WO2014109712A1 - PALLADIUM-CATALYZED ASYMMETRIC (HETERO)ARYLATION AND VINYLATION OF KETONE ENOLATES TO PRODUCE TERTIARY STEREOCENTERS AT ALPHA(α)-POSITION - Google Patents

PALLADIUM-CATALYZED ASYMMETRIC (HETERO)ARYLATION AND VINYLATION OF KETONE ENOLATES TO PRODUCE TERTIARY STEREOCENTERS AT ALPHA(α)-POSITION Download PDF

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WO2014109712A1
WO2014109712A1 PCT/SG2014/000005 SG2014000005W WO2014109712A1 WO 2014109712 A1 WO2014109712 A1 WO 2014109712A1 SG 2014000005 W SG2014000005 W SG 2014000005W WO 2014109712 A1 WO2014109712 A1 WO 2014109712A1
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mmol
hetero
nmr
ligand
mhz
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WO2014109712A8 (en
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Jianrong ZHOU (Steve)
Zhiyan Huang
Li Hui LIM
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Nanayng Technological University
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Definitions

  • the invention relates to new ligands that are used in a palladium catalyst system and in a palladium catalyzed method for asymmetric a-(hetero)arylation and a-vinylation of ketones.
  • the invention further relates to a process for preparing an asymmetric a- (hetero)arylated or a-vinylated ketone which comprises reacting the tin enolate of the ketone in the presence of a catalyst system comprising a ligand of the invention and a palladium source.
  • a stereogenic center in position a of the ketone is established with high enantiomeric excess (ee).
  • Transition-metal catalyzed a-arylation of carbonyl compounds has become a very useful tool to prepare a-arylcarboxylic acids and derivatives.
  • Asymmetric couplings that can form quaternary a-carbon centers have been developed for enolates of ketones (cf. Ahman, et al J. Am. Chem. Soc. 1998, 120, 1918; Hamada, et al J. Am. Chem. Soc. 2002, 124, 1261 ; Chen et al. Chem. Commun. 2006, 1413; Ge & Hartwig, J. Am. Chem. Soc. 2011 , 133, 16330, or Liao et al J. Am. Chem. Soc.
  • Zhou et al disclosed a palladium catalyst for asymmetric arylation and vinylation of esters for the formation of tertiary a- centers (cf. Huang, Z.; Liu, 2.; Zhou, J. J. Am. Chem. Soc. 2011 , 133, 15882).
  • Asymmetric coupling between a-haloketones and aryl-metal reagents was also reported by Fu and coworkers recently (cf. Lou & Fu, G. C. J. Am. Chem. Soc. 2010, 132, 1264 and Lundin, P. M.; Esquivias, J.; Fu, G. C. Angew. Chem., Int. Ed. 2009, 48, 154).
  • a-arylated or a-vinylated ketones are important intermediates and versatile building blocks for the synthesis of many chiral compounds and some active pharmaceutical ingredients (APIs).
  • the present invention addresses this need by providing a new chiral Iigand and a new catalyst system based on palladium source and the new Iigand to be used in the a- (hetero)arylation or a-vinylation of ketones, in particular in the a-arylation or a-vinylation of the tin enolate derivative of said ketone.
  • a stereogenic center in a position of the ketone is created with a high ee.
  • the present invention is directed to a chiral Iigand of formula (I):
  • A is a single bond or oxygen atom or CH 2 ;
  • Cy is cyclohexyl
  • Ri is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (hetero)aryl-methyl.
  • the present invention is directed to a catalyst system comprising a palladium source and a ligand of the above formula (I).
  • the present invention provides the use of a ligand of above formula (I) in asymmetric a-(hetero)arylation or a-vinylation of ketones wherein the a- (hetero)arylation or the ⁇ -vinylation creates a tertiary carbon center in the a-(hetero)arylated or a-vinylated position.
  • the a-(hetero)arylation or ⁇ -vinylation creates the stereogenic center with a high ee.
  • the reaction preferably occurs on the tin enolate derivative of the ketone.
  • the present invention provides a process for asymmetrically a- (hetero)arylating or a-vinylating a ketone comprising reacting a tin enolate derivative of said ketone in the presence of an (hetero)arylating or a vinylating reagent and of a catalyst system wherein the catalyst system comprises: a) a palladium source and
  • A is a single bond, oxygen atom or CH 2 ;
  • Cy is cyclohexyl
  • Ri is selected from H, one of optionally substituted groups of alkyl, cycloalkyl, aryl, heteroaryl, and (hetero)aryl-methyl.
  • FIG. 1 a shows examples of prior art asymmetric arylations.
  • Fig. 1 b shows examples of arylation according to the present invention performed using ligands L1 and L3.
  • Fig. 2 shows the arylation performed with the catalyst of the invention using different ligands. The yields were measured by GC and the ee values are determined with HPLC analysis with a chiral stationary phase.
  • Fig. 3a shows examples of the arylation of tetralone-enolate using ligand L1 and the reported aryl triflate derivatives.
  • Fig. 3b shows examples of the arylation of tetralone-enolate using ligand L1 and the reported aryl-CI and aryl-Br derivatives.
  • the yields were measured by GC and the ee values are determined with HPLC analysis with a chiral stationary phase.
  • the reaction conditions are those reported in in the reaction disclosed in Fig.2.
  • Fig. 4a shows examples of the arylation of cyclohexanone using ligand L1 and the reported aryl or heteroaryl triflate derivatives.
  • Fig. 4b shows an example of the arylation of cyclohexanone using ligand L1 and the reported aryl or heteroaryl triflate derivatives.
  • the yields were measured by GC and the ee values are determined with HPLC analysis with a chiral stationary phase.
  • the reaction conditions are those reported in the reaction disclosed in Fig.2.
  • Fig. 5 shows examples of the arylation and vinylation of a ketone using ligand L3 and the reported aryl-OTf (triflate) or aryl-CI or aryl -Br or heteroaryl-OTf or heteroaryl-CI or heteroaryl-Br derivatives.
  • the yields were measured by GC and the ee values are determined with HPLC analysis with a chiral stationary phase.
  • the reaction conditions are those reported in Fig.2.
  • Fig. 6 shows the product of the arylation of various ketones using ArOTf and 2 mol% Pd/L3 (or L1 when specified). The results in parentheses are obtained with 2 mol% Pd/L1.
  • Fig. 8 shows the stoichiometric reaction of a [(L1 )Pd(Ar)(Br)] complex and a tin enolate.
  • the ORTEP of fra/7s-[(ligand L1)Pd(Ar) ⁇ -Br)] 2 was shown in 50% probability of thermal ellipsoids with hydrogen atoms omitted for clarity.
  • the two aryl groups are trans to each other on two palladium centers DETAILED DESCRIPTION
  • ligand L1 originated from strategically positioned CH/O hydrogen bonding between the catalyst (e.g. side chain naphthyl) and the carbonyl of Pd- enolates.
  • the present inventors to prepare new catalysts L2 and L3 that are capable of conventional NH/O(carbonyl) hydrogen bonds. Indeed, the selectivity afforded by ligand L2 and L3 was better than L1 in the model reaction ( Figure 2). Based on the same principles other excellent ligands have been prepared by the present inventors.
  • the arylation products can be easily converted to other chiral building blocks. For example, reduction of 2-phenylcyclohexanone using K-Selectride gave c/ ' s-alcohol without erosion of ee and in 80:1 dr. Li/naphthalene reduction of the ketone can selectively give frans-2-arylcycohexanol. The frans-alcohol is commonly used as chiral auxiliary in asymmetric transformations.
  • the 2-arylketones can also be converted to aryl-lactones via Baeyer-Villiger oxidation and aryl-lactams via Beckmann rearrangement. Notably, it is important to prepare the (£)- oxime selectively, since the (Z)-isomer can rearrange to give a different lactam.
  • One more example is deoxygenation of 2-aryltetralones via catalytic hydrogenolysis.
  • Some 2-aryltatralins were potential drugs for treatment of arrhythmias (irregular heartbeat), by acting as inhibitors of Na Ca 2+ exchange mechanism. No asymmetric synthesis of these compounds was reported previously.
  • the present inventors have also prepared an oxidative adduct from an aryl bromide, Pd(dba) 2 and ligand L1 (Figure 8).
  • the palladium complex was a dimer bridged by two bromides.
  • Ligand L1 binds to each palladium center in a monodentate fashion.
  • Each Pd unit 14 000005 showed a square-planar geometry.
  • the coupling product was obtained in good yield and 93% ee (eq 2).
  • the ee was identical to the ee obtained from the catalytic reaction.
  • the formation of the dimeric complex unfortunately, prevented putative interaction between of the Pd center and the bottom naphthyl ring of L1.
  • the inventors have examined the bonding mode of the bottom ring of ligand L1 in complexes of (L1)Pd(aryl)(enolate). They have found that Pd bonding with the ipso carbon of the L1 bottom ring was more favored over bonding with the aryl ether by 5-6 kcal/mol. The isomerization of the O-bound form to C-bound form was almost barrier-free. Thus, the inventors focused on studying enolate complexes with Pd bonding with the carbon(ipso) of L1.
  • the source of the stabilization was identified to be double CH"O hydrogen bonds between O-naphthyl CH bonds and the carbonyl of C-enolates.
  • the hydrogen bonds were absent, because the carbonyl of the enolate pointed away from L1 side chain. This provides a clear explanation for the origin of stereoselectivity in the asymmetric coupling.
  • the present inventors have also calculated the reductive elimination step of C-enolate complexes supported by ligand L2. Again in the main pathway, both ground state (Int2a) and transition state (TS2a) were more stable than those in the minor pathway by 4.5 and 3.2 kcal/mol, respectively.
  • the source of stabilization was double hydrogen bonds with both ortho-hydrogen and NH of the aniline side chain. In the minor pathway, they were absent.
  • the present invention is directed to a ligand of formula (I)
  • A is a single bond or oxygen atom or CH 2 ;
  • Cy is cyclohexyl
  • Ri is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (hetero)aryl-methyl.
  • Ri is selected from 2-naphthyl, 1 - naphthyl, CH 2 -(2-naphthyl), phenyl, 4-amino-phenyl, 3-amino-phenyl, 3-(iPr)NH-phenyl, 3- CH 3 CONH-phenyl and cyclohexyl.
  • A is an oxygen atom.
  • Ri is selected from 2-naphthyl, 1 -naphtyl, CH 2 -(2-naphthyl), phenyl, 4-amino-pheny, 3-amino-phenyl, 3-(iPr)NH-phenyl, 3- CH 3 CONH-phenyl, cyclohexyl and A is oxygen atom.
  • Preferred ligands according to the present invention are the ligands of formulae:
  • the present invention is directed to a catalyst system comprising catalysts in situ derived from a combination of a palladium source and a biarylphosphine ligand of formula (I) as disclosed in the first aspect of the invention and in any of the embodiments of the first aspect.
  • the catalysts system of the invention may be formed in situ.
  • Preferred catalytic systems are those comprising anyone of a ligand of formulae
  • catalytic systems are those comprising a ligand of formulae L1 , L2 or L3.
  • the present invention is directed to the use of a ligand of formula (I) as defined in the first aspect and in any of its embodiments and preferred embodiments, in the asymmetric a-(hetero)arylation or a-vinylation of ketones wherein the a-(hetero) arylation or the a-vinylation creates a tertiary center in the a-(hetero)arylated or a-vinylated position.
  • the a-(hetero)arylation or the ⁇ -vinylation of ketones is a palladium catalyzed a- (hetero)arylation or the ⁇ -vinylation reaction.
  • the asymmetric a-(hetero)arylation or a- vinylation reaction preferably occurs in the presence of the catalyst system of the invention as is defined in the above second aspect of the invention and in any of its embodiments and preferred embodiments.
  • the reaction preferably occurs on the tin enolate derivative of said ketone.
  • the tin enolate may be prepared and then reacted with the catalytic system of the invention in a two steps process.
  • the present inventors have advantageously found that the preparation of the tin enolate and the subsequent asymmetric a-(hetero)arylation or ⁇ -vinylation reaction can occur in one pot reaction, without the need of purifying the tin enolate.
  • the tin enolate may be prepared with any suitable reagent for the purpose of preparing a tin enolate.
  • a suitable and preferred reagent for tin enolation of ketones is (nBu) 3 Sn(OMe).
  • the reaction of forming the tin enolate may occur in the presence of an activator that activates the trans-metalation.
  • the a-(hetero)arylation or a-vinylation of ketones requires a (hetero)arylating or vinylating reagent.
  • the (hetero)arylating or vinylating reagent is an organic electrophile reagent. This may include but it is not limited to electrophiles such as aryl-, heteroaryl- or vinyl- triflate, bromides, chlorides.
  • the (hetero)aryl electrophiles can have electron-donating, electron-withdrawing and electron-neutral groups on the (hetero)aryl rings and can also have ortho groups and (hetero)benzofused rings.
  • a preferred (hetero)arylating reagent is of formula
  • X is OTf, Br or CI
  • Ar is selected from: an optionally substituted phenyl, an optionally substituted naphtyl, and optionally substituted quinoline, an optionally substituted indole, an optionally substituted benzothiazole, an optionally substituted thiophene, and an optionally substituted benzopyran,
  • substituent is selected from: (Ci-C 4 ) alkyl, OMe, CN, C0 2 Et,
  • Ar is selected from:
  • Y is H, OMe, CN, C0 2 Et, COMe, CF 3 , CI, F; or Ar is selected from
  • the vinylating reagent has formula:
  • X is OTf, CI or Br; preferably OTf and
  • any ketone suitable for a-(hetero)arylation or a-vinylation can be used.
  • the present ligands which are chiral ligands are particularly advantageous in a- (hetero)arylation or a-vinylation of ketones which lead to the introduction of a tertiary stereogenic center in the a-(hetero)arylated or ⁇ -vinylated position.
  • ketones having a pre-stereogenic center in said position are particularly preferred according to the present invention.
  • cyclic ketones are ketones according to the present invention.
  • the cyclic ketones can be of various ring sizes (6-9 membered rings) and can also be (hetero)benzofused ketones.
  • the ring of cyclic ketones can contain also a heteroatom such as O, N or S.
  • Cyclic ketones such as cyclohexanone, cyclopentanone, cycloheptanone, cyclooctanone, 1-tetralone, cromene, 4-oxo-4H-cromene all optionally substituted are ketones within the scope of the present invention.
  • Substituents of the ketones are for example: (C C 4 ) alkyl, aryl, heteroaryl, halogen (F, CI, Br, and I), -NH 2 , -CN, OH, (C r C 4 ) alkoxy, CHO, COOH, -COO(C C 4 ) alkyl and others.
  • the present invention is directed to a process for asymmetrically a- (hetero)arylating or a-vinylating a ketone comprising a) reacting a tin enolate derivative of said ketone in the presence of an (hetero)arylating or a vinylating reagent and of a catalyst system based on palladium source and a ligand of formulae (I) or (II)
  • A is a single bond, oxygen atom or CH 2 ;
  • Cy is cyclohexyl
  • Ri is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (hetero)aryl-methyl. b) obtaining the a-(hetero)arylated or a-vinylated ketone having a stereogenic (tertiary) carbon center in the a-(hetero)arylated or vinylated position.
  • the process further comprises reacting an alkenyl-acetate derivative of the starting ketone with nBu 3 Sn(OMe) to obtain the corresponding tin enolate of the ketone.
  • the overall process is a two steps or one step reaction. In a "one step" (or one pot reaction) the tin enolate is formed in the presence of the catalytic system according to the invention.
  • the reaction occurs in the presence of an (hetero)arylating or a vinylating agent.
  • the (hetero)arylating or vinylating reagent is an organic electrophile reagent. This may include but it is not limited to electrophiles such as aryl, heteroaryl or vinyl triflate, bromides, chlorides.
  • the (hetero)aryl electrophiles can have electron-donating, electron-withdrawing and electron-neutral groups on the (hetero)aryl rings and can also have ortho groups and (hetero)benzofused rings.
  • a preferred (hetero)arylating reagent is of formula
  • X is OTf, Br or CI; and Ar is selected from: an optionally substituted phenyl, an optionally substituted naphtyl, and optionally substituted quinoline, an optionally substituted indole, an optionally substituted benzothiazole, an optionally substituted thiophene, and an optionally substituted benzopyran wherein the substituent is selected from: (C1-C4) alkyl, OMe, CN, C0 2 Et, COMe, CF 3 , CI, F, Boc.
  • Ar is selected from:
  • Y is H, OMe, CN, C0 2 Et, COMe, CF 3 , CI, F;
  • the vinylating reagent is formula
  • X is OTf, CI or Br, preferably OTf, and
  • the catalysts system of the invention may be formed in situ.
  • Preferred catalytic systems are those comprising anyone of the ligands of formulae:
  • the tin enolate is preferably prepared using (nBu) 3 Sn(OMe) before use.
  • the tin enolate may be easily obtained by stirring at room temperature the alkyl acetate of the ketone and (nBu) 3 Sn(OMe). The tin enolate may be then used even without further purification.
  • the reaction may occur in the presence of an activator which is preferably selected from LiOAc, NaOAc, LiOPiv, CsF, LiF, ZnF 2 , CuF 2 or nBuSnF.
  • an activator which is preferably selected from LiOAc, NaOAc, LiOPiv, CsF, LiF, ZnF 2 , CuF 2 or nBuSnF.
  • NaOAc is the preferred activator according to the invention.
  • the solvent of the process of the invention is any solvent suitable for performing the reactions of the inventions.
  • Preferred solvents are selected from diethyl ether, tetrahydrofuran, 1 ,4-dioxane, f-butyl methyl ether, cyclopentyl-methyl-ether, toluene, benzene, ⁇ , ⁇ , ⁇ -trifluoromethylbenzene, fluorobenzene, dichloromethane and 1 ,2- dichloroethane.
  • Even more preferred solvents according to the invention are diethyl ether, 1 ,4-dioxane, f-butyl methyl ether and cyclopentyl-methyl-ether.
  • R is phenyl, substituted aryl, secondary alkyl such as cyclohexyl, isopropyl, cyclopentyl;
  • X is OTf, Br or CI
  • Y is F, OMe, or an ester
  • Z is alkenyl, N, or O, or S, when Z is alkenyl is preferably -CH 2 . or-CH 2 -CH 2 -;
  • n 1 , 2, 3, or 4;
  • the Pd source is Pd(OAc) 2 , Pd(dba) 2 Pd 2 (dba) 3 ;
  • the chiral ligand is a ligand of formula (I) or (II) of the present invention
  • the activator is LiOAc, NaOAc, LiOPiv, CsF, LiF, ZnF 2 CuF 2 or nBuSnF.
  • any ketone suitable for a-(hetero)arylation or a-vinylation can be used in the process of the forth aspect of the invention and in its embodiments.
  • the present ligands which are chiral ligands are particularly advantageous in a-(hetero)arylation or a- vinylation of ketones which lead to the introduction of a stereogenic center in the a- (hetero)arylated or a-vinylated position.
  • ketones having in a position a secondary carbon atom bearing two different substituents are particularly preferred according to the present invention.
  • Cyclic ketones are an example of suitable ketones according to the invention.
  • the cyclic ketones can be of various ring sizes (4-9 membered rings, preferably 6- 9 membered rings) and can also be (hetero)benzofused ones.
  • the ring of cyclic ketones can contain also a heteroatom such as O, N or S.
  • Cyclic ketones such as cyclohexanone, cyclopentanone, cycloheptanone, cyclooctanone, 1 -tetralone, cromene, 4oxo-4H-cromene all optionally substituted are suitable ketones within the scope of the present invention.
  • the solvent of the process of the invention is any solvent suitable for performing the reactions of the inventions.
  • Preferred solvents are selected from diethyl ether, tetrahydrofuran, 1 ,4-dioxane, i-butyl methyl ether, cyclopentyl-methyl-ether, toluene, benzene, ⁇ , ⁇ , ⁇ -trifluoromethylbenzene, fluorobenzene, dichloromethane and 1 ,2- dichloroethane.
  • Even more preferred solvents according to the invention are diethyl ether, 1 ,4-dioxane, i-butyl methyl ether and cyclopentyl-methyl-ether.
  • the present invention provides for the first time catalytic a-(hetero)arylation or a- vinylation of ketone enolates that produced tertiary centers with high level of enantioselectivity (generally >90% ee).
  • the method is applicable to various aryl triflates, bromides and chlorides and some vinyl triflates, with variations in both electronic and steric properties.
  • the present invention is advantageous over other methods to prepare a- arylketones such as catalytic asymmetric protonation of silyl enolates of ketones, because the present method is convergent by establishing the new stereocenters and at the same time, forming the new carbon-carbon bonds between enolates and aryl, heteroaryl and vinyl electrophiles.
  • the (hetero)aryl electrophiles can have electron-donating, electron-withdrawing and electron-neutral groups on the (hetero)aryl rings and can also have ortho groups and (hetero)benzofused rings.
  • the cyclic ketones can be of various ring sizes (6-9 membered rings) and can also be (hetero)benzofused ones.
  • the cyclic ketones can contain substituents (Z) such as alkyl, aza and oxa in the rings.
  • Solvents for the coupling processes include but are not limited to diethyl ether, tetrahydrofuran, 1 ,4-dioxane, f-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, ⁇ , ⁇ , ⁇ -trifluoromethylbenzene, fluorobenzene, dichloromethane and 1 ,2- dichloroethane.
  • activators include but are not limited to LiOAc, NaOAc, LiOPiv CsF, LiF, KF, ZnF 2 , CuF 2 , and nBuSnF.
  • the palladium source of the chiral catalysts may include but is not limited to Pd(OAc) 2 , Pd(dba) 2 and Pd 2 (dba) 3 .
  • the chiral phosphorus ligands are typically of general structures I and II
  • R group is phenyl, substituted aryl, secondary alkyl such as but not limited to cyclohexyl, isopropyl and cyclopentyl; and the R1 group is H, alkyl, (hetero)arylmethyl and aryl group.
  • R1 examples include but are not limited to cyclohexyl, isopropyl, phenyl, 2-naphthyl, 1 -naphthyl, benzyl, (2-naphthyl)methyl, (l -naphthyl)methyl, mefa-xylyl, 3,5-di-(f-butyl)phenyl, ortho- ⁇ o ⁇ y ⁇ , mesityl, A/-R m R think- 77efa-aminophenyl and N-R m R n -para- aminophenyl.
  • the R m R n group include but are not limited to H, alkyl, aryl and acyl groups, including methyl, ethyl, isopropyl, f-butyl, acetyl, pivaloyl and phenyl, carbazoyl.
  • Some of the catalysts made of ligands L1 , L2 and L3 are capable of NH/carbonyl and CH/carbonyl hydrogen bonding with palladium enolates in the catalytic cycle, through the side chain NH and arene CH bonds.
  • catalyst system indicates those materials that, in combination, cause the (hetero)arylation or the vinylation to start and to be carried out.
  • alkyl indicates preferably (C1-C4) straight chain and (C 1 -C ) branched chain of alkyl groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like.
  • the alkyl may be substituted.
  • Substituents are, for example H, OMe, CN, C0 2 Et, COMe, CF 3 , or halogen atoms such as CI or F.
  • cycloalkyl refers to a saturated monocyclic hydrocarbon groups having from three to seven carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • the cyclic group may be optionally substituted with, for example, (C 1 -C4) alkyl, hydroxy, halogen or an amino group.
  • (hetero)aryl indicates heteroaryl and aryl.
  • Aryl as herein employed alone or in combination refers to substituted or unsubstituted aromatic group, which may be optionally fused to other aromatic or non-aromatic cyclic groups. Representative examples of aryl groups include, but are not limited to, phenyl, benzyl, naphthyl, benzylidine, xylyl, styrene, styryl, phenethyl, phenylene, benzenetriyl and the like.
  • Heteroaryl refers to a cyclic aromatic group containing a heteroatom.
  • Heteroatom are, for example, O, N and S.
  • Representative examples of heterocycles include, but are not limited to, pyridine, piperidine, pyrimidine, pyridazine, piperazine, pyrrole, pyrrolidinone, pyrrolidine, morpholine, thiomorpholine, indole, isoindole, imidazole, triazole, tetrazole, furan, benzofuran, dibenzofuran, thiophene, thiazole, benzothiazole, benzoxazole, benzothiophene, quinoline, isoquinoline, azapine, naphthopyran, furanobenzopyranone and the like.
  • Substituents of the "(hetero)aryl” group or the aryl group or the heteroaryl group are, for example, H, (C 1 -C4) alkyl, OMe, CN, C0 2 Et, C0 2 Me, COMe, Boc, CF 3 , or halogen such as CI or F.
  • reaction mixture was cooled to RT, loaded onto a pad of Celite and washed with ethyl acetate (30 mL).
  • the filtrate was concentrated on a rotary evaporator and the resulting residue was purified by flash chromatography (ethyl acetate/hexane 3:2) to afford the desired compound (163 mg, 94%) as white foam.
  • the mixture was cooled to RT, loaded onto a pad of Celite and washed with ethyl acetate (10 mL).
  • the filtrate was concentrated on a rotary evaporator and the resulting residue was purified by flash chromatography (ethyl acetate/hexane 1 :2) to afford the desired compound (63 mg, 51 %) as white solid.
  • Typical procedure for reduction of phosphine oxide under argon, a dry 100-mL Schlenk tube was charged with the phosphine oxide (760 mg, 1.25 mmol), triethylamine (7.0 mL, 50.0 mmol) and dry toluene (30 ml_). After the resulting solution was cooled to 0 °C, trichlorosilane (1.3 mL, 12.5 mmol) was added via a syringe. The resulting mixture was capped tightly and vigorously stirred in a 120 °C oil bath for 24 hours, until all the phosphine oxide was consumed (monitored by 31 P NMR spectroscopy).
  • the mixture was cooled to room temperature in the glove box and diluted with degassed diethyl ether (20 mL). After the resulting suspension was briefly chilled in a -30 °C fridge attached to the glove box, degassed, saturated Na 2 C0 3 (3.0 mL) was slowly added to quench the reaction. The whole mixture was directly dried over MgS0 4 , filtered through a pad of silica gel, and eluted with degassed 1 :10 diethyl ether/hexane until no more product came out (monitored by TLC). The filtrate was concentrated under vacuum, and afforded the pure phosphine (629 mg, 85%) as white solid.
  • the desired ligand was purified in a glove box by filtration through a pad of silica gel with 1 :10 diethyl ether/hexane. The filtrate was concentrated under vacuum and afforded the desired compound (53 mg, 77%) as white solid.
  • the tube was capped tightly and the resulting mixture was heated in a 110 °C oil bath for 48 hours. After cooling to 0 °C, the reaction was quenched with saturated NH 4 CI (10 mL), and extracted with ethyl acetate (30 mL x 2). The extracts were washed with brine and dried with anhydrous Na 2 S0 4 . After concentration on a rotary evaporator, the resulting residue was purified by flash chromatography (ethyl acetate/hexane 1 :2) to afford the desired compound (119 mg, 31%) as white solid.
  • the phosphine oxide (50 mg, 0.09 mmol), triethylamine (0.50 mL, 3.4 mmol), trichlorosilane (0.1 mL, 0.9 mmol) and dry toluene (2 mL) were used.
  • the reaction was conducted at 120 °C for 24 hours.
  • the desired compound was purified by filtration in the glove box through a pad of silica gel pad with 1 :10 diethyl ether/hexane. The filtrate was concentrated under vacuum and afforded the desired compound (25 mg, 51%) as yellow solid.
