WO2000056691A1

WO2000056691A1 - Synthesis of vapol ligands

Info

Publication number: WO2000056691A1
Application number: PCT/US2000/006412
Authority: WO
Inventors: William D. Wulff; Su Yu; Jon Antilla
Original assignee: Arch Development Corp
Current assignee: Arch Development Corp
Priority date: 1999-03-19
Filing date: 2000-03-17
Publication date: 2000-09-28
Anticipated expiration: 2001-09-19
Also published as: AU3739300A

Abstract

The present invention relates to a process for making the chiral ligand 2,2'-diphenyl-[3,3'-biphenanthrene]-4,4'-diol, also known as VAPOL, as well as other novel chiral ligands.

Description

SYNTHESIS OF VAPOL LIGANDS

FIELD OF THE INVENTION

The present invention relates to a process for making the chiral ligand 2,2'-diphenyl-[3,3'-biphenanthrene]-4,4'-diol, also known as VAPOL.

BACKGROUND OF THE INVENTION

History has shown the importance of chirality in medicinal applications and consequently the need for chiral ligands is increasing. One such ligand, 2,2'-diphenyl-[3_I3'-biphenanthrene]-4,4'-diol has been disclosed in Bao, J.; Wulff, W. D. J. Am. Chem. Soc. 1993, 115, 3814-3815; Bao, J.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C; Whitcomb, M. C; Yeung, S.; Ostrander, R. L; Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 3392-3405; Bao, J.; Wulff, W. D. Tetrahedron Letters 1995, 36(19), 3321-3324, and in Heller, D. P.; Goldberg, D. R.; Wulff, W. D. J. Am. Chem. Soc. 1997, 119, 10551-10552. The 2,2'-diphenyl-[3,3'-biphenanthrene]-4,4'-diol optically active ligand, may be represented by:

Where "Ph" represents a phenyi group. For ease of explanation, the optically active ligand described above and in the cited references will be referred to herein as the "VAPOL" ligand. VAPOL has been synthesized through the reaction of a 1-naphthyl carbene complex with phenylacetylene, followed by reductive cleavage with aluminum chloride and ethanethiol to form 2-phenyl-4-hydroxyphenanthrene. Oxidative coupling of 2-phenyl-4-hydroxyphenanthrene with air resulted in VAPOL. However, for large-scale production, an alternate synthesis that does not involve the use of heavy metal chromium is desired.

Others have performed synthesis of 1-hydroxynaphthenes via methyllithium-induced cyclization of 2-propenylbenzamides, but such an approach has not been applied to 4-hydroxyphenanthrenes, see Sibi, M. P.; Dakwardt, J. W.; Snieckus, V. J. Org. Chem. 1986, 51, 273, and see Sibi, M. P.;Jalil Miah, M. A.; Snieckus, V. J. Org. Chem. 1984, 49, 737. The present invention provides a synthesis of the VAPOL ligand and other chiral ligands with low cost, high yields, using more desirable reagents.

SUMMARY OF THE INVENTION The purpose of the invention is to provide several novel chiral ligands:

where Ph is a phenyi group and R1 , R2, R3, and R4 are selected from the group consisting of hydrogen and alkyl groups having from 1 to about 14 carbon atoms, and where at least one of R1 , R2, R3, or R4 is an alkyl group. In a preferred embodiment, R1 and R3 are identical, and R2 and R4 are identical.

Another purpose of the invention is to provide a synthesis of the new chiral ligands above, as well as a synthesis of the VAPOL ligand. A preferred chiral ligand:

where Ph is a phenyi group and R1 and R2 are selected from the group consisting of hydrogen and alkyl groups having from 1 to about 14 carbon atoms, is synthesized by: (1) reacting a starting material:

where X is selected from the group consisting of OH and NR₂ with R being at least one moiety selected from the group consisting of hydrogen and alkyl groups containing from 1 to about 10 carbon atoms, with sec-butyllithium, π-butyllithium, tetf-butyllithium, methyllithium, or lithium diisopropylamide to afford the corresponding lithiated compound:

(2) transmetalating the lithiated compound with magnesium bromide and reacting the product formed thereby with α-bromomethyl styrene to form a corresponding first intermediate:

(3) deprotonating the first intermediate with methyllithium or methyl magnesium bromide to form a corresponding second intermediate:

and (4) oxidatively coupling the second intermediate with air to form the chiral ligand. Similarly, the chiral ligands:

where Ph is a phenyi group, are synthesized by (1) reacting a starting material

where X is selected from the group consisting of OH and NR₂ with R being at least one moiety selected from the group consisting of hydrogen and alkyl groups containing from 1 to about 10 carbon atoms, with sec-butyllithium, n-butyllithium, tetf-butyllithium, methyllithium, or lithium diisopropylamide to afford the corresponding lithiated compound:

and (4) oxidatively coupling the second intermediate with air to form the chiral ligand II or III.

