P-CHIRAL PHOSPHOLANES AND PHOSPHOCYCLIC COMPOUNDS AND THEIR USE IN ASYMMETRIC CATALYTIC REACTIONS |
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| 申请号 | EP02803182.1 | 申请日 | 2002-11-08 | 公开(公告)号 | EP1451133B1 | 公开(公告)日 | 2017-10-25 |
| 申请人 | THE PENN STATE RESEARCH FOUNDATION; | 发明人 | ZHANG, Xumu; TANG, Wenjun; | ||||
| 摘要 | |||||||
| 权利要求 | |||||||
| 说明书全文 | The present invention relates to novel chiral ligands derived from P-chiral phospholanes and P-chiral phosphocyclic compounds and catalysts for applications in asymmetric catalysis. More particularly, the present invention relates to transition metal complexes of these chiral phosphine ligands, which are useful as catalysts in asymmetric reactions, such as, hydrogenation, hydride transfer, hydrocarboxylation, hydrosilylation, hydroboration, hydrovinylation, hydroformylation, allylic alkylation, olefin metathesis, isomerization, cyclopropanation, Diels-Alder reaction, Heck reaction, Aldol reaction, Michael addition, epoxidation, kinetic resolution and [m+n] cycloaddition. Molecular chirality plays an important role in science and technology. The biological activities of many pharmaceuticals, fragrances, food additives and agrochemicals are often associated with their absolute molecular configuration. A growing demand in pharmaceutical and fine chemical industries is to develop cost-effective processes for the manufacture of single-enantiomeric products. To meet this challenge, chemists have explored many approaches for acquiring enantiomerically pure compounds ranging from optical resolution and structural modification of naturally occurring chiral substances to asymmetric catalysis using synthetic chiral catalysts and enzymes. Among these methods, asymmetric catalysis is perhaps the most efficient because a small amount of a chiral catalyst can be used to produce a large quantity of a chiral target molecule [ Asymmetric hydrogenation accounts for major part of all asymmetric synthesis on a commercial scale. Some dramatic examples of industrial applications of asymmetric synthesis include Monsanto's L-DOPA synthesis (asymmetric hydrogenation of a dehydroamino acid, 94 % ee, 20,000 turnovers with a Rh-DIPAMP complex) Invention of chiral ligands for transition metal-catalyzed reactions plays a critical role in asymmetric catalysis. Not only the enantioselectivity depends on the framework of chiral ligands, reactivities can often be altered by changing the steric and electronic structure of the ligands. Since small changes in the ligand can influence the (delta)(delta)G of the rate-determining step, it is very hard to predict which ligand can be effective for any particular reaction or substrate. Accordingly, discovery of new chiral ligands sets the foundation of highly enantioselective transition metal-catalyzed reactions. In recent years, a large number of chiral ligands have been developed for use in asymmetric catalysis reactions. Despite this, only few chiral ligands have been found to be suitable for use in industry for the production of chiral molecules that require high selectivity. One of the earliest P-chiral phosphine ligands is DIPAMP, which was developed by There are continuing efforts from many groups to develop strategies for making P-chiral ligands for asymmetric catalysis, including, for example, the following: These ligands have been used effectively in many asymmetric reactions, especially in asymmetric hydrogenation reactions, such as those described in Some of these ligands are depicted below: Despite the wide variation in the substituted groups in the above ligands, the majority of these ligands are derivatives of the DIPAMP ligand. A possible drawback of these ligands is that ligands having a DIPAMP structure are conformationally flexible and, as a result, enantioselectivity is difficult to optimize. In contrast to the ligands of the prior art, the present invention provides a phospholane and phosphocyclic