  • reaction mixture was cooled to RT and passed through a pad of Celite with ethyl acetate washings (60 mL).
  • the filtrate was concentrated on a rotary evaporator and the residue was purified by flash chromatography (3:2 ethyl acetate/hexane to 50:1 DCM/methanol) to afford the desired compound (998 mg, 80%) as off-white solid.
  • reaction mixture was filtered through a short Celite pad with ethyl acetate washing (15 mL). The filtration was concentrated on a rotary evaporator and the resulting white foam was directly subjected to the next step.
  • the phosphine oxide (286 mg, 0.5 mmol), triethylamine (2.7 mL, 19.6 mmol), trichlorosilane (0.5 mL, 4.9 mmol) and dry toluene (12 mL) were used.
  • the reaction was finished after stirring for 24 h at 120 °C.
  • the desired compound was purified by filtration through a short pad of silica gel with diethyl ether washing in the glove box. The filtrate was concentrated under vacuum and afforded the desired compound (187 mg, 67%) as white foam.
  • the phosphine oxide (741 mg, 1.2 mmol), triethylamine (6.7 mL, 48.0 mmol), trichlorosilane (1.2 mL, 12.0 mmol) and dry toluene (28 mL) were used.
  • the reaction was finished after stirring for 24 h at 120 °C.
  • the desired ligand was purified by filtration through a pad of silica gel with diethyl ether washing in the glove box. The filtrate was concentrated under vacuum to give the desired compound (597 mg, 83%) as white foam.
  • the vial was capped tightly and stirred at 25 °C until the aryl triflate was fully consumed. At intervals, an aliquot of the reaction mixture was taken and passed through a short plug of silica gel with diethyl ether washings to remove the Pd catalyst and inorganic salts. The filtrate was directly used for GC analysis to determine the conversion of phenyl triflate and yield of the coupling product.
  • the solvent of the filtrate was removed by argon blowing and the residue was redissolved in 1 :9 / ' -PrOH and n-hexane to prepare sample for chiral HPLC analysis (Daicel CHIRALCEL AS-H; 2% /-PrOH in hexanes).
  • racemic compound was prepared using the same procedure, except that Sphos was used instead of chiral ligand L1.
  • Ee of the purified products was determined to be 91% based by chiral HPLC analysis.
  • (S)-2-(p-Anisyl)-1-tetralone The reaction was set up using Pd(OAc) 2 (5.6 mg, 0.025 mmol), ligand L1 (22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), p-Anisyl bromide (94 mg, 0.50 mmol) and 4-tri(n-butyl)stannyloxy-1 ,2-dihydro- naphthalene (1.0 mmol, 458 mg). The reaction was stopped after 48 hours at 25 °C. The titled compound was obtained as white solid (113 mg, 90% yield) by flash chromatography using EA/hexane (1 :30) as eluent.
  • Ee of the purified products was determined to be 92% based by chiral HPLC analysis.
  • Ee of the purified products was determined to be 91 % based by chiral HPLC analysis.
  • Ee of the purified products was determined to be 90% based by chiral HPLC analysis.
  • Ee of the purified products was determined to be 90% based by chiral HPLC analysis.
  • (S)-2-(3-Thienyl)-1-tetralone The reaction was set up with Pd(OAc) 2 (5 mol%, 5.6 mg, 0.025 mmol), ligand L1 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), 3-bromothiophlene (81.5 mg, 0.50 mmol) and 4-tri(/7-butyl)stannyloxy-1 ,2- dihydronaphthalene (0.75 mmol, 343 mg). The reaction finished after 48 hours at 25 °C.
  • (S)-2-Phenyl-1-tetralone The reaction was set up with Pd(OAc) 2 (5 mol%, 5.6 mg, 0.025 mmol), ligand L1 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), phenyl chloride (56 mg, 0.50 mmol) and 4-tri(n-butyl)stannyloxy-1 ,2- dihydronaphthalene (0.75 mmol, 343 mg). The reaction finished after 36 hours at 25 °C. The titled compound was obtained as white solid (96 mg, 86% yield).
  • Ee of the purified products was determined to be 91 % based by chiral HPLC analysis.
  • Ee of the purified products was determined to be 92% based by chiral HPLC analysis.
  • Ee of the purified products was determined to be 90% based by chiral HPLC analysis.
  • Ee of the purified products was determined to be 90% based by chiral HPLC analysis.
  • (S)-2-Phenylcyclohexanone The reaction was set up with Pd(OAc) 2 (5 mol%, 5.6 mg, 0.025 mmol), ligand L1 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), phenyl chloride (56 mg, 0.50 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (1.0 mmol, 430 mg, 90% purity). The reaction finished after 48 hours at 50 °C.
  • the titled compound was obtained as white solid (78 mg, 90% yield) by flash chromatography using EA/hexane (1 :20) as eluent. Ee of the purified products was determined to be 88% based by chiral HPLC analysis.
  • Fluoro-1 ,2-dihydro-4-naphthyl acetate (1.0 g, 4.85 mmol) and tri(n-butyl)tin methoxide (1.48 g, 4.62 mmol) were stirred at 25 °C for 12 hours until full conversion of the latter.
  • Methyl acetate was removed under vacuum and the purity of the tin enolate was estimated to be 90% by 1 H NMR spectroscopy.
  • the tin enolate was used directly in the coupling reaction.
  • the resulting solid was suspended in 10 mL of n-pentane and loaded onto a fritted funnel. After quick washing with n-pentane (10 mL), the pure product was obtained as white solid (1.27 g, 91 %) after drying under vacuum. The filtrate contained little product as checked by TLC.
  • T R 11.1 min (minor) and 17.3 min (major).
  • the arylation products can be easily converted to other chiral compounds, including but not limited to the exemplary compounds described below.
  • the illustrative reduction of 2-phenylcyclohexanone using K-Selectride gave c/ ' s-alcohol without erosion of ee and in 80: 1 dr.
  • Li/naphthalene reduction of the ketone can selectively give trans-2- arylcycohexanol (cf. Kruger, D.; Sopchik, A. E.; Kingsbury, C. A. J. Org. Chem. 1984, 49, 778).
  • the frans-alcohol is commonly used as chiral auxiliary to induce stereo-selectivity in many asymmetric transformations (cf. van Beek, H. L; Gonzalo, G. d.; Fraaije, M. W. Chem. Commun. 2012, 48, 3288).
  • the 2-arylketones can also be converted to aryl-lactones via Baeyer-Villiger oxidation and aryl-lactams via Beckmann rearrangement, via the (E)-oxime (cf. Murakata, M.; Imai, M.; Tamura, M.; Hoshino, O. Tetrahedron: Asymmetry 1994, 5, 2019).
  • 2-aryltetralones via catalytic hydrogenolysis.
  • Some 2-aryltatralins were potential drugs for treatment of arrhythmias (irregular heartbeat), by acting as inhibitors of Na + /Ca 2+ exchange mechanism (cf. Huitric, A. C; Nelson, S. D. J. Org. Chem. 1969, 34, 1230). No asymmetric synthesis of these compounds was reported previously, which further illustrates the contribution of the present invention.
  • the optically enriched a-arylketones are used as intermediates in synthesis of bioactive natural and synthetic compounds.
  • the method describe herein provides a general way to access these chiral compounds that contain tertiary stereocenters in one enantiomeric form.
  • the arylketones can be chemically converted to other chiral compounds such as lactones, lactams, trans and cis alcohols and after deoxygenation of the ketone groups, chiral arylalkanes. Some of these derivatives show important pharmacological activities.

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Abstract

The invention relates to new ligands that are used in a palladium source catalyst system and in palladium catalyzed method for asymmetric α-(hetero)arylation and a-vinylation of ketones. The invention further relates to a process for preparing an asymmetric α-(hetero)arylated or a-vinylated ketone which comprises reacting the tin enolate of the ketone in the presence of catalyst system comprising a ligand of the invention and palladium source. By means of the ligands and process of the invention a stereogenic center in position a of the ketone is established with high enantiomeric excess.

Description

PALLADIUM-CATALYZED ASYMMETRIC (HETERO)ARYLATION AND VINYLATION OF KETONE ENOLATES TO PRODUCE TERTIARY STEREOCENTERS AT ALPHA((X)-POSITION
CROSS REFERENCE TO RELATED APPLICATIONS
[001] This application claims the benefit of priority to United States Provisional Application No. 61/751 ,753 titled "Palladium-Catalyzed Asymmetric Arylation and Vinylation of Ketone Enolates to Produce Tertiary Stereocenters at alpha(a)-Position" filed with the US Patent and Trademark Office on January 11 , 2013, the content of which is hereby incorporated by reference in its entirety for all purposes.
FIELD OF THE INVENTION
[002] The invention relates to new ligands that are used in a palladium catalyst system and in a palladium catalyzed method for asymmetric a-(hetero)arylation and a-vinylation of ketones. The invention further relates to a process for preparing an asymmetric a- (hetero)arylated or a-vinylated ketone which comprises reacting the tin enolate of the ketone in the presence of a catalyst system comprising a ligand of the invention and a palladium source. By means of the ligands and process of the invention a stereogenic center in position a of the ketone is established with high enantiomeric excess (ee).
BACKGROUND OF THE INVENTION
[003] Transition-metal catalyzed a-arylation of carbonyl compounds has become a very useful tool to prepare a-arylcarboxylic acids and derivatives. Asymmetric couplings that can form quaternary a-carbon centers have been developed for enolates of ketones (cf. Ahman, et al J. Am. Chem. Soc. 1998, 120, 1918; Hamada, et al J. Am. Chem. Soc. 2002, 124, 1261 ; Chen et al. Chem. Commun. 2006, 1413; Ge & Hartwig, J. Am. Chem. Soc. 2011 , 133, 16330, or Liao et al J. Am. Chem. Soc. 2008, 130, 195), aldehydes (cf. Garcia-Fortanet & Buchwald Angew. Chem., Int. Ed. 2008, 47, 8108), oxindoles (cf. Taylor et al J. Am. Chem. Soc. 2009, 131 , 9900 or Lee & Hartwig Org. Chem. 2001 , 66, 3402) and a- methylacetoacetates (Xie et al J. Am. Chem. Soc. 2006, 28, 16050). For example, Liao et al J. Am. Chem. Soc. 2008, supra reported nickel-catalyzed asymmetric coupling of cyclic ketones. These asymmetric processes cannot be used to construct tertiary centers due to facile racemization of products under basic conditions. Recently, MacMillan and Gaunt reported copper-catalyzed asymmetric arylations of aldehydes and silyl ketenimides for the formation of tertiary centers, using diaryliodonium salts (cf. Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011 , 133, 4260, Harvey, J. S.; Simonovich, S. P.; Jamison, C. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133, 13782, and Bigot, A.; Williamson, A. E.; Gaunt, M. J. J. Am. Chem. Soc. 2011 , 133, 13778). In 2011 , Zhou et al disclosed a palladium catalyst for asymmetric arylation and vinylation of esters for the formation of tertiary a- centers (cf. Huang, Z.; Liu, 2.; Zhou, J. J. Am. Chem. Soc. 2011 , 133, 15882). Asymmetric coupling between a-haloketones and aryl-metal reagents was also reported by Fu and coworkers recently (cf. Lou & Fu, G. C. J. Am. Chem. Soc. 2010, 132, 1264 and Lundin, P. M.; Esquivias, J.; Fu, G. C. Angew. Chem., Int. Ed. 2009, 48, 154).
[004] a-arylated or a-vinylated ketones are important intermediates and versatile building blocks for the synthesis of many chiral compounds and some active pharmaceutical ingredients (APIs).
[005] There is hence the need to provide further means to improve the quantitative and ee yield of asymmetric a-arylation and a-vinylation of ketones.
SUMMARY OF THE INVENTION
[006] The present invention addresses this need by providing a new chiral Iigand and a new catalyst system based on palladium source and the new Iigand to be used in the a- (hetero)arylation or a-vinylation of ketones, in particular in the a-arylation or a-vinylation of the tin enolate derivative of said ketone. By means of the chiral Iigand and of the catalytic system of the invention a stereogenic center in a position of the ketone is created with a high ee.
[007] Hence, in a first aspect the present invention is directed to a chiral Iigand of formula (I):
Figure imgf000003_0001
(I) wherein T 2014/000005
A is a single bond or oxygen atom or CH2;
Cy is cyclohexyl; and
Ri is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (hetero)aryl-methyl.
[008] In a second aspect, the present invention is directed to a catalyst system comprising a palladium source and a ligand of the above formula (I).
[009] In a third aspect, the present invention provides the use of a ligand of above formula (I) in asymmetric a-(hetero)arylation or a-vinylation of ketones wherein the a- (hetero)arylation or the α-vinylation creates a tertiary carbon center in the a-(hetero)arylated or a-vinylated position. The a-(hetero)arylation or α-vinylation creates the stereogenic center with a high ee. The reaction preferably occurs on the tin enolate derivative of the ketone.
[0010] In a fourth aspect, the present invention provides a process for asymmetrically a- (hetero)arylating or a-vinylating a ketone comprising reacting a tin enolate derivative of said ketone in the presence of an (hetero)arylating or a vinylating reagent and of a catalyst system wherein the catalyst system comprises: a) a palladium source and
b) a ligand of formulae (I) or
Figure imgf000004_0001
wherein
A is a single bond, oxygen atom or CH2;
Cy is cyclohexyl; and
Ri is selected from H, one of optionally substituted groups of alkyl, cycloalkyl, aryl, heteroaryl, and (hetero)aryl-methyl.
DESCRIPTION OF THE DRAWINGS [0011] The invention will be better understood with reference to the detailed description when considered in conjunction with the non-limiting examples and the accompanying drawings, in which:
[0012] Fig. 1 a shows examples of prior art asymmetric arylations. Fig. 1 b shows examples of arylation according to the present invention performed using ligands L1 and L3.
[0013] Fig. 2 shows the arylation performed with the catalyst of the invention using different ligands. The yields were measured by GC and the ee values are determined with HPLC analysis with a chiral stationary phase.
[0014] Fig. 3a shows examples of the arylation of tetralone-enolate using ligand L1 and the reported aryl triflate derivatives. Fig. 3b shows examples of the arylation of tetralone-enolate using ligand L1 and the reported aryl-CI and aryl-Br derivatives. The yields were measured by GC and the ee values are determined with HPLC analysis with a chiral stationary phase. The reaction conditions are those reported in in the reaction disclosed in Fig.2.
[0015] Fig. 4a shows examples of the arylation of cyclohexanone using ligand L1 and the reported aryl or heteroaryl triflate derivatives. Fig. 4b shows an example of the arylation of cyclohexanone using ligand L1 and the reported aryl or heteroaryl triflate derivatives. The yields were measured by GC and the ee values are determined with HPLC analysis with a chiral stationary phase. The reaction conditions are those reported in the reaction disclosed in Fig.2.
[0016] Fig. 5 shows examples of the arylation and vinylation of a ketone using ligand L3 and the reported aryl-OTf (triflate) or aryl-CI or aryl -Br or heteroaryl-OTf or heteroaryl-CI or heteroaryl-Br derivatives. The yields were measured by GC and the ee values are determined with HPLC analysis with a chiral stationary phase. The reaction conditions are those reported in Fig.2.
[0017] Fig. 6 shows the product of the arylation of various ketones using ArOTf and 2 mol% Pd/L3 (or L1 when specified). The results in parentheses are obtained with 2 mol% Pd/L1.
[0018] Fig. 7 shows the synthetic application of 2-arylketones (mCPBA = metachloroperbenzoic acid, Ts = 4-toluenesulfonyl).
[0019] Fig. 8 shows the stoichiometric reaction of a [(L1 )Pd(Ar)(Br)] complex and a tin enolate. The ORTEP of fra/7s-[(ligand L1)Pd(Ar)^-Br)]2 was shown in 50% probability of thermal ellipsoids with hydrogen atoms omitted for clarity. The two aryl groups are trans to each other on two palladium centers DETAILED DESCRIPTION
[0020] The present inventors have synthetized ligand L1 of formula
Figure imgf000006_0001
as a ligand to be used in a palladium catalyst system and in a palladium catalyzed method for asymmetric a-(hetero)arylation and a-vinylation of ketones. DFT calculation indicated that the excellent stereoselectivity of ligand L1 originated from strategically positioned CH/O hydrogen bonding between the catalyst (e.g. side chain naphthyl) and the carbonyl of Pd- enolates. This led the present inventors to prepare new catalysts L2 and L3 that are capable of conventional NH/O(carbonyl) hydrogen bonds. Indeed, the selectivity afforded by ligand L2 and L3 was better than L1 in the model reaction (Figure 2). Based on the same principles other excellent ligands have been prepared by the present inventors.
[0021] When catalyst L3 was used, the stereoselectivity was indeed significantly improved than L1 in couplings of cyclohexanone and tetralone enolates (Figure 6). The couplings of aryl, heteroaryl and vinyl bromides and triflates worked very well at RT. Some aryl chlorides also coupled smoothly.
[0022] The arylation products can be easily converted to other chiral building blocks. For example, reduction of 2-phenylcyclohexanone using K-Selectride gave c/'s-alcohol without erosion of ee and in 80:1 dr. Li/naphthalene reduction of the ketone can selectively give frans-2-arylcycohexanol. The frans-alcohol is commonly used as chiral auxiliary in asymmetric transformations.
[0023] The 2-arylketones can also be converted to aryl-lactones via Baeyer-Villiger oxidation and aryl-lactams via Beckmann rearrangement. Notably, it is important to prepare the (£)- oxime selectively, since the (Z)-isomer can rearrange to give a different lactam.
[0024] One more example is deoxygenation of 2-aryltetralones via catalytic hydrogenolysis. Some 2-aryltatralins were potential drugs for treatment of arrhythmias (irregular heartbeat), by acting as inhibitors of Na Ca2+ exchange mechanism. No asymmetric synthesis of these compounds was reported previously.
[0025] The present inventors have also prepared an oxidative adduct from an aryl bromide, Pd(dba)2 and ligand L1 (Figure 8). The palladium complex was a dimer bridged by two bromides. Ligand L1 binds to each palladium center in a monodentate fashion. Each Pd unit 14 000005 showed a square-planar geometry. When the dimeric complex was subjected to tetralone enolate and NaOAc, the coupling product was obtained in good yield and 93% ee (eq 2). The ee was identical to the ee obtained from the catalytic reaction. The formation of the dimeric complex, unfortunately, prevented putative interaction between of the Pd center and the bottom naphthyl ring of L1.
[0026] Further the present inventors have conducted DFT calculation (B3LYP) of C-C reductive elimination of the model reaction using ligand L1. One of purposes was to understand why this naphthyl side chain in L1 is so special in promoting stereoselectivity.
[0027] First, the inventors have examined the bonding mode of the bottom ring of ligand L1 in complexes of (L1)Pd(aryl)(enolate). They have found that Pd bonding with the ipso carbon of the L1 bottom ring was more favored over bonding with the aryl ether by 5-6 kcal/mol. The isomerization of the O-bound form to C-bound form was almost barrier-free. Thus, the inventors focused on studying enolate complexes with Pd bonding with the carbon(ipso) of L1.
[0028] Next, the inventors explored the possibility of direct C-C reductive elimination from O- enolate complexes. Surprisingly they found that no smooth pathway can be found that directly led to the coupling products. Instead, an abrupt "jumping" of atoms was observed at a certain point as the C-C distance was reduced. Also, isomerization of the O-enolate complexes to C-enolates had barriers of about 15-18 kcal/mol.
[0029] In contrast, direct C-C reductive elimination from the C-enolate complexes proceeded smoothly. The barriers leading to major and minor products were 13 and 15 kcal/mol, respectively. In the major pathway, both ground state (Int a) and transition state (TS1a) were more stable by 4.2 and 2.0 kcal/mol, respectively, than those in the minor pathway.
[0030] Surprisingly, the source of the stabilization was identified to be double CH"O hydrogen bonds between O-naphthyl CH bonds and the carbonyl of C-enolates. In the minor pathway, the hydrogen bonds were absent, because the carbonyl of the enolate pointed away from L1 side chain. This provides a clear explanation for the origin of stereoselectivity in the asymmetric coupling.
[0031] The weak hydrogen bonding of arene CH--O type is typically worth 0.5-4 kcal/mol of stabilization, depending on the acidity of CH bonds and CH-O=C bond angle and length. This kind of weak interaction was rarely observed in transition metal catalysis. In the optimized structures of enolate complexes, the bond angles and lengths of CH/O hydrogen bonds all fell into the prescribed range.
[0032] The present inventors have also calculated the reductive elimination step of C-enolate complexes supported by ligand L2. Again in the main pathway, both ground state (Int2a) and transition state (TS2a) were more stable than those in the minor pathway by 4.5 and 3.2 kcal/mol, respectively. The source of stabilization was double hydrogen bonds with both ortho-hydrogen and NH of the aniline side chain. In the minor pathway, they were absent.
[0033] Experimentally, 3 equivalents of HMPA, a hydrogen bond disruptor, were added in the model reaction of tetralone (Figure 2). In the presence of ligand L1 , the product ee dropped from 91% in the absence of HMPA to 77% in its presence. In the case of ligand L3, the selectivity also decreased from 98% ee to 66% ee. Hence, the present inventors have prepared new ligands for a Pd based catalyst and have developed a general method for asymmetric a-(hetero)arylation of ketones that established tertiary carbon centers in high ee.
[0034] Various (hetero)aryl triflates, bromides and chlorides reacted well with many enolates of cyclic ketones. Moreover, the in situ generation procedure of the tin enolates advantageously circumvented the need for handling and purification of tin enolates. After coupling, the residue tin can be easily removed by filtering through silica gel. The 2- arylketones are versatile building blocks for synthesis of many chiral compounds and some preclinical drugs. More significantly, the present inventors have identified weak arene CH/O hydrogen bonding between the catalysts and Pd-enolates. The hydrogen bonding represents a new way of stereocontrol in asymmetric transition-metal catalysis.
[0035] Based on the above findings of the inventors which are part of the present invention in their entirety, the present inventors have developed the present invention.
[0036] Hence, in a first aspect, the present invention is directed to a ligand of formula (I)
Figure imgf000008_0001
wherein
A is a single bond or oxygen atom or CH2;
Cy is cyclohexyl; and
Ri is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (hetero)aryl-methyl.
I
[0037] In a preferred embodiment of the first aspect, Ri is selected from 2-naphthyl, 1 - naphthyl, CH2-(2-naphthyl), phenyl, 4-amino-phenyl, 3-amino-phenyl, 3-(iPr)NH-phenyl, 3- CH3CONH-phenyl and cyclohexyl. [0038] In a preferred embodiment of the first aspect, A is an oxygen atom.
[0039] In a further preferred embodiment of the first aspect, Ri is selected from 2-naphthyl, 1 -naphtyl, CH2-(2-naphthyl), phenyl, 4-amino-pheny, 3-amino-phenyl, 3-(iPr)NH-phenyl, 3- CH3CONH-phenyl, cyclohexyl and A is oxygen atom.
[0040] Preferred ligands according to the present invention are the ligands of formulae:
Figure imgf000009_0001
[0041] Even more preferred ligands are the ligands of formulae:
Figure imgf000009_0002
[0042] In a second aspect, the present invention is directed to a catalyst system comprising catalysts in situ derived from a combination of a palladium source and a biarylphosphine ligand of formula (I) as disclosed in the first aspect of the invention and in any of the embodiments of the first aspect. The sources of palladium source of the catalysts system of the invention are Pd(OAc)2, Pd(dba)2, Pd2(dba)3 (dba=dibenzyleneacetone) or other palladium salts. The catalysts system of the invention may be formed in situ.
[0043] Preferred catalytic systems are those comprising anyone of a ligand of formulae
Figure imgf000010_0001
[0044] Even more preferred catalytic systems are those comprising a ligand of formulae L1 , L2 or L3.
[0045] In a third aspect, the present invention is directed to the use of a ligand of formula (I) as defined in the first aspect and in any of its embodiments and preferred embodiments, in the asymmetric a-(hetero)arylation or a-vinylation of ketones wherein the a-(hetero) arylation or the a-vinylation creates a tertiary center in the a-(hetero)arylated or a-vinylated position. The a-(hetero)arylation or the α-vinylation of ketones is a palladium catalyzed a- (hetero)arylation or the α-vinylation reaction. The asymmetric a-(hetero)arylation or a- vinylation reaction preferably occurs in the presence of the catalyst system of the invention as is defined in the above second aspect of the invention and in any of its embodiments and preferred embodiments. The reaction preferably occurs on the tin enolate derivative of said ketone. The tin enolate may be prepared and then reacted with the catalytic system of the invention in a two steps process. However, the present inventors have advantageously found that the preparation of the tin enolate and the subsequent asymmetric a-(hetero)arylation or α-vinylation reaction can occur in one pot reaction, without the need of purifying the tin enolate.
[0046] The tin enolate may be prepared with any suitable reagent for the purpose of preparing a tin enolate. A suitable and preferred reagent for tin enolation of ketones is (nBu)3Sn(OMe). The reaction of forming the tin enolate may occur in the presence of an activator that activates the trans-metalation. Activators of the reaction may be selected from LiOAc, NaOAc, LiOPiv (Piv=pivalic), CsF, LiF, ZnF2, CuF2 or nBuSnF. NaOAc is preferred as activator according to the present invention.
[0047] The a-(hetero)arylation or a-vinylation of ketones requires a (hetero)arylating or vinylating reagent. The (hetero)arylating or vinylating reagent is an organic electrophile reagent. This may include but it is not limited to electrophiles such as aryl-, heteroaryl- or vinyl- triflate, bromides, chlorides. The (hetero)aryl electrophiles can have electron-donating, electron-withdrawing and electron-neutral groups on the (hetero)aryl rings and can also have ortho groups and (hetero)benzofused rings.
[0048] In particular, a preferred (hetero)arylating reagent is of formula
Ar-X
wherein
X is OTf, Br or CI;
Ar is selected from: an optionally substituted phenyl, an optionally substituted naphtyl, and optionally substituted quinoline, an optionally substituted indole, an optionally substituted benzothiazole, an optionally substituted thiophene, and an optionally substituted benzopyran,
wherein the substituent is selected from: (Ci-C4) alkyl, OMe, CN, C02Et,
COMe, CF3, CI, F, BocNH (t-buthylcarbonyl)
[0049] More preferably, Ar is selected from:
Figure imgf000011_0001
wherein Y is H, OMe, CN, C02Et, COMe, CF3, CI, F; or Ar is selected from
Figure imgf000011_0002
Figure imgf000012_0001
[0050] The vinylating reagent has formula:
V-X
wherein
X is OTf, CI or Br; preferably OTf and
V is
Figure imgf000012_0002
[0051] Any ketone suitable for a-(hetero)arylation or a-vinylation can be used. However, the present ligands which are chiral ligands are particularly advantageous in a- (hetero)arylation or a-vinylation of ketones which lead to the introduction of a tertiary stereogenic center in the a-(hetero)arylated or α-vinylated position. Hence, ketones having a pre-stereogenic center in said position are particularly preferred according to the present invention. For example, cyclic ketones are ketones according to the present invention. The cyclic ketones can be of various ring sizes (6-9 membered rings) and can also be (hetero)benzofused ketones. The ring of cyclic ketones can contain also a heteroatom such as O, N or S. Cyclic ketones such as cyclohexanone, cyclopentanone, cycloheptanone, cyclooctanone, 1-tetralone, cromene, 4-oxo-4H-cromene all optionally substituted are ketones within the scope of the present invention. Substituents of the ketones are for example: (C C4) alkyl, aryl, heteroaryl, halogen (F, CI, Br, and I), -NH2, -CN, OH, (CrC4) alkoxy, CHO, COOH, -COO(C C4) alkyl and others.
