FIELD OF THE INVENTION The present invention relates to electronically perturbed asymmetric aromatic ligands. In one aspect it relates to polyfluorinated aromatic ligand catalysts that may be nucleophilically modifed. The ligands may be used in catalytic processes.

BACKGROUND OF THE INVENTION Modern asymmetric synthesis often calls for catalytic transformations. Understanding the balance of steric and electronic factors is required in order to fine-tune a catalyst to achieve optimal rate and selectivity in a particular reaction. The analysis of steric environments around metal centers has traditionally dominated attempts to explain and predict the outcome of metal-based enantioselective processes. In comparison, the importance of electronic effects in asymmetric induction was appreciated only in recent years.

Several known catalytic systems employ electronically diverse substituents on ligands in order to modulate reactivity of the metal center.

For example, in the catalytic asymmetric epoxidation of unfunctionalized olefins, electronic properties of substituents on chiral salen ligands determine the nature of transition state (M. Palucki et al J.

Am. Chem Soc. 1998,120,948). The later transition state leads to higher enantioselectivities and electronic attenuation of electrophilic Mn=O

centers affords higher levels of enantiomeric excess. Enhancement of enantioselectivity through incorporation of fluorine atoms on chiral phosphine ligands in the asymmetric hydrocyanation of olefins was documented (T. V. Rajanbabu, A. L. Casalnuovo J. Am. Chem. Soc. 1996, 118,6325). The concept of induced electronic asymmetry allows one to increase the enantioselectivity of rhodium-catalyzed hydroboration of olefins (A. Schnyder et al. Angew Chem. Int. Ed. Engl. 1995,34,931).

Much research has been devoted to the development of chiral ligands. Among these, the ("BINOL") and related molecules with axial chirality have found wide utility in asymmetric catalysis. Over the years, several modifications to the BINOL skeleton aimed at modifying its steric and electronic properties have been reported. For example, partially hydrogenated BINOL was used as a catalyst precursor in enanatioselective alkylation of aldehydes (A. S. C.

Chan et al. J. Am. Chem. Soc. 1997,119,4080), conjugate addition of diethylzinc to cyclic enones (F. Y. Zhang, A. S. C. Chan Tetrahedron: Asymmetry 1998,9,1179), and ring opening of epoxides (T. lida et al.

Angew. Chem. Int. Ed. Engl. 1998,37,2223). Incorporation of bromines into the 6 and 6'positions of BINOL, rather remote from the catalytic site, was shown to increase the enantioselectivity of the corresponding titanium catalysts in glyoxolate-ene reactions (M. Terada et al.

Tetrahedron Lett. 1994,35,1994). Bulky triarylsilyl groups at the 3 and 3' positions of BINOL led to increased levels of enantiofacial discrimination of prochiral aldehydes in asymmetric Diels-Alder reactions (Pu; L Chem.

Rev. 3,3'-dinitrooctahydrobinaphthol was applied in titanium-catalyzed asymmetric oxidation of methyl-p-tolylsulfide (Reetz, M. T. et al. Tetrahedron Lett. 1997,38,5273).

SUMMARY OF THE INVENTION The present invention relates to new asymmetric aromatic ligands that may be used as catalysts. The ligand may be any aromatic ring system

containing one or more electronegative substituents. Preferably, the electronegative substituents are fluorine and the aromatic ring system is axially chiral, such as a biphenyl, binaphthyl or bipyridine derivative. In one preferred embodiment, the aromatic ring system is a binaphthyl derivative.

Fluorine substitution of aromatic groups modifies their properties including configurational stability and catalytic activity. One issue is the nature of steric and electronic effects of fluorination on aromatic based catalysts. The basic premise is that alteration of stabilizing stacking and edge-face interactions significantly affects approach of certain substrates to catalytic reaction centers. Due to fluorine's high electronegativity, electron density in fluoronaphthyl rings is locoated at the periphery, rather than in the ring's centre. The present invention will be illustrated by examples such as preparation of enantiomerically pure fluorobinaphthyl ligands and their application in catalytic asymmetric processes.

