Diastereoselective reduction of ketones

Stereoselectivity in reductions of acyclic oximes depends on the configuration of C=N bond. ( )-Isomer of oxime 89 produced syn-hydroxylamine 90 in excellent stereoselectivity in reaction with phenyldimethylsilane-trifluroacetic acid while giving anti-product in the reaction with lithium aluminium hydride. Stereoselectivity in reductions of (Z)-isomers of 89 was substantially lower in both cases (equation 62) . It can be assumed that the rules of stereoselectivity established in diastereoselective reduction of ketones can be applied to reduction of oximes as well. 

Highly diastereoselective reduction of ketones.3 The stereoselective reduction of ketones has been previously reported using chirally modified hydride... 

Diastereoselective reduction of ketones. Trialky Isilanes can reduce aldehydes and ketones in the presence of a catalytic amount of tetrabutylammonium fluoride in HMPT cf. reductions with activated hydrosilanes, II, 554). Under these conditions esters and nitriles are not reduced. The reaction is stereoselective. Thus 2-methylcyclohcxanone is reduced selectively to cA-2-methylcyclohexanol the cvT-selectivity depends on the bulkiness of the hydrosilanc, being highest (95%) with triphenylsilane. 

The combination of NaBILj and CeCH used for chemoselec-tive or diastereoselective reduction of ketones (see Original Commentary and Hirst Update) could also be employed for the reduction of carboxylic esters. In the presence of a catalytic amount of CeCl3-7H20 (1 mol%), various methyl carboxylates were reduced to alcohols with NaBHj in EtOH at ambient temperature in good to high yields (75-95%). 

Diastereoselective Reduction of Ketones by Baker s Yeast. Asymmetric microbial reduction of oc-substituted ketones leads to the formation of diastereomeilc syn-and anh -products. Because the chiral center on the a-position of the ketone is stereochemically labile, rapid in-situ racemization of the substrate enantiomers occurs via enolization ° - leading to dynamic resolution [67, 895, 896]. Thus, the ratio between the diastereomeric syn- and anti-products is not 1 1, but is determined by the selectivities of the enzymes involved in the reduction process [897]. Under optimal conditions it can even be as high as 100 0 [898]. 

Diastereoselective Reduction of Ketone Carbonyl Group of 1,3-Keto Ester... 

Sodium or tetramethylammonium triacetoxyborohydride has become the reagent of choice for diastereoselective reduction of P-hydroxyketones to antidiols. Trialkylborohydrides, eg, alkaH metal tri-j -butylborohydrides, show outstanding stereoselectivity in ketone reductions (39). 

Scheme 5. Corey s diastereoselective catalytic reduction of ketone 21.

As practiced in the preceding syntheses by Evans and Nishiyama and Yamamura, the A-ring fragment 43 is formed through substrate-directed vinylogous aldol reaction of the Brassard-type diene 19 and the chiral aldehyde 42, which is prepared using Brown s protocols for enantioselective allylation [53], followed by hydroxy-directed nnn-diastereoselective reduction of the C3 ketone (Me4NB(OAc)3H) [41],... 

Diastereoselective reduction of the aldol 221/ can be achieved using AIH3 in toluene at —78°C. The corresponding ra-diol is preferentially formed. The diol can be protected with isopropylidene acetal to provide tricyclic compound 222. This can be converted to conformationally rigid C-l ketone 223 by deprotection of the PMB group and successive oxidation with PDC (Scheme 7-73). 

The cathodic reduction of ketones ( )-RCHMeC(0)R (R = Ph, R = Ph, Me R = cyclohexyl, R = Me) afforded mixtures of diastereomeric alcohols. The origin of the diastereoselectivity, which depends on R and R and the electrolysis conditions, is discussed [333]. Acyclic and cyclic ketones with a chiral center in the fi-position yielded diastereomers in a ratio different from that obtained by LiAlH4-reduction [334]. 

Reduction of chiral ketoximes results in formation of a new stereogenic center. Although mixtures of stereoisomers are generally obtained, kineticaUy controlled reduction of cyclic oximes (e.g. 86, equation 59 and 87, equation 60) with sodium cyanoborohydride can proceed with high diastereoselectivity Stereoselectivity in these reactions closely resembles that of reduction of ketones with complex hydrides featuring attack from the least hindered side. 

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... 

A series of 2-substituted cyclohexanones was studied over a wide range of temperature in an attempt to optimize the diastereoselectivity of diisobutylaluminium phenoxides in the reduction of ketones.161 Hydride transfer dominates at high temperature, but a Meerwein-Ponndorf-Verley-type interconversion of the aluminium alcoholate intermediates (via the reactant ketone) is an important factor in diastereoselection at low temperature. 

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. 

Usually, a stoichiometric amount of metal hydride, such as a selectride reagent, is required for diastereoselective reduction of aliphatic ketones to secondary alcohols. Now the same purpose can be achieved by the Ru-catalysed diastereoselective... 

Finally, Corey reduction was used to solve the particular problem of the diastereoselective reduction of the ketone in C-15 in a prostaglandin synthesis. Corey reported a selectivity of 90 10.39 We have investigated the reduction of a modified prostaglandin and, despite considerable efforts,... 

Fig. 10.22. Diastereoselective reduction of /3-hydroxy-ketones to onh-configured 1,3-diols.

Diastereoselective reduction of acyclic a, -dialkoxy ketones.3 Reduction of the ketone 2 with this hydride results in the alcohol 3 with high syn-selectivity (97 3). The same syn-selectivity is observed with lithium trisiamylborohydride, but the yield is lower. The product was used for a synthesis of (+ )-4, a pheromone of a species of ants. 

Ketone reduction using Sml2 can be highly diastereoselective. For example, in Corey s synthesis of the diterpenoid natural product atractyligenin, Sml2-mediated reduction of ketone 7 proceeded with complete diastereocontrol to give secondary alcohol 8 in 90% yield (Scheme 4.6).12... 

Keck also reported the diastereoselective reduction of p-amino ketones using Sml2 in THF with MeOH as the proton source.17 In this case, reduction of A-acyl derivatives gave l,3-,syra-amino alcohols, whereas the reduction of A-aryl derivatives afforded l,3-a n -amino alcohols (Scheme 4.9).17... 

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