Enantioselective Strecker Synthesis

Both the ureas and thioureas are highly suitable organocatalysts for the asymmetric Strecker synthesis. For example, the thiourea function was replaced by an urea function (note the opposite configurations). The organocatalysts thus obtained showed similar activity and slightly higher enantioselec-tivities with N-allyl benzaldimine (Scheme 39,74% yield with 95% ee for Ri = Bn and R2 = H). Once again, better enantioselectivity (up to 99% ee) was at-... 

Davis and Fanelli applied the sulfinimine mediated asymmetric Strecker synthesis to the enantioselective synthesis of the racemization-prone (/ )-(4-methoxy-3,5-dihydroxyphenyl)glycine (134) from 133.81 This amino acid is the central amino acid of the clinically important glycopeptide antibiotic vancomycin as well as related antibiotics. 

DSM developed a slightly different approach towards enantiopure amino acids. Instead of performing the Strecker synthesis with a complete hydrolysis of the nitrile to the acid it is stopped at the amide stage. Then a stereoselective amino acid amidase from Pseudomonas putida is employed for the enantioselective second hydrolysis step [83], yielding enantiopure amino acids [34, 77, 78]. Although the reaction is a kinetic resolution and thus the yields are never higher than 50% this approach is overall more efficient. No acylation step is necessary and the atom efficiency is thus much higher. A drawback is that the racemisation has to be performed via the Schiff s base of the D-amide (Scheme 6.23). 

Lipton and co-workers employed the cyclic dipeptide 13 (Figure 10.13) bearing a guanidinium moiety as a catalyst in the Strecker synthesis in 1996. Corresponding a-aminonitriles were obtained with high enantioselectivities (Equation 10.27). 

Strecker synthesis. The 3,3 -disubstituted BINOL 1 is used in promoting addition of Me3SiCN to A -tosylketimines. Adding one equivalent of 1-adamantanol enhances reaction rates and enantioselectivity. ... 

Cyanohydrination and Strecker synthesis. A high enantioselectivity in the anohydrination (with MCjSiCN as the cyanide source) is achieved by using (i-PrO)4Ti as... 

The a-amino acids prepared by the synthetic methods just described are racemic unless a resolution step is included, enantiomerically enriched reactants are used, or the reaction is modified so as to become enantioselective. Considerable progress has been made in the last of these methods, allowing chemists to prepare not only L-amino acids, but also their much rarer D-enantiomers. We have already seen one example of this approach in the synthesis of the anti-parkinsonism drug L-dopa by enantioselective hydrogenation (see Section 14.14). A variation of the Strecker synthesis using a chiral catalyst has recently been developed that gives a-amino acids with greater than 99% enantioselectivity. 

Racemic mixtures of amino acids can be prepared in the laboratory via a-haloacids, via the amidomalonate nthesis, or via the Strecker synthesis. Optically active amino acids are obtained either via resolution of a racemic mixture or via enantioselective synthesis. 

There has been striking success in adapting the Strecker synthesis to the preparation of a-amino acids with greater than 99% enantioselectivity. The numerous methods that have been developed employ specialized chiral reagents or catalysts and feature enantiose-lective generation of a chirality center by nucleophilic addition to an imine. 

A new enantioselective Strecker synthesis of a-aminonitriles and a-amino-acids reacts A-benzhydrylimines with hydrogen cyanide in the presence of achiral guanidine catalyst the mechanistic basis of the enantioselectivity is analysed." ... 

Lipton et al employed a cyclic dipeptide bearing guanidine moiety (20) as a catalyst for the Strecker synthesis [120, 121]. Corresponding a-amino nitrile was obtained highly enantioselectively (Scheme 2.61). 

Enantioselective synthesis of amino acids may be achieved by modification of the Strecker synthesis with a chiral additive or hydrogenation of dehydroamino acid derivative (prepared via an aziactone synthesis) in the presence of a metal complex of a chiral phosphine. 

Shibasaki et al. developed a polymer-supported bifunctional catalyst (33) in which aluminum was complexed to a chiral binaphtyl derivative containing also two Lewis basic phosphine oxide-functionahties. The binaphtyl unit was attached via a non-coordinating alkenyl Hnker to the Janda Jel-polymer, a polystyrene resin containing flexible tetrahydrofuran-derived cross-Hnkers and showing better swelling properties than Merifield resins (Scheme 4.19) [105]. Catalyst (33) was employed in the enantioselective Strecker-type synthesis of imines with TMSCN. 

Pll The asymmetric synthesis of a-amino acids and derivatives is an important topic as a result of their extensive use in pharmaceuticals and agrochemicals and as chiral ligands. Many highly enantioselective approaches have been reported. Industrial production of a-amino acids via the Strecker reaction is historically one of the most versatile methods to obtain these compounds in a cost-effective manner, making use of inexpensive and easily accessible starting materials. (From Boesten et al., 2001)... 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

An enantioselective Strecker reaction involving Brpnsted acid catalysis uses a BINOL-phosphoric acid, which affords ees up to 93% in hydrocyanations of aromatic aldimines in toluene at -40 °C.67 The asymmetric induction processes in the stereoselective synthesis of both optically active cis- and trans-l-amino-2-hydroxycyclohexane-l -carboxylic acids via a Strecker reaction have been investigated.68 A 2-pyridylsulfonyl group has been used as a novel stereocontroller in a Strecker-type process ees up to 94% are suggested to arise from the ability of a chiral Lewis acid to coordinate to one of the sulfonyl (g)... 

Kobayashi S, Ishitani H (2000) Novel binuclear chiral zirconium catalysts used in enantioselective strecker reactions. Chirality 12 540-543 Kobayashi S, Ishitani H, Nagayama S (1995) Synthesis 1995 1195 Kobayashi S, Ishitani H, Ueno M (1998) J Am Chem Soc 120 431 Kobayashi S, Kobayashi J, Ishitani H, Ueno M (2002) Catalytic enantioselective addition of propionate units to imines an efficient synthesis of anti-alpha-methyl-beta-amino acid derivatives. Chem Eur J 8 4185 1190 Krohn K, Kirst HA, Maag H (eds) (1993) Antibiotics and antiviral compounds. VCH, Weinheim... 

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