Takuto Nagano

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.

Asymmetric Hydrogenation of Isoquinolinium Salts Catalyzed by Chiral Iridium Complexes: Direct Synthesis for Optically Active 1,2,3,4‐Tetrahydroisoquinolines

1,2,3,4-Tetrahydroisoquinolines (THIQs), a class of highly important molecular skeletons abundant in natural alkaloids and biologically active compounds, are often used as key intermediates for the synthesis of pharmaceutical drugs and drug candidates. To date, synthetic efforts have focused on introducing chirality at the C1 position with configurational integrity by employing the following synthetic methodologies: 1) the formation of the six-membered ring through a Bischler–Napieralski cyclization/reduction or a Pictet– Spengler reaction, 2) the C1–Ca connectivity approach by attaching nucleophilic or electrophilic carbon units to the C1 position of tetrahydroisoquinoline derivatives, and 3) the asymmetric hydrogenation of alkylidene-1,2,3,4-tetrahydroisoquinoline derivatives. However, these methods have some limitations, such as a limited substrate scope and the need for stoichiometric amounts of a chiral auxiliary. In contrast to 1substituted THIQs, the synthesis of 3-substituted THIQs has rarely been achieved, although their unique structural and diverse biologic properties have been noted. Accordingly, the development of more general and straightforward synthetic methods toward 1and 3-substituted THIQs is in high demand. Although asymmetric hydrogenation of substituted isoquinolines is considered the most attractive and straightforward synthetic protocol, isoquinoline is regarded as the most challenging substrate in asymmetric hydrogenation. An efficient catalytic system has not even been found for the reduction of isoquinolines in a nonenantioselective manner. Nonetheless, the recent development of an asymmetric hydrogenation of aromatic and heteroaromatic compounds was remarkable, and Zhou and co-workers reported the catalytic asymmetric hydrogenation of isoquinolines, although the substrate scope is limited and an activating reagent is sometimes required (Scheme 1). As part of our continuing interest in the asymmetric hydrogenation of N-heteroaromatic compounds using halogen-bridged dinuclear iridium(III) complexes, we previously reported the additive effect of aryl amine derivatives in the asymmetric hydrogenation of quinoxalines, where the addition of more-basic aliphatic amines retarded the reaction, presumably because of their tight coordination to the iridium center. These findings strongly suggested that the difficulties of catalytic hydrogenation of isoquinolines upon catalysis by iridium complexes might be due to the strong basicity of the corresponding THIQs. This hypothesis prompted us to study the asymmetric hydrogenation of isoquinolinium chlorides to give the corresponding tetrahydroisoquinolinium chlorides, thus avoiding the deactivation of the iridium catalyst and providing a direct transformation of isoquinolines to THIQs in an enantioselective manner by a simple basic workup (Scheme 1). We first examined the asymmetric hydrogenation of the 3phenylisoquinolinium salt 2 a-HCl with H2 (30 bar) and the catalyst [{Ir(H)[(S)-binap]}2(m-Cl)3]Cl (1a) in methanol at Scheme 1. Asymmetric hydrogenation of isoquinoline derivatives.

Efficient cyclic carbonate synthesis catalyzed by zinc cluster systems under mild conditions

An efficient catalytic system of a zinc cluster and tetrabutylammonium iodide (TBAI) was developed for cyclic carbonate synthesis from epoxides and carbon dioxide (CO2) without the use of any organic solvents under very mild conditions (25 °C, 1 atm), even in the presence of impurities such as water and air. Electrophilicity of the central Zn(II) ion, the number of trifluoromethyl groups, nucleophilicity and leaving ability of the anion of alkylammonium salts, and various reaction parameters have a great effect on the catalytic activity of the bifunctional catalyst. Therefore, this solvent-free process represents an environmentally friendly example for the catalytic conversion of CO2 into value-added chemicals and also has the potential to contribute towards decreasing atmospheric CO2 emission from the burning of fossil fuels.

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).