WO2009014362A2

WO2009014362A2 - Novel bimetallic salen catalyst and method for the synthesis of chiral compounds using the same

Info

Publication number: WO2009014362A2
Application number: PCT/KR2008/004256
Authority: WO
Inventors: Kun Jung Kim
Original assignee: Rstech Corporation
Priority date: 2007-07-25
Filing date: 2008-07-21
Publication date: 2009-01-29
Also published as: WO2009014362A3; KR20090011312A; KR100910067B1

Abstract

There is provided novel bimetallic salen catalyst. The bimetallic salen catalyst is represented by SaI(M1 )M2 (X) n, wherein Sal represents a chiral salen ligand, M1 and M2 represent each inde- pendently transition metal ions coordinated with the salen ligand, X represents anion that binds to M2 to form a salt, n has a value corresponding to oxidation number of M2. The bimetallic salen catalyst provides chiral compounds in a high optical purity by kinetic chiral resolution. The bimetallic salen catalyst exhibits sufficiently improved reactivity and activity, compared to conventional salen catalysts obtained from 1: 1 coordination complex between one salen ligand and one transition metal ion. Therefore, the bimetallic salen catalyst can be suitably used for the synthesis of chiral compounds through kinetic chiral resolution.

Description

NOVEL BIMETALLIC SALEN CATALYST AND METHOD FOR THE SYNTHESIS OF CHIRAL COMPOUNDS USING THE

SAME

Technical Field

[1] The present invention relates to bimetallic salen catalyst and method for the synthesis of chiral compound using the same. Background Art

[2] Drugs which are recently developed or commercially available are mostly chiral ones. This is attributed to the fact that one isomer exhibits superior efficacy while the other isomer shows severe side effects. As thus, demands for the drugs comprising certain one isomer having high stability and superior efficacy is increasing.

[3] As a result, various researches are focused on the development of the effective techniques for the synthesis of chiral compounds having high optical purity [C&EN, 2001, 79, 45; C&EN, 2001,79,79; and C&EN, 2004, 82,47].

[4] Among them, there are some drugs such as simvastatin and pravastatin in which chiral compounds are obtainable from biological conversion techniques. However, most of chiral compounds are obtainable from synthetic techniques using chiral intermediates for chiral building block.

[5] While synthetic techniques for preparing chiral intermediates having high optical purity are important, the technique that manufactures chiral material in an economic manner is also one of the most important things. This field is called as chi- rotechnology. Novel prize of 2001 year was endowed to this field, indicating that the chirotechnology is very important field [Press release: The 2001 Novel prize in Chemistry, The Royal Swedish Academy of Sciences].

[6] Among the chiral compounds, epoxy compounds such as epihalohydrin, propylene oxide, styrene oxide, glycidol, glycidate are very useful starting materials or intermediates due to possibility for versatile chemical modification [J. Org. Chem., 1979, 44, 1826; J. Med. Chem., 1981, 24, 1320; Chem. Pharm. Bull. 1981, 29, 2157; Bull. Soc. Chim. Fr., 1982, 304; Tetrahedron Lett, 1986, 27, 6329; Tetrahedron Lett., 1987, 28, 1783; Chem Lett, 1987, 2017; J. Org. Chem., 1990, 55, 4849; Chem. Pharm. Bull. 1990, 38, 2092; Chemistry and Industry 1991, 3, Oct, 615; Chemical Reviews 1991, 91, 437; and Swiss patent No. 495983(1968)]

[7] References related to the methods for preparing chiral epoxy compounds are as follows: Tetrahedron Lett, 1992, 33, 1211; J. Am. Chem. Soc. 1984, 106, 7250; Tetrahedron Asymmetry 1991, 2, 481; Enzyme Microb. Technol. 1991, 13, 306; Biotech.Tech, 1998, 12, 225; Tetrahedron 1994, 40, 8885; Biotech. Bioeng, 1996, 49, 70; J. Chem. Soc. Chem. Commun., 1984, 1600; European patent No. 171832; US patent No. 4,471,130; US patent No. 4,594,439; J. Am. Chem. Soc. 1980, 102, 5974; J. Am. Chem. Soc. 1981, 103, 464; Tetrahedron Letter 1985, 2543; US patent No. 5,563,263; and J. Am. Chem. Soc. 1983, 105, 5791.

[8] Recently, chiral salen-metal complex (briefly, chiral salen catalyst) has been variously studied. Salen compounds were firstly synthesized as a ligand by Dubsky in 1931 by condensation reaction of one diamine compound with two salicylaldehydes [Collect. Czech. Chem. Commun., 1931, 3, 548]. Such salen ligands have an advantages that salen ligands having various substitutents can be easily synthesized by condensation of various diamine with salicylaldehydes substituted with various substitutents. The salen ligand has two imine groups and two hydroxyl groups having planer array and show stable complex structure.

[9] Jacobsen et al. disclosed a method for stereoselectively preparing chiral compounds by kinetic resolution of racemic epoxide with a nucleophile in a presence of 1 : 1 coordination complex between one chiral salen ligand and one transition metal, thereby obtaining un-reacted chiral epoxy compound or a reaction product [Tetrahedron Lett, 1997, 38, 773: US patent No. 5,665,890; US patent No. 5,929,532; US patent No. 6,841,667; J. Am. Chem. Soc. 1995, 117, 5897; J. Am. Chem. Soc. 1996, 118, 7420; J. Org. Chem. 1997, 62, 4197; Science, 1997, 277, 936; Tetrahedron Asymmetry 1997, 8, 3927; J. Org. Chem. 1998, 63, 6776; US patent No. 6,262,278; US patent No. 6,448,414; US patent No. 6,693,236; US patent No. 6,800,766; WO 00/09463; and Jay F. Larrow, Thesis, Harvard Univ., Jan. 9th, 1998].

