Asymmetric hydrocyanation, synthesis

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. 

Jacobsen et al. have also demonstrated the usefulness of this method for asymmetric hydrocyanation of cyclic imines [10]. An example is the efficient synthesis of (R)-14 in 88% yield and with 91% ee (Scheme 5.7). Thus, in addition to the hydrocyanation of acyclic imines which are mainly fc-isomcrs, Z-i mines can also be used efficiently. 

The asymmetric catalytic Strecker reaction is an elegant means of synthesis of optically active a-amino acids. The Jacobsen group developed optimized organocata-lysts [21, 44-48], optically active urea or thiourea derivatives, which were found to be the most efficient type of catalyst yet for asymmetric hydrocyanation of imines (see also Section 5.1 on the hydrocyanation of imines). Because of its high efficiency, Jacobsen hydrocyanation technology has already been used commercially at Rodia ChiRex [49]. The concept of the reaction is shown in Scheme 14.7. In the presence of a catalytic amount (2 mol%) of the readily available organocatalyst... 

A further important asymmetric biocatalytic synthesis represents the hydrocyanation of aldehydes [116] for the production of cyanohydrins which are intermediates for a broad variety of life science molecules. For example, (/ )-mandelonitrile is a versatile intermediate for the synthesis of ( )-mandelic acid, and (S)-m-phenoxybenzaldehyde cyanohydrin is a building block for the preparation of pyrethroids. 

The non-equivalence of enantiomers through the spontaneous breaking of mirror-symmetry in nature is amplified by asymmetric autocatalytic reaction [34], e.g. Frank s spontaneous asymmetric synthesis [35, 36] (Fig. 7-8). Alberts and Wyn-berg have reported in enantioselective autoinduction that chiral lithium alkoxide products may be involved in the reaction to increase the enantioselectivity (Eq. (7.9)) [37]. The product % ee however does not exceed the level of catalyst % ee. In asymmetric hydrocyanation catalyzed by cyclic dipeptides, the (Si-cyanohydrin product complexes with the cyclic peptide to increase the enantioselectivity in the (S)-cyanohydrin product, the reaction going up to 95.8% ee (Eq. (7.10)) [38]. In the presence of achiral amine, (/ )-l-phenylpropan-l-ol catalyzed carbonyl-addition reaction of diethylzinc has been reported to show lower % ee than that of the catalyst employed [39]. 

Since the pioneering work by Ojima et al. [653] the Strecker-type reaction of imines bearing a chiral auxihary with TMSCN has frequently been used for asymmetric synthesis of a-aminonitriles [654]. In recent years catalytic asymmetric hydrocyanation of imines with TMSCN has been intensively studied to establish a more efficient route to optically active a-aminonitriles [655]. 

One of the few available examples is represented by the synthesis of cilastatine by a chiral Cu complex promoted cyclopropanation reaction developed by Sumitomo Chemical Co. [78]. Another is the catalytic asymmetric hydrocyanation of vinylarenes developed at DuPont [79]. In this process (Fig. 27) sugar-derived phosphinites are used in combination with a Ni catalyst to prepare enantiomerically enriched precursors of the NSAID naproxen. 

Synthesis of (/ )-mandelonitrile via asymmetric hydrocyanation of benzaidehyde with aimond meai containing an (/ )-oxynitriiase. 

When an aldehyde is allowed to react with an optically active amine and hydrocyanic acid, one of the two diastereomeric amino nitriles, (124a) or (124b), may be formed in excess. To prepare the chiral amino acids (125a) or (125b), the nitriles (124a) and (124b), respectively, are hydrolyzed with mineral acids, whereupon R is split off. However, this asymmetric synthesis of amino acids has no industrial significance. 

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)... 

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]. 

Interest in the synthesis of enantiopure 2-hydroxycarboxylic acids via asymmetric enzymatic transformations is still increasing and two pathways have risen into prominence recently. The first is based on enantioselective hydrocyanation of the appropriate aldehyde in the presence of an oxynitrilase (hydroxynitrile lyase, EC 4.1.2.10), which gives rise to the corresponding enantiomerically pure cyanohydrin, followed by chemical hydrolysis in the presence of strong acid (Figure 16.1, route a). This latter step generates copious quantities of salt and is not compatible with sensitive functional groups, which is a serious limitation. 

Naproxen, an anti-inflammatory drug, is synthesized by utilizing an asymmetric enantioselective hydrocyanation of vinylnaphthalene 1.65 utilizing a chiral ligand 1.66. Since the S-enantiomer is medicinally desirable whereas the i -enantiomer produces harmful health effects, the enantioselectivity of this reaction is important. The synthesis of naproxen nitrile (1.67) shown below produces the S-(—)-enantiomer with 75% ee. 

Examples include acetal hydrolysis, base-catalyzed aldol condensation, olefin hydroformylation catalyzed by phosphine-substituted cobalt hydrocarbonyls, phosphate transfer in biological systems, enzymatic transamination, adiponitrile synthesis via hydrocyanation, olefin hydrogenation with Wilkinson s catalyst, and osmium tetroxide-catalyzed asymmetric dihydroxylation of olefins. 

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]. 

Olefin hydrocyanation using palladium catalysts has been less well studied than with nickel. Nevertheless, zerovalent complexes of palladium, particulrly triarylphosphite complexes, hydrocyanate a wide range of olefins in useful yields (see Table 1). Early work reported the merit of excess phosphorus ligand to promote the reaction, and further paralleling the observations with nickel, Lewis acids have been used to improve catalytic activity. However, addition of ZnClj fails to improve nitrile product yield . Asymmetric induction in hydrocyanation results in optical yields of 30% in the synthesis of exo-2-cyanonorbomane using the chiral ligand DIOP, and studies on the stereochemistry of HCN and DCN addition to terminal alkenes and a substituted cyclohexene with the same catalyst have been reported. ... 

Asymmetric water-soluble ligands are known for the metal-catalyzed hydrocyanation of achiral alkenes. However, neither Jenck [21] or Davis [22] actually provides any examples of hydrocyanation catalysis in these patents so the performance of these mono- and bisphosphines in aqueous and supported aqueous media cannot be assessed although this may be a promising route for the synthesis of biologically active nitrile intermediates and products. 

We describe the extension of this class of bisphosphite catalysts to asymmetric hydroformylation and hydrocyanation of vinylarenes.(3) These enantiose-lective catalytic transformations are employed for the asymmetric synthesis of S-Naproxen, a widely used non-steroidal anti-inflammatory drug (NSAID). Factors which influence regioselectivity and enantioselectivity, as well as characterization of the catalyst resting states, are discussed. 

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