Air-stable, storable, and highly efficient chiral zirconium catalysts for enantioselective Mannich-type, aza Diels–Alder, aldol, and hetero Diels–Alder reactions Shu៮ Kobayashi*, Masaharu Ueno, Susumu Saito, Yumiko Mizuki, Haruro Ishitani, and Yasuhiro Yamashita Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan Edited by Barry M. Trost, Stanford University, Stanford, CA, and approved February 24, 2004 (received for review November 26, 2003) ␦ ϭ For the synthesis of optically active compounds, chiral catalysts CDCl3. Tetramethylsilane served as internal standard ( 0) for 1 ␦ ϭ have attracted much attention because large quantities of optically H NMR, and CDCl3 was used an internal standard ( 77.0) 13 active molecules can be prepared from a small amount of a chiral for C NMR. When dichloromethane-d2 was used, it served as source. However, many chiral catalysts are often unstable in air internal standard (␦ ϭ 5.32) for 1H NMR, and ␦ ϭ 53.8 for 13C (oxygen) and͞or in the presence of water. This is especially the case NMR. HPLC was carried out by using the following apparatuses: in chiral Lewis acid catalysis, because most Lewis acids are air- and liquid chromatograph Shimadzu LC-10AT (liquid chromato- moisture-sensitive. Therefore, many catalysts are prepared in situ graph), Shimadzu SPD-10A (UV detector), and Shimadzu in an appropriate solvent just before use, and they cannot be C-R6A or C-R8A (chromatopac). Fluorescence x-ray analysis stored for extended periods. We have developed air-stable, stor- was measured with Shimadzu Rayny EDX-800. Column chro- able, and highly efficient chiral zirconium Lewis acids. The catalysts matography was performed on Silica gel 60 (Merck), and promoted asymmetric Mannich-type, aza Diels–Alder, aldol, and preparative TLC was carried out by using Wakogel B-5F. hetero Diels–Alder reactions efficiently with high enantioselectivi- MS 3A, 4A, and 5A (powder) were purchased from Aldrich ties. A key to stabilizing the catalysts is an appropriate combination and dried [200°C, 0.2 mmHg (1 mmHg ϭ 133 Pa), 8 h] before use. t of chiral zirconium Lewis acids with molecular sieves, and the Zr(O Bu)4 was purchased from Trichemical Laboratory Co. zirconium–molecular sieves-combined catalysts can be stored for (Yamanashi, Japan). N-methylimidazole (NMI) was purchased extended periods in air at room temperature without loss of from Tokyo Chemical Industry (Tokyo). Aldimines of aromatic activity. Moreover, it has been demonstrated that the catalysts can aldehydes and heteroaromatic aldehydes were prepared from be recovered and reused. the corresponding aldehydes and 2-aminophenol by usual meth- ods. The crude aldimines were recrystallized from ethanol to nzymatic reactions that attain perfect yields and selectivities give the pure materials. Ketene silyl acetals were prepared under mild conditions are an ideal goal for organic chemists according to the literature (7, 8). (R)-6,6Ј-bis(pentafluoro- E Ј Ј Ј who are developing new reactions. Instead of enzymes, chemists ethyl)2-1,1 -binaphthene-2,2 -diol (BINOL), (R)-3,3 -(m- Ј Ј often like to use ‘‘artificial catalysts’’ to reach the goal. The CF3C6H4)2BINOL, (R)-3,3 -Br2BINOL, and (R)-3,3 -I2BINOL catalysts have advantages over enzymes and antibodies such as were prepared according to the literature (9–11). Dichlorometh- a wide scope of substrates applied and large-scale preparation of ane (CH2Cl2) was distilled from P2O5, then from CaH2, and target products, etc. For the synthesis of optically active com- dried over MS 4A. Toluene and benzene were dried over CaCl2, pounds, chiral catalysts have attracted much attention because distilled, and stored over MS 4A. Tetrahydrofuran (THF) was large quantities of optically active molecules can be prepared freshly distilled from Na-benzophenone ketyl before use. All from a small amount of a chiral source (1, 2). Although several other solvents and chemical compounds were purified based on excellent chiral catalysts have been developed in oxidation and standard procedures. All reactions were carried out under an reduction, carbon–carbon bond-forming reactions, and other argon atmosphere in dried glassware. transformations, they are often unstable in air and͞or in the presence of water. This is especially the case in chiral Lewis acid Preparation of (R)-6-C2F5-ZrMS. To a suspension of powdered MS catalysis, because most Lewis acids are air- and moisture- 5A (240 mg) in benzene (0.5 ml) were added (R)-6,6Ј- Ј sensitive (3). Therefore, many catalysts are prepared in situ in an bis(pentafluoroethyl)-BINOL [(R)-6,6 -C2F5BINOL, 35.5 mg, appropriate solvent just before