P-hydroxynitriles

Two more examples ia Table 5 iaclude the hydrolysis of esters of trans-alcohols that proceed with high efficiency practically regardless of the nature of the substituents (72) and resolution of P-hydroxynitriles with Upase from Pseudomonas sp. In the latter case the enantioselectivity of the hydrolysis was improved by iatroduciag sulfur iato the acyl moiety (73). 

Nakamura T, Nagasawa T et al (1991) A new catalytic function of halohydrin hydrogen-halide-lyase, synthesis of P-hydroxynitriles from epoxides and cyanide. Biochem Biophys Res Commun 180 124—130... 

A substoichiometric protocol for Reformatsky-type addition of a-halo esters, a-halo ketones, a-halonitriles, and a-halophosphonates to carbonyl compounds has been developed via samarium-mediated reaction.150 p-Hydroxy esters and P-hydroxynitriles have been obtained in good to excellent yields. 

An electrocatalytic method for the reductive N-O bond cleavage of 3-methoxyisoxazoline in the presence of Ni bpy was studied. The nickel complex, generated in situ, acts as the actual electron source. Under these conditions, isoxazoline 59 afforded a mixture of p-hydroxyester 60 and p-hydroxynitrile 61 in high overall yields, and in different ratios depending on the amount of Ni°bpy used <03TL8217>. 

The successful synthesis of p-hydroxynitriles was reported in good to excellent yields from aldehydes and ketones in a simple reaction that is promoted by proazaphosphatrane bases. The reaction occurs in the presence of magnesium salts, which activate the carbonyl group and stabilize the enolate thus produced [68] (Scheme 5.46). 

Diethylaluminium cyanide p-Hydroxynitriles from oxido compds. 

The selectivity of PSL-catalyzed hydrolyses may be significantly improved by substrate-modification through variation of the nonchiral acyl moiety (Scheme 2.65) [462]. Whereas alkyl- and chloroalkyl esters gave poor selectivities, again, the introduction of a sulfur atom to furnish the thioacetates proved to be advantageous. Thus, optically active p-hydroxynitriles, precursors of p-hydroxy acids and p-aminoalcohols, were conveniently resolved via the methyl- or phenyl-thioacetate derivatives. 

Table 7.6 The preparation of p-hydroxynitriles by the reaction of bromoacetonitriles with aldehydes mediated by the metallic nickel."... 

Our original studies with unprotected P-hydroxynitriles showed that these compounds were hydrolyzed by R. rhodochrous ATCC BAA-870, expressing a benzamide-induced cobalt type nitrile hydratase, to the corresponding amides and acids [11]. The formation of the amide implies a nitrile hydratase and amidase system (although sometimes nitrilases can release partially hydrolyzed substrates as amides [63]). Further studies in our laboratories demonstrated that the system was indeed a nitrile hydratase and amidase cascade reaction functioning via a two... 

Dihydroisoxazoles 1 with a free 3-position undergo ring-cleavage on treatment with a base to give P-hydroxynitriles 2 ... 

The irreversibility of the latter reaction allowed the formation of the corresponding P-azidoalcohols and P-hydroxynitriles in good to excellent yields and with perfect enantiopurity. As some ADHs, for example, ADH-A from R. ruber used in this study, suffer from inactivation from cyanide, addition of the nucleophile must be carried out after complete reduction of the a-chloro ketone substrate. 

Scheme 11.17 One-pot processes for the synthesis ofenantiopure 3-azidoalcohols and P-hydroxynitriles (a) and enantiopure P-hydroxytriazoles (b).

The Backvall group also reported the enantioselective S5mthesis of duloxetine (23), a drug for the treatment of major depressive disorder and generalized anxiety disorder, including the DKR of p-hydroxynitrile as the key step (Scheme 5.42) [65]. The DKR of racemic p-hydroxynitrile (rac-20) was performed with CAL-B (Novoz)m 435), 6, and isopropenyl acetate to obtain an enantioenriched acetate (R)-21 (98% ee), which was converted to (R)-duloxetine (96% ee) via a key intermediate (R)-22. The target molecule was synthesized in a 37% overall yield from the starting material. 

DIPE as solvent [168]. The access to both (R)- and (S)-enantiomers was elegantly developed by the enzyme-catalyzed KR. Similarly, the lipase-catalyzed acetylation of 3-hydroxy-3-(2-thienyl)propanenitrile using PSL and later chemical modifications led to the synthesis of duloxetine enantiomers, which are also antidepressant agents [169]. The DKR of the p-hydroxynitrile precursor of duloxetine reported by Backvall and coworkers has allowed the improvement of the overall yield for the synthesis of these drug enantiomers (Figure 9.17) [170]. 

The enzyme mentioned above from B. japonicum also transformed p-hydroxynitriles into acids but with low enantioselectivities. This problem was circumvented by using optically pure p-hydroxynitriles as substrates, which were prepared by the enantiose-lective reduction of p-ketonitriles catalyzed by carbonyl reductase [58]. The advantage of the nitrilase-catalyzed step was its mild and stereoretentive conditions. In this way, various substituted 3-aryl-3-hydroxypropanoic acids were prepared in both enantiopure forms (Figure 12.5). 

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