Ketone stereoselective reduction

Other Borohydrides. Potassium borohydride was formerly used in color reversal development of photographic film and was preferred over sodium borohydride because of its much lower hygroscopicity. Because other borohydrides are made from sodium borohydride, they are correspondingly more expensive. Generally their reducing properties are not sufficiently different to warrant the added cost. Zinc borohydride [17611-70-0] Zn(BH 2> however, has found many appHcations in stereoselective reductions. It is less basic than NaBH, but is not commercially available owing to poor thermal stabihty. It is usually prepared on site in an ether solvent. Zinc borohydride was initially appHed to stereoselective ketone reductions, especially in prostaglandin syntheses (36), and later to aldehydes, acid haHdes, and esters (37). 

A noteworthy development is the use of KH for complexing alkylboranes and alkoxyboranes to form various boron hydrides used as reducing agents in the pharmaceutical industry. Potassium tri-j -butylborohydride [54575-50-7] KB(CH(CH2)C2H )2H, and potassium trisiamylborohydride [67966-25-0] KB(CH(CH2)CH(CH2)2)3H, are usefiil for the stereoselective reduction of ketones (66) and for the conjugate reduction and alkylation of a,P-unsaturated ketones (67). 

A McMurry coupling of (176, X = O Y = /5H) provides ( )-9,ll-dehydroesterone methyl ether [1670-49-1] (177) in 56% yield. 9,11-Dehydroestrone methyl ether (177) can be converted to estrone methyl ether by stereoselective reduction of the C —double bond with triethyi silane in triduoroacetic acid. In turn, estrone methyl ether can be converted to estradiol methyl ether by sodium borohydride reduction of the C17 ketone (199,200). 

Stereoselective reduction of ketones to alcohols by means of boiohydncle reagents (U S-BU3BH or t-BuCIBR (or lormation ol chiral alcohols)... 

Bicyclo[3.3.1]nonan-9-one is another ketone that exhibits interesting stereoselectivity. Reduction by hydride donors is preferentially syn to electron-attracting substituents at C-5 (X = EWG in the structure shown below) and anti to electron-releasing substituents (X = ERG below). These effects are observed even for differentially substituted phenyl... 

The properties of chlorine azide resemble those of bromine azide. Pon-sold has taken advantage of the stronger carbon-chlorine bond, i.e., the resistance to elimination, in the chloro azide adducts and thus synthesized several steroidal aziridines. 5a-Chloro-6 -azidocholestan-3 -ol (101) can be converted into 5, 6 -iminocholestan-3l -ol (102) in almost quantitative yield with lithium aluminum hydride. It is noteworthy that this aziridine cannot be synthesized by the more general mesyloxyazide route. Addition of chlorine azide to testosterone followed by acetylation gives both a cis- and a trans-2iddMct from which 4/S-chloro-17/S-hydroxy-5a-azidoandrostan-3-one acetate (104) is obtained by fractional crystallization. In this case, sodium borohydride is used for the stereoselective reduction of the 3-ketone... 

The milder metal hydnde reagents are also used in stereoselective reductions Inclusion complexes of amine-borane reagent with cyclodexnins reduce ketones to opucally active alcohols, sometimes in modest enantiomeric excess [59] (equation 48). Diisobutylaluminum hydride modified by zmc bromide-MMA. A -tetra-methylethylenediamme (TMEDA) reduces a,a-difluoro-[i-hydroxy ketones to give predominantly erythro-2,2-difluoro-l,3-diols [60] (equation 49). The three isomers are formed on reduction with aluminum isopropoxide... 

Based on information accrued during the stereochemical elucidation, macrolactone 85 was identified as a viable synthetic intermediate (Scheme 12). The authors were cognizant of the potential challenges that could arise. First, the required formation of a trisubstituted alkene in a projected Horner-Emmons macrocyclization was without strong precedent. Also, this strategy would necessitate a stereoselective reduction of the Cl5 ketone, which was predicted to be feasible based on MM2 calculations. 

