Ketones chiral reduction

Reduction of ot, -epoxy ketones chiral aldols.3 a,p-Epoxy ketones are reduced by Sml2 in THF/CH3OH at -90° to p-hydroxy ketones with retention of stereochemistry at the p-, but not at the a-position. 

Asymmetric reduction of prochiral ketones. Chiral metal hydrides previously investigated have been effective only for asymmetric reduction of aromatic or a,p-ucclylenic ketones. This new reagent unexpectedly reduces straight-chain aliphatic ketones such as 2-bulanonc and 2-octanone to the corresponding (S)-alcohols in 76%... 

Another Ru(BINAP)-catalyzed asymmetric hydrogenation that has been performed at manufacturing scale involves the reduction of a functionalized ketone. The reduction of hydroxyacetone catalyzed by [NH2Et2]+[ RuCl(p-tol-BINAP) 2 (li-CI)3 (39) proceeds in 94% ee (Scheme 12.11).46 The chiral diol (40) is incorporated into the synthesis of levofloxacin (41), a quinolinecarboxylic acid that exhibits marked antibacterial activity. Current production of 40 is 40 tons per year by Takasago International Corp.46... 

Y. Senda, Role of the Fleteroatom on Stereoselectivity in the Complex Metal Flydride Reduction of Six-membered Cyclic Ketones, Chirality 2002, 14, 110-120. 

Rh and Ir complexes stabilized by tertiary (chiral) phosphorus ligands are the most active and the most versatile catalysts. Although standard hydrogenations of olefins, ketones and reductive aminations are best performed using heterogeneous catalysts (see above), homogeneous catalysis becomes the method of choice once selectivity is called for. An example is the chemoselective hydrogenation of a,/ -unsaturated aldehydes which is a severe test for the selectivity of catalysts. 

Asymmetric reduction of ketones. Chiral ketals 2, obtained by reaction of 1 with prochiral ketones, are reduced diastereoselectively to 3 by several aluminum hydride reagents, the most selective of which is dibromoalane (LiAIHj-AIBr, 1 3). Oxidation and cleavage of the chiral auxiliary furnishes optically active alcohols (4) in optical yields of 78-96% ee (equation 1). 

Chiral Ligand of LiAlH4 for the Enantioselective Reduction of a,p-Unsaturated Ketones. Enantioselective reductions of a,p-unsaturated ketones afford optically active ally lie alcohols which are useful intermediates in natural product synthesis. Enantioselective reduction of a,p-unsaturated ketones with LiAlH4 modified with chiral amino alcohol (1) affords optically active (S)-allylic alcohols with high ee s. When 2-cyclohexen-l-one is employed, (5)-2-cyclohexen-l-ol with 100% ee is obtained in 95% yield (eq 2). This is comparable with the results obtained using LiAlH4-chiral binaphthol and chiral 1,3,2-oxazaborolidine. ... 

In their role as enantioselective catalysts for the reduction of prochiral ketones, chiral oxazaborolidines have been used for the preparation of prostaglandins, PAF antagonists, a key intermediate of ginkgolide B, bilobalide, a key intermediate of forskolin, (/ )- and (S)-fluoxetine, (R)- and (S)-isopreterenol, vitamin D analogs, the carbonic anhydrase inhibitor the dopamine D1 agonist A-77636, ... 

Enantioselective Reduction of Imines and Ketoxime O-Ethers. In addition to the reduction of prochiral ketones, chiral oxazaborolidines have been employed as enantioselective reagents and catalysts for the reduction of imines (eq 11) and ketoxime O-ethers (eq 12) - to give chiral amines. It is interesting to note that the enantioselectivity for the reduction of ketoxime O-ethers is opposite that of ketones and imines. For more information, see 2-Amino-3-methyl-l,l-diphenyl-I-butanol. 

Several polymers can be synthesized (Chapter 67), enzymes are used to carry out chiral reduction of a ketone (Chapter 64), and a unique synthesis of ferrocene is presented (Chapter 29). 

Most often, asymmetry is created on conversion of a prochiral trigonal carbon of carbonyl, enol, imine, enamine, and olefin groups to a tetrahedral center. One of the easiest methods for the preparation of optically active alcohols is the reduction of prochiral ketones. This transformation is achieved using chiral reductants in which chiral organic moieties are ligated to boron or to a metal hydride (Table 4.9). 

Oxazaborolldines have emerged as important reagents for the enantioselective reduction of a variety of prochiral ketones. CBS reduction (chiral oxazaborolidine-catalyzed reduction)of unsymmetrical ketones with diphenyl oxazaborolidine in the presence of BH3 proceeds catalytically to provide alcohols of predicable absolute stereochemistry in high enantiomeric excess. 

Chiral reductions are now quite common with these reagents when used either in stoichiometric amounts [CT4, MT6, SCI] or in catalytic amounts in the presence of BH3 THF, catecholborane [G6, GB6, QWl, SK5], or BH3 Me2S as achiral reducing co-reagent [DS6, JM3, N5, S5, SCI, SM6, TA3, TBl, YL4]. The asymmetric reduction of aldehydes, various ketones, a-enones, and a-ynones usually take place with an excellent enantiomeric excess [BB13, CL2, CL6, CR2, CT4, DS5, DK2, GB6, MT6, NNl, PL2, S4, SM6, WM2] (Figure 3.24). The reduction of ketones is carried out between -20°C and r.t., while that of aldehydes requires - 126°C for a good asymmetric induction. 

The synthesis of (5S,15S)-diHETE is shown in Scheme 4.16 and makes use of Pd-Cu coupling of a terminal acetylene to trans vinyl bromides (48 + 50 —> 51 and 51 + 49 — 52) to obtain eneynes. The acetylenes are reduced by catalytic hydrogenation to give the requisite cis-trans dienes. Acetylenes 46 and 47 bear the suitable optically active secondary alcohols for the (5S)and (155)-alcohol functions in the natural product and are derived from chiral reductions of the corresponding ketones. ... 

Halo-substituted acetophenones such as m-bromo- [74] or p-chloroacetophe-none [46] were reduced with borane in high enantioselectivity in the presence of oxazaborolidines 4b and 47, respectively. Other important halogen-containing ketones are chloromethyl or bromomethyl ketones. Oxazaborolidine reduction of co-chloro- or co-bromoacetophenone gives enantio-enriched halohydrins that can be converted into chiral oxiranes [20]. Martens found that the sulfur-containing oxazaborolidine catalysts 60 show high enantioselectivity in this kind of reduction [44, 86, 87]. Enantiopure halohydrins were obtained as shown in Scheme 8. 

Deprotonation with n-butyllithium and addition of aldehyde 148 generated alcohol 149 as a 2 l-diastereomeric mixture. Again the stereochemistry at the newly created center was corrected by an oxidation reduction sequence via ketone 151. This time the chiral reduction had to be performed with using Corey s oxazaborolidine catalysts (19). In this way both the (31 )- and (3S)-diastereomer of alcohol were available. LAH-reduction of (3S)-149 led to the -alkene 150 which was eventually oxidized to aldehyde 154 after protection-deprotection via 152 and 153. Addition of the potassium salt of pyrone 131 gave 155 as a 4 l-epimeric mixture. Removal of the PMB protective group led to selective destruction of the minor diastereomer, so that a 95 5-mixture in favor of the desired stereoisomer 156 was obtained (Scheme 26). 

Chiral amines. Synthesis of chiral amines from ketones through reductive amination with (-(-)- or (-)-norephedrine requires selective C-N bond cleavage. Sacrificial dissection of the chiron by periodate oxidation completes the operation. 

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