Aldol reaction, direct catalytic

Onium ion-tagged proline catalysts 7 and 8 in [bmini][Tf2N] proved to be an excellent catalytic system for the direct asymmetric aldol reaction. The catalytic protocol developed makes use of use of a 6-fold lower amount of catalyst with respect to the proceeding reports based on the use of proline 12 and affords greater chemical yields and higher enantioselectivity. In particular, 8 in [bmim][Tf2N] gave better results compared both to the use of proline in the same IL and of 7 in DMSO. ... 

The values of x = 0.5 and = 1 for the kinetic orders in acetone [1] and aldehyde [2] are not trae kinetic orders for this reaction. Rather, these values represent the power-law compromise for a catalytic reaction with a more complex catalytic rate law that corresponds to the proposed steady-state catalytic cycle shown in Scheme 50.3. In the generally accepted mechanism for the intermolecular direct aldol reaction, proline reacts with the ketone substrate to form an enamine, which then attacks the aldehyde substrate." A reaction exhibiting saturation kinetics in [1] and rate-limiting addition of [2] can show apparent power law kinetics with both x and y exhibiting orders between zero and one. 

The aldol reaction can be applied to dicarbonyl compounds in which the two groups are favorably disposed for intramolecular reaction. Kinetic studies on cyclization of 5-oxohexanal, 2,5-hexanedione, and 2,6-heptanedione indicate that formation of five-membered rings is thermodynamically somewhat more favorable than formation of six-membered rings, but that the latter is several thousand times faster.170 A catalytic amount of acid or base is frequently satisfactory for formation of five- and six-membered rings, but with more complex structures, the techniques required for directed aldol condensations are used. 

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... 

Montmorillonite K10 was also used for aldol the reaction in water.280 Hydrates of aldehydes such as glyoxylic acid can be used directly. Thermal treatment of K10 increased the catalytic activity. The catalytic activity is attributed to the structural features of K10 and its inherent Bronsted acidity. The aldol reactions of more reactive ketene silyl acetals with reactive aldehydes proceed smoothly in water to afford the corresponding aldol products in good yields (Eq. 8.104).281... 

Sc(OTf)3 is effective in aldol reactions in aqueous media (water-THF, Scheme 15).49 Direct treatment of aqueous solutions of water-soluble formaldehyde and chloroacetaldehyde with silyl enol ethers affords the corresponding aldol adducts in good yields. Water-sensitive silicon enolates can be used in aqueous solutions in the presence of a catalytic amount of Sc(OTf)3. 

Recently, novel bifunctionalized zinc catalysts have been developed (compounds (N) and (P), Scheme 55). They have both Lewis-acid and Lewis-base centers in their complexes, and show remarkable catalytic activity in direct aldol reactions.233-236 A Zn11 chiral diamine complex effectively catalyzes Mannich-type reactions of acylhydrazones in aqueous media to afford the corresponding adducts in high yields and selectivities (Scheme 56).237 This is the first example of catalytic asymmetric Mannich-type reactions in aqueous media, and it is remarkable that this chiral Zn11 complex is stable in aqueous media. 

Table 3. Direct catalytic asymmetric aldol reactions promoted by (R)-LLB (20 mol%).

LLB, KHMDS (0.9 equiv to LLB) and H20 (1 equiv to LLB), which presumably forms a heteropolymetallic complex (LLB-ID, was found to be a superior catalyst for the direct catalytic asymmetric aldol reaction giving 49 in 89 % yield and 79 % ee (using 8 mol% of LLB). We employed this method to generate KOH in situ because of its insolubility in THE The use of KO-t-Bu instead of KHMDS gave a similar result, indicating that HMDS dose not play a key role. Interestingly, further addition of H20 (1 equiv with respect to LLB) resulted in the formation of 49 in 83 % yield and higher ee. The powder obtained from the cata-... 

Scheme 6. Possible mechanism of direct catalytic asymmetric aldol reaction.

Y. M. A Yamada, N. Yoshikawa, H. Sasai, M. Shibasaki, Direct Catalytic Asymmetric Aldol Reactions of Aldehydes and Unmodified Ketones, Angew. Chem. Int. Ed EngL 1997, 36,1871-1873. 

Trost s group reported direct catalytic enantioselective aldol reaction of unmodified ketones using dinuclear Zn complex 21 [Eq. (13.10)]. This reaction is noteworthy because products from linear aliphatic aldehydes were also obtained in reasonable chemical yields and enantioselectivity, in addition to secondary and tertiary alkyl-substituted aldehydes. Primary alkyl-substituted aldehydes are normally problematic substrates for direct aldol reaction because self-aldol condensation of the aldehydes complicates the reaction. Bifunctional Zn catalysis 22 was proposed, in which one Zn atom acts as a Lewis acid to activate an aldehyde and the other Zn-alkoxide acts as a Bronsted base to generate a Zn-enolate. The... 

Notz W, Tanaka F, Barbas CF (2004) Enamine-based organocatalysis with proline and diamines the development of direct catalytic asymmetric aldol, Mannich, Michael, and Diels-Alder reactions. Acc Chem Res 37(8) 580-591... 

Studies of catalytic asymmetric Mukaiyama aldol reactions were initiated in the early 1990s. Until recently, however, there have been few reports of direct catalytic asymmetric aldol reactions [1]. Several groups have reported metallic and non-metallic catalysts for direct aldol reactions. In general, a metallic catalysis involves a synergistic function of the Bronsted basic and the Lewis acidic moieties in the catalyst (Scheme 2). The Bronsted basic moiety abstracts an a-pro-ton of the ketone to generate an enolate (6), and the Lewis acidic moiety activates the aldehyde (3). 

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... 

The asymmetric catalytic aldol reaction of a silyl enol ether can be performed in a double and two-directional fashion to give the 1 2 adduct in the silyl enol ether form with >99% ee and 99% de in 77% isolated yield (Scheme 8C.25) [59]. The present catalytic asymmetric aldol reaction is characterized by a kinetic amplification phenomenon of the product chirality, going from the one-directional aldol intermediate to the two-directional product (Figure 8C.8). Further transformation of the pseudo C2 symmetric product, while still being protected as the silyl enol ether, leads to a potent analog of an HIV protease inhibitor. 

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