Asymmetric Strecker

Asymmetric synthesis of a,a-disubstituted a-amino acids via an intramolecular Strecker synthesis using l,4-oxazin-3-one derivatives as key intermediates 97YGK982. 

The importance of chemical syntheses of a-amino acids on industrial scale is limited by the fact that the standard procedure always yields the racemic mixture (except for the achiral glycine H2N-CH2-COOH and the corresponding amino acid from symmetrical ketones R-CO-R). A subsequent separation of the enantiomers then is a major cost factor. Various methods for the asymmetric synthesis of a-amino acids on laboratory scale have been developed, and among these are asymmetric Strecker syntheses as well. ... 

The asymmetric Strecker synthesis of a-amino nitriles from Schiff bases of a-methylbenzyl-aminc is improved by the use of trimethylsilyl cyanide, instead of hydrogen cyanide and by promotion of the transformation with a Lewis acid, preferably zinc chloride43. Thus, from the butyraldimine 2, the amino nitrile is synthesized with a yield of 98.5% and an ee of 68.5%. 

In asymmetric Strecker synthesis ( + )-(45,55 )-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has been introduced as an alternative chiral auxiliary47. The compound is readily accessible from (lS,25)-2-amino-l-phcnyl-l,3-propancdioI, an intermediate in the industrial production of chloramphenicol, by acctalization with acetone. This chiral amine reacts smoothly with methyl ketones of the arylalkyl47 or alkyl series48 and sodium cyanide, after addition of acetic acid, to afford a-methyl-a-amino nitriles in high yield and in diastereomerically pure form. 

The (/ (-enantiomer of 5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has also been successfully used for asymmetric Strecker syntheses4In addition, the acetal protecting moiety of the auxiliary has been modified. No significant change in the Strecker syntheses of a-mcthylamino nitriles has been reported for these alternative auxiliaries50. 

In Ugi four-component reactions (for mechanism, see Section 1.4.4.1.) all four components may potentially serve as the stereodifferentiating tool65. However, neither the isocyanide component nor the carboxylic acid have pronounced effects on the overall stereodiscrimination60 66. As a consequence, the factors influencing the stereochemical course of Ugi reactions arc similar to those in Strecker syntheses. The use of chiral aldehydes is commonly found in substrate-controlled syntheses whereas the asymmetric synthesis of new enantiomerically pure compounds via Ugi s method is restricted to the application of optically active amines as the chiral auxiliary group. 

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]. 

For a review of asymmetric Strecker syntheses, see Williams, R.M. Synthesis of Optically Active d-Amino Acids, Pergamon Elmsford, NY, 1989, p. 208. 

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). 

The asymmetric Strecker-type reaction developed by the Jacobsen group is suitable for both aUphatic and aromatic imines, giving high enantiomeric excesses for a wide range of substrates. In this reaction the urea derivative also acts as the catalyst (Scheme 36). 

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-... 

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). 

Moreover, it seemed to be a rational extension to apply the catalyst 123 to the asymmetric Strecker-type reaction.1291 Actually, as shown in Table 13, an efficient and general catalytic asymmetric Strecker-type reaction has been realized. Products were successfully converted to the corresponding amino acid derivatives in high yields without loss of enantiomeric purity.1301... 

Table 13. Asymmetric Strecker-type reaction of imines catalyzed by 123.

Shibasaki, A Catalytic Asymmetric Strecker-type Reaction Interesting Reactivity Difference between TMSCN and HCN, Angew. Chem Int. Ed. Engl. 2000,39,1650-1652... 

Scheme 4.19 Asymmetric Strecker-type synthesis of a-amino nitriles.

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. 

Matsumoto, K. Kim, J. C. Hayasbi, N. Jenner, G. Tetrahedron Lett. 2002, 43, 9167. Yet, L. Recent Developments in Catalytic Asymmetric Strecker-Type Reactions, in Organic Synthesis Highlights V, Scbmalz, H.-G. Wirtb, T. eds., Wiley-VCH Weinbeim, Germany, 2003, pp 187-193. (Review). 

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. 

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