Asymmetric cyanation reactions

In addition to metal catalysts, organocatalysts could also be used in asymmetric cyanation reactions. Chiral Lewis bases, modified cinchona alkaloids, catalyzed asymmetric cyanation of ketones by using ethyl cyanoformate as the cyanide source (Scheme 5.34)." Similar to metal-catalyzed reactions, ethyl cyanoformate was first activated by chiral Lewis bases to form active nucleophiles. Various acyclic and cyclic dialkyl ketones were transformed into the desired products. Because of using... 

Cyano(trimehyl)silane (TMSCN) serves as a cyanating agent for carbonyl groups in the presence of a catalytic or stoichiometric amount of a Lewis acid such as boron trifluoride, titanium(IV) chloride, tin(IV) chloride, etc. Thereby, a wide variety of chiral ligands was designed and used for asymmetric cyanation reactions. Among them, titanium complexes have mostly been employed as the catalysts. 

Shibasaki et al. reported asymmetric cyanation reactions of p,p-disubstituted a,p-unsamrated carbonyl compotuids using a chiral strontium catalyst [72] for selected examples of asymmetric cyanation reactions, see [73-80]. The catalytic... 

Table 18 Catalytic asymmetric cyanation reactions of p,p-disubstituted a,p-imsaturated ketones using a chiral strontium catalyst...

Kurono N, Ohkuma T (2016) Catalytic asymmetric cyanation reactions. ACS Catal 6... 

Sn(OTf)2 can function as a catalyst for aldol reactions, allylations, and cyanations asymmetric versions of these reactions have also been reported. Diastereoselective and enantioselective aldol reactions of aldehydes with silyl enol ethers using Sn(OTf)2 and a chiral amine have been reported (Scheme SO) 338 33 5 A proposed active complex is shown in the scheme. Catalytic asymmetric aldol reactions using Sn(OTf)2, a chiral diamine, and tin(II) oxide have been developed.340 Tin(II) oxide is assumed to prevent achiral reaction pathway by weakening the Lewis acidity of Me3SiOTf, which is formed during the reaction. 

Thus transition metal complexes capable of effecting cyanation reactions on aromatic nuclei under mild conditions have been discovered Cassar et al. describe such a catalytic system. The past few years have also seen the discovery of asymmetric catalysis. Asymmetric catalysts contain optically active ligands and, like enzymes, can promote catalytic reactions during which substantial levels of optical activity are introduced into the products. This volume contains examples of asymmetric hydrogenation and asymmetric hydroformylation catalysis in the papers, respectively, by Knowles et al. and Pino et al. 

Asymmetric Cyanation of C=N Bonds (Strecker-Type Reaction). . 121... 

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... 

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

Extension of this reaction toward a one-pot asymmetric Mannich-hydrocyanation reaction sequence was also reported by the Barbas group [29]. In this one-pot two-step process proline-catalyzed asymmetric Mannich reaction of unmodified aldehydes with the a-imino glyoxylate was performed first, then diastereoselective in situ cyanation. The resulting /i-cyanohydroxymethyl a-amino acids were obtained with high enantioselectivity (93-99% ee) [29]. Another one-pot two-step reaction developed by Barbas et al. is the Mannich-allylation reaction in which the proline-catalyzed Mannich reaction is combined with an indium-promoted allylation [30], This one-pot synthesis was conducted in aqueous media and is the first example of a direct organocatalytic Mannich reaction in aqueous media [28, 30]. 

Asymmetric cyanation of aldehydes is important in organic synthesis. Mukaiyama and Minowa have developed a new chiral Lewis acid catalyst which is readily prepared from l,l -dimethylstannocene, triflic acid, and (+)-cinchonine [49]. In the presence of this Lewis acid reaction of TMSCN with aldehydes proceed smoothly at -78 °C in dichloromethane to give the corresponding cyanohydrin trimethylsilyl ether in high yield with good to excellent ee. In this reaction the products are isolated as trimethylsilyl ethers and the reaction proceeds smoothly in the presence of 30 mol % tin(II) Lewis acid (Eq. 31). The catalyst, Sn(II) monoalkoxymonotriflate, is assumed to be regenerated from the initially produced Sn(II) alkoxide and trimethylsilyl triflate. 