[10] Paddok and Coates et al. disclosed a method for preparing chiral carbonates by stereoselectively reacting an epoxide with carbon monoxide in a presence of chiral salen ligand-transition metal coordination complex [US patent No. 6,870,004; and US patent No. 6,852,865].

[11] Katsuki et al. disclosed a method for preparing chiral butyrolactone by stereoselective Baeyer-Villiger reaction of carbonyl group with an oxidizing agent in the presence of chiral salen ligand-Zr or Co transition metal catalyst [US patent No. 6,713,435; US patent No. 6,783,302; and Tetrahedron lett, 2001, 42, 6911]

[12] In a meanwhile, the salen catalysts used in the above such as Jacobsen and Katsuki are 1:1 complex obtained from coordination between one salen ligand and one transition metal. The salen catalysts have disadvantages that they require re-activation at the time of recycling. Specifically, representative chiral salen catalysts used for kinetic resolution of epoxy compounds are salen ligand-Co complex. The salen ligand- Co catalysts comprises quadruple coordinated Co ion at the center. When the oxidation number of Co ion is +2, the salen ligand-Co catalysts show very little activity. To the contrary, when the oxidation number of Co ion is +3, they show increased catalytic activity. Therefore, in order to use the salen ligand-Co catalysts for kinetic resolution of epoxy compounds, Co ion should retain +3 oxidation states. According to the studies on the mechanism of kinetic resolution of epoxy compounds by Jacobsen et al. [J. Am. Chem. Soc. 1998, 120, 10780], Co ion of the salen ligand-Co catalysts is converted to +2 oxidation states at a time of completion of kinetic resolution. As thus, Co ion should be reactivated to +3 oxidation states at a time of recycling. Consequently, the salen catalysts obtained from 1:1 coordination between one salen ligand and one transition metal requires reactivation. In addition, the salen catalysts obtained from 1:1 coordination show relatively low activity. As thus, salen catalysts having enhanced catalytic activity are demanded.

[13] Further, the salen catalysts obtained from 1:1 coordination between one salen ligand and one transition metal showed decreased yield of chiral epoxide and racemization. Specifically, the salen catalysts obtained from 1:1 coordination between one salen ligand and one transition metal stereoselectively hydrolyze any one isomer, R or S form, when racemic epihalohydrin reacts with 0.5 equivalents water. As a result, hydrolyzed chiral halo-l,2-propandiol and un-reacted chiral epihalohydrin are obtaine d. Herein, halo-l,2-propanol which is the hydrolysis product is believed to produce side product such as glycidol by the salen catalysts [Bull. Chem. Soc. Jpn. 1979, 52, 2614; Tetrahedron 1980, 36, 3391; Tetrahedron: Asymmetry, 2003, 14, 3589; WO 00/09463; Tetrahedron:Asymmetry 2003, 14, 3589; J. Org. Chem. 1998, 63, 6776; and Tetrahedron Lett. 1996, 37, 7937].

[14] In a meanwhile, there was disclosed dimeric chiral salen catalyst in which two monomeric salen coordination complexes are covalently cross linked through two salen ligands [Tetrahedron Lett. 2001, 42, 2915; J. MoI. Catalyst A: Chemical 2003, 203, 69; and J. Catalysis 2004, 224, 229]. In addition, Ning et al. disclosed asymmetric epoxidation using dimeric salen catalysts having no C2-symmetry [J. MoI, Catalysis A: Chemical 2004, 212, 353].

[15] Jacobsen et al. disclosed asymmetric ring opening of racemic epoxy butane using dimeric chiral salen catalyst in which one chiral salen ligand is coordinated with one Cr metal ion. [Applied Catalyst A: General 2005, 282, 181]. Further, they applied dimeric catalyst, olygomeric catalyst and polymeric catalyst to kinetic resolution of racemic epoxides [J. Am. Chem. Soc. 1998, 120, 10780; J. Am. Chem. Soc. 1998, 123, 2687; J. Am. Chem. Soc. 1999, 121, 4154; Angew. Chem. Int. Ed, Engl. 2000, 39, 3604; Angew. Chem. Int. Ed, Engl. 2002, 41, 1374; and Tetrahedron Asymmetry. 2003, 14, 3633].

[16] However, the dimeric salen catalysts mentioned in the above have a structure such that two salen-metal complexes are cross linked by covalent bond. Therefore, the prior catalysts require complicated synthetic process and high manufacturing cost, thereby decreasing applicability to industrial mass production.

[17] As an alternative, there were disclosed dimeric salen catalysts in which two salen- titanium metal complexes are linked through oxygen and their use for stereoselective cyanization reaction of aldehyde [Tetrahedron 2004, 60, 10433; Tetrahedron Lett., 2004, 45, 7625; Tetrahedron 2001, 57, 771; Tetrahedron Lett, 1999, 40, 8747; Tetrahedron 2004, 60, 10469; and Tetrahedron Lett., 2004, 45, 4763]. However, the dimeric salen catalysts did not show sufficient catalytic activity.

[18] As mentioned above, the conventional chiral salen catalysts obtained from 1:1 coordination between one salen ligand and one transition metal and dimeric chiral salen catalysts thereof has one or more disadvantages such as racemization, low optical purity, side product, low recycling, complicated synthetic process, while they possess high potential to stereoselective chiral resolution.

