Enantioselective reactions aldol reaction

After the initial two reports of Rh- and Co-catalyzed reductive aldol couplings, further studies did not appear in the literature until the late 1990s. Beyond 1998, several stereoselective and enantioselective reductive aldol reactions were developed, which are catalyzed by a remarkably diverse range of metal complexes, including those based upon Pd, Cu, Ir, and In. In this chapter, transition metal-catalyzed aldol, Michael, and Mannich reactions that proceed via transition metal hydride-promoted conjugate reduction are reviewed. 

Riant et al. in 2006 reported an enantioselective reductive aldol reaction of acetophenone and methyl acrylate mediated by PhSiH3 (140 mol %) and catalyzed by a complex generated in situ from [CuF(Ph3P)3]2MeOH (1-3 mol %) and a chiral bisphosphine (1-3 mol %) [57]. According to Mori s... 

The enantioselective nitro-aldol reaction catalyzed by (R)-LLB is effectively applied to the synthesis of three kinds of optically active (3-receptor blocking drugs (5)-metoprolol,123a (S)-propanolol,123b and ( -pindolol1230 (Scheme 3.17). 

Enantioselective nitro-aldol reaction (see Section 3.3) or Michael reaction (see Section 4.4) followed by radical denitration is useful as an alternative indirect method of enantioselective 1,2- or 1,4-addition of alkyl anions (see Eq. 7.7087 and Eq. 7.7188). 

A nondirect enantioselective cross-aldol reaction between two discrete aldehyde components has been achieved see Denmark, S. E. Ghosh, S. K. Angew. Chem. Int. Ed. 2001, 40, 4759 762. 

The phase-transfer-catalyzed enantioselective direct aldol reactions of glycine donor with aldehyde acceptors provide an ideal method for the simultaneous construction of the primary structure and stereochemical integrity of P-hydroxy-a-amino acids, which are extremely important chiral units. In the first report from the Miller s group, N-benzyldnchorudinium chloride (4a) was employed as a catalyst for the reaction of 1 with heptanal, and the corresponding aldol product 21 was obtained in 74% yield, though the diastereo- and enantioselectivities were unfortunately not satisfactory (Scheme 2.18) [40]. 

Maruoka and coworkers recently developed an efficient, highly diastereo- and enantioselective direct aldol reaction of glycine Schiff base 2 with a wide range of aliphatic aldehydes under mild phase-transfer conditions employing N-spiro chiral quaternary ammonium salt li as a key catalyst, as shown in Table 5.12 [41a]. 

Three types of one-pot catalytic enantioselective reductive aldol reactions of ketones have been described,158 giving fair to excellent ees with a BINAP auxiliary. (g)... 

The Denmark phosphoramide organocatalyst has recently been applied in the first catalytic, diastereoselective, and enantioselective crossed-aldol reaction of aldehydes [86]. It is worthy of note that such controlled stereoselective selfcondensation of aldehydes has previously found no general application, because of many side-reactions, e.g. polyaldolization, and dehydration of the products. Several previously developed solutions have limitations. In a first step the Denmark group developed a procedure for generation of stereodefined trichlorosilyl enolates of aldehydes with high geometrical purity. Use of these geometrically pure (Z) and... 

Guillena G, Najera C et al (2007) Enantioselective direct aldol reaction the blossoming of modem organocatalysis. Tetrahedron Asymmetry 18 2249-2293... 

Catalytic, enantioselective, vinylogous aldol reactions have been reviewed, from the first report in 1994 to date.137 Many examples from natural products are given, and the remaining problems - especially the need to push beyond dienolates derived from esters - are highlighted. 

Trost et al. have discovered a novel design of dinuclear zinc catalyst that can catalyze diastereoselective and enantioselective direct aldol reactions [17]. The dinuclear zinc catalysts 5a-7a are generated in situ by exposing the appropriate ligands 5-7, respectively, to 2equiv. diethylzinc in THF (Scheme 3). 