Chemo- and stereoselective reduction of (56) to (55) is achieved In highest yield by sodium borohydride in ethanol. The isolated ketone is reduced more rapidly than the enone and (55) is the equatorial alcohol. Protection moves the double bond out of conjugation and even the distant OH group in (54) successfully controls the stereochemistry of the Simmons-Smith reaction. No cyclopropanation occurred unless the OH group was there. Synthesis ... 

Preparative-scale fermentation of papaveraldine, the known benzyliso-quinoline alkaloid, with Mucor ramannianus 1839 (sih) has resulted in a stereoselective reduction of the ketone group and the isolation of S-papaverinol and S-papaverinol M-oxide [56]. The structure elucidations of both metabolites were reported to be based primarily on ID and 2D NMR analyses and chemical transformations [56]. The absolute configuration of S-papaverinol has been determined using Horeau s method of asymmetric esterification [56]. The structures of the compounds are shown in Fig. 7. 

Carballeira, J.D., Alvarez, E., Campillo,M,etal. (2004)DiplogelasinosporagrovesiilNll 171018, anew whole cell biocatalyst for the stereoselective reduction of ketones. Tetrahedron Asymmetry, 15 (6), 951-962. 

One of the fundamental operations in organic synthesis remains the stereoselective reduction of carbonyl groups1241. In a process related to that reported by Hosomi et u/.[25], using hydrosilanes as the stoichiometric oxidant and amino acid anions as the catalytic source of chirality, a variety of ketones were reduced in good to excellent yield and with good stereoselectivity1261. This process reduces the amount of chiral catalyst needed and utilizes catalysts from the chiral pool that can be used directly in their commercially available form. 

The stereoselective reduction may be applied to a variety of ketones. Some examples of reductions, as a function both of ketone substrate and amino acid catalyst are provided in Table 11.9. The full scope of this procedure 26-281 has... 

LaRonde, F.J., Brook, M.A. Stereoselective Reduction of Ketones Using Extracoordinate Silicon Cj-Symmetric Ligands, Inorganica Chim. Acta. 

Compound 59 was prepared in six steps starting from iV-(/>-methoxybenzyl)glycine ethyl ester and (i )-O-acetyl-atrolactic chloride, as reported in Section 11.11.7.3. Stereoselective reduction of 59 with BH3 at the carbonyl in position 8 (the only ketone among the other carbonyls) gave compound 60 in high diastereomeric purity (>95%). This diol was further opened in basic conditions and lactonized (Scheme 5) to produce an omuralide analogue 61 which can be potentially selective for proteasome inhibition <20010L1395>. 

Stereoselective reduction of a,(i-unsaturated ketones using lithium aluminium hydride has only been reported in conjunction with the ephedrine bases either in a two-phase system (80-90% yield, ee >70%) or immobilized on a polymer [18, 19]. 

For steroidal ketones and a-ketols, stereoselective cathodic reductions have been described [343]. The stereoselective reductive ring opening of epoxyketones to a ke-toalcohol has been used in the conversion of the corresponding steroids [344, 345]. 

Racemic warfarin (65), a vitamin K antagonist, has been used for decades both as an oral anticoagulant in man and as a rodenticide. The metabolism of this drug has been found to be substrate-enantioselective 9S-warfarin is considered as more active than the 9R-antipode. In mammalian systems, warfarin undergoes a stereoselective reduction of the ketonic side chain [176,177], affording mainly the 9R,llS-alcohol (71), but the major biotransformation route involves substrate-enantioselective aromatic hydroxylations at 4 -, 6-, 7- or 8-positions... 

The applications of sodium acyloxyborohydrides, formed from sodium borohydrides in carboxylic acid media, are reviewed. ° Useful reviews of the stereoselective reduction of endocyclic C=N compounds and of the enantioselective reduction of ketones have appeared. ... 

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