Enantiomerically pure nitrile

Extensive studies on diastereoselectivity in the reactions of 1,3-dipoles such as nitrile oxides and nitrones have been carried out over the last 10 years. In contrast, very little work was done on the reactions of nitrile imines with chiral alkenes until the end of the 1990s and very few enantiomerically pure nitrile imines were generated. The greatest degree of selectivity so far has been achieved in cycloadditions to the Fischer chromium carbene complexes (201) to give, initially, the pyrazohne complexes 202 and 203 (111,112). These products proved to be rather unstable and were oxidized in situ with pyridine N-oxide to give predominantly the (4R,5S) product 204 in moderate yield (35-73%). 

Enantiomerically pure nitrile imines (211) have also been generated by the lead tetraacetate oxidation of aldehydo sugar p-nitrophenyl hydrazones. Reaction with methyl acrylate gave the pyrazolines as a 1 1 mixture of the (55) and (5R) epimers, which were resolvable in some cases (116). 

Fig. 17.37. A hydrazone hydrazone N-oxide oxidation as part of a one-pot reaction for the conversion of SAMP hydra-zones into enantiomerically pure nitriles.

Enantiomerically pure alkylboranes arc known to be excellent reagents for asymmetric reduction but they can also be used to generate enantiomerically pure /V-borylimines by partial reduction of nitriles. Addition of organolithium and Grignard reagents to these compounds affords secondary carbinamines in moderate to good yield but low enantioselectivity13,14. The best results reported so far are shown below. 

Herrmann has prepared several unsymmetrical salts 7 from 1-alkyl-imidazoles (Scheme 6). The chirality was introduced, after N-alkylation of the imidazole by chloro acetonitrile, by addition of enantiomerically pure aminoalcohols onto the nitrile to form an oxazolidine ring [14],... 

Asymmetric synthesis based on INOC using a chiral nitrile oxides is a standard method for obtaining enantiomerically pure compounds. A useful synthesis of enantiomerically pure pyrano- and oxepanoisoxazole derivatives by application of INOC is presented in Eq. 8.71.109... 

Mateo, C., Chmura, A., Rustler, S. et al. (2006) Synthesis of enantiomerically pure (S)-mandelic acid using an oxynitrilase-nitrilase bienzymatic cascade a nitrilase surprisingly shows nitrile hydratase activity. Tetrahedron Asymmetry, 17, 320-323. 

Treatment of isoxazoline-fiised [60]fullerene 48 with NaOMe in the presence of MeOH gave the p-hydroxy nitrile derivative 49 in good yield <00SL361>. The synthesis of the enantiomerically pure cyclopropane amino acid 51 covalently attached to a fulleroisoxazoline has been achieved . 

The 1,3-dipolar cycloaddition of nitrile oxides and 2-methylfuran provides suitable precursors for a-amino acids such as L-furanomycin 448 that contains a dihydrofuran ring (495). By using a chiral nitrile oxide derived from mannitol bis(acetonide), the enantiomerically pure furoisoxazoline 449 has been obtained. Hydroboration-oxidation of the latter leads to the hydroxy-substituted annulated THF derivative 450, which is converted via dihydrofuran 451 to furanomycin 448 in enantiomerically pure form (Scheme 1.55). 

Cross coupling between an aryl halide and an activated alkyl halide, catalysed by the nickel system, is achieved by controlling the rate of addition of the alkyl halide to the reaction mixture. When the aryl halide is present in excess, it reacts preferentially with the Ni(o) intermediate whereas the Ni(l) intermediate reacts more rapidly with an activated alkyl halide. Thus continuous slow addition of the alkyl halide to the electrochemical cell already charged with the aryl halide ensures that the alkyl-aryl coupled compound becomes the major product. Activated alkyl halides include benzyl chloride, a-chloroketones, a-chloroesters and amides, a-chloro-nitriles and vinyl chlorides [202, 203, 204], Asymmetric induction during the coupling step occurs with over 90 % distereomeric excess from reactions with amides such as 62, derived from enantiomerically pure (-)-ephedrine, even when 62 is a mixture of diastereoisomcrs prepared from a racemic a-chloroacid. Metiha-nolysis of the amide product affords the chiral ester 63 and chiral ephedrine is recoverable [205]. 

The third group of target molecules comprises chiral carboxylic acid and their derivatives esters, amides and nitriles. Enantiomerically pure esters are prepared in an analogous manner to the enantiomerically pure alcohols discussed earlier [i.e. by esterase- or lipase-catalyzed hydrolysis or (trans)esterification]. However, these reactions are not very interesting in the present context of cascade reactions. Amides can be produced by enantioselective ammoniolysis of esters or even the... 

