Enantioselectivity Strecker amino acid synthesis

Strecker amino acid synthesis starting with the cyclopropanone hemiacetal provides a enantioselective route to a cyclopropane amino acid (eq 16). ... 

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)... 

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. 

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... 

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). 

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. 

One of the most interesting developments in the field of stereoselective synthesis of amino acids is unquestionably the enantioselective Strecker reaction. Being a fairly recent discovery, the reaction has not yet been advanced to the industrial... 

J. Martens, ChemCatChem 2010, 2,379-381. Enantioselective organocatalytic Strecker reactions in the synthesis of a-amino acids. 

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." ... 

In addition to the studies mentioned above, chiral alcohols have been used as H-bonding catalysts in a vinylogous aldol reaction of Chan s diene with aldehydes [73], in an enantioselective Strecker reaction [74], and in the enantioselective addition of aza-enamines to imines [75]. Taddol has also found use as a memory of chirality enhancer in the stereoselective synthesis of (i-lactams from amino acid derivatives [76, 77]. 

For better enantiopurities with aliphatic substrates, structural elements crucial for a high stereoinduction were revised by library screening on a solid phase. It was found that the presence of a bulky substituent at both the amino acid and at the 3-position of the salicylimine moiety were key elements responsible for high enantioselectivity. By employing of a pivaloyl substituent at the 5-position of the salicylaldehyde moiety, 24 was found to be a superior catalyst for the Strecker reaction of aliphatic imines 23 (Scheme 30.5) [16]. By adaptation of solid-supported 24 to homogenous conditions, the thiourea was replaced with a urea moiety because of the more convenient synthesis. By applying the so-synthesized catalyst 25, Strecker adducts 26 were obtained in high ee s and yields. Transformation of 3,4-dihydroisoquinoline, a fixed (Z)-imine, into the Strecker adduct (in 88% yield ... 

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. 

The eponymous reaction reported in 1850 by Adolph Strecker is the oldest known method for the synthesis of a-amino acids [100]. It involves condensation of an aldehyde, ammonia, and hydrogen cyanide, followed by hydrolysis of the intermediate a-aminonitrile 130 (Scheme 10.20). To date it constitutes one of the most direct and convenient methods for the preparation of racemic a-amino acids. In parallel with the development of various other stereoselctive methods discussed above, there have been intense research efforts directed towards the identification of enantioselective variants of the Strecker reaction [19, 21, 22, 25, 28]. 

Jacobsen has documented the preparation of a library of peptide-derived chiral thioureas in the context of a combinatorial strategy for the generation of catalysts for asymmetric synthesis [108]. The modular natures of these structures, incorporating amino acids, thioureas, diamines, and salicyl aldehydes, make them particularly well suited for facile catalyst optimization [109], With support from ab initio calculations, an optimal catalyst 151 was identified that displays impressively wide substrate scope together with excellent enantioselectivity in enantioselective Strecker reactions (> 90% ee. Equation 22) [110], For example, asymmetric addition of HCN to imine 150 mediated by 1 mol% of thiourea 151 affords amino nitrile 152 in 97% ee. 

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