Hydrolysis Strecker amino acid synthesis

The Strecker amino acid synthesis, which involves treatment of aldehydes with ammonia and hydrogen cyanide (or equivalents) followed by hydrolysis of the intermediate a-amino nitriles to provide a-amino acids (Scheme 1), was first reported in 1850 [1], This method has been applied on an industrial scale toward the synthesis of racemic a-amino acids, but more recently interest in nonproteinogenic a-amino acids in a variety of scientific disciplines has prompted intense activity in the asymmetric syntheses of a-amino acids [2]. The catalytic asymmetric Strecker-type reaction offers one of the most direct and viable methods for the asymmetric synthesis of a-amino acid derivatives. It is the purpose of this Highlight to disclose recent developments in this emerging field of importance. 

Strecker amino acid synthesis. Synthesis of a-amino acids by simultaneous reaction of aldehydes with ammonia and hydrogen cyanide followed by hydrolysis of the resulting amino nitriles. 

When an aldehyde such as ethanal (acetaldehyde, CH3CHO, Scheme 9.68) is brought into reaction with ammonium cyanide (NH4CN) (or sodium cyanide [NaCN]/ammonium chloride [NH4CI]), the product obtained results from capture of the iminium ion intermediate by cyanide (CN ) ion. As noted in Scheme 9.68, capture can occur from either the re or si face of the aldehyde, thus creating a chiral a-aminonitrile. As we will learn (this Chapter, vide infra) acid-catalyzed hydrolysis of nitriles produces carboxylic acids so that if the nitrile is hydrolyzed to the corresponding carboxylic acid, the Strecker amino acid synthesis will have been accomplished. 

The amino acid synthesis from Strecker has been known since 1850 [25]. Stereoselective versions of this synthesis start with chiral amines, which are condensed with carbonyl compounds to form imines. Addition of hydrogen cyanide and subsequent hydrolysis of the amino nitriles yields the amino acids. When ketones are used for the condensation, a-alkylated amino acids are obtained in high yields and optical purities... 

In 1959 a new non-protein L-a-amino acid was isolated from the seeds of Acacia willardiana and later from other species of Acacia-, it proved to be l-/3-amino-/3-carboxyethyluracil (977) (59ZPC(316)164). The structure was confirmed by at least four syntheses in the next few years. The most important involves a Shaw synthesis (Section 2.13.3.1.2e) of the acetal (975) and hydrolysis to the aldyhyde (976) followed by a Strecker reaction (potassium cyanide, ammonia and ammonium chloride) to give DL-willardiine (977) after resolution, the L-isomer was identical with natural material (62JCS583). Although not unambiguous, a Principal Synthesis from the ureido acid (978) and ethyl formylacetate is the most direct route (64ZOB407). 

In the Strecker synthesis an aldehyde is converted to an a-amino acid with one more carbon atom by a two-stage procedure in which an a-fflnino nitrile is an intenne-diate. The a-fflnino nitrile is fonned by reaction of the aldehyde with ffliimonia or an fflTtmonium salt and a source of cyanide ion. Hydrolysis of the nitrile group to a carboxylic acid function completes the synthesis. 

An a-amino acid 3 can be prepared by treating aldehyde 1 with ammonia and hydrogen cyanide and a subsequent hydrolysis of the intermediate a-amino nitrile 2. This so-called Strecker synthesis - is a special case of the Mannich reaction-, it has found application for the synthesis of a-amino acids on an industrial scale. The reaction also works with ketones to yield a, a -disubstituted a-amino acids. 

The synthesis of a-amino acids by reaction of aldehydes or ketones with ammonia and hydrogen cyanide followed by hydrolysis of the resulting a-aminonitrile is called the Strecker synthesis. Enzymatic hydrolysis has been applied to the kinetic resolution of intermediate a-aminonitriles [90,91]. The hydrolysis of (rac)-phenylglycine nitrile... 

Glycine and the other amino acids are probably formed via the Strecker-cyano-hydrin synthesis (which has been known for more than 150 years) from aldehyde, HCN and ammonia, with subsequent hydrolysis (Strecker, 1850,1854 Miller, 1953). 

A nice example of the chemical similarity between imines and carbonyl compounds is the Strecker synthesis of amino acids. This involves reaction of an aldehyde with ammonia and HCN (usually in the form of ammonium chloride plus KCN) to give an intermediate a-aminonitrile. Hydrolysis of the a-aminonitrile then produces the a-amino acid. 

