CN101235052A - Asymmetric chirality diphosphine ligand - Google Patents
Asymmetric chirality diphosphine ligand Download PDFInfo
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- CN101235052A CN101235052A CNA2007103077912A CN200710307791A CN101235052A CN 101235052 A CN101235052 A CN 101235052A CN A2007103077912 A CNA2007103077912 A CN A2007103077912A CN 200710307791 A CN200710307791 A CN 200710307791A CN 101235052 A CN101235052 A CN 101235052A
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Abstract
The invention relates to a new asymmetry chiral diphosphine of fatty group-aromatic mixed type, represented as right formulas (Ia, Ib), relative synthesis methods, a relative complex containing the compounds and relative applications in the use as catalyst field.
Description
Technical field
The present invention relates to novel asymmetric chirality diphosphine ligand of aliphatic-aromatic mixed type and their synthetic method, contain the network and the thing of these compounds, and they are as the purposes of catalyzer.
Background technology
In homogeneous catalysis, three replacement organo phosphorous compoundss are very important parts.By changing the substituting group on the phosphorus in this compound, can influence the electronics and the space performance of phosphorus part targetedly, thereby can control selectivity and activity in the homogeneous catalysis process.
Use the chiral ligand of enantiomorph enrichment in asymmetric synthesis or asymmetry catalysis, wherein, it is very important that the electronics of part and stereochemistry performance and described catalysis problem reach optimum matching.The best " customization " part in order to seek specific asymmetry catalysis is starved of the chiral ligand with different stereochemistry and/or Electronic Performance.Therefore, ideally, can obtain a kind of chirality basis ligand structure, this structure can be come modification by a lot of methods, and can in very large range be changed aspect solid and the Electronic Performance.
Prior art discloses have two aromatic rings (Benineori, T., et al., J.Org.Chem.65 (7), 2000,2043-2047; Cereghetti, M., et al., Tetrahedron Letters 37 (30), and 1996,5347-5350) or two cycloaliphatic rings (Zhu, G., et al., J.Am.Chem.Soc.119 (7), 1997, biphosphine ligands 1799-1800).
So far known phosphorus part structurally tool is very different.These parts can be classified, for example, can classify according to the kind of material, the example of this substance classes has: trialkyl-and triaryl phosphine, phosphorous acid ester (phosphites), phosphinous acid ester (phosphinites), phosphinate (phosphonite), amino phosphine (aminophosphanes) etc.This classification according to substance classes is useful especially for the Electronic Performance of describing part.
In addition, can also classify to the phosphorus part according to the dentation character of symmetrical performance or part.This structure especially considers to have as the metal network of the phosphorus part of catalyst precursor/catalyzer and stability, activity and (potential) stereoselectivity of thing.In asymmetry catalysis, except widely used C
2Outside-symmetrical bidentate ligand the system (for example DUPHOS, DIPAMP, BINAP or DEGUPHOS), asymmetric bidentate organophosphor ligand comes into one's own just day by day.Important example comprises chiral ferrocene phosphine part (ferrocenylphosphine), for example JOSIPHOS, DPPM, and they can use in many ways; Two phosphinous acid esters (bisphosphinite) part, CARBOPHOS for example, particularly they are successfully used in the asymmetric hydrogenation of alkene and imines; Perhaps phosphine phosphite ester ligand, for example BINAPHOS or BIPHEMPHOS, milestone is set up in their uses in the unsymmetrical alkenes hydroformylation.Some phosphorus ligand structures that success is used in asymmetry catalysis show below:
The success of these species compound, an important aspect is that these Fas lignand systems have produced a kind of remarkable asymmetric environment around metal center.In order to make such environment help effective transfer of chirality, the flexibility of control Fas lignand system is favourable as the inherent limitation of asymmetric induction.
The shortcoming of known so far chiral phosphorus ligand system is: on the one hand, their preparation needs higher relatively expense, and on the other hand, for the use of wide region, the possibility that changes given basic ligand structure performance is restricted relatively.
Summary of the invention
Target of the present invention is to provide the phosphorus Fas lignand system of novel asymmetric, bidentate and chirality, it combines the feature of above-mentioned effective asymmetric induction, promptly, the organophosphorus donor that use can be modified independently of one another produces highly asymmetric coordination sphere (coordination sphere), and can use simple method that its solid and Electronic Performance are carried out modification in the scope of non-constant width.
Realized this target by general formula (Ia) and the asymmetric bidentate organophosphor ligand of chirality (Ib).The foundation structure of The compounds of this invention all comprises the ring system of chirality cyclic aliphatic or heterocycle aliphatic series and the ring system of aromatics or heteroaromatic, and they connect by direct carbon single bond to each other.In this basic structure, three valent phosphors functional group is bonded to these two ring systems at the ortho position with respect to this direct carbon single bond.
Therefore, the present invention relates to general formula (Ia) and compound (Ib):
Wherein o and p can be 0 or 1 independently of one another, and
Ar is the part of six-membered aromatic or 5-or 6-unit heteroaromatic ring system, and heteroaromatic ring system can comprise 1 to 3 nitrogen-atoms, 1 Sauerstoffatom or 1 sulphur atom on A, B, D and E position.Six-membered Hetero-aromatic is preferably pyridyl, and five yuan of hetero-aromatic rings are preferably furyl, thiophenyl or pyrryl.
CyAli is the part of 5-or 6-unit's cyclic aliphatic or heterocycle aliphatic series ring system, and heterocycle aliphatic series ring system can comprise 1 or 2 heteroatomss that are selected from N, O, S on F, G, H and I position.
The cyclic aliphatic ring system is preferably cyclohexyl and cyclopentyl, or as the indenyl and the tetralyl that condense the system part.The heterolipid loop systems is preferably tetrahydrofuran (THF), tetrahydrochysene thiophenyl, pyrrolidyl, piperidyl.
R
1-R
2Be C independently of one another
1-C
24-alkyl, C
3-C
8-cycloalkyl, this ring also can contain 1 or 2 heteroatoms, the C that are selected from N, O, S
6-C
14-aryl, phenyl, naphthyl, fluorenyl, C
2-C
13-heteroaryl, the heteroatoms quantity that is selected from N, O, S can be 1 to 4, cyclic aliphatic or aromatic group are preferably 5-or 6-unit ring; Wherein above-mentioned group itself can coverlet or polysubstituted, and substituting group is independently of one another: hydrogen; C
1-C
20-alkyl; C
2-C
20-thiazolinyl; C
1-C
10-haloalkyl; C
3-C
8-cycloalkyl; C
2-C
9-assorted alkyl; C
6-C
8-aryl; Phenyl; Naphthyl; Fluorenyl; C
2-C
6Heteroaryl, number of heteroatoms, the number of heteroatoms that particularly is selected from N, O, S can be 1 to 4; C
1-C
10-alkoxyl group, preferred OMe; C
1-C
9-trihalogenmethyl alkyl, preferred trifluoromethyl and trichloromethyl; Halogen, especially fluorine and chlorine; Hydroxyl; The trifluoromethane sulfonic acid base; Oxo (oxo); Sulfo-(thio); Sulfydryl; Amino; The C of following form
1-C
8Substituted-amino: NH
2, NH-C
1-C
8-alkyl, NH-C
5-C
6-aryl, N-C
1-C
8-alkyl
2, N-C
5-C
6-aryl
2, N-C
1-C
8 +-alkyl
3, N-C
5-C
6 +-aryl
3, NH-CO-C
1-C
8-alkyl, NH-CO-C
5-C
6-aryl; Cyano group; (wherein Q represents monovalent cation or C to the carboxylic acid group of COOH and COOQ form
1-C
8-alkyl); C
1-C
6-acyloxy; Sulfino; SO
3H and SO
3(wherein Q represents monovalent cation, C to the sulfonic group of Q form
1-C
8-alkyl or C
6-aryl); PO
3H
2, PO
3HQ and PO
3Q
2(wherein Q represents monovalent cation, C to the phosphate of form
1-C
8-alkyl or C
6-aryl); Three-C
1-C
6-alkyl silyl, particularly SiMe
3Perhaps R wherein
1With phosphorus atom or R
2Form 4-to 8-unit cycloaliphatic ring with phosphorus atom, this cycloaliphatic ring randomly can be by line style or ramose C
1-C
10-alkyl, C
6-aryl, benzyl, C
1-C
10-alkoxyl group, hydroxyl or benzyloxy replace.
R
3-R
14Be hydrogen atom or C independently of one another
1-C
24-alkyl, C
1-C
10-haloalkyl, C
3-C
8-cycloalkyl, C
3-C
8-cycloalkenyl group, this ring also can contain 1 or 2 heteroatoms, the C that are selected from N, O, S
6-C
14-aryl, phenyl, naphthyl, fluorenyl, C
2-C
13-heteroaryl, the heteroatoms quantity that is selected from N, O, S can be 1 to 4, ring-type fat base or aryl are preferably 5-or 7-unit ring; Wherein above-mentioned group itself can be replaced by one or more identical or different separate substituting groups that are selected from following group: hydrogen; C
1-C
20-alkyl; C
2-C
20-thiazolinyl; C
1-C
10-haloalkyl; C
3-C
8-cycloalkyl; C
3-C
8-cycloalkenyl group; C
2-C
9-assorted alkyl; C
1-C
9-assorted thiazolinyl; C
6-C
8-aryl; Phenyl; Naphthyl; Fluorenyl; C
2-C
6Heteroaryl, heteroatomic number, the heteroatomic number that especially is selected from N, O, S can be 1 to 4; C
1-
C10-alkoxyl group; C
1-C
9-trihalogenmethyl alkyl; Trifluoromethyl; Trichloromethyl; Fluorine; Chlorine; Bromine; Iodine; Hydroxyl; The trifluoromethane sulfonic acid base; Oxo; Sulfo-; Sulfydryl; Amino; The C of following form
1-C
8Substituted-amino: NH
2, NH-C
1-C
8-alkyl, NH-C
5-C
6-aryl, N-C
1-C
8-alkyl
2, N-C
5-C
6-aryl
2, N-C
1-C
8 +-alkyl
3, N-C
5-C
6 +-aryl
3, NH-CO-C
1-C
8-alkyl, NH-CO-C
5-C
6-aryl; Cyano group; (wherein Q represents monovalent cation or C to the carboxylic acid group of COOH and COOQ form
1-C
8-alkyl); C
1-C
6-acyloxy; Sulfino; SO
3H and SO
3(wherein Q represents monovalent cation, C to the sulfonic group of Q form
1-C
8-alkyl or C
6-aryl); PO
3H
2, PO
3HQ and PO
3Q
2(wherein Q represents monovalent cation, C to the phosphate of form
1-C
8-alkyl or C
6-aryl); Three-C
1-C
6-alkyl silyl, and wherein two in these substituting groups also can Cheng Qiao, preferably Cheng Qiao as follows: adjacent substituting group forms 5-to 7-unit's ring-type aromatics or aliphatic cpd each other in bridge,
M, n are 1 or 0 independently of one another, and
P is a three valent phosphors.
The present invention also relates to complex compound, it comprises general formula (Ia) and (Ib) this chiral ligand system and at least a metal.
