Hydrocyanation and Strecker Reactions

In 1850, A. Strecker accidently accomplished the first synthesis of the amino acid alanine by mixing of acetaldehyde, ammonia, and HCN and subsequent hydrolysis of the formed adduct [1]. Whereby this three-component-reaction is in general known as the Strecker reaction, the addition of a cyanide source to a preformed imine species is often referred to as the modified Strecker reaction, The so-formed a-amino nitriles, or from cyanide addition to carbonyl compounds the so-obtained cyanohydrins, are versatile building blocks that can be converted, for example, into a-hydroxy carbon acids, amino acids, amino alcohols and diamines. 

Several catalysts have been developed for the asymmetric organocatalyzed hydrocyanation of carbonyls and for the Strecker reaction. This chapter divides the catalysts into several subgroups, defined according to important structural motifs responsible for catalytic activity. Each catalyst group will be discussed in detail with regard to substrate scope, hmitations, and other important factors. In addition, mechanistic insights will be provided, if transition states are satisfyingly revealed by experimental work or in silica studies. 

Comprehensive Enantioselective Organocatalysis Catalysts, Reactions, and Applications, First Edition. 

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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). 

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). 

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... 

An enantioselective Strecker reaction involving Brpnsted acid catalysis uses a BINOL-phosphoric acid, which affords ees up to 93% in hydrocyanations of aromatic aldimines in toluene at -40 °C.67 The asymmetric induction processes in the stereoselective synthesis of both optically active cis- and trans-l-amino-2-hydroxycyclohexane-l -carboxylic acids via a Strecker reaction have been investigated.68 A 2-pyridylsulfonyl group has been used as a novel stereocontroller in a Strecker-type process ees up to 94% are suggested to arise from the ability of a chiral Lewis acid to coordinate to one of the sulfonyl (g)... 

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. 

The Strecker reaction is defined as the addition of HCN to the condensation product of a carbonyl and amine component to give a-amino nitriles. Lipton and coworkers reported the first highly effective catalytic asymmetric Strecker reaction, using synthetic peptide 43, a modification of Inoue s catalyst (38), which was determined to be inactive for the Strecker reactions of aldimines (see Scheme 6.5) [62], Catalyst 43 provided chiral a-amino nitrile products for a number of N-benzhydryl imines (42) derived from substituted aromatic (71-97% yield 64->99% ee) and aliphatic (80-81% yield <10-17% ee) aldehydes, presumably through a similar mode of activation to that for hydrocyanations of aldehydes (Table 6.14). Electron-deficient aromatic imines were not suitable substrates for this catalyst, giving products in low optical purities (<10-32% ee). The a-amino nitrile product of benzaldehyde was converted to the corresponding a-amino acid in high yield (92%) and ee (>99%) via a one-step acid hydrolysis. 

The assymetric Strecker reaction of diverse imines, including aldimines as well as ketoimines, with HCN or TMSCN provides a direct access to various unnatural and natural amino acids in high enantiomeric excesses, using soluble or resin-linked non-metal Schiff bases the corresponding chiral catalysts are obtained and optimized by parallel combinatorial library synthesis [93]. A rather general asymmetric Strecker-type synthesis of various imines and a, 9-unsaturated derivatives is catalyzed by chiral bifunctional Lewis acid-Lewis base aluminum-containing complexes [94]. When chiral (salen)Al(III) complexes are employed for the hydrocyanation of aromatic substituted imines, excellent yields and enatio-selectivities are obtained [94]. 

In 2002, Jacobsen s group reported an improved analogue for the as5mimetric Strecker reaction based on detailed mechanistic studies. Both aldimines and ketimines underwent hydrocyanation with high enantioselectivities utilising thiourea 4 in just 1 mol% catalyst loading (Scheme 19.4). 

Initial mechanistic analysis of the Strecker reaction catalyzed by a urea-based organocatalyst (Scheme 3.18) revealed that the catalytic activity is provided by the urea functionality of structurally complex catalyst 1. However, further studies revealed a bifunchonal character of urea and thiourea-based catalysts " as well as the possibility of multiple mechanistic pathways in catalysis of nucleophile-electrophile addition reactions. " Simplified but sufficiently effective (thio)urea catalysts 4a and 4b were used in the hydrocyanation reaction (Scheme 3.19) that was subjected to a combined experimental and computational study. °... 

Hydrolysis of aminonitriles prepared by reaction of ammonia and hydrocyanic acid with aldehydes (Strecker reaction). 

Typical other trademark applications of asymmetric Brpnsted base catalysis include hydrocyanation reactions, Strecker reactions, or also desymmetrizing esterifications, to mention a few examples only (see Scheme 6.31 for selected seminal reports and Brpnsted base catalysts used therein) [89-91]. 

Hydrocyanation to imines with HCN, the Strecker reaction, is one of the most direct and efficient methods for natural and unnatural a-amino acids. Asymmetric Strecker-type reaction with chiral aluminum Lewis acids has been developed. As shown in Scheme 6.48, the research group of Jacobsen reported chiral Al(salen)Cl complex (67a) as an effective asymmetric catalyst for catalytic enantioselective Strecker reaction of aromatic N-allylimines with HCN [62]. Compared to the reactions of aromatic imines, that of a-branched aliphatic imines (R = Cy and t-Bu) gave Strecker products in only moderate optical yield. Additionally, the use of TMSCN instead of HCN dramatically reduced in the enantioselectivity. 

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