Reduction of Diketones

Edegger, K., Stampfer, W., Seisser, B. et al. (2006) Regio- and stereoselective reduction of diketones and oxidation of diols by biocatalytic hydrogen transfer. European Journal of Organic Chemistry, (8), 1904—1909. 

Much the same situation pertains to the asymmetric reduction of diketones and ketoesters. Thus, some years ago, a yeast reduction of the diketone (12) formed a key step in the preparation of important steroids (Scheme 9). Work in... 

Reduction of diketones such as pentane-2,4-dione using (RfBiNAP-RuCF under hydrogen (75 100 atm) gives the corresponding diol, in this case (R),(R)-2,4-pentanediol with an excellent diastereomer ratio (98 %) and optical purity (>99 %)[48]. 

Table 9.1 Enzyme-catalysed stereoselective reduction of diketones/keto esters to keto alcohols/hydroxy esters...

The reduction of diketones is very complex. They can be partially reduced to ketols (hydroxy ketones) or ketones, or completely reduced to hydrocarbons. Depending on the mutual distance of the two carbonyl groups and reagents used, carbon-carbon bond cleavage may occur and may be followed by recyclizations or rearrangements. Some reactions may result in the formation of alkenes. Quinones react in their own specific way. 

Reduction of diketones to either hydroxy ketones or diols can be accomplished by different biochemical reductions [327, 834] Procedure 50, p. 218). 

A very important application of ADH from I. kefir is the diastereoselective reduction of diketones. The enzyme reduces both oxo functions highly diastereoselec-tively so that (2R,5R) -hexanediol could be produced starting from 2,5-hexanedione in quantitative yields with ee > 99% and de > 99% [7] (Scheme 2.2.4.2). For this process, resting whole cells of L. kefir were used. 

For a review of Clemmensen reduction of diketones and unsaturated ketones, see Buchanan Woodgate Q. Rev. Chem. Soc. 1969, 23, 522-536. 

So far, most microorganisms and enzymes derived therefrom have been used in the reduction of a single keto group of p-keto or a-keto compounds [68-71], Recently, Patel et al. [72] have demonstrated the stereoselective reduction of 3,5-dioxo-6-(benzyloxy)hexanoic acid, ethyl ester (41), to (3,S, 5R)-dihydroxy-6-(benzyloxy)hexanoic acid, ethyl ester (42a) (Fig. 14). The compound (42a) is a key chiral intermediate required for the chemical synthesis of [4-[4a,6P(E)]]-6-[4,4-bis(4-fluorophenyl)-3-(l-methyl-lH-tetrazol-5-yl)-l,3-butadienyl]-tetrahydro-4-hydroxy-2H-pyran-2-one, compound R-( + )-(43), a new anticholesterol drug that acts by inhibition of HMG CoA reductase [73], Among various microbial cultures evaluated for the stereoselective reduction of diketone (41), cell suspensions of Aci-... 

The Ni/tartaric acid/NaBr catalyst system has been extensively studied. A variety of ketone substrates have been reduced with Ni/tartaric acid/NaBr catalysts with variable enantioselectivities, but the highest (>85% ee) are obtained for the reductions of P-keto esters and P-diketones (Schemes 12.60 and 12.61).5 Asymmetric reduction of diketones results in the formation of mesa and chiral diols. The highest meso chiral diol ratio of 2 98 and enantioselectivities of 98% ee are obtained with modified Raney nickel catalysts treated by sonication.5... 

The excellent enantioselectivity and wide scope of the CBS reduction have motivated researchers to make new chiral auxiliaries [3]. Figure 1 depicts examples of in situ prepared and preformed catalyst systems reported since 1997. Most of these amino-alcohol-derived catalysts were used for the reduction of a-halogenated ketones and/or for the double reduction of diketones [16-28]. Sulfonamides [29,30], phosphinamides [31], phosphoramides [32], and amine oxides [33] derived from chiral amino alcohols were also applied. The reduction of aromatic ketones with a chiral 1,2-diamine [34] and an a-hydroxythiol [35] gave good optical yields. Acetophenone was reduced with borane-THF in the presence of a chiral phosphoramidite with an optical yield of 96% [36]. 

The C2-symmetric azetidines 34 can be synthesized from anti- 1,3-diols <2000EJ01815>. An enantioselective reduction of diketones 32 using [Ru/(7 )or(A)-BINAP] catalytic systems leads to the synthesis of 1,3-diols 33, which, after mesylation followed by cyclization with amines, afford azetidines 34 with ee higher than 95% (Scheme 27). 

Reduction of diketone 169 with sodium boro hydride proceeded stereoselectively to give diol 170, as a single isomer in 83% yield (Scheme 33) <1999T7471>. 

Three main types of redox reactions of keto compounds leading to the formation of metal enolates have been reported (i) two-electron reduction of diketones or a,(f-unsaturated ketones or esters (equation 1), (ii) oxidative addition reactions (equation 2) and (iii) threefold deprotonation of diketoamines followed by a two-electron oxidation of the trianion by the metal (equation 3). 

Other reactions dealing with the reduction of -diketonates by amines have been reported by Nemykin and coworkers, such as the reduction of LnPc(dik)2, Ln = Sm, Eu, Gd and Lu, with aliphatic amines with formation of amine radicals identified by EPR, and by Yamamoto and coworkers , stating that pyridine promotes the reduction of NiR(acac)(PPh3), R = Me, Et, to Ni(PPh3)2(C2H4) with formation of methane or ethane, depending on R. 

Generally, reduction of diketones 12 (or in some cases their hexacarbonyldicobalt complexes) yields better stereoselectivities than the related ethylenic diketones 11, especially when R is a sterically demanding group. In addition, the propargylic diols obtained can be easily transformed not only into the saturated... 

The concept of in situ protection of the less hindered or more Lewis basic of two ketones to enable selective reduction of the usually less reactive groups has been successfully developed. The sterically hindered Lewis acid MAD (78) derived from BHT and trimethyl aluminum was used to coordinate preferentially to the less hindered ketone and DIBAL-H reduced the more hindered ketone that remained un-complexed. An approximate order of comparative reactivity for various classes of ketones has been established. The selectivity was improved by using the more hindered Lewis acid MAB (79) and/or di-bromoalane as the reducing agent. The discrimination between aromatic ketones is good but less successful between two dialkyl ketones. The chemoselectivity was demonstrated in the reduction of diketone (80) to keto alcohol (81) in 87% yield and excellent selectivity (equation 20). 

The NaBH4 reduction of a pentacyclic cage diketone in EtOH afforded a 38 62 mixture of endo-endo and exo-endo diol. " In contrast, solid-state NaBH4 reduction of diketone provided exclusively the corresponding endo-endo diol. " This indicates that the hydride transfer occurs exclusively at the exo-face of the carbonyl group in solid state reaction (Scheme 5.52). 

Asymmetric reduction of diketone is one of the easiest ways to obtain chiral di-ols. Bisoxazaborolidine having two catalytic centers seems to be especially good at catalyzing the enantioselective reduction of prochiral diketones. 1,6-Diphe-... 

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