Nitriles desymmetrization

The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

Desymmetrization is not restricted to a single class of enzyme. For example, Madrell et reported the gram-scale preparation of a key intermediate of the lovastatin lactone through the desymmetrization of 3-(benzyloxy)glutaronitrile using whole cells from Brevibacterium R312. The transformation occurs via a dual nitrile hydratase/amidase-catalysed hydrolysis to afford acid in 65 % yield and 88 % ee (Scheme 1.49). 

The enzymatic hydrolysis of nitriles provides a viable alternative for the generally harsh chemical conditions that are most often used. As a result of the ability of many nitrilehydrolyzing enzymes to give selective monohydrolysis, in the case of dinitriles, additional opportunities such as desymmetrization can be explored. With the previous examples, we have shown that, for several substrate classes, enzymatic desymmetrization of dinitriles is indeed a synthetically viable option. 

This screening system has also been applied successfully in the directed evolution of enantioselective EHs acting as catalysts in the kinetic resolution of chiral epoxides 95,96) (Section IV.A.4). Moreover, the firm Diversa has applied the MS-based method in the desymmetrization of a prochiral dinitrile (l,3-dicyano-2-hydroxypropane) catalyzed by mutant nitrilases 46). In this industrial application, one of the nitrile moieties was labeled selectively with as in N-17, which means that the two pseiido-eaaniiovaenc products (S)- N-18 and (J )-18 differ by one mass unit. This is sufficient for the MS system to distinguish between the two products quantitatively 46). 

Nitrilases catalyze the synthetically important hydrolysis of nitriles with formation of the corresponding carboxylic acids 7-11). Enantioselectivity is relevant in the kinetic resolution of racemic nitriles or desymmetrization of prochiral dinitriles. Both versions have been applied successfully to a number of different substrates using one of the known currently available nitrilases. Recently, scientists at Diversa expanded the collection of nitrilases by metagenome panning 150). Nevertheless, in numerous cases the usual limitations of enzyme catalysis become visible, including poor or only moderate enantioselectivity and limited activity. 

The Lewis acid-catalyzed reaction of epoxides with cyanotrimethylsilane (Me3SiCN) forms /3-siloxy nitriles.252 Highly enantioselective desymmetrization of / >-epoxides with Me3SiCN can be achieved by chiral Ti and Yb catalysts (Equation (67)).255 256... 

Hydrolases catalyse the hydrolysis of esters, amides and nitriles under mild conditions. As mentioned above, they also display an often-remarkable enantioselec-tivity. This opens the opportunity to employ these enzymes for the preparation of enantiopure compounds. This desymmetrization has been reviewed [16-24] and different approaches [25-27] are possible. 

Enzymatic desymmetrization of substituted 1,3-propanediols has been used as key step in the synthesis of y-butyrolactones by Itoh and coworkers, Scheme (8) [54],The diols 43 were treated with lipase PS (Pseudomenas sp.) in the presence of vinyl acetate as acyl donor to afford acetates 44 in excellent chemical yields and very high enantiomeric excesses (90-98%). These monoacetates were then converted into hydroxy nitriles 46 using a three step procedure. Tosylation of the hydroxyl group of 44, followed by treatment with potassium cyanide in dimethyl sulfoxide at 80°C gave the corresponding acetates 45. The acetoxy groups of 45 were finally hydrolysed with lithium hydroxide in a... 

Improved efficiency in the synthesis of 24 was ultimately achieved via an enzymatic desymmetrization approach (Scheme 7). In the key step of this route, an asymmetric oxidation of achiral amine 41 promoted by monoamine oxidase (MAON) under an oxygen atmosphere afforded intermediate 42. In this streamlined process, sodium bisulfite was included in the enzymatic oxidation mixture to effect direct conversion to sulfonate 44. Treatment of 44 with sodium cyanide provided the trans-nitrile 43 as a single diastereomer in approximately 90% yield from pyrrolidine 41. As in the second-generation synthesis, the nitrile is hydrolyzed to the methyl ester under Pinner conditions (HCI, methanol). In the manufacturing process, the product was converted to its free base using NaOH, then crystallized as the HCI salt from i-propanol and methyl t-... 

Desymmetrization of Prochiral Dinitriles. Prochiral a,a-disubstituted malono-nitriles can be hydrolyzed in an asymmetric manner by the aid of Rhodococcus rhodochrous [678] (Scheme 2.106). In accordance with the above-mentioned trend, the dinitrile was nonselectively hydrolyzed by the nitrile hydratase in the cells to give the dicarboxamide. In a second consecutive step, the latter was subsequently transformed by the amidase with high selectivity for the pro-(/ ) amide group to yield the (/ )-amide-acid in 96% e.e. and 92% yield. This pathway was confirmed by the fact that identical results were obtained when the dicarboxamide was used as substrate. The nonracemic amide-acid product thus obtained serves as a starting material for the synthesis of nonnatural a-methyl-a-amino acids [679]. 

The requisite dihydroxyketones are commonly assembled via iterative aldol coupling reactions [1], but other methods including Nef reactions [17,18], acetylide additions [19, 20], 1,3-dipolar nitrile oxide cycloadditions [21], iterative alkylation of dithianes [22-28], hydrazones [29], oximes [30], nitriles [31], or dihalomethylene species [32-34], cross-metathesis/hydroboration/oxidation [35], iterative substitution of a xanthate [36], dihydroxylation/desymmetrization of alkenes [37], Homer-Wadsworth-Emmons olehnations [38, 39], allylmetallations [40], and alkyne-alkyne cross-coupling [41] have also been reported. 

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