Another purpose of the invention is to provide catalytic compounds comprising a molar ratio of metahchiral ligand ranging from 1:1 to about 1:2 where the chiral ligand is selected from:

where Ph is a phenyi group and R1 , R2, R3, and R4 are selected from the group consisting of hydrogen and alkyl groups having from 1 to about 14 carbon atoms, and where at least one of R1 , R2, R3 or R4 is an alkyl group. The metal is preferably selected from the group consisting of zirconium, titanium and hafnium. When the molar ratio of metal:chiral ligand is 1 :2, both chiral ligands are the same enantiomer. A specific embodiment of the invention is one where the catalytic compound further contains an activator such as N-methylimidazole, imidazole, N-benzoimidazole, pyridine, and dimethylaminopyridine in the molar ratio from 1:L:1 to 1:L:2 metal:chiral ligand :activator, where L is 1 or 2.

Yet another purpose of the invention is to provide a method of preparing the catalytic compound by forming a reaction mixture containing chiral ligand of at least 95% ee, and preferably at least 99% ee, and a metal alkoxide where the metal is zirconium, titanium or hafnium to form a catalytic compound having from 1 :1 to about 1:2 metahchiral ligand where both chiral ligands are the same enantiomer. In a more specific embodiment, the reaction mixture may also contain an activator such as N-methylimidazole, imidazole, N-benzoimidazole, pyridine, or dimethylaminopyridine to form a catalytic compound having from 1 :L:1 to 1 :L:2 metakchiral ligand:activator where L is 1 or 2, and when L is 2, both chiral ligands are the same enantiomer. DETAILED DESCRIPTION OF THE INVENTION

As a general exemplary outline, one embodiment of the present invention is a synthesis of VAPOL ligand involving the treatment of N,N-dialkyl-1-naphthamide with sec-butyllithium, n-butyllithium, terf-butyllithium, methyllithium, or lithium diisopropylamide to afford 2-lithio-naphthamide followed by transmetalation with magnesium bromide and reaction with α-bromomethyl styrene to form the 2-(2-phenyl-2-propenyl)-naphthamide. Deprotonation with methyllithium or methyl magnesium bromide leads to ring-closure and the formation of 2-phenyl-4-hydroxyphenanthrene, which is the precursor to VAPOL that is employed in the previously disclosed method, see above.

In addition to being used to form the VAPOL ligand, the process of the present invention may also be used to form additional chiral ligands, which will be described in greater detail below. The invention provides for two general reactions for the synthesis of VAPOL, a first will be described in detail and a second will be described in combination with the synthesis of a new chiral ligand. As one embodiment of the invention, one general reaction for the VAPOL synthesis may be expressed as follows:

where Ph is a phenyi group, and R is hydrogen or at least one alkyl group having from 1 to about 10 carbon atoms. The first portion of the invention involves the preparation of 2-(2-phenyl-2-propenyl)naphthamide (IC). The starting material is N,N'-dialkyl-1-naphthamide (IA), to which sec-butyllithium, π-butyllithium, terf-butyllithium, methyllithium, or lithium diisopropylamide is added, preferably at a temperature ranging from about -78°C to about -20°C, with about -78°C being the preferred temperature. The mixture is allowed to react, to form the 2-lithio- N,N'-dialkyl-1-naphthamide (IB). After a reasonable time, magnesium bromide is added and the mixture is brought to ambient temperature. It is preferred that one equivalent of magnesium bromide be used. The reaction is still successful with three equivalents of magnesium bromide, but there is no increase in yield resulting from more equivalents of magnesium bromide. The mixture is again cooled to from about -78°C to about -20°C, with about -78°C being the preferred temperature, and an electrophile, α-bromomethyl styrene, is added. It is preferred that one equivalent of the electrophile be used, but the reaction is still successful if two equivalents of the electrophile are used although there is no increase in yield due to the excess electrophile. The mixture is brought to ambient temperature and stirred from about 1 to about 18 hours, with 12 hours being preferred. The reaction is quenched using water or a Bronsted acid including hydrochloric acid, with saturated ammonium chloride being preferred, and the resulting 2-(2-phenyl-2-propenyl)-N,N'-dialkyl naphthamide (IC) is collected.

