Direct catalytic asymmetric aldol reaction

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. 

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). 

C. DIRECT CATALYTIC ASYMMETRIC ALDOL REACTION OF AN ACETYLENE KETONE... 

Table 2. Direct Catalytic Asymmetric Aldol Reaction...

A highly diastereo- and enantioselective synthesis of trans-l,2-disubstituted cyclohexanes by means of the first direct catalytic asymmetric 6-enolexo aldoliza-tion has been developed very recently by the List group [120] (previously only 6-enolendo aldolizations had been reported). Dialdehydes were usually used as starting materials and proline was a very effident catalyst for this reaction also. A selected example of this 6-enolexo-aldolization is given in Scheme 6.50 in this... 

Other reviews deal with aldol additions of group 1 and 2 enolates,103 direct catalytic asymmetric aldol reactions catalysed by chiral metal complexes,104 the exploitation of multi-point recognition in catalytic asymmetric aldols,105 and recent progress in asymmetric organocatalysis of aldol, Mannich, Michael, and other reactions.106... 

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]. 

Figure 1. Some outstanding metal-ligand complexes of utility in the direct catalytic asymmetric aldol addition reaction.

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],... 

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 design for a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones with bifunctional catalysts is shown in Figure 36. A Brpnsted basic functionality (OM) in the heterobimetallic asymmetric catalyst (I) could deprotonate the a-proton of a ketone to generate the metal enolate (II), while at the same time a Lewis acidic functionality (LA) could activate an aldehyde to give (III), which would then react with the metal enolate (in a chelation-controlled fashion) in an asymmetric environment to afford a P-keto metal alkoxide (IV). 

Benito Alcaide, Pedro Almendros The Direct Catalytic Asymmetric Cross-Aldol Reaction of Aldehydes, Angew. Chem. 115(8), 884-886 (2003), Angew. Chem. Int. Ed. 42(8), 858-860 (2003)... 

Bpgevig A, Kumaragurubaran N, Jprgensen KA (2002a) Direct catalytic asymmetric aldol reactions of aldehydes. Chem Commun (Camb) Mar 21 620-621... 

Yamada YM, YoshikawaN, SasaiH, Shibasaki M (1997) Direct catalytic asymmetric aldol reactions of aldehydes with unmodified ketones. Angew Chem Int Ed Engl 36 1871-1873... 

An intramolecular diastereoselective Refor-matsky-type aldol approach was demonstrated by Taylor et al. [47] with an Sm(II)-mediated cy-clization of the chiral bromoacetate 60, resulting in lactone 61, also an intermediate in the synthesis of Schinzer s building block 7. The alcohol oxidation state at C5 in 61 avoided retro-reaction and at the same time was used for induction, with the absolute stereochemistry originating from enzymatic resolution (Scheme II). Direct re.solution of racemic C3 alcohol was also tried with an esterase adapted by directed evolution [48]. In other, somewhat more lengthy routes to CI-C6 building blocks, Shibasaki et al. used a catalytic asymmetric aldol reaction with heterobimetallic asymmetric catalysts [49], and Kalesse et al. used a Sharpless asymmetric epoxidation [50]. 

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