Preferably,
R
1-R
2Represent C independently of one another
1-C
6-alkyl; C
5-C
6-cycloalkyl; C
6-aryl; Phenyl; Naphthyl; C
4-C
5-heteroaryl, the heteroatoms quantity that is selected from N, O, S is 1, and wherein above-mentioned aryl or heteroaryl itself can be by one to three replacements, and substituting group is hydrogen independently of one another; C
1-C
6-alkyl; C
2-C
4-thiazolinyl; C
1-C
6-haloalkyl; C
2-C
6-assorted alkyl; C
6-aryl; Phenyl; Naphthyl; Fluorenyl; C
3-C
5Heteroaryl, the number of heteroatoms that is selected from N, O, S can be 1 or 2; C
1-C
6-alkoxyl group, preferred OMe; C
1-C
9-trihalogenmethyl alkyl, preferred trifluoromethyl and trichloromethyl; Halogen, especially fluorine and chlorine; Hydroxyl; The trifluoromethane sulfonic acid base; Oxo; Sulfo-; Sulfydryl; Amino; The C of following form
1-C
6Substituted-amino: NH
2, NH-C
1-C
6-alkyl, NH-C
6-aryl, N-C
1-C
6-alkyl
2, N-C
6-aryl
2, N-C
1-C
6 +-alkyl
3, N-C
6 +-aryl
3, NH-CO-C
1-C
6-alkyl, NH-CO-C
6-aryl, especially NMe
2, NEt
2, cyano group; (wherein Q represents monovalent cation or C to the carboxylic acid group of COOH and COOQ form
1-C
4-alkyl); C
1-C
6-acyloxy; Sulfino; SO
3H and SO
3(wherein Q represents monovalent cation, C to the sulfonic group of Q form
1-C
4-alkyl or C
6-aryl); PO
3H
2, PO
3HQ and PO
3Q
2(wherein Q represents monovalent cation, C to the phosphate of form
1-C
4-alkyl or C
6-aryl); Three-C
1-C
6-alkyl silyl, especially SiMe
3
The advantage of these parts is that they can produce highly asymmetric coordination sphere in metal complex.Because they are easy to modification, so can change the electronics and the space performance of these parts in wide region.For example, can be by on part foundation structure, introducing the rigidity that different substituents changes the part skeleton.
R according to Fas lignand system of the present invention
1-R
14Preferably be alkyl, thiazolinyl, cycloalkyl, alkoxyl group, three silylation independently of one another or/and dialkyl amido, they contain 1 to 20 separately, especially 1 to 6 carbon atom.
For alkyl and alkoxy substituent, preferable methyl, ethyl, n-propyl, the 1-methylethyl, normal-butyl, the 1-methyl-propyl, 1, the 1-dimethyl ethyl, n-pentyl, the 1-methyl butyl, the 2-methyl butyl, the 3-methyl butyl, 2, the 2-dimethyl propyl, the 1-ethyl propyl, n-hexyl, 1, the 1-dimethyl propyl, 1, the 2-dimethyl propyl, the 1-methyl amyl, the 2-methyl amyl, the 3-methyl amyl, the 4-methyl amyl, 1, the 1-dimethylbutyl, 1, the 2-dimethylbutyl, 1, the 3-dimethylbutyl, 2, the 2-dimethylbutyl, 2, the 3-dimethylbutyl, 3, the 3-dimethylbutyl, the 1-ethyl-butyl, the 2-ethyl-butyl, 1,1,2-trimethylammonium propyl group, 1,2,2-trimethylammonium propyl group, 1-ethyl-1-methyl-propyl, n-heptyl, n-octyl, n-nonyl, positive decyl, methoxyl group, oxyethyl group, the 1-propoxy-, the 2-propoxy-, the 1-butoxy, the 2-butoxy, 1,1-dimethyl oxyethyl group.
In naphthenic substituent, preferred especially replacement and unsubstituted cyclopentyl, cyclohexyl, suberyl.
Preferred thiazolinyl is vinyl, propenyl, pseudoallyl, 1-butylene base, crotyl, 1-pentenyl, pentenyl, 2-methyl-1-butene thiazolinyl, 2-methyl-2-butene base, 3-methyl-1-butene base, 1-hexenyl, 1-heptenyl, 2-heptenyl, 1-octenyl and 2-octenyl.In the cycloalkenyl group substituting group, special cyclopentene base, cyclohexenyl, cycloheptenyl and norcamphyl.
Particularly preferred substituent R
1-R
2It is 1-methyl-ethyl; cyclohexyl; cyclopentyl; phenyl; 2-methyl-phenyl; 3; 5-dimethyl-phenyl; 4-methyl-phenyl; 4-methoxyl group-phenyl; 3; two (the trifluoromethyl)-phenyl of 5-; 4-trifluoromethyl-phenyl; 3; 5-dimethyl-4-methoxyl group-phenyl; the 4-phenoxy group; the 4-dialkyl amido; the 2-alkyl phenyl; the 3-alkyl phenyl; the 4-alkyl phenyl; 2; the 6-dialkyl phenyl organic; 3; the 5-dialkyl phenyl organic; 3; 4; 5-trialkyl phenyl; the 2-alkoxyl phenyl; the 3-alkoxyl phenyl; the 4-alkoxyl phenyl; 2; 6-dialkoxy phenyl; 3; 5-dialkoxy phenyl; 3; 4; the 5-tri-alkoxy phenyl; 3; 5-dialkyl group-4-alkoxyl phenyl; 3; 5-dialkyl group-4-dialkyl amido phenyl; 4-dialkyl amido, abovementioned alkyl and alkoxyl group preferably comprise 1 to 6 carbon atom separately; 3, the 5-trifluoromethyl; the 4-trifluoromethyl; the 2-alkylsulfonyl; the 3-alkylsulfonyl; the 4-alkylsulfonyl; single-to tetrahalogeno-benzene base and naphthyl.Preferred halogenic substituent is F, Cl and Br.
All haloalkyls are or/and halogenated aryl preferably has CHal
3, CH
2CHal
3, C
2Hal
5General formula, wherein Hal especially can represent F, Cl and Br.Special preferred structure formula CF
3, CH
2CF
3, C
2F
5Haloalkyl or/and halogenated aryl.
At last, formula (Ia) and the Fas lignand system (Ib) that preferably exists with the optically active ligands system form of enrichment enantiomorph.Preferred especially enantiomorph enrichment is greater than 90%, especially greater than 99% Fas lignand system.In Fig. 1,2 and 3, shown particularly preferred Fas lignand system.
Can pass through hereinafter described method of the present invention, prepare these preferred parts from following foundation structure commercially available or that be easy to get:
Synthetic general formula (Ia) and compound (Ib) can use several different methods.
The being easy to get property and the desired substitution pattern of corresponding raw material depended in corresponding preparation method's selection.Hereinafter synthetic method of the present invention is described with reference to simple embodiment.These methods are for example understood by the available Fas lignand system kind of these methods.A special benefits according to the inventive method is, can use simple method to prepare a large amount of Fas lignand systems with a small amount of reactions steps.
The preparation of biphosphine ligand
Preferably the Negishi cross-coupling (Negishi cross-coupling) by cyclic vinyl iodine and halogenated aromatic compound prepares aliphatics-aromatics foundation structure.With the modified form of general method in the document (H.C.Brown et al.J.Org.Chem.1982,47,5074), in single still reaction, carry out asymmetric hydroboration by using the chirality borine, chirality phosphine unit is incorporated in the aliphatics system.For the preparation of The compounds of this invention, follow-up trans boronation (transboronation) is proved to be favourable.The method according to this invention can use two organic radical zinc (zinc diorganyls) that the chirality borine is carried out that metal transfer (transmetallated) is handled and racemization (Micouin, L. not; Oestreich, M.; Knochel, P., Angew.Chem., Int.Ed.Engl.1997,36,245-246; A.Boudier, P.Knochel, TetrahedronLett.1999,40,687-690),, and keep structure then with its phosphonous acidization.By (for example: butyllithium) carry out bromine/lithium and replace, and carry out phosphineization with phosphonium chloride subsequently, thereby realize the introducing of second phosphine groups with highly basic.Use the ordinary method in the document that phosphorous intermediate and part are purified.Be implemented in three-dimensional supercentral upset by changing aforesaid method.Under oxidizing condition, carry out asymmetric hydroboration aftertreatment, be used in protecting group stable in the alkali then and protect this chiral alcohol.By removing of bromine/lithium replacement and phosphineization subsequently and protecting group, obtain chirality phosphino-alcohol.Subsequently, be translated into corresponding leavings group, and at S
NCarry out phosphorylation under 2 conditions, make to be accompanied by three-dimensional completely upset and the biphosphine ligand of formation cis-configuration.
The preparation of phosphinous acid ester phosphine part and phosphorous acid ester phosphine part
Can prepare by chiral alcohol according to phosphinous acid ester phosphine part of the present invention and phosphorous acid ester phosphine part.By Negishi coupling and the asymmetric hydroboration that carries out with oxide treatment subsequently, can easily obtain chiral alcohol.The meso-epoxide is carried out nucleophilic ring opening, and subsequently racemoid is split, equally also can promptly obtain chiral alcohol, as the infrastructure element of part of the present invention.In the presence of nitrogenous base and phosphonium chloride, the alcohol of transconfiguration changes phosphinate into.By using grignard compound (Grignard compound) can improve these methods greatly as alkali.Especially true for the conversion of using aliphatic phosphonium chloride.Replace and carry out phosphineization with phosphonium chloride subsequently by carry out bromine/lithium with strong lithium alkali, thereby realize the introducing of second phosphine groups.In order to prepare the part of cis-configuration, must overturn to three-dimensional center.Can realize upset with the single step reaction step of Mitsunobu reaction, perhaps also can realize upset succeeded by cis-selectivity reductive two-step approach through peroxidation.According to aforesaid method, after the upset of three-dimensional center, form the phosphinous acid ester, and replace, and carry out the phosphinous acid ester phosphine part that phosphineization prepares cis-configuration with phosphonium chloride subsequently by carry out bromine/lithium with strong lithium alkali.
A preparation based on 3; in the preferred method of the phosphinous acid ester phosphine part of 5-dimethyl-thiophene; by aforesaid method, with the epoxide open loop and subsequently the resolution of racemic thing obtain chiral alcohol, and the hydroxy functional group of this chiral alcohol is protected with alkali stable protecting group.Replace by bromine/lithium, carry out phosphorylation subsequently and remove protecting group, obtain chirality phosphino-alcohol.In the presence of Grignard reagent, adopt with above-mentioned similar methods to prepare phosphinous acid ester phosphine part.
Fig. 4 has shown the summary of single synthetic route.In Fig. 4, the various substituting groups of substituting group position mark R and R ' ordinary representation are meant the R1-R2 in the above-mentioned definition or rather.For the sake of clarity, in example, selected simple basic ligand structure, for example phenyl-cyclopentyl and thiophenyl-tetrahydrofuran base, but this and do not mean that and produce any qualification or restriction thus.
Fig. 4 shows, though must comprise a large amount of different substituents in the method, but can obtain part of the present invention with simple synthesis mode.Can prepare part with the three-step reaction Stereoselective, and can use simple raw material for this reason.This makes plant-scale possibility that becomes.
Hereinafter with reference to the preferred synthetic method of the present invention, the preparation route of the part of being summarized in the more detailed key drawing 4 of the present invention.
The preparation of basis ligand structure:
Synthetic route A:
In single still reaction, realize the synthetic of aliphatic-aromatic foundation structure by the Negishi cross-coupling of known cyclic vinyl iodine and halogenated aromatic compound in the document.(vinyl iodide is prepared by currently known methods, for example, makes raw material with ketone, uses hydrazine/I
2/ alkali (Barton, D.K.Tetrahedron 1988,44,147-62) or LDA/CIP (O) (OEt)
2/ ISiMe
3(Lee, K.; Wiemer, D.F.Tetrahedron Lett.1993,34,2433-6) prepare) (scheme 1).
Synthetic route B:
Alternatively, foundation structure of the present invention also can prepare by the basic ring-opening reaction and the subsequent removal water of meso-epoxide.The racemic modification of racemic alcohol is split, thereby obtain the alcohol (scheme 2) of the enantiomer-pure of trans connection.
Phosphitylation (Phosphinations)
The part that in the aliphatic series ring, has transconfiguration
In the reaction of single still,, carry out asymmetric hydroboration with the chirality borine, thereby be implemented in introducing chirality phosphine unit in the aliphatics system by with the improving one's methods of general method in the document (H.C.Brown et al.J.Org.Chem.1982,47,5074).For the preparation of The compounds of this invention, follow-up trans boronation (transboronation) is proved to be favourable.The method according to this invention can be used two organic radical zinc that the chirality borine is carried out metal transfer and handle (transmetallated) and do not carry out racemization (Micouin, L.; Oestreich, M.; Knochel, P., Angew.Chem., Int.Ed.Engl.1997,36,245-246; A.Boudier, P.Knochel, Tetrahedron Lett.1999,40,687-690), then with its phosphonous acidization and keep this structure.Carry out oxide treatment, so that required product separated (scheme 3).
