Asymmetric Strecker reaction

Hydantoinases belong to the E.C.3.5.2 group of cyclic amidases, which catalyze the hydrolysis of hydantoins [4,54]. As synthetic hydantoins are readily accessible by a variety of chemical syntheses, including Strecker reactions, enantioselective hydantoinase-catalyzed hydrolysis offers an attractive and general route to chiral amino acid derivatives. Moreover, hydantoins are easily racemized chemically or enzymatically by appropriate racemases, so that dynamic kinetic resolution with potential 100% conversion and complete enantioselectivity is theoretically possible. Indeed, a number of such cases using WT hydantoinases have been reported [54]. However, if asymmetric induction is poor or ifinversion ofenantioselectivity is desired, directed evolution can come to the rescue. Such a case has been reported, specifically in the production of i-methionine in a whole-cell system ( . coli) (Figure 2.13) [55]. 

Even if organocatalysis is a common activation process in biological transformations, this concept has only recently been developed for chemical applications. During the last decade, achiral ureas and thioureas have been used in allylation reactions [146], the Bayhs-Hillman reaction [147] and the Claisen rearrangement [148]. Chiral organocatalysis can be achieved with optically active ureas and thioureas for asymmetric C - C bond-forming reactions such as the Strecker reaction (Sect. 5.1), Mannich reactions (Sect. 5.2), phosphorylation reactions (Sect. 5.3), Michael reactions (Sect. 5.4) and Diels-Alder cyclisations (Sect. 5.6). Finally, deprotonated chiral thioureas were used as chiral bases (Sect. 5.7). 

Similar organocatalytic species to those successfully used for the Strecker reaction were used for the asymmetric Mannich reaction. Catalyst structure/ enantioselectivity profiles for the asymmetric Strecker and Mannich reactions were compared by the Jacobsen group [160]. The efficient thiourea... 

Pyridine A-oxides have been utilized as asymmetric catalysts in the allylation of aldehydes <06JOC1458> and in the Strecker reaction <06T4071>. In the latter, the chiral A-oxides played a key role in the initial activation of the Si-C bond by coordinating an O atom to the Si atom of silyl cyanide and stabilizing the three-membered complex proposed by the... 

The addition of cyanide to imines, the Strecker reaction, constitutes an interesting strategy for the asymmetric synthesis of a-amino acid derivatives. Sigman and Jacobsen150 reported the first example of a metal-catalyzed enan-tioselective Strecker reaction using chiral salen Al(III) complexes 143 as the catalyst (see Scheme 2-59). 

Methylcyclopropanone hemiacetal (4) undergoes an asymmetric Strecker reaction to give IR, 25 )-(- -)-a/to-norcoronic acid (5) in good yield and high de. The induction depends on the use of a chiral amine [e.g. (5 )-a -methylbenzylamine] to control the face on which the intermediate iminium cation (6) is attacked. 

Optically active a-amino acids are prepared by a cyanide addition to imines, known as the Strecker reaction. Several organobase catalysts and metal complex catalysts have been successfully applied to the asymmetric catalytic Strecker amino... 

Representative metal complexes employed for the catalytic asymmetric Strecker reaction are summarized in Figure 4.2. Aluminum-, titanium-, lanthanoid-, and zirconium-based catalysts are highly efficient. Direct one-pot synthesis starting from aldehydes, and amines is reported using the Zr complex described in Figure 4.2. ... 

In 1998, Jacobsen and co-workers synthesized and screened a library of peptide catalysts for the asymmetric Strecker reaction [14]. The peptide catalysts were... 

The chiral guanidine s role as a strong Brpnsted base for the reactions of protic substrates has been proposed. In 1999, Corey developed a C -symmetric chiral guanidine catalyst to promote the asymmetric Strecker reaction [117]. The addition of HCN to imines was promoted high yields and high enantioselectivities for both electron-withdrawing and electron-donating aromatic imines (Scheme 64). 

Recently, Kunz et al. reported a new organocatalyst for the asymmetric Strecker reaction [132]. The paracyclophane-derived imine catalyst (280) promotes the hydrocyanation of various imines, both aromatic and aliphatic (Scheme 79). 

Chiral Br0nsted Acids for Asymmetric Organocatalysis 2.3.8 Strecker Reactions... 

One of the most important approaches to a-amino acids is based on the Strecker reaction. Although there are already a number of catalytic asymmetric variants, the cyanation of imines still challenges modem organic chemists. 