The N,N'-dialkyl-1 -naphthamide starting material may be any N,N'-dialkyl-1 -naphthamide where at least one alkyl group contains from about 1 to about 10 carbon atoms. Preferred starting materials include N,N'-diethyl-1 -naphthamide and N,N'-diisopropyl-1-naphthamide, with the N,N'-diisopropyl-1 -naphthamide being most preferred owing to higher yields of reaction. Although it is preferred, the two alkyl groups of the N,N'-dialkyl-1 -naphthamide starting material need not be identical. The starting material, N,N'-dialkyl-1-naphthamide, may be prepared through the reaction of 1-naphthoyl chloride, which is formed from the reaction of 1-naphthoic acid and thionyl chloride, and a dialkylamine, see Example 2.

The magnesium bromide is typically used in the form of magnesium bromide etherate, which is commercially available. However, experiments have shown that the commercially available magnesium bromide etherate contains undesired amounts of water which adversely affects the yield of the desired reaction. Therefore, it is preferred that the magnesium bromide etherate be prepared so that it is as dry as possible. Magnesium bromide etherate may be prepared from the reaction of 1 ,2-dibromoethane with magnesium turnings in dry ethyl ether. Freshly prepared, dry, magnesium bromide etherate is capable of providing the desired reaction product in yields from about 75 to about 80 mole percent. The α-bromomethyl styrene can be prepared by the bromination of α-methyl styrene with N-bromosuccinimide, see Example 1.

The reactions above may be conducted in a solvent such as etheral solvents including tetrahydrofuran, diethylether, dibutylether, t-butyl methylether and 1 ,4-dioxane. The preferred solvent is tetrahydrofuran.

The next portion of the VAPOL synthesis deals with the preparation of 2-phenyl-4-hydroxyphenanthrene (ID). The product

2-(2-phenyl2-propenyl)-N,N'-dialkyl naphthamide (IC) of the first portion of the synthesis is brought to a temperature ranging from about -78°C to about 75°C, with about -78°C or about 68°C being the preferred temperatures. A suitable base is added and the reaction mixture is stirred. Suitable base compounds include methyllithium and methyl magnesium bromide. When using methyllithium, the preferred temperature is about -78°C and when using methyl magnesium bromide, the preferred temperature is about 68°C. For ease of understanding, methyllithium will be referred to herein as the base reactant. One skilled in the art would readily adapt the procedure to use methyl magnesium bromide instead of methyllithium including the appropriate temperature adjustment. While stirring, the mixture is brought to ambient temperature and after a reasonable period of time stirring at ambient temperature, generally from about 1 to about 18 hours, and preferably about 8 hours, the reaction is quenched using a Bronsted acid including hydrochloric acid. The preferred compound for the quenching is saturated ammonium chloride. The resulting product is the desired 2-phenyl-4-hydroxyphenanthrene (ID). It is preferred to use the minimum equivalents of methyllithium necessary for acceptable yields since it appears that excess methyllithium tends to result in undesired impurities in the product 2-phenyl-4-hydroxyphenanthrene. Therefore, it is preferred to use two equivalents of methyllithium which results in yields ranging from about 86 to about 90 percent.

The above sequence of reactions may be conducted sequentially or in a one-pot reaction mode. The one-pot reaction mode is less preferred due to the greater amount of impurities found in the product 2-phenyl-4-hydroxyphenanthrene.