Can realize the unitary introducing of phosphine in the aromatic systems by the method that changes in the document:
Reaction sequence as follows has been proved to be the synthetic particularly advantageous method of The compounds of this invention.All reactions steps are all carried out in a container, and the processing of not carrying out intermediate is favourable (scheme 4).
Reduction-oxidation phosphine at first carries out bromine/lithium with n-Butyl Lithium subsequently and replaces after the back, with corresponding chlorinated phosphine phosphonous acid aromatic substance.The method according to this invention can change the free phosphine into currently known methods then once more advantageously with the isolated in form of resulting pair of phosphine (bisphosphane) with borane adduct.
The part that in the aliphatic series ring, has cis-configuration
Alternatively, in the improving one's methods of general method, use H in the document (H.C.Brown et al.J.Org.Chem.1982,47,5074)
2O
2Change the chirality borine alcohol of corresponding transconfiguration into, this alcohol be the O-protection and on aromatic ring by phosphonous acidization.Use fluorochemical to make this alcohol dissociate (scheme 5).
Scheme 5
According to (the U.Nagel for example of known reaction scheme substantially; H.G.Nedden; Chem.Ber./Recueil; 1997; 130; 385), subsequent transformation is that corresponding methanesulfonates can make the conversion to the two phosphines (bisphosphine) of chirality cis-configuration have three-dimensional completely the conversion, and this pair phosphine (bisphosphine) can carry out purifying (scheme 6) with oxidation/method of reducing or borine protection/deprotection subsequently.
Scheme 6
The preparation of phosphinous acid ester phosphine part (phosphine phosphinites) or phosphorous acid ester phosphine part (phosphine phosphites)
With chirality phosphino-alcohol is raw material, in the presence of the alkaline of stoichiometry, carries out single step reaction by adding phosphonium chloride or phosphite chloride, can obtain the corresponding phosphinous acid ester of the present invention phosphine part and phosphorous acid ester phosphine part.Beat allly be, have been found that, according to known method in the document chloro phosphine (chlorophosphane) is added (method of the type substitution reaction: Reetz et al.Angew.Chem.1999 for example, 111,134 with triethylamine or pyridine as alkali; RajanBabu et al., J.Org.Chem.1997,62,6012; Onuma et al.Bull.Chem.Soc.Jpn.1980,53,2012), this reacts completely and does not take place or only be very inadequate.Particularly aliphatic phosphonium chloride (chlorophosphanes) almost can not prepare with this route.On the other hand, can prepare with separating as alkali with EtMgBr and to obtain phosphinous acid ester phosphine part of the present invention, productive rate is good in very good (scheme 7).
Scheme 7
According to the present invention, alternatively, can prepare two identical parts of the unitary substituting group of phosphorus by direct more route, this method is in single still reaction, react with 2 normal highly basic (for example n-Butyl Lithium or tert-butyl lithium), and use 2 normal corresponding chloro phosphines (chlorophosphane) to react subsequently, thereby introduce these groups (scheme 8) simultaneously.
Scheme 8
Equally also can make phosphinous acid ester phosphine part of the present invention (scheme 9) by the combination aforesaid method.
Scheme 9
In the reaction of asymmetric, metal catalytic (for example: hydrogenation, hydroformylation, rearrangement, allyl group alkanisation, Cyclopropanated, hydrosilylation, hydride transfer, hydroboration, hydrocyanation, hydrocarboxylation, aldolisation or He Ke reaction) and in polymerization, general formula (Ia) and compound (Ib) can be used as the part on the metal.They are specially adapted to asymmetric reaction.
The complex compound of suitable complex compound, especially general formula (II) contains general formula of the present invention (Ia) and compound (Ib) as part
[M
xP
yL
zS
q]A
r (II)
Wherein, in general formula (II), M represents metal center, be preferably the transition metal center, L represents identical or different coordination organic or inorganic part, and P represents general formula of the present invention (Ia) and bidentate organophosphor ligand (Ib), S represents the coordinate solvent molecule, and A represents non-coordination anion equivalent, and wherein x and y are the integers more than or equal to 1, and z, q and r are the integers more than or equal to 0.
The upper limit of y+z+q summation is determined that by metal center place available hapto not all hapto all must be occupied.The complex compound that preferably has the coordination sphere of octahedron, accurate octahedron, tetrahedron, accurate tetrahedron, square plane, this coordination sphere be centered around described transition metal center around, it also can twist.The summation of y+z+q is less than or equal to 6x in this complex compound.
Complex compound of the present invention comprises an atoms metal or ion at least, and preferred transition metal atoms or ion, especially palladium, platinum, rhodium, ruthenium, osmium, iridium, cobalt, nickel are or/and copper.
The preferable alloy center is less than four complex compound, and preferred especially those metal centers are one or two complex compound.Described metal center can be occupied by different atoms metals and/or ion.
The preferred ligand L of this complex compound is a halogen, especially Cl, Br and I; Diene, especially cyclooctadiene, norbornadiene; Alkene, especially ethene and cyclooctene; Acetoxyl; The trifluoroacetic acid base; Acetylacetone based; Allyl group; Methylallyl; Alkyl, especially methyl and ethyl; Nitrile, especially acetonitrile and benzonitrile; And carbonyl and hydrogenation part.
Preferred ligand solvent S is an amine, especially triethylamine; Alcohol, especially methyl alcohol; And aromatic substance, especially benzene and isopropyl benzene.
Preferred non-coordination anion A is trifluoracetic acid root, trifluoromethanesulfonic acid root, BF
4, ClO
4, PF
6, SbF
6And BAr
4
In single complex compound, differing molecular, atom or the ion of M, P, L, S and the single component of A can appear.
In the complex compound of ionic structure, preferred [RhP (diene)]
+A
-The compound of type, wherein P represents general formula of the present invention (Ia) and part (Ib).
These metal ligand complex compounds can react in-situ preparing by metal-salt or corresponding precursor complexes and general formula (Ia) and part (Ib).In addition, can also pass through metal-salt or corresponding preceding complex compound and general formula (Ia) and the reaction of part (Ib), and separate subsequently, obtain the metal ligand complex compound.
The example of metal-salt has: metal, especially palladium, platinum, rhodium, ruthenium, osmium, iridium, cobalt, nickel are or/and the muriate of copper, bromide, iodide, prussiate, nitrate, acetate, acetylacetonate, hexafluoroacetylacetone salt, a tetrafluoro borate, perfluor acetate (perfluoroacetates) or fluoroform sulphonate.
The example of precursor network and thing has: the cyclooctadiene Palladous chloride, the cyclooctadiene palladium iodide, 1,5-hexadiene Palladous chloride, 1,5-hexadiene palladium iodide, two (dibenzalacetone) palladium, two (acetonitrile) Palladous chloride (II), two (acetonitrile) palladium bromide (II), two (benzonitrile) Palladous chloride (II), two (benzonitrile) palladium bromide (II), two (benzonitrile) palladium iodide (II), two (allyl group) palladium, two (methylallyl) palladium, propenyl chlorination palladium dimer, methylpropenyl Palladous chloride dimer, the Tetramethyl Ethylene Diamine palladium chloride, Tetramethyl Ethylene Diamine dibrominated palladium, the Tetramethyl Ethylene Diamine palladium diiodide, Tetramethyl Ethylene Diamine dimethyl palladium, the cyclooctadiene Palladous chloride, the cyclooctadiene palladium iodide, 1,5-hexadiene platinum chloride, 1,5-hexadiene platinic iodide, two (cyclooctadiene) platinum, (ethene three Platinic chlorides) potassium, cyclooctadiene rhodium chloride (I) dimer, norbornadiene rhodium chloride (I) dimer, 1,5-hexadiene rhodium chloride dimer, three (triphenylphosphine) rhodium chloride (I), hydrogenized carbonyl (hydridocarbonyl) three (triphenyl phosphorus) rhodium chloride (I), two (cyclooctadiene) perchloric acid rhodium (I), two (cyclooctadiene) Tetrafluoroboric acid rhodium (I), two (cyclooctadiene) trifluoromethanesulfonic acid rhodium (I), two (acetonitrile cyclooctadiene) perchloric acid rhodiums (I), two (acetonitrile cyclooctadiene) Tetrafluoroboric acid chloric acid rhodiums (I), two (acetonitrile cyclooctadiene) trifluoromethanesulfonic acid rhodiums (I), cyclopentadiene rhodium chloride (III) dimer, pentamethyl-cyclopentadiene rhodium chloride (III) dimer, (cyclooctadiene) Ru (η
3-allyl group)
2, ((cyclooctadiene) Ru)
2(acetate)
4, ((cyclooctadiene) Ru)
2(trifluoroacetate)
4, RuCl
2(aromatic hydrocarbons) dimer, three (triphenylphosphine) ruthenium chloride (II), cyclooctadiene ruthenium chloride (II), OsCl
2(aromatic hydrocarbons) dimer, cyclooctadiene iridium chloride (I) dimer, two (cyclooctene) iridium chloride (I) dimer, two (cyclooctadiene) nickel, (cyclododecatriene) nickel, three (norbornylene) nickel, nickel tetracarbonyl, acetylacetonate nickel (II), (aromatic hydrocarbons) copper trifluoromethanesulfcomposite, (aromatic hydrocarbons) cupric perchlorate, (aromatic hydrocarbons) trifluoroacetic acid copper, cobalt-carbonyl.
Complex compound based on one or more metals (especially to be selected from the metal of Ru, Co, Rh, Ir, Ni, Pd, Pt, Cu) of metallic element, it can be a catalyzer, and perhaps it can be used to prepare the catalyzer based on one or more (especially to be selected from the metal of Ru, Co Rh, Ir, Ni, Pd, Pt, Cu) of metallic element.All these complex compounds all are particularly suitable for the asymmetric hydrogenation of C=C, C=O or C=N key, and they can demonstrate high activity and selectivity in these hydrogenations, and these complex compounds also are suitable for asymmetric carbonylation.Particularly, here verified: owing to can make the modification of a lot of modes with simple method mutual-through type (Ia) and part (Ib), so they spatially with on the electronics can well be adjusted so that it adapts to above-mentioned specific substrate and catalyzed reaction, this is favourable.
Corresponding catalyzer comprises at least a complex compound of the present invention.
Hereinafter will provide some non-limiting examples, be used to explain the present invention.
Embodiment
Embodiment
Summary
Being reflected in the glove box that is full of argon gas or in standard Shi Lanke test tube (Schlenk tube) of compound to air-sensitive carried out.Use solvent seasoning equipment (available from InnovativeTechnologies), the post filtration of filling activated alumina, thereby the degassing and purifying by tetrahydrofuran (THF) (THF), diethyl ether and dichloromethane solvent are passed; In addition, use the post fill copper catalyst to remove oxygen in toluene and the pentane.
Following examples are used to illustrate the present invention.They are construed as limiting the present invention never in any form.
Embodiment 11-(cyclopentenes-1-yl)-2-bromobenzene
Under-78 ℃, and slow adding uncle-BuLi in the THF of cyclopentenyl iodine (16mmol) (16ml) solution (32mmol, 2eq.).After next hour, add 1M ZnBr in this temperature
2THF (16ml) solution.Stirred 30 minutes down at-40 ℃, and at room temperature further stirred 30 minutes.
Simultaneously, at room temperature stir Pd (dba)
2(6mol%) and PPh
3THF (12mol%) (16ml) solution 10 minutes.(16mmol 1eq) joins in this solution with 2-bromo-1-iodobenzene.Further at room temperature stirred 10 minutes.The solution that will obtain thus with sleeve pipe is transferred in another solution.Stirred 12 hours down at 50 ℃.At extraction (Et
2O/NaCl) handle after, obtain required product 1-(cyclopentenes-1-yl)-2-bromobenzene from ether mutually, with column chromatography (pentane) purifying and separation, yield 61%.