[19] In the previous studies, the present inventor disclosed dimeric salen catalyst having new configuration [Tetrahedron Lett. 2003, 45 7429; US patent No. 6,884,750; European patent No. 1,292,602]. Referring to the documents, the dimeric salen catalysts has a configuration that neutral boron compound or neutral aluminum compound is sandwiched between two salen ligand-metal complexes. The neutral boron compound or neutral aluminum compound resides even after reaction has been completed and the dimeric salen catalysts showed sufficiently improved recycling of the catalysts. Further, the catalysts showed high stereoselectivity and provided chiral compound having high optical purity. Disclosure of Invention

Technical Problem

[20] The present inventor performed extensive studies to develop new salen catalysts having improved catalytic activity and low production cost. Throughout extensive researches to solve the aforesaid problems, there is provided new bimetallic catalyst having new structure and composition. The novel bimetallic salen catalyst of the present invention is particularly useful for chiral resolution of racemic epoxides and provides chiral compounds in an economic and industrial manner. Technical Solution

[21] According to the present invention, there is provided bimetallic chiral salen catalyst represented by SaI(M )M (X) , or solvate thereof. Herein, Sal represents chiral salen n ligand, M and M represent each independently transition metal ions coordinated with the salen ligand, X represents anion that binds to M to form a salt, n has a value corresponding to oxidation number of M . The bimetallic salen catalyst is obtainable by coordinating the salen ligand with the transition metal ion M , followed by co- ordination with transition metal salt represented by M (X) . n

Advantageous Effects

[22] The bimetallic salen catalyst provides improved effects in terms of catalytic activity, stereoselectivity and recycling, and accomplished stereoselective chiral resolution even with phenolic alcohol and protected amine as a nucleophile as well as water, organic acid and inorganic acid to provide various chiral compounds. Further, the bimetallic salen catalyst exhibited superior catalytic activity and productivity to the dimeric salen catalysts. Therefore, the bimetallic salen catalyst having the above mentioned structure and composition provides improved advantages: (i) high catalytic activity and stereoselectivity; (ii) simple and economic manufacture of the bimetallic catalyst; (iii) extension of the range of nucleophile in the kinetic chiral resolution; and (iv) improved recycling. Mode for the Invention

[23] According to the preferred embodiment of the present invention, there is provided bimetallic chiral salen catalyst having formula 1 or solvate thereof:

[24] Formula 1

[25] SaI(M^M²CX) n

1 9

[26] In the formula 1, Sal represents chiral salen ligand, M and M represent each independently transition metal ions coordinated with the salen ligand, X represents anion that binds to M to form a salt, n has a value corresponding to oxidation number of M .

[27] As used herein, "salen ligand" means a ligand formed by condensation between two salicylaldehydes and one diamine compound. The salen ligand has two imine groups and two hydroxyl groups having planer array. The method for preparing chiral salen ligands are well known in the art: J. Am. Chem. Soc, vol. 108, No. 9, (1986); Synlett, Sep. 1991, pp. 691-692; Am. J. Org. Chem., 1991, vol. 56, No. 7, pp. 2296-2298; Tetrahedron:Assymetry, vol. 2, No. 7, pp. 481-494, 1991; Synlett, Apr. 1991, pp. 265-266; and Tetrahedron Letters, vol. 32, No. 8, pp. 1055-1058, 1991.

[28] According to the present invention, the salen ligand is coordinated with two transition metal ions. In the formula 1, the transition metal ion M is positioned at a center of the salen ligand. The transition metal ion M is incorporated into the bimetallic salen catalyst in a form of transition metal salt. The transition metal ion M is believed to be coordinated with two oxygen atoms of the salen ligand. Transition

1 9 metal ion M , and transition metal ion M incorporated as transition metal salt may be the same or different. Preferable example of the transition metal ion M is an ion of Co, Mn, Cr, V, Fe, Mo, W, Ru or Ni. Most preferable is Co ion. According to specific test of the present invention, the cobalt ion had +2 oxidation number and exhibited superior catalytic activity even at +2 oxidation status. This eliminates the process for converting oxidation status of the cobalt ion into +3 states to endow catalytic activity, compared with the conventional Jacobsen catalysts (salen catalysts obtained from 1:1 coordination between one salen ligand and one transition metal). The transition metal M is incorporated as a transition metal salt. Example of the transition metal M is an ion of Co, Fe, Zn, Ni, Cu, Mn, Cr, V, Mo, W or Ru. More preferable is an ion of Co, Fe, Zn, Ni or Cu. Most preferable is an ion of Co, Fe or Zn. Anion (X) that binds to transition metal ion M to form a salt is not particularly limited. For example, anions such as halide ion (F^", Cl^", Br and I^"), NO ^", CO ^2", CH COO^" and OH^" can be used. Preferable is halide ion (F^", Cl^", Br and I^") or NO . And, n has a value corresponding to oxidation number of M . For example, when oxidation status of M is +2 and the anion has -1 status, n is 2. when oxidation status of M is +3 and the anion has -1 status, n is 3. In a similar manner, n is defined. Typically, n is an integer of 1-4, preferably 1-3, most preferably 2-3.

[29] Herein, the bimetallic salen catalyst may be present in a form of solvates in which solvents such as water and ether are incorporated into the crystal structure of the bimetallic salen catalyst. In a meanwhile, the conventional Jacobsen catalysts exhibit catalytic activity at +3 oxidation status and central cobalt metal ion (Co ⁺) is bonded to acetate anion. It is reported that during the reaction, the Jacobsen catalysts undergo anion replacement of acetate anion with chloride anion (Cl^"). The Jacobsen catalysts replaced with chloride anion show decreased catalytic activity. However, the bimetallic catalyst of the present invention having formula 1 showed high catalytic activity even at the status of Co ⁺.