The 2-phenyl-4-hydroxyphenanthrene (ID) may then be oxidatively coupled to form the 2,2'-diphenyl-[3,3'-biphenanthrene]-4,4'-diol (I), or VAPOL. The oxidative coupling is conducted as described in Bao, J.; Wulff, W. D. J. Am. Chem. Soc. 1993, 115, 3814-3815; Bao, J.; Wulff, W. D.; Dominy, J. B.; Fumo, M. J.; Grant, E. B.; Rob, A. C; Whitcomb, M. C; Yeung, S.; Ostrander, R. L.; Rheingold, A. L. J. Am. Chem. Soc. 1996, 118, 3392-3405; and in Bao, J.; Wulff, W. D. Tetrahedron Letters 1995, 36(19), 3321-3324. It is preferred that the oxidative coupling of the 2-phenyl-4-phenanthrol be conducted with air. The resultant VAPOL ligand may be separated from any other compounds, and then the racemic mixture of VAPOL may be resolved into its two entantiomers using any common resolution technique, with the preferred resolution technique being simulated moving bed chromatography. In an alternate embodiment, the starting material (IA) the intermediates (IB) and (IC) may contain a hydroxyl group in place of the NR₂ group shown above. This alternate embodiment is discussed in greater detail below.

The invention described above may be applied to the synthesis of additional chiral ligands having the vaulted aryl-type structure of VAPOL. For example, the following is a general reaction scheme for another chiral ligand:

The chiral ligand having the structure (II) where "Ph" represents a phenyi group can be synthesized from the starting material of phenanthrene-1-carboxylic acid (IIA). As described in greater detail above, the starting material is treated with sec-butyllithium, n-butyllithium, tetf-butyllithium, methyllithium, or lithium diisopropylamide to afford the 2-lithio-phenanthrene-1-carboxylic acid (IIB) followed by transmetalation with magnesium bromide and reaction with α-bromomethyl styrene to form the 2-(2-phenyl-2-propenyl)- phenanthrene-1-carboxylic acid (IIC). Deprotonation with methyllithium or methyl magnesium bromide leads to ring-closure and the formation of 2-phenyl-4-hydroxychrysene (IID). Oxidative coupling, preferably with air, results in the formation of the structure (II) above, 2,2'-diphenyl-[3,3'-bichrysene]-4,4'-diol, which can be resolved into two enantiomers using common resolution techniques. Additional specific embodiments can be readily extrapolated from the detailed descriptions of the chiral ligand (II) synthesis, such solvent choices, reaction temperatures, resolution of the product ligand and the like. In an alternate, less preferred, embodiment, the starting material (IIA) the intermediates (IIB) and (IIC) may contain an NR₂ group where R is at least one moiety selected from the group consisting of hydrogen and alkyl groups having from about 1 to about 10 carbon atoms, in place of the OH group shown above. The combined embodiments may be shown as:

where X is selected from the group consisting of OH and NR₂ with R being at least one moiety selected from the group consisting of hydrogen and alkyl groups having from about 1 to about 10 carbon atoms.

In another embodiment describing the synthesis of another novel chiral ligand, the general reaction is as follows:

In this embodiment, a chiral ligand having the structure (III) where "Ph" represents a phenyi group, can be synthesized from the starting material of dibenzofuran-1-carboxylic acid (IIIA). Again, as described in greater detail above, the starting material is treated with sec-butyllithium, π-butyllithium, tetf-butyllithium, methyllithium, or lithium diisopropylamide to afford 2-lithio-dibenzofuran-1-carboxylic acid (NIB) followed by transmetalation with magnesium bromide and reaction with α-bromomethyl styrene to form the 2-(2-phenyl-2-propenyl)- dibenzofuran-1-carboxylic (IIIC). Deprotonation with methyllithium or methyl magnesium bromide leads to ring-closure and the formation of 2-phenyl-4-naphtholbenzofuran (HID). Oxidative coupling, preferably with air, results in the formation of the structure (III) above,

2,2'-diphenyl-[3,3'-binaphthobenzofuran]-4,4'-diol, which can be resolved into two enantiomers using common resolution techniques. Additional specific embodiments can be readily extrapolated from the detailed descriptions of the chiral ligand (III) synthesis, such as solvent choices, reaction temperatures, resolution of the product ligand and the like. Conditions for each of the reactions are as described in detail above.