1H-NMR(CDCl
3)：
δ＝7.43(d，1H)，7.20-7.10(m，2H)，6.87(m，1H)，5.88(d，1H)，2.65(m，2H)，2.43(m，2H)，1.95(m，2H)ppm。
Under-30 ℃, in 30 minutes time, THF (0.5ml) solution of 1-(cyclopentenes-1-yl)-2-bromobenzene (1mmol) is joined freshly prepd IpcBH
2(the THF solution of 1M is 1ml) in the solution.Under this temperature, stirred 2 days.Under high vacuum, remove then and desolvate, and with the borine and the Et of gained
2BH solution (1ml, the DMS solution of 7.3M) reacted 12 hours down at 50 ℃.Under high vacuum,, add Zn (iPr) except that after desolvating
2(2.25ml, the Et of 4M
2O solution).Stirred gained solution 5 hours under the room temperature.Under high vacuum after 3 hours, the resistates of light ash-black in the flask is placed THF (2ml), and centrifugation in ar gas environment.The settled solution on upper strata is shifted and be cooled to 0 ℃ with sleeve pipe, and to wherein slowly adding Ph
2PCl (4mmol).At room temperature stirred 4 days.Add H carefully
2O
2After (1ml, 30%), at room temperature stirred 30 minutes.By extraction (CH
2Cl
2/ NaCl) with column chromatography purifying (CH
2Cl
2/ MeOH 49: 1) handles, obtain required diastereo-isomerism pure products, total recovery 45%.
1H-NMR(CD
3OD)：
δ＝7.92-7.30(m，14H)，4.05(m，1H)，3.41(m，1H)，2.33-1.51(m，6H)ppm。
31P-NMR(CD
3OD)：
δ＝38.7(s，1P)ppm。
With 1-(cyclopentyl-2-diphenylphosphine oxygen base)-2-bromine) benzene (0.4mmol) is dissolved in the 9ml toluene, and uses Cl
3SiH (10eq.) refluxed 12 hours.After during this period of time, applied high vacuum 2 hours.The KOH solution that further adds toluene (10ml) and outgas (2M, 10ml).Remove after the water, use MgSO
4Carry out drying.This suspension is filtered under ar gas environment, under high vacuum, remove and desolvate, and colourless resistates is placed THF (6ml).This solution is cooled to-78 ℃, and just adds-BuLi (1.2eq.).After keeping 2 hours under this temperature, add Ph
2PCl (1.2eq.).Slowly thaw to room temperature (7 hours), add BH subsequently
3DMS (10eq.).Stirred this solution 12 hours under the room temperature.At CH
2Cl
2After handling in/NaCl the solution, with raw product column chromatography (CH
2Cl
2/ pentane, and then use CH
2Cl
2) purifying, thereby obtain product, total recovery 76%.
1H-NMR (CDCl
3) borane adduct:
δ＝7.62-6.90(m，24H)，4.25(m，1H)，3.31(m，1H)，2.18-1.01(m，6H)ppm。
31P-NMR (CDCl
3) borane adduct:
δ＝25.0(s，1P)，20.5(s，1P)ppm。
31P-NMR(CDCl
3)：
δ＝-4.2(d，J＝5.7Hz，1P)，-17.4(d，J＝5.7Hz，1P)ppm。
With the n-Butyl Lithium (hexane solution of 1.6M; 0.239mol) be added drop-wise to be cooled to-78 ℃ 3,4-two bromo-2 in the 325mlTHF solution of 5-thioxene (0.239mol), and stirred 30 minutes.With 3,4-epoxy tetrahydrofuran (THF) (0.217mol) and boron trifluoride ethyl ether complex (0.217mol) are added drop-wise in this solution.This reaction soln is heated to 0 ℃ and further stirred 3 hours.Be hydrolyzed with saturated ammonium chloride solution then, and twice of aqueous phase extracted with t-butyl methyl ether.After the drying, solvent removed in vacuo, and with chromatography raw product is purified.Obtain the buttery product, yield is 64%.
1H-NMR(CDCl
3)：
δ＝4.82(q，1H)，4.29-4.21(m，2H)，4.11(t，1H)，3.99(dd，1H)，3.67-3.60(m，1H)，2.50(s，3H)，2.41(s，3H)ppm。
Embodiment 5 (3R, 4S)-(bromo-2,5-dimethyl-3-thienyl)-tetrahydrochysene-3-furans is pure and mild for 4-
(3S, 4R)-4-(bromo-2,5-dimethyl-3-thienyl)-tetrahydrochysene-3-furans alcohol acetate
Solid Novozym 435 is joined in the 425ml vinyl acetate solution of trans-4-(4-bromo-2,5-dimethyl-3-thienyl) tetrahydrochysene-3-furans alcohol (0.153mol), stirred then 24 hours.By removing by filter enzyme, and resistates washs with t-butyl methyl ether.Except that after desolvating, two kinds of products are separated with chromatography.Obtain (3R, 4S)-4-(bromo-2,5-dimethyl-3-thienyl)-tetrahydrochysene-3-furans alcohol, yield 49% (＞99%ee), and (3S, 4R)-4-(bromo-2,5-dimethyl-3-thienyl)-tetrahydrochysene-3-furans alcohol acetate, yield 50% (＞97%ee).
1H-NMR(CDCl
3)：
δ＝5.65-5.60(m，1H)，4.44(dd，1H)，4.26(t，1H)，4.07(d，1H)，4.03(d，1H)，3.82(ddd，1H)，2.51(s，3H)，2.46(s，3H)，2.17(s，3H)ppm。
Embodiment 6 (3R, 4S)-4-(bromo-2,5-dimethyl-3-thienyl)-tetrahydrochysene-3-furyl uncle fourth
Base dimetylsilyl ether
TERT-BUTYL DIMETHYL CHLORO SILANE (82mmol) and imidazoles (97mmol) are joined in the 200ml dichloromethane solution of (75mmol) that be cooled to 0 ℃, and with this reaction soln heated overnight at room temperature.With this reaction soln of 1M hydrochloric acid hydrolysis of 150ml, and with methylene dichloride with water extraction three times.Organic phase with saturated sodium bicarbonate solution washing merging.After the drying, solvent removed in vacuo obtains the orange oily product of quantitative yield.
1H-NMR(CDCl
3)：
δ＝4.9(q，1H)，4.28-4.18(m，3H)，3.82(dd，1H)，3.68(ddd，1H)，2.54(s，3H)，2.47(s，3H)，0.96(s，9H)，0.04(s，3H)，0.00(s，3H)ppm。
Embodiment 7 1-(tertiary butyl-1, the 1-dimetylsilyl-((3R, 4S)-((1,1-two for 4-for 4-
(3,5-two (trifluoromethyl) phenyl)-phosphino-)-2,5-dimethyl-3-thienyl) four oxygen-3-furyl) ether
Under-78 ℃, in 10 minutes time, tert-butyl lithium (25.5mmol) is joined (3R, 4S)-4-(bromo-2,5-dimethyl-3-thienyl)-the 50ml THF solution of tetrahydrochysene-3-furyl t-butyldimethylsilyl ether (12.8mmol) in, stirred then one hour.Two-(3,5-two-(trifluoromethyl)-phenyl) phosphonium chloride of 15.3mmol is added drop-wise in this solution, and at room temperature heats this reaction soln and spend the night.Be hydrolyzed with de aerated water then, dilute this solution with methylene dichloride, and twice of dichloromethane extraction of water.In drying and except that after desolvating, with this raw product of chromatographic purification, and crystallization from cold pentane.Yield with 22% obtains this product.
1H-NMR(C
6H
6)：
δ＝7.86(t，4H)，7.79(s，2H)，4.92-4.99(m，1H)，4.41(dd，1H)，4.30-4.23(m，1H)，4.11-4.01(m，2H)，3.97(dd，1H)，2.22(s，3H)，1.60(s，3H)，0.99(s，9H)，0.00(s，3H)，-0.04(s，3H)ppm。
Embodiment 8 1-(tertiary butyl-1, the 1-dimetylsilyl-((3R, 4S)-((1,1-two for 4-for 4-
(neighbour-toluene) phosphino-)-2,5-dimethyl-3-thienyl) tetrahydrochysene-3-furyl) ether
Carrying out this with the method that is similar to embodiment 7 synthesizes.
Yield: 59%
1H-NMR(C
6H
6)：
δ＝7.00-7.30(m，8H)，4.90-5.11(m，1H)，4.52(dd，J＝10,8Hz，1H)，4.15-4.40(m，3H)，4.07(dd，J＝10,3Hz，1H)，2.51(s，3H)，2.47(s，3H)，2.40(s，3H)，1.88(s，3H)，1.06(s，9H)，0.00(s，6H)ppm。
31P-NMR(C
6H
6)：
δ＝-22.0ppm。
Embodiment 9 1-(tertiary butyl-1, the 1-dimetylsilyl-((3R, 4S)-((1,1-two is (right for 4-for 4-
-(fluoro)) phosphino-phenyl))-2,5-dimethyl-3-thienyl) tetrahydrochysene-3-furyl) ether
Carrying out this with the method that is similar to embodiment 7 synthesizes.
Yield: 37%
1H-NMR(C
6H
6)：
δ＝7.43-7.52(m，4H)，7.27(q，J＝8Hz，4H)，4.98-5.03(m，1H)，4.48(dd，J＝10,8Hz，1H)，4.32(dt，J＝9,2Hz，1H)，4.17(t，J＝9Hz，1H)，4.00-4.08(m，1H)，3.93(dd，J＝8,3Hz，1H)，2.69(s，3H)，2.01(s，3H)，1.01(s，9H)，0.03(s，3H)，0.00(s，3H)ppm。
31P-NMR(C
6H
6)：
δ＝-25.3ppm。
Embodiment 10 1-(tertiary butyl-1, the 1-dimetylsilyl-((3R, 4S)-((1,1-two for 4-for 4-
(3,5-two (methyl)) phenyl) phosphino-)-2,5-dimethyl-3-thienyl) tetrahydrochysene-3-furyl) ether
Carrying out this with the method that is similar to embodiment 7 synthesizes.
Yield: 6%
1H-NMR(C
6H
6)：
δ＝7.34(t，J＝8Hz，4H)，6.88(s，1H)，6.84(s，1H)，5.23-5.28(m，1H)，4.64(dd，J＝10,8Hz，1H)，4.57(t，J＝9Hz，1H)，4.40(dt，J＝8,2Hz，1H)，4.07-4.19(m，2H)，2.34(s，3H)，2.20(s，6H)，2.14(s，6H)，2.12(s，3H)，1.02(s，9H)，0.03(s，3H)，0.00(s，3H)ppm。
31P-NMR(C
6H
6)：
δ＝-10.9ppm。
Embodiment 11
Under-78 ℃, in 10 minutes time, tert-butyl lithium (25.5mmol) is joined (3R, 4S)-4-(bromo-2,5-dimethyl-3-thienyl)-the 50ml THF solution of tetrahydrochysene-3-furyl t-butyldimethylsilyl ether (12.8mmol) in, stirred then one hour.15.3mmol dicyclohexyl chloro phosphine (dicyclohexylchlorophosphane) is added drop-wise in this solution, and at room temperature heated this reaction soln 2 hours.And then once solution is cooled to-78 ℃, add 5 normal borines (the THF solution of 1M).Then this solution is heated to room temperature and uses the de aerated water hydrolysis, dilute this solution with methylene dichloride, and twice of dichloromethane extraction of water.Drying reaches except that after desolvating, raw product chromatography purification and crystallization from cold pentane.Yield with 58% obtains this product.