structure to restrict the conformational flexibility such that a high enantioselectivity can be achieved in the transition metal catalysts prepared from these ligands. Thus, from a stereochemical point of view, additional stereogenic centers (e.g. four or more stereogenic centers) are typically created to make the novel ligands of the present invention substantially more selective in asymmetric catalytic reactions than, for example, the DIPAMP and BisP* ligands, which have only two stereogenic centers. The present invention provides a chiral ligand represented by the following formula or its enantiomer:
More particularly, the present invention provides a chiral ligand represented by the formula and its enantiomer:
The present invention further provides a catalyst prepared by a process including:
The present invention still further provides a process for preparation of an asymmetric compound including:
The present invention still further provides a process for preparing (1R, 1R', 2R, 2R')-1,1'-di-alkyl -[2,2']-diphospholanyl-1,1'-disulfide including the steps of:
Further still, the present invention provides a process for preparing (1S, 1S', 2R, 2R')-1,1'-di-alkyl-[2,2']-diphospholanyl including the steps of:
The presence of additional stereogenic centers (e.g. four or more stereogenic centers) in the novel ligands of the present invention makes them substantially more selective in asymmetric catalytic reactions than, for example, the DIPAMP and BisP* ligands, which have only two stereogenic centers. The present invention provides novel P-chiral phospholane and phosphocyclic compounds and described their use in asymmetric catalysis. Introduction of cyclic structures can restrict the rotation of substituents adjacent to the phosphines and control of orientations of these groups around phosphine can lead effective chiral induction for asymmetric reactions. Metal complexes of these phosphines, and related none C2 symmetric ligands are useful for many asymmetric reactions. Tunability of ligand chiral environment is crucial for achieving high enantioselectivity. The steric and electronic structure of the conformationally rigid cyclic phosphines can be fine-tuned by variation of ring size and substituents. Several new chiral phosphines are developed for asymmetric catalytic reactions. A variety of asymmetric reactions, such as, hydrogenation, hydride transfer, allylic alkylation, hydrosilylation, hydroboration, hydrovinylation, hydroformylation, olefin metathesis, hydrocarboxylation, isomerization, cyclopropanation, Diels-Alder reaction, Heck reaction, isomerization, Aldol reaction, Michael addition, epoxidation, kinetic resolution and [m+n] cycloaddition were developed with these chiral ligands systems. The ligand of the present invention is a single enantiomer. Representative examples of chiral ligands of the current invention are shown below. A number of chiral ligands with desired structures according to the present invention can be made and used in the preparation of the catalysts described in the present invention. In a preferred embodiment, the ligand of the present invention includes compounds represented by the formulas wherein:
More particularly, the chiral ligand can be represented by the formula and its enantiomer:
Examples of such ligands include a ligand represented by the formula and its enantiomer: and a ligand represented by the formula and its enantiomer: The ligands according to the present invention can be in the form of a phosphine borane, phosphine sulfide or phosphine oxide. Selective examples of specific chiral ligands are listed below to illustrate the new P-chiral phospholanes and P-chiral phosphocyclic compounds. For each ligand, the corresponding enantiomer is also contemplated. These compounds can be prepared from corresponding phosphine-boranes, phosphine sulfides and phosphine oxides. Since Ir-catalyzed asymmetric hydrogenation is still highly substrate-dependent, development of new efficient chiral ligands for Ir-catalyzed hydrogenation is a continuing challenge. After development of phosphinooxazoline ligands for Ir-catalyzed asymmetric hydrogenation, Pfaltz and others have continued their efforts for the search of new efficient P, N ligands ( The present invention further provides a catalyst prepared by a process including:
As mentioned above, the catalyst can be prepared by contacting a transition metal salt or its complex and a ligand according to the present invention. Suitable transition metal salts or complexes include the following:
Each R and R' in these is independently selected from alkyl or aryl; Ar is an aryl group; and X is a counteranion. In the above transition metal salts and complexes, L is a solvent and the counteranion X can be halogen, BF4, B(Ar)4 wherein Ar is fluorophenyl or 3,5-di-trifluoromethyl-1-phenyl, ClO4, SbF6, PF6, CF3SO3, RCOO or a mixture thereof. In another aspect, the present invention includes a process for preparation of an asymmetric compound using the catalysts described above. The process includes the step of contacting a substrate capable of forming an asymmetric product by an asymmetric reaction and a catalyst according to the present invention prepared by contacting a transition metal salt, or a complex thereof, and a chiral ligand or its enantiomer according to claim 9. Suitable asymmetric reactions include asymmetric hydrogenation, hydride transfer, allylic alkylation, hydrosilylation, hydroboration, hydrovinylation, hydroformylation, olefin metathesis, hydrocarboxylation, isomerization, cyclopropanation, Diels-Alder reaction, Heck reaction, isomerization, Aldol reaction, Michael addition; epoxidation, kinetic resolution and [m+n] cycloaddition wherein m = 3 to 6 and n = 2. Preferably, the asymmetric reaction is hydrogenation and the substrate to be hydrogenated is an ethylenically unsaturated compound, imine, ketone, enamine, enamide, and vinyl ester. The present invention still further includes a process for preparation of an asymmetric compound including:
The present invention still further includes a process for preparing (1R, 1R', 2R, 2R')-1,1'-di-alkyl-[2,2']-diphospholanyl-1,1'-disulfide including the steps of:
Further still, the present invention includes a process for preparing (1S, 1S', 2R, 2R')-1,1'-di-alkyl-[2,2']-diphospholanyl. The process includes the steps of:
Preferably, (1S, 1S', 2R, 2R')-1,1'-di-alkyl-[2,2']-diphospholanyl is (1S, 1S', 2R, 2R')-1,1'-di-tert-butyl-[2,2']-diphospholanyl, which is prepared from suitable tert-butyl group containing starting materials. Several suitable procedures to prepare the chiral ligands according to the present invention are described herein below. All reactions and manipulations were performed in a nitrogen-filled glovebox or using standard Schlenk techniques. THF and toluene were dried and distilled from sodium-benzophenone ketyl under nitrogen. Methylene chloride was distilled from CaH2. Methanol was distilled from Mg under nitrogen. (R, R)-BDNPB was made a solution of 10mg/ml in toluene before use. Column chromatography was performed using EM silica gel 60 (230∼400 mesh). 1H, 13C and 31P NMR were recorded on Bruker WP-200, AM-300, and AMX-360 spectrometers. Chemical shifts were reported in ppm down field from tetramethylsilane with the solvent resonance as the internal standard. Optical rotation was obtained on a Perkin-Elmer 241 polarimeter. MS spectra were recorded on a KRATOS mass spectrometer MS 9/50 for LR-EI and HR-EI. GC analysis was carried on Helwett-Packard 6890 gas chromatography using chiral capillary columns. HPLC analysis was carried on Waters™ 600 chromatography. An efficient three-step synthetic of chiral C2 symmetric P-chiral bisphospholane route has been developed. Preparation of BrMgCH2(CH2)2CH2MgBr. To a dry Schlenk flask held with magnesium turning (7.92 g, 0.33 mol) in 300 ml dry THF was added dropwise 