use, and they cannot be stored for 0.08 mmol] in benzene (0.5 ml), NMI (13.1 mg, 0.16 mmol) in t extended periods (some chiral Lewis acid catalysts are stable; see benzene (0.5 ml), and Zr(O Bu)4 (15.3 mg, 0.04 mmol) in ref. 4). benzene (0.5 ml) at room temperature. The mixture was stirred To address this issue, we focused on molecular sieves (MS), and heated at 80°C for 2 h. After removal of the solvent under which are a kind of zeolite and often used as dehydration agents reduced pressure (0.2 mmHg) at 50°C for 1 h, the Zr–(R)-6,6Ј- in organic synthesis. MS contain Lewis acidic and Lewis basic (C2F5)2BINOL MS-combined catalyst [(R)-6-C2F5-ZrMS] was sites in their structure. We assumed that the Lewis basic sites formed. The (R)-6-C2F5-ZrMS was handled in air and stored at might interact with chiral Lewis acids under equilibrium condi- ambient temperature. tions, leading to stabilization of the chiral Lewis acids. In this article, we describe air-stable, storable, and highly Preparation of (R)-3-(m-CF3C6H4)-ZrMS. To a suspension of pow- selective chiral zirconium Lewis acid catalysts for asymmetric dered MS 3A (240 mg) in benzene (0.5 ml) were added (R)- carbon–carbon bond-forming reactions such as Mannich-type, 3,3Ј-bis(m-trifluoromethylphenyl)-BINOL [(R)-3,3Ј-(m- aza Diels–Alder, aldol, and hetero Diels–Alder reactions. The CF3C6H4)2BINOL, 68.9 mg, 0.12 mmol] in benzene (1.0 ml), catalyst is prepared by using MS and can be stored for Ͼ3 months in air at room temperature without loss of activity (for prelim- inary communications see refs. 5 and 6). This paper was submitted directly (Track II) to the PNAS office. Abbreviations: MS, molecular sieves; NMI, N-methylimidazole; BINOL, 1,1Ј-binaphthene- Experimental Procedures 2,2Ј-diol; THF, tetrahydrofuran; ee, enantiomeric excess. General. 1H and 13C NMR spectra were recorded on a JEOL *To whom correspondence should be addressed. E-mail: [email protected]. JNM-LA300, JNM-LA400, or JNM-LA500 spectrometer in © 2004 by The National Academy of Sciences of the USA 5476–5481 ͉ PNAS ͉ April 13, 2004 ͉ vol. 101 ͉ no. 15 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0307870101 Downloaded by guest on September 23, 2021 t NMI (13.1 mg, 0.16 mmol) in benzene (0.5 ml), and Zr(O Bu)4 (15.3 mg, 0.04 mmol) in benzene (0.5 ml) at room temperature. SPECIAL FEATURE The mixture was stirred and heated at 80°C for 2 h. After removal of the solvent under reduced pressure (0.2 mmHg) at 50°C for 1h,the(R)-3-(m-CF3C6H4)-ZrMS catalyst was formed. t Preparation of (R)-3-Br-ZrMS. To a solution of Zr(O Bu)4 (15.3 mg, 0.04 mmol) in THF (0.5 ml) was added (R)-3,3Ј-dibromo- Ј BINOL (3,3 -Br2BINOL, 17.8 mg, 0.04 mmol) in THF (1.0 ml) at room temperature, and the mixture was stirred for 30 min at the same temperature. H2O (1.4 mg, 0.08 mmol) then was added, and after the whole was stirred for an additional 30 min, MS 3A (240 mg) was added to the mixture. After stirring for 5 min, the solvent was removed under reduced pressure (0.2 mmHg) at room temperature for1htoformthe(R)-3-Br-ZrMS catalyst. Preparation of (R)-3-I-ZrMS. To a suspension of (R)-3,3Ј-diiodo- Fig. 1. BINOLs, silicon enolates, and Danishefsky’s dienes. Ј BINOL [(R)-3,3 -I2BINOL, 645 mg, 1.2 mmol] in toluene (9 ml) was added zirconium propoxide propanol complex [Zr(OPr)4- portant compounds including ␤-amino acids, ␤-lactams, etc. PrOH, 1.0 mmol] in toluene (11 ml) at room temperature, and Compared with asymmetric Mannich-type reactions using stoi- the whole was stirred for3hatthesame temperature. MS 5A chiometric amounts of chiral sources (13–16), little is known (2.5g), which contained 10% (wt͞wt) H O, then was added, and 2 concerning catalytic asymmetric versions. In 1997, we reported the mixture was stirred for 5 min. After removal of the solvents an example of truly catalytic enantioselective Mannich-type under reduced pressure (0.2 mmHg) at room temperature for reactions of imines with silicon enolates by using a zirconium 1h,the(R)-3-I-ZrMS catalyst was formed. catalyst prepared from zirconium (IV) tert-butoxide [Zr(OtBu) ],2eqof(R)-6,6Ј-dibromo-BINOL [(R)-6,6Ј- A Typical Experimental Procedure for the Enantioselective Mannich- 4 Br2BINOL], and NMI [ref. 17; for recent examples of catalytic CHEMISTRY Type Reactions Using (R)-6-C2F5-ZrMS. A typical experimental pro- asymmetric Mannich-type reactions, see refs. 5 (and references cedure is described for the reaction of aldimine 1a with ketene therein) and 18]. After that, several modifications have been silyl acetal 2a. To a suspension of the (R)-6-C F -ZrMS catalyst 2 5 made to improve catalytic activity of the chiral Zr catalysts (9).