1H-NMR(C
6H
6)：
δ＝4.89(q，J＝7Hz，1H)，4.17-4.28(m，1H)，4.63(t，J＝8Hz，1H)，4.20-4.26(m，1H)，3.93(t，J＝8Hz，1H)，3.76(dd，J＝9,8Hz，1H)，2.44(s，3H)，2.29(s，3H)，2.13-2.39(m，2H)，1.09-2.00(m，20H)，0.97(s，9H)，0.00(s，6H)ppm。
31P-NMR(C
6H
6)：
δ＝39.1ppm。
Embodiment 12 (3R, 4S)-4-(4-{1,1-two [3,5-two (trifluoromethyl)-phenyl] phosphine
Base }-2,5-dimethyl-3-thienyl)-tetrahydrochysene-3-furans alcohol
Under 0 ℃, tetrabutylammonium solution (5.7mmol) is added drop-wise to the 1-(tertiary butyl-1,1-dimetylsilyl-((3R, 4S)-(4-(1 for 4-, 1-two (3,5-two (trifluoromethyl) phenyl) phosphino-)-2,5-dimethyl-3-thienyl)-and tetrahydrochysene-3-furyl) in the 22ml tetrahydrofuran solution of ether (2.86mmol), and at room temperature heat this mixture overnight.Solvent removed in vacuo, and crude product chromatography purification and separation, yield 87%.
1H-NMR(C
6H
6)：
δ＝8.08(t，6H)，7.97(s，1H)，7.92(s，1H)，4.45-4.38(m，1H)，4.10(dd，1H)，4.01-3.92(m，1H)，3.89-3.82(m，1H)，3.58(dd，1H)，2.29(s，3H)，2.15(s，3H)ppm。
31P-NMR(C
6H
6)：
δ＝-9.93(s，1P)ppm。
Embodiment 13 (3R, 4S)-4-(4-{1,1-two [adjacent toluene] phosphino-}-2,5-dimethyl-3-thiophene
Base) tetrahydrochysene-3-furans alcohol
Carrying out this with the method that is similar to embodiment 12 synthesizes.
Yield: 93%
1H-NMR(CDCl
3)：
δ＝7.46-7.54(m，4H)，7.38(t，J＝7Hz，2H)，7.29(dd，J＝8,6Hz，1H)，7.20(dd，J＝8,6Hz，1H)，4.68-4.84(m，1H)，4.34-4.41(m，1H)，4.03-4.12(m，2H)，3.83-3.93(m，2H)，2.69(s，3H)，2.57(s，3H)，2.56(s，3H)，2.26(s，3H)，1.60(br s，1H)ppm。
Embodiment 14 (3R, 4S)-4-(4-{1,1-two [3,5-two (methyl)-phenyl]-phosphino-}-2,5-two
Methyl-3-thienyl)-tetrahydrochysene-3-furans alcohol
Carrying out this with the method that is similar to embodiment 12 synthesizes.
Yield: 99%
1H-NMR(CDCl
3)：
δ＝7.32(d，J＝7Hz，2H)，7.30(d，J＝7Hz，2H)，6.78(s，2H)，4.64(q，J＝7Hz，1H)，4.22(dd，J＝11,9Hz，1H)，4.00-4.09(m，2H)，3.88-3.96(m，1H)，3.76(dd，J＝11,4Hz，1H)，2.40(s，3H)，2.27(s，3H)，2.10(s，6H)，2.08(s，6H)ppm。
Embodiment 15 ((3R, 4S)-4-(4-{1,1-two [3,5-two (right-(fluoro)-phenyl)]-phosphine
Base }-2,5-dimethyl-3-thienyl)-tetrahydrochysene-3-furans alcohol
Carrying out this with the method that is similar to embodiment 12 synthesizes.
Yield: 99%
1H-NMR(C
6H
6)：
δ＝7.30-7.40(m，4H)，6.93-7.02(m，4H)，4.72-4.77(m，1H)，4.33(dd，J＝11，9Hz，1H)，4.09-4.20(m，2H)，3.98-4.06(m，1H)，3.89(dd，J＝10，4Hz，1H)，2.43(s，3H)，2.10(s，3H)，1.32(br s，1H)ppm。
Embodiment 16
Carrying out this with the method that is similar to embodiment 12 synthesizes.
Yield: 76%
1H-NMR(C
6H
6)：
δ＝4.28(t，J＝9Hz，1H)，4.18-4.24(m，1H)，3.90-4.03(m，1H)，3.87(dd，J＝11，8Hz，1H)，3.70(t，J＝7Hz，1H)，3.56(dd，J＝10，5Hz，1H)，2.70(s，3H)，2.50-2.64(m，1H)，2.12-2.23(m，1H)，2.03(s，3H)，0.88-1.98(m，20H)ppm。
Embodiment 17 trans-4-(4-bromo-2,5-dimethyl-3-thienyl)-tetrahydrochysene-3-pyrans alcohol
Carrying out this with the method that is similar to embodiment 4 synthesizes.
Yield: 64%
1H-NMR(CDCl
3)：
δ＝4.25-4.62(br m，1H)，2.92-3.11(br m，1H)，2.64(br s，3H)，2.55(s，3H)，2.30-2.40(m，1H)，1.48-2.11(m，7H)ppm。
Embodiment 18 (3R, 4S)-and (3S, 4R)-4-(bromo-2,5-dimethyl-3-thienyl)-tetrahydrochysene-3-
The pyrans alcohol acetic ester
Use ChiroCLEC PC, carry out this with the method that is similar to embodiment 5 and synthesize.
1H-NMR(CDCl
3)：
δ＝5.40-5.54(br m，1H)，3.03-3.15(br m，1H)，2.50(s，3H)，2.42(s，3H)，2.20-2.28(m，1H)，1.91(s，3H)，1.81-2.00(m，3H)，1.38-1.66(m，4H)ppm。
Embodiment 19 (3R, 4S)-4-(bromo-2,5-dimethyl-3-thienyl)-tetrahydrochysene-3-pyranyl uncle
Butyl dimetylsilyl ether
Carrying out this with the method that is similar to embodiment 6 synthesizes.
Yield: 78%
1H-NMR(CDCl
3)：
δ＝4.13-4.28(m，1H)，2.73-2.90(m，1H)，2.43(s，3H)，2.38(s，3H)，2.03-2.10(m，1H)，1.66-1.88(m，3H)，1.27-1.48(m，4H)，0.78(s，9H)，0.00(s，3H)，-0.28(s，3H)ppm。
Carrying out this with the method that is similar to embodiment 11 synthesizes.
Yield: 78%
1H-NMR(CDCl
3)：
δ＝3.93(dt，J＝10，4Hz，1H)，2.40(s，3H)，2.37-2.41(m，1H)，2.16(s，3H)，2.01-2.12(m，1H)，0.90-1.96(m，29H)，0.80(s，9H)，0.00(s，3H)，-0.18(s，3H)ppm。
Embodiment 21
Under-78 ℃, in 10 minutes time, tert-butyl lithium (10.0mmol) is joined (3R, 4S)-4-(bromo-2,5-dimethyl-3-thienyl)-the 20ml THF solution of 2-cyclohexyl t-butyldimethylsilyl ether (5.0mmol) in, then this mixture was stirred one hour.Two-(3,5-dimethyl-phenyl) phosphonium chloride of 6mmol is added drop-wise in this solution, and at room temperature heats this reaction soln and spend the night.With this mixture of superoxol hydrolysis and further stirred 2 hours, dilute this solution then, and water is with twice of dichloromethane extraction with methylene dichloride.In drying and except that after desolvating, raw product is with chromatography purification and from cold pentane crystallization.Yield with 59% obtains this product.
1H-NMR(CDCl
3)：
δ＝7.30-7.38(m，3H)，7.10-7.22(m，3H)，3.93(dt，J＝11,5Hz，1H)，2.50-2.60(m，1H)，2.48(s，3H)，2.37(s，12H)，2.22(s，3H)，1.07-1.80(m，5H)，0.83-0.96(m，1H)，0.80(s，9H)，0.65-0.77(m，1H)，0.50-0.60(m，1H)，0.00(s，3H)，-0.13(s，3H)ppm。
Embodiment 22
Carrying out this with the method that is similar to embodiment 21 synthesizes.
Yield: 55%
1H-NMR(d
6-DMSO)：
δ＝7.77-7.88(m，10H)，4.10(dt，J＝10,4Hz，1H)，2.84-2.93(m，1H)，2.60(s，3H)，2.25(s，3H)，1.90-1.99(m，1H)，1.28-1.70(m，6H)，0.91(s，9H)，0.54-0.69(m，1H)，0.16(s，3H)，0.00(s，3H)ppm。
Embodiment 23
The 10ml toluene solution 3 hours of heating 2.89mmol phosphine oxide (embodiment 22) and 28.9mmol trichlorosilane is cooled to room temperature then under refluxing., at room temperature stirred 30 minutes and it is diluted this reaction mixture hydrolysis with 30% sodium hydroxide solution with 30ml water.With twice of TBME aqueous phase extracted.Dry reaching except that after desolvating used the chromatography purification raw product.Yield with 77% obtains this product.
1H-NMR(d
6-DMSO)：
δ＝6.90-7.00(m，6H)，4.09-4.23(m，1H)，3.76(br s，1H)，2.95-3.08(m，1H)，2.43(s，3H)，2.30(s，6H)，2.28(s，6H)，1.92-2.00(m，1H)，1.90(s，3H)，0.96-1.70(m，7H)ppm。
31P-NMR(d
6-DMSO)：
δ＝-24.8，-26.1ppm。
Embodiment 24
Carrying out this with the method that is similar to embodiment 23 synthesizes.
Yield: 69%
1H-NMR(d
6-DMSO)：
δ＝7.27-7.40(m，10H)，4.10-4.27(m，1H)，3.80(br s，1H)，3.00-3.10(m，1H)，2.42(s，3-H)，1.90-2.00(m，1H)，1.78(s，3H)，1.00-1.70(m，7H)ppm。
31P-NMR(d
6-DMSO)：
δ＝-24.4，-26.0ppm。
Embodiment 25
Carrying out this with the method that is similar to embodiment 12 synthesizes.
Yield: 27%
1H-NMR(C
6H
6)：
δ＝3.73-3.83(m，1H)，3.28(br s，1H)，2.70(br s，3H)，2.13-2.27(m，1H)，2.10(s，3H)，2.00-2.06(m，1H)，1.93(s，3H)，1.80-1.87(m，1H)，0.95-1.73(m，27H)ppm。
31P-NMR(C
6H
6)：
δ＝36.7ppm。
Embodiment 26
The 400ml dichloromethane solution of 92.4mmol oxalyl chloride is cooled to-50 ℃, and in 5 minutes time, the DMSO of 185mmol is joined in this solution.After 5 minutes, the 77mmol alcohol (embodiment 5) that will be dissolved in the 100ml methylene dichloride joins in this solution.Further stirred this solution 30 minutes, add the 385mmol triethylamine then, and this reaction soln is heated to room temperature.With 200ml water, 200ml 3M hydrochloric acid and 200ml sodium hydrogen carbonate solution flushing organic phase.Dry this organic phase is removed in the vacuum and is desolvated and this raw product of use in next step.
1H-NMR(CDCl
3)：
δ＝4.44(t，J＝12Hz，1H)，4.20(t，J＝11Hz，1H)，4.13(d，J＝12Hz，2H)，3.86(t，J＝11Hz，1H)，2.27(s，3H)，2.26(s，3H)ppm。
Embodiment 27
77mmol ketone (embodiment 26) is dissolved among the 200ml THF.Add 100mmol K-Selectrid down at-78 ℃, and at room temperature heat this solution and spend the night.In this solution, add the ethanol of 150ml, 150 milliliters 4N sodium hydroxide solution and 30% hydrogen peroxide continuously.Further stirred this solution 2 hours and use the TBME of 250ml to dilute, and will respectively be separated.Water also removes in a vacuum and desolvates with 100ml TBME extracting twice, dry then organic phase.Raw product heptane recrystallization.
Yield: 69%
1H-NMR(CDCl
3)：
δ＝4.65-4.70(m，1H)，4.56(t，J＝11Hz，1H)，4.23(dd，J＝12,5Hz，1H)，4.18(t，J＝10Hz，1H)，4.11(d，J＝12Hz，1H)，3.82-3.90(m，1H)，2.68(s，3H)，2.52(s，3H)，1.78(br s，1H)ppm。
Embodiment 28
Use ChiroCLEC PC, carry out this with the method that is similar to embodiment 5 and synthesize.