In an alternate, less preferred, embodiment, the starting material (IIIA) the intermediates (IIIB) and (IIIC) may contain an NR₂ group where R is at least one moiety selected from the group consisting of hydrogen and alkyl groups having from about 1 to about 10 carbon atoms; the NR₂ group being present in place of the OH group shown above. The combined embodiment may be shown as:

In yet another embodiment of the invention, the general reaction is as follows:

In this embodiment, a chiral ligand having the structure (IV) where "Ph" represents a phenyi group, and R1 can be hydrogen or an alkyl group having from 1 to about 14 carbon atoms, and R2 can be hydrogen or an alkyl group having from 1 to about 14 carbon atoms can be synthesized from the starting material of substituted naphthoic acids. Note however, that if both R1 and R2 are hydrogen, the VAPOL ligand is the chiral ligand that is formed. For ease of understanding this example will be explained for the specific case where R1 and R2 are methyl groups. It must be understood, however, that other alkyl groups as well as hydrogen may be successfully employed as R1 and R2. As described in greater detail above, the starting material is treated with sec-butyllithium, π-butyllithium, tetf-butyllithium, methyllithium, or lithium diisopropylamide to afford 2-lithio-7,8-dimethyl-naphthoic amide (IVB) followed by transmetalation with magnesium bromide and reaction with α-bromomethyl styrene to form the 2-(2-phenyl2-propenyl)-7,8-dimethyl-naphthoic amide (IVC). Deprotonation with methyllithium or methyl magnesium bromide leads to ring-closure and the formation of 2-phenyl-7,8-dimethyl-4-hydroxyphenanthrene

(IVD). Oxidative coupling, preferably with air, results in the formation of the structure

(IV) above 3,3'-bi-2-phenyl-7,8-dimethyl-4-hydroxyphenanthrene, which can be resolved into two enantiomers using common resolution techniques. One skilled in the art would readily extrapolate the foregoing description to applications where R1 and R2 are hydrogen or other alkyl groups having from about 2 to about 14 carbon atoms. Additional specific embodiments can be readily extrapolated from the detailed descriptions of the chiral ligand (IV) synthesis, such as solvent choices, reaction temperatures, resolution of the product ligand and the like. Conditions for each of the reactions are as described in detail above The VAPOL ligand may be synthesized by the preferred approach used for the chiral ligand (IV), and similarly, the chiral ligand (IV) may be synthesized by the approach discussed in detail above for the VAPOL ligand. The combined approaches may be as shown by the general reaction:

where Ph is a phenyi group, R1 and R2 are selected from the group consisting of hydrogen and alkyl groups having from 1 to about 14 carbon atoms, X is selected from the group consisting of OH and NR2 with R being at least one moiety selected from the group consisting of hydrogen and alkyl groups having from about 1 to about 10 carbon atoms.

It is further contemplated that the present invention may be used to form the chiral ligand:

where Ph is a phenyi group and R1 , R2, R3, and R4 are independently selected from the group consisting of hydrogen and alkyl groups having from 1 to about 14 carbon atoms, is synthesized by: (1) reacting starting materials:

where X is selected from the group consisting of OH and NR₂ with R being at least one moiety selected from the group consisting of hydrogen and alkyl groups containing from 1 to about 10 carbon atoms, with sec-butyllithium, ti-butyllithium, tetf-butyllithium, methyllithium, or lithium diisopropylamide to afford the corresponding lithiated compounds:

(2) transmetalating the lithiated compounds with magnesium bromide and reacting the product formed thereby with α-bromomethyl styrene to form a set of corresponding first intermediates:

(3) deprotonating the first intermediates with methyllithium or methyl magnesium bromide to form a set of corresponding second intermediates:

and (4) oxidatively coupling the set of second intermediates with air to form the chiral ligand:

Each of reactions (1)-(3) above may be carried out using the sets of reactants as shown, or each of reactions (1)-(3) may be carried out independently using only one of the two starting materials and the corresponding intermediates for the chosen starting material. In the latter case, the intermediate products of reaction (3) derived from each starting material are combined in reaction (4). Conditions for each of the reactions are as described in detail above.

Of the many possible uses of the chiral ligands described herein, use as a chiral catalyst is very desirable. In a catalytic compound, the chiral ligand may be present as a complex with a metal. The ratio of metal to chiral ligand in the catalytic compound is in the range of from about 1 :1 metakchiral ligand ratio to about a 1 :2 metahchiral ligand ratio. Although not required, it is preferred that the metal have a +4 valence. The metal is selected from those capable of forming the complex with the chiral ligand(s) and capable of catalyzing the reaction of interest. For example, to catalyze an aldol reaction, suitable metals include those in Group IVB of the Periodic Table, including zirconium, hafnium and titanium. In an aldol reaction application, it is preferred that the ligands (II) and (IV) be present in a ratio of 1:2 metal to ligand, and the preferred metal is zirconium. When forming the catalytic complex in a 1:2 metal:ligand ratio, it is preferred that either two R- ligands or two S- ligands are complexed with the metal to form the novel catalytic compound. Which enantiomer is chosen depends on the desired enantiomeric product. One skilled in the art would readily be able to determine which ligand enantiomer is required for the formation of the desired enantiomer product.