The catalytic asymmetric cyanation of imines-the Strecker reaction-represents one of the most direct and viable methods for the asymmetric synthesis of a-amino... 

On the other hand, only few studies have been successful in the asymmetric cyanation of imines compared with that of carbonyl compounds since imines,in general, themselves promote the cyanation reaction without a catalyst. 

The reaction of benzaldehyde with hydrogen cyanide in the presence of 2 mol % of the catalyst in toluene at -20 °C for 8 h furnished the corresponding (i )-cyanohydrin in 97% yield and an enantioselectivity of 97%. The asymmetric cyanation of various aromatic and heteroaromatic aldehydes similarly proceeded to give the optically active cyanohydrins, although aromatic aldehydes with electron withdrawing groups such as NO2 and CN and aliphatic aldehydes... 

It is remarkable that Danda reported enantioselective autoinduction in asymmetric cyanation. When a small amount of the optically pure cyanohydrin was added to the reaction mixture, highly enantioselective cyanation occurred even by using almost racemic catalyst 5, Fig. 1 (2% ee) [32]. 

Asymmetric Cyanation of C=0 Bonds by Metal-Catalyzed Reactions... 

Cyanadons. Aluminum complexes of BINOLs (1) that are armed at C-3 and C-3 with diarylphosphine oxide groups possess both Lewis acid and base centers. Asymmetric cyanation of aldehydes and mines with MeaSiCN, and of quinolines and isoquinolines in a manner analogous to the Reissert reaction is successful (ee 70-90%). The asymmetric Strecker synthesis is applicable to conjugated aldimines and the higher reactivity of Me SiCN than HCN in the presence of 10 mol% of PhOH enables its use in catalytic amount while supplying stoichiometric HCN as the cyanide source. 

The first examples of asymmetric short peptide catalysis emerged in the 1980s. An important milestone for short peptide-catalysed asymmetric reactions in general, was reported by Inoue and coworkers in 1979 in the context of an asymmetric cyanation of benzaldehyde employing synthetic... 

Discovered in the middle of the 19th century, the Strecker reaction is one of the earliest atom-economic multicomponent reactions. Amino nitriles were simply obtained from ammonia, hydrogen cyanide and an aldehyde. These products are important intermediates for the synthesis of natural and unnatural a-aminoacids. Due to the ever-increased demand for enantioenri-chied a-aminoacids, the asymmetric Strecker reaction has emerged as a viable synthetic method. Since the first report published in 1996, the catalytic enantioselective cyanation of preformed imines was intensively studied and several excellent reviews were devoted to this topic. ... 

Recent developments in the catalytic asymmetric cyanation of ketimines. (c) T. Vilaivan, W. Bhanthumnauin, Y. Sritana-Anant, Curr. Org. Chem. 2005, 9, 1315-1392. Recent advances in catalytic asymmetric addition to imines and related C=N systems, (d) S. J. Connon, Angew. Chem. Int. Ed. 2008,47,1176-1178. The catalytic asymmetric Strecker reaction ketimines continue to join the fold. 

However, in contrast to the relatively well-developed cyanation of aldimines, limited reports were related to the cyanation of ketoimines. In this context, Feng et al. have designed a novel Ai, A -dioxide catalyst derived from BINOL and prolinamide in order to be applied as organocatalyst for the asymmetric Strecker reaction of ketoimines with fairly wide substrate scope and excellent enantioselectivities of up to 99% ee (Scheme 3.34)." A low catalyst loading of 2 mol % combined with mild reaction conditions and an operational simplicity made this strategy facile to be used for the synthesis of pharmaceutically important chiral disubstituted a-amino nitriles. 

Johnson s group developed a catalytic asymmetric cyanation/1,2-Brook rearrangement/C-acylation of acylsilanes with cyanoformates (Scheme 19.14). In the presence of (i ,/ )-(salen)Al 19, the corresponding cyanohydrin trimethylsilyl ethers of a-keto esters were obtained in moderate to good enantioselectivities (61-82% enantiomeric excess). Access to chiral (silyloxy)nitrile anions is facilitated by metal cyanide-promoted Brook rearrangement reaction of acylsilanes. 

---