[30] It was confirmed that the bimetallic salen catalyst showed sufficiently enhanced effect on the synthesis of chiral compounds by stereoselective chiral resolution of racemic compounds. Specifically, in the stereoselective chiral resolution of racemic epoxides, the bimetallic salen catalyst provided optically pure chiral compound (chiral ring-opened product or un-reacted chiral epoxy compound) by stereoselective ring opening of any one isomer among the racemic mixture. Further, the catalyst showed high stereoselectivity and reactivity even when organic acid and inorganic acid was used as a nucleophile, as well as water.

[31] According to more preferred embodiment of the present invention, there is provided a bimetallic chiral salen catalyst having formula 2, or solvate thereof:

[32] Formula 2

[34] In the formula 2, R 1 ,R2 , R'1 , R'2 , X1 , X2 , X3 , X4 , X5 , X6 , X7 , X8 , Y1 and Y 2 are each in- dependently H, C ~C alkyl group, C ~C alkenyl group, C ~C alkynyl group, C ~C alkoxy group, C ~C cycloalkyl group, C ~C heterocycloalkyl group, C ~C aryl

3 6 3 6 6 10 group, C ~C heteroaryl group, C ~C aralkyl group, halogen atom, hydroxy group, amino group, thiol group, nitro group, amine group, imine group, amide group, C ~C acyl group, C ~C acyloxy group, silyl group, ether group, thioether group, seleno ether group, ketone group, aldehyde group, ester group, phosphoryl group, phosphonate group, phosphine group, sulfonyl group or (CH ) -R , wherein, R is C ~C

2 k 4 4 1 alkyl group, C ~C alkenyl group, C ~C alkynyl group, C ~C alkoxy group, C ~C cycloalkyl group, C ~C heterocycloalkyl group, C ~C aryl group, C ~C heteroaryl group, C ~C aralkyl group, halogen atom, hydroxy group, amino group, thiol group, nitro group, amine group, imine group, amide group, C ~C acyl group, C ~C acyloxy group, silyl group, ether group, thioether group, seleno ether group, ketone group, aldehyde group, ester group, phosphoryl group, phosphonate group, phosphine group or sulfonyl group, and k is an integer of 1 to 8), or any two or more neighboring R 1 ,R2 ,R'1 , R'2 , X1 , X2 , X3 , X4 , X5 , X6 , X7 , X8 , Y1 and Y 2 together forms a ring of carbocycle or heterocycle comprising 4 to 10 atoms; R is direct bond, -CH -, -CH CH -, -NH-, -O- or -S-; M and M represent each independently transition metal ions co- ordinated with the salen ligand; X represents anion that binds to M to form a salt; and n has a value corresponding to oxidation number of M . Preferably, X , X , X , X , X , X , X , X , Y and Y are each independently selected from a group of H, C ~C alkyl group and C ~C alkoxy group, and most preferably, X , X , X , X , X , X , X and X t^{o r} 1 6 ^{J to r r J} 1 2 3 4 5 6 7 8 are each independently H or t-butyl group, and both Y and Y are H. In the above formula 2, R and R' may be the same or different, preferably the same; R and R' may be the same or different, preferably the same. When R is identical with R' and R is identical with R' , the chiral center forms RR or SS configurations. Preferable examples of R ,R , R' and R' are as follows; R and R' together forms C ~C

1 2 1 2 1 1 4 6 carbocycle, and R' and R are H, C ~C alkyl group or C ~C alkoxy group; or R' and R are H, C ~C alkyl group or C ~C alkoxy group, and R' and R together forms C ~C carbocycle.

[35] Preferable example of the transition metal ion M is an ion of Co, Mn, Cr, V, Fe, Mo,

W, Ru or Ni. Most preferable is Co ion. According to specific test of the present invention, the cobalt ion had +2 oxidation number and exhibited superior catalytic activity even at +2 oxidation status. The transition metal M is incorporated into the bimetallic salen catalyst in a form of a transition metal salt. Example of the transition metal ion M² is an ion of Co, Fe, Zn, Ni, Cu, Mn, Cr, V, Mo, W or Ru. More preferable is an ion of Co, Fe, Zn, Ni or Cu. Most preferable is an ion of Co, Fe or Zn.

[36] Preferable example of the anion (X) that binds to the M to form a slat is halide ion

(F^", Cl^", Br and I^") or NO . Preferable example of n is 2 or 3.

[37] The process for manufacturing the bimetallic salen catalyst represented by formula 1 of the present invention is as follows. The chiral salen ligand reacts with a suitable transition metal compound (for example, cobalt acetate) in a suitable organic solvent to obtain chiral salen ligand-transition metal coordination complex. The obtained chiral salen ligand-transition metal coordination complex and then reacts with transition metal salt M X n in a presence of a suitable solvent to obtain the targeted bimetallic salen catalyst. The above reactions are carried out in a mild condition and do not require special knowhow. Sometimes, the solvent used in the reaction can be incorporated into crystal structure of the bimetallic catalyst such that the bimetallic salen catalyst may be present as solvates such as hydrates and ethrates.

[38] In order to facilitate recovery of the bimetallic salen catalyst, the catalyst may be used in a fixed form to solid phase such as MCM-41. Please refer to Journal of Organometallic Chemistry 691 (2006) 1862-1872.