In one aspect of the present invention, there is provided an asymmetric ligand comprising an aromatic ring system substituted with at least one electronegative radical.

In another aspect, there is provided a method of producing a fluorinated asymmetric ligand having an aromatic ring system comprising fluorinating the aromatic ring sytem.

In yet another aspect, the present invention relates to asymmetric ligands comprising an aromatic ring system substituted with at least one electronegative substituent that is modified through nucleophilic substitution. Preferably, the electronegative substituent is fluorine, and the modification consists of displacing fluorine atoms on a polyfluorinated aromatic ring system with a nucleophile. As one example, the fluorine atoms at the 7 and 7'positions of 5,5', 6,6', 7,7', 8,8'- octafluoro-2,2'-dihydroxy-1-1'-binaphthyl (F8BINOL) are selectively displaced with a nucleophile.

Accordingly, the present invention also provides a compound having the Formula III: Formula III wherein R2 and R2'are the same or different and are OR where R may be hydrogen, or Cl-C20 aromatic, aliphatic, linear or branched, saturated or unsaturated, unsubstituted or substituted with N, O, S, or P; PR'R"where R'and R"are the same or different and are hydrogen, or Cl-C20 aromatic, aliphatic, linear or branched, saturated or unsaturated, unsubstituted or substituted with N, O, S, or P; phosphine oxide; NR"'R""where R"'and R""are the same or different and are hydrogen, or Cl-C2. aromatic, aliphatic, linear or branched, saturated or unsaturated, unsubstituted or substituted with N, O, S, or P; SR""'R"""where R""'and R"""are the same or different and are hydrogen, or Cl-C20 aromatic, aliphatic, linear or branched, saturated or unsaturated, unsubstituted or substituted with N, O, S, or P; and R5, R5', R6, R6', R7, R7', R8 and R8'are independently hydrogen, fluorine, CN, NO2, OR (where R is as defined above), SO2Ar where Ar is any aromatic ring system, SOPh, Cl, Br, I, N3, NR3+ where each R is the same or different and may be as defined above, OAr where Ar is as defined above, SR where R is as defined above, NH2, a

nucleophile X, wherein X may be OR9, NR10R11, SR12, SiR13R14R15, SeR16 and wherein each of R9, R10, R11, R12, R13, R14, R15 and R16 may be the same or different and may be hydrogen, Cl-C20 aromatic, aliphatic, linear or branched, saturated or unsaturated, unsubstituted or substituted with N, O, S, or P; with the proviso that at least one of R5 and R5', R6 and R6', R7 and R7', and R8 and R8'is electronegative.

In one preferred embodiment, R5, R6, R7 and R8 are the same and are H or F, and R5', R6', R7'and R8'are the same and are H or F, with the proviso that R5, R6, R7 and R8 are not the same as R5', R6', R7'and R8'.

In another embodiment, R5, R5', R6, R6', R7, R7', R8 and R8'are all the same and are F.

More preferably, each of R, R', R", R"', R"", R""', and R"""are H, or Cl-C6 aromatic, aliphatic, linear or branched, saturated or unsaturated, unsubstituted or substituted with N, O, S or P; R7 and R7'are the same and are a nucleophile X, and R5, R5', R6, R6', R8 and R8'are the same and are F.

In still another aspect of the present invention, there is provided a method of generating a library of a predetermined number of asymmetric ligands comprising: a) Providing an aromatic ring system having at least one electronegative substituent; b) Selective substituting at least one electronegative substituent with a nucleophile; and c) Repeating steps a) and b) a predetermined number of times to obtain a predetermined number of ligands.

Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and

modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be better understood when the following description is read in connection with the accompanying drawings, in which: Figure 1 shows the preparation of a modified polyfluorinated catalyst; Figure 2 shows the configurational integrity of the polyfluorobinaphthyl core during nucleophilic modification; Figure 3 is a schematic diagram showing the chemistry at the 7 and 7'positions of the modified catalyst; Figure 4 shows the attachment of a modified catalyst to an electrode surface; Figure 5 shows experimentally observed cyclic voltammogram for the modified electrode surface; Figure 6 shows the attachment of a modified catalyst to a solid surface; Figure 7 shows the nucleophilic substitution at the 6,6'positions of the modified catalyst; Figure 8 is a schematic showing the chemistry of the nucleophilic modification at the 6 and 6'positions; Figure 9 illustrates internal nucleophilic displacement in monoprotected F8BINOL; and Figure 10 illustrates a synthesis scheme for preparing H4F4 ligands.

DESCRIPTION OF THE PREFERRED EMBODIMENT As previously mentioned, the present invention relates to aromatic asymmetric ligands containing at least one electronegative substituent.

Optionally, the ligands may be modified with a nucleophile.

The present invention will be exemplified, by way of example by disclosing the design a new family of polyfluoroaryl ligands that originate from ("BINOL"), a catalyst precursor of broad utility in asymmetric catalysis (R. Noyori Asymmetric Catalysis in Organic Synthesis, Wiley: New York, 1994). The structure of BINOL is shown in Formula I: Formula I While the present invention will be described herein in relation to BINOL derivatives, it will be readily appreciated by those skilled in the art that other compounds having similar structures and properties may be substituted for BINOL. In particular, any aromatic ring structure is suitable for use in connection with the invention. For example, benzene, pyridine, naphthalene, anthracene and their derivatives are suitable for use with the invention (e. g. polyfluorinated benzene and polyfluorinated naphthalene). More preferably, the aromatic ring is one that exhibits axial chirality due to steric hinderance, i. e. the rings are not free to rotate about an axis because of steric hinderance. Such ring systems are known to those skilled in the art, and include biphenyl, binaphthyl, bipyridine and their derivatives.

More preferably, the aromatic ring structure is binaphthyl or a derivative thereof. Most preferably, the aromatic ring structure is a 2,2' di-substituted binaphthyl derivative, where the substituent is hydroxy, Cl- C6 alkoxy, phenoxy, phosphino, phosphine oxide, primary or secondary

Cl-C6 amine, or primary or secondary sulfides. Some specific examples of such ring structures include the 2,2'dihydroxy, 2,2'dimethoxy, 2,2' diphosphine, 2,2'diphosphine oxide, and 2,2'diamino derivatives of binaphthyl. Further, while it may be desirable, it is not necessary that the substituents at the 2 and 2'positions be the same. For example, the aromatic ring may be a 2-hydroxy, 2'-amino derivative or the like.

Furthermore, while the present invention is described generally in relation to being an aromatic ring substituted with fluorine, it will be appreciated that any relatively small electronegative radical may be utilized. Electronegative radicals are well known to those skilled in the art and include radicals such as CN and NO2, OR where R is as defined above, SO2Ar where Ar is any aromatic ring system, SOPh, Cl, Br, I, N3, NR3+ where each R is the same or different and may be as defined above, OAr where Ar is as defined above, SR where R is as defined above, and NH2, that may be utilized in accordance with the present invention.

Preferable electronegative substituents include F, Cl, Br, I, CN, and NO2.

Fluorine is particularly useful in accordance with the present invention, since it is highly electronegative, and does not significantly affect the torsion angle of the aromatic moiety.