[0052] In a fourth aspect, the present invention is directed to a process for asymmetrically a- (hetero)arylating or a-vinylating a ketone comprising a) reacting a tin enolate derivative of said ketone in the presence of an (hetero)arylating or a vinylating reagent and of a catalyst system based on palladium source and a ligand of formulae (I) or (II)
Figure imgf000013_0001
wherein
A is a single bond, oxygen atom or CH2;
Cy is cyclohexyl; and
Ri is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted (hetero)aryl-methyl. b) obtaining the a-(hetero)arylated or a-vinylated ketone having a stereogenic (tertiary) carbon center in the a-(hetero)arylated or vinylated position.
[0053] In an embodiment of the fourth aspect, the process further comprises reacting an alkenyl-acetate derivative of the starting ketone with nBu3Sn(OMe) to obtain the corresponding tin enolate of the ketone. The overall process is a two steps or one step reaction. In a "one step" (or one pot reaction) the tin enolate is formed in the presence of the catalytic system according to the invention.
[0054] The reaction occurs in the presence of an (hetero)arylating or a vinylating agent. The (hetero)arylating or vinylating reagent is an organic electrophile reagent. This may include but it is not limited to electrophiles such as aryl, heteroaryl or vinyl triflate, bromides, chlorides. The (hetero)aryl electrophiles can have electron-donating, electron-withdrawing and electron-neutral groups on the (hetero)aryl rings and can also have ortho groups and (hetero)benzofused rings.
[0055] In particular, a preferred (hetero)arylating reagent is of formula
Ar-X
wherein
X is OTf, Br or CI; and Ar is selected from: an optionally substituted phenyl, an optionally substituted naphtyl, and optionally substituted quinoline, an optionally substituted indole, an optionally substituted benzothiazole, an optionally substituted thiophene, and an optionally substituted benzopyran wherein the substituent is selected from: (C1-C4) alkyl, OMe, CN, C02Et, COMe, CF3, CI, F, Boc.
[0056] More preferably, Ar is selected from:
Figure imgf000014_0001
wherein Y is H, OMe, CN, C02Et, COMe, CF3, CI, F;
orAr is selected from
Figure imgf000014_0002
[0057] The vinylating reagent is formula
V-X
wherein
X is OTf, CI or Br, preferably OTf, and
V is
Figure imgf000015_0001
[0058] In the process of the fourth aspect, a catalyst system comprising
a) a palladium source; and
b) a ligand of formula (I) as disclosed in the first aspect of the invention and any embodiments of the first aspect or a ligand of formula (II)
is used.
[0059] The source of palladium of the catalysts system of the invention include but are not limited to Pd(OAc)2, Pd(dba)2 and Pd2(dba)3 (dba=dibenzyleneacetone). The catalysts system of the invention may be formed in situ.
[0060] Preferred catalytic systems are those comprising anyone of the ligands of formulae:
Figure imgf000015_0002
[0061] In the process according to the present invention, the tin enolate is preferably prepared using (nBu)3Sn(OMe) before use. The tin enolate may be easily obtained by stirring at room temperature the alkyl acetate of the ketone and (nBu)3Sn(OMe). The tin enolate may be then used even without further purification.
[0062] The reaction may occur in the presence of an activator which is preferably selected from LiOAc, NaOAc, LiOPiv, CsF, LiF, ZnF2, CuF2 or nBuSnF. NaOAc is the preferred activator according to the invention. 0005
[0063] The solvent of the process of the invention is any solvent suitable for performing the reactions of the inventions. Preferred solvents are selected from diethyl ether, tetrahydrofuran, 1 ,4-dioxane, f-butyl methyl ether, cyclopentyl-methyl-ether, toluene, benzene, α,α,α-trifluoromethylbenzene, fluorobenzene, dichloromethane and 1 ,2- dichloroethane. Even more preferred solvents according to the invention are diethyl ether, 1 ,4-dioxane, f-butyl methyl ether and cyclopentyl-methyl-ether.
[0064] In an embodiment of the forth aspect, the process is performed as follows:
Figure imgf000016_0001
wherein
R is phenyl, substituted aryl, secondary alkyl such as cyclohexyl, isopropyl, cyclopentyl;
X is OTf, Br or CI;
Y is F, OMe, or an ester;
Z is alkenyl, N, or O, or S, when Z is alkenyl is preferably -CH2. or-CH2-CH2-;
n is 1 , 2, 3, or 4;
the Pd source is Pd(OAc)2, Pd(dba)2 Pd2(dba)3;
the chiral ligand is a ligand of formula (I) or (II) of the present invention; and the activator is LiOAc, NaOAc, LiOPiv, CsF, LiF, ZnF2 CuF2 or nBuSnF.
[0065] Any ketone suitable for a-(hetero)arylation or a-vinylation can be used in the process of the forth aspect of the invention and in its embodiments. However, the present ligands which are chiral ligands are particularly advantageous in a-(hetero)arylation or a- vinylation of ketones which lead to the introduction of a stereogenic center in the a- (hetero)arylated or a-vinylated position. Hence, ketones having in a position a secondary carbon atom bearing two different substituents are particularly preferred according to the present invention. Cyclic ketones are an example of suitable ketones according to the invention. The cyclic ketones can be of various ring sizes (4-9 membered rings, preferably 6- 9 membered rings) and can also be (hetero)benzofused ones. The ring of cyclic ketones can contain also a heteroatom such as O, N or S. Cyclic ketones such as cyclohexanone, cyclopentanone, cycloheptanone, cyclooctanone, 1 -tetralone, cromene, 4oxo-4H-cromene all optionally substituted are suitable ketones within the scope of the present invention. [0066] The solvent of the process of the invention is any solvent suitable for performing the reactions of the inventions. Preferred solvents are selected from diethyl ether, tetrahydrofuran, 1 ,4-dioxane, i-butyl methyl ether, cyclopentyl-methyl-ether, toluene, benzene, α,α,α-trifluoromethylbenzene, fluorobenzene, dichloromethane and 1 ,2- dichloroethane. Even more preferred solvents according to the invention are diethyl ether, 1 ,4-dioxane, i-butyl methyl ether and cyclopentyl-methyl-ether.
[0067] The present invention provides for the first time catalytic a-(hetero)arylation or a- vinylation of ketone enolates that produced tertiary centers with high level of enantioselectivity (generally >90% ee). The method is applicable to various aryl triflates, bromides and chlorides and some vinyl triflates, with variations in both electronic and steric properties. The present invention is advantageous over other methods to prepare a- arylketones such as catalytic asymmetric protonation of silyl enolates of ketones, because the present method is convergent by establishing the new stereocenters and at the same time, forming the new carbon-carbon bonds between enolates and aryl, heteroaryl and vinyl electrophiles.
[0068] The organic electrophiles include but are not limited to aryl, heteroaryl and vinyl triflates, bromides and chlorides (X = OTf, Br, CI, etc). The (hetero)aryl electrophiles can have electron-donating, electron-withdrawing and electron-neutral groups on the (hetero)aryl rings and can also have ortho groups and (hetero)benzofused rings. The cyclic ketones can be of various ring sizes (6-9 membered rings) and can also be (hetero)benzofused ones. The cyclic ketones can contain substituents (Z) such as alkyl, aza and oxa in the rings.
[0069] The ketone enolates can be derived from nBuSnOMe and the corresponding vinyl acetates by simple stirring at room temperature. The resulting tin enolates can be used directly without purification. Various groups (Y = F, OMe and ester, etc) can be present on the benzo-fused rings of the ketones.
[0070] Solvents for the coupling processes include but are not limited to diethyl ether, tetrahydrofuran, 1 ,4-dioxane, f-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluoromethylbenzene, fluorobenzene, dichloromethane and 1 ,2- dichloroethane.
[0071] Examples of activators include but are not limited to LiOAc, NaOAc, LiOPiv CsF, LiF, KF, ZnF2, CuF2, and nBuSnF.
Figure imgf000018_0001
activator
[0072] The palladium source of the chiral catalysts may include but is not limited to Pd(OAc)2, Pd(dba)2 and Pd2(dba)3.
[0073] The chiral phosphorus ligands are typically of general structures I and II
Figure imgf000018_0002
where the R group is phenyl, substituted aryl, secondary alkyl such as but not limited to cyclohexyl, isopropyl and cyclopentyl; and the R1 group is H, alkyl, (hetero)arylmethyl and aryl group. Illustrative examples of R1 include but are not limited to cyclohexyl, isopropyl, phenyl, 2-naphthyl, 1 -naphthyl, benzyl, (2-naphthyl)methyl, (l -naphthyl)methyl, mefa-xylyl, 3,5-di-(f-butyl)phenyl, ortho-\o\y\, mesityl, A/-RmR„- 77efa-aminophenyl and N-RmRn-para- aminophenyl. The RmRn group include but are not limited to H, alkyl, aryl and acyl groups, including methyl, ethyl, isopropyl, f-butyl, acetyl, pivaloyl and phenyl, carbazoyl. Some of the catalysts made of ligands L1 , L2 and L3 are capable of NH/carbonyl and CH/carbonyl hydrogen bonding with palladium enolates in the catalytic cycle, through the side chain NH and arene CH bonds.
DEFINITIONS
[0074] The term "catalyst system" as herein used indicates those materials that, in combination, cause the (hetero)arylation or the vinylation to start and to be carried out.
[0075] The term "alkyl" as herein used indicates preferably (C1-C4) straight chain and (C1-C ) branched chain of alkyl groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like. The alkyl may be substituted. Substituents are, for example H, OMe, CN, C02Et, COMe, CF3, or halogen atoms such as CI or F.
[0076] The term "cycloalkyl" as used herein refers to a saturated monocyclic hydrocarbon groups having from three to seven carbon atoms in the ring, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The cyclic group may be optionally substituted with, for example, (C1-C4) alkyl, hydroxy, halogen or an amino group.
[0077] The term "(hetero)aryl" as herein used indicates heteroaryl and aryl. "Aryl" as herein employed alone or in combination refers to substituted or unsubstituted aromatic group, which may be optionally fused to other aromatic or non-aromatic cyclic groups. Representative examples of aryl groups include, but are not limited to, phenyl, benzyl, naphthyl, benzylidine, xylyl, styrene, styryl, phenethyl, phenylene, benzenetriyl and the like. "Heteroaryl" as used herein refers to a cyclic aromatic group containing a heteroatom. Heteroatom are, for example, O, N and S. Representative examples of heterocycles include, but are not limited to, pyridine, piperidine, pyrimidine, pyridazine, piperazine, pyrrole, pyrrolidinone, pyrrolidine, morpholine, thiomorpholine, indole, isoindole, imidazole, triazole, tetrazole, furan, benzofuran, dibenzofuran, thiophene, thiazole, benzothiazole, benzoxazole, benzothiophene, quinoline, isoquinoline, azapine, naphthopyran, furanobenzopyranone and the like. Substituents of the "(hetero)aryl" group or the aryl group or the heteroaryl group are, for example, H, (C1-C4) alkyl, OMe, CN, C02Et, C02Me, COMe, Boc, CF3, or halogen such as CI or F.
[0078] The term "vinyl" as herein used indicates the functional group -CH=CH2 and other alkenyl groups. In alkenyl groups, the vinyl "-CH=CH2" can bear one or more substituent in place of one of the hydrogen. Suitable substituents are for example optionally substituted alkyl, aryl and heteroaryl.
[0079] The invention will be further illustrated by non-limiting examples.
EXAMPLES
[0080] SYNTHESIS OF CHIRAL PHOSPHINES: [0081] Example : Synthesis of the ligand L1 :
Figure imgf000020_0001
[0082] (fl)-2-(Dicyclohexylphosphinyl)-2' -(2-naphthyloxy)-1,1'-binaphthyl. (L1 ) The O- arylation procedure using diaryliodonium salts used a reported procedure (Jalalian, N.; Ishikawa, E. E.; Silva, L. F.; Olofsson, B. Org. Lett. 201 1 , 13, 1552). Under argon, to a dry 100-mL Schlenk flask was added KOi-Bu (278 mg, 2.5 mmol) and freshly distilled THF (30 mL). After the solution was cooled to 4 °C in an ice-water bath, a solution of (R)-2- (dicyclohexylphosphinyl)- 2'-hydroxy-1 ,1 '-binaphthyl (Huang, Z.; Liu, Z.; Zhou, J. J. Am. Chem. Soc. 201 1 , 133, 15882) (1.00 g, 2.1 mmol) in THF (15 mL) was added via a syringe over 5 min. The reaction solution turned yellow immediately. After 20 min stirring at 0 °C, (2- naphthyl)(2'-mesityl)iodonium tetrafluoroborate (1.43 g, 3.1 mmol) was added in portions. The resulting mixture was stirred vigorously in a 40 °C oil bath. After 12 hours, the reaction was completed (monitored by TLC). The mixture was cooled to room temperature, loaded onto a pad of Celite and washed with ethyl acetate (50 mL) to remove solid byproducts. The filtrate was concentrated on a rotary evaporator and the resulting residue was purified by flash chromatography (ethyl acetate/hexane 1 :2 to 2:3) to afford the desired compound (860 mg, 68%) as white foam.
[0083] 1H NMR (400 MHz, CDCI3): δ 7.95 (d, J = 8.5 Hz, 1 H), 7.90-7.85 (m, 3H), 7.75-7.69 (m, 2H), 7.66 (d, J = 8.9 Hz, 1 H), 7.61 (d, J = 8.1 Hz, 1 H), 7.48-7.16 (m, 10H), 7.00 (d, J = 8.5 Hz, 1 H), 1.98-0.7 (m, 22H). 13C NMR (100 MHz, CDCI3): δ 155.1 , 152.6, 140.7 (JCP = 4.8 Hz), 134.9, 134.4 (JCp = 2.0 Hz), 134.3, 133.9 (JCP = 10.2 Hz), 130.25, 130.16, 129.8, 129.6 (JCP = 81.6 Hz), 129.5, 128.4, 128.0, 127.7, 127.6, 127.5 (JCp = 11.0 Hz), 127.24, 127.19, 127.1 , 126.8, 126.5, 126.4, 126.0, 124.7 (JCp = 3.5 Hz), 124.6, 124.4, 120.6, 1 18.7, 115.0, 38.5 (JCP = 65.7 Hz), 37.6 (JCp = 66.3 Hz), 27.1 , 26.9, 26.8 (JCP = 2.9 Hz), 26.7, 26.6, 26.5, 26.27, 26.24, 26.21 , 26.0, 25.9 (JCP = 2.9 Hz), 25.8. Some doublets due to C-P couplings cannot be assigned due to complexity of the spectrum and they are listed as single peak. 31P{ H} NMR (162 MHz, CDCI3): δ 46.0. ESI-MS: Calcd for C42H42O2P (M+H)+: 609.29. Found: 609.39
[0084] Example 2: Synthesis of the ligand of formula:
Figure imgf000021_0001
[0085] (fl)-2-(Dicyclohexylphosphinyl)-2' -phenyloxy-1,1 '-binaphthyl. The same O- arylation procedure as in Example 1 was used. KOf-Bu (42 mg, 0.37 mol), (fi)-2- (dicyclohexylphosphinyl)-2' -hydroxy- 1 ,1 '-binaphthyl (150 mg, 0.31 mmol), diphenyliodonium triflate (200 mg, 0.47 mmol) and THF (5 mL) were used. After stirring for 12 hours, the reaction was finished. The reaction mixture was cooled to RT, loaded onto a pad of Celite and washed with ethyl acetate (30 mL). The filtrate was concentrated on a rotary evaporator and the resulting residue was purified by flash chromatography (ethyl acetate/hexane 3:2) to afford the desired compound (163 mg, 94%) as white foam.
[0086] 1H NMR (400 MHz, CDCI3): δ 7.96 (dd, J= 8.6, 1.6 Hz, 1 H), 7.90 -7.85 (m, 3H), 7.79 (i|rt, J = 9.0 Hz, 1 H), 7.48 (t, J = 7.0 Hz, 1 H), 7.36 -7.32 (m, 2H), 7.28 -7.15 (m, 5H), 6.96 - 6.94 (m, 4H), 1.97-0.72 (m, 22H).13C NMR (100 MHz, CDCI3): δ 157.4, 152.7, 140.5 (d, JCP = 5.0 Hz), 134.9, 134.5, 133.9 (d, JCP = 10.3 Hz), 130.1 , 129.9 (d, JCP = 81.5 Hz), 129.8, 129.5, 128.3, 128.1 , 127.6, 127.5 (d, JCP = 10.8 Hz), 127.4 (d, JCP = 10.4 Hz), 127.2, 126.7, 126.5, 126.1 , 124.5 (d, JCP = 3.3 Hz), 124.4, 123.1 , 1 19.6, 118.6, 38.3 (d, JCP = 65.6 Hz), 37.7 (d, JCP = 66.2 Hz), 27.0, 26.9, 26.8 (d, JCP = 1 .5 Hz), 26.76, 26.7 (d, JCP = 1 .7 Hz), 26.6, 26.5, 26.4 (d, JCP = 3.2 Hz), 26.2 (d, JCP = 3.1 Hz), 26.0, 25.98. Some doublets due to C-P couplings cannot be assigned due to complexity of the spectrum and they are listed as single peak. 31P{1H} NMR (162 MHz, CDCI3): δ 46.2. ESI-MS: Calcd for C38H40O2P (M+H)+: 559.28. Found: 559.39
[0087] Example 3: Synthesis of the ligand of formula
Figure imgf000021_0002
[0088] (fl)-2-(Dicyclohexylphosphinyl)-2' -(1-naphthyloxy)-1,1 '-binaphthyl. The same
O-arylation procedure as in Example 1 was used. KOf-Bu (69 mg, 0.62 mol), (fl)-2- (dicyclohexylphosphinyl)-2' -hydroxy-1 ,1 '-binaphthyl (200 mg, 0.41 mmol), bis(1 - naphthyl)iodonium tetrafluoroborate (230 mg, 0.49 mmol and THF (5 mL) were used. The reaction was stirred at 60 °C for 24 hours. The mixture was cooled to RT, filtered through a pad of Celite and washed with ethyl acetate (30 mL). The filtrate was concentrated on a rotary evaporator and the resulting residue was purified by flash chromatography (ethyl acetate/hexane 1 :2) to afford the desired compound (153 mg, 61%) as white solid.
[0089] 1H NMR (400 MHz, CDCI3): δ 8.00-7.96 (m, 2H), 7.92 (d, J = 8.1 Hz, 1 H), 7.87-7.83 (m, 2H), 7.77 (d, J = 8.2 Hz, 1 H), 7.92 (ipt, J = 9.0 Hz, 1 H), 7.57-7.53 (m, 3H), 7.43-7.27 (m, 6H), 7.20 (ifitd, J= 8.2, 0.9 Hz, 1 H), 7.16 (d, J = 9.1 Hz, 1 H), 7.06 (d, J = 8.4 Hz, 1 H), 2.04- 0.88 (m, 22H). 13C NMR (100 MHz, CDCI3): δ 153.5, 152.8, 141.3 (d, JCP = 4.6 Hz), 134.9, 134.8, 134.5 (d, JCP = 1.7 Hz), 134.1 (d, JCP = 10.2 Hz), 130.0, 129.7, 129.4 (d, JCP = 82.2 Hz), 128.3, 128.1 , 127.8, 127.6, 127.5 (d, JCP = 1 1.0 Hz), 127.4, 127.2, 127.0 (d, JCP = 1 1.3 Hz), 126.8, 126.4, 125.94, 125.87, 125.7, 124.2, 123.6 (d, JCP = 3.6 Hz), 123.4, 122.6, 117.6, 1 15.4, 38.6 (d, JCP = 65.6 Hz), 37.4 (d, JCP = 66.4 Hz), 26.89, 26.86, 26.76, 26.70, 26.64, 26.57, 26.22, 26.19, 26.00, 25.96. Some doublets due to C-P couplings cannot be assigned due to complexity of the spectrum and they are listed as single peak.31P{1H} NMR (162 MHz, CDCI3): δ 45.9. ESI-MS: Calcd for C42H42O2P (M+H)+: 609.29. Found: 609.35
[0090] Example 4: Synthesis of the ligand of formula:
Figure imgf000022_0001
[0091] (fl)-2-(Dicyclohexylphosphinyl)-2' -(2-naphthyloxy)-5,5',6,6',7,7',8,8'-octahydro- 1,1'-binaphthyl. The same O-arylation procedure as in Example 1 was used. KOf-Bu (27 mg, 0.24 mol), (fl)-2-(dicyclohexylphosphinyl)-2' -hydroxy-5,5',6,6',7,7',8,8'-octahydro-1 ,1 '- binaphthyl (98 mg, 0.2 mmol), (2-naphthyl)(2-mesityl)iodonium tetrafluoroborate (138 mg, 0.3 mmol) and dry THF (2 mL) were used. The reaction was stirred at 40 °C for 12 hours. At the end of the reaction, the mixture was cooled to RT, loaded onto a pad of Celite and washed with ethyl acetate (10 mL). The filtrate was concentrated on a rotary evaporator and the resulting residue was purified by flash chromatography (ethyl acetate/hexane 1 :2) to afford the desired compound (63 mg, 51 %) as white solid. 1H NMR (400 MHz, CDCI3): δ 7.76 (d, J = 8.0 Hz, 1 H), 7.71 (d, J = 8.9 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.42-7.33 (m, 3H), 7.29-7.25 (m, 1 H), 7.22 (dd, J = 8.9, 2.3 Hz, 1 H), 7.09 (dd, J = 8.0, 2.3 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1 H), 2.84-2.76 (m, 4H), 2.45-0.92 (m, 34H).13C NMR (100 MHz, CDCI3): δ 155.0, 152.2, 142.5 (d, JCP = 5.2 Hz), 140.7 (d, JCP = 2.4 Hz), 137.9 (d, JCP = 9.3 Hz), 137.2, 134.5, 131.5, 130.2, 130.0 (d, JCp = 2.9 Hz), 129.4, 128.9, 128.6 (d, JCP = 10.7 Hz), 127.8, 127.7 (d, JCP = 11.8 Hz), 127.6 (d, JCP = 84.6 Hz), 127.3, 126.4, 124.5, 121.1 , 115.2, 114.6, 38.5 (d, JCP = 65.8 Hz), 37.7 (d, JCP = 66.0 Hz), 30.4, 29.6, 28.2, 27.5, 27.1 , 27.06, 27.02, 26.98, 26.94, 26.86, 26.53, 26.50, 26.47, 26.18, 26.16, 26.12, 26.09, 26.04, 26.02, 23.4, 23.31 , 23.26, 22.7. Some doublets due to C-P couplings cannot be assigned due to complexity of the spectrum and they are listed as single peak. 31P{1H} NMR (162 MHz, CDCI3): δ 44.2. ESI-MS: Calcd for C42H50O2 (M+Hf: 617.35. Found: 617.45
[0092] Example 5: Synthesis of the ligand of formula:
Figure imgf000023_0001
[0093] (fl)-2-(Dicyclohexylphosphino)-2 ' -(2-naphthyloxy)-1 ,1 '-binaphthyl.
[0094] Typical procedure for reduction of phosphine oxide: under argon, a dry 100-mL Schlenk tube was charged with the phosphine oxide (760 mg, 1.25 mmol), triethylamine (7.0 mL, 50.0 mmol) and dry toluene (30 ml_). After the resulting solution was cooled to 0 °C, trichlorosilane (1.3 mL, 12.5 mmol) was added via a syringe. The resulting mixture was capped tightly and vigorously stirred in a 120 °C oil bath for 24 hours, until all the phosphine oxide was consumed (monitored by 31 P NMR spectroscopy). At the conclusion of the reaction, the mixture was cooled to room temperature in the glove box and diluted with degassed diethyl ether (20 mL). After the resulting suspension was briefly chilled in a -30 °C fridge attached to the glove box, degassed, saturated Na2C03 (3.0 mL) was slowly added to quench the reaction. The whole mixture was directly dried over MgS04, filtered through a pad of silica gel, and eluted with degassed 1 :10 diethyl ether/hexane until no more product came out (monitored by TLC). The filtrate was concentrated under vacuum, and afforded the pure phosphine (629 mg, 85%) as white solid. [0095] 1H NMR (400 MHz, CDCI3): δ 7.91 -7.86 (m, 3H), 7.83 (d, J = 8.1 Hz, 1 H), 7.77 (d, J = 8.5 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.66 (d, J = 8.9 Hz, 1 H), 7.60 (d, J = 8.2 Hz, 1 H), 7.40- 7.27 (m, 7H), 7.24-7.19 (m, 2H), 7.1 1 (dd, J = 8.9, 2.2 Hz, 1 H), 7.05 (d, J = 8.5 Hz, 1 H), 1.93- 0.86 (m, 22H). 13C NMR (100 MHz, CDCI3): δ 154.9, 152.5 (d, JCP = 1.7 Hz), 142.6 (d, JCP = 32.3 Hz), 135.9 (d, JCP = 18.6 Hz), 134.8 (d, JCP = 1.5 Hz), 134.4, 133.7, 133.5 (d, JCp = 7.1 Hz), 130.24, 130.18, 129.68, 129.64, 129.4 (d, JCP = 2.7 Hz), 128.2, 128.0, 127.8, 127.3, 127.2, 127.1 , 126.51 , 126.48, 126.4 (d, CP = 8.2 Hz), 126.2, 124.6, 120.7, 1 18.6, 115.1 , 35.6 (ipt, JCP = 13.9 Hz, 2C), 31.2, 31.0, 30.8, 30.4 (d, JCP = 10.4 Hz), 30.2 (d, JCP = 10.1 Hz), 27.7-27.5 (5 overlapping signals), 26.6 (d, JCP = 2.68 Hz). Some doublets due to C-P couplings cannot be assigned due to complexity of the spectrum and they are listed as single peak.31P{1H} NMR (121 MHz, CDCI3): δ -9.0. [a]20 D = -73.0° (c = 1.0, CH2CI2). ESI-MS: Calcd for C42H42OP (M+H)+: 593.30. Found: 593.38.
[0096] Example 6: Synthesis of the ligand of formula:
Figure imgf000024_0001
[0097] (R)-2-(Dicyclohexylphosphino)-2' -(2-phenyloxy)-1,1 '-binaphthyl. The same reduction procedure was used. The phosphine oxide (100 mg, 0.18 mmol), triethylamine (0.95 ml_, 7.2 mmol), trichlorosilane (0.18 ml_, 1.8 mmol) and dry toluene (4 ml_) were used. The desired ligand was purified by filtration through a pad of silica gel with 1 :10 diethyl ether/hexane in the glove box. The filtrate was concentrated under vacuum and afforded the desired compound (85 mg, 87%) as white foam.