[39] According to most preferred embodiment of the present invention, the bimetallic chiral salen catalyst has formula 3:

[40] Formula 3 [41]

[42] In the formula 3, two asterisks (*) mean chiral centers having RR or SS configuration, and M , M , X and n are the same as defined in formula 2. [43] The bimetallic salen catalyst showed sufficiently enhanced effects on the synthesis of chiral compounds by stereoselective chiral resolution of racemic compounds. Specifically, only one isomer stereoselectively reacts with a reactant in the presence of the bimetallic salen catalyst such that reaction product or un-reacted chiral compound can be obtainable. As a racemate, epoxy compounds, 1,2-halo alcohols, 1,2-sulfonyl alcohols, 1,3-halo alcohols and 1,3-sulfonyl alcohols may be used. The bimetallic salen catalyst is particularly useful for stereoselective chiral resolution of epoxy compounds. Routes for preparing chiral compounds by stereoselective chiral resolution are as follows:

[44] (a) In the presence of the bimetallic salen catalyst of the present invention, stereoselective ring opening of epoxy compounds by nucleophile; [45] (b) In the presence of the bimetallic salen catalyst of the present invention, stereoselective ring opening of epoxy compounds by nucleophile and subsequent ring formation of the ring opened product; and

[46] (c) In the presence of the bimetallic salen catalyst of the present invention, stereoselective chiral resolution of epoxy compounds by CO to form a chiral cyclic carbonates [47] Herein, epoxy compounds are not particularly limited. Preferably, the epoxy compounds are terminal epoxy compounds, "terminal epoxy compounds" means compounds in which only one carbon of two carbons that form epoxy ring is substituted with another substituents in replacement of hydrogen. Epoxy compounds having various substituents such as halogen atom, alkyl group, alkoxy group, haloalkyl group, aryl group, aralkyl group, heteroaryl group, cycloalkyl group, hydroxy group, nitro group, silyl group, alkoxyalkyl group, acyloxy group, silyloxyalkyl group, carbonyl group, carboxyl group, ketonyl group, aldehyde group, ester group, phosphoryl group, phosphonate group, phosphine group and sulfonyl group can be used, provided that the substituents do not participate into the chiral resolution.

[48] Specific examples of the epoxy compounds include the compound having formula 4:

[49] Formula 4

[50] O

R

[51] In the formula 4, R represents C ~C alkyl group, C ~C alkenyl group, C ~C alkynyl group, C ~C cycloalkyl group, C ~C alkoxy group, C ~C aryl group, C ~C heteroaryl group, C ~C aralkyl group, halogen atom, hydroxy group, amino group, thiol group, nitro group, amine group, imine group, amide group, C ~C acyl group, C ~C acyloxy group, ether group, thioether group, seleno ether group, ketone group, aldehyde group, ester group, phosphoryl group, phosphonate group, phosphine group, sulfonyl group or (CH ) -R (herein R is C ~C alkyl group, C ~C alkenyl group, C ~C alkynyl group, C ~C cycloalkyl group, C ~C alkoxy group, C ~C aryl group, C ~C heteroaryl group, C ~C aralkyl group, halogen atom, hydroxy group, amino group, thiol group, nitro group, amine group, imine group, amide group, C ~C acyl group, C ~C acyloxy group, ether group, thioether group, seleno ether group, ketone group, aldehyde group, ester group, phosphoryl group, phosphonate group, phosphine group or sulfonyl group, 1 is an integer of 1 to 8). As a nucleophile, chemical moieties having unpaired electron pair can be widely used. According to the specific embodiment of the present invention, water, inorganic acid, organic acid, amine, alcohol and phenol were found to be useful for stereoselective chiral resolution of epoxy compounds.

[52] In the stereoselective chiral resolution of epoxy compounds, (R) -configured epoxide stereoselectively binds to the chiral bimetallic salen catalyst having RR configuration and undergoes ring opening by nucleophilic attack to produce ring-opened product, and (S)-configured epoxide does not participate into the reaction and remains in the reaction mixture, even though this is may be dependent upon the kind of substituents of the salen ligand. (S)-configured epoxide stereoselectively binds to the chiral bimetallic salen catalyst having SS configuration and undergoes ring opening by nucleophilic attack to produce ring-opened product, and (R) -configured epoxide does not participate into the reaction and remains in the reaction mixture. As a result, the epoxy compound (or ring opened product) can be obtained in a high optical purity.

[53] Hereinafter, stereoselective chiral resolution of epoxy compounds will be more fully explained.

[54] 1. Synthesis of chiral compounds by stereoselective ring opening of epoxy compounds with nucleophile in the presence of the bimetallic salen catalyst of the present invention [55] The bimetallic salen catalyst of the present invention can be used for stereoselective ring opening reaction. Representative Example of the chiral resolution is summarized in the following scheme 1 : [56] Scheme 1

[58] In the scheme 1, R is the same as defined in formula 4.

[59] As shown in the scheme 1, the bimetallic salen catalyst of the present invention can be suitably applicable to the synthesis of chiral compounds by asymmetric ring opening of epoxy compounds with nucleophile. In the asymmetric ring opening ("ARO") of epoxy compounds, the bimetallic salen catalyst may be used in an amount of about 5 mol%-0.05 mol%. Particularly, the conventional Jacobsen catalyst (1:1 coordination complex between salen ligand and transition metal ion) was used in an amount of 7 mol%-0.2 mol%. When the Jacobsen catalyst is used in an amount of 0.3 mol%, reaction time was typically 12-48 hours. When dimeric salen catalyst disclosed in the previous report of the present invention was used in an amount of about 0.3 mol%, reaction time was typically 6-12 hours. Particularly, even at a doze of 0.05 mol% of the bimetallic salen catalyst, reaction was completed within 12 hours, compared to the Jacobsen catalyst. This implies that the bimetallic salen catalyst shows sufficiently improved catalytic activity. As a nucleophile, water, inorganic acid, organic acid, alcohol, amine and phenol can be used. Particularly, reaction using phenol and protected amine also showed high activity, as well as water. Specifically, asymmetric ring opening of epoxy compounds using BOCNH (BOC = t- butyloxycarbonyl) was completed within 6-8 hours and produced chiral ring opened product having 95-99%ee of optical purity. The bimetallic salen catalyst of the present invention can be also used in combinational stereoselective chiral resolution to produce chiral epoxy compounds.