1H-NMR(CDCl
3)：
δ＝5.60-5.64(m，1H)，4.54(t，J＝10Hz，1H)，4.26(dd，J＝12,5Hz，1H)，4.10-4.21(m，2H)，3.98-4.06(m，1H)，2.63(m，3H)，2.50(m，3H)，2.03(m，3H)ppm。
Embodiment 29
Carrying out this with the method that is similar to embodiment 6 synthesizes.
Yield: 95%
1H-NMR(CDCl
3)：
δ＝4.85(dt，J＝6,2Hz，1H)，4.67(dd，J＝13,11Hz，1H)，4.36(dd，J＝13,6Hz，1H)，4.26(t，J＝11Hz，1H)，4.08(dd，J＝10,2Hz，1H)，3.78-3.96(m，1H)，2.70(s，3H)，2.60(s，3H)，1.00(s，9H)，0.11(s，3H)，0.00(s，3H)ppm。
Embodiment 30
Carrying out this with the method that is similar to embodiment 21 and embodiment 12 synthesizes.
Yield: 37%
1H-NMR(C
6H
6)：
δ＝7.80-7.94(m，4H)，7.18-7.31(m，6H)，4.93(q，J＝8Hz，1H)，4.62(dd，J＝11,8Hz，1H)，4.40-4.45(m，1H)，4.31(dd，J＝11,8Hz，1H)，4.25(q，J＝8Hz，1H)，3.97(t，J＝11Hz，1H)，2.62(s，3H)，1.79(s，3H)ppm。
31P-NMR(C
6H
6)：
δ＝40.4ppm。
Embodiment 31
Carrying out this with the method that is similar to embodiment 21 and embodiment 12 synthesizes.
Yield: 35%
1H-NMR(C
6H
6)：
δ＝7.60-7.73(m，4H)，6.68-6.73(m，4H)，6.14(br s，1H)，4.85(q，J＝7Hz，1H)，4.58(dd，J＝9,7Hz，1H)，4.30(dd，J＝10,8Hz，1H)，4.14-4.23(m，2H)，3.89(t，J＝9Hz，1H)，3.23(s，3H)，3.22(s，3H)，2.47(s，3H)，1.82(s，3H)ppm。
31P-NMR(C
6H
6)：
δ＝40.3ppm。
Embodiment 32
Carrying out this with the method that is similar to embodiment 21 and embodiment 12 synthesizes.
Yield: 40%
1H-NMR(CDCl
3)：
δ＝7.42-7.52(m，4H)，7.04-7.12(m，4H)，4.23(q，J＝7Hz，1H)，4.10(dd，J＝9,8Hz，1H)，3.96(dd，J＝10,7Hz，1H)，3.63-3.70(m，2H)，3.58(t，J＝9Hz，1H)，2.40(s，3H)，2.23(br s，1H)，1.59(s，3H)ppm。
31P-NMR(CDCl
3)：
δ＝27.3ppm。
Embodiment 33
Carrying out this with the method that is similar to embodiment 21 and embodiment 12 synthesizes.
Yield: 45%
1H-NMR(CDCl
3)：
δ＝7.06-7.14(m，6H)，4.20(q，J＝8Hz，1H)，4.12(dd，J＝10,11Hz，1H)，3.96(dd，J＝11,9Hz，1H)，3.65-3.76(m，2H)，3.60(t，J＝10Hz，1H)，2.45(s，3H)，2.28(s，6H)，2.27(s，6H)，1.61(s，3H)ppm。
31P-NMR(CDCl
3)：
δ＝30.0ppm。
Embodiment 34
Carrying out this with the method that is similar to embodiment 23 synthesizes.
Yield: 43%
1H-NMR(C
6H
6)：
δ＝7.48-7.55(m，4H)，6.94(d，J＝9Hz，2H)，6.88(d，J＝9Hz，2H)，4.52(t，J＝9Hz，1H)，4.21-4.30(m，1H)，4.05-4.10(m，1H)，4.00(t，J＝9Hz，1H)，3.77-3.80(m，2H)，3.45(s，3H)，3.43(s，3H)，2.62(s，3H)，2.40(s，3H)，1.66(br s，1H)ppm。
31P-NMR(C
6H
6)：
δ＝-11.5ppm。
Embodiment 35
Carrying out this with the method that is similar to embodiment 23 synthesizes.
Yield: 51%
1H-NMR(C
6H
6)：
δ＝7.43-7.50(m，4H)，7.03-7.20(m，6H)，4.35(t，J＝8Hz，1H)，3.90-3.98(m，2H)，3.82(t，J＝9Hz，1H)，3.60(dd，J＝11,5Hz，1H)，3.32-3.37(m，1H)，2.52(s，3H)，2.35(s，3H)，1.33(br s，1H)ppm。
31P-NMR(C
6H
6)：
δ＝-11.6ppm。
Embodiment 36
Carrying out this with the method that is similar to embodiment 23 synthesizes.
Yield: 56%
1H-NMR(C
6H
6)：
δ＝7.33(d，J＝9Hz，4H)，6.86(s，1H)，6.80(s，1H)，4.49(t，J＝8Hz，1H)，4.12-4.21(m，1H)，3.98-4.03(m，2H)，3.68(dd，J＝11,5Hz，1H)，3.49-3.54(m，1H)，2.58(s，6H)，2.19(s，6H)，2.12(s，6H)，1.56(br s，1H)ppm。
31P-NMR(C
6H
6)：
δ＝-12.1ppm。
Embodiment 37
Use ChiroCLEC PC, carry out this with the method that is similar to embodiment 4 and embodiment 5 and synthesize.
1H-NMR(d
6-DMSO)：
δ＝7.05-7.23(m，3H)，6.76(d，J＝9Hz，1H)，4.68-4.76(m，1H)，4.47(d，J＝7Hz，1H)，3.28(dd，J＝18,9Hz，1H)，3.18(br s，1H)，2.90(dd，J＝8,18Hz，1H)，2.31(s，3H)，2.12(s，3H)ppm。
Embodiment 38
Carrying out this with the method that is similar to embodiment 6 synthesizes.
Yield: 94%
1H-NMR(CDCl
3)：
δ＝7.17-7.30(m，3H)，6.88-7.03(m，1H)，5.09-5.18(m，1H
a)，4.69-4.87(m，2H
b)，4.57(d，J＝8Hz，1H
a)，3.28-3.43(m，1H)，3.08(dd，J＝9,16Hz，1H)，2.56(s，3H
a)，2.50(s，3H
b)，2.40(s，3H
a)，2.00(s，3H
b)，0.95(s，9H)，0.00(s，3H)，-0.06(s，3H)ppm。
Embodiment 39
Carrying out this with the method that is similar to embodiment 21 synthesizes.Yield: 74%
1H-NMR(d
6-DMSO)：
δ＝7.69-7.87(m，10H)，7.36(d，J＝8Hz，1H)，7.30(t，J＝9Hz，1H)，7.23(t，J＝8Hz，1H)，6.77(d，J＝9Hz，1H)，5.60(d，J＝9Hz，1H)，5.00(q，J＝9Hz，1H)，3.40(dd，J＝9,17Hz，1H)，2.84(dd，J＝9,17Hz，1H)，2.08(s，3H)，2.02(s，3H)，0.98(s，9H)，0.06(s，3H)，0.00(s，3H)ppm。
Embodiment 40
Carrying out this with the method that is similar to embodiment 21 synthesizes.
Yield: 65%
1H-NMR(d
6-DMSO)：
δ＝7.28-7.44(m，9H)，6.86-6.90(m，1H)，5.20(d，J＝8Hz，1H)，4.96(q，J＝9Hz，1H)，3.39(dd，J＝8,15Hz，1H)，2.75(dd，J＝10,15Hz，1H)，2.50(s，6H)，2.46(s，6H)，2.12(s，3H)，2.08(s，3H)，1.00(s，9H)，0.05(s，3H)，0.00(s，3H)ppm。
Embodiment 41
Carrying out this with the method that is similar to embodiment 23 synthesizes.
Yield: 77%
1H-NMR(d
6-DMSO)：
δ＝6.80-7.40(m，13H)，6.60(d，J＝8Hz，1H)，4.60-5.00(m，2H)，3.30(dd，J＝8,16Hz，1H)，2.85(dd，J＝7,16Hz，1H)，2.10(br s，3H)，1.80(s，3H)ppm。
31P-NMR(d
6-DMSO)：
δ＝-23.4，-26.9ppm。
Embodiment 42
Carrying out this with the method that is similar to embodiment 23 synthesizes.
Yield: 77%
1H-NMR(d
6-DMSO)：
δ＝7.13(d，J＝8Hz，1H)，7.05(t，J＝8Hz，1H)，6.71-6.95(m，7H)，6.55(d，J＝9Hz，1H)，4.58-4.90(m，2H)，3.32(dd，J＝9,17Hz，1H)，2.81(dd，J＝8,17Hz，1H)，2.25(s，6H)，2.21(s，6H)，2.10(br s，3H)，1.90(s，3H)ppm。
31P-NMR(d
6-DMSO)：
δ＝-23.0，-26.7ppm。
Embodiment 43
Carrying out this with the method that is similar to embodiment 7 synthesizes.
Yield: 96%
1H-NMR(CDCl
3)：
δ＝7.69(d，J＝9Hz，1H)，7.40-7.43(m，1H)，7.35(dd，J＝9,2Hz，1H)，7.18(dt，J＝8,2Hz，1H)，4.38(q，J＝7Hz，1H)，3.67(q，J＝8Hz，1H)，2.33-2.42(m，1H)，1.83-2.19(m，5H)，0.96(s，9H)，0.03(s，3H)，0.00(s，3H)ppm。
Embodiment 44
Carrying out this with the method that is similar to embodiment 21 synthesizes.Yield: 56%
1H-NMR(C
6H
6)：
δ＝7.77-7.83(m，2H)，7.66-7.72(m，2H)，7.13-7.20(m，1H)，6.93-7.08(m，8H)，6.72-6.78(m，1H)，4.35(q，J＝8Hz，1H)，4.22-4.31(m，1H)，2.22-2.33(m，1H)，1.20-1.82(m，5H)，0.92(s，9H)，0.00(s，6H)ppm。
31P-NMR(C
6H
6)：
δ＝43.4ppm。
Embodiment 45
Carrying out this with the method that is similar to embodiment 21 synthesizes.
Yield: 56%
1H-NMR(C
6H
6)：
δ＝7.09-7.20(m，3H)，6.91(t，J＝8Hz，1H)，4.70-4.81(m，1H)，4.30(q，J＝9Hz，1H)，2.50-2.61(m，1H)，2.16-2.25(m，1H)，0.95-2.00(m，26H)，0.87(s，9H)，0.00(s，3H)，-0.09(s，3H)ppm。
31P-NMR(C
6H
6)：
δ＝62.8ppm。
Embodiment 46
Carrying out this with the method that is similar to embodiment 12 synthesizes.
Yield: 67%
1H-NMR(C
6H
6)：
δ＝7.62(m，4H)，7.21-7.29(m，1H)，6.96-7.12(m，8H)，6.79(t，J＝8Hz，1H)，6.46(br s，1H)，4.32(q，J＝8Hz，1H)，4.05(q，J＝10Hz，1H)，1.95-2.12(m，2H)，1.55-1.77(m，4H)ppm。
31P-NMR(C
6H
6)：
δ＝48.2ppm。
Embodiment 47
Carrying out this with the method that is similar to embodiment 21 synthesizes.
Yield: 45%
1H-NMR(C
6H
6)：
δ＝7.38-7.49(m，4H)，7.25-7.31(m，2H)，6.86-6.92(m，2H)，6.63-6.75(m，4H)，6.30(br s，1H)，4.33(q，J＝8Hz，1H)，3.90-4.00(m，1H)，1.99-2.17(m，2H)，1.60-1.80(m，4H)ppm。
31P-NMR(C
6H
6)：
δ＝42.0ppm。
Embodiment 48
Carrying out this with the method that is similar to embodiment 21 synthesizes.