The catalytic complexes are produced by forming a reaction mixture containing the ligand and a metal alkoxide in a solvent. It is preferred that the mixture be at room temperature. It is also preferred that the ligand be of greater than about 95% enantiomeric excess, and also preferred that the ligand be of greater than about 99% enantiomeric excess. It is most preferred that the ligand be chemically pure. In an aldol reaction application, the preferred metals of the metal alkoxide are zirconium, hafnium and titanium. The mixture is stirred to form the catalytic complex, preferably at room temperature, and the catalytic complex is recovered. Generally, it is the ratio of ligand and metal alkoxide that are added to the reaction mixture that controls the ratio of metal to ligand in the end catalytic compound.

The catalytic compound may additionally contain an activator. The activator is typically a monodentate ligand capable of binding to the apical site of the catalytic compound to maintain an octohedral geometry. Both the size of the activator and the bacisity of the activator influence the enantioselectivity of the catalytic compound. Too large of an activator may inhibit the induction. In the aldol reaction application, suitable activators include N-methylimidazole, imidazole, N-benzoimidazole, pyridine, dimethylaminopyridine, with preferred activators being N-methyiimidazole and imidazole. The activator may be incorporated into the catalytic compound at the time the compound is formed, or it may be added later. For instance, the activator may be part of the reaction mixture where the catalytic compound is used. Even if the activator is incorporated at the time the catalytic compound is formed, it may also be added to the reaction mixture in an excess to facilitate a high degree of enantiomeric excess in the product. Regardless of when the activator is incorporated, it is preferred to have the amount of activator in the reaction mixture exceed that of the catalytic compound in order to maintain the desired ratio metal:ligand:activator ranging from 1 :L:1 to about 1 :L:2 where L is 1 or 2.

EXAMPLE 1

To prepare the α-bromomethyl styrene reactant, a mixture of 94.4 g (0.8 mol) of α-methyl styrene, 90.0 g (0.5 mol) N-bromosuccinimide and 50 mL of carbon tetrachloride contained in a flask fitted with a reflux condenser and magnetic stirrer was heated to 160-170°C until the mixture was refluxing and dissolving. As the exothermic reaction subsided, the mixture was allowed to cool down slowly over a period of 3 hours. The precipitated succinimide was separated by filtration and the carbon tetrachloride and excess α-bromomethyl styrene were removed under reduced pressure. The residue was distilled and 74% yield of a mixture of α-bromomethyl styrene and β-bromomethyl styrene as an 80:20 mixture was obtained. The mixture was not separated due to the lack of effect due to the presence of β-bromomethyl styrene on later reactions.

EXAMPLE 2

To prepare N,N-diisopropylnaphthamide as a starting material for the process of the invention, first 1-naphthol chloride was prepared. A benzene solution (30 mL) of 1-naphthoic acid (25 g) and thionyl chloride (11.6 mL) was prepared and dimethylformamide (5 mL) was added with stirring. Vigorous gas evolution ensued with gradual dissolution of the solid. After 2 hours, the benzene and excess thionyl chloride were evaporated under reduced pressure. The residue was distilled under reduced pressure and 1-naphthoyl chloride was obtained as light yellow oil in 96% yield. Using this 1-naphthol chloride, N,N-diisopropylnaphthamide was formed by the Schotten-Baumann method. Diisopropylamine (14 mL) and 10 weight % aqueous sodium hydroxide (90 mL) were added to a flask. Then 22 g of the 1-naphthoyl chloride was added with vigorous stirring. After 10-15 minutes, the crude N,N-diisopropylnaphthamide was obtained as a white powder in 80% yield after recrystallization from ethyl acetate.