1,4-dibromobutane (23.7 g, 0.11 mol) in 50 mL of THF at room temperature. The reaction was very exothermic during the addition. After the addition was complete (within 1h), the resulting dark solution was kept at r.t. for 2 more hours. The whole solution was used directly for the following reaction. To a solution of phosphorous trichloride (13.7 g, 0.10 mol) in THF (300 mL) was added dropwise a solution of t-BuMgCl in THF (100 mL, 1.0M) at -78°C. The addition was complete within 2 hrs. After the mixture was stand at -78°C for 1 h, a solution of BrMgCH2(CH)2CH2MgBr in THF (made above) was added dropwise. The addition was complete within 2 hrs. The mixture was then allowed to warm to r. t over 2 h and stirred overnight. At room temperature, to the reaction mixture was added sulfur powder (4.8g, 0.15 mol) through one portion. The resulting solution was further stirred at r.t. for 2 h. Water (300 mL) was then added. To the THF layer was added 500 mL EtOAc. The organic layer was washed with water (300 mL) followed by brine (300 mL), dried over Na2SO4, and concentrated. The resulting oil was passed through a silica gel column followed by recrystallization to give colorless crystalline product 1-tert-butyl-phospholane 1-sulfide 8g (45% yield). At -78°C, to a solution of (-)-sparteine (7.83 mL, 34 mmol) in ether (200 mL) was added n-butyllithium (21.3 mL, 34 mmol, 1.6M in hexane) dropwise. The resulting solution was kept at -78°C for 30 min. Then at this temperature, to the solution was added dropwise a solution of 1-tert-butyl-phospholane 1-sulfide (5.0 g, 28.4 mmol in ether (100 mL). The addition was complete within 1 hr. The resulting mixture was kept at -78°C and stirred for 8 more hrs. Then dry CuCl2 (5.73 g, 42.6 mmol) was added into the solution through one portion. The resulting suspension was vigorously stirred and allowed to warm to r. t. over 4hrs. 150ml of concentrated ammonia was added. The water layer was washed twice with EtOAc (2 x 100 mL). The combined organic phase was further washed in a sequence with 5% ammonia (100 mL), 1N HCl (100 mL), water (100 mL), and brine (100 mL). After dried over Na2SO4, the solution was concentrated under reduced pressure to give an oily solid, which was subsequently purified by passing a silica gel column to give a solid mixture (4 g) of (1R, 1R', 2R, 2R')-1,1'-di-tert-butyl-[2,2']-diphospholanyl 1, 1'-disulfide (72% ee, 83%) and meso compound (1R, 1R', 2S, 2S')-1, 1'-di-tert-butyl-[2,2']-diphospholanyl 1, 1'-disulfide (17%). The mixture was recrystallized from ethyl acetate and ethanol to give 700mg of pure product (1R, 1R', 2R, 2R')-1, 1'-di-tert-butyl-[2,2']-diphospholanyl 1, 1'-disulfide (ee: >99% according to HPLC, total yield: 14%). To a solution of (1R, 1R', 2R, 2R')-1,1'-di-tert-butyl-[2,2']-diphospholanyl 1,1'-disulfide (440 mg, 1.26 mmol) in 25ml benzene was added hexachlorodisilane (3.25 mL, 5.08 g, 18.9 mmol). The mixture was stirred at reflux for 4 h. After the solution was cooled to r.t., 50 mL of degassed 30% (w/w) NaOH solution was carefully added to the reaction mixture with an ice-water bath. The resulting mixture was then stirred at 60 °C until the aqueous layer became clear. The two phases were separated. The water phase was washed twice with degassed benzene (2 x 30 mL). The combined benzene was dried over Na2SO4 and concentrated. The solid residue was re-dissolved in a minimum amount of degassed dichloromethane, which was subsequently passed through a basic Al2O3 plug (eluent: Et2O:hexane=1:10) to give pure white product (1) 320 mg (88% yield). To a solution of [Rh(COD)2]BF4 (5.0 mg, 0.012 mmol) in THF (10 mL) in a glovebox was added a chiral phosphine ligand (TangPhos 0.15 mL of 0.1 M solution in toluene, 0.015 mmol). After stirring the mixture for 30 min, the dehydroamino acid (1.2 mmol) was added. The hydrogenation was performed at rt under 1,38 bar (20 psi) of hydrogen for 24 h. The reaction mixture was treated with CH2N2, then