Yield: 57%
1H-NMR(C
6H
6)：
δ＝7.52-7.62(m，4H)，7.21-7.28(m，1H)，7.02-7.18(m，2H)，6.81(t，J＝8Hz，1H)，6.53-6.60(m，4H)，4.30(q，J＝8Hz，1H)，4.10(q，J＝9Hz，1H)，3.11(s，3H)，3.06(s，3H)，1.92-2.06(m，2H)，1.60-1.80(m，2H)，1.25-1.36(m，2H)ppm。
31P-NMR(C
6H
6)：
δ＝47.9ppm。
Embodiment 49
Carrying out this with the method that is similar to embodiment 12 synthesizes.
Yield: 67%
1H-NMR(C
6H
6)：
δ＝7.42(dd，J＝10,4Hz，1H)，7.25-7.32(m，1H)，7.01-7.09(m，2H)，6.45(br s，1H)，4.76(q，J＝9Hz，1H)，4.25(q，J＝7Hz，1H)，2.42-2.50(m，1H)，0.90-2.30(m，27H)ppm。
31P-NMR(C
6H
6)：
δ＝66.5ppm。
Embodiment 50
Carrying out this with the method that is similar to embodiment 23 synthesizes.
Yield: 57%
1H-NMR(C
6H
6)：
δ＝7.54-7.62(m，4H)，7.30-7.39(m，3H)，7.24-7.29(m，6H)，7.15(dt，J＝9,2Hz，1H)，4.26-4.40(m，2H)，2.23-2.32(m，1H)，2.02-2.11(m，1H)，1.67-1.91(m，4H)，1.60(br s，1H)ppm。
31P-NMR(C
6H
6)：
δ＝0.0ppm。
Embodiment 51
Carrying out this with the method that is similar to embodiment 23 synthesizes.
Yield: 37%
1H-NMR(C
6H
6)：
δ＝7.40-7.48(m，4H)，7.21-7.31(m，3H)，7.12(dt，J＝9,2Hz，1H)，6.81(d，J＝11Hz，4H)，4.16-4.31(m，2H)，3.31(s，3H)，3.30(s，3H)，2.15-2.25(m，1H)，1.92-2.03(m，1H)，1.59-1.85(m，4H)，1.56(br s，1H)ppm。
31P-NMR(C
6H
6)：
δ＝-5.3ppm。
Embodiment 52
Carrying out this with the method that is similar to embodiment 23 synthesizes.
Yield: 60%
1H-NMR(C
6H
6)：
δ＝7.00-7.05(m，1H)，6.92-7.03(m，5H)，6.80-6.90(m，2H)，6.55-6.63(m，4H)，4.00(q，J＝7Hz，1H)，3.85(quin，J＝8Hz，1H)，1.82-1.91(m，1H)，1.69-1.78(m，1H)，1.27-1.60(m，4H)ppm。
31P-NMR(C
6H
6)：
δ＝-3.0ppm。
Embodiment 53
Carrying out this with the method that is similar to embodiment 21 and embodiment 12 synthesizes.
Yield: 45%
1H-NMR(C
6H
6)：
δ＝7.80-7.94(m，4H)，6.91-7.21(m，13H)，6.70(d，J＝9Hz，1H)，6.51(d，J＝9Hz，1H)，5.49(d，J＝10Hz，1H)，4.32-4.40(m，1H)，2.90-3.00(m，1H)，2.84(dt，J＝16,6Hz，1H)，2.50-2.58(m，1H)，2.12-2.23(m，1H)ppm。
31P-NMR(C
6H
6)：
δ＝48.2ppm。
Embodiment 54
Carrying out this with the method that is similar to embodiment 21 and embodiment 12 synthesizes.
Yield: 52%
1H-NMR(C
6H
6)：
δ＝7.86-7.99(m，4H)，7.38-7.43(m，1H)，7.30-7.36(m，2H)，7.00-7.20(m，5H)，6.90(dd，J＝12,3Hz，2H)，6.83(dd，J＝12,3Hz，2H)，6.70(d，9Hz，1H)，5.69(d，J＝10Hz，1H)，4.42-4.51(m，1H)，3.43(s，3H)，3.30(s，3H)，3.00-3.12(m，1H)，2.94(dt，J＝16,4Hz，1H)，2.60-2.69(m，1H)，2.30(ddd，J＝18，12,6Hz，1H)ppm。
31P-NMR(C
6H
6)：
δ＝48.1ppm。
Embodiment 55
Carrying out this with the method that is similar to embodiment 21 and embodiment 12 synthesizes.
Yield: 43%
1H-NMR(C
6H
6)：
δ＝7.42-7.50(m，2H)，7.32-7.41(m，2H)，6.99-7.05(m，2H)，6.78-6.94(m，4H)，6.63(dt，J＝9,3Hz，2H)，6.54(dt，J＝9,3Hz，2H)，6.29(d，J＝8Hz，1H)，6.25(d，J＝8Hz，1H)，5.20(d，J＝8Hz，1H)，4.10-4.20(m，1H)，2.64-2.83(m，2H)，2.31-2.39(m，1H)，2.01(ddd，J＝18，12,6Hz，1H)ppm。
31P-NMR(C
6H
6)：
δ＝46.8ppm。
Embodiment 56
Carrying out this with the method that is similar to embodiment 23 synthesizes.
Yield: 50%
1H-NMR(C
6H
6)：
δ＝7.05-7.15(m，5H)，6.85-7.01(m，6H)，6.65-6.76(m，5H)，5.06-5.20(m，1H)，4.09-4.18(m，1H)，2.68-2.85(m，2H)，1.91-2.00(m，1H)，1.63-1.74(m，1H)，1.37(d，J＝5Hz，1H)ppm。
31P-NMR(C
6H
6)：
δ＝-4.1ppm。
Embodiment 57
Carrying out this with the method that is similar to embodiment 23 synthesizes.
Yield: 45%
1H-NMR(C
6H
6)：
δ＝7.48-7.55(m，5H)，7.32-7.38(m，1H)，7.12-7.20(m，6H)，6.99-7.11(m，5H)，6.91(d，J＝7Hz，1H)，5.31-5.41(m，1H)，4.28-4.37(m，1H)，2.78-2.98(m，2H)，2.03-2.12(m，1H)，1.73-1.86(m，1H)，1.73(s，1H)ppm。
31P-NMR(C
6H
6)：
δ＝0.00ppm。
Embodiment 58
Carrying out this with the method that is similar to embodiment 23 synthesizes.
Yield: 53%
1H-NMR(C
6H
6)：
δ＝7.32-7.40(m，4H)，7.25-7.30(m，1H)，6.94-6.99(m，4H)，6.86-6.92(m，2H)，6.82(d，J＝7Hz，1H)，6.70(d，J＝8Hz，4H)，5.26-5.33(m，1H)，4.19-4.25(m，1H)，3.19(s，6H)，2.81(dt，J＝16,6Hz，1H)，2.63-2.74(m，1H)，1.96-2.04(m，1H)，1.63-1.77(m，2H)ppm。
31P-NMR(C
6H
6)：
δ＝-4.4ppm。
Embodiment 59 (3R, 4S)-4-(4-{1,1-two [3,5-two (trifluoromethyl)-phenyl] phosphino-}-2,5-
Dimethyl-3-thienyl)-tetrahydrochysene-3-furyl phenylbenzene phosphinous acid ester
Will be with ice-cooled ethyl-magnesium-bromide (the THF solution of 1M; 0.102mmol) join 1-(tertiary butyl-1, the 1-dimetylsilyl-((3R, 4S)-(4-(1 for 4-, 1-two (3,5-two-(trifluoromethyl) phenyl) tetrahydrochysene-3-furyl phosphino-)-2,5-dimethyl-3-thienyl)) in the toluene solution of ether (0.107mmol), and stirred one hour.Then diphenyl phosphorus chloride (0.107mmol) is added drop-wise in this solution, and with this mixture heated overnight at room temperature.Filtering with aluminum oxide and, separating this product, yield 77% except that after desolvating.
1H-NMR(C
6H
6)：
δ＝8.11(d，2H)，8.06(d，2H)，7.9(s，2H)，7.77-7.68(m，4H)，7.38-7.24(m，6H)，5.50-5.40(m，1H)，4.49-4.31(m，4H)，4.13(t，1H)，2.03(s，3H)，1.75(s，3H)ppm。
31P-NMR(C
6H
6)：
δ＝127.9(s，1P)，-9.9(s，1P)ppm。
Embodiment 60 to 89
The method that embodiment 60 to 89 usefulness are similar to embodiment 59 prepares.
| Embodiment | R1 | R2 | Yield [%] | 31P-NMR [ppm] |
| 60 | Ph | C 6H 11 | 47 | 126.6；0.0 |
| 61 | 2-Me-Ph | C 6H 11 | 78 | 115.1；0.0 |
| 62 | 3，5-Me-Ph | C 6H 11 | 92 | 128.0；-1.0 |
| 63 | i-Pr | C 6H 11 | 61 | 165.1；0.0 |
| 64 | 4-F-Ph | C 6H 11 | 68 | 125.9；-1.6 |
| Embodiment | R1 | R2 | Yield [%] | 31P-NMR [ppm] |
| 65 | C 6H 11 | Ph | 57 | 151.4；-9.5 |
| 66 | i-Pr | Ph | 67 | 162.3；-9.4 |
| 67 | 4-F-Ph | Ph | 35 | 121.1；-9.2 |
| 68 | Ph | Ph | 80 | 123.2；-9.0 |
| 69 | 3，5-Me-Ph | Ph | 53 | 125.0；-8.6 |
| Embodiment | R1 | R2 | Yield [%] | 31P-NMR [ppm] |
| 70 | C 6H 11 | Ph | 62 | 160.7；-8.6 |
| 71 | Ph | Ph | 68 | 126.7；-8.4 |
| 72 | i- |
3，5-Me-Ph | 52 | 164.5；-8.4 |
| 73 | |
3，5-Me-Ph | 57 | 127.4；-8.0 |
| 74 | 4-F- |
3，5-Me-Ph | 51 | 120.3；-9.0 |
| Embodiment | R1 | R2 | Yield [%] | 31P-NMR [ppm] |
| 75 | C 6H 11 | Ph | 65 | 159.9；0.0 |
| 76 | i-Pr | Ph | 71 | 164.7；0.0 |
| 77 | 4-F-Ph | Ph | 79 | 123.4；0.3 |
| 78 | 2-Me-Ph | Ph | 80 | 113.7；0.0 |
| 79 | 3，5-Me-Ph | 4-MeO-Ph | 87 | 125.9；-2.9 |
| Embodiment | R1 | R2 | Yield [%] | 31P-NMR [ppm] |
| 80 | Ph | C 6H 11 | 48 | 125.3；0.0 |
| 81 | 4-F-Ph | C 6H 11 | 69 | 123.8；-1.0 |
| 82 | C 6H 11 | C 6H 11 | 68 | 158.3；0.0 |
| 83 | 2-Me-Ph | Ph | 80 | 113.7；0.0 |
| 84 | 4-F-Ph | 4-F-Ph | 79 | 122.6；-3.5 |
| Embodiment | R1 | R2 | Yield [%] | 31P-NMR [ppm] |
| 85 | Ph | Ph | 75 | 124.4；-0.0 |
| 86 | 4-F-Ph | Ph | 77 | 122.6；-1.5 |
| 87 | i-Pr | Ph | 74 | 157.4；0.0 |
| 88 | 4-F-Ph | 4-F-Ph | 70 | 121.9；-4.2 |
| 89 | i-Pr | 4-F-Ph | 68 | 155.5；-4.4 |
Embodiment 90: hydrogenation
The general method of hydrogenation kharophen methyl cinnamate
With 0.6 μ mol Rh (COD)
2OTf and 0.66 μ mol part stirred 10 minutes in 1ml methyl alcohol.Measuring 300 μ mol kharophen methyl cinnamates (methanol solution of 1ml) adds in this solution.In autoclave, under the hydrogen pressure of room temperature and 5bar, stirred this reaction mixture 2 hours.With silica gel this reaction mixture is filtered, and measure the enantiomeric excess value of this raw product with HPLC.
