymmetric Mannich reactions provide Mannich adducts in moderate yield with 50-86 % ee. 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

The six-membered transition-state is stabilized by hydrogen-bonding between the nitrogen of the imine and the carboxyl group of proline. Switching of the facial selectivity is disfavored, because of to steric repulsion between the PMP group of the imine and the pyrrolidine moiety of the enamine. This is opposite to similar direct asymmetric aldol reaction in which re-facial attack occurs [27, 30, 36]. 

Table 2.8 Direct asymmetric aldol reactions in water [14].

Table 2.9 Direct asymmetric aldol reactions with water catalyzed by 12 [15].

List B, Lerner RA, Barbas CF 3rd (2000) Proline-catalyzed direct asymmetric aldol reactions. J Am Chem Soc 122 2395-2396 List B, Pojarliev P, Martin HJ (2001) Efficient proline-catalyzed Michael additions of unmodified ketones to nitro olefins. Org Lett 3 2423-2425 List B, Pojarliev P, Biller WT, Martin HJ (2002) The proline-catalyzed direct asymmetric three-component Mannich reaction scope, optimization, and application to the highly enantioselective synthesis of 1,2-amino alcohols. J Am Chem Soc 124 827-833... 

List B, Lerner RA, Barbas CF 3rd (2000) Proline-catalyzed direct asymmetric aldol reactions. J Am Chem Soc 122 2395... 

Scheme 13. Barium-catalyzed direct asymmetric aldol reaction.

ASYMMETRIC ORGANOCATALYSIS OF ALDOL REACTIONS 409 TABLE 6.11 Effect of Catalyst on the Direct Asymmetric Aldol Reaction"... 

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