Hydrocyanation enantioselective

Jacobsen and co-workers also described the highly enantioselective hydrocyanation of ketimines with the urea analogue. After recrystallisation of the corresponding Strecker adduct, formylation and hydrolysis, the N-benzyl R-methylphenylglycine, was obtained. The R-amino acid hydrochloride is obtained in 93% overall yield with > 99.9% ee on a gram scale [149]. 

Van Langen, L.M., Selassa, R.P, van Rantwijk, F. and Sheldon, R.A. (2005) Cross-linked aggregates of (A )-oxynilrilase a stable, recyclable biocatalyst for enantioselective hydrocyanation. Organic Letters, 7, 327-331. 

L-lactic add formation by fermentation of glucose or lactose with Lactobacilli enantioselective hydrocyanation... 

An impressive example of autoinduction (28) has been observed in the enantioselective hydrocyanation of 3-phenoxybenzaldehyde catalyzed by cyclo[( )-phenylalanyl-(ff)-hystidyl] (Scheme 8) (29). The ee... 

The reaction can be carried out asymmetrically, using nickel complexes of chiral phosphite ligands. Examples are the enantioselective hydrocyanation of norbomene using ligand (22-XVIII),48 and of vinylnaphthalene derivatives with (22-XIX).49 The latter is a precursor for the anti-inflammatory drug naproxen. 

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. 

Figure 16.1 Synthetic routes to enantiomerically pure 2-hydroxycarboxylic acids, via oxynitrilase (hydroxynitrile lyase) catalysed enantioselective hydrocyanation (route A) and (R)-nitrilase (nitrilase) mediated dynamic kinetic resolution (route B).

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. 

Table 2. Catalyst screening for the enantioselective hydrocyanation of methoxyvinylnaph-thalene (30).

The enantioselective hydrocyanation of alkenes has the potential to serve as an efficient method to generate optically active nitriles, as well as amides, esters, and amines after functional group interconversions of the nitrile group. As in asymmetric hydroformylation, asymmetric hydrocyanation requires control of both regiochemistry and stereochemistry because simple olefins tend to generate achiral terminal nitrile products. The hydrocyanation of norbomene will give a single constitutional isomer and was studied initially. However, modest enantioselectivities were obtained, and the synthetic value is limited. ... 

More success has been achieved with the enantioselective hydrocyanation of vinylar-enes. For reasons described below, the hydrocyanation of vinylarenes tends to generate the branched, chiral, a-aryl nitrile product, instead of the linear, achiral, P-aryl nitrile product. Much research has focused on the hydrocyanation of 6-methoxyvinylnaphtha-lene because hydrolysis of the nitrile product would lead to the profen drug Naproxen. As shown in Equation 16.9, the hydrocyanation of this vinylarene occurs with high enanti-oselectivity in the presence of a nickel catalyst containing a phosphinite derived from a... 

Hydrocyanation of vinylarenes provides an interesting access to antiinflammatory and pain killer drugs such as naproxen and dexibuprofen (the pharmacologically active enantiomer of ibuprofen, Scheme 8.3). However, the enantioselective hydrocyanation of these substrate types remains a challenge. In 1994, RajanBabu and Casalnuovo [14] reported the application of glucophosphinite ligands 1 for the hydrocyanation of P-vinylnaphathalene 3. 

Scheme 8.4 Examples for enantioselective hydrocyanation of substituted 13-dienes [20],...

Other notable addition reactions catalyzed by sol-gel entrapped catalysts are the (enantioselective) hydrocyanation of benzaldehyde (Scheme 24-17) (Shvo, 1994) hydrocar-boxylation of amines by a sol-gel bound ruthenium catalyst (Scheme 24-18) (Krocher, 1996), the hydrosilylation of olefins by an immobilized rhodium catalyst (Scheme 24-19) (Capka, 1992b), and the hydration ofalkynes by sol-gel entrapped palladium or platinum compounds (Scheme 24-20) (Blum, 2000 Israelsohn, 2002). 

Enantioselective hydrocyanation of a range of A(-benzyloxycarbonyl aldimines by HCN has been promoted with 92-99% ee by Ru[(5 )-phgly]2[(5)-binap] systems the imine-to-catalyst molar ratio required was 500-5000. 0... 

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