[0098] 1H NMR (400 MHz, CDCI3): δ 7.83-7.77 (m, 4H), 7.70 (d, J = 8.5 Hz, 1 H), 7.34 (i td, J = 7.9, 1.1 Hz, 1 H), 7.27 (t, J = 7.8 Hz, 1 H), 7.21-7.10 (m, 6H), 6.94 (d, J = 8.5 Hz, 1 H), 6.89 (ψί, J = 7.4 Hz, 1 H), 6.85 (d, J = 7.9 Hz, 2H), 1.82-0.77 (m, 22H). 13C NMR (100 MHz, CDCI3): δ 157.2, 152.6 (d, JCP = 2.0 Hz), 142.7 (d, JCP = 32.3 Hz), 135.9 (d, JCP = 18.8 Hz), 134.8 (d, JCP = 2.0 Hz), 133.8, 133.5 (d, JCP = 7.1 Hz), 130.0, 129.6, 129.4 (d, JCP = 2.8 Hz), 128.2, 128.0, 127.2, 127.1 (d, JCP = 1.8 Hz), 127.0, 126.4, 126.14, 126.1 1 , 126.07, 124.5, 123.2, 1 19.7, 118.3, 35.6 (d, JCP = 14.6 Hz), 35.5 (d, JCP = 14.3 Hz), 31.1 , 31.0, 30.95, 30.86, 30.4, 30.3, 30.2, 30.1 , 27.79, 27.75, 27.71 , 27.63, 27.56, 27.45, 26.73, 26.59. Some doublets due to C-P couplings cannot be assigned due to complexity of the spectrum and they are listed as single peak. 31P{1H} NMR (121 MHz, CDCI3): δ -9.0. [α];
ESI-MS: Calcd for C38H4oOP (M+H)+: 543.28. Found: 543.37.
[0099] Example 7: Synthesis of the ligand of formula:
Figure imgf000025_0001
[00100] (fl)-2-(Dicyclohexylphosphino)-2' -(1-naphthyloxy)-1,1 '-binaphthyl. The same reduction procedure was used. The phosphine oxide (200 mg, 0.33 mmol), triethylamine (1.7 mL, 13.2 mmol), trichlorosilane (0.33 mL, 3.3 mmol) and dry toluene (6 mL) were used. The desired ligand was purified in a glove box by filtration through a pad of silica gel with 1 :10 diethyl ether/hexane. The filtrate was concentrated under vacuum and afforded the desired compound (180 mg, 92%) as white foam. H NMR (400 MHz, CDCI3): δ 7.89 (d, J = 8.4 Hz, 1 H), 7.83-7.76 (m, 4H), 7.69 (ipt, J = 8.9 Hz, 2H), 7.44 (d, J = 8.2 Hz, 1 H), 7.39- 7.13 (m, 8H), 7.07 (d, J = 9.0 Hz, 1 H), 7.03-7.00 (m, 2H), 1.89-0.81 (m, 22H). 13C NMR (100 MHz, CDCI3): δ 152.3 (d, JCP = 1.4 Hz), 152.9, 142.7 (d, JCP = 32.3 Hz), 136.0 (d, JCP = 18.5 Hz), 134.95, 134.8 (d, JCP = 2.3 Hz), 133.8, 133.6 (d, JCP = 7.2 Hz), 130.0, 129.7, 129.4 (d, JCP = 2.6 Hz), 128.2, 128.1 , 127.7, 127.4, 127.3, 127.2 (d, JCP = 1.6 Hz), 127.1 , 126.55, 126.53, 126.2, 126.1 , 125.9, 125.7, 125.6 (d, JCP = 8.1 Hz), 124.5, 123.5, 122.7, 117.9, 1 14.9, 35.8 (d, Jcp = 14.7 Hz), 35.5 (d, JCP = 14.4 Hz), 31.2, 31.0, 30.9, 30.73, 30.70, 30.6, 30.5, 30.4, 27.7-27.5 (5 overlapping signals), 26.6 (d, JCP = 5.9 Hz). Some doublets due to C- P couplings cannot be assigned due to complexity of the spectrum and they are listed as single peak. 3 P{1H} NMR (121 MHz, CDCI3): δ -8.8. [a]20 D = +21.3° (c = 1.0, CH2CI2). ESI- MS: Calcd for C42H42OP (M+H)+: 593.30. Found: 593.39.
[00101] Example 8: Synthesis of the ligand of formula:
Figure imgf000025_0002
[00102] (fl)-2-(Dicyclohexylphosphino)-2 ' -(2-naphthyloxy)-5,5',6,6',7,7',8,8'- octahydro-1,1'-binaphthyl. The same reduction procedure was used. The phosphine oxide (71 mg, 0.12 mmol), triethylamine (0.7 mL, 4.8 mmol), trichlorosilane (0.12 mL, 1.2 mmol) and dry toluene (3 mL) were used. The desired ligand was purified in a glove box by filtration through a pad of silica gel with 1 :10 diethyl ether/hexane. The filtrate was concentrated under vacuum and afforded the desired compound (53 mg, 77%) as white solid. 1H NMR (400 MHz, CDCI3): δ 7.78-7.72 (m, 2H), 7.66 (d, J = 8.0 Hz, 1 H), 7.43-7.34 (m, 4H), 7.14 (dd, J = 8.8, 2.1 Hz, 1 H), 7.05 (d, J = 7.8 Hz, 1 H), 7.00 (d, J = 8.4 Hz, 1 H), 6.68 (d, J = 8.4 Hz, 1 H), 2.89-2.73 (m, 4H), 2.46-1.99 (m, 4H), 1.94-1.01 (m, 30H). 13C NMR (100 MHz, CDCI3): δ 154.6, 152.9 (d, JCP = 1.4 Hz), 144.7 (d, JC = 31.5 Hz), 138.1 , 137.1 , 136.2 (d, JCP = 6.4 Hz), 134.5, 132.8 (d, JCP = 15.6 Hz), 131.5, 131.4 (d, JCP = 7.2 Hz), 130.3, 129.9 (d, JCP = 2.6 Hz), 129.6, 129.0, 127.9, 127.3, 126.4, 124.6, 121.2, 115.5, 1 14.2, 35.6 (d, JCP = 15.0 Hz), 34.3 (d, JCP = 13.8 Hz), 30.8, 30.67, 30.64, 30.56, 30.47, 30.44, 30.2, 30.1 , 30.0, 29.7, 28.4 (d, JCP = 2.3 Hz), 28.1 , 28.02, 27.96, 27.93, 27.86, 27.7, 27.6, 27.5, 26.8, 26.7, 23.6, 23.3, 23.27, 23.0. Some doublets due to C-P couplings cannot be assigned due to complexity of the spectrum and they are listed as single peak.31P{1H} NMR (121 MHz, CDCI3): δ -9.0.[a]20 D = -58.8° (c = 0.9, CH2CI2). ESI-MS: Calcd for C42H50OP (M+H)+: 601.36. Found: 601.47.
[00103] Example 9: Synthesis of the ligand of formula:
Figure imgf000026_0001
[00104] (fl)-2-(Dicyclohexylphosphinyl)-2' -(2-naphthyl)-1,1'-binaphthyl. The
Kumada coupling was conducted by modifying a reported procedure (Hayashi, T.; Ishigedani, M. J. Am. Chem. Soc. 2000, 122, 976). Under argon, to a 100-mL Schlenk tube was added (dppe)NiCI2 (69 mg, 0.13 mmol), (fl)-2-(dicyclohexylphosphinyl)-2' - trifluoromethanesulfonoxy-1 ,1 '-binaphthyl (400 mg, 0.65 mmol) and freshly prepared 2- naphthylmagnesium bromide (4.56 mmol) in a solution of 12 mL of THF. The tube was capped tightly and the resulting mixture was heated in a 110 °C oil bath for 48 hours. After cooling to 0 °C, the reaction was quenched with saturated NH4CI (10 mL), and extracted with ethyl acetate (30 mL x 2). The extracts were washed with brine and dried with anhydrous Na2S04. After concentration on a rotary evaporator, the resulting residue was purified by flash chromatography (ethyl acetate/hexane 1 :2) to afford the desired compound (119 mg, 31%) as white solid.
[00105] 1H NMR (400 MHz, CDCI3): δ 8.05 (d, J = 8.4 Hz, 1 H), 7.96 (d, J = 8.1 Hz, 1 H), 7.93 (d, J = 8.1 Hz, 1 H), 7.86 (dd, J = 8.5, 2.0 Hz, 1 H), 7.79 (d, J = 8.5 Hz, 1 H), 7.72 (s, 1 H), 7.64-7.58 (m, 3H), 7.49-7.37 (m, 4H), 7.33-7.28 (m, 3H), 7.19 (dd, J = 8.5, 1.8 Hz, 1 H), 7.17-7.13 (m, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 1.64-0.21 (m, 22H). 13C NMR (100 MHz, CDCI3): δ 144.8 (d, JCP = 4.3 Hz), 140.1 , 139.5, 136.0 (d, JCP = 10.2 Hz), 133.7 (d, JCP = 2.1 Hz), 133.61 , 133.6 (d, JCP = 3.4 Hz), 133.3, 132.8, 132.1 , 129.9, 129.02 (d, JCP = 81.6 Hz), 129.0, 128.7, 128.34, 128.3, 128.27, 128.21 , 128.0, 127.7, 127.4, 127.3, 127.2 (d, JCP = 11.3 Hz), 126.9 (d, JCP = 1 1.6 Hz), 126.7, 125.7, 125.6, 125.4, 125.3, 39.2 (d, JCP = 65.5 Hz), 36.5 (d, JCP = 66.5 Hz), 26.78, 26.75, 26.66, 26.63, 26.60, 26.54, 26.48, 26.41 , 26.29, 26.04, 26.02, 25.98, 25.74, 25.71 , 25.68, 25.00 (d, JCp = 3.4 Hz). Some doublets due to C-P couplings cannot be assigned due to complexity of the spectrum and they are listed as single peak. 31 P {1H} NMR (162 MHz, CDCI3): δ 44.2. ESI-MS: Calcd for C42H42OP (M+H)+: 593.30. Found: 593.41.
[00106] Example 10: Synthesis of the ligand of formula:
Figure imgf000027_0001
[00107] (A7)-2-(Dicyclohexylphosphino)-2' -(2-naphthyl)-1,1'-binaphthyl. The same procedure for reduction of phosphine oxide as above was used. The phosphine oxide (50 mg, 0.09 mmol), triethylamine (0.50 mL, 3.4 mmol), trichlorosilane (0.1 mL, 0.9 mmol) and dry toluene (2 mL) were used. The reaction was conducted at 120 °C for 24 hours. The desired compound was purified by filtration in the glove box through a pad of silica gel pad with 1 :10 diethyl ether/hexane. The filtrate was concentrated under vacuum and afforded the desired compound (25 mg, 51%) as yellow solid.
[00108] 1H NMR (400 MHz, CDCI3): δ 8.08 (d, J = 8.5 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.4 Hz, 1 H), 7.82 (d, J = 8.4 Hz, 1 H), 7.70 (s, 1 H), 7.62-7.52 (m, 3H), 7.46- 7.30 (m, 7H), 7.17 J = 7.8 Hz, 1 H), 7.06 (d, J = 8.5 Hz, 1 H), 7.00 (d, J = 8.5 Hz, 1 H), 1.55-0.24 (m, 22H). 13C NMR (100 MHz, CDCI3): δ 145.6, 145.3, 140.0, 139.0 (d, JCP = 3.2 Hz), 135.6 (d, JCP = 7.0 Hz), 135.49, 135.42, 135.1 , 134.9, 134.1 , 133.6, 133.1 , 132.8, 132.3, 129.8 (d, JCP = 2.6 Hz), 129.7, 129.1 , 128.7, 128.5, 128.3, 128.1 , 128.0, 127.4, 127.1 , 127.0, 126.8, 126.5, 125.9, 125.8, 125.7 (d, JCP = 2.8 Hz), 36.9 (d, JCP = 15.8 Hz), 33.9 (d, JCp = 13.7 Hz), 31.1 , 30.9, 30.7, 30.6, 30.5, 30.4, 28.8, 28.7, 27.67, 27.63, 27.56, 27.3, 27.14, 27.07, 26.98, 26.5, 26.2. Some doublets due to C-P couplings cannot be assigned due to complexity of the spectrum and they are listed as single peak. 31 P{1 H} NMR (121 MHz, CDCI3): δ -8.7. [a]20 D = +190.0° (c = 0.6, CH2CI2). ESI-MS: Calcd for C42H42P (M+H)+: 577.30. Found: 577.42.
[00109] Example 11 : Synthesis of the ligand of formula:
Figure imgf000028_0001
[00110] (fl)-2-(Dicyclohexylphosphinyl)-2 ' -(m-nitrophenoxy)-1,1 '-binaphthyl.
The same O-arylation procedure as above was used. KOf-Bu (280 mg, 2.5 mol), (R)-2- (dicyclohexylphosphinyl)-2 ' -hydroxy-1 ,1 '-binaphthyl (1 .0 g, 2.1 mmol), bis(m- nitrophenyl)iodonium tetrafluoroborate (Ling, H.-Z.; Xie, C. Chin. J. Syn. Chem. 2006, 17, 170) (1.4 g, 3.1 mmol) and dry THF (50 mL) were used. After stirring at 40 °C for 24 hours, the reaction was stopped. The reaction mixture was cooled to RT and passed through a pad of Celite with ethyl acetate washings (60 mL). The filtrate was concentrated on a rotary evaporator and the residue was purified by flash chromatography (3:2 ethyl acetate/hexane to 50:1 DCM/methanol) to afford the desired compound (998 mg, 80%) as off-white solid.
[00111] 1H NMR (400 MHz, CDCI3): δ 7.98-7.95 (m, 2H), 7.90 (ψΧ, J = 8.1 Hz, 2H), 7.78-7.76 (m, 2H), 7.63 J = 9.0 Hz, 1 H), 7.51 -7.47 (m, 1 H), 7.44-7.37 (m, 2H), 7.34-7.26 (m, 3H), 7.24-7.19 (m, 2H), 7.03 (d, J = 8.4 Hz, 1 H), 1 .96-0.96 (m, 22H). 13C NMR (100 MHz, CDCI3): δ 158.3, 151 .3, 149.1 , 140.5 (d, JCP = 4.3 Hz), 134.7, 134.3 (d, JCP = 2.0 Hz), 133.8 (d, JCP = 10.0 Hz), 130.8, 130.3, 129.9, 129.6, 128.8, 128.5, 128.1 , 127.8, 127.7, 127.0, 126.72, 126.70, 126.6, 126.2, 125.8 (d, CP = 3.6 Hz), 125.1 , 125.0, 1 18.6, 1 17.5, 1 14.0, 38.8 (d, JCP = 65.8 Hz), 37.2 (d, JCp = 66.8 Hz), 27.1 , 27.0, 26.94, 26.93, 26.74, 26.70, 26.67, 26.62, 26.58, 26.55, 26.21 , 26.18, 26.12, 26.08, 26.0, 25.71 , 25.69. Some doublets due to C- P couplings are listed as single signals due to complexity of the spectrum. 31 P{1H} NMR (121 MHz, CDCI3): δ 46.1. ESI-MS: Calcd for C38H39NO4P (M+H)+: 604.26. Found: 604.39.
[00112] Example 12: Synthesis of the ligand of formula:
Figure imgf000029_0001
[00113] (fl)-2-(Dicyclohexylphosphino)-2' -(m-aminophenoxy)-1,1'-binaphthyl. In an argon-filled glove box, to a 20-mL Parr bomb was added (R)-2-(dicyclohexyl-phosphinyl)- 2' -(m-nitrophenyl)-1 ,1'-binaphthyl (300 mg, 0.5 mmol), 5% w/w Pd/C (106 mg, 0.05 mmol) and 10 mL of dry toluene. The mixture was heated at 100 °C for 24 hours with stirring under 60 psi of hydrogen gas. After cooling to RT, the reaction mixture was filtered through a short Celite pad with ethyl acetate washing (15 mL). The filtration was concentrated on a rotary evaporator and the resulting white foam was directly subjected to the next step.
[00114] Following the same reduction procedure as above, the phosphine oxide (286 mg, 0.5 mmol), triethylamine (2.7 mL, 19.6 mmol), trichlorosilane (0.5 mL, 4.9 mmol) and dry toluene (12 mL) were used. The reaction was finished after stirring for 24 h at 120 °C. The desired compound was purified by filtration through a short pad of silica gel with diethyl ether washing in the glove box. The filtrate was concentrated under vacuum and afforded the desired compound (187 mg, 67%) as white foam.
[00115] 1H NMR (400 MHz, CDCI3): δ 7.81 -7.62 (m, 4H), 7.69 (d, J = 8.5 Hz, 1 H), 7.33 (dd, J = 7.7, 7.0 Hz, 1 H), 7.26 (dd, J = 7.5, 7.3 Hz, 1 H), 7.20-7.09 (m, 4H), 6.93 (d, J = 8.5 Hz, 1 H), 6.87 (ψΐ, J = 8.0 Hz, 1 H), 6.25 (dd, J = 8.1 , 1.9 Hz, 1 H), 6.21 (dd, J = 7.9, 1.8 Hz, 1 H), 6.16 (ψί, J = 1.8 Hz, 1 H), 3.45 (s, 2H), 1.81 -0.78 (m, 22H). 13C NMR (100 MHz, CDCI3): δ 158.2, 152.6 (d, JCP = 2.0 Hz), 147.8, 142.9, 142.6, 135.9, 135.7, 134.7 (d, JCp = 1 -9 Hz), 133.8, 133.5 (d, JCP = 7.2 Hz), 130.2, 130.0, 129.5, 129.4 (d, JCP = 2.7 Hz), 128.1 , 128.0, 127.2, 127.1 (d, JCP = 2.0 Hz), 127.0, 126.4, 126.05, 126.02, 125.9 (d, JCp = 8.2 Hz), 124.4, 118.6, 110.1 , 110.0, 106.6, 35.7, 35.59, 35.56, 35.4, 31.1 , 31.0, 30.97, 30.8, 30.4, 30.3, 30.2, 30.1 , 27.81 , 27.76, 27.7, 27.65, 27.62, 27.5, 27.4, 26.7, 26.6. Some doublets due to C-P couplings are listed as single signals due to complexity of the spectrum. 31P{ H} NMR (121 MHz, CDCI3): δ -9.1. [a]20 D = -18.6° (c = 1.0, CH2CI2). ESI-MS: Calcd for C38H4iNOP (M+H)+: 558.29. Found: 558.39.
[00116] Example 13: Synthesis of the ligand of formula:
Figure imgf000030_0001
[00117] (fl)-/V-lsopropyl-2-(dicyclohexylphosphino)-2' -(3-aminophenoxy)-1,1'- binaphthyl.5 Under argon, to a two-necked RBF was added (f?)-2-(dicyclohexyl-phosphinyl)- 2' -(3-nitrophenyl)-1 ,†'-binaphthyl (760.0 mg, 1.26 mmol), analytical-grade acetic acid (6 ml_), acetone (6 mL) and deionized water (0.6 ml_). After the solution was cooled to 0 °C, zinc powder (650 mg, 10 mmol) was added. The mixture was stirred at RT for 1 hour and then heated at 60 °C for 16 hours (monitored by ESI-MS). At the end of the reaction, the reaction mixture was cooled to RT and passed through a short Celite pad with ethyl acetate washing (30 mL). The filtration was concentrated on a rotary evaporator, and the resulting crude product was diluted with DCM and neutralized with saturated NaHC03. The DCM layer was dried over anhydrous Na2S04 and concentrated on a rotary evaporator. The resulting yellow foam was directly used in the next step.
[00118] Following the same reduction procedure as above, the phosphine oxide (741 mg, 1.2 mmol), triethylamine (6.7 mL, 48.0 mmol), trichlorosilane (1.2 mL, 12.0 mmol) and dry toluene (28 mL) were used. The reaction was finished after stirring for 24 h at 120 °C. The desired ligand was purified by filtration through a pad of silica gel with diethyl ether washing in the glove box. The filtrate was concentrated under vacuum to give the desired compound (597 mg, 83%) as white foam.
[00119] 1H NMR (400 MHz, CDCI3): δ 7.82-7.76 (m, 4H), 7.70 (d, J = 8.5 Hz, 1 H), 7.35-7.31 (m, 1 H), 7.26 (dd, J = 7.8, 7.0 Hz, 1 H), 7.21 -7.09 (m, 4H), 6.93 (d, J = 8.4 Hz, 1 H), 6.88 (ψί, J = 8.1 Hz, 1 H), 6.16 (dd, J = 8.0, 1.7 Hz, 1 H), 6.13 (dd, J = 7.9, 1.8 Hz, 1 H), 6.07- 6.06 (i|Jt, J = 1.8 Hz, 1 H), 3.41-3.35 (heptet, J = 6.3 Hz, 1 H), 3.31 (s, 1 H), 1.82-0.79 (m, 28H). 13C NMR (100 MHz, CDCI3): δ 158.4, 152.9 (d, JCp = 1.7 Hz), 149.0, 143.0, 142.7, 136.0, 135.8, 134.7 (d, JCP = 1.8 Hz), 133.8, 133.5 (d, JCp = 7.2 Hz), 130.0, 129.9, 129.43, 129.39, 129.36, 128.1 , 128.0, 127.14, 127.12, 127.10, 126.9, 126.4, 126.05, 125.98, 125.7 (d, JCP = 8.1 Hz), 124.3, 118.6, 108.7, 108.4, 104.5, 44.4, 35.8, 35.6, 35.5, 35.4, 31.1 , 31.02, 30.97, 30.8, 30.3, 30.2, 30.1 , 27.87, 27.81 , 27.78, 27.69, 27.62, 27.55, 27.4, 26.7, 26.6, 23.2. Some doublets due to C-P couplings are listed as single signals due to complexity of the spectrum.31 P{1H} NMR (121 MHz, CDCI3): δ -9.0. [a]20 D = -34.2° (c = 1.0, CH2CI2). ESI-MS: Calcd for C4iH47NOP (M+H)+: 600.34. Found: 600.43.
[00120] Example 14: Synthesis of the ligand of formula:
Figure imgf000031_0001
[00121] (R)-W-Acetyl-2-(dicyclohexylphosphino)-2' -(3-aminophenoxy)-1,1'- binaphthyl. In argon-filled glove box, to a 4-mL vial was added (R)-2- (dicyclohexylphosphino)-2' -(3-aminophenyl)-1 ,1'-binaphthyl (160 mg, 0.27 mmol), dry DCM (2 mL) and freshly distilled acetic anhydride (40 mg, 0.4 mmol) successively. The resulting mixture was stirred at RT for 3 hours (monitored by TLC), then quenched with degassed saturated Na2C03 (0.5 mL) and extracted with DCM (2 mL x 2). The combined DCM layer was dried with anhydrous Na2S04 and concentrated in the glove box to give the desired ligand in quantitative yield as white foam.
[00122] 1H NMR (400 MHz, CDCI3): δ 7.93-7.85 (m, 4H), 7.78 (dd, J = 8.5, 1.1 Hz, 1 H), 7.44-7.40 (m, 1 H), 7.37 (ψί, J = 7.3 Hz, 1 H), 7.29-7.03 (m, 9H), 6.68 (d, J = 7.7 Hz, 1 H), 2.07 (s, 3H), 1.92-0.87 (m, 23H). 13C NMR (100 MHz, CDCI3): δ 168.2, 157.8, 152.1 , 142.7, 142.4, 139.2, 136.0, 135.8, 134.8 (d, JCp = 1 -5 Hz), 133.7, 133.5, 133.4, 130.0, 129.9, 129.7, 129.36, 129.33, 128.2, 128.0, 127.2, 127.10, 127.07, 126.6, 126.5, 126.1 , 124.7, 118.7, 115.1 , 1 14.4, 110.8, 35.6 (d, JCp = 14.5 Hz), 35.5 (d, JCP = 14.3 Hz), 31.1 , 31.0, 30.97, 30.84, 30.4, 30.3, 30.2, 30.1 , 27.74, 27.70, 27.65, 27.63, 27.58, 27.55, 27.4, 26.7, 26.6, 24.8. Some doublets due to C-P couplings are listed as single signals due to complexity of the spectrum. 31P{1H} NMR (121 MHz, CDCI3): δ -9.1. ESI-MS: Calcd for C4oH43 02P (M+H)+: 600.30. Found: 600.37.
[00123] Example 15: Synthesis of the ligand of formula:
Figure imgf000031_0002
[00124] (fl)-2-(Dicyclohexylphosphino)-2 ' -(4-aminophenoxy)-1 ,1 '-binaphthyl.
The same O-arylation procedure as above was used. KOrBu (77 mg, 0.68 mmol), (fl)-2- (dicyclohexylphosphinyl)-2' -hydroxy- 1 ,1'-binaphthyl (300 mg, 0.62 mmol), freshly distilled THF (20 mL) and (4-nitrophenyl)(2-mesityl)iodonium triflate (385 mg, 0.75 mmol) were used. After stirring for 24 hours at 40 °C, the reaction was complete. The reaction mixture was cooled to RT, loaded onto a pad of Ceiite and eluted with ethyl acetate (30 mL). The filtrate was concentrated on a rotary evaporator and the resulting residue was purified by flash chromatography (1 :1 ethyl acetate/hexane to 50:1 DCM/methanol) to afford the O-arylated compound (321 mg, 86%) as white foam and used in the next step.
[00125] To a 20-mL Parr bomb was added (fl)-2-(dicyclohexylphosphinyl)-2' -(4- nitrophenyl)-1 ,1'-binaphthyl (220 mg, 0.36 mmol), 5% w/w Pd/C (76 mg, 36 μιτιοΙ) and 10 mL of toluene, the resulting mixture was heated to 100 °C gas with stirring for 24 hours under 60 psi of hydrogen gas. After cooling to RT, the reaction mixture was filtered through a short Ceiite pad with ethyl acetate washing (15 mL). The filtration was concentrated on a rotary evaporator, and the resulting white foam was directly subjected to the next step.
[00126] Following the reduction procedure as above, (fl)-2-(dicyclohexylphosphinyl)-2 ' -(4-aminophenyl)-1 ,1'-binaphthyl (100 mg, 0.17 mmol), triethylamine (1.0 mL, 6.8 mmol), trichlorosilane (170 uL, 1.7 mmol) and dry toluene (4 mL) were used. The reaction was finished after stirring for 24 h at 120 °C. The desired ligand was purified by passing the crude mixture through a pad of silica gel with diethyl ether washing in the glove box. The filtrate was concentrated under vacuum and afforded the desired compound (76 mg, 80%) as white foam.
[00127] 1H NMR (400 MHz, CDCI3): δ 7.83-7.74 (m, 4H), 7.70 (dd, J = 8.5, 1.0 Hz, 1 H), 7.37-7.33 (m, 1 H), 7.25-7.05 (m, 5H), 6.92 (d, J = 8.4 Hz, 1 H), 6.69-6.67 (m, 2H), 6.49- 6.47 (m, 2H), 3.40 (s, 2H), 1.82-0.79 (m, 22H). 13C NMR (100 MHz, CDCI3): δ 154.0 (d, JCP = 1.5 Hz), 149.1 , 143.2, 142.9, 142.6, 135.8, 135.6, 134.7 (d, JCP = 1.9 Hz), 133.8, 133.5, 133.4, 129.5, 129.44, 129.4, 128.1 , 128.05, 127.1 , 127.06, 127.05, 126.8, 126.4, 126.1 , 126.0, 124.5 (d, JCP = 8.1 Hz), 124.1 , 121.6, 117.1 , 1 16.3, 35.6 (d, JCP = 14.6 Hz), 35.3 (d, JCP = 14.3 Hz), 31.2, 31.0, 30.9, 30.8, 30.4, 30.3, 30.2, 30.1 , 27.82, 27.79, 27.74, 27.68, 27.61 , 27.5, 27.4, 26.8, 26.6. Some doublets due to C-P couplings are listed as single signals due to complexity of the spectrum. 31P{1H} NMR (121 MHz, CDCI3): δ -9.1. ESI-MS: Calcd for C38H4iNOP (M+H)+: 558.29. Found: 558.39.