[60] 2. Synthesis of chiral cyclic carbonates by coupling reaction with CO in the presence of the bimetallic salen catalyst of the present invention

[61] The bimetallic salen catalyst of the present invention can be used for the synthesis of chiral cyclic carbonates by coupling reaction with CO . Such a chiral resolution is summarized in the following scheme 2:

[62] Scheme 2

[64] In the scheme 2, R is the same as defined in formula 4.

[65] The coupling reaction with CO can be carried out in the presence of the bimetallic salen catalyst of the present invention or in combination with co-catalyst such as tetraalkylammonium salt and K CO . The reaction also carried out in a mild condition and provides chiral cyclic carbonates in relatively high optically purity, which is compared to the Jacobsen catalyst.

[66] The present invention will be more fully illustrated referring to the following

Examples. However, it should be construed that the examples are suggested only for the illustration and the scope of the present invention is limited thereto.

[67] Example

[68] As a representative example of the salen catalyst, salen coordination complex having

M =Co was used to manufacture various bimetallic salen catalysts, and catalytic activity thereof was tested using various epoxy compounds.

[69] Example 1: Synthesis of bimetallic salen catalyst

[70] Example a: Synthesis of (R.R)-N.N-Bis (3.

5-tert-butylsalicylideney 1.2-cvclohexanediamine Co(II)-CoCl 2 bimetallic salen catalyst

[71] To a solution of (R,R)-N, N-Bis (3, 5-tertbutylsalicylidene)-l,2-cyclohexanediamine

Co(II) coordination complex (1.00 g, 0.0016 moles, 1 equiv.) in 15ml THF was added CoCl .6H O (0.473 g, 0.0019 mole 1.2 equiv.) in 5ml THF. The solution was stirred in open atmosphere at room temperature for 2h and solvent was removed in vacuo. The residue was dissolved in methylene chloride and filtered; the solvent was removed in vacuo. The targeted product was obtained as dark brown solid (1.19 g, 0.00162 moles, 98% yield).

[72] ¹H-NMR(400 MHz, DMSO-d ): δ 1.28(s; 18H), 1.50-1.62(m; 2H), 1.72(s; 18H),

1.80-1.95(m; 4H), 1.96-1.98(m; 2H), 3.1-3.2(m; 2H), 3.5-3.7(m; 2H), 7.40(d; J=2.4Hz, 2H), 7.45(d; J=2.4Hz 2H), 7.78(s; 2H).

[73] ¹³C-NMR (400 MHz, DMSO-d ): δ 25.8, 31.1, 32.2, 36.4, 67.6, 69.9, 119.2, 129.3,

136.4, 142.3, 162.5.

[74] FT-IR (KBr): [cm ¹] 2954, 2866, 1637, 1611, 1525, 1465, 1369, 1249, 1202, 1165,

1023, 925, 835, 782, 754, 636, 595.

[75] Atomic Analysis: MoI. Formula C H Cl Co N O calculated C, 58.94; H, 7.14; Cl,

36 52 2 2 2 2

9.67; Co, 16.07; N, 3.82; O, 4.36. Found C, 59.03; H, 7.00; Cl, 9.52; Co, 16.00; N, 3.79; O, 4.45. [76] MS(ESI) m/z: 731.6 (calculated for 732 C 36 H 52 Cl 2Co 2N 2O 2)

[77] Example b: Synthesis of (R.RVN.N-Bis (3.

5-tert-butylsalicylidene)- 1.2-cvclohexanediamine Co(II)-FeCl bimetallic salen catalyst

[78] To a solution of (R, R)-N, N-Bis (3, 5-tertbutylsalicylidene)- 1 ,

2-cyclohexanediamine coordination Co(II) complex (1.00 g, 0.0016 moles, 1 equiv.) in 15m THF was added FeCl (0.322 g, 0.0019 mole 1.2 equiv.) in 5ml THF. The solution was stirred in open atmosphere at room temperature for 2h and solvent was removed in vacuo. The residue was dissolved in methylene chloride and filtered; the solvent was removed in vacuo. The targeted product was obtained as dark brown solid (1.20 g, 0.00150 moles, 95% yield).

[79] ¹H-NMR^OO MHz, DMSO-d ): δ 1.27(s; 18H), 1.55-1.68(m; 2H), 1.71(s; 18H),

1.86-1.95(m; 4H), 1.96-2.20(m; 2H), 3.0-3.2(m; 2H), 3.5-3.8(m; 2H), 7.41(d; J=2.4Hz, 2H), 7.59(d; J=2.4Hz 2H), 7.76(s; 2H).

[80] ¹³C-NMR(400 MHz, DMSO-d^: δ 24.5, 25.8, 29.3, 30.9, 31.5, 35.7, 69.21, 119.3,

128.4, 134.1, 142.3, 158.5, 162.1, 164.8.

[81] FT-IR(KBr): [cm^"1] 2954, 2866, 1634, 1609, 1511, 1459, 1365, 1251, 1208, 1169,

1035, 985, 834, 785, 734, 640, 597. [82] Atomic Analy ^J sis:: MoI. Foumula C 36 H 52 Cl 3 CoFeN 2 O 2 calculated C, 56.90; H, 7.10;

Cl, 13.62; Co, 7.55; Fe, 7.15; N, 3.59; O, 4.10. Found C, 56.85; H, 7.13; Cl, 13.66; Co, 7.60; Fe, 7.20; N, 3.62; O, 4.09. [83] MS(ESI) m/z: 764.8 (calculated for 765 C 36 H 52 Cl 3 CoFeN 2 O 2 ).

[84] Example c: Synthesis of (R.RVN.N-Bis (3.

