Lithium borohydride, reduction ketones

A convenient method for the specific introduction of 2H or 3h (or both) into a molecule is by ketone reduction with labeled metal hydride. Beale and MacMillan (10) have utilized this method for the preparation of GAs labeled at the 1, 2 or 3 positions from GA3 or GA7 (Figure 12). One point of interest is the lithium borohydride reduction of the enone formed by manganese dioxide oxidation of GA3 or GA7. When the reaction is carried out in anhydrous tetrahydrofuran it proceeds in two steps. Initially the lithium enolate is formed which incorporates a proton at carbon-2 from the acid used in the work-up, forming the 3 ketone. This ketone is reduced to the 3 -alcohol by the borohydride which is decomposed more slowly than is the lithium enolate. Thus it is possible to introduce two different labels in a single reaction. 

In non-hydroxylic solvents, the effects of the cation co-ordination become important, particularly if the cation is Li+ or Zn + 2. Lithium borohydride reductions of cyclohexanone, in THF, for example, are strongly inhibited by addition of the stoichiometric amount of the lithium specific [2.1.1]cryptand (Handel and Pierre, 1975). In the reduction of a,P-unsaturated ketones, lithium borohydride shows a strong selectivity for 1,2-addition (D Incan et al., 1982a,b) but in the presence of the cryptand, conjugate addition is favoured indeed, the selectivity is then indistinguishable from tetrabutyl-ammonium borohydride (D lncan and Loupy, 1981 Loupy and Seyden-Penne, 1979, 1980). 

In contrast to the usual reaction of aromatic aldehydes with cyclic ketones o-nitrobenzaldehyde condenses with 17-ketones to produce good yields of seco-acids, a reaction which has been applied to the preparation of 16-oxa-steroids. Thus, 3 -hydroxy-5a-androstan-17-one or its acetate affords the seco-steroid (153), which can be oxidised either as the free acid by ozone and alkaline hydrogen peroxide to the diacid (155) or, as its methyl ester (154), with chromium trioxide to the monomethyl ester (156). Diborane reduction of the diacid (155) or lithium aluminium hydride reduction of the dimethyl ester (157) gave the trans-diol (158), cyclised with toluene-p-sulphonic acid to 16-oxa-androstan-3)5-ol (159) or, by oxidation with Jones reagent to the lactone (152) (as 3-ketone) in quantitative yield. This lactone could also be obtained by lithium borohydride reduction of the monomethyl ester (156), whilst diborane reduction of (156) and cyclisation of the resulting (151) afforded the isomeric lactone (150). The diacid (155) reacted with acetic anhydride to afford exclusively the cis-anhydride (161) which was reduced directly with lithium aluminium hydride to the cis-lactone (160) or, as its derived dimethyl ester (162) to the cis-diol (163) which cyclised to 16-oxa-14)5-androstan-3) -ol (164). 

The interesting conversion of nornarceine (181) into the rhoeadine analogues (187) and (188) has been carried out as shown in Scheme 9. Nornarceine (181), obtained from (— )-a-narcotine, was heated in base to afford the enamine (182) which readily cyclized in dilute acetic acid to the y-lactone (183). Upon standing, (183) was oxidized to the ketone (184). Lithium borohydride reduction led to the c/.s-acid (185). The derived ds-fused lactone (186) was then reduced to the hemi-acetal (187) which upon O-methylation with trimethyl orthoformate gave (188). The structure of the methiodide salt of (187) was confirmed by an X-ray analysis. The phthalideisoquinoline alkaloid (— )-bicuculline (189) was then converted into naturally occurring (+ )-rhoeadine (190) by an analogous route. Since (— )-bicuculline was obtained from (—)-)3-hydrastine, whose synthesis had been reported in 1950, this transformation represents the first total synthesis of a rhoeadine alkaloid. ... 

Sodium borohydride and lithium aluminum hydride react with carbonyl compounds in much the same way that Grignard reagents do except that they function as hydride donors rather than as carbanion sources Figure 15 2 outlines the general mechanism for the sodium borohydride reduction of an aldehyde or ketone (R2C=0) Two points are especially important about this process... 

The success of the halo ketone route depends on the stereo- and regio-selectivity in the halo ketone synthesis, as well as on the stereochemistry of reduction of the bromo ketone. Lithium aluminum hydride or sodium borohydride are commonly used to reduce halo ketones to the /mm-halohydrins. However, carefully controlled reaction conditions or alternate reducing reagents, e.g., lithium borohydride, are often required to avoid reductive elimination of the halogen. 

The stereoselective total synthesis of both ( )-corynantheidine (61) (170,171) (alio stereoisomer) and ( )-dihydrocorynantheine (172) (normal stereoisomer) has been elaborated by Szdntay and co-workers. The key intermediate leading to both alkaloids was the alio cyanoacetic ester derivative 315, which was obtained from the previously prepared ketone 312 (173) by the Knoevenagel condensation accompanied by complete epimerization at C-20 and by subsequent stereoselective sodium borohydride reduction. ( )-Corynantheidine was prepared by modification of the cyanoacetate side chain esterification furnished diester 316, which underwent selective lithium aluminum hydride reduction. The resulting sodium enolate of the a-formyl ester was finally methylated to racemic corynantheidine (171). 