[00128] CONDITION OPTIMIZATION OF ASYMMETRIC ARYLATION
[00129] Synthesis of tri(n-butyl)tin enolate of 1-tetralone. The conversion of alkenyl acetate to moisture-sensitive tri(n-butyl)tin enolate of 1 -teralone was conducted by modifying a reported procedure [00130] Synthesis 1991, 1991, 1043). Under argon, a dry 20-mL vial was charged with 1 ,2-dihydro-4-naphthyl acetate (Noji, M.; Ohno, T.; Fuji, K.; Futaba, N.; Tajima, H.; Ishii, K. J. Org. Chem. 2003, 68, 9340) (2.0 g, 10.6 mmol) and tri(n-butyl)tin methoxide (3.25 g, 10.1 mmol) at room temperature. The reaction was stirred at RT for 12 h until full consumption of tri(n-butyl)tin methoxide (monitored by 1H NMR spedtroscopy). The byproduct, methyl acetate was removed under vacuum. The resulting yellowish oil was 95% pure, judged by H NMR spectroscope, and it was directly used in asymmetric arylation.
[00131] Typical procedure for asymmetric arylation. In an argon-filled glove box, a dry 20-mL vial was charged with Pd(OAc)2 (0.9 mg, 0.004 mmol), ligand L1 (3.6 mg, 0.006 mmol), NaOAc (18 mg, 0.22 mmol), phenyl triflate (45.2 mg, 0.20 mmol) and 4.0 mL of dry diethyl ether. After stirring at 25 °C for 10 minutes, the mixture was treated with 4-tri(n- butyl)stannyloxy-1 ,2-dihydronaphthalene (0.24 mmol, 1 10 mg) and n-dodecane (GC standard, 20 μί). The vial was capped tightly and stirred at 25 °C until the aryl triflate was fully consumed. At intervals, an aliquot of the reaction mixture was taken and passed through a short plug of silica gel with diethyl ether washings to remove the Pd catalyst and inorganic salts. The filtrate was directly used for GC analysis to determine the conversion of phenyl triflate and yield of the coupling product. For determination of enantioselectivity of the coupling product from the reaction mixture, the solvent of the filtrate was removed by argon blowing and the residue was redissolved in 1 :9 /'-PrOH and n-hexane to prepare sample for chiral HPLC analysis (Daicel CHIRALCEL AS-H; 2% /-PrOH in hexanes).
[00132] Table 1: Effect of Biarylphosphine Ligands.
PhOTf
Figure imgf000034_0001
Figure imgf000034_0002
%,32%(S¾> 70%,β1%ββ S ,54%es
Table SI . Effect of solvents.
PhOTT
0-2mmol
Figure imgf000034_0003
Entry Solvent Time (h) Conv (%) GC Yield (%) Ee (%)
3h 12 8 70
1 PhCF3
6h 20 17 70 2 Toluene 3h 12 8 81 6h 21 17 81
3h 17 15 77
3 PhF
6h 34 31 77
3h 20 16 70
4 DCM
6h 33 28 70
3h 12 10 70
5 DCE
6h 21 , 17 70
6 THF 3h 100 98 87
3h 79 77 89
7 CPME
6h 100 97 89
3h 83 81 89
8 TBME
6h 100 97 89
3h 89 87 91
9 Et20
6h 100 98 91
3h 99 97 87
10 Dioxane
6h 100 98 87
11 DMF 3h 100 80 0
12 DMSO 3h 100 86 5
[00134] Table S2. Effect of metal sources.
Figure imgf000035_0001
Entry Catalyst Time (h) Conv (%) GC yield (%) Ee (%)
2% Pd(OAc)2 3h 89 87
1 3% ligand L1
6 100 98 91
2% Pd(TFA)2 3h 71 69
2 3% ligand L1
6h 100 98 91
2% Pd(dba)2 3h 4 0
3 3% ligand L1
6h 6 0
1%Pd2(dba)3 ' 3 4 0
4 3% ligand L1
6h 5 0
2% PdMe2(tmeda) 3h 15 9
5 3% ligand L1
6h 32 27 92
0
2% Ni(cod)2 6h 1
6 4% ligand L1 n
12 h, 50 °C 4
[00135] Table S3. Effect of inorganic acetate and fluoride activators. QAo
PhO f
Figure imgf000036_0001
O-mmot C 1.2aOqulv AcSvator
Entry Activator Time ( ) Conv (%) GC yield (%) Ee (%)
3h 15 7
1 none
6h 15 9 65
3h 89 87
2 LiOAc
6h 100 98 91
3h 100 98 91
3 NaOAc
6h 100 98 91
3h 40 34
4 CsF
6h 54 47 80
3h 18 8
5 ZnF2
6h 18 11 60
3 h 16 8
6 CuF2
6h 16 11 69
3h 49 40
7 (n-Bu)3SnF
6h 56 48 76
Figure imgf000036_0002
Table S5. Model arylation reaction using (f?)-difluorphos ligand.
Figure imgf000036_0003
5
Figure imgf000037_0001
[00138] Table S6. Asymmetric arylation of silyl enolates
PhOTf
Figure imgf000037_0002
Q-Zmmol
GC yld
Entry S/' group Time (h) Conv (%) Ee (%)
(%)
6 h, RT 0
1 SiMe3 12 h (50
0
°C)
6 h, RT 0
2 Si(OEt)3 12 h (50
0
°C)
6 h, RT 0
SiMe(CH2)3 - 3 12 h, 50
10 <1
°C
[00139] ISOLATION OF COUPLING PRODUCTS USING LIGAND L1
[00140] Procedure for synthesis of tin enolate: Under argon, a dry 20-mL vial was charged with 1 ,2-dihydro-4-naphthyl acetate (2.0 g, 10.6 mmol) and tri(n-butyl)tin methoxide (3.25 g, 10.1 mmol) at room temperature. The reaction was stirred at RT for 12 h until full consumption of tri(n-butyl)tin methoxide (monitored by H NMR spedtroscopy). The byproduct, methyl acetate was removed under vacuum. The resulting yellowish oil was 95% pure, judged by 1H NMR spectroscope, and it was directly used in asymmetric arylation.
[00141] Procedure for asymmetric arylation: In an argon-filled glove box, a dry 20- mL vial was charged with Pd(OAc)2 (2 mol%, 2.3 mg, 0.010 mmol), ligand L1 (3 mol%, 8.9 mg, 0.015 mmol), NaOAc (45 mg, 0.55 mmol), phenyl triflate (113 mg, 0.50 mmol) and 5.0 mL of dry diethyl ether. After stirring at room temperature for 10 minutes, the mixture was treated with 4-tri(n-butyl)stannyloxy-1 ,2-naphthalene (275 mg, 0.60 mmol, 95% purity) and n- dodecane (GC standard, 20 μΙ_). The vial was capped tightly and stirred at 25 °C until aryl triflate was fully consumed (monitored by GC). The reaction mixture was directly filtered through a pad of silica gel with diethyl ether washings (20 mL) to remove the palladium catalyst and inorganic salts. The filtrate was concentrated on a rotary evaporator and the residue was directly purified by flash chromatography. Enantioselectivity of the purified product was determined by chiral HPLC analysis. The typical procedure was used for isolation of all coupling products using 0.50 mmol of aryl triflate and 2 mol% palladium catalyst, unless stated otherwise.
[00142] To facilitate chiral HPLC analysis, the racemic compound was prepared using the same procedure, except that Sphos was used instead of chiral ligand L1.
[00143] (1) Couplings of 4-tri(n-buty)stannyloxy-1,2-dihydronaphthalene.
[00144] (a) Couplings of aryl triflates and 4-tri(n-buty)stannyloxy-1,2-dihydro- naphthalene.
Figure imgf000038_0001
[00145] (S)-2-Phenyl-1-tetralone [247170-33-8 for (fl)-isomer]. The reaction was set up using phenyl triflate (0.50 mmol, 113 mg) and 4-tri(n-butyl)stannyloxy-1 ,2- dihydronaphthalene (0.60 mmol, 275 mg). The reaction finished after 2 hours at 25 °C. Some 1 -tetralone coeluted with the desired coupling product during flash chromatography (1 :40 EA/hexane) and was removed afterwards by washing the solid with cold n-pentane. The titled compound was obtained as white solid (109 mg, 98% yield).
[00146] Ee of the purified products was determined to be 91% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wave- lengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 11.3 min (minor) and 18.0 min (major). [00147] [a]20 D = +3.3° (c = 1.0, CHCI3) for a sample of 91 % ee. 1H NMR (400 MHz, CDCI3): δ 8.11 (dd, J = 7.8, 1.0 Hz, 1 H), 7.51 (i|rtd, J = 7.5, 1.4 Hz, 1 H), 7.37-7.27 (m, 5H), 7.21-7.19 (m, 2H), 3.83-3.79 (m, 1 H), 3.17-3.02 (m, 2H), 2.51 -2.42 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 198.4, 144.3, 139.9, 133.6, 133.1 , 129.0, 128.7, 128.6, 128.0, 127.1 , 127.0, 54.6, 31.4, 29.0. GCMS (El): calcd for C16H140 M: 222.10. Found: 222.07.
[00148] Synthesis of the compound of formula:
Figure imgf000039_0001
[00149] (S)-2-(p-Anisyl)-1-tetralone. The reaction finished within 3 hours at 25 °C. The titled compound was obtained as white solid (123 mg, 98% yield) by flash chromatography using EA/hexane (1 :30) as eluent.
[00150] Ee of the purified products was determined to be 92% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 70:30; detection wave- lengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 10.9 min (major) and 14.3 min (minor).
[00151] [a]20D = +16.7° (c = 1.0, CHCI3) for a sample of 92% ee.
[00152] 1H NMR (400 MHz, CDCI3): δ 8.11 (dd, J = 7.8, 1.0 Hz, 1 H), 7.51 (qrtd, J = 7.5, 1.4 Hz, 1 H), 7.35 (ipt, J = 7.6 Hz, 1 H), 7.29 (d, J = 7.6 Hz, 1 H), 7.15-7.11 (m, 2H), 6.92-6.89 (m, 2H), 3.72-3.68 (m, 4H), 3.17-3.02 (m, 2H), 2.44-2.39 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 198.6, 158.6, 144.2, 133.5, 133.0, 131.9, 129.5, 128.9, 127.9, 126.9, 114.1 , 55.4, 53.7, 31.4, 29.0. GCMS (El): calcd for C17H1602 M: 252.12. Found: 252.06.
[00153] Synthesis of the compound of formula:
Figure imgf000039_0002
[00154] (S)-2-(p-Cyanophenyl)-1-tetralone. The reaction finished within 2 hours at 25 °C. The titled compound was obtained as white solid (1 19 mg, 96% yield) by flash chromatography using EA/hexane (1 :5) as eluent.
[00155] Ee of the purified products was determined to be 91 % based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 19.1 min (major) and 22.9 min (minor).
[00156] [a]20 D = +37.0° (c = 1.0, CHCI3) for a sample of 91% ee.
[00157] 1H NMR (400 MHz, CDCI3): δ 8.07 (dd, J = 7.8, 1 .0 Hz, 1 H), 7.64-7.62 (m,
2H), 7.53 (i)Jtd, J = 7.5, 1 .3 Hz, 1 H), 7.29 (d, J = 7.6 Hz, 1 H), 7.32-7.30 (m, 2H), 3.87-3.83 (m, 1 H), 3.22-3.14 (m, 1 H), 3.07 (ipdt, J = 16.9, 4.2 Hz, 1 H), 2.46-2.40 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 197.0, 145.4, 143.9, 134.0, 132.5, 132.4, 129.6, 129.0, 128.0, 127.1 , 1 19.0, 1 1 1 .1 , 54.7, 31.0, 29.1 . GCMS (El): calcd for Ci7H13NO M: 247.10. Found: 247.06.
[00158] Synthesis of the compound of formula:
Figure imgf000040_0001
[00159] (S)-2-(4-Ethylbenzoate)-1-tetralone. The reaction finished within 2 hours at 25 °C. The titled compound was obtained as white solid (147 mg, 99% yield) by flash chromatography using EA/hexane (1 :5) as eluent.
[00160] Ee of the purified products was determined to be 93% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 10.1 min (major) and 1 1.2 min (minor).
[00161] [a]20 D = +17.3° (c = 1.0, CHCI3) for a sample of 93% ee.
[00162] 1H NMR (400 MHz, CDCI3): δ 8.01 (dd, J = 7.8, 1.0 Hz, 1 H), 7.96-7.94 (m,
2H), 7.43 (4Jtd, J = 7.5, 1.4 Hz, 1 H), 7.26 (ψί, J = 7.6 Hz, 1 H), 7.22-7.18 (m, 3H), 4.29 (q, J =
7.1 Hz, 2H), 3.78 (dd, J = 10.4, 5.9 Hz, 1 H), 3.11 -2.94 (m, 2H), 2.39-2.33 (m, 2H), 1.30 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, CDCI3): δ 197.6, 166.6, 145.1 , 144.1 , 133.8, 132.8, 130.0, 129.4, 129.0, 128.7, 128.0, 127.1 , 61.0, 54.6, 31.2, 29.0, 14.5. GCMS (El): calcd for Ci9H1803 M: 294.13. Found: 294.09.
[00163] Synthesis of the compound of formula:
Figure imgf000041_0001
[00164] (S)-2-(p-Acetylphenyl)-1-tetralone. The reaction finished within 2 hours at 25 °C. The titled compound was obtained as white solid (124 mg, 94% yield) by flash chromatography using EA/hexane (1 :5) as eluent.
[00165] Ee of the purified products was determined to be 94% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 17.1 min (major) and 26.4 min (minor).
[00166] [a]20 D = +22.3° (c = 1.0, CHCI3) for a sample of 94% ee.
[00167] 1H NMR (400 MHz, CDCI3): δ 8.08 (dd, J = 7.8, 0.9 Hz, 1 H), 7.94 (d, J = 8.3 Hz, 2H), 7.52 (ijJtd, J = 7.5, 1.3 Hz, 1 H), 7.34 (ψί, J = 7.6 Hz, 1 H), 7.31 -7.29 (m, 3H), 3.86 (dd, J = 10.8, 5.7 Hz, 1 H), 3.20-3.02 (m, 2H), 2.59 (s, 3H), 2.48-2.41 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 197.9, 197.5, 145.5, 144.1 , 136.0, 133.8, 132.7, 129.01 , 128.95, 128.8, 128.0, 127.1 , 54.7, 31.1 , 29.0, 26.8. GCMS (El): calcd for Ci8H1602 M: 264.12. Found: 264.08.
[00168] Synthesis of the compound of formula:
Figure imgf000041_0002
[00169] (S)-2-(p-Trifluoromethylphenyl)-1-tetralone. The reaction finished within 2 hours at 25 °C. Some 1 -tetralone coeluted with the desired coupling product during flash chromatography (1 :40 EA/hexane) and was removed afterwards by washing with cold n- pentane. The titled compound was obtained as white solid (138 mg, 95% yield).
[00170] Ee of the purified products was determined to be 93% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mlJmin). TR = 1 1.1 min (minor) and 13.2 min (major).
[00171] [a]20 D = +19.0° (c = 1.0, CHCI3) for a sample of 93% ee.
[00172] 1H NMR (400 MHz, CDCI3): δ 8.10 (d, J = 7.8 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 2H), 7.54 (HJtd, J = 7.5, 1.3 Hz, 1 H), 7.38-7.30 (m, 4H), 3.87 (dd, J = 10.4, 6.2 Hz, 1 H), 3.22- 3.04 (m, 2H), 2.48-2.40 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 197.5, 144.08, 144.03, 133.9, 132.7, 129.4 (q, JCF = 32.4 Hz), 129.1 , 129.0, 128.0, 127.1 , 125.6 (q, CF = 3.8 Hz), 124.4 (q, JCF = 271.9 Hz), 54.6, 31.2, 29.1. 19F NMR (376 MHz, CDCI3): δ -62.4. GCMS (El): calcd for C17H13F30 M: 290.09. Found: 290.05.
[00173] Synthesis of the compound of formula:
Figure imgf000042_0001
[00174] (S)-2-(p-Chlorophenyl)-1-tetralone. The reaction finished within 3 hours at 25 °C. Some 1 -tetralone coeluted with the desired coupling product during flash chromatography (1 :40 EA/hexane). It was removed afterwards by washing with cold n- pentane. The titled compound was obtained as white solid (1 19 mg, 93% yield).
[00175] Ee of the purified products was determined to be 92% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 20.6 min (major) and 28.6 min (minor).
[00176] [a]20 D = +29.3° (c = 1.0, CHCI3) for a sample of 92% ee.
[00177] 1H NMR (400 MHz, CDCI3): δ 8.07 (dd, J = 7.8, 0.9 Hz, 1 H), 7.50 (ijJtd, J = 7.5, 1.3 Hz, 1 H), 7.35-7.24 (m, 4H), 7.13-7.10 (m, 2H), 3.76 (dd, J = 8.8, 7.6 Hz, 1 H), 3.17-3.00 (m, 2H), 2.41 -2.36 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 197.8, 144.1 , 138.4, 133.8, 132.9, 132.8, 130.0, 129.0, 128.8, 128.0, 127.0, 54.0, 31.3, 29.1. GCMS (El): calcd for C16H13CIO M: 256.07. Found: 256.02.
[00178] Synthesis of the compound of formula:
Figure imgf000043_0001
[00179] (S)-2-(p-Fluorophenyl)-1-tetralone. The reaction finished within 3 hours at 25 °C. Some 1 -tetralone coeluted with the desired coupling product during flash chromatography (1 :40 EA/hexane). It was removed afterwards by washing the solid with cold n-pentane. The titled compound was obtained as white solid (1 13 mg, 94% yield).
[00180] Ee of the purified products was determined to be 93% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 20.1 min (minor) and 21.8 min (major).
[00181] [a] 0D = +15.3° (c = 1.0, CHCI3) for a sample of 93% ee.
[00182] 1H NMR (400 MHz, CDCI3): δ 8.10 (d, J = 7.8 Hz, 1 H), 7.52 (iptd, J = 7.5, 1 .2 Hz, 1 H), 7.35 (ψί, J = 7.6 Hz, 1 H), 7.30 (d, J = 7.7 Hz, 1 H), 7.18-7.14 (m, 2H), 7.07-7.01 (m, 2H), 3.82-3.75 (m, 1 H), 3.19-3.02 (m, 2H), 2.44-2.36 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 198.1 , 162.0 (d, JCF = 244.0 Hz), 144.1 , 135.6 (d, JCF = 3.4 Hz), 133.7, 132.8, 130.1 (d, JCF = 8.1 Hz), 129.0, 128.0, 127.0, 1 15.5 (d, JCF = 21 .4 Hz), 53.9, 31 .4, 29.1. 19F NMR (376 MHz, CDCI3): δ -1 16.0. GCMS (El): calcd for Ci6H13FO M: 240.10. Found: 240.05.
[00183] Synthesis of the compound of formula:
Figure imgf000043_0002
[00184] (S)-2-(2-Naphthyl)-1-tetralone. The reaction finished within 3 hours at 25 °C. Some 1 -tetralone coeluted with the desired coupling product during flash chromatography (1 :40 EA/hexane). It was removed afterwards by washing the solid with cold n-pentane. The titled compound was obtained as white solid (131 mg, 96% yield).
[00185] Ee of the purified products was determined to be 91 % based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 17.1 min (minor) and 35.1 min (major).
[00186] [a]20D = +10.0° (c = 1.0, CHCI3) for a sample of 91% ee.
[00187] 1H NMR (400 MHz, CDCI3): δ 8.20 (d, J = 7.8 Hz, 1 H), 7.89-7.81 (m, 3H), 7.69 (s, 1 H), 7.55 (i|Jtd, J = 7.5, 1.2 Hz, 1 H), 7.52-7.47 (m, 2H), 7.42-7.36 (m, 2H), 7.32 (d, J = 7.6 Hz, 1 H), 3.99 (dd, J= 1 1.2, 4.8 Hz, 1 H), 3.21-3.05 (m, 2H), 2.62-2.46 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 198.4, 144.2, 137.5, 133.6, 133.0, 132.6, 129.0, 128.2, 127.90, 127.88, 127.76, 127.2, 126.91 , 126.86, 126.1 , 125.8, 54.6, 31.3, 29.0. GCMS (El): calcd for C20Hi6O M: 272.12. Found: 272.09.
[00188] Synthesis of the compound of formula:
Figure imgf000044_0001
[00189] (S)-2-(1-Naphthyl)-1-tetralone. The reaction finished within 3 hours at 25 °C. Some 1 -tetralone coeluted with the desired coupling product during flash chromatography (1 :40 EA/hexane). It was removed afterwards by washing the solid with cold n-pentane. The titled compound was obtained as white solid (133 mg, 98% yield).
[00190] Ee of the purified products was determined to be 90% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 21.6 min (minor) and 42.4 min (major).
[00191] [a]20 D = -34.7° (c = 1.0, CHCI3) for a sample of 90% ee.
[00192] H NMR (400 MHz, CDCI3): δ 8.16 (d, J = 7.8 Hz, 1 H), 7.90-7.85 (m, 2H), 7.78 (d, J = 8.2 Hz, 1 H), 7.54 (qjtd, J = 7.5, 1.2 Hz, 1 H), 7.49-7.45 (m, 2H), 7.42-7.36 (m, 2H), 7.33 (d, J = 7.6 Hz, 1 H), 7.26 (d, J = 7.0 Hz, 1 H), 4.54 (dd, J = 10.8, 4.6 Hz, 1 H), 3.21 -3.04 (m, 2H), 2.70-2.60 (m, 1 H), 2.52-2.46 (m, 1 H). 3C NMR (100 MHz, CDCI3): δ 198.4, 144.3, 136.7, 134.3, 133.7, 133.3, 131.9, 129.2, 129.0, 128.0, 127.9, 127.0, 126.2, 125.71 , 125.66, 125.6, 123.9, 51.3, 30.8, 29.2. GCMS (El): calcd for C20H16O M: 272.12. Found: 272.09.
[00193] Synthesis of the compound of formula:
Figure imgf000045_0001
[00194] (S)-2-(o-Anisyl)-1-tetralone. The reaction finished after 24 hours at 25 °C. The titled compound was obtained as white solid (122 mg, 97% yield) by flash chromatography using EA/hexane (1 :30) as eluent.
[00195] Ee of the purified products was determined to be 91% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL min). TR = 15.4 min (minor) and 19.6 min (major).
[00196] [a]20 D = +-8.6° (c = 1.0, CHCI3) for a sample of 91 % ee.
[00197] 1H NMR (400 MHz, CDCI3): δ 8.10 (dd, J= 7.8, 1.0 Hz, 1 H), 7.48 (i|Jtd, J = 7.5, 1.4 Hz, 1 H), 7.33 J = 7.7 Hz, 1 H), 7.29-7.23 (m, 2H), 7.54 (dd, J = 7.4, 1.6 Hz, 1 H), 6.95- 6.90 (m, 2H), 4.05 (dd, J = 12.3, 4.7 Hz, 1 H), 3.74 (s, 3H), 3.16-2.98 (m, 2H), 2.55-2.44 (m, 1 H), 2.30-2.24 (m, 1 H). 13C NMR (100 MHz, CDCI3): δ 198.3, 157.3, 144.3, 133.4, 133.3, 129.6, 129.5, 128.9, 128.4, 127.8, 126.8, 120.9, 111.3, 55.7, 50.2, 30.2, 29.7. GCMS (El): calcd for d7H1602 M: 252.12. Found: 252.05.
[00198] Synthesis of the compound of formula:
Figure imgf000045_0002
[00199] (S)-2-(m-Anisyl)-1-tetralone. The reaction finished within 2 hours at 25 °C. The titled compound was obtained as white solid (123 mg, 98% yield) by flash chromatography using EA/hexane (1 :30) as eluent.
[00200] Ee of the purified products was determined to be 91 % based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mlJmin). TR = 17.1 min (minor) and 29.0 min (major).
[00201] [a]20D = +3.7° (c = 1.0, CHCI3) for a sample of 91% ee.
[00202] 1H NMR (400 MHz, CDCI3): δ 8.02 (dd, J = 7.8, 1 .0 Hz, 1 H), 7.42 (l td, J = 7.5, 1 .4 Hz, 1 H), 7.25 (ψί, J = 7.6 Hz, 1 H), 7.20-7.16 (m, 2H), 6.75-6.67 (m, 3H), 3.72-3.68 (m, 4H), 3.07-2.93 (m, 2H), 2.38-2.32 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 198.2, 159.9, 144.2, 141.4, 133.6, 133.0, 129.7, 129.0, 128.0, 126.9, 121.0, 1 14.6, 1 12.4, 55.3, 54.6, 31 .3, 28.9.GCMS (El): calcd for C17H1602 M: 252.12. Found: 252.05.
[00203] Synthesis of the compound of formula:
Figure imgf000046_0001
[00204] (S)-2-(2-methyl-8-quinolinyl)-1-tetralone. The reaction finished within 8 hours at 25 °C. The titled compound was obtained as yellow oil (123 mg, 98% yield) by flash chromatography using EA/hexane (1 :20) as eluent.
[00205] Ee of the purified products was determined to be 94% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 18.6 min (minor) and 27.2 min (major).
[00206] 1H NMR (400 MHz, CDCI3): δ 8.14 (d, J = 7.8, 1 .0 Hz, 1 H), 8.01 (d, J= 8.4 Hz, 1 H), 7.70 (dd, J= 8.1 , 1.3 Hz, 1 H), 7.56-7.50 (m, 2H), 7.45 (ψί, J= 7.8 Hz, 1 H), 7.37 (ψ., J = 7.6 Hz, 1 H), 7.33 (d, J = 7.6 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 4.96 (dd, J = 12.2, 4.7 Hz, 1 H), 3.30-3.22 (m, 1 H), 3.06 (lydt, J = 16.4, 3.9 Hz, 1 H), 2.73 (ddd, J = 16.4, 12.4, 4.0 Hz, 1 H), 2.53 (s, 3H), 2.43-2.36 (m, 1 H). 13C NMR (100 MHz, CDCI3): δ 199.4, 157.9, 145.6, 144.2, 139.8, 136.4, 134.0, 133.0, 129.0, 128.8, 127.8, 126.87, 126.80, 126.7, 125.6, 122.0, 50.8, 31.3, 29.8, 25.4. ESI-MS: calcd for C20H18NO (M+H)+: 288.14. Found: 288.25.
[00207] Synthesis of the compound of formula:
Figure imgf000047_0001
[00208] (S)-2-(AA-Boc-5-indolyl)-1-tetralone. The reaction finished within 3 hours at 25 °C (judged by TLC). The titled compound was obtained as white foam (178 mg, 98% yield) by flash chromatography using EA/hexane (1 :40 to 1 :30) as eluent.
[00209] Ee of the purified products was determined to be 90% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 90:10; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 9.6 min (minor) and 18.3 min (major).
[00210] [a]20 D = +3.4° (c = 1.0, CHCI3) for a sample of 90% ee.
[00211] 1H NMR (400 MHz, CDCI3): δ 8.15-8.1 1 (m, 2H), 7.6 (d, J = 3.5 Hz, 1 H), 7.51 (qrtd, J = 7.5, 1.4 Hz, 1 H), 7.39-7.34 (m, 2H), 7.29 (d, J = 7.6 Hz, 1 H), 7.16 (dd, J = 8.6, 1.7 Hz, 1 H), 6.53 (d, J = 3.6 Hz, 1 H), 3.91 (dd, J = 10.2, 5.5 Hz, 1 H), 3.18-3.03 (m, 2H), 2.56- 2.44 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 198.8, 150.0, 144.3, 134.4, 134.3, 133.6, 133.1 , 131.0, 129.0, 128.0, 126.9, 126.3, 124.9, 120.7, 1 15.4, 107.5, 83.8, 54.4, 31.7, 29.0, 28.4. LC-MS (El): calcd for C23H24N03 M: 362.18. Found: 362.01.
