Guanidines Strecker reaction

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). 

Several years later, Corey disclosed the C2 symmetric bicyclic guanidine 19 as an effective bifunctional catalyst for the Strecker reaction (Scheme 5.40) [74]. According to the catalytic cycle, HCN should hydrogen bond to the catalyst to form guanidinium-cyanide complex A. A subsequent increase in acidity of the catalyst N—H proton allows donation of a hydrogen bond to the aldimine to form TS assembly B. Enantiofacial attack of CN to the bound aldimine gives the Strecker product. 

Scheme 6.164 Strecker reaction for examination of the catalytic efficiency of guanidine-functionalized diketopiperazine 177.

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. 

Corey and Grogan recently developed a novel catalytic enantioselective Strecker reaction which utilized the readily available chiral C2-symmetric guanidine 19 as a bifunc-tional catalyst [12], The addition of hydrogen cyanide to achiral aromatic and aliphatic N-benzhydrylimines 18 gave N-benzhydryl-a-aminonitriles 20 (Scheme 7), which were readily converted to the corresponding amino acids with 6 N HCI. The use of N-benzyl- or N-fluorenylimines afforded products of poor enantiomeric purity. 

Corey and co-workers reported the use of a C2-symmetric guanidine catalyst (53) for the Strecker reactions of N-benzhydryl aldimines [65]. The catalyst is be-... 

Scheme 6.9 Guanidine-catalyzed Strecker reactions of aldimines.

Corey and Grogan reported an enantioselective Strecker reaction via the C2-symmetric guanidine 14 (Equation 10.28) [56]. They proposed the transition-state structure shown in Figure 10.14, where the imine is activated by hydrogen bonding. 

While this catalyst could not be applied to the Strecker reaction, Lipton was able to modify this species and was the first to report an asymmetrically catalyzed Strecker reaction. He reasoned the imidazole did not possess sufficient basicity and prepared the corresponding guanidine derivative, cyclo[(5)-phenylalanyl-(5)-norarginyl] 56. 

Strecker reaction to establish a new stereocenter is subject to asymmetric induction, capable of creating either a tertiary" or quaternary carbon atom in the presence of 59. The peptido-imine 60 proves to be an excellent ligand for the Ti(IV)-mediated cyanation of aldimines. On catalysis of the bicyclic guanidine 61 the addition of HCN to A-benzhydrylaldimines affords a-amino nitrile derivatives with moderate to good ee. ... 

A diketopiperazine 8 with an external guanidine function is proven to be an effective catalyst for the Strecker reaction of benzhydrylimine [14]. Corey s bicyclic guandine 20 [12b], which is the original of 12 (Scheme 4.12), also works well in the same reaction and the mode of action has been elucidated by density functional theory [63] (Scheme 4.22). 

A review elsewhere discusses catalytic Strecker reactions including guanidine catalysts [64]. 

Li, J., Jiang, W.-Y, Han, K.-L. et al. (2003) Density functional study on the mechanism of bicyclic guanidine-catalysed Strecker reaction. The Journal of Organic Chemistry, 68, 8786-8789. 

Inspired by the work of Inoue, Lipton and coworkers replaced the imidazole side chain of t icZo-peptide 50, which was efficient as catalyst in cyanohydrin synthesis from aldehydes (Scheme 13.29), with a more basic guanidine moiety in order to afford a catalyst capable of accelerating proton transfer in the Strecker reaction. The modified catalyst 52 was found to be effective in the synthesis of a-amino nitriles with very high yields from aromatic and aliphatic M-benzhydiyl imines, giving enantioselectivities of up to 99% (Scheme 13.30). ... 

Although numerous organocatalytic asymmetric Strecker reactions have been reported, guanidine-catalysed asymmetric Strecker reactions are scarce. The works of Lipton and Corey and their coworkers are amongst these rare reports. However, the validity of the former has been questioned by Kunz and coworkers, who found no enantioselectivity, when the reactions of Lipton and coworkers were repeated by them. ... 

Scheme 23.11 Guanidine-catalysed modified Strecker reaction reported by Corey and Grogan.

Corey et al. reported enantioselective Strecker reaction catalyzed by C2-symmetric guanidine (21) (Scheme 2.62) [122]. A guanidium salt, generated from (21) and HCN, served as hydrogen bond donor to the aldimine, generating hydrogen-bond activated aldimine (Figure 2.23). 

The first highly enantioselective reaction catalyzed by a chiral guanidine was reported by Corey and coworkers in 1999 [128], C2-symmetric guanidine 46 was shown to be a highly effective catalyst in the Strecker reaction of aromatic aldi-mines, affording the Strecker products in high yields and enantioselectivities (Scheme 10.43). 

Scheme 10.43 Enantioselective Strecker reaction catalyzed by guanidine 46.

Upton and coworkers [32] reported the use of a cyclic dipeptide guanidine catalyst for the asymmetric Strecker reaction. In a comparison between an imidazole moiety and a guanidine moiety for the Bronsted basic unit of the catalyst, a large discrepancy in the reactivity became evident The highly basic guanidine... 

Inspired from the usage of cyclic peptides for the hydrocyanation of carbonyls, cyclic peptides were applied to the Strecker reaction (Table 30.3) [12, 13]. Employment of 2 to the mechanistically similar Strecker reaction did not provide any asymmetric introduction In the reaction of benzaldehyde (1) catalyzed by 2, proton transfer takes place from HCN to the imidazole residue in 2. The resulting imidazolium ion can serve as an acid catalyst for the asymmetric cyanation of 1 meanwhile, in the case of the Strecker reaction, the more basic benzaldimine (17) becomes protonated directly by HCN without interaction with the catalyst [4j. Thus, replacement of the imidazole function with the more basic guanidine turned... 

More recently, a number of exciting advances in catalytic enantioselective versions of the Strecker reaction have been described [19, 28]. Lipton reported in 1996 that the cyclic guanidine dipeptide 141 promotes the asymmetric addition of HCN to imines with high yields and optical purities (Equation 19) [103]. The importance of the basic guanidine moiety was borne out by comparison of 141 with the histidine analogue 143, known to be effective for enantioselective cyanohydrin formation (see Chapter 2, Section 2.9) [104]. However, 143 failed to lead to high enantioinduction in the corresponding Strecker reactions [103]. 

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