Enantioselective synthesis asymmetric reductive amination

Kadyrov R, Riermeier TH (2003) Highly enantioselective hydrogen-transfer reductive amination catalytic asymmetric synthesis of primary amines. Angew Chem Int Ed Engl 42 5472-5474 Kang Q, Zhao ZA, You SL (2007) Highly enantioselective Friedel-Crafts reaction of indoles with imines by a chiral phosphoric acid. J Am Chem Soc 129 1484-1485... 

After taking up the challenge for the synthesis of (5)-metolachlor on an industrial scale, Blaser reported on the very first example of asymmetric reductive amination and succeeded to synthesize the desired (5)-enantiomer of metolachlor 77 up to 78% ee ° Blaser optimized the reaction condition where the 2-methyl-5-ethylaniline (MEA, 79) was treated with 1.2 equivalents of dry methoxyacetone (MOA, 78), 0.01 mol% Ir-xyliphos catalyst 81 in the presence of tetrabutylammonium iodide (TBAI), and a small amount of trifluoroacetic acid in cyclohexane as the solvent under 80 bar hydrogen pressure at 50 °C. Within 16 hours, almost complete conversion was reached furnishing the chiral amine 80 with 99% conversion and 78% ee. Upon chloroa-cetylization, 80 afforded the desired compound metolachlor 77 without any loss of enantioselectivity (Scheme 39.20). 

Synthesis of Chiral a-Amino Acids by Asymmetric Reductive Amination of Keto Acid Substrates In 2003, Rh-Deguphos catalyzed enantioselective reductive amination of a-keto acids 106 with benzylamine (BnNH2)... 

The reductive amination of ketones with useful functional groups would be important in organic synthesis. In 2007, Kocovsky et al. proposed that the asymmetric reductive amination product of a-chloroketone 96 could be a precursor for preparing chiral aziridines 98 (Scheme 32.20). After optimizing the reaction conditions they found that sigamide 76 can catalyze the reductive amination reaction to afford corresponding chiral a-chloroamines 97 with up to 96% ee and 98% yield. A further cyclization under basic conditions yields chiral 1,2-diarylaziridines 98 in excellent yield without losing enantioselectivity [61]. 

Peroxidases have been used very frequently during the last ten years as biocatalysts in asymmetric synthesis. The transformation of a broad spectrum of substrates by these enzymes leads to valuable compounds for the asymmetric synthesis of natural products and biologically active molecules. Peroxidases catalyze regioselective hydroxylation of phenols and halogenation of olefins. Furthermore, they catalyze the epoxidation of olefins and the sulfoxidation of alkyl aryl sulfides in high enantioselectivities, as well as the asymmetric reduction of racemic hydroperoxides. The less selective oxidative coupHng of various phenols and aromatic amines by peroxidases provides a convenient access to dimeric, oligomeric and polymeric products for industrial applications. 

Organometallic compounds asymmetric catalysis, 11, 255 chiral auxiliaries, 266 enantioselectivity, 255 see also specific compounds Organozinc chemistry, 260 amino alcohols, 261, 355 chirality amplification, 273 efficiency origins, 273 ligand acceleration, 260 molecular structures, 276 reaction mechanism, 269 transition state models, 264 turnover-limiting step, 271 Orthohydroxylation, naphthol, 230 Osmium, olefin dihydroxylation, 150 Oxametallacycle intermediates, 150, 152 Oxazaborolidines, 134 Oxazoline, 356 Oxidation amines, 155 olefins, 137, 150 reduction, 5 sulfides, 155 Oxidative addition, 5 amine isomerization, 111 hydrogen molecule, 16 Oxidative dimerization, chiral phenols, 287 Oximes, borane reduction, 135 Oxindole alkylation, 338 Oxiranes, enantioselective synthesis, 137, 289, 326, 333, 349, 361 Oxonium polymerization, 332 Oxo process, 162 Oxovanadium complexes, 220 Oxygenation, C—H bonds, 149... 

Chiral addition of allyl metals to imines is one of the useful approaches toward the synthesis of homoallylic amines. These amines can be readily converted to a variety of biologically important molecules such as a-, / -, and y-amino acids. Itsuno and co-workers utilized the allylborane 174 derived from diisopropyl tartrate and cr-pinene for the enantioselective allylboration of imines. The corresponding iV-aluminoimines 173 are readily available from the nitriles via partial reduction using diisobutylaluminium hydride (DIBAL-H) <1999JOM103>. Recently, iV-benzyl-imines 176 have also been utilized for the asymmetric allylboration with allylpinacol boronate 177 in the presence of chiral phosphines as the chiral auxiliaries to obtain homoallylic A -benzylamines 178 in high yield and selectivity (Scheme 29) <2006JA7687>. 

The enantioselective synthesis of optically active secondary amines via asymmetric reduction of prochiral ketimines was studied by screening various chiral hydrides. In this case, K-glucoride gave only disappointing results and was inferior to other reagents. Better results were obtained in the asymmetric reduction of prochiral Af-diphenylphosphinylimines to chiral N-(diphenylphosphinyl)amines (eq 1), which can then be readily converted into optically active primary amines. For this reaction the stereochemical course depends dramatically on the relative bulkiness of the groups R and R. The reaction conditions for reduction of C=N double bonds are the same as used for ketones, but the high reactivity of diphenylphosphinylimines dramatically reduces the reaction time. 

Maikov, Kocovsky, and co-workers have developed different L-valine-based Lewis basic catalysts such as 81 [176, 177], for the efficient asymmetric reduction of ketimines 76 with trichlorosilane 2, or catalyst 82 [178] with a fluorous tag, which allows an easy isolation of the product and can be used in the next cycles, while preserving high enantioselectivity in the process. Sigamide catalyst 83 [179, 180] and Lewis base 84 [181] were employed in a low amount (5 mol%) affording final chiral amines 80 with high enantioselectivity (Scheme 30) [182]. Interestingly, 83 was used for the enantioselective preparation of vicinal a-chloroamines and the subsequent synthesis of chiral 1,2-diaryl aziridines. In these developed approaches the same absolute enantiomer was observed in the processes. 

Prize in Chemistry. (The other half of the 2001 prize was awarded to W. Knowles and R. Noyori for their development of catalytic asymmetric reduction reactions see Section 7.14A.) The following reaction, involved in an enantioselective synthesis of the side chain of the anticancer drug paclitaxel (Taxol), serves to illustrate Sharpless s catalytic asymmetric dihydroxylation. The example utilizes a catalytic amount of K20s02(0H)4, an OSO4 equivalent, a chiral amine ligand to induce enan-tioselectivity, and NMO as the stoichiometric co-oxidant. The product is obtained in 99% enantiomeric excess (ee) ... 

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