[00212] (b) COUPLINGS OF ARYL BROMIDES WITH 4-TRI(W-BUTYL)STANNYLOXY-1 ,2-
DIHYDRONAPHTHALENE.
[00213] Synthesis of compounds of formula:
Figure imgf000047_0002
[00214] (S)-2-Phenyl-1-tetralone. The reaction was set up using phenyl bromide (78.5 mg, 0.50 mmol) and 4-tri(n-butyl)stannyloxy-1 ,2-dihydronaphthalene (0.75 mmol, 343 mg). The reaction finished after 12 hours at 25 °C. The titled compound was obtained as white solid (99 mg, 89% yield).
Ee of the purified products was determined to be 91% based by chiral HPLC analysis.
[00215] Synthesis of the compound of formula:
Figure imgf000048_0001
[00216] (S)-2-(p-Anisyl)-1-tetralone. The reaction was set up using Pd(OAc)2 (5.6 mg, 0.025 mmol), ligand L1 (22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), p-Anisyl bromide (94 mg, 0.50 mmol) and 4-tri(n-butyl)stannyloxy-1 ,2-dihydro- naphthalene (1.0 mmol, 458 mg). The reaction was stopped after 48 hours at 25 °C. The titled compound was obtained as white solid (113 mg, 90% yield) by flash chromatography using EA/hexane (1 :30) as eluent.
[00217] Ee of the purified products was determined to be 92% based by chiral HPLC analysis.
[00218] Synthesis of the compound of formula:
Figure imgf000048_0002
[00219] (S)-2-(4-Methylbenzoate)-1-tetralone. The reaction finished within 6 hours. The titled compound was obtained as white solid (137 mg, 98% yield) by flash chromatography using EA/hexane (1 :10) as eluent. [00220] Ee of the purified products was determined to be 92% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mlJmin). TR = 26.7 min (minor) and 36.2 min (major).
[00221] [a]20 D = +17.7° (c = 1.0, CHCI3) for a sample of 92% ee.
[00222] 1H NMR (300 MHz, CDCI3): δ 8.09 (d, J = 7.8 Hz, 1 H), 8.02 (d, J = 8.2 Hz, 2H), 7.52 (ψί, J = 7.4 Hz, 1 H), 7.35 (ψί, J = 7.6 Hz, 1 H), 7.30-7.26 (m, 3H), 3.91 (s, 3H), 3.86 (dd, J =9.7, 6.7 Hz, 1 H), 3.21 -3.00 (m, 2H), 2.48-2.40 (m, 2H). 13C NMR (75 MHz, CDCI3): δ 197.4, 167.0, 145.1 , 143.9, 133.6, 132.6, 129.8, 128.9, 128.6, 127.8, 126.9, 54.5, 52.0, 31.0, 28.8. GCMS (El): calcd for C18H1603 M: 280.11. Found: 280.08.
[00223] Synthesis of the compound of formula:
Figure imgf000049_0001
[00224] (S)-2-(o-Anisyl)-1-tetralone. The reaction was set up with Pd(OAc)2 (5 mol%, 5.6 mg, 0.025 mmol), ligand L1 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), o-anisyl bromide (93.5 mg, 0.50 mmol) and 4-tri(n-butyl)stannyloxy-1 ,2- dihydronaphthalene (1.0 mmol, 458 mg). The reaction finished after 48 hours at 25 °C. The titled compound was obtained as white solid (121 mg, 96% yield) by flash chromatography using EA/hexane (1 :30) as eluent.
[00225] Ee of the purified products was determined to be 91 % based by chiral HPLC analysis.
[00226] Synthesis of the compound of formula:
Figure imgf000049_0002
[00227] (S)-2-(1-Naphthalene)-1-tetralone. The reaction finished after 20 hours. The titled compound was obtained as white solid (133 mg, 98% yield).
[00228] Ee of the purified products was determined to be 90% based by chiral HPLC analysis.
[00229] Synthesis of the compound of formula:
Figure imgf000050_0001
[00230] (S)-W-Boc-2-(5-indolyl)-1-tetralone. The reaction was set up with Pd(OAc)2 (5 mol%, 5.6 mg, 0.025 mmol), ligand L1 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), A/-Boc-5-bromoindole (148 mg, 0.50 mmol) and 4-tri(n-butyl)stannyloxy-1 ,2- dihydronaphthalene (0.75 mmol, 343 mg). The reaction finished after 24 hours at 25 °C (judged by TLC). The titled compound was obtained as white solid (175 mg, 97% yield).
[00231] Ee of the purified products was determined to be 90% based by chiral HPLC analysis.
[00232] Synthesis of the compound of formula:
Figure imgf000050_0002
[00233] (S)-2-(3-Thienyl)-1-tetralone. The reaction was set up with Pd(OAc)2 (5 mol%, 5.6 mg, 0.025 mmol), ligand L1 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), 3-bromothiophlene (81.5 mg, 0.50 mmol) and 4-tri(/7-butyl)stannyloxy-1 ,2- dihydronaphthalene (0.75 mmol, 343 mg). The reaction finished after 48 hours at 25 °C. The titled compound was obtained as white solid (95 mg, 83% yield) by flash chromatography using EA/hexane (1 :50) as eluent. [00234] Ee of the purified products was determined to be 89% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mlJmin). TR = 5.6 min (minor) and 6.3 min (major).
[00235] [a]20D = +4.9° (c = 0.7, CHCI3) for a sample of 89% ee.
[00236] 1H NMR (400 MHz, CDCI3): δ 8.09 (d, J = 7.8 Hz, 1 H), 7.49 (ijJtd, J = 7.6, 1.0 Hz, 1 H), 7.34-7.30 (m, 2H), 7.25 (d, J = 7.4 Hz, 1 H), 7.05 (d, J = 2.7 Hz, 1 H), 7.02 (d, J = 5.0 Hz, 1 H), 3.92 (dd, J =9.5, 5.0 Hz, 1 H), 3.06-3.04 (m, 2H), 2.50-2.37 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 197.6, 144.1 , 139.3, 133.7, 132.7, 128.9, 128.0, 127.9, 127.0, 125.7, 121.8, 49.5, 30.6, 28.4. GCMS (El): calcd for CuHi2OS M: 228.06. Found: 228.02.
[00237] Synthesis of the compound of formula:
Figure imgf000051_0001
[00238] (S)-2-(2-Methyl-5-benzothiazolyl)-1-tetralone. The reaction was set up with Pd(OAc)2 (5 mol%, 5.6 mg, 0.025 mmol), ligand L1 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), 5-bromo-2-methylbenzothiazole (114 mg, 0.50 mmol) and 4- tri(n-butyl)stannyloxy-1 ,2-dihydronaphthalene (0.75 mmol, 343 mg). The reaction finished after 48 hours at 25 °C. The titled compound was obtained as white solid (132 mg, 90% yield) by flash chromatography using EA/hexane (1 :5) as eluent.
[00239] Single crystals suitable for X-ray diffractional analysis were obtained by vapor diffusion of n-pentane into a concentrated solution in dichloromethane at RT. Ee of the sample was improved to 97% after crystallization. The absolute configuration of the major enantiomer was determined to be (S).
[00240] Ee of the purified product was determined to be 88% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 6.6 min (minor) and 8.6 min (major).
[00241] [a]20 D = +17.6° (c = 1.0, CHCI3) for a sample of 97% ee.
[00242] 1H NMR (400 MHz, CDCI3): δ 8.10 (d, J = 7.8 Hz, 1 H), 7.79-7.76 (m, 2H), 7.52-7.48 (m, 1 H), 7.36-7.26 (m, 2H), 7.21-7.18 (m, 1 H), 3.96-3.91 (m, 1 H), 3.15-3.03 (m, 2H), 2.81 (d, J = 5.5 Hz, 3H), 2.53-2.45 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 198.1 , 167.5, 153.9, 144.2, 138.0, 134.4, 133.7, 133.0, 129.0, 128.05, 128.03, 127.0, 125.7, 122.2, 121.5, 54.4, 31.4, 28.9, 20.3. ESIMS: calcd for Ci8H16NOS M: 294.10. Found: 294.30.
(c) COUPLINGS OF ARYL CHLORIDES WITH 4-TRI(W-BUTYL)STANNYLOXY-1 ,2-DIHYDRO
NAPHTHALENE.
[00243] Synthesis of the com ound of formula:
Figure imgf000052_0001
[00244] (S)-2-Phenyl-1-tetralone. The reaction was set up with Pd(OAc)2 (5 mol%, 5.6 mg, 0.025 mmol), ligand L1 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), phenyl chloride (56 mg, 0.50 mmol) and 4-tri(n-butyl)stannyloxy-1 ,2- dihydronaphthalene (0.75 mmol, 343 mg). The reaction finished after 36 hours at 25 °C. The titled compound was obtained as white solid (96 mg, 86% yield).
[00245] Ee of the purified products was determined to be 91 % based by chiral HPLC analysis.
[00246] Synthesis of the compound of formula:
Figure imgf000052_0002
[00247] (S)-2-(p-Anisyl)-1-tetralone. The reaction was set up with Pd(OAc)2 (5.6 mg, 0.025 mmol), ligand 2 (22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), p-anisyl chloride (71 mg, 0.50 mmol) and 4-tri(n-butyl)stannyloxy-1 ,2-dihydro-naphthalene (1.0 mmol, 458 mg). The reaction was stopped after 48 hours at 25 °C. The titled compound was obtained as white solid (77 mg, 61 % yield). [00248] Ee of the purified products was determined to be 92% based by chiral HPLC analysis.
[00249] Synthesis of the compound of formula:
Figure imgf000053_0001
[00250] (S)-2-(4-Methylbenzoate)-1-tetralone. The reaction finished after 6 hours at 25 °C. The titled compound was obtained as white solid (134 mg, 96% yield).
[00251 ] Ee of the purified products was determined to be 92% based by chiral HPLC analysis.
[00252] Synthesis of the compound of formula:
Figure imgf000053_0002
[00253] (S)-2-(/V-Boc-5-indolyl)-1-tetralone. The reaction was set up with Pd(OAc)2 (5 mol%, 5.6 mg, 0.025 mmol), ligand 2 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), A/-Boc-5-chloroindole (125.7 mg, 0.50 mmol) and 4-tri(n-butyl)stannyloxy-1 ,2- dihydronaphthalene (0.75 mmol, 343 mg). The reaction finished after 48 hours at 25 °C (judged by TLC). The titled compound was obtained as white solid (166 mg, 92% yield).
[00254] Ee of the purified products was determined to be 90% based by chiral HPLC analysis.
[00255] 2) EXAMPLES OF COUPLINGS WITH 1 -TRI(W-BUTYL)STANNYLOXY-1-CYCLOHEXENE.
[00256] Synthesis of 1-tri(n-butyl)stannyloxy-1-cyclohexene. Under argon, 1 - cyclohexenyl acetate (3.0 g, 21.3 mmol) and tri(n-butyl)tin methoxide (6.54 g, 20.4 mmol) were stirred at 25 °C for 12 hours unitl the latter was fully consumed (checked by H NMR spectroscopy). The byproduct, methyl acetate was removed under vacuum and the purity of the tin enolate was assessed to be 90% by 1H NMR spectroscopy. The tin enolate was used directly without purification in the coupling reaction.
[00257] a) EXAMPLES OF COUPLINGS OF ARYL TRIFLATES WITH 1 -TRI(W-
BUTYL)STANNYLOXY-1 -CYCLOHEXENE.
[00258] Synthesis of the comp la:
Figure imgf000054_0001
[00259] (S)-2-Phenylcyclohexanone [CAS No: 34281-94-2]. The reaction was set up with phenyl triflate (1 13 mg, 0.50 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (0.60 mmol, 258 mg, 90% purity). The reaction finished after 6 hours at 25 °C. The titled compound was obtained as white solid (84 mg, 96% yield) by flash chromatography using EA/hexane (1 :20) as eluent.
[00260] Ee of the purified products was determined to be 90% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: -PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 11.2 min (minor) and 12.2 min (major).
[00261] [a]20 D = -91.3° (c = 1.0, CHCI3) for a sample of 90% ee.
[00262] 1H NMR (400 MHz, CDCI3): δ 7.36-7.32 (m, 2H), 7.28-7.23 (m, 1 H), 7.15-7.13 (m, 2H), 3.61 (dd, J = 12.2, 5.4 Hz, 1 H), 2.55-2.45 (m, 2H), 2.29-2.25 (m, 1 H), 2.17-2.14 (m, 1 H), 2.06-1.98 (m, 2H), 1.86-1.79 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 210.5, 138.9, 128.7, 128.5, 127.1 , 57.6, 42.4, 35.3, 28.0, 25.5. GC-MS (El): calcd for Ci2H140 M: 174.10. Found: 174.07.
[00263] Synthesis of the compound of formula:
Figure imgf000054_0002
[00264] (S)-2-(p-Anisyl)cyclohexanone [CAS No: 211996-56-4]. The reaction finished after 24 hours at 25 °C. The titled compound was obtained as white solid (96 mg, 94% yield) by flash chromatography using EA/hexane (1 :10) as eluent.
[00265] Ee of the purified products was determined to be 91 % by chiral HPLC analysis (Daicel CHIRALCEL IC-H; hexanes: /-PrOH = 80:20; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 21.3 min (major) and 22.5 min (minor).
[00266] [a]20o = -83.7° (c = 1.0, CHCI3) for a sample of 91 % ee.
[00267] 1H NMR (400 MHz, CDCI3): δ 7.06 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 3.80 (s, 3H), 3.57 (dd, J = 12.2, 5.4 Hz, 1 H), 2.55-2.41 (m, 2H), 2.28-2.24 (m, 1 H), 2.18- 2.12 (m, 1 H), 2.05-1.95 (m, 2H), 1.88-1.78 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 210.8, 158.6, 131.0, 129.6, 1 14.0, 56.7, 55.4, 42.4, 35.5, 28.0, 25.6. GCMS (El): calcd for Ci3H1602 M: 204.12. Found: 204.05.
[00268] Synthesis of the compound of formula:
Figure imgf000055_0001
[00269] (S)-2-(p-Chlorophenyl)cyclohexanone [CAS No: 643760-72-9] (Cheon, C. H.; Yamamoto, H. J. Am. Chem. Soc. 2008, 130, 9246). The reaction finished after 9 hours. The titled compound was obtained as white solid (100 mg, 96% yield) by flash chromatography using EA/hexane (1 :20) as eluent.
[00270] Ee of the purified products was determined to be 92% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 12.3 min (minor) and 13.8 min (major).
[00271] [a]20 D = +76.0° (c = 1.0, CHCI3) for a sample of 92% ee.
[00272] H NMR (400 MHz, CDCI3): δ 7.30 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 3.59 (dd, J = 12.2, 5.3 Hz, 1 H), 2.55-2.41 (m, 2H), 2.28-2.24 (m, 1 H), 2.19-2.15 (m, 1 H), 2.01 -1.92 (m, 2H), 1 .88-1.79 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 209.9, 137.4, 132.9, 130.1 , 128.7, 57.0, 42.4, 35.4, 28.0, 25.6. GC-MS (El): calcd for d2H13CIO M: 208.07. Found: 208.01 . [00273] Synthesis of the compound of formula:
Figure imgf000056_0001
[00274] (S)-2-(o-Anisyl)cyclohexanone [CAS No: 1042326-48-6] (Ling, H. Z.; Xie, C. Chin. J. Syn. Chem. 2006, 17, 170). The reaction was set up with Pd(OAc)2 (5.6 mg, 0.025 mmol), ligand L1 (22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), o-anisyl triflate (128 mg, 0.50 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (1.5 mmol, 645 mg, 90% purity). The reaction finished after 72 hours at 25 °C. The titled compound was obtained as white solid (86 mg, 85% yield) by flash chromatography using EA/hexane (1 :15) as eluent.
[00275] Ee of the purified products was determined to be 94% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 13.7 min (major) and 17.7 min (minor).
[00276] [a]20 D = -25.6° (c = 1.0, CHCI3) for a sample of 94% ee.
[00277] 1H NMR (400 MHz, CDCI3): δ 7.24 (iptd, J = 8.2, 1 .6 Hz, 1 H), 7.1 1 (d, J = 7.5 Hz, 1 H), 6.95 (ipt, J = 7.5 Hz, 1 H), 6.88 (d, J = 8.2 Hz, 1 H), 3.94 (dd, J = 12.5, 5.3 Hz, 1 H), 3.77 (s, 3H), 2.52-2.49 (m, 2H), 2.23-2.14 (m, 2H), 2.07-1.99 (m, 2H), 1.85-1.77 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 210.1 , 157.1 , 128.9, 128.2, 128.1 , 120.7, 1 10.7, 55.6, 51.2, 42.5, 33.6, 27.8, 25.9. GC-MS (El): calcd for Ci3H1602 M: 204.12. Found: 204.05.
[00278] Synthesis of the compound of formula:
Figure imgf000056_0002
[00279] (S)-2-(m-Acetylphenyl)cyclohexanone. The reaction finished after 6 hours at RT. The titled compound was obtained as white solid (106 mg, 98% yield) by flash chromatography using EA/hexane (1 :4) as eluent. [00280] Ee of the purified products was determined to be 89% by chiral HPLC analysis (Daicel CHIRALCEL ID-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 12.2 min (major) and 14.3 min (minor).
[00281 ] [a]20 D = -82.6° (c = 1.0, CHCI3) for a sample of 89% ee.
[00282] 1H NMR (400 MHz, CDCI3): δ 7.84 (d, J = 7.7 Hz, 1 H), 7.73 (s, 1 H), 7.43 (ψί, J = 7.7 Hz, 1 H), 7.34 (d, J = 7.7 Hz, 1 H), 3.94 (dd, J = 12.4, 5.3 Hz, 1 H), 2.59 (s, 3H), 2.56- 2.44 (m, 2H), 2.32-2.28 (m, 1 H), 2.21 -2.17 (m, 1 H), 2.08-2.02 (m, 2H), 1.99-1 .81 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 209.9, 198.3, 139.6, 137.4, 133.7, 128.7, 128.6, 127.3, 57.5, 42.4, 35.4, 27.9, 26.8, 25.6. GC-MS (El): calcd for Ci4H1602 M: 216.12. Found: 216.08.
[00283] Synthesis of the compound of formula:
Figure imgf000057_0001
[00284] (S)-2-(1-Naphthyl)cyclohexanone [CAS No: 643760-73-0] (Beck, E. M.; Hyde, A. M.; Jacobsen, E. N. Org. Lett. 201 1 , 13, 4260). The reaction finished after 20 hours. The titled compound was obtained as white solid (101 mg, 90% yield) by flash chromatography using EA/hexane (1 :20) as eluent.
[00285] Ee of the purified products was determined to be 91 % by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 90:10; detection wavelengths = 254 nm and 227 nm; flow rate = 1 .0 mL/min). TR = 9.2 min (major) and 1 1 .4 min (minor).
[00286] [a]20 D = -3.4° (c = 1 .0, CHCI3) for a sample of 91% ee.
[00287] 1H NMR (400 MHz, CDCI3): δ 7.89-7.87 (m, 1 H), 7.80 (d, J = 8.2 Hz, 1 H), 7.75-7.73 (m, 1 H), 7.51 -7.46 (m, 3H), 7.38 (d, J = 7.1 Hz, 1 H), 3.38 (dd, J = 12.6, 5.3 Hz, 1 H), 2.71 -2.62 (m, 2H), 2.46-2.39 (m, 1 H), 2.34-2.24 (m, 2H), 2.17-2.12 (m, 1 H), 2.09-1.98 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 210.2, 135.4, 134.0, 132.0, 129.2, 127.8, 126.1 , 125.56, 125.52, 125.49, 123.5, 53.5, 42.8, 34.5, 28.1 , 26.1. GC-MS (El): calcd for Ci6H160 M: 224.12. Found: 224.06.
[00288] Synthesis of the compound of formula:
Figure imgf000058_0001
[00289] (S)-2-(3,4-Dihydro-1-naphthyl)cyclohexanone. The reaction finished after 20 hours at RT. The titled compound was obtained as white solid (100 mg, 88% yield) by flash chromatography using EA/hexane (1 :20) as eluent. Ee of the purified products was determined to be 90% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 imL/min). TR = 12.3 min (major) and 15.7 min (minor).
[00290] [a]20 D = -29.4° (c = 1.0, CHCI3) for a sample of 90% ee.
[00291] 1H NMR (400 MHz, CDCI3): δ 7.13-7.08 (m, 3H), 6.91 -6.89 (m, 1 H), 5.92 (t, J = 4.6 Hz, 1 H), 3.61 (dd, J = 1 1.8, 5.0 Hz, 1 H), 2.80-2.72 (m, 2H), 2.54-2.50 (m, 2H), 2.38- 2.14 (m, 4H), 2.04-1.98 (m, 2H), 1.83-1.77 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 21 1.1 , 136.7, 134.9, 134.7, 127.9, 126.80, 126.77, 126.4, 122.8, 53.8, 42.8, 33.2, 28.4, 28.3, 25.8, 23.3. GC-MS (El): calcd for Ci6H180 M: 226.14. Found: 226.09.
[00292] Synthesis of the compound of formula:
Figure imgf000058_0002
[00293] (S)-2-(/V-Boc-5-indolyl)cyclohexanone. The reaction finished after 10 hours at RT (judged by TLC). The titled compound was obtained as white solid (150 mg, 96% yield) by flash chromatography using EA/hexane (1 :15) as eluent.
[00294] Ee of the purified products was determined to be 91 % by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 17.9 min (minor) and 24.0 min (major).
[00295] [a]20 D = -61.4° (c = 1.0, CHCI3) for a sample of 91 % ee. [00296] 1H NMR (400 MHz, CDCI3): δ 8.1 1 (d, J = 8.1 Hz, 1 H), 7.59 (d, J = 3.3 Hz,
1 H), 7.35 (s, 1 H), 7.10 (d, J = 8.6 Hz, 1 H), 6.54 (d, J = 3.7 Hz, 1 H), 3.71 (dd, J = 12.1 , 5.4 Hz, 1 H), 2.57-2.45 (m, 2H), 2.33-2.30 (m, 1 H), 2.18-2.00 (m, 3H), 1 .90-1.82 (m, 2H), 1.67 (s, 9H). 13C NMR (100 MHz, CDCI3): δ 210.9, 150.0, 133.3, 130.9, 126.2, 125.1 , 120.8, 1 15.2, 107.5, 83.7, 57.5, 42.4, 35.6, 28.4, 28.1 , 25.6. ESIMS: calcd for C19H24NO3 M: 314.18. Found: 313.95.
[00297] (b) EXAMPLES OF COUPLING WITH ARYL BROMIDES WITH 1 -TRI(W- BUTYL)STANNYLOXY-1 -CYCLOHEXENE
[00298] Synthesis of the compound of formula:
Figure imgf000059_0001
[00299] (S)-2-Phenylcyclohexanone. The reaction was set up with phenyl bromide (78.5 mg, 0.50 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (0.75 mmol, 323 mg, 90% purity). The reaction finished after 44 hours at 25 °C. The titled compound was obtained as white solid (80 mg, 93% yield) by flash chromatography using EA/hexane (1 :20) as eluent.
[00300] Ee of the purified products was determined to be 90% based by chiral HPLC analysis.
[00301 ] Synthesis of the compound of formula:
Figure imgf000059_0002
[00302] (S)-2-(2-Methyl-5-benzothiazolyl)cyclohexanone. The reaction was set up with Pd(OAc)2 (5 mol%, 5.6 mg, 0.025 mmol), ligand L1 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), 2-methyl-5-bromobenzothiazole (1 14 mg, 0.50 mmol) and 1 - tri(n-butyl)stannyloxy-1 -cyclohexene (1.0 mmol, 430 mg, 90% purity). The reaction finished after 48 hours at 25 °C. The titled compound was obtained as white solid (102 mg, 83% yield) by flash chromatography using EA/hexane (1 :4) as eluent.
[00303] Ee of the purified products was determined to be 88% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 95:5; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 16.3 min (minor) and 19.8 min (major).
[00304] [a]20 D = -75.4° (c = 1.0, CHCI3) for a sample of 88% ee.
[00305] 1H NMR (400 MHz, CDCI3): δ 7.77 (d, J = 8.3 Hz, 1 H), 7.72 (s, 1 H), 7.13 (d, J = 8.3 Hz, 1 H), 3.75 (dd, J = 12.3, 5.4 Hz, 1 H), 2.82 (s, 3H), 2.58-2.45 (m, 2H), 2.35-2.32 (m, 1 H), 2.19-2.03 (m, 3H), 1.91 -1.83 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 210.3, 167.3, 153.9, 137.2, 134.4, 125.8, 122.3, 121.3, 57.5, 42.4, 35.5, 28.0, 25.6, 20.3. ESIMS: calcd for Ci4H16NOS M: 246.10. Found: 246.27.
[00306] (c) EXAMPLES OF COUPLING OF ARYL CHLORIDES AND 1 -TRI(W-
BUTYL)STANNYLOXY-1 -CYCLOHEXENE
[00307] Synthesis of the compound of formula:
Figure imgf000060_0001
[00308] (S)-2-Phenylcyclohexanone. The reaction was set up with Pd(OAc)2 (5 mol%, 5.6 mg, 0.025 mmol), ligand L1 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), phenyl chloride (56 mg, 0.50 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (1.0 mmol, 430 mg, 90% purity). The reaction finished after 48 hours at 50 °C. The titled compound was obtained as white solid (78 mg, 90% yield) by flash chromatography using EA/hexane (1 :20) as eluent. Ee of the purified products was determined to be 88% based by chiral HPLC analysis.
[00309] Synthesis of the compound of formula:
Figure imgf000061_0001
[00310] (S)-2-(4-Methylbenzoate)cyclohexanone [CAS No: 1316848-62-0] Micovic, I. V.; Ivanovic, M. D.; Piatak, D. M.; Bojic, V. D. Synthesis 1991 , 1991, 1043). The reaction finished after 20 hours at 25 °C. The titled compound was obtained as white solid (115 mg, 98% yield) by flash chromatography using EA/hexane (1 :10) as eluent.
[00311] Ee of the purified products was determined to be 92% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 10.9 min (minor) and 3.0 min (major).
[00312] [a]20 D = -71.6° (c = 1.0, CHCI3) for a sample of 92% ee.
[00313] 1H NMR (400 MHz, CDCI3): δ 8.00 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 8.2 Hz, 2H), 3.90 (s, 3H), 3.67 (dd, J = 12.2, 5.3 Hz, 1 H), 2.56-2.43 (m, 2H), 2.30-2.26 (m, 1 H), 2.19- 2.16 (m, 1 H), 2.07-1.98 (m, 2H), 1.88-1.80 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 209.6, 167.2, 144.2, 129.8, 129.0, 128.9, 57.6, 52.2, 42.4, 35.2, 27.9, 25.5. GC-MS (El): calcd for C14H1603 M: 232.11. Found: 232.05.
[00314] 3) EXAMPLES OF COUPLINGS OF ARYL TRIFLATES WITH OTHER TIN ENOLATES.
[00315] Synthesis of 4-tri(n-butyl)stannyloxy-7-methoxy-1 ,2-dihydronaphthalene.