EXAMPLE 3

The N.N-diisopropylnaphthamide prepared in Example 2 (1.02 g, 4 mmol) was placed in solution with tetrahydrofuran (50 mL). At -78°C and under argon, 3.4 mL of 1.3 M sec-butyllithium solution (4.4 mmol) was added by syringe. After 30 minutes, a freshly prepared 1.0 M solution of magnesiumbromide etherate in ether (12 mmol) was added to the reaction mixture. The reaction mixture was allowed to warm to room temperature and again cooled to -78°C and stirred for 40 minutes. α-Bromomethyl styrene (0.87 g, 4.4 mmol), prepared in Example 1 , was then added and the solution was allowed to warm to room temperature overnight. The reaction was quenched by the addition of 50 mL of saturated aqueous ammonium chloride solution. After flash chromatography 1.19 g of

2-(2-phenyl-2-propenyl)-N,N-diisopropyl naphthamide was obtained as a white solid in 80% yield.

The 2-(2-phenyl-2-propenyl)-N,N-diisopropyl naphthamide (0.9 g, 2.4 mmol) was placed in solution with tetrahydrofuran (50 mL) and stirred. At -78°C and under argon, 3.4 mL of 1.4 M methyllithium ether solution was added. The reaction mixture immediately turned black, and was allowed to warm to room temperature and stirred at room temperature overnight. A saturated aqueous solution of ammonium chloride (50 mL) was added to quench the reaction. After flash chromatography, 0.59 g of 2-phenyl-4-hydroxyphenanthrene was obtained as a light brown solid in 90% yield.

Claims

WHAT IS CLAIMED IS:

1. A chiral ligand selected from the group consisting of:

where Ph is a phenyi group and R1 , R2, R3, and R4 are selected from the group consisting of hydrogen and alkyl groups having from 1 to about 14 carbon atoms, and where at least one of R1 , R2, R3, or R4 is an alkyl group. The chiral ligand of Claim 1 wherein R1 and R3 are identical, and R2 and R4 are identical. A process for making chiral ligand

where Ph is a phenyi group and R1 and R2 are selected from the group consisting of hydrogen and alkyl groups having from 1 to about 14 carbon atoms, said process comprising: a) reacting starting material:

where X is selected from the group consisting of OH and NR₂ with R being at least one moiety selected from the group consisting of hydrogen and alkyl groups containing from 1 to about 10 carbon atoms, with sec-butyllithium, n-butyllithium, tetτ-butyllithium, methyllithium, or lithium diisopropylamide to afford the corresponding lithiated compound:

b) transmetalating the lithiated compound with magnesium bromide and reacting the product formed thereby with α-bromomethyl styrene to form a corresponding first intermediate:

c) deprotonating the first intermediate with methyllithium or methyl magnesium bromide to form a corresponding second intermediate:

d) oxidatively coupling the second intermediate to form the chiral ligand.

4. The process of Claim 3 wherein the deprotonating of 3(c) uses methyllithium and where the reactions of 3(a), 3(b) and 3(c) are each conducted initially at a temperature in the range of from about -78°C to about -20°C.

5. The process of Claim 4 wherein the reactions of 3(b) and 3(c) are each warmed from the initial temperature to ambient temperature during the course of the reaction.

6. The process of Claim 5 wherein the reactions of 3(b) and 3(c) are stirred at ambient temperature for a period of time ranging from about 1 to about 18 hours.

7. The process of Claim 3 wherein the reactions of 3(b) and 3(c) are quenched using water or a Bronsted acid.

8. The process of Claim 3 wherein the reactions of 3(b) and 3(c) are quenched using saturated ammonium chloride. A process for making a chiral ligand selected from the group consisting of:

where Ph is a phenyi group, said process comprising: a) reacting a starting material selected from the group consisting of:

where X is selected from the group consisting of OH and NR₂ with R being at least one moiety selected from the group consisting of hydrogen and alkyl groups containing from 1 to about 10 carbon atoms with sec-butyllithium, n-butyllithium, tetf-butyllithium, methyllithium, or lithium diisopropylamide to afford the corresponding lithiated compound selected from the group consisting of:

b) transmetalating the lithiated compound with magnesium bromide and reacting the product formed thereby with α-bromomethyl styrene to form a corresponding first intermediate selected from the group consisting of:

c) deprotonating the first intermediate with methyllithium or methyl magnesium bromide to form a corresponding second intermediate selected from the group consisting of:

d) oxidatively coupling the second intermediate to form the chiral ligand II or III.

10. The process of Claim 9 wherein the reactions of 9(a), 9(b) and 9(c) are each conducted initially at a temperature of from about -78°C to about -20°C.

