Remarkably diastereoselective synthesis of a chiral SPECIAL FEATURE biphenyl diphosphine ligand and its application in asymmetric hydrogenation Liqin Qiu*, Jing Wu*, Shusun Chan*, Terry T.-L. Au-Yeung*, Jian-Xin Ji*, Rongwei Guo*, Cheng-Chao Pai*, Zhongyuan Zhou*, Xingshu Li*, Qing-Hua Fan†, and Albert S. C. Chan*‡ *Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong; and †Center for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China Edited by Jack Halpern, University of Chicago, Chicago, IL, and approved February 17, 2004 (received for review November 22, 2003) Essentially complete atropdiastereoselectivity was realized in the (42–45) with central-to-axial chirality transfer, resulting in a preparation of biaryl diphosphine dioxide by asymmetric intramo- concomitant eight-membered ring closure. The introduction of lecular Ullmann coupling and oxidative coupling with central-to- the chiral bridge restricted the conformational rotation of the axial chirality transfer. A bridged C2-symmetric biphenyl phosphine diphosphine and made it more rigid than other biaryl diphos- ligand possessing additional chiral centers on the linking unit of phine ligands (5–15, 46). The diphosphine ligand was found to be the biphenyl groups was synthesized. No resolution step was highly effective in the asymmetric hydrogenation of ␣- and required for the preparation of the enantiomerically pure chiral ␤-ketoesters, 2-(6Ј-methoxy-2Ј-naphthyl)propenoic acid, ␤- ligand. These findings offer a general and practical tool for the alkyl-substituted ␤-(acylamino)acrylates, and enol acetates. development of previously uninvestigated atropdiastereomeric biaryl phosphine ligands. The diphosphine ligand was found to be Materials and Methods highly effective in the asymmetric hydrogenation of ␣- and ␤- General Information. Unless otherwise noted, all reactions were ketoesters, 2-(6؅-methoxy-2؅-naphthyl)propenoic acid, ␤-(acyl- carried out under an inert atmosphere of dry nitrogen and were CHEMISTRY amino)acrylates, and enol acetates. monitored by TLC. Glassware was flame-dried before use. Standard syringe techniques were applied to transfer dry sol- xially chiral biaryls are not only common structural motifs vents and reagents. The preparation of samples and the setup of Ain many natural products, but they are also the core of many high-pressure reactors were either carried out in a nitrogen- highly effective chiral ligands for asymmetric reactions. Atropi- filled, continuously purged Lab Master 230 glovebox someric, C2-symmetric diphosphine ligands have played a par- (MBRAUN, Shanghai, Republic of China) or by using standard ticularly crucial role in the development of asymmetric catalysis Schlenk-type techniques. 1H NMR, 31P NMR, and 13C NMR (1–4). Therefore, it is not surprising that considerable efforts spectra were recorded on a Varian 500 spectrometer (500, 202, have been taken for the design and synthesis of atropisomeric and 125 MHz, respectively). Chemical shifts (␦) are given in ppm ligands based on the biphenyl, binaphthyl, or other biaryl and are referenced to residual solvent peaks (1H NMR and 13C 31 backbones (5–15). Enantiomerically pure biaryls can be obtained NMR) or to an external standard (85% H3PO4, P NMR). by aryl-aryl coupling followed by a classical resolution of the High-resolution mass measurements were carried out with a VG resulting atropisomers. The disadvantage of the path by resolu- Micromass (Manchester, U.K.), Fison VG platform (VG Bio- tion is that the maximum yield of the desired atropisomer is only tech, Cheshire, U.K.), or a Finnigan model Mat 95 ST instrument 50% and the enantiomeric excesses (ee’s) are usually Ͻ100%, (Finnigan MAT, Bremen, Germany). Optical rotations were not to mention that resolution procedures are frequently tedious. recorded on a Perkin–Elmer 341 polarimeter in a 10-cm cell. From a practical standpoint, it is desirable to develop efficient Enantiomeric excesses of the asymmetric hydrogenation prod- atroposelective methodologies for the synthesis of biaryls ligands ucts were determined by chiral GC and HPLC. HPLC analyses to expand the scope of the useful catalysts. Various approaches, were performed by using a Waters model 600 with a Waters 486 including desymmetrization of prochiral biaryls (16), kinetic UV detector. Gas chromatographic analyses were performed on resolution of racemic substrates (17), asymmetric catalytic cou- an Hewlett–Packard 4890A GC with an flame ionization detec- pling (18–23), and chirality transfer from central, axial, and tor. Crystal structural data were collected by the single-crystal planar asymmetry have been reported (24–38). Oxazoline- x-ray diffraction method with a Bruker CCD Area Detector mediated asymmetric Ullmann coupling was studied by Meyers Diffractometer and PC computer with the BRUKER SMART and and coworkers (28–30) to produce diastereomerically pure BRUKER SHELXTL