7-Methoxy-1 ,2-dihydro-4-naphthyl acetate (1.00 g, 4.59 mmol) and tri(n-butyl)tin methoxide (1.40 g, 4.37 mmol) were stirred at 25 °C for 12 hours. After methyl acetate was removed under vacuum, the purity of the tin enolate was estimated to be 90% by 1H NMR spectroscopy. The tin enolate was used directly in the coupling reaction.
[00316] Synthesis of the compound of formula:
Figure imgf000062_0001
[00317] (S)-2-Phenyl-6-methoxy-1-tetralone. The reaction was set up with phenyl triflate (1 13 mg, 0.50 mmol) and 4-tri(/T-butyl)stannyloxy-7-methoxy-1 ,2-dihydronaphehalene (0.6 mmol, 310 mg, 90% purity). The reaction finished after 2 hours at 25 °C. The titled compound was obtained as white solid (124 mg, 98% yield) by flash chromatography using EA/hexane (1 :10) as eluent.
[00318] Ee of the purified products was determined to be 90% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 8.1 min (minor) and 10.8 min (major).
[00319] [a]20D = +24.0° (c = 1.0, CHCI3) for a sample of 90% ee.
[00320] 1H NMR (400 MHz, CDCI3): δ 8.08 (d, J = 8.8 Hz, 1 H), 7.35-7.32 (m, 2H), 7.26 (t, J = 7.5 Hz, 1 H), 7.19 (d, J = 7.3 Hz, 2H), 6.86 (dd, J = 8.8, 2.4 Hz, 1 H), 6.73 (d, J = 2.0 Hz, 1 H), 3.88 (s, 3H), 3.77 (i|rt, J = 7.7 Hz, 1 H), 3.09-2.97 (m, 2H), 2.43-2.38 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 197.2, 163.8, 146.8, 140.3, 130.5, 128.71 , 128.65, 127.0, 126.8, 1 13.5, 1 12.8, 55.7, 54.2, 31.5, 29.2. GCMS: calcd for Ci7H1602 M: 252.12. Found: 252.08.
[00321] Synthesis of the compound of formula:
Figure imgf000062_0002
[00322] Synthesis of 6-Fluoro-1 ,2-dihydro-4-naphthyl acetate. Under argon, a 50- ml_ two-necked RBF was charged with p-toluenesulfonic acid monohydrate (46 mg, 0.24 mmol), 7-fluoro-1 -tetralone (2.0 g, 12.2 mmol) and distilled isopropenyl acetate (10 mL). The whole mixture was heated in a 1 10 °C oil bath and the acetone byproduct was distilled off continuously. The reaction was monitored by TLC and stopped after 30 hours. After cooling to room temperature, the crude mixture was filtered through a short pad of silica gel with diethyl ether washings (30 mL). The filtrate was concentrated on a rotary evaporator and the resulting residue was purified by flash chromatography using EA/hexane (1 :20) as eluent. The titled compound was obtained as white solid (2.26 g, 90% yield).
[00323] 1H NMR (400 MHz, CDCI3): δ 7.09 (dd, J = 8.2, 5.6 Hz, 1 H), 6.86 (i|Jtd, J = 8.5, 2.6 Hz, 1 H), 6.80 (dd, J = 9.6, 2.6 Hz, 1 H), 5.77 (t, J = 4.6 Hz, 1 H), 2.82 (t, J = 8.3 Hz, 2H), 2.45 (td, J = 8.3, 4.6 Hz, 1 H), 2.30 (s, 3H). 13C NMR (100 MHz, CDCI3): δ 169.3, 162.0 (d, JCF = 242.9), 145.0 (d, JCF = 2.3), 132.4 (d, JCF = 7.8), 132.0 (d, JCF = 3.1 ), 129.0 (d, JCF = 7.8), 117.0, 114.4 (d, JCF = 21.4), 108.3 (d, J = 23.8), 26.8, 22.4, 21.0. 19F NMR (376 MHz, CDCI3): δ -116.4. GCMS (El): calcd for CizHnFOa M: 206.07. Found: 206.00.
[00324] Synthesis of 4-tri(n-butyl)stannyloxy-6-fluoro-1,2-dihydronaphehalene. 6-
Fluoro-1 ,2-dihydro-4-naphthyl acetate (1.0 g, 4.85 mmol) and tri(n-butyl)tin methoxide (1.48 g, 4.62 mmol) were stirred at 25 °C for 12 hours until full conversion of the latter. Methyl acetate was removed under vacuum and the purity of the tin enolate was estimated to be 90% by 1H NMR spectroscopy. The tin enolate was used directly in the coupling reaction.
[00325] Synthesis of the compound of formula:
Figure imgf000063_0001
[00326] (S)-2-Phenyl-7-fluoro-1-tetralone. The reaction was set up with phenyl triflate (113 mg, 0.50 mmol) and 4-tri(n-butyl)stannyloxy-7-fluoro-1 ,2-dihydronaphehalene (0.60 mmol, 302 mg, 90% purity). The reaction finished after 3 hours at 25 °C. The titled compound was obtained as white solid (116 mg, 97% yield) by flash chromatography using EA/hexane (1 :25) as eluent.
[00327] Ee of the purified products was determined to be 91% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 9.2 min (minor) and 13.4 min (major).
[00328] [a]20 D = +14.6° (c = 1.0, CHCI3) for a sample of 91 % ee.
[00329] 1H NMR (400 MHz, CDCI3): δ 7.75 (dd, J = 9.2, 2.8 Hz, 1 H), 7.37-7.33 (m, 2H), 7.30-7.25 (m, 2H), 7.22 (dd, J = 8.2, 2.8 Hz, 1 H), 7.19-7.17 (m, 2H), 3.79 (ipt, J = 8.1 Hz, 1 H), 3.10-3.00 (m, 2H), 2.46-2.40 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 197.4, 161 .8 (d, JCF = 246.2 Hz), 139.9 (d, JCF = 3.0 Hz), 139.5, 134.6 (d, JCF = 6.1 Hz), 130.8 (d, JCF = 7.2 Hz), 128.8, 128.6, 127.3, 121.0 (d, JCF = 22.3 Hz), 1 13.8 (d, JCF = 22.0 Hz), 54.2, 31.3, 28.3. 19F NMR (376 MHz, CDCI3): δ -1 15.0. GCMS: calcd for C16H13FO M: 240.10. Found: 240.06.
[00330] Synthesis of 1-tri(n-butyl)stannyloxy-4,4-dimethyl-1-cyclohexene.
[00331] 4,4-Dimethyl-1 -cyclohexene acetate (1.0 g, 5.95 mmol) and tri(n-butyl)tin methoxide (1.82 g, 5.67 mmol) were stirred at 25 °C for 12 hours. After removing the produced methyl acetate under vacuum, the purity of the tin enolate was assigned to be 95% by 1H NMR spectroscopy. The tin enolate was used directly in the coupling reaction.
[00332] Synthesis of the compound of formula:
Figure imgf000064_0001
[00333] (S)-2-(1-Naphthyl)-4,4-dimethylcyclohexanone. The reaction was set up with 1 -naphthyl triflate (138 mg, 0.50 mmol) and 1 -tri(n-butyl)stannyloxy-4,4-dimethyl-1 - cyclohexene (0.75 mmol, 328 mg, 95% purity). The reaction finished after 30 hours at 25 °C. The titled compound was obtained as white solid (1 15 mg, 91% yield) by flash chromatography using EA/hexane (1 :20) as eluent.
[00334] Ee of the purified products was determined to be 90% by chiral HPLC analysis (Daicel CHIRALCEL IC-H; hexanes: /-PrOH = 80:20; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 10.7 min (major) and 16.0 min (minor).
[00335] [a]20 D = -51.6° (c = 1.0, CHCI3) for a sample of 90% ee.
[00336] 1H NMR (400 MHz, CDCI3): δ 7.89-7.85 (m, 1 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.74-7.72 (m, 1 H), 7.51 -7.44 (m, 3H), 7.37 (dd, J = 7.2, 0.8 Hz, 1 H), 4.52 (dd, J = 13.4, 5.2 Hz, 1 H), 2.85-2.76 (m, 1 H), 2.52 (qjdt, J = 14.4, 3.8 Hz, 1 H), 2.25 (qrt, J = 13.4 Hz, 1 H), 2.07- 2.02 (m, 1 H), 1.93-1.89 (m, 2H), 1.42 (s, 3H), 1.14 (s, 3H). 13C NMR (100 MHz, CDCI3): δ 210.7, 135.3, 134.1 , 132.0, 129.3, 127.9, 126.1 , 125.9, 125.61 , 125.55, 123.3, 48.8, 47.2, 40.0, 39.0, 31.8, 31.5, 24.6. GC-MS (El): calcd for Ci8H20O M: 252.15. Found: 252.08.
[00337] Synthesis of the compound of formula:
Figure imgf000065_0001
[00338] (S)-2-(p-Methoxycarbonylphenyl)-4,4-dimethylcyclohexanone. The reaction was set up with p-methoxycarbonylphenyl triflate (142 mg, 0.50 mmol) and 1 -tri(n- butyl)stannyloxy-4,4-dimethyl-1-cyclohexene (0.75 mmol, 328 mg, 95% purity). The reaction finished after 8 hours at 25 °C. The titled compound was obtained as white solid (127 mg, 98% yield) by flash chromatography using EA/hexane (1 :10) as eluent.
[00339] Ee of the purified products was determined to be 89% by chiral HPLC analysis (Daicel CHIRALCEL IC-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mlJmin). TR = 18.6 min (major) and 22.0 min (minor).
[00340] [a]20 D = -57.0° (c = 1.0, CHCI3) for a sample of 89% ee.
[00341] 1H NMR (400 MHz, CDCI3): δ 8.01 -7.99 (m, 2H), 7.21 -7.19 (m, 2H), 3.90 (s, 3H), 3.79 (dd, J = 13.2, 5.9 Hz, 1 H), 2.68-2.60 (m, 1 H), 2.41 (ipdt, J = 14.3, 4.1 Hz, 1 H), 1.98 (qrt, J = 13.2 Hz, 1 H), 1.94-1.90 (m, 1 H), 1.84-1.80 (m, 2H), 1.32 (s, 3H), 1.08 (s, 3H). 13C NMR (100 MHz, CDCI3): δ 210.1 , 167.2, 144.3, 129.8, 129.1 , 129.0, 53.4, 52.2, 48.0, 39.9, 38.6, 31.6, 31.3, 24.5. GC-MS (El): calcd for C16H2o03 M: 260.14. Found: 260.07.
[00342] Synthesis of 1-tri(n-butyl)stannyloxy-1-cycloheptene.
[00343] 1 -Cycloheptenyl acetate (1.00 g, 6.51 mmol) and tri(n-butyl)tin methoxide (1.99 g, 6.21 mmol) were stirred at 25 °C for 12 hours. After methyl acetate was removed under vacuum, the purity of the tin enolate was estimated to be 95% by 1H NMR spectroscopy. The tin enolate was used directly in next step. [00344] Synthesis of the compound of formula:
Figure imgf000066_0001
[00345] (S)-2-Phenylcycloheptanone [CAS No: 60492-36-6] Beck, E. M.; Hyde, A. M.; Jacobsen, E. N. Org. Lett. 2011 , 13, 4260). The reaction was set up with phenyl triflate (1 13 mg, 0.50 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cycloheptene (0.75 mmol, 316 mg, 95% purity). The reaction finished after 3 hours at 25 °C. The titled compound was obtained as colorless oil (91 mg, 97% yield) by flash chromatography using EA/hexane (1 :30) as eluent.
[00346] Ee of the purified products was determined to be 89% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: -PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1 .0 mL/min). TR = 9.5 min (minor) and 12.8 min (major).
[00347] [a]20 D = -161.4° (c = 1.1 , CHCI3) for a sample of 89% ee.
[00348] 1H NMR (400 MHz, CDCI3): δ 7.31 -7.29 (m, 2H), 7.24-7.21 (m, 3H), 3.71 (dd, J = 11.4, 4.1 Hz, 1 H), 2.72-2.65 (m, 1 H), 2.54-2.49 (m, 1 H), 2.17-2.1 1 (m, 1 H), 2.05-1.91 (m, 4H), 1.68-1.59 (m, 1 H), 1.50-1.43 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 213.6, 140.6, 128.7, 128.0, 127.0, 59.0, 42.9, 32.2, 30.2, 28.7, 25.5. GC-MS (El): calcd for C13H160 M: 188.12. Found: 188.05.
[00349] Synthesis of tri(n-butyl)stannyloxy-2W-4-chromene.
[00350] 2 V-4-Chromenyl acetate (1 .88 g, 9.87 mmol) and tri(n-butyl)tin methoxide (3.01 g, 9.40 mmol) were stirred at 25 °C for 3 hours. After methyl acetate was removed under vacuum, the purity of the tin enolate was estimated to be 67% by 1H NMR spectroscopy. The tin enolate decomposed easily upon heating and was used directly in the coupling reaction.
[00351] Synthesis of the compound of formula:
Figure imgf000066_0002
[00352] (ff)-lsoflavanone [CAS No: 1362858-72-7]. The reaction was set up with Pd(OAc)2 (5 mol%, 5.6 mg, 0.025 mmol), ligand L1 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), phenyl triflate (113 mg, 0.50 mmol) and tri(n-butyl)stannyloxy- 2H-4-chromene (1.0 mmol, 652 mg). The reaction finished after 8 hours at 25 °C. The titled compound was obtained as white solid (108 mg, 96% yield) by flash chromatography using EA/hexane (1 :35) as eluent.
[00353] Ee of the purified products was determined to be 87% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mlJmin). TR = 1 1.3 min (minor) and 17.5 min (major).
[00354] [a]20 D = +3.6° (c = 1.0, CHCI3) for a sample of 87% ee.
[00355] 1H NMR (400 MHz, CDCI3): δ 7.98 (dd, J = 1 1.4, 4.1 Hz, 1 H), 7.54-7.49 (m, 1 H), 7.39-7.27 (m, 5H), 7.08-7.02 (m, 2H), 4.70-4.64 (m, 2H), 4.01 (dd, J = 7.7, 6.7 Hz, 1 H). 13C NMR (100 MHz, CDCI3): δ 192.3, 161.8, 136.2, 135.2, 129.1 , 128.8, 128.0, 127.9, 121.8, 121.2, 1 18.0, 71.6, 52.5. GC-MS (El): calcd for Ci5Hi202 M: 224.08. Found: 224.03.
[00356] Synthesis of the compound of formula:
Figure imgf000067_0001
[00357] (fl)-4'-Methoxyisoflavanone. The reaction was set up with Pd(OAc)2 (5 mol%, 5.6 mg, 0.025 mmol), ligand L1 (7.5 mol%, 22.2 mg, 0.0375 mmol), NaOAc (45 mg, 0.55 mmol), p-anisyl triflate (128 mg, 0.50 mmol) and tri(/>butyl)stannyl- oxy-2H-4-chromene (1.0 mmol, 652 mg). The reaction finished after 0 hours at 25 °C. The titled compound was obtained as white solid (117 mg, 92% yield) by flash chromatography using EA/hexane (1 :15) as eluent.
[00358] Ee of the purified products was determined to be 88% by chiral HPLC analysis (Daicel CHIRALCEL IC-H; hexanes: /-PrOH = 80:20; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 12.9 min (minor) and 15.4 min (major).
[00359] [a]20 D = +13.4° (c = 1.0, CHCI3) for a sample of 88% ee. [00360] 1H NMR (400 MHz, CDCI3): δ 7.96 (dd, J = 7.8, 1.6 Hz, 1 H), 7.52-7.48 (m, 1 H), 7.20 (d, J = 8.6 Hz, 2H), 7.06-7.00 (m, 2H), 6.90 (d, J = 8.6 Hz, 2H), 4.67-4.60 (m, 2H), 3.95 (dd, J = 8.4, 5.8 Hz, 1 H), 3.79 (s, 3H). 13C NMR (100 MHz, CDCI3): δ 192.7, 161.8, 159.4, 136.2, 129.8, 128.0, 127.1 , 121.8, 121.2, 118.0, 114.5, 71.8, 55.5, 51.7. GC-MS (El): calcd for C16H1403 M: 254.09. Found: 254.04.
[00361] Synthesis of the compound of formula:
Figure imgf000068_0001
[00362] (fl)-4'-Methoxycarbonylisoflavanone. The reaction was set up with Pd(OAc)2 (2 mol%, 4.6 mg, 0.02 mmol), ligand 1 (3 mol%, 17.8 mg, 0.03 mmol), NaOAc (90 mg, 1.1 mmol), p-(methoxycarbonyl)phenyl triflate (284 mg, 1.0 mmol) and tri(n- butyl)stannyloxy-2H-4-chromene (1.5 mmol, 978 mg). The reaction finished after 4 hours at 25 °C (judged by TLC).
[00363] The crude mixture was passed through a short pad of Grade III neutral alumina (containing 6% w/w water) with washings of diethyl ether (15 mL) until no more product came out (monitored by TLC). The combined filtrate was concentrated on a rotary evaporator. The resulting solid was suspended in 5 mL of n-pentane and loaded onto a fritted funnel. After quick washing with n-pentane (5 mL), the white solid (238 mg, 84%) after drying under vacuum proved to be pure by NMR spectroscopy. The filtrate contained a small amount of the product and no attempt was made to isolate it.
[00364] Ee of the crude sample and purified product was determined to be 86% and 94% by chiral HPLC analysis (Daicel CHIRALCEL IC-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 15.4 min (minor) and 18.0 min (major).
[00365] [a]20 D = +8.3° (c = 1.0, CHCI3) for a sample of 94% ee.
[00366] 1H NMR (400 MHz, CDCI3): δ 8.04-8.01 (m, 2H), 7.95 (dd, J = 7.8, 1.6 Hz, 1 H), 7.54-7.50 (m, 1 H), 7.38-7.36 (m, 2H), 7.08-7.01 (m, 2H), 4.69-4.67 (m, 2H), 4.06 (ipt, J = 7.1 Hz, 1 H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCI3): δ 191.6, 166.9, 161.7, 140.3, 136.5, 130.3, 129.9, 128.9, 128.0, 122.0, 121.1 , 118.1 , 71.3, 52.43, 52.37. GC-MS (El): calcd for Ci7H1404 M: 282.09. Found: 282.05. [00367] V. GRAM-SCALE ASYMMETRIC ARYLATION
Figure imgf000069_0001
[00368] Synthesis of 1-tri(n-butyl)stannyloxy-1-cyclohexene. Under argon, 1 - cyclohexenyl acetate (1.32 g, 9.45 mmol) and tri(n-butyl)tin methoxide (2.89 g, 9.0 mmol) were stirred at 25 °C for 12 hours until the latter was fully consumed (checked by 1H NMR spectroscopy). The byproduct, methyl acetate was removed under vacuum and the purity of the tin enolate was assessed to be 90% by 1H NMR spectroscopy. The tin enolate was used directly without purification in the coupling reaction.
[00369] Asymmetric arylation procedure. In air, a dry 100-mL Schlenk tube was charged with Pd(OAc)2 (1 mol%, 13.4 mg, 0.06 mmol), ligand L1 (1.5 mol%, 53.3 mg, 0.09 mmol) and NaOAc (6.6 mmol, 541 mg). The tube was evacuated and refilled with argon three times. Then, dry diethyl ether (30 ml) was added, followed by p- (methoxycarbonyl)phenyl triflate (1.70 g, 6.0 mmol) and n-dodecane (GC standard, 50 uL). The resulting mixture was stirred for 10 min at 25 °C. 1 -Tri(n-butyl)stannyloxy-1 -cyclohexene (90% purity from previous step) was added slowly over 2 minutes against an argon flow. The reaction mixture was vigorously stirred at 25 °C for 12 hours until full conversion of aryl triflate (monitored by GC). At the end of the reaction, the coupling product precipitated out. Dichloromethane (10 mL) was added to dissolve the product. The resulting mixture was filtered through a short pad of silica gel with diethyl ether washings (150 mL) until no more product was eluted out (monitored by TLC). The combined filtrate was concentrated on a rotary evaporator. The resulting solid was suspended in 10 mL of n-pentane and loaded onto a fritted funnel. After quick washing with n-pentane (10 mL), the pure product was obtained as white solid (1.27 g, 91 %) after drying under vacuum. The filtrate contained little product as checked by TLC.
[00370] The ee of the product in the crude mixture and purified sample was determined to be 92% and 94% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 1 1.0 min (minor) and 13.0 min (major). [00371 ] [a]20 D = -75.4° (c = 1.0, CHCI3) for a sample of 94% ee.
[00372] VI. MECHANISTIC STUDY
Figure imgf000070_0001
L1. lOOtmj IL1
[00373] Synthesis of oxidative adduct of ArBr. In an argon-filled glove box, a dry 25-mL Schlenk tube containing a magnetic stir bar was charged with Pd(dba)2 (97 mg, 0.17 mmol) and ligand L1 (100 mg, 0.17 mmol). Then, dry toluene (5 ml) was added, followed by 4-bromobenzotrifluoride (152 mg, 0.68 mmol). The resulting mixture was vigorously stirred in a 60 °C oil bath for 24 hours (monitored by 31P NMR spectroscopy). At the end of the reaction, the suspension was cooled to RT and loaded onto a fritted funnel. After washing with toluene (5 mL) and drying under vacuum, the pure palladium complex was obtained as yellow solid (120 mg, 77%).
[00374] Single crystals suitable for X-ray diffractional analysis were obtained by layering n-hexane on a concentrated solution in dichloromethane at room temperature in a 8- mL vial.
[00375] 1H NMR (400 MHz, CD2CI2): δ 8.44 (d, J = 9.1 Hz, 1 H), 8.06 (d, J = 8.6 Hz, 1 H), 7.96 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 2.2 Hz, 1 H), 7.87-7.79 (m, 3H), 7.76 (d, J = 7.7 Hz, 1 H), 7.53-7.41 (m, 5H), 7.37-7.32 (m, 2H), 7.27 (d, J = 8.0 Hz, 1 H), 7.20-7.11 (m, 4H), 6.98 (d, J = 8.2 Hz, 1 H), 5.94 (d, J = 8.6 Hz, 1 H), 2.33-2.19 (m, 2H), 1.92-1.67 (m, 8H), 1.39-0.59 (m, 12H). 19F NMR (376 MHz, CD2CI2): -62.2. 31 P NMR (162 MHz, CD2CI2): 34.2. ESIMS: calcd for C98H9oBr2F602P2Pd2 [M-Br ]+: 1765.36 (14%), [M-2Br +HCOO"]+: 1732.87 (59%), [LPdAr]+: 843.13 (100%).
Figure imgf000071_0001
SS%GCyteM.e3%ss
ZA ©qutv
[00376] Stoichiometric coupling of [(L1)Pd(Ar)Br]2 and a tin enolate. In an argon- filled glove box, a dry 4-mL vial containing a magnetic stir bar was charged with [(L1)Pd(Ar)Br]2 (30 mg, 0.016 mmol), NaOAc (2.9 mg, 0.036 mmol), dry Et20 (2 mL) and n- dodecane (GC standard, 10 uL). After stirring at 25 °C for 10 min, the reaction mixture was treated with 4-tri(n-butyl)stannyloxy-1 ,2-dihydronaphthalene (17 mg, 0.039 mmol, 95% purity). At intervals, aliquots of the reaction mixture were taken in the glove box and passed through a short plug of silica gel. The filtrates were used directly for determination of the yield of the coupling product by GC analysis. The results were as follows: 1 h, 28% yield; 3 h, 56% yield; 5 h, 66% yield; 7 h, 84% yield; 10 h, 95% yield. The selectivity after 10 h was determined to 93% ee by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2, 1.0 mlJmin).
[00377] VII. Isolation of coupling products using L3
[00378] Procedure forasymmetric arylation: In an argon-filled glove box, a dry 20- ml_ vial was charged with Pd(OAc)2 (2 mol%, 2.3 mg, 0.010 mmol), ligand L3 (3 mol%, 9.0 mg, 0.015 mmol), NaOAc (45 mg, 0.55 mmol), phenyl triflate (1 13 mg, 0.50 mmol) and 5.0 mL of dry diethyl ether. After stirring at room temperature for 10 minutes, the mixture was treated with 4-tri(n-butyl)-stannyloxy-1 ,2-naphthalene (275 mg, 0.60 mmol, 95% purity) and n-dodecane (GC standard, 20 DL). The vial was capped tightly and stirred at 25 °C until aryl triflate was fully consumed (monitored by GC). The reaction mixture was directly filtered through a pad of silica gel with diethyl ether washings (20 mL) to remove the palladium catalyst and inorganic salts. The filtrate was concentrated on a rotary evaporator and the residue was directly purified by flash chromatography. Enantioselectivity of the purified product was determined by chiral HPLC analysis. The typical procedure was used for isolation of all coupling products using 0.50 mmol of aryl triflate and 2 mol% palladium catalyst, unless stated otherwise.
[00379] Synthesis of the compound of formula:
Figure imgf000072_0001
[00380] (S)-2-Phenyl-1-tetralone. The reaction was set up using phenyl triflate (113 mg, 0.50 mmol) and 4-tri(n-butyl)stannyloxy-1 ,2-dihydronaphthalene (275 mg, 0.60 mmol). The reaction finished after 2 hours at 25 °C. The titled compound was obtained as white solid (107 mg, 97% yield). Ee of the purified products was determined to be 98% based by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wave- lengths = 254 nm and 227 nm; flow rate = 1 .0 mL/min). TR = 11.1 min (minor) and 17.3 min (major).
[00381] The coupling of ArBr was set up with bromobenzene (79 mg, 0.5 mmol) and 4- tri(n-butyl)stannyloxy-1 ,2-dihydronaphthalene (344 mg, 0.75 mmol). The reaction finished after 12 hours at 25 °C. The titled compound was obtained as white solid (105 mg, 94% yield) with 98% ee.
[00382] The reaction using ArCI was set up with chlorobenzene (56 mg, 0.5 mmol) and 4-tri(n-butyl)stannyloxy-1 ,2-dihydronaphthalene (344 mg, 0.75 mmol). The reaction was stopped after 36 hours at 25 °C. The titled compound was obtained as white solid (100 mg, 90% yield) with 97% ee.
[00383] Synthesis of the compound of formula:
Figure imgf000072_0002
[00384] (S)-2-Phenylcyclohexanone. The reaction of ArOTf was set up with phenyl triflate (452 mg, 2.0 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (1 .0 g, 2.4 mmol, 90% purity). The reaction finished after 6 hours at 25 °C. The titled compound was obtained as white solid (334 mg, 96% yield) by flash chromatography using EA/hexane (1 :20) as eluent. Ee of the purified products was determined to be 97% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 1 1.6 min (minor) and 12.9 min (major). [00385] The reaction of ArBr was set up with bromobenzene (79 mg, 0.5 mmol) and 1 - tri(n-butyl)stannyloxy-1 -cyclohexene (322 mg, 0.75 mmol, 90% purity). The reaction finished after 26 hours at 25 °C. The titled compound was obtained as white solid (83 mg, 95% yield) with 97% ee.
[00386] The reaction of ArCI was set up with chlorobenzene (56 mg, 0.5 mmol) and 1 - tri(/7-butyl)stannyloxy-1 -cyclohexene (322 mg, 0.75 mmol, 90% purity). The reaction finished after 36 hours at 50 °C. The titled compound was obtained as white solid (75 mg, 86% yield) with 90% ee.