11. The process of Claim 10 wherein the reactions of 9(b) and 9(c) are each warmed from the initial temperature to ambient temperature during the course of the reaction.

12. The process of Claim 11 wherein the reactions of 9(b) and 9(c) are stirred at ambient temperature for a period of time ranging from about 1 to about 18 hours.

13. The process of Claim 9 wherein the reactions of 9(b) and 9(c) are quenched using water or a Bronsted acid.

14. The process of Claim 9 wherein the reactions of 9(b) and 9(c) are quenched using saturated ammonium chloride.

15. A process for making chiral ligand

where Ph is a phenyi group and R1 , R2, R3, and R4 are selected from the group consisting of hydrogen and alkyl groups having from 1 to about 14 carbon atoms, said process comprising: a) reacting starting material:

where X is selected from the group consisting of OH and NR₂ with R being at least one moiety selected from the group consisting of hydrogen and alkyl groups containing from 1 to about 10 carbon atoms, with sec-butyllithium, n-butyllithium, tetf-butyllithium, methyllithium, or lithium diisopropylamide to afford the corresponding lithiated compounds:

b) transmetalating the lithiated compounds with magnesium bromide and reacting the products formed thereby with α-bromomethyl styrene to form corresponding first intermediates:

c) deprotonating the first intermediates with methyllithium or methyl magnesium bromide to form corresponding second intermediates:

d) oxidatively coupling the second intermediates to form the chiral ligand.

16. The process of Claim 15 wherein the deprotonating of 15(c) uses methyllithium and where the reactions of 15(a), 15(b) and 15(c) are each conducted initially at a temperature in the range of from about -78°C to about -20°C.

17. The process of Claim 16 wherein the reactions of 15(b) and 15(c) are each warmed from the initial temperature to ambient temperature during the course of the reaction.

18. The process of Claim 17 wherein the reactions of 15(b) and 15(c) are stirred at ambient temperature for a period of time ranging from about 1 to about 18 hours.

19. The process of Claim 15 wherein the reactions of 15(b) and 15(c) are quenched using water or a Bronsted acid.

20. The process of Claim 15 wherein the reactions of 15(b) and 15(c) are quenched using saturated ammonium chloride.

21. A catalytic compound comprising a metal and chiral ligand where the ratio of metakchiral ligand is in the range of from about 1 :1 to about 1 :2 and where the chiral ligand is selected from the group consisting of:

where Ph is a phenyi group and R1 , R2, R3 and R4 are selected from the group consisting of hydrogen and alkyl groups having from 1 to about 14 carbon atoms, and where at least one of R1 , R2, R3, or R4 is an alkyl group, said catalytic compound further characterized in that when the molar ratio of metal hiral ligand is 1 :2, both chiral ligands are the same enantiomer.

22. The catalytic compound of Claim 20 wherein the metal is selected from the group consisting of zirconium, titanium and hafnium.

23. The catalytic compound of Claim 20 wherein R1 and R3 are identical and R2 and R4 are identical.

24. The catalytic compound of Claim 20 further comprising an activator in an amount so that the ratio of metal:Iigand:activator is in the range of from about 1 :L:1 to about 1:L:2 where L is selected from the group consisting of 1 and 2.

25. The catalytic compound of Claim 20 wherein the activator is selected from the group consisting of N-methylimidazole, imidazole, N-benzoimidazole, pyridine, dimethylaminopyridine.

26. A process for making a catalytic compound having a metal and chiral ligand where the ratio of metal:chiral ligand is in the range of from about 1 :1 to about 1 :2 and where the chiral ligand is selected from the group consisting of:

where Ph is a phenyi group and R1 , R2, R3 and R4 are selected from the group consisting of hydrogen and alkyl groups having from 1 to about 14 carbon atoms, and where at least one of R1 , R2, R3, or R4 is an alkyl group, said process comprising forming a reaction mixture containing a chiral ligand and a metal alkoxide and recovering the catalytic compound.

27. The process of Claim 26 wherein the metal of the metal alkoxide is selected from the group consisting of zirconium, titanium, and hafnium.

28. The process of Claim 26 wherein the reaction mixture further comprises an activator.

29. The process of Claim 26 wherein the activator is selected from the group consisting of N-methylimidazole, imidazole, N-benzoimidazole, pyridine, dimethylaminopyridine.