5-tert-butylsalicylidene)- 1.2-cvclohexanediamine Co(II)-Zn (NO ) bimetallic salen — — 2Tz. catalyst [85] To a solution of (R, R)-N, N-Bis (3, 5-tertbutylsalicylidene)- 1 ,

2-cyclohexanediamine coordination Co(II) complex (1.00 g, 0.0016 mole 1 equiv.) in

15ml THF was added Zn(NO ) 6H O (0.591 g, 0.0019 mole 1.2 equiv.) in 5mL THF.

The solution was stirred at open atmosphere at room temperature for 2h and solvent was removed in vacuo. The residue was dissolved in methylene chloride and filtered; the solvent was removed in vacuo. The targeted product was obtained as dark green solid (1.26g, 0.00160 moles, 96% yield). [86] ¹H-NMR(400 MHz, DMSO-d ): δ 1.25(s; 18H), 1.54-1.64(m; 2H), 1.71(s; 18H),

1.80-1.90(m; 4H), 1.95-1.97(m; 2H), 3.1-3.2(m; 2H), 3.5-3.6(m; 2H), 7.40(d; J=2.4Hz,

2H), 7.42(d; J=2.4Hz 2H), 7.74(s; 2H). [87] ¹³C-NMR(400 MHz, DMSO-d ): δ 24.3, 25.1, 29.5, 30.5, 31.5, 33.5, 67.0, 69.2,

118.5, 128.6, 129.0, 135.8, 141.7, 161.8, 164.4.

[88] FT-IR(KBr): [cm¹] 2950, 2863, 1635, 1608, 1523, 1461, 1361, 1253, 1200, 1172, 1026, 926, 833, 783, 744, 640, 597.

[89] Atomic Analysis:: MoI. Foumula C H CoN O Zn calculated C, 54.52; H, 6.61; Co,

36 52 4 8

7.43; N, 7.06; O, 16.14; Zn, 8.24. Found C, 54.50; H, 6.65; Co, 7.39; N, 7.10; O, 16.20; Zn, 8.20.

[90] MS(ESI) m/z: 791.8 (calculated for 792 C 36 H 52 CoN 4 O 8 Zn) [91] Example d: Synthesis of (R.RVN.N-Bis G.

5-tert-butylsalicylidene)- 1.2-cvclohexanediamine Co(II)-Co(NO ) bimetallic salen — — sTz. catalyst

[92] In the same manner as disclosed in Exmaple c, the procedure was carried out except that [93] Co(NO ) Η O was used instead of Zn(NO ) -H O. The targeted catalyst was obtained as dark green solid (95% yield). [94] ¹H-NMR(400 MHz, DMSO-d ): δ 1.24(s; 18H), 1.55-1.68(m; 2H), 1.69(s; 18H), 1.86-1.95(m; 2H), 1.96-2.20(m; 2H), 3.0-3.2(m; 2H), 3.5-3.8(m; 2H), 7.40(d; J=2.4Hz, 2H), 7.59(d; J=2.4Hz 2H), 7.74(s; 2H).

[95] ¹³C-NMR(400 MHz, DMSO-d ): δ 24.3, 25.1, 29.5 30.4, 31.5, 33.5, 35.7, 66.9, 69.2, 118.5, 128.6, 129.0, 135.8, 141.6, 161.8, 164.4. [96] FT-IR(KBr): [cm^"1] 2950, 2863, 1635, 1608, 1523, 1461, 1361, 1253, 1200, 1172, 1026, 926, 833, 783, 744, 640, 597. [97] Atomic Analysis: MoI. Formula e H Co N O calculated C, 54.96; H, 6.66; Co, 14.98; N, 7.12; O, 16.27, Found C, 54.55; H, 6.67; Co, 15.00; N, 7.15; O, 16.3.

[98] [99] Changing the kind of transition metal salts, the similar procedures were carried out. The obtained bimetallic salen catalysts are summarized in Table 1:

[100] Table 1 [Table 1] [Table ]

[101] [102] [103] Example II: Chiral resolution of epoxy compounds using the bimetallic salen catalyst [104] Example II- 1 : Hydrolytic kinetic resolution [105] Hydrolytic kinetic resolution reaction was carried out according to a conventional procedure. General procedure is as follows: An oven dried 25 ml flask equipped with a stir bar was charged with (R,R)-bimetallic salen catalysts (0.05-0.5 mol %) obtained from Example a to h and racemic epoxides (40 mmol, 1.0 equiv.), and the substrates were stirred at room temperature. H O (22 mmol. 0.55 equiv.) was added slowly dropwise. The reaction was mildly exothermic. The reaction mixture was stirred up to the occurrence of optically pure epoxides. The reaction mixture was checked periodically by Chiral GC (Hewlett-Packard 6890 Series II instruments). Hydrolytic kinetic resolution of epoxy compounds is summarized in the following Table 2:

[106] Table 2

[Table 2]

[107] Example II-2: Asymmetric ring opening of epoxy compounds with phenol

[108] Hydrolytic kinetic resolution reaction was carried out using phenol as a nucleophile instead of water and the results are summarized in the following Table 3: [109] Table 3 [Table 3]

(R,R)-catalyst

[HO] [111]

[112] Hydrolytic kinetic resolution reaction was carried out using HCl as a nucleophile instead of water and the results are summarized in the following Table 4: [113] Table 4

[Table 4]

(R,R)-catalyst

[114] Example II-4: Asymmetric ring opening of epoxy compounds with isopropyl amine [115] Hydrolytic kinetic resolution reaction was carried out using isopropyl amine as a nucleophile instead of water and the results are summarized in the following Table 5: [116] Table 5 [Table 5]

(R,R)-catalyst

(R.R)-catalyst

[117] Example II-5: Ring extension of epoxy compounds by coupling with CO

[118] Coupling reaction of epoxy compounds with CO was carried out according to a conventional procedure. General procedure is as follows: To a 50 ml pressure reactor (CO = 6 atm), racemic propylene oxide (0.0172mol) was added and applied to coupling with CO in a presence of (R,R) catalysts (0.001-0.4 mol%) alone, or in combination with cocatalyst (0.05 mol%).