[00387] Synthesis of the compound of formula:
Figure imgf000073_0001
[00388] (S)-2-(o-Tolyl)cyclohexanone. The reaction was set up with o-tolyl triflate (120 mg, 0.5 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (322 mg, 0.75 mmol, 90% purity). The reaction finished after 24 hours at 25 °C. The titled compound was obtained as white solid (90 mg, 96% yield) by flash chromatography using EA/hexane (1 :20) as eluent. Ee of the purified products was determined to be 92% by chiral HPLC analysis (Daicel CHIRALCEL IC-H; hexanes: /-PrOH = 80:20; detection wavelengths = 254 nm and 227 nm; flow rate = 0.5 mL/min). TR = 16.0 min (major) and 17.2 min (minor).
[00389] 1H NMR (400 MHz, CDCI3): δ 7.24-7.13 (m, 4H), 3.80 (dd, J = 13.0, 5.4 Hz, 1 H), 2.60-2.46 (m, 2H), 2.32-2.25 (m, 1 H), 2.24-2.18 (m, 4H), 2.12-2.01 (m, 2H), 1.91 -1.80 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 210.1 , 137.6, 136.3, 130.5, 127.8, 127.0, 126.2, 54.0, 42.7, 34.4, 28.0, 26.1 , 19.9. GC-MS (El): calcd for d3Hi60 M: 188.12. Found: 188.09.
[00390] Synthesis of the :
Figure imgf000073_0002
[00391] (S)-2-(o-Anisyl)cyclohexanone. The reaction was set up with o-anisyl triflate (128 mg, 0.5 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (322 mg, 0.75 mmol, 90% purity). The reaction finished after 72 hours at 25 °G. The titled compound was obtained as white solid (98 mg, 96% yield) by flash chromatography using EA/hexane (1 :15) as eluent. [00392] Ee of the purified products was determined to be 97% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 12.5 min (major) and 16.1 min (minor).
[00393] Synthesis of the compound of formula:
Figure imgf000074_0001
[00394] (S)-2-(p-Anisyl)cyclohexanone. The reaction was set up with p-anisyl bromide (93 mg, 0.5 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (322 mg, 0.75 mmol, 90% purity). The reaction finished after 36 hours at 25 °C. The titled compound was obtained as white solid (98 mg, 96% yield) by flash chromatography using EA/hexane (1 :15) as eluent. The coupling of ArCI was less efficient (after 24 h at 50 °C, 40% conversion, 94% ee).
[00395] Ee of the purified products was determined to be 97% by chiral HPLC analysis (Daicel CHIRALCEL IC-H; hexanes: /-PrOH = 80:20; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 20.7 min (major) and 22.0 min (minor).
[00396] Synthesis of the compound of formula:
Figure imgf000074_0002
[00397] (S)-2-(4-Methoxycarbonylphenyl)cyclohexanone. The reaction was set up with 4-(methoxycarbonyl)phenyl chloride (85 mg, 0.5 mmol) and 1-tri(n-butyl)stannyloxy-1 - cyclohexene (322 mg, 0.75 mmol, 90% purity). The reaction finished after 15 hours at 25 °C. The titled compound was obtained as white solid (112 mg, 97% yield) by flash chromatography using EA/hexane (1 :10) as eluent.
[00398] Ee of the purified products was determined to be 95% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 12.0 min (minor) and 14.0 min (major).
[00399] Synthesis of the compound of formula:
Figure imgf000075_0001
[00400] (S)-2-(3-Acetylphenyl)cyclohexanone. The reaction was set up with 3- acetylphenyl bromide (99 mg, 0.5 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (322 mg, 0.75 mmol, 90% purity). The reaction finished after 24 hours at 25 °C. The titled compound was obtained as white solid (103 mg, 96% yield) by flash chromatography using EA/hexane (1 :4) as eluent.
[00401] Ee of the purified products was determined to be 94% by chiral HPLC analysis (Daicel CHIRALCEL ID-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 12.2 min (major) and 14.2 min (minor).
[00402] Synthesis of the compound of formula:
Figure imgf000075_0002
[00403] (S)- V-Boc-2-(5-indolyl)cyclohexanone. The reaction was set up with W-Boc- 5-indolyl triflate (183 mg, 0.5 mmol) and 1-tri(n-butyl)stannyloxy-1 -cyclohexene (322 mg, 0.75 mmol, 90% purity).The reaction finished after 6 hours at RT O'udged by TLC). The titled compound was obtained as white solid (153 mg, 98% yield) by flash chromatography using EA/hexane (1 :15) as eluent.
[00404] Ee of the purified products was determined to be 97% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 15.5 min (minor) and 20.8 min (major).
[00405] Synthesis of the compound of formula:
Figure imgf000076_0001
[00406] (S)-2-(2-Methyl-5-benzothiazolyl)cyclohexanone. The reaction was set up with 5-bromo-2-methylbenzothiazole (1 14 mg, 0.50 mmol) and 1 -tri(n-butyl)stannyloxy-1 - cyclohexene (322 mg, 1 .0 mmol, 90% purity). The reaction was stopped after 36 hours at 25 °C. The titled compound was obtained as white solid (1 14 mg, 93% yield) by flash chromatography using EA/hexane (1 :4) as eluent.
[00407] Ee of the purified products was determined to be 96% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 95:5; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 17.3 min (minor) and 21.5 min (major).
[00408] Synthesis of the c :
Figure imgf000076_0002
[00409] (S)-2-(3,4-Dihydro-1-naphthyl)cyclohexanone. The reaction was set up with 3,4-dihydro-1 -naphthyl triflate (139 mg, 0.50 mmol) and 1 -tri(n-butyl)stannyloxy-1 - cyclohexene (322 mg, 1 .0 mmol, 90% purity). The reaction finished after 15 hours at 25 °C. The titled compound was obtained as white solid (105 mg, 94% yield) by flash chromatography using EA/hexane (1 :20) as eluent.
[00410] Ee of the purified products was determined to be 96% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 98:2; detection wavelengths = 254 nm and 227 nm; flow rate = 1 .0 mL/min). TR = 11.1 min (major) and 14.1 min (minor).
[00411] Synthesis of the compound of formula:
Figure imgf000077_0001
[00412] (S)-2-(1-lndenyl)cyclohexanone. The reaction was set up with 1 -indenyl triflate (132 mg, 0.50 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (322 mg, 1 .0 mmol, 90% purity). The reaction finished after 15 hours at 25 °C. The titled compound was obtained as white solid (100 mg, 94% yield) by flash chromatography using EA/hexane (1 :20) as eluent.
[00413] Ee of the purified products was determined to be 98% by chiral HPLC analysis (Daicel CHIRALCEL IC-H; hexanes: /-PrOH = 90:10; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 13.7 min (major) and 19.0 min (minor).
[00414] 1H NMR (400 MHz, CDCI3): δ 7.45 (d, J = 7.4 Hz, 1 H), 7.24 (d, J = 7.6 Hz, 1 H), 7.20-7.16 (m, 2H), 6.36 (d, J = 1.0 Hz, 1 H), 3.68 (dd, J = 1 1 .3, 5.4 Hz, 1 H), 3.46-3.32 (m, 2H), 2.58-2.45 (m, 2H), 2.34-2.27 (m, 1 H), 2.18-2.08 (m, 2H), 2.05-1 .99 (m, 1 H), 1 .91 - 1.77 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 210.1 , 144.7, 144.3, 142.4, 130.1 , 126.1 , 124.8, 124.0, 1 19.8, 50.8, 42.3, 38.2, 33.1 , 28.2, 25.2. GC-MS (El): calcd for Ci5H160 M: 212.12. Found: 212.06.
[00415] Synthesis of the compound of formula:
Figure imgf000077_0002
[00416] (S)-2-(2#-4-Chromenyl)cyclohexanone. The reaction was set up with 2H-4- chromenyl triflate (140 mg, 0.50 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (322 mg, 1 .0 mmol, 90% purity). The reaction finished after 12 hours at 25 °C. The titled compound was obtained as white solid (99 mg, 87% yield) by flash chromatography using EA/hexane (1 :20) as eluent.
[00417] Ee of the purified products was determined to be 95% by chiral HPLC analysis
(Daicel CHIRALCEL IC-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and
227 nm; flow rate = 1.0 mL/min). TR = 15.0 min (minor) and 17.0 min (minor). [00418] 1H NMR (400 MHz, CDCI3): δ 7.10-7.07 (m, 1 H), 6.87-6.80 (m, 3H), 5.65 (ψΐ, J = 3.7 Hz, 1 H), 4.83 (dd, J = 14.5, 3.7 Hz, 1 H), 4.75 (ddd, J = 14.5, 3.7, 1.2 Hz, 1 H), 3.53 (dd, J = 1 1 .9, 4.7 Hz, 1 H), 2.55-2.46 (m, 2H), 2.23-2.14 (m, 2H), 2.04-1.89 (m, 2H), 1 .85-1.81 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 210.1 , 154.5, 132.9, 129.0, 123.6, 123.3, 121.3, 1 19.7, 1 16.4, 65.3, 52.6, 42.7, 32.8, 28.2, 25.6. GC-MS (El): calcd for Ci5H1602 M: 228.12. Found: 228.07.
[00419] Synthesis of the compound of formula:
Figure imgf000078_0001
[00420] (S)-2-(or-Styryl)cyclohexanone. The reaction was set up with ostyryl triflate (126 mg, 0.50 mmol) and 1 -tri(n-butyl)stannyloxy-1 -cyclohexene (322 mg, 1.0 mmol, 90% purity). The reaction finished after 15 hours at 25 °C. The titled compound was obtained as colorless oil (91 mg, 91% yield) by flash chromatography using EA/hexane (1 :20) as eluent.
[00421] Ee of the purified products was determined to be 96% by chiral HPLC analysis (Daicel CHIRALCEL OJ-H; hexanes: /-PrOH = 98:32; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 18.4 min (major) and 24.2 min (minor).
[00422] 1H NMR (400 MHz, CDCI3): δ 7.30-7.23 (m, 5H), 5.48 (s, 1 H), 5.1 1 (s, 1 H), 3.57 (dd, J = 11.4, 5.1 Hz, 1 H), 2.53-2.38 (m, 2H), 2.22-2.15 (m, 1 H), 2.12-2.06 (m, 1 H), 1 .98-1.85 (m, 2H), 1 .84-1.72 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 210.8, 146.9, 142.1 , 128.4, 127.5, 126.8, 1 15.4, 56.8, 42.6, 33.4, 28.2, 25.2. GC-MS (El): calcd for d4H160 M: 200.12. Found: 200.1 1.
[00423] VIII. SYNTHETIC APPLICATIONS
[00424] The arylation products can be easily converted to other chiral compounds, including but not limited to the exemplary compounds described below. The illustrative reduction of 2-phenylcyclohexanone using K-Selectride gave c/'s-alcohol without erosion of ee and in 80: 1 dr. Li/naphthalene reduction of the ketone can selectively give trans-2- arylcycohexanol (cf. Kruger, D.; Sopchik, A. E.; Kingsbury, C. A. J. Org. Chem. 1984, 49, 778). The frans-alcohol is commonly used as chiral auxiliary to induce stereo-selectivity in many asymmetric transformations (cf. van Beek, H. L; Gonzalo, G. d.; Fraaije, M. W. Chem. Commun. 2012, 48, 3288). The 2-arylketones can also be converted to aryl-lactones via Baeyer-Villiger oxidation and aryl-lactams via Beckmann rearrangement, via the (E)-oxime (cf. Murakata, M.; Imai, M.; Tamura, M.; Hoshino, O. Tetrahedron: Asymmetry 1994, 5, 2019). One more example is deoxygenation of 2-aryltetralones via catalytic hydrogenolysis. Some 2-aryltatralins were potential drugs for treatment of arrhythmias (irregular heartbeat), by acting as inhibitors of Na+/Ca2+ exchange mechanism (cf. Huitric, A. C; Nelson, S. D. J. Org. Chem. 1969, 34, 1230). No asymmetric synthesis of these compounds was reported previously, which further illustrates the contribution of the present invention.
[00425] Synthesis of the compound of formula:
Figure imgf000079_0001
[00426] ( iS,2S)-2-Phenylcyclohexanol [17540-18-0] (cf. Xie, J. H.; Liu, S.; Huo, X.-H.; Cheng, X.; Duan, H.-F.; Fan, B.-M.; Wang, L.-X.; Zhou, Q.-L J. Org. Chem. 2005, 70, 2967). The reported reduction procedure was modified to improve diastereoselectivity (cf. Kruger, D.; Sopchik, A. E.; Kingsbury, C. A. J. Org. Chem. 1984, 49, 778). Under argon, to a flame-dried 10-mL Schlenk tube was added freshly distilled THF (1 mL) and a 1 M solution of K-Selectride in THF (0.24 ml_, 0.24 mmol). After the solution was cooled to -78 °C, (S)-2-phenylcyclohexanone (35 mg, 0.2 mmol) in 0.5 mL THF was added via syringe over 2 min. The mixture was stirred at - 78 °C for 16 hours until completion (monitored by GC). The reaction mixture maintained at -78 °C was quenched with saturated aq NH4CI. After stirring at 0 °C for 5 min, the resulting mixture was extracted with ethyl acetate (5 mL x 3) and the combined organic layer was dried over Na2S04. The cis/trans ratio in the crude product was determined to be 80:1 by GC and GC/MS. The filtrate was concentrated on a rotary evaporator and the residue was purified by flash chromatography (EtOAc/hexane 1 :20) to afford the titled compound as white solid (27 mg, 78% yield). Ee of the purified product was determined to be 97% by chiral HPLC analysis (Daicel CHIRALCEL OJ-H; hexanes: /-PrOH = 90:10; detection wavelengths = 254 nm and 227 nm; flow rate = 1 .0 mL/min). TR = 7.0 min (major) and 9.0 min (minor).
[00427] [a]20 D = +139.8° (c = 1.2, CHCI3) for a sample of 97% ee. [00428] 1H NMR (400 MHz, CDCI3): δ 7.29-7.14 (m, 5H), 3.97-3.96 (m, 1 H), 2.68 (ψΛ, J = 12.8, 2.8 Hz, 1 H), 2.00 (ddd, J = 25.8, 12.8, 3.6 Hz, 1 H), 2.94-1.90 (m, 1 H), 1.85-1.80 (m, 1 H), 1.66-1.55 (m, 3H), 1.49-1.45 (m, 1 H), 1.37-1 .28 (m, 1 H), 1.17 (d, J = 1.6 Hz, 1 H, OH). 13C NMR (100 MHz, CDCI3): δ 144.2, 128.8, 128.0, 126.7, 70.8, 48.3, 33.2, 26.5, 24.6, 19.8. GC-MS (El): calcd for d2H160 M: 176.12. Found: 1 6.09.
[00429] Synthesis of the compound of formula:
Figure imgf000080_0001
[00430] (S)-7-Phenylcaprolactone [180582-73-4] (cf. van Beek, H. L; Gonzalo, G. d.; Fraaije, M. W. Chem. Commun. 2012, 48, 3288). Under argon, to a 10-mL Schlenk tube was added (S)-2-phenylcyclohexanone (35 mg, 0.2 mmol) and DCM (2 mL). Then mCPBA (77% purity, 67 mg, 0.3 mmol) was added. After stirring at 25 °C for 16 hours (monitored by TLC), the mixture was quenched with saturated aq NaHC03 (2 mL). After stirring for 10 min, the mixture was extracted with DCM (5 mL x 3) and the combined organic layer was dried with Na2S04. The filtration was concentrated on a rotary evaporator and the residue was purified by flash chromatography (EtOAc/hexane 1 :4) to afford the titled compound as white solid (33 mg, 87% yield).
[00431] Ee of the purified products was determined to be 97% by chiral HPLC analysis (Daicel CHIRALCEL ID-H; hexanes: /-PrOH = 70:30; detection wavelengths = 254 nm and 227 nm; flow rate = 1.0 mL/min). TR = 8.7 min (major) and 10.6 min (minor).
[00432] [a]20 D = -40.2° (c = 1.0, CHCI3) for a sample of 97% ee.
[00433] 1H NMR (400 MHz, CDCI3): 7.40-7.28 (m, 5H), 5.29 (d, J = 9.4 Hz, 1 H), 2.79-
2.76 (m, 2H), 2.15-1.98 (m, 4H), 1.84-1.69 (m, 2H). 13C NMR (100 MHz, CDCI3): δ 175.1 , 141 .0, 128.8, 128.3, 126.1 , 82.3, 37.7, 35.2, 28.8, 23.1. GC-MS (El): calcd for Ci2H1602 M: 190.10. Found: 190.06.
[00434] Synthesis of the compound of formula:
Figure imgf000081_0001
[00435] (S)-7rans-2-phenylcyclohexanone oxime [160154-27-8]. In air, to a mixture of (S)-2- phenylcyclohexanone (87 mg, 0.5 mmol) and hydroxylamine hydrochloride (70 mg, 1.0 mmoi) in 2 mL of methanol was added a solution of potassium carbonate (76 mg, 0.55 mmol) in 1 mL of water at room temperature. The mixture was stirred for 0.5 h at RT, cooled in ice- water bath, and then treated with 1 mL of ice-cold water. The precipitate was collected by filtration and then dried under vacuum. Pure frans-(S)-2-phenylcyclohexanone oxime was obtained as white solid (76 mg, 80% yield). The ratio of trans/cis oxime in the crude product was determined to be 7.3:1 by 1H NMR spectroscopy (cf. Murakata, M.; Imai, M.; Tamura, M.; Hoshino, O. Tetrahedron: Asymmetry 1994, 5, 2019).
[00436] 1H NMR (300 MHz, CDCI3): δ 7.52 (s, 1 H), 7.34-7.20 (m, 5H), 3.48 (dd, J = 9.1 , 5.4 Hz, 1 H), 2.98-2.90 (m, 1 H), 2.23-1.98 (m, 3H), 1.85-1 .79 (m, 2H), 1.66-1.57 (m, 3H).
[00437] Ee of the frans-oxime was determined to be 96% by chiral HPLC analysis (Daicel CHIRALCEL AS-H; hexanes: /-PrOH = 90:10; detection wavelengths = 254 nm and 227 nm; flow rate = 0.5 mL/min). TR = 12.6 min (minor) and 14.6 min (major).
[00438] Synthesis of the compound of formula:
Figure imgf000081_0002
[00439] (S)-7-Phenylcaprolactam [racemate: 25882-81-9]. The compound was prepared according to a reported procedure (ref. Huitric, A. C; Nelson, S. D. J. Org. Chem. 1969, 34, 1230). Under argon, to a flame-dried Schlenk tube was added (S)-trans-2- phenylcyclohexanone oxime (96% ee, 76 mg, 0.4 mmol) and dry pyridine (0.4 mL). After the resulting solution was cooled to 0 2C, p-TsCI (92 mg, 0.48 mmol) in 0.15 mL of dry pyridine was added. The resulting mixture was stirred at 0 SC for 8 h. After the reaction was complete, 0000S the mixture was poured into 10% aq HCI (2 mL) and then 4 mL of water was added. The mixture was extracted with CH2CI2 (5 mL x 3) and the combined organic layer was sequentially washed with saturated aq NaHC03 and brine, dried over Na2S04 and concentrated on a rotary evaporator. The residue was purified by flash chromatography (40:1 CH2CI2/MeOH) to afford the titled lactam as white solid (58 mg, 76% yield).
[00440] Ee of the purified products was determined to be 96% by chiral HPLC analysis (Daicel CHIRALCEL OJ-H; hexanes: /-PrOH = 80:20; detection wavelengths = 254 nm and 227 nm; flow rate = 0.5 mL/min). TR = 12.7 min (minor) and 14.0 min (major).
[00441] [a]20 D = -46.3° (c = 2.9, CHCI3) for a sample of 96% ee.
[00442] 1H NMR (300 MHz, CDCI3) δ 7.40-7.26 (m, 5H), 5.66 (br s, 1 H), 4.48-4.43 (m, 1 H), 2.64-2.52 (m, 2H), 2.11-1.86 (m, 4H), 1.77-1.60 (m, 2H). 3C NMR (75 MHz, CDCI3) δ 177.2, 142.3, 129.1 , 128.1 , 126.2, 58.6, 37.1 , 37.0, 29.8, 23.0. GC-MS (El): Calcd for C12H15NO M: 189.12. Found: 189.06.
[00443] Synthesis of the compound of formula:
Figure imgf000082_0001
[00444] (fl)-2-Phenyltetralin [racemate: 29422-13-7] (ref. Kuwano, R.; Shige, T. J. Am. Chem. Soc. 2007, 129, 3802). In an argon-filled glove box, an 8-mL vial was charged with (S)-2-phenyl-1 -tetralone (45 mg, 0.2 mmol), analytical-grade ethanol (2 mL) and 5% Pd/C (21 mg, 0.1 mmol). The vial was placed in a 125-mL Parr bomb. The mixture was stirred under 30 psi of H2 gas at 25 °C for 24 hours until completion (monitored by TLC). The mixture was passed through a pad of Celite with ethyl acetate washing (5 mL). After concentration of the filtrate, the residue was purified by flash chromatography (hexane) to afford the titled compound as colorless oil (40 mg, 96% yield).
[00445] Ee of the purified products was determined to be 94% by chiral HPLC analysis (Daicel CHIRALCEL OJ-H; hexanes:. /-PrOH = 00. ; detection wavelengths = 254 nm and 227 nm; flow rate = 0.5 mL/min). TR = 33.1 min (major) and 36.5 min (major).
[00446] [a]20 D = +136.5° (c = 2.9, CHCI3) for a sample of 96% ee.
[00447] 1H NMR (300 MHz, CDCI3): δ 7.35-7.20 (m, 5H), 7.13-7.10 (m, 4H), 3.06-2.91 (m, 5H), 2.16-2.11 (m, 1 H), 2.00-1.87 (m, 1 H). 13C NMR (75 MHz, CDCI3): δ 146.6, 136.7, 136.3, 0000S
129.0, 128.9, 128.5, 126.9, 126.2, 125.7, 125.6, 40.7, 37.7, 30.3, 29.7. GC-MS (El): calcd for Ci6H16 M: 208.13. Found: 208.10.
[00448] COMMERCIAL APPLICATIONS OF THE INVENTION
[00449] The optically enriched a-arylketones are used as intermediates in synthesis of bioactive natural and synthetic compounds. The method describe herein provides a general way to access these chiral compounds that contain tertiary stereocenters in one enantiomeric form. The arylketones can be chemically converted to other chiral compounds such as lactones, lactams, trans and cis alcohols and after deoxygenation of the ketone groups, chiral arylalkanes. Some of these derivatives show important pharmacological activities.
[00450] The invention has been described broadly and generically herein. Each of the narrower species and sub-generic groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.
[00451] Other embodiments are within the following claims. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

Claims

Claims What is claimed is:
1 . A ligand of formula (I)
Figure imgf000084_0001
wherein
A is a single bond or an oxygen atom or CH2;
Cy is cyclohexyl; and
Ri is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted (hetero)aryl-methyl.
2. The ligand according to claim 1 , wherein Ri is selected from the group consisting of 2-naphthyl, 1 -naphthyl, CH2(2-naphthyl), phenyl, 4-amino-pheny, 3-amino-phenyl, 3- (iPr)NH-phenyl, 3-CH3CONH-phenyl and cyclohexyl.
3. The ligand according to anyone of the preceding claims, wherein A is an oxygen atom.
4. A catalyst system comprising a palladium source and a ligand, wherein the ligand is as defined in anyone of claims 1 -3.
5. The use of a ligand of formula (I) as defined in anyone of claims 1 -3, in an asymmetric a-(hetero)arylation or a-vinylation of ketones, wherein the a- (hetero)arylation or the α-vinylation creates a tertiary center in the a-arylated or a- vinylated position.
6. The use according to claim 5, wherein the a-(hetero)arylation or the α-vinylation of ketones is a palladium catalyzed a-(hetero)arylation or the a-vinylation.
7. The use according to claims 5 or 6 wherein the a-(hetero)arylation or the a-vinylation occurs on the tin enolate derivative of said ketone.
8. A process for asymmetrically a-(hetero)arylating or a-vinylating a ketone comprising: a) reacting a tin enolate derivative of said ketone in the presence of an (hetero)arylating or a vinylating reagent and of a catalyst system based on palladium source and a ligand of formulae (I) or (II)
Figure imgf000085_0001
wherein
A is a single bond or oxygen atom or -CH2.;
Cy is cyclohexyl; and
Ri is selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted (hetero)aryl-methyl b) obtaining the a-(hetero)arylated or a-vinylated ketone having a tertiary center in the (hetero)arylated or vinylated position.
9. The process according to claim 8, further comprising reacting an acetate derivative of the starting ketone with nBu3Sn(OMe) to obtain the corresponding tin enolate.
10. The process according to claim 8 or 9 wherein the (hetero)arylating or the vinylating reagent is an (hetero)aryl triflate, bromide or chloride or a vinyl triflate, bromide or chloride.
1 1. The process according to anyone of claims 8-10 wherein the (hetero)arylating reagent is of formula
Ar-X wherein
X is OTf, Br or CI;
Ar is selected from the group consisting of optionally substituted groups of phenyl, naphthyl, quinoline, indole, benzothiazole, thiophene and benzopyran,
wherein the substituent is selected from: (CrC4) alkyl, OMe, CN, C02Et,
COMe, CF3, CI, F, and Boc.
12. The process of claim 11 , wherein Ar is:
Figure imgf000086_0001
wherein Y is H, OMe, CN, C02Et, COMe, CF3, CI, F;
or Ar is
Figure imgf000086_0002
13. The process according to anyone of claims 8-10, wherein the vinylating reagent has formula:
V-X
wherein
X is OTf, CI or Br, preferably OTf and
V is
Figure imgf000087_0001
14. The process according anyone of claims 8-12, comprising the step:
Figure imgf000087_0002
wherein
R is phenyl, substituted aryl, secondary alkyl such as cyclo-hexyl, isopropyl, cyclopentyl;
X is OTf, Br or CI;
Y is F, OMe, or an ester;
Z is alkenyl, N, or O, or S, when Z is alkenyl is preferably -CH2. or-CH2-CH2- n is 1 , 2, 3, or 4;
the Pd source is Pd(OAc)2, Pd(dba)2 Pd2(dba)3;
the chiral ligand is a ligand of formula (I) or (II) as defined in any of claims 1-3 and 8 the activator is LiOAc, NaOAc, LiOPiv, CsF, LiF, ZnF2,CuF2 or nBuSnF.
15. The process according to anyone of claims 8-14 which is a one pot process.
16. The process according to anyone of claims 8-15, wherein the solvent is selected from diethyl ether, tetrahydrofuran, 1 ,4-dioxane, i-butyl methyl ether, cyclopentyl methyl ether, toluene, benzene, α,α,α-trifluoromethylbenzene, fluorobenzene, dichloromethane and 1 ,2-dichloroethane
PCT/SG2014/000005 2013-01-11 2014-01-10 PALLADIUM-CATALYZED ASYMMETRIC (HETERO)ARYLATION AND VINYLATION OF KETONE ENOLATES TO PRODUCE TERTIARY STEREOCENTERS AT ALPHA(α)-POSITION WO2014109712A1 (en)

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WO2001014299A1 (en) * 1999-08-23 2001-03-01 The Penn State Research Foundation Chiral ligands, transition-metal complexes thereof and uses thereof in asymmetric reactions
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WO2001014299A1 (en) * 1999-08-23 2001-03-01 The Penn State Research Foundation Chiral ligands, transition-metal complexes thereof and uses thereof in asymmetric reactions
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