Y-amino nitrile

Figure 15.6 Novel ( ) Y-amino nitriles for enzymatic transformations to enantioenriched y-amino carboxylic acids (only one enantiomer is depicted).

During our work on enzymatic nitrile transformation, carbocyclic y-amino nitriles have emerged from a comprehensive screening among structurally diverse amino nitriles as being weU-suited substrates for nitrilase-mediated hydrolysis. In contrast, as stated in the previous section, the analogous carbocychc 5-amino nitriles are strictly non-substrates for nitrilases. 

The alkylation products of SAMP-h dra. to chiral y-amino nitriles and ketones.- 4. have been studied in the context of their cj alkylation of their Al-acyF" and A-meth> lihi Under phase-transfer conditions a qua Darzens condensation. ... 

The [Ir(ppy)2bpy] complex photo-catalyses inter- and intramolecular C-H functionalisation reactions of tertiary amines under the visible light irradiation. Oxygen behaves as a chemical switch, triggering different reaction pathways and leading to different products from the same starting material. In anaerobic conditions, the intermolecular addition of iV,iV-dimethyl-anilines to electron-deficient alkenes yields y-amino nitriles. Aerobic conditions, on the other hand, favour a radical addition/ cyclisation reaction, leading to tetrahydroquinoline derivatives. The intramolecular version of the radical addition produces unexpectedly indole-3-carboxaldehyde derivatives. ... 

Enantioselectivity at the y position of alicyclic substrates has also been observed. Winkler and colleagues [48] used commercial nitrilases (NIT 106 and NIT 107, from Codexis, USA) to enantioselectively hydrolyze, conformationally constrained y-aminonitriles. Racemic five- and six-membered carbocyhc y-amino nitriles (both cis and trans) were hydrolyzed enantioselectively to the corresponding amino acid using the nitrilases. Cis isomers gave excellent enantiomeric excesses up to 99%, while the reaction was less enantioselective for trans isomers (86% ee) (Table 14.1). 

Nitrilases suitable for the transformations of alicyclic five- and six-membered y-amino nitriles were selected from the set of commercial nitrilases available from BioCatalytics Inc. (now Codexis) [59] and the effects of the substrate structure (ring size, protecting group, and trans versus cis configuration) were studied. N-tosylated derivatives of cis-3-amino cydopentane- and cyclohexanecarboxylic acids were obtained with the highest enantiopurities. Production of N-substituted pyrrolidine-and piperidinecarboxylic acids was also possible using the same nitrilases, but the enantiopurities of these products were generally low [60]. 

Nitrile oxides are usually prepared via halogenation and dehydrohalogenation of aldoximes [11] or via dehydration of primary nitro alkanes (Scheme 1) [12]. However, it is important to note that nitrile oxides are relatively unstable and are prone to dimerization or polymerization, especially upon heating. 1,3-Dipolar cycioaddition of a nitrile oxide with a suitable olefin generates an isoxazoline ring which is a versatile synthetic intermediate in that it provides easy access to y-amino alcohols, )5-hydroxy ketones, -hydroxy nitriles, unsaturated oximes, and a host of other multifunctional molecules (Scheme 1) [5a]. Particularly for the formation of )5-hydroxy ketones, nitrile oxide-olefin cycioaddition serve as an alternative to the Aldol reaction. 

The construction of novel tetracyclic ring systems 1-142, which can be considered as hybrids of the I e Ira h y dropy r ro I o 12,3 - fo] i ndo le and tetrahydroimidazol[l,2-o]in-dole ring system, has been described by Herranz and coworkers [40]. The exposure of tryptophan-derived a-amino nitrile 1-140 to acidic conditions triggers a stereoselective tautomerization to give 1-142 in quantitative yield (Scheme 1.35). 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

Dipolar cycloaddition reactions between nitrile oxides and aUcenes produce 2-isoxazolines. Through reductive cleavage of the N—O bond of the 2-isoxazohnes, the resulting heterocycles can be readily transformed into a variety of important synthetic intermediates such as p-hydroxy ketones (aldols), p-hydroxy esters, a,p-unsaturated carbonyl compounds, y-amino alcohols, imino ketones and so forth (7-12). 

Chiral addition of allyl metals to imines is one of the useful approaches toward the synthesis of homoallylic amines. These amines can be readily converted to a variety of biologically important molecules such as a-, / -, and y-amino acids. Itsuno and co-workers utilized the allylborane 174 derived from diisopropyl tartrate and cr-pinene for the enantioselective allylboration of imines. The corresponding iV-aluminoimines 173 are readily available from the nitriles via partial reduction using diisobutylaluminium hydride (DIBAL-H) <1999JOM103>. Recently, iV-benzyl-imines 176 have also been utilized for the asymmetric allylboration with allylpinacol boronate 177 in the presence of chiral phosphines as the chiral auxiliaries to obtain homoallylic A -benzylamines 178 in high yield and selectivity (Scheme 29) <2006JA7687>. 

Arylidenemalonitriles react with 6-amino- and 6-hydroxyamino-1,3-dimethyl and 3-methyl-pyrimidinedione to give the derivatives (342 R3 = CN) <84CC1549>. This ring was also constructed by the reaction of /J,y-unsaturated nitriles with 2,4-diamino-6(l/f)-pyrimidinone <89EUP314280). 

For reasons already outhned in the introduction (Section 15.1), we were especially interested in the enantioselective synthesis of cyclic y-amino acids serving as conformational GABA mimics in neuroreceptor research. The stractures of amino nitriles ( )-13a-( )-16a are depicted in Figure 15.6 [43]. 

I 75 Nitrilase- and Nitrile Hydratase-catalyzed Enantiosekctive Preparation Table 15.5 Synthesis of enantioenriched y-amino acids... 

Cycloadditions. [2+1], [2 + 2], and [4 + 2] cycloadditions with electrophilic reactants such as carbenes (eq 5), tetracya-noethylene (eq 6), and a-keto-, Y-unsaturated nitriles (eq 7) lead to interesting products which are all enantiopure see, for instance, the 5-amino-6-hydroxy-2-keto acid (5). 

Harusawa, S., Hamada, Y, and Shioiri, T., Diethyl phosphorocyanidate (DEPC). A novel reagent for the classical Strecker s a-amino nitrile synthesis. Tetrahedron Ij- tt.. 20, 4663, 1979. 

Low-pressure hydrogenation of a-aminonitriles occurs without hydrogenolysis over platinum oxide in acetic anhydride (to the a,j8-diacetamido compound) or in alcohol-HCl (to the a,jS-diamine) . This procedure is not applicable to N-substituted amino-nitriles that are efficiently reduced using rhodium-on-alumina in alcoholic ammonia [equation (h)] the catalytic system also reduces )8-, y-, 5-aminonitriles to diamines. 

J5-, y- und d-Amino-nitrile lassen sich meist glatt zu Diaminen hydrieren, wobei die Hydrierung unter milden Bedingungen mit Rhodium/Aluminiumoxid in athanolischer Am-moniak-Losung die beste ist2 (vgl. Arbeitsvorschrift S. 121). 

Y.-B. Xiang, S. Drenkard, K. Baumann, D. Hickey and A. Eschenmoser, Chemistry of a-amino-nitriles. 12. Exploratory experiments on thermal-reactions of a-amino-nitriles, Helv. ChimicaActa, 1994, 77, 2209-2250. 

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