Diastereoselective Slrecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an In situ crystallization-induced asymmetric transformation, whereby one diastereomer selecliveiy precipitates and can be isolated in 76-33% yield and dr > gsti. The diastereomeilcaily pure a-amino nitrtie obtained from pivaidehyde (R, = t-Bu, Rj = H) was converted in three steps to (S)-tert-leucine in 73% yieid and >98% ee. 

Given the background provided on the asymmetric Strecker reaction, complete the following tasks as you read excerpt 4G ... 

The asymmetric Strecker reaction of (R)-phenylglycine amide 1, pivaldehyde 2, and HCN generated in situ from NaCN and AcOH was studied (Table 1). Amino nitriles (R,S)-3 and (R,R)-3 were obtained in 80% yield in a ratio of 65 35 by stirring an equimolar mixture of 1 (as AcOH salt) with 2 and NaCN in MeOH overnight at room temperature, followed by evaporation of the solvent (entry 1). The diastereo-meric ratio (dr) of (R,S)-3 and (R,R)-3 was determined by NMR on the basis of the relative integration between the t-Bu signals at 1.05 ppm for (R,S)-3 and 1.15 ppm for (R,R)-3. 

Because in methanol crystallization of amino nitrile 3 did not take place, first the solvent was varied in order to attempt to find conditions for a crystallization-induced asymmetric transformation. At a MeOH/2-PrOH ratio of 1/9, the amino nitrile (R,S)-3 was isolated in 51% yield and dr 99/1 (entry 2). Other combinations of alcoholic solvents failed to lead to a higher yield of precipitated (R,S)-3 in high dr (entries 3 and 4). On further screening of solvents, it was observed that upon addition of HjO to the methanol solution selective precipitation of amino nitrile (R,S)-3 occurred giving (R,S)-3 and (R,R)-3 in a ratio of 81 19 and 69% yield (entry 5). The asymmetric Strecker reaction was further studied in HjO alone using temperature as a variable. The results of these experiments are given in Table 1 (entries 6-9). After addition of NaCN/AcOH at 23-28 °C... 

Table 1. Asymmetric Strecker Reactions of (R)-Phenylglycine Amide 1 and Pivaldehyde 2...

In summary, (R)-phenylglycine amide 1 is an excellent chiral auxiliary in the asymmetric Strecker reaction with pivaldehyde or 3,4-dimethoxyphenylacetone. Nearly diastereomerically pure amino nitriles can be obtained via a crystallization-induced asymmetric transformation in water or water/methanol. This practical one-pot asymmetric Strecker synthesis of (R,S)-3 in water leads to the straightforward synthesis of (S)-tert-leucine 7. Because (S)-phenylglycine amide is also available, this can be used if the other enantiomer of a target molecule is required. More examples are currently under investigation to extend the scope of this procedure. ... 

To present the take-home message of the current work Present-active In summary, (R)-phenylglycine amide 1 is an excellent chiral auxiliary in the asymmetric Strecker reaction with pivaldehyde or 3,4-dimethoxyphenyl-acetone. (From Boesten et al.. 2001)... 

Consider passages P19 and P20, adapted from the Introduction sections of articles on particulate matter and the asymmetric Strecker reaction ... 

Diastereoselective Strecker reactions based on (R)-phenylglycine amide as chiral auxiliary are reported. The Strecker reaction is accompanied by an in situ crystallization-induced asymmetric transformation, whereby one diastereomer selectively precipitates and... 

R)-Phenylglycine amide I is an excellent chiral auxiliary in the asymmetric Strecker reaction of pivaldehyde 2. In water at 70 °C, the (R,S)-3 product was isolated in 93% yield and dr > 99/1. Work is underway to convert (R,S)-3 to (S)-tert-leucine and thereby complete the asymmetric Strecker reaction. 

R)-Phenylglycine amide 1 is an excellent chiral auxiliary in the asymmetric Strecker reaction of pivaldehyde 2. 

Active voice We present an asymmetric Strecker reaction where... 

The asymmetric synthesis of a-amino acids is an important topic due to their extensive use in pharmaceuticals and agrochemicals and as chiral ligands. The Strecker reaction is historically one of the most versatile ways to produce a-amino acids, but this method has a maximum yield of only 50% for a single enantiomer. Higher yields can be achieved by using chiral auxiliaries, but auxiliaries have other drawbacks, such as high cost, low availability, the need for purification, and high loss rates. A possible solution to these problems would be to use a chiral auxiliary in a crystallization-induced asymmetric transformation. 

The asymmetric Strecker reaction of (R)-phenylglycine amide 1, pyvaldehyde 2, and FICN generated in situ from NaCN and AcOH was studied. (From... 

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