Tahar Ayad

Unprecedented halide dependence on catalytic asymmetric hydrogenation of 2-aryl- and 2-alkyl-substituted quinolinium salts by using Ir complexes with difluorphos and halide ligands.

Asymmetric hydrogenation by using chiral transitionmetal complexes represents one of the cleanest and most environmentally benign processes available for producing optically pure organic compounds. Currently, a wide variety of chiral compounds with outstanding levels of enantioselectivity has been synthesized by reduction of C=C, C= O, C=N, and, more recently, heteroaromatics compounds. Among heteroaromatics, 2-substituted quinolines have been targeted because optically active 2-substituted-1,2,3,4-tetrahydroquinoline derivatives are key components of many bioactive natural products and drugs. In contrast with the successful asymmetric hydrogenation of 2alkyl-substituted quinolines catalyzed by chiral iridium complexes with an iodide source or iodine, which dramatically enhances both catalytic activity and enantioselectivity, 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 2phenylquinoline (72 % ee (enantiomeric excess)), described by Zhou and co-workers, is based on an [IrACHTUNGTRENNUNG(cod)Cl]2/ MeO-biphep/I2 (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. In recent years, only a few examples of the catalytic hydrogenation of 2-phenylquinoline have been reported with ee values up to 88 %. We describe herein a highly enantioselective hydrogenation of the HX salts (X= Cl, Br, and I) of various 2aryl-substituted quinolines by using cationic dinuclear iridium complexes with [(4,4’-bi-2,2-difluoro-1,3-benzodioxole)-5,5’-diyl]bis(diphenylphosphine) (difluorphos), 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) 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 halogenbridged iridium complexes [{Ir[(S)-diphosphine](H)}2 ACHTUNGTRENNUNG(mX)3]X (3–8 ; X=Cl, Br, and I) (Figure 1), which were conveniently prepared by adding excess aqueous HX to a mixture of [{IrCl ACHTUNGTRENNUNG(coe)2}2] (coe =cyclooctene) and the required chiral diphosphine ligand in toluene at room temperature. Thus, we first examined the asymmetric hydrogenation of 2-phenylquinolinium salts 9·X (X=Cl, Br, and I) promoted by Ir–binap complex (S)-3·X. Each reaction was conducted at 30 8C under hydrogen (30 bar) with 2 mol % of Ir complex in THF followed by a basic workup (Table 1, en[a] H. Tadaoka, T. Nagano, Prof. Dr. T. Ohshima, Prof. Dr. K. Mashima Department of Chemistry Graduate School of Engineering Science, Osaka University Toyonaka, Osaka 560-8631 (Japan) Fax: (+81) 6-6850-6245 E-mail : ohshima@chem.es.osaka-u.ac.jp mashima@chem.es.osaka-u.ac.jp [b] D. Cartigny, Dr. T. Gosavi, Dr. T. Ayad, Prof. Dr. J.-P. GenÞt, Dr. V. Ratovelomanana-Vidal Laboratoire Charles Friedel, UMR CNRS 7223 Ecole Nationale Sup rieure de Chimie de Paris 11 rue P. et M. Curie 75231 Paris cedex 05 (France) Fax: (+33) 144-071-062 E-mail : virginie-vidal@enscp.fr Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200901477.

Highly Diastereo- and Enantioselective Synthesis of Monodifferentiated syn-1,2-Diol Derivatives through Asymmetric Transfer Hydrogenation via Dynamic Kinetic Resolution

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.

Enantioselective synthesis of 1-aryl-tetrahydroisoquinolines through iridium catalyzed asymmetric hydrogenation.

Asymmetric hydrogenation of 1-aryl-3,4-dihydroisoquinolines using the [IrCODCl](2)/(R)-3,5-diMe-Synphos catalyst is reported. Under mild reaction conditions, this atom-economical process provides easy access to a variety of enantioenriched 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives, which are important pharmacophores found in several pharmaceutical drug candidates, in high yields and enantiomeric excesses up to 99% after a single crystallization.

(R)-3,5-diCF3-SYNPHOS and (R)-p-CF3-SYNPHOS, Electron-Poor Diphosphines for Efficient Room Temperature Rh-Catalyzed Asymmetric Conjugate Addition of Arylboronic Acids

Two new atropisomeric electron-poor chiral diphosphine ligand analogues of SYNPHOS were prepared, and their electronic properties are described. These two ligands afforded high performance for the Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds at room temperature.

Ruthenium-catalyzed enantioselective hydrogenation of aryl-pyridyl ketones.

Various substituted aryl-pyridyl ketones were hydrogenated in the presence of Ru-XylSunPhos-Daipen bifunctional catalytic system with enantiomeric excesses up to 99.5%. Upon introduction of a readily removable ortho-bromo atom to the phenyl ring, enantiomerically enriched 4-chlorophenylpyridylmethanol was obtained by hydrogenation method with 97.3% ee, which provided an important chiral intermediate for some histamine H(1) antagonists.

General asymmetric hydrogenation of 2-alkyl- and 2-aryl-substituted quinoxaline derivatives catalyzed by iridium-difluorphos: Unusual halide effect and synthetic application

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 Total Synthesis and Stereochemical Revision of Gymnangiamide

The asymmetric total synthesis of the originally proposed structure of gymnangiamide, a cytotoxic pentapeptide isolated from the marine hydroid Gymnangium regae Jaderholm, has been achieved. Key to the synthesis was the use of asymmetric hydrogenation of alpha-substituted beta-ketoesters through dynamic kinetic resolution for the preparation of nonproteinogenic chiral amino acids. The disparity of the NMR spectra between the synthetic material containing the L-serine residue and the natural product required a revision of the proposed structure.

Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated ketones with DIFLUORPHOS and SYNPHOS analogues.

Applications of electron-deficient DIFLUORPHOS and SYNPHOS analogues in the rhodium-catalyzed asymmetric conjugate addition of boronic acids to α,β-unsaturated ketones afford the 1,4-addition adducts in yields up to 92% and with 99% ee. Particularly, a Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to nonsubstituted maleimide substrates using the (R)-3,5-diCF(3)-SYNPHOS ligand is also reported. This protocol provides access to various enantioenriched 3-substituted succinimide units of biological interest, in high yields and good to excellent ee up to 93%, which could be upgraded up to 99% ee, after a single crystallization.

Efficient enantioselective synthesis of 3-aminochroman derivatives through ruthenium-Synphos catalyzed asymmetric hydrogenation.

A highly enantioselective asymmetric hydrogenation of various trisubstituted enamides derived from chroman-3-ones promoted by cationic Ru-Synphos catalysts is reported. This atom-economical and clean method provides an efficient route to optically active 3-aminochroman derivatives, which are important pharmacophores found in numerous drug candidates, in high chemical yields and enantiomeric excesses up to 96%.

Ru-catalyzed highly chemo- and enantioselective hydrogenation of γ-halo-γ,δ-unsaturated-β-keto esters under neutral conditions

Finely-tuned ruthenium-catalyzed highly chemoselective and enantioselective hydrogenation of γ-halo-γ,δ-unsaturated-β-keto esters at the carbonyl group was achieved under neutral reaction conditions (ee up to 97%). Both olefin and alkenyl halogen moieties, which are labile under hydrogenation conditions, remained untouched during the reaction.