Virginie Ratovelomanana-Vidal

Enantioselective hydrogenation reactions with a full set of preformed and prepared in situ chiral diphosphine-ruthenium (II) catalysts.

Abstract The new class of 2-methylallyl ruthenium chiral diphosphines 1 are efficient in asymmetric hydrogenation of α,β unsaturated acids and allylic alcohols. The related chiral halogen-containing ruthenium catalysts 2 are prepared from 1 or in situ from (COD)Ru(η) 3 -(CH 2 ) 2 CHCH 3 ) 2 by ligand exchange with the chelating diphosphine followed by protonation (HX) in acetone. This procedure allows rapid screening of chiral phosphines, such as Diop, Chiraphos, Cbd, Bppm, Binap, β-glucophos, Biphemp, MeO-Biphep, Me-Duphos, in ruthenium mediated hydrogenations of prochiral substrates. A high efficiency is displayed by Ru-catalysts having atropisomeric ligands (e.e. up to 99%), and a C 2 symmetric bis(phospholane) has also emerged as a valuable ligand (Me-Duphos, e.e. up to 87% not optimized). Asymmetric hydrogenation of β-keto esters can be conducted under quite mild conditions (4 atm. of H 2 , 50°C, e.e. up to 99%), β-keto esters having a disubstituted double bond are also hydrogenated chemoselectively to unsaturated chiral alcohols under controlled conditions with excellent optical purities.

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.

Novel, general synthesis of the chiral catalysts diphosphine-ruthenium (II) diallyl complexes and a new practical in situ preparation of chiral ruthenium (II) catalysts

Abstract A general and new synthesis of hexacoordinate chiral 1-[2-methylallyl]Ru II 2 complexes is presented. This synthesis uses the very accessible CODRu(2-methylallyl) 2 complex as starting material. These complexes (P*P)Ru(η 3 -(CH 2 ) 2 CCH 3 ) 2 (e.g. P*P=DIOP, CBD, DEGUPHOS, BINAP, BIPHEMP, CHIRAPHOS, PROPHOS, DIMPC, BPPM, BDPP, DIPAMP, DIPAMPSi, β-PO-OP) have been characterized spectroscopically. X-Ray structures were obtained for (S,S)-DIOP and (S,S)-CHIRAPHOS. They are suitable for the preparation of chiral dihalide ruthenium (II) catalysts. In addition, we have found that it was possible to prepare these same catalysts directly in situ from (COD)Ru(η 3 -(CH 2 ) 2 CCH 3 ) 2 by adding 1-1.3 equiv. of the appropriate chiral ligand in the presence of HX in acetone at room temperature.

A practical synthetic approach to chiral α-aryl substituted ethylphosphonates

Abstract A convenient general method is reported for the synthesis of α-aryl substituted ethylphosphonic acids and esters by hydrogenation of α-aryl substituted ethenylphosphonic acids and esters. Racemic α-arylethylphosphonic acids and esters were prepared in 70–88% yield under palladium-assisted transfer hydrogenation conditions using ammonium formate. Asymmetric hydrogenation of α-arylethenylphosphonic acids using chiral Ru(II) catalysts led to α-arylethylphosphonic acids with enantiomeric excesses up to 86%.

Enantioselective hydrogenation of β-keto sulfones with chiral Ru(II)-catalysts: synthesis of enantiomerically pure butenolides and γ-butyrolactones

Abstract A series of β-hydroxy sulfones were synthesized with high enantioselectivities via a new enantioselective ruthenium-catalyzed hydrogenation using MeO-BIPHEP as a ligand. Some β-hydroxy sulfones were used in the synthesis of optically active butenolides and γ-butyrolactones with high yields and enantioselectivities over 95%.

CeCl3·7H2O: An Effective Additive in Ru-Catalyzed Enantioselective Hydrogenation of Aromatic α-Ketoesters

In the presence of catalytic amounts of CeCl 3.7H 2O, [RuCl(benzene)(S)-SunPhos]Cl is a highly effective catalyst for the asymmetric hydrogenation of aromatic alpha-ketoesters. A variety of ethyl alpha-hydroxy-alpha-arylacetates have been prepared in up to 98.3% ee with a TON up to 10,000. Challenging aromatic alpha-ketoesters with ortho substituents are also hydrogenated with high enantioselectivities. The addition of CeCl 3.7H 2O not only improves the enantioselectivity but also enhances the stability of the catalyst. The ratio of CeCl 3.7H 2O to [RuCl(benzene)(S)-SunPhos]Cl plays an important role in the hydrogenation reaction with a large substrate/catalyst ratio.

An efficient synthesis of (2S,3R)-3-hydroxylysine via ruthenium catalyzed asymmetric hydrogenation

Abstract An efficient synthesis of the natural occuring amino acid (2S,3R)-3-hydroxylysine is reported. The five step sequence features a highly enantioselective dynamic kinetic resolution of racemic α-acetamido β-keto phtalimidohexanoate using ruthenium(II) catalyzed hydrogenation reaction.

Recyclable diguanidinium-BINAP and PEG-BINAP supported catalysts: syntheses and use in Rh(I) and Ru(II) asymmetric hydrogenation reactions

Abstract The syntheses of new recyclable cationic BINAP type ligand diguanidinium 1 and PEG-bound BINAP ligand 2 are described. The use of ethylene glycol instead of water increased the enantioselectivity in the ruthenium-promoted hydrogenation reaction of functionalized ketones. These catalysts are highly active (catalyst/substrate ratio up to 1:10u2008000, up to 99% e.e.). The rhodium-mediated hydrogenation of acetamidoacrylic acid was also examined using 1 and 3 as chiral auxiliaries.

Asymmetric hydrogenation reactions using a practical in situ generation of chiral ruthenium–diphosphine catalysts from anhydrous RuCl3

Abstract A very simple in situ preparation of chiral ruthenium–diphosphine catalysts from anhydrous RuCl 3 is reported. Prochiral Cue5fbO and Cue5fbC bonds have been reduced with high enantioselectivities via ruthenium-catalyzed hydrogenation.

ENANTIOSELECTIVE RUTHENIUM-MEDIATED HYDROGENATION: DEVELOPMENTS AND APPLICATIONS

Abstract A general preparation of chiral ruthenium(II) catalysts and the homogeneous enantioselective hydrogenation of prochiral olefins and keto groups are presented. Some applications to the synthesis of biologically active compounds are reported.