concentrated in Vacuo. The residue was passed through a short silica gel column to remove the catalyst. The enantiomeric excesses were measured by GC using a Chirasil-VAL III FSOT column. The absolute configuration of products was determined by comparing the observed rotation with the reported value. All reactions went in quantitative yield with no by-products found by GC. Asymmetric hydorgenation for making alpha amino acid derivatives using TangPhos (1) as the ligand is shown in the Table below: Typical procedure: The starting material methyl 3-acetamido-3-phenyl-2-propenoate can be conveniently synthesized from cheap acetophenone in three steps according to known literature procedure in good yields. The literatures are For general synthetic procedures of β-aryl β-acetamidoacrylate esters, see Z/E = 9:1; 1H NMR (360 MHz, CDCl3) δ (Z isomer) 2.06 (s, 3H), 3.65 (s, 3H), 4.98 (s, 2H), 5.18 (s, 1H), 6.86 (d, J = 6.8 Hz, 2H), 7.28 (m, 7H), 10.46 (s, 1H); (E isomer) 2.27 (s, 3H), 3.65 (s, 3H), 4.98 (s, 2H), 6.44 (s, 1H), 6.86 (d, J = 6.8 Hz, 2H), 7.28 (m, 7H). To a solution of β-acetamidoacrylic ester (0.5 mmol) in 4 mL of degassed THF Rh[(TangPhos)nbd]SbF6 (2.5 µmol) was added in a glovebox filled with nitrogen. The whole solution was transferred into an autoclave. The autoclave was then purged three times with hydrogen and filled with hydrogen with 1,38 bar (20 psi) pressure. The resulting reactor was stirred at room temperature for 24 hr. After release of the hydrogen, the autoclave was opened and the reaction mixture was evaporated. The residue was passed through a short silica gel plug to give hydrogenation product β-amino acid derivatives. A small amount of sample was subjected to chiral GC or HPLC analysis. 98.5% ee, [α]25D = -79.5°; 1H NMR (300 MHz, CDCl3) δ 2.00 (s, 3H), 2.83 (dd, J = 15.7, 6.2 Hz, 1H), 2.93 (dd, J = 15.6, 6.0 Hz, 1H), 3.63 (s, 3H), 5.05 (s, 2H), 5.40 (m, 1H), 6.93 (d, 1H), 6.94 (dd, J = 6.7, 2.0 Hz, 2H), 7.23 (dd, J = 6.8, 1.8 Hz, 2H), 6.72 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 23.8, 40.2, 49.5, 52.2, 115.4, 127.9, 128.0, 128.4, 129.0, 133.3, 137.3, 158.6, 169.7, 172.1; MS (ESI) m/z 328 (M++1); HRMS calculated for C19H22NO4 3281549, found 328.1553. Chiral HPLC conditions ((s, s)-whelk-01): solvent hexane:isopropanol(1:1); flow rate 1 mL/min; retention time 8.2 min (R), 13.1 min (S). Asymmetric hydrogenation with [Rh(NBD)TangPhos(1)]+SbF6- as the catalyst: To a solution of methyl α-(acetylamino)-2-phenylacrylate (2.19 g, 10 mmol) in 20 mL of degassed methanol in glovebox was added [Rh(nbd)(1)]SbF6 (1 ml of 0.001M solution in methanol, 0.001 mmol). The hydrogenation was performed at room temperature under 2,76 bar (40 psi) of H2 for 8 h. After carefully releasing the hydrogen, the reaction mixture was passed through a short silica gel column to remove the catalyst. The enantiomeric excesses of (R)-methyl 2-acetylamino-3-phenylpropionate were measured by chiral GC directly. (Conversion: 100%, ee: 99.8%, TON: 10,000) A chiral bisphosphine with the following structure was prepared by the procedure outlined above: The X-ray structure of the corresponding bisphosphine sulfide was obtained and is shown below: Rh-compound with this ligand is an effective catalyst for hydrogenation of enamides (e.g., E/Z mixture of PhCH(NHAc)CHCOOEt) to make beta amino acids (up to 99% ee has been achieved). The present invention has been described with particular reference to the preferred embodiments. It should be understood that the foregoing descriptions and examples are only illustrative of the invention. Various alternatives and modifications thereof can be devised by those skilled in the art without departing from the scope of the present invention. Accordingly, the present invention is intended to embrace all such alternatives, modifications, and variations that fall within the scope of the appended claims. |
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