Figure 2.5 Treating an aldehyde with ammonia and hydrogen cyanide produces an df-ammo nitrile. By hydrolysis of the nitrile group an df-amino acid is produced. This synthesis is called the Strecker synthesis.

There are several laboratory-size methods for synthesizing amino acids, but few of these have been scaled up for industrial production. Glycine and m.-alanine are made by the Stnecker synthesis, commencing with formaldehyde and acetaldehyde, respectively. In tile Strecker synthesis, aldehydes react with hydrogen cyanide and excess ammonia to give amino niiriles which, in turn, are converted into a -amino adds upon hydrolysis. 

The Strecker Synthesis is a preparation of a-aminonitriles, which are versatile intermediates for the synthesis of amino acids via hydrolysis of the nitrile. 

In another synthesis of the amino acid components, an asymmetric Strecker reaction with a 1,2-amino alcohol template was used where phenylglycinol was the nitrogen component (Scheme 2.9). Some epimerization occurred during the hydrolysis of the nitrile group.25 26... 

Since HCN and aldehydes were produced directly from the electric discharge in the Miller s experiment [33], the Strecker reaction was very early proposed as a likely pathway for the prebiotic synthesis of amino acids. This reaction discovered in 1850 [34] is the most anciently known abiotic synthesis of a-amino acids, it originally consisted in the formation of an a-aminonitrile 1 from a carbonyl compound (either aldehyde or ketone), ammonia and hydrogen cyanide in moderately alkaline aqueous solution followed by aminonitrile hydrolysis in strong acid. 

The duration of the reaction time alone determines whether carbonyl compounds, sodium cyanide and ammonium chloride will generate a cyanohydrin (Figure 9.9, top) or an a-aminonitrile (Figure 9.9, bottom). We are already familiar with the first reaction pattern from the initial reaction of the three-step Kiliani-Fischer synthesis of aldoses (Figure 7.15). The second reaction pattern initiates the Strecker synthesis of a-amino acids, which is completed by a total hydrolysis of the C=N group, as in the Bucherer modification discussed elsewhere (Figure 7.11). 

Cyanide will attack iminium ions the Strecker synthesis of amino acids Cyanide will react with iminium ions to form oc amino nitriles. Although these compounds are relatively unimportant in their own right, a simple hydrolysis step produces a amino acids. This route to amino acids is known as the Strecker synthesis. Of course, it s not usually necessary to make the amino acids that Nature produces for us in living systems they can be extracted from hydrolysed proteins. 

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). 

An amino nitrile may be formed instead of a cyanohydrin if the carbonyl compound is treated with aqueous ammonium chloride and sodium cyanide. Hydrolysis of the amino nitrile gives an a-amino acid as in the Strecker synthesis of r>L-alanine (Scheme 3.46). 

The addition of HCN to aldehydes has been a well-known reaction since the 19th century, especially in the context of the Kiliani-Fischer synthesis of sugars. Even older is the Strecker synthesis of amino acids by simultaneous reaction of aldehydes with ammonia and HCN followed by hydrolysis. The challenge in recent years has been to achieve face-selectivity in the addition to chiral aldehydes. These face-selective additions, known as nonchelation-controlled processes, refer to the original formulation of Cram s for the reaction of nucleophiles with acyclic chi carbonyl compounds. The chelation-controlled reactions refer also to a formulaticxi of Cram s, but whose stereochemical consequences sometimes differ. 2... 

The sulfinimine-mediated asymmetric Strecker reaction was developed by F.A. Davis et al. This method involves the addition of ethylaluminumcyanoisopropoxide to functionalized sulfinimines and the resulting diastereomeric a-amino nitriles are easily separated. Subsequent hydrolysis directly affords the enantiopure a-amino acids. This protocol was applied for the synthesis of polyoxamic acid lactone. ... 

The first total synthesis of amiclenomycin, an inhibitor of biotin biosynthesis, was completed by A. Marquet and co-workers. In order to prove its structure unambiguously, both the cis and trans isomers were prepared. The L-amino acid functionality was installed by a Strecker reaction using TMSCN in the presence of catalytic amounts of Znla. The resulting O-TMS protected cyanohydrin was exposed to saturated methanolic ammonia solution, which gave rise to the corresponding a-amino nitrile. Enzymatic hydrolysis with immobilized pronase afforded the desired L-amino acid. 

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