To make the DERA-catalyzed process commercially attractive, improvements were required in catalyst load, reaction time, and volumetric productivity. We undertook an enzyme discovery program, using a combination of activity- and sequence-based screening, and discovered 15 DERAs that are active in the previously mentioned process. Several of these enzymes had improved catalyst load relative to the benchmark DERA from E. coli. In the first step of our process, our new DERA enzymes catalyze the enantioselective tandem aldol reaction of two equivalents of acetaldehyde with one equivalent of chloroacetaldehyde (Scheme 20.6). Thus, in 1 step a 6-carbon lactol with two stereogenic centers is formed from achiral 2-carbon starting materials. In the second step, the lactol is oxidized to the corresponding lactone 7 with sodium hypochlorite in acetic acid, which is crystallized to an exceptionally high level of purity (99.9% ee, 99.8% de). 

The phase-transfer-catalyzed enantioselective direct aldol reactions of a glycine donor with aldehyde acceptors provide an ideal method for the simultaneous con-... 

Masamune et al. applied the newly developed enantioselective anti-aldol reaction to the syntheses of two key fragments of miyakolide 5, a bryostatin-like marine metabolite5 (Scheme 2.2e). The readily synthesized aldehyde 8 was treated with chiral enol borinate generated from the ester 3 to give the aldol 9 in 85%... 

Northrup AB, MacMillan DWC (2002a) The first direct and enantioselective cross-aldol reaction of aldehydes. J Am Chem Soc 124 6798-6799 Northrup AB, MacMillan DWC (2002b) First general enantioselective catalytic Diels-Alder reaction with simple alpha,beta-unsaturated ketones. J Am Chem Soc 124 2458-2460... 

Enantioselective cross aldol reactions. A 3-acylthiazolidine-2-thione can be used as an equivalent of an aldehyde or carboxylic arid in cross aldol reactions to provide p-hydroxy aldehydes or carboxylic acids. The tin enolates formed from Sn(OTf), react with aromatic and aliphatic aldehydes with high svn-selectivity (equation I),... 

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). 

Aldol Addition. A catalyst generated upon treatment of Cu(OTf)2 with the (5,5)-r-Bu-box ligand has been shown to be an effective Lewis acid for the enantioselective Mukaiyama aldol reaction. The addition of substituted and unsubstituted enolsilanes at -78 °C in the presence of 5 mol % catalyst was reported to be very general for various nucleophiles, including silyl dienolates and enol silanes prepared from butyrolactone as well as acetate and propionate esters. 

As above (eq 1), a major drawback of this reagent is the lack of a readily available enantiomer. There are many alternative methods for the enantioselective propionate aldol reaction. The most versatile chirally modified propionate enolates or equivalents are N-propionyl-2-oxazolidinones, a-siloxy ketones, boron enolates with chiral ligands, as well as tin enolates. Especially rewarding are new chiral Lewis acids for the asymmetric Mukaiyama reaction of 0-silyl ketene acetals. Most of these reactions afford s yw-aldols good methods for the anri-isomers have only become available recently. ... 

Enantioselective Mukaiyama Aldol Reaction Promoted by Chiral Lanthanide Complexes... 

Catalyzed enantioselective Mukaiyama-aldol reactions have been developed extensively [101] and chiral polymer-supported Lewis acids are the catalysts of choice. Polymer-supported chiral A(-sulfonyloxazaborohdinones 86 and 87, prepared by copolymerization of styrene, divinylbenzene, and chiral monomers derived from L-valine and L-glutamic acid, respectively, have been used for aldol reactions [102]. The rates of reaction using the polymeric catalysts were slow and enantioselectivity was lower than was obtained by use of the low-molecular-weight counterpart (88). The best ee obtained by use of the polymeric catalyst was 90 % ee with 28 % isolated yield in the asymmetric aldol reaction of benzaldehyde with 89 (Eq. 27). 

The first catalytic, diastereoselective and enantioselective cross-aldol reactions of aldehydes have also been documented. Geometrically defined trichlorosilyl enolate derivatives of aldehydes undergo diastereoselective addition to a wide range of aldehyde acceptors with good enantioselectivity. The use of chiral Lewis base (138) was critical for achieving useful enantioselectivity. ... 

The enamine geometry 32 is cmcial for the stereocontrol in organocatalytic aldehyde-aldehyde couplings amines of type 31 are convenient catalysts for enantioselective enamine-aldol reactions. Examples are shown in Scheme 24 [126,131,132,133,134,135]. 

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