Keto nitriles, reduction

White-rot fungus has been used as a biocatalyst for reduction and alkylation. The reaction of aromatic -keto nitriles with the white-rot fungus Curvularia lunata CECT 2130 in the presence of alcohols afforded alkylation-reduction reaction [291]. Alcohols such as ethanol, propanol, butanol, and isobutanol could be used (Figure 8.39d). 

Keto nitriles, such as 138, function admirably as substrates in reductive cycliza-tions [56, 57], Two product types are obtained, one the simple ketone 140, the other 139, incorporating the a-hydroxy ketone (ketol) functionality that is present in many natural products (note Eq. 42). Both controlled potential and constant current conditions have been utilized. Of the electrodes examined (Ag, Cd, Pb, Zn, C-fiber, and Sn), tin generally proved most effective. Using tin, the controlled potential reduction of 138 in i-PrOH at —2.8 V vs SCE (divided cell, ceramic diaphragm) afforded a 76% yield of ketol 139 accompanied by 2% of ketone 140. As illustrated in Table 7, the preference for ketol formation drops when the transformation is carried out at constant current or without using a diaphragm. 

Selective reduction of the nitrile group in 87% yield without the reduction of the carbonyl was achieved by stannous chloride [1153]. Oximes of keto nitriles are reduced preferentially at the oximino group by catalytic hydrogenation in acetic anhydride over 5% platinum on carbon (yield 85%)... 

XLIV) centers about elaboration of hydroxymethylene ketone (574) into the tricyclic diketone (578). Alkylation of keto nitrile 575 proceeds exclusively cis to the angular methyl groups as does the subsequent reductive methylation. These authors were not able to achieve aldol cycUzation of keto aldehyde 576 and consequently proceeded to enol lactone 577 The addition of a methyl group to 578 could be achieved regioselectively. Subsequently dehydration gave 579 and its endocyclic isomer which were separated chromatographically. 

POLYMER-SUPPORTED CHIRAL SULFONAMIDE CATALYZED REDUCTION OF j -KETO NITRILES A PRACTICAL SYNTHESIS OF (R)-FLUOXETINE... 

Enantioselective reduction of jS-keto nitriles to optically active 1,3-amino alcohols has been carried out in one step using an excess of borane-dimethyl sulfide complex as a reductant and a polymer-supported chiral sulfonamide as a catalyst with moderate to high enantioselectivity (Figure 3.11). The facile and enantioselective method to prepare optically active 1,3-amino alcohols has been used to prepare 3-aryloxy-3-arylpropylamine type antidepressant drugs, for example (l )-fluoxetine. 

The latter, with methylacrylate, using Triton B as a catalyst, was transformed into the methylpimelate 189 yielding, on Dieckmann cyclization, the ketoester 190. Upon acid treatment 190 gave the keto nitrile 191. Reduction (LiAlHJ of 191 led, in poor yield, to the hydroxyaldehyde 192. A two carbon unit was added to the aldehydic... 

Table 5 Reduction of Keto Nitriles Little and Mikesell... 

Polymer-supported chiral sulfonamides also proved to be efficient catalysts for the enantioselective reduction of P-keto-nitriles [54]. This was demonstrated in the synthesis of anti-depressant drugs -fluoxetine 43 and -duloxetine (Scheme 4.11). 

Oximes and Related Derivatives.—Beckmann fragmentation of a-hydroxy-ketoximes occurred with dichlorocarbene. For example, a chloroform-ethyl acetate solution of the 5a-hydroxy-6-oximinocholestane (134) gave the keto-nitrile (135) with acqueous NaOH in the presence of benzyltriethylammonium chloride. Improved reduction of nitrimines to nitramines with NaBH4 and acetic acid has been reported and is exemplified by the conversion of the nitrimino-cholestane (136) into the 6 8-nitramino-compound (137). ... 

Reductive amination of a-branched ketones and p-anisidine using Hantzsch ester as a hydride source and chiral Bronsted acid, TRIP, as a catalyst gave chiral p-branched amine (Scheme 5.17) [58]. This catalyst system was extended to three-component Kabachnik-Eields reaction, which uses phosphite as nucleophile instead of hydride, to give p-branched a-amino phosphonate [59]. Reductive ami-nation of p-keto ester or p-keto nitrile with trichlorosilane as a hydride source... 

The enantio- and diastereoselective bioreduction of 2-oxocycloalkanecarboni-triles 10 lead to the cis relative configuration of (3-hydroxy nitriles 10a [17]. These reductions were accomplished by whole cells of the yeast Saccharomyces montanus (Scheme 12.5). The presence of the acidic a-hydrogen is very important since (3-keto nitriles that are fully substituted in the a-position do not racemize under the bioreduction conditions. The products were transformed into optically active 2-amino and 2-aminomethyl cycloalkanols. 

This strategy has been extended by Maikov and Kocovsky to the reduction of imines/enamines derived from a-substituted P-keto nitriles and P-keto esters (Scheme 15.27, 131-134, H) [97dj. In this case, the fast enamine-imine... 

An efficient synthetic route to (10Z)- and (10 )-19-lluoro-la,25-dihydroxy vitamin D3 has been developed (488). The key feature of this pathway is the introduction of a 19-fluoromethylene group to a (5 )-19-nor-10-oxo-vitamin D derivative. The 10-oxo compound 445 has been obtained via a 1,3-dipolar cycloaddition reaction of (5 )-la,25-dihydroxyvitamin D with in situ generated nitrile oxide, followed by ring cleavage of the formed isoxazoline moiety with molybdenum hexacarbonyl. Conversion of the keto group of (5 )-19-nor-10-oxo-vitamin D to the E and Z fluoromethylene group has been achieved via a two-step sequence, involving a reaction of lithiofluoromethyl phenyl sulfone, followed by the reductive de-sulfonylation of the u-lluoro-j3-hydroxysulfone. The dye-sensitized photoisomerization of the (5 )-19-fluorovitamin D affords the desired (5Z)-19-fluorovitamin D derivatives, (10Z)- and (10 )-19-fluoro-la,25-dihydroxy-vitamin D3. 

Reduction of vinyloxiranes The substrates are reduced rapidly by Sml2 to (E)-allylic alcohols without effect on keto, ester, or nitrile groups. Chiral substrates are reduced to optically active alcohols with complete retention of stereochemistry. 

A different approach involving cyanohydrin formation from the 3-keto sugar was also explored in the D-Fru series (Scheme 17). A mixture of epimeric cyanohydrins was quantitatively formed by reaction with sodium cyanide in methanol, albeit without stereoselectivity. Chromatographic separation of (R)- and (A)-isomers was straightforward and the former epimer was selected to exemplify the two-step transformation into an OZT. Reduction of this nitrile by lithium aluminum hydride led to the corresponding aminoalcohol, which was further condensed with thiophosgene to afford the (3i )-spiro-OZT in ca. 30% overall yield. Despite its shorter pathway, the cyanohydrin route to the OZT was not exploited further, mainly because of the disappointing yields in the last two steps. 

Keto ester 67 was converted to the unsaturated nitrile 70 in a routine manner. The latter proved to be an exceptionally useful intermediate. Concern that the significant steric demands which are associated with the formation of a sigma bond to the fully substituted beta carbon of the unsaturated nitrile would prevent reaction from occurring, were allayed by the discovery that the controlled potential reduction of 70 at —2.4 V in the presence of dimethyl malonate as the proton donor, alforded a 90% isolated yield of the requisite [3.2.1] adduct 71. This material was subsequently converted to enone 72 [42], a convergent point with an existing synthesis of quadrone (59). 

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