Asymmetric hydrogenation by using chiral transitionmetal complexes represents one of the cleanest and most environmentally benign processes available for producing optically pure organic compounds.[1] Currently, a wide variety of chiral compounds with outstanding levels of enantioselectivity has been synthesized by reduction of C=C, [1] C= O, [2,3] C=N, [4][5][6] and, more recently, heteroaromatics compounds. [7][8][9][10][11][12][13][14][15][16][17][18] Among heteroaromatics, 2-substituted quinolines have been targeted [9][10][11][12][13][14][15][16][17][18] because optically active 2-substituted-1,2,3,4-tetrahydroquinoline derivatives are key components of many bioactive natural products and drugs. [19] In contrast with the successful asymmetric hydrogenation of 2-alkyl-substituted quinolines catalyzed by chiral iridium complexes with an iodide source or iodine, [9][10][11][12][13] which dramatically enhances both catalytic activity and enantioselectivity, [5, 9a] only limited success has been achieved in the catalytic hydrogenation of 2-aryl-substituted quinolines. So far, the only known examples used 2-phenylquinoline as a unique model substrate. The first example of catalytic hydrogenation of 2-phenylquinoline (72 % ee (enantiomeric excess)), described by Zhou and co-workers, [9a] is based on anMeO-biphep/I 2 (cod = 1,5-cyclooctadiene; MeO-biphep = 6,6'-dimethoxy-2,2'-bis(diphenylphosphino)-1,1'-biphenyl) catalytic system that was recently improved to 80 % ee with a moderate yield of 41 % by using benzyl chloroformate as an activating agent, although this required an additional deprotection step on the resulting carbamate. [18] In recent years, only a few examples of the catalytic hydrogenation of 2-phenylquinoline have been reported with ee values up to 88 %. [14] We describe herein a highly enantioselective hydrogenation of the HX salts (X = Cl, Br, and I) of various 2-aryl-substituted quinolines by using cationic dinuclear iridium complexes [6,17] with [(4,4'-bi-2,2-difluoro-1,3-benzodioxole)-5,5'-diyl]bis(diphenylphosphine) (difluorphos), [20] which demonstrates an unexpected halide effect in which iridium complexes with chloro and bromo ligands serve as better catalysts than an iodo-iridium complex. The present catalyst was also effective for the hydrogenation of 2-alkyl-substituted quinolinium salts, which shows the high versatility of this new catalyst system. Furthermore, this system was applied to a formal asymmetric synthesis of selective estrogen receptor modulator (SERM) 6-hydroxy-2-(4-hydroxyphenyl)-1-{4-[2-(pyrrolidin-1-yl)ethoxy]-benzyl}-1,2,3,4-tetrahydroquinoline (1) [21] by asymmetric hydrogenation of the HCl salt of 6-methoxy-2-(4-methoxyphenyl)quinoline (2·Cl) as a key step.We recently developed cationic dinuclear triply halogen- [3][4][5][6][7][8] X= Cl, Br, and I) (Figure 1), which were conveniently prepared by adding excess aqueous HX to a mixture of [{IrClA C H T U N G T R E N N U N G (coe) 2 } 2 ] (coe = cyclooctene) and the required chiral diphosphine ligand in toluene at room...

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The first enantio- and diastereoselective approach to alpha-alkoxy-substituted syn-beta-hydroxyesters through highly efficient catalytic asymmetric transfer hydrogenation via dynamic kinetic resolution reactions from the corresponding racemic beta-ketoesters is described. In this atom-economical process, two contiguous stereogenic centers are generated simultaneously with an excellent diastereoselectivity (up to 99/1) and enantioselectivity (up to 99%), allowing a rapid access to a wide variety of aromatic and heteroaromatic monodifferentiated syn-1,2-diols.

A highly efficient and general iridium-difluorphos-catalyzed asymmetric hydrogenation of diverse 2-alkyl-and 2-aryl-substituted quinoxalines into biologically and pharmaceutically relevant 2-substituted-1,2,3,4-tetrahydroquinoxaline units has been developed. High isolated yields and excellent enantioselectivities of up to 95% for 2-alkyl-substituted quinoxalines and of up to 94% for 2-aryl-substituted quinoxalines were obtained.

A general asymmetric hydrogenation of a wide range of 2-alkyl- and 2-aryl-substituted quinoxaline derivatives catalyzed by an iridium-difluorphos complex has been developed. Under mild reaction conditions, the corresponding biologically relevant 2-substituted-1,2,3,4-tetrahydroquinoxaline units were obtained in high yields and good to excellent enantioselectivities up to 95%. With a catalyst ratio of S/C = 1000 and on a gram scale, the catalytic activity of the Ir-difluorphos complex was maintained showing its potential value. Finally, we demonstrated the application of our process in the synthesis of compound (S)-9, which is an inhibitor of cholesteryl ester transfer protein (CETP).

Asymmetric transfer hydrogenation was applied to a wide range of racemic aryl α-alkoxy-β-ketoesters in the presence of well-defined, commercially available, chiral catalyst Ru(II) -(N-p-toluenesulfonyl-1,2-diphenylethylenediamine) and a 5:2 mixture of formic acid and triethylamine as the hydrogen source. Under these conditions, dynamic kinetic resolution was efficiently promoted to provide the corresponding syn α-alkoxy-β-hydroxyesters derived from substituted aromatic and heteroaromatic aldehydes with a high level of diastereoselectivity (diastereomeric ratio (d.r.)>99:1) and an almost perfect enantioselectivity (enantiomeric excess (ee)>99 %). Additionally, after extensive screening of the reaction conditions, the use of Ru(II) - and Rh(III) -tethered precatalysts extended this process to more-challenging substrates that bore alkenyl-, alkynyl-, and alkyl substituents to provide the corresponding syn α-alkoxy-β-hydroxyesters with excellent enantiocontrol (up to 99 % ee) and good to perfect diastereocontrol (d.r.>99:1). Lastly, the synthetic utility of the present protocol was demonstrated by application to the asymmetric synthesis of chiral ester ethyl (2S)-2-ethoxy-3-(4-hydroxyphenyl)-propanoate, which is an important pharmacophore in a number of peroxisome proliferator-activated receptor α/γ dual agonist advanced drug candidates used for the treatment of type-II diabetes.

The reactivity of a new titanium triflimide salt (see Part 1) was investigated for the direct amination of alcohols. The combination of this new Lewis acid with pyridine‐based ligands allowed a significant increase of activity. The scope of the reaction was increased compared to other Lewis‐acid‐based protocols. Finally, mechanistic insights based on EPR spectroscopy and DFT calculations are provided.

Halide Ligands. -An unexpected superiority of the axially chiral chloro-and bromo-iridium complexes (I) over the corresponding iodo-complex as catalysts for the title reaction of 2-aryl-and 2-alkylquinolinium halides is observed. The method is applied as key step for the synthesis of bioactive compound (X).