Chiral Strecker reaction

The chiral Strecker reaction has been used in an effective synthesis of the substituted phenylglycine 46 (Scheme 17)J81 a-Phenylglycinol was used as the chiral amine supply. 

Scheme 17 Synthesis of a Substituted Phenylglycine via the Chiral 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). 

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). 

Scheme 2-59. Chiral Al-salen-catalyzed Strecker reaction. 

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. 

Snapper and Hoveyda reported a catalytic enantioselective Strecker reaction of aldimines using peptide-based chiral titanium complex [Eq. (13.11)]. Rapid and combinatorial tuning of the catalyst structure is possible in their approach. Based on kinetic studies, bifunctional transition state model 24 was proposed, in which titanium acts as a Lewis acid to activate an imine and an amide carbonyl oxygen acts as a Bronsted base to deprotonate HCN. Related catalyst is also effective in an enantioselective epoxide opening by cyanide "... 

New catalyst design further highlights the utility of the scaffold and functional moieties of the Cinchona alkaloids. his-Cinchona alkaloid derivative 43 was developed by Corey [49] for enantioselective dihydroxylation of olefins with OsO. The catalyst was later employed in the Strecker hydrocyanation of iV-allyl aldimines. The mechanistic logic behind the catalyst for the Strecker reaction presents a chiral ammonium salt of the catalyst 43 (in the presence of a conjugate acid) that would stabilize the aldimine already activated via hydrogen-bonding to the protonated quinuclidine moiety. Nucleophilic attack by cyanide ion to the imine would give an a-amino nitrile product (Scheme 10). 

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). 

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

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. 

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)... 

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. 

The synthesis of a-amino acids is important because they are used extensively in pharmaceuticals, agrochemicals, and as chiral ligands. The Strecker reaction is historically one of the most versatile ways to synthesize a-amino acids, but this method yields only 50% of a single enantiomer. Higher yields can be achieved by using chiral auxiliaries, but auxiliaries are often high in cost and low in availability. 

The modification of thiourea catalyst 93 through incorporation of the (S,S)-diaminocyclohexane backbone as an additional chirality element and a Schiff base imidazoyl-moiety led to the bifunctional catalyst 94 that, in contrast to 93 in the Strecker reaction (Scheme 6.99), exhibited enantioinduction (83-87% ee) in the nitro-Michael addition of acetone to trons-P-nitrostyrenes. The desired adducts were isolated in moderate yields (46-62%) as depicted in Scheme 6.100) [259]. 

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