programs. Tetrahydrofuran (THF) and tolu- bis(oxazoline)s and corresponding enantiomerically pure biphe- ene were freshly distilled from sodium͞benzophenone ketyl, nols and binaphthols. Previously, most of the research was whereas DMSO, dimethylformamide (DMF), CH2Cl2, and Bu3N focused on the syntheses of biphenols and binaphthols; in were distilled from CaH2 under nitrogen atmosphere. MeOH contrast, less attention was paid to the atroposelective syntheses and EtOH were distilled from magnesium under nitrogen at- of biaryl diphosphine oxides, the precursors of widely used mosphere. All other chemicals were used as received from diphosphine ligands. Recently, we successfully developed two Aldrich, Acros (Geel, Belgium), or Strem (Newburyport, MA) diastereomeric diphosphine ligands for use in asymmetric hy- without further purification. All substrates used in moisture- drogenation reactions by stereoselective intermolecular Ull- mann coupling of two chiral phosphine oxide precursors with moderate atropdiastereoselectivity (39). However, very careful This paper was submitted directly (Track II) to the PNAS office. separation of the diastereomers by column chromatography on Abbreviations: rt, room temperature; ee, enantiomeric excess; MeO-BIPHEP, 2,2Ј- silica gel was still needed. Herein, we report an example of bis(diphenylphosphino)-6,6Ј-dimethoxy-1,1Ј-biphenyl; BINAP, 2,2Ј-bis(diphenylphos- essentially complete atropdiastereoselectivity in the synthesis of phino)-1,1Ј-binaphthyl; DMF, dimethylformamide; THF, tetrahydrofuran. diphosphine dioxide by means of intramolecular Ullmann cou- ‡To whom correspondence should be addressed. E-mail: [email protected]. pling (27, 34, 40, 41) or Fe(III)-promoted oxidative coupling © 2004 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0307774101 PNAS ͉ April 20, 2004 ͉ vol. 101 ͉ no. 16 ͉ 5815–5820 Downloaded by guest on September 29, 2021 Scheme 1. Synthetic route. Path a: Cs2CO3, DMSO, 55°C, 53%. Path b: (i) n-BuLi, THF, Ϫ78°C; (ii)Ph2PCl, Ϫ78°C to rt. Path c: H2O2, acetone, 0°C, 85% from 3. Path d: (i) lithium diisopropylamide (LDA), THF, Ϫ78°C; (ii)I2, Ϫ78°C to rt, 85%. Path e: Cu, DMF, 140°C, 91%. Path f: LDA, FeCl3, Ϫ20°C to rt, 61% yield and 80% conversion. Path g: HSiCl3,Bu3N, toluene, reflux, 96%. sensitive reactions were predried twice with toluene azeotrope filtrate was washed successively with saturated aqueous ammo- before use. nium chloride and brine and was dried over anhydrous Na2SO4. After the solvent was removed, the residue was purified by silica Synthesis of Compound 6. The synthetic route for the ligand was gel column chromatography to give 7 as a white solid (406 mg, 1 ␦ ϭ shown in Scheme 1. Here we report the synthetic methods for 0.634 mmol, 91% yield). H NMR (500 MHz, CDCl3): 1.26 compounds 6, 7, and 8. The synthesis of compounds 3, 4, and 5, (d, J ϭ 6.0 Hz, 6H), 3.65–3.71 (m, 2H), 6.85 (d, J ϭ 7.5 Hz, 2H), the spectra and data for all new compounds, and the general 6.93–6.97 (m, 2H), 7.08–7.13 (m, 6H), 7.21–7.24 (m, 2H), procedures for the asymmetric hydrogenation are provided in 7.27–7.34 (m, 8H), 7.37–7.40 (m, 2H) and 7.63–7.67 (m, 4H). 31P ␦ ϭ 13 Supporting Text, which is published as supporting information on NMR (202 MHz, CDCl3): 28.46. C NMR (125 MHz, ␦ ϭ the PNAS web site. CDCl3): 18.97, 86.33, 123.80, 123.82, 127.16, 127.26, 127.66, A solution of lithium diisopropylamide (1.7 ml, 2.0 M) was 127.76, 127.79, 127.87, 129.34, 129.46, 130.20, 130.22, 130.74, added dropwise to compound 5 (1.00 g, 1.56 mmol) in THF (40 130.76, 131.97, 132.04, 132.33, 132.40, 132.92, 133.65, 133.76, ml) at Ϫ78°C for 0.5 h. After stirring for an additional 3 h, the 134.49, 134.72, 135.56, 158.97, and 159.08. HRMS (ESI): calcd ϩ ϩ ␣ 20 ϭ reaction mixture was cannulated into a flask containing I2 (1.584 for C40H35P2O4 [M H] 641.2011, found 641.1991. [ ]D Ϫ Ϫ ϭ g, 6.24 mmol) and 40 ml of THF at 78°C over 30 min. The 197.4 ° (c 1, CHCl3). HPLC conditions for the analysis of de: mixture was warmed to ambient temperature for 2 h, and the AD column, eluent ϭ 80:20 hexane͞i-PrOH, ␭ ϭ 254 nm, flow ϭ ͞ ϭ reaction was continued overnight. After the evaporation of rate 1.0 ml min); t1 13.2 min for 7. The other diastereomer, ϭ the solvent with a rotary evaporator, the residue was dissolved which has a retention time t2 18.8 min under otherwise in CH2Cl2 (50 ml). The resulting solution was washed succes- identical conditions, was not detected. sively with saturated aqueous ammonium chloride solution, Synthetic route II: Asymmetric oxidative coupling. A solution of lithium water, and saturated sodium thiosulfate solution, followed by diisopropylamide (0.68 ml, 2.0 M) was added dropwise to a drying over anhydrous Na2SO4, and concentration in vacuo gave solution of compound 5 (0.400 g, 0.622 mmol) in dried THF (6 a crude product that contained diiodide 6 (88.5%), monoiodide ml) in 4 ml of THF at Ϫ20°C for 30 min.