The general method of hydrogenating itaconic acid methyl esters
With 0.6 μ mol Rh (COD)
2OTf and 0.66 μ mol part stirred 10 minutes in 1ml methyl alcohol.Measuring 300 μ mol methylene-succinic acid methyl esters (methanol solution of 1ml) adds in this solution.In autoclave, under the hydrogen pressure of 40 ℃ and 50bar, stirred this reaction mixture 3 hours.With silica gel this reaction mixture is filtered, and measure the enantiomeric excess value of this raw product with HPLC.
The general method of hydrogenation N-acetyl-2-phenyl-1-vinyl-amine
With 0.6 μ mol Rh (COD)
2OTf and 0.66umol part stirred 10 minutes in 1ml methyl alcohol.Measuring 300 μ mol N-acetyl-2-phenyl-2-vinyl amine (methanol solution of 1ml) adds in this solution.In autoclave, under the hydrogen pressure of 40 ℃ and 10bar, stirred this reaction mixture 2 hours.With silica gel this reaction mixture is filtered, and measure the enantiomeric excess value of this raw product with HPLC.
Part type A
The part type B
The part Type C
Part type D
Description of drawings
Fig. 1, Fig. 2 and Fig. 3 have shown particularly preferred Fas lignand system.
Fig. 4 has shown the summary of single synthetic route.
Claims (16)
1. general formula (Ia) and bidentate organophosphor ligand (Ib)
Wherein
O and p can be 0 or 1 independently of one another, and
Ar is the part of hexa-atomic aromatics or 5-or heteroaromatic ring-type system of 6-unit, and heteroaromatic ring-type system can contain 1 to 3 nitrogen-atoms, 1 Sauerstoffatom or 1 sulphur atom on A, B, D and E position, and wherein
CyAli is the part of 5-or 6-unit's cyclic aliphatic or heterocycle aliphatic series ring system, and heterocycle aliphatic series ring system can contain 1 or 2 heteroatoms that is selected from N, O, S on F, G, H and I position, and wherein
R
1-R
2Be C independently of one another
1-C
24-alkyl; C
3-C
8-cycloalkyl, this ring also can contain 1 or 2 heteroatoms, the C that are selected from N, O, S
6-C
14-aryl, phenyl, naphthyl, fluorenyl, C
2-C
13-heteroaryl, the heteroatoms quantity that is selected from N, O, S can be 1 to 4, wherein above-mentioned group itself can be replaced by one or more independent substituent separately that are selected from following group: hydrogen; C
1-C
20-alkyl; C
2-C
20-thiazolinyl; C
1-C
10-haloalkyl; C
3-C
8-cycloalkyl; C
2-C
9-assorted alkyl; C
6-C
8-aryl; Phenyl; Naphthyl; Fluorenyl; C
2-C
6Heteroaryl, the number of heteroatoms that is selected from N, O, S can be 1 to 4; C
1-C
10-alkoxyl group; C
1-C
9-trihalogenmethyl alkyl; Halogen; Hydroxyl; The trifluoromethane sulfonic acid base; Oxo; Sulfo-; Sulfydryl; Amino; The C of following form
1-C
8Substituted-amino: NH
2, NH-C
1-C
8-alkyl, NH-C
5-C
6-aryl, N-C
1-C
8-alkyl
2, N-C
5-C
6-aryl
2, N-C
1-C
8 +-alkyl
3, N-C
5-C
6 +-aryl
3, NH-CO-C
1-C
8-alkyl, NH-CO-C
5-C
6-aryl; Cyano group; (wherein Q represents monovalent cation or C to the carboxylic acid group of COOH and COOQ form
1-C
8-alkyl); C
1-C
6-acyloxy; Sulfino; SO
3H and SO
3(wherein Q represents monovalent cation, C to the sulfonic group of Q form
1-C
8-alkyl or C
6-aryl); PO
3H
2, PO
3HQ and PO
3Q
2(wherein Q represents monovalent cation, C to the phosphate of form
1-C
8-alkyl or C
6-aryl); Three-C
1-C
6-alkyl silyl; R
1Or R
2Can be connected with the phosphorus atom adjacent with it to form 4-to 8-unit cycloaliphatic ring, this cycloaliphatic ring can be by line style or ramose C
1-C
10-alkyl, C
6-aryl, benzyl, C
1-C
10-alkoxyl group, hydroxyl or benzyloxy replace, and wherein
R
3-R
14Be hydrogen atom or C independently of one another
1-C
24-alkyl; C
1-C
10-haloalkyl; C
3-C
8-cycloalkyl; C
3-C
8-cycloalkenyl group, this ring also can contain 1 or 2 heteroatoms that is selected from N, O, S; C
6-C
14-aryl; Phenyl; Naphthyl; Fluorenyl; C
2-C
13-heteroaryl, the heteroatoms quantity that is selected from N, O, S can be 1 to 4; Wherein above-mentioned group itself can be replaced by one or more identical or different substituting groups that are selected from following group: hydrogen; C
1-C
20-alkyl; C
2-C
20-thiazolinyl; C
1-C
10-haloalkyl; C
3-C
8-cycloalkyl; C
3-C
8-cycloalkenyl group; C
2-C
9-assorted alkyl; C
1-C
9-assorted thiazolinyl; C
6-C
8-aryl; Phenyl; Naphthyl; Fluorenyl; C
2-C
6Heteroaryl, heteroatomic number, the heteroatomic number that especially is selected from N, O, S can be 1 to 4; C
1-C
10-alkoxyl group; C
1-C
9-trihalogenmethyl alkyl; Trifluoromethyl; Trichloromethyl; Fluorine; Chlorine; Bromine; Iodine; Hydroxyl; The trifluoromethane sulfonic acid base; Oxo; Sulfo-; Sulfydryl; Amino; The C of following form
1-C
8Substituted-amino: NH
2, NH-C
1-C
8-alkyl, NH-C
5-C
6-aryl, N-C
1-C
8-alkyl
2, N-C
5-C
6-aryl
2, N-C
1-C
8 +-alkyl
3, N-C
5-C
6 +-aryl
3, NH-CO-C
1-C
8-alkyl, NH-CO-C
5-C
6-aryl; Cyano group; (wherein Q represents monovalent cation or C to the carboxylic acid group of COOH and COOQ form
1-C
8-alkyl); C
1-C
6-acyloxy; Sulfino; SO
3H and SO
3(wherein Q represents monovalent cation, C to the sulfonic group of Q form
1-C
8-alkyl or C
6-aryl); PO
3H
2, PO
3HQ and PO
3Q
2(wherein Q represents monovalent cation, C to the phosphate of form
1-C
8-alkyl or C
6-aryl); Three-C
1-C
6-alkyl silyl, and wherein two in these substituting groups also can Cheng Qiao, and wherein
M, n are 1 or 0 independently of one another, and
P is a three valent phosphors.
2. compound as claimed in claim 1, it is characterized in that described six-membered Hetero-aromatic is that pyridyl or five yuan of hetero-aromatic rings are that furyl, thiophenyl or pyrryl and/or described cyclic aliphatic ring system are cyclohexyl, cyclopentyl, be indenyl and tetralyl perhaps, or described assorted aliphatics ring system is tetrahydrofuran base, tetrahydrochysene thiophenyl, pyrrolidyl, piperidyl as the thick and system of part.
3. compound as claimed in claim 1 or 2; it is characterized in that described substituent R 1 and R2 are the 1-methylethyl independently of one another; cyclohexyl; cyclopentyl; phenyl; 2-methyl-phenyl; 3; 5-dimethyl-phenyl; 4-methyl-phenyl; 4-methoxyl group-phenyl; 3; two (the trifluoromethyl)-phenyl of 5-; 4-trifluoromethyl-phenyl; 3; 5-dimethyl-4-methoxyl group-phenyl; the 4-phenoxy group; the 4-dialkyl-7-amino; the 2-alkyl phenyl; the 3-alkyl phenyl; the 4-alkyl phenyl; 2; the 6-dialkyl phenyl organic; 3; the 5-dialkyl phenyl organic; 3; 4; 5-trialkyl phenyl; the 2-alkoxyl phenyl; the 3-alkoxyl phenyl; the 4-alkoxyl phenyl; 2; 6-dialkoxy phenyl; 3; 5-dialkoxy phenyl; 3; 4; the 5-tri-alkoxy phenyl; 3; 5-dialkyl group-4-alkoxyl phenyl; 3,5-dialkyl group-4-dialkyl amido phenyl; the 4-dialkyl amido; 3, the 5-trifluoromethyl; the 4-trifluoromethyl; the 2-alkylsulfonyl; the 3-alkylsulfonyl; the 4-alkylsulfonyl; one to tetrahalogeno-benzene base and naphthyl.
4. compound as claimed in claim 1, the compound that it is characterized in that general formula I a and Ib are the enantiomorph enrichments.
5. compound as claimed in claim 4 is characterized in that the enantiomorph enrichment is greater than 90%.
6. as any described compound of above claim, it has following structure
N=0,1 wherein
Wherein X1, X2, X3=H, OMe, OEt, F, Me, Et; N=0,1
Wherein R=OMe, the tertiary butyl.
7. the complex compound of general formula (II)
[M
xP
yL
zS
q]A
r (II)
Wherein in general formula (II)
M represents metal center,
L represents identical or different coordinate organic or inorganic part,
S represent the coordinate solvent molecule and
A represents the Equivalent of non-coordination anion, and wherein x and y are the integers more than or equal to 1, and z, q and r are the integers more than or equal to 0, and the upper limit of y+z+q summation depends on metal center place available coordination center, and not every hapto all must be occupied,
It is characterized in that P is general formula (Ia) and/or bidentate organophosphor ligand (Ib) according to the present invention.
8. complex compound, compound as claimed in claim 7 is characterized in that described compound contains palladium, platinum, rhodium, ruthenium, osmium, iridium, cobalt, nickel or/and copper.
9. as claim 7 or 8 described complex compounds purposes as catalyzer.
10. prepare the general formula (Ia) and (Ib) method of compound, it comprises following method steps:
A) Negishi cross-coupling by cyclic vinyl iodine and halogenated aromatic compound or the nucleophilic ring opening by the meso-epoxide then the resolution of racemic thing synthesize aliphatic series-aromatics foundation structure,
B) by carrying out asymmetric hydroboration, in the reservation or the three-dimensional center of overturning, carry out phosphineization, in described foundation structure, introduce chirality phosphine unit with the chirality borine, and
C) replace and add subsequently second phosphine groups of phosphonium chloride introducing by carry out bromine/lithium with strong lithium alkali.
11. the method for preparing biphosphine ligand as claimed in claim 10 is characterized in that, for the phosphineization that keeps three-dimensional center, before phosphineization, with two organic radical zinc the hydroboration product is carried out metal transfer and handles.
12. the method for preparing biphosphine ligand as claimed in claim 10; it is characterized in that; phosphineization for the upset of three-dimensional center; thereby the hydroboration product is carried out oxide treatment form chiral alcohol; then chiral hydroxyl group is protected, wherein, after step c) phosphineization as claimed in claim 10; by removing protecting group hydroxyl is converted into phosphine alcohol, then at S
NCarry out phosphineization under 2 conditions.
13. the method for preparing phosphinous acid ester phosphine part and phosphorous acid ester phosphine part as claimed in claim 10, it is characterized in that, for the phosphineization that keeps three-dimensional center, thereby being carried out oxide treatment, the hydroboration product forms chiral alcohol, in the presence of alkali, carry out phosphineization subsequently.
14. the method for preparing phosphinous acid ester phosphine part and phosphorous acid ester phosphine part as claimed in claim 13, it is characterized in that, phosphineization for the upset of three-dimensional center, thereby the hydroboration product is carried out oxidative work-up form chiral alcohol, and realize the upset at three-dimensional center with the Mitsonubu reaction or through peroxidation and follow-up cis-selectivity reductive two-step approach.
15. as the purposes of any described complex compound of claim 7 to 9 as the catalyzer of asymmetric reaction.
16. as the purposes of any described complex compound of claim 7 to 9 as the catalyzer of asymmetric hydrogenation, hydroformylation, rearrangement, allyl group alkylated, cyclopropyleneization, hydrosilylation, hydrocyanation or aldolisation.
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