Strecker reaction, enantioselective

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]. 

A very efficient and universal method has been developed for the production of optically pue L- and D-amino adds. The prindple is based on the enantioselective hydrolysis of D,L-amino add amides. The stable D,L-amino add amides are effidently prepared under mild reaction conditions starting from simple raw materials (Figure A8.2). Thus reaction of an aldehyde with hydrogen cyanide in ammonia (Strecker reaction) gives rise to the formation of the amino nitrile. The aminonitrile is converted in a high yield to the D,L-amino add amide under alkaline conditions in the presence of a catalytic amount of acetone. The resolution step is accomplished with permeabilised whole cells of Pseudomonas putida ATCC 12633. A nearly 100% stereoselectivity in hydrolysing only the L-amino add amide is combined with a very broad substrate spedfidty. 

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... 

Zr-Catalyzed Enantioselective Cyanide Additions to Imines (Strecker Reactions)... 

A new cinchona alkaloid-derived catalyst has been developed for the enantioselective Strecker reaction of aryl aldimines via hydrogen-bonding activation. For reference, see Huang, J. Corey, E. J. Org. Lett. 2004, 6, 5027-5029. 

Furthermore, a highly efficient route to A-tert-butoxycarbonyl (Boc)-protected p-amino acids via the enantioselective addition of silyl ketene acetals to Al-Boc-aldimines catalyzed by thiourea catalyst 4 has been reported (Scheme 12.2)." From a steric and electronic standpoint, the A-Boc imine substrates used in this reaction are fundamentally different from the A-alkyl derivatives used in the Strecker reaction. 

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 "... 

For catalytic enantioselective Strecker reaction of ketoimines from other groups, see ... 

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). 

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)... 

Groger H (2003) Catalytic enantioselective Strecker reactions and analogous syntheses. Chem Rev 103(8) 2795-2827... 

Schiff base thiourea catalysts (2 mol%) first enantioselective (polymer-bound) thioureas, Strecker reactions (92% yl. 91% ee)... 

Scheme 6.43 Recycling study Polymer-bound Schiff-base thiourea 41 catalyzed the Strecker reaction of pivalaldimine without loss of activity or enantioselectivity even after 10 catalytic cycles.

On the basis of the observed stereoinduction trend, the addition of HCN took place over the diaminocyclohexane portion of the catalyst away from the amino acid and amide unit. The last hypothesis led to the prediction that a more sterically demanding amino acid or amide unit (Figure 6.14) could additionally favor the cyanide attack compared to the less bulky diaminocyclohexane unit and thus making the Schiff base catalyst more enantioselective in Strecker reactions of aldimines and ketimines. To evaluate this perspechve, the authors performed a model-(mechanism-) driven systematic structure optimizations by stepwise modification of the amide, the amino acid, and the (thio)urea unit of catalyst 42 and examined these derivatives of 42 (lmol% loading ) in the model Strecker reaction (toluene ... 

This tertiary amide-functionalized Schiff base thiourea was found to efficiently catalyze the asymmetric Strecker reaction [157] of N-benzyl-protected aldimines and also one ketimine in high enantioselectivities (86-99% ee) and proved superior to 42 examined under the same conditions (1 mol% loading, toluene, -78 °C, HCN) (Scheme 6.46) [198]. 

Figure 6.16 Structure optimization of 42 in the asymmetric Strecker reaction of N-benzyl-protected 2-methylpropionaldehyde imine identified tertiary amide-functionalized Schiff base thiourea 47 as the most enantioselective catalyst stmcture.

Tsogoeva and co-workers explored the catalytic potential of pyridyl- and imida-zoyl-containing thiourea derivatives (e.g., thiourea 92 and 93) in the asymmetric model Strecker reactions [157] of N-benzyl- and benzhydryl-protected benzaldi-mine with HCN [258], The observed enantioselectivities were consistently very low (4—14% ee) for all catalyst candidates and were far below synthetically useful levels, while imidazoyl-thiourea 93 was reported to be highly active and displayed 100% conversion (at 7% ee) of the N-benzhydryl-protected benzaldimine (Scheme 6.99). X-ray structure analysis of a pyridyl-thiourea revealed an intramolecular hydrogen-bond between the basic ring nitrogen and one amide proton. This could make this... 

Scheme 6.165 Enantioselective Strecker reactions catalyzed by biflinctional hydrogen-bonding guanidine organocatalyst 178. Catalytic action of 178 HCN hydrogen bonds to 178 and generates a guanidinium cyanide complex after protonation, which activates the aldimine through single hydrogen bonding and facilitates stereoselective cyanide attack and product formation.

Reagent 8 has also been used to add guanidine groups to a supported dipeptide intermediate to a diketopiperazine4 1 that is reported to be a catalyst for enantioselective Strecker reactions.44 The key step is shown in Scheme 19. 

Vallee reported another example of a BINOL-based Lewis acid catalyst for the asymmetric Strecker reaction of ketoimines. While a traditional (BINOL)Ti(IV)-based system provided poor enantioselectivity [61], Sc(BINOL)2Li proved to be highly enantioselective for the cyanation of N-benzyl acetophenonimine (95% ee at 50% conversion, 91% ee at 80% conversion) [62], Unfortunately, results were provided only for a single ketoimine and a single aromatic aldimine, leaving the generality of the methodology in question. 

Shibasaki and co-workers applied (BINOL)Al(III)-derived catalyst 5a, previously developed for the cyanation of aldehydes [28], to the asymmetric Strecker reaction. This catalyst proved to be highly enantioselective for both aromatic and a,p-unsaturated acyclic aldimines (>86% ee for most substrates) (Scheme 8) [63-65]. Aliphatic aldimines underwent cyanide addition with lower levels of enantioselectivity (70-80% ee). A significant distinction of 5 relative to other catalysts is, undoubtedly, its successful application to the hydrocyanation of quinolines and isoquinolines, followed by in situ protection of the sensitive cx-amino nitrile formed (this variant of the Strecker reaction is also known as the Reissert reaction [66]). Thus, Shibasaki has shown that high enantioselectivities (>80% ee for most substrates) and good yields are generally obtainable in the Reissert reaction catalyzed by 5b [67,68]. When applied to 1-substituted... 

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