Bromination to 4 and substitution of the bromine by an amine gives 5. Sodium borohydride reduction of the ketone to an alcohol 6 is followed by a resolution with (-)-di-/ -toluoyltartaric acid and reduction of the ester group with lithium aluminum hydride to give diol 7. Catalytic debenzylation gives albuterol, sometimes called salbutamol. 

The original racemic patents described the use of resolution to give a chiral oxirane, such as 25, as an intermediate or the use of a chiral auxiliary (20) to produce the salmeterol enantiomers. Alkylation of chiral amine 20 with 2-benzyloxy-5-(2-bromo-acetyl)-benzoic acid methyl ester, followed by diastereoselective reduction of the ketone with lithium borohydride furnished intermediate 21 after chromatographic separation of the diasteromers. Removal of the benzyl group and the chiral auxiliary was... 

Isosorbide (3) and isomannide (4) act as chiral auxiliaries for the sodium borohydride reduction of some prochiral ketones optical yields of up to 20% were achieved. It seems that the isohexides form chiral complexes with sodium borohydride, whereby the chiral information is transferred to the substrate.219 Optical active alcohols were obtained by reduction of appropriate ketones with sodium or lithium borohydride in the presence of isosor-bide.219 Asymmetric reduction of propiophenone using sodium borohydride, modified with (+)-camphoric acid and isosorbide, resulted in C -phenylethylcarbinol in 35% enantiomeric excess.2,9b... 

In other reports, /i-cyclodcxtrins have been used to induce asymmetry in borohydride reduction of ketones,166 a diastereoselective reduction has been controlled167 by a real lyltricarbonyl iron lactone tether , a phosphinamide has been combined with a dioxaborolidine unit as an activated, directed catalyst for ketone reduction,168 reductive amination using benzylamine-cyanoborohydride converts 3-hydroxy ketones into syn-1,3-amino alcohols,169 l-(3,4-dimethoxyphenyl)-2-(2-methoxyphenoxy)propan-l-one has been reduced diastereoselectively,170 and production of chiral alcohols via (i) Itsuno-Corey and Brown procedures171 and (ii) lithium aluminium hydride modified by chiral nucleophiles172 has been reviewed. 

Lithium borohydride is intermediate in activity as a reducing agent between lithium aluminium hydride and sodium borohydride. In addition to the reduction of aldehydes and ketones it will readily reduce esters to alcohols. It can be prepared in situ by the addition of an equivalent quantity of lithium chloride to a 1m solution of sodium borohydride in diglyme. Lithium borohydride should be handled with as much caution as lithium aluminum hydride. It may react rapidly and violently with water contact with skin and clothing should be avoided. 

Methylation of the lactam nitrogen and condensation with methyl benzoate in the presence of lithium diethylamide in THF afforded a ketone, which, on sodium borohydride reduction, yielded racemic isocynometrine (99) as the major component of a mixture of two epimeric phenyl carbinols (Scheme 8) (155). Racemic anantine (94) and cynometrine (95) have been synthesized analogously, starting from 4-formyl- 1-methylimidazole (155). 

Lithium borohydride decomposed by /V-benzoylcysteine (61) or /V/v -dibenzoylcystine (62), a sulfur-containing modifier, is a highly efficient chiral reducing agent. A complex prepared from (61), t-butyl alcohol and LiBH4 affords carbinols in maximum 92% ee by the reduction of aryl alkyl ketones in THF at -78 °C (Scheme 13). A LiBH4 complex with (62) and t-butyl alcohol is useful for the reduction of -keto esters to give (R)-P-hydroxy esters in up to 91 % ee. In both cases the use of r-butyl alcohol is essential in order to achieve efficient enantiofacial differentiation. ... 

Comins has reported that simple esters can be converted to secondary alcohols in cxie step with a mixture of Grignard reagent and lithium borohydride (LiBH4) in THF. The reaction is conducted at 0 to -10 C to preclude undesired reduction of the ester by LiBH4. Once acylation has occurred, reduction of the intermediate ketone occurs more rapidly than does addition of a second equivalent of the Grignard... 

Reductions can also be performed in water. Systems for reduction of ketones in water can be water-compatible sodium and lithium borohydrides, amino acid-based cationic surfactants to reduce aryl ketones [19], iridium hydrides used in transfer hydrogenations, such as [Cp Irm(bpy)H]+ (Cp — q5-C5Mes, bpy = 2,2 - bipyridine) [20], and IrHCI2(cod) 2 with a chiral diaminodiphosphine ligand to form secondary alcohols in high enantioselectivity and almost quantitative yield (Equation 4.12) [21]. 

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