Intramolecular cycloaddition of nitrile ylides to olefinic dipolarophiles linked to the dipole by a three-atom chain leads to pyrazoles fused to five-membered rings. Work on stereoselectivity in such reactions has been carried out using the reactant 266 in which the alkene moiety is linked to the C-terminus via a tether that incorporates an enantiomerically pure (R) stereogenic group (165). Both diastereo-isomers 267 and 268 were isolated and it was found that the reaction showed moderate stereoselectivity favoring 267. 

In recent work, a homochiral substituent has been incorporated into the reactant to allow the separation of enantiomerically pure products. Thus, the homochiral reactant 288, prepared from (5)-1-phenylethylamine, gave a pair of diastereoisomers (289) and (290) that were separated by chromatography and identified via X-ray crystallography (178). The nitrile imine was generated by the hydrazonyl chloride-base route. The reaction showed only modest stereoselectivity that favored 289 when silver carbonate was used as the base but it was found that this was reversed when triethylamine was used. However, this was not the case for a related reaction (179). 

Enantiomerically pure 4,5-dihydroisoxazoles are prepared by controlling the stereochemistry of the cycloaddition by chiral auxiliaries connected either to the alkene31 33,37 41 or to the nitrile oxide22 26,4 2 4 3 components (see Section D. 1.6.1.2.1.). 

In general, the method of enzymatic cyanohydrin synthesis promises to be of considerable value in asymmetric synthesis because of the synthetic potential offered by the rich chemistry of enantiomerically pure cyanohydrins, including their stereoselective conversion into other classes of compounds such as a-hydroxy carboxylic acids or respective esters, w c-diols, / -aminoalcohols, aziridins, a-azido(amino/fluoro)nitriles, and acyloins [501, 516]. 

The use of a cationic aza-Cope rearrangement in concert with a Mannich cyclization has also been applied to the total synthesis of enantiomerically pure (—)-crinine (359) (205). In the event, nucleophilic opening of cyclopentenoxide with the aluminum amide that was formed on reaction of (/ )-a-methylbenzyl-amine and trimethylaluminum gave the amino alcohol 485 together with its (15,25) diastereomer. Although there was essentially no asymmetric induction in this process, the diastereomeric amino alcohols were readily separated by chromatography, and the overall procedure therefore constitutes an efficient means for the preparation of enantiomerically pure 2-amino alcohols from epoxides. When the hydrochloride salt derived from 485 was treated with paraformaldehyde and potassium cyanide, the amino nitrile 486 was formed. Subsequent Swem oxida-... 

The potential of the Darzens condensation as an alternative means of access to enantiomerically pure epoxy ketones, esters, nitriles, sulfones, etc., has long been recognized. Synthetically useful enantioselectivity was, nevertheless, not achieved until a few years ago when Arai and Shiori introduced the trifluoro-... 

Accordingly, we conducted experiments with CLEAs of MeHnL and PfNLase in tandem in a 90 10 DlPE-bulFer pH 5.5 medium [19]. The reaction proceeded to nearly full conversion (see Figure 16.4a) and the product ee was 94%. Combining both enzymes in a bienzymatic catalyst (combi-CLEA, Figure 16.4b) resulted in further improvement and 98% enantiomerically pure (S)-3a was obtained. It would seem that the nitrile intermediate is immediately hydrolysed in the combiCLEA particles, which supresses dififiision into the water phase and possible racemisa-tion. The amount of (S)-mandeUc amide ((S)-4a, see Figures 16.3 and 16.4, approx. 40%) that accompanied the formation of (S)-3a was more than would be expected from the data in Table 16.1 and made us aware of possible stereochemical effects on the acid/amide mechanistic switch [5] in PfNLase as will be discussed later. 

To aqcuire more insight in amide formation we undertook to study the hydrolysis of enantiomerically pure cyanohydrins. Nitrile le racemises too readily but the stereochemical integrity of (R)- and (S)-la could be maintained with careful adjustment of the reaction conditions (pH 6, 0°C). Thus, enantiomerically pure (R)- and (S)-la were subjected to hydrolysis in the presence of PfNLase (see Figure 16.9) [5]. It became clear that only 11% of amide was formed from the (R)-enan-tiomer, whereas the (S)-enantiomer was hydrolyzed into 55% amide and 45% acid under otherwise identical conditions (see Figure 16.9). Stereochemical integrity was fully maintained under the reaction conditions and 3a and 4a were formed with complete retention of configuration, as would be expected. 

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