[119] Coupling reaction of epoxy compounds with CO is summarized in the following Table 6:

[120] Table 6 [Table 6]

sΔ

[121] TB ACl = tetrabutylammoniium chloride

[122] TBAOH = tetrabutylammoniium hydroxide

[123] [EMIm] OH= l-ethyl-3-methylimidazolium hydroxide

[124] [BMIm]Br= l-Ethyl-3-methylimidazolium bromide

[125] [BMIm]OH=l-Bu-3-methylimidazolium hydroxide.

Claims

[1] A bimetallic chiral salen catalyst having composition and structure represented by formula 1 or solvate thereof: Formula 1

SaI(M^M²CX) n wherein Sal represents a chiral salen ligand, M and M represent each independently transition metal ions coordinated with the salen ligand, X represents anion that binds to M to form a salt, n has a value corresponding to oxidation number of M .

[2] The bimetallic salen catalyst as set forth in claim 1, wherein the transition metal ion M is positioned at a center of the salen ligand, and the transition metal ion M is coordinated with two oxygen atoms of the salen ligand.

[3] The bimetallic salen catalyst as set forth in claim 1, wherein the transition metal ion M is a metal ion selected from the group consisting of Co, Mn, Cr, V, Fe,

Mo, W, Ru and Ni.

[4] The bimetallic salen catalyst as set forth in claim 1, wherein the transition metal ion M is cobalt ion having +2 oxidation number (Co ⁺).

[5] The bimetallic salen catalyst as set forth in claim 1, wherein the transition metal ion M is a metal ion selected from the group consisting of Co, Fe, Zn, Ni, Cu,

Mn, Cr, V, Mo, W and Ru.

[6] The bimetallic salen catalyst as set forth in claim 5, wherein the transition metal ion M is a metal ion selected from the group consisting of Co, Fe, Zn, Ni and

Cu. [7] The bimetallic salen catalyst as set forth in claim 6, wherein the transition metal ion M is a metal ion selected from the group consisting of Co, Fe and Zn. [8] The bimetallic salen catalyst as set forth in claim 1, wherein the bimetallic salen catalyst is represented by formula 2:

Formula 2

wherein R ,R , R' , R' , X , X , X , X , X , X , X , X , Y and Y are each inde-

1 2 1 2 1 2 3 4 5 6 7 8 1 2 pendently H, C ~C alkyl group, C ~C alkenyl group, C ~C alkynyl group, C ~C alkoxy group, C ~C cycloalkyl group, C ~C heterocycloalkyl group, C ~C

6 3 6 3 6 6 aryl group, C ~C heteroaryl group, C ~C aralkyl group, halogen atom, hydroxy group, amino group, thiol group, nitro group, amine group, imine group, amide group, C ~C acyl group, C ~C acyloxy group, silyl group, ether group, thioether group, seleno ether group, ketone group, aldehyde group, ester group, phosphoryl group, phosphonate group, phosphine group, sulfonyl group or (CH ) k -R 4 , wherein, R 4 is C1 ~C6 alkyl group, C 2 ~C6 alkenyl group, C 2 ~C6 alkynyl group, C 1 ~C6 alkoxy group, C 3 ~C 6 cycloalkyl group, C 3 ~C 6 heterocycloalkyl group, C ~C aryl group, C ~C heteroaryl group, C ~C aralkyl group, halogen atom, hydroxy group, amino group, thiol group, nitro group, amine group, imine group, amide group, C ~C acyl group, C ~C acyloxy group, silyl group, ether group, thioether group, seleno ether group, ketone group, aldehyde group, ester group, phosphoryl group, phosphonate group, phosphine group or sulfonyl group, and k is an integer of 1 to 8), or any two or more neighboring R ,R ,R' , R' , X , X , X , X , X , X , X , X , Y and Y together forms a ring of carbocycle or

2 1 2 3 4 5 6 7 8 1 2 heterocycle comprising 4 to 10 atoms; R is direct bond, -CH -, -CH CH -, -NH-, -O- or -S-; M and M represent each independently transition metal ions coordinated with the salen ligand; X represents anion that binds to M to form a salt; and n has a value corresponding to oxidation number of M .

[9] The bimetallic salen catalyst as set forth in claim 1, wherein the bimetallic salen catalyst is represented by formula 3: Formula 3

wherein two asterisks (*) mean chiral centers having RR or SS configuration, M and M represent each independently transition metal ions coordinated with the salen ligand, X represents anion that binds to M to form a salt, and n has a value corresponding to oxidation number of M .

[10] A method for preparing a chiral compound comprised of stereoselectively reacting any one isomer among racemic mixture with a reactant in a presence of chiral catalyst and obtaining the chiral compound from reaction mixture, characterized in that the chiral catalyst is bimetallic salen catalyst according to any one of claims 1 to 9.

[H] The method as set forth in claim 10, wherein the racemic mixture is selected from the group consisting of racemic epoxy compound, racemic 1,2-halo alcohol, racemic 1,2-sulfonyl alcohol, racemic 1,3-halo alcohol and racemic 1,3-sulfonyl alcohol.

[12] The method as set forth in claim 10, wherein the reactant is selected from the group consisting of water, inorganic acid, organic acid, alcohol, amine, phenol and carbon dioxide.

[13] The method as set forth in claim 12, wherein the reactant is water.