Without being limited by theory, the inventors postulate that since the van der Waals radius of fluorine atoms is about 0.27Å larger than that of hydrogen atoms (B. E. Smart Organofluorine Compound: Principles and Commerical Applications, R. E. Banks, ed., Chapter 3, Plenum Press: New York, 1994), the replacement of hydrogens for fluorines at the 5,5', 6, 6', 7,7', 8, and 8'positions of BINOL may affect the torsion angle minimally in the resulting 5,5', 6,6', 7,7', binaphthyl ("F8BINOL", Formula II below). More importantly, considerable electronic perturbations take place due to the net effect of eight fluorine atoms. The electron-deficient nature of the aromatic rings in Formula II should result in a higher oxidative stability compared to Formula I and increased acidity of the hydroxyl groups which could

potentially affect binding to metals and the corresponding substrates in the F8BINOL-mediated reactions. The increased acidity of the hydroxyl could also result in an increase in the lewis acidity of the bound metal compared to a non fluorinated binol analogue.

Formula II Optionally, one or more of the electronegative radicals may be selectively substituted with a nucleophile. More preferably, one or more fluorine atoms on the aromatic ring system are selectively displaced with a nucleophile on a polyfluorinated catalyst such as the catalyst 5,5', 6,6', 7,7', (F8BINOL).

Ligands suitable for use as nucleophiles are well known to those skilled in the art and generally include radicals such as alcohols, amines, thiols and phenols. Some examples of suitable nucleophiles include NH2-, PH3C-, PhNH-, ArS-, RO-, R2NH, ArO~, OH-, ArNH2, NH3, halogen, where, in each case, Ar is aromatic, and R may be the same or different and is Cl- C20 aromatic, aliphatic, linear or branched, saturated or unsaturated, unsubstituted or substituted with N, O, S, or P.

The present invention also relates to compounds of the Formula III: Formula III wherein R2 and R2'are the same or different and are OR where R may be hydrogen, Cl-C20 aromatic, aliphatic, linear or branched, saturated or unsaturated, unsubstituted or substituted with N, O, S, or P; PR'R"where R'and R"are the same or different and are hydrogen, or Cl-C20 aromatic, aliphatic, linear or branched, saturated or unsaturated, unsubstituted or substituted with N, O, S, or P; phosphine oxide; NR"'R""where R"'and R"" are the same or different and are hydrogen, or C,-C20 aromatic, aliphatic, linear or branched, saturated or unsaturated, unsubstituted or substituted with N, O, S, or P; SR""'R"""where R""'and R"""are the same or different and are hydrogen, or Cl-C20 aromatic, aliphatic, linear or branched, saturated or unsaturated, unsubstituted or substituted with N, O, S, or P; and R5, R5', R6, R6', R7, R7', R8 and R8'are independently hydrogen, fluorine, CN, NO2,, OR (where R is as defined above), SONAR where Ar is any aromatic ring system, SOPh, Cl, Br, I, N3, NR3+ where each R is the same or different and may be as defined above, OAr where Ar is as defined above, SR where R is as defined above, NH2, a

each R is the same or different and may be as defined above, OAr where Ar is as defined above, SR where R is as defined above, NH2, a nucleophile X, wherein X may be OR9, NR10R11, SR12, SiR13R14R15, SeR16 wherein each of R9, R10, R11, R12, R13, R14, R15, and R16 may be the same or different and may be hydrogen, Cl-C20 aromatic, aliphatic, linear or branched, saturated or unsaturated, unsubstituted or substituted with N, O, S, or P; with the proviso that at least one of R5 and R5', R6 and R6', R7 and R7', and R8 and R8'is electronegative.

In one preferred embodiment, R5, R6, R7 and R8 are the same and are H or F, and R5', R6', R7'and R8'are the same and are H or F, with the proviso that R5, R6, R7 and R8 are not the same as R5', R6', R7'and R8'.

In another embodiment, R5, R5', R6, R6', R7, R7', R8 and R8'are all the same and are F.

In a preferred embodiment, R5, R5', R6, R6', R8 and R8'are fluorine atoms; R7 and R7'are the same, and are a nucleophile X. In another preferred embodiment, R5, R5', R8 and R8'are fluorine atoms, R6 and R6'are the same and are a nucleophile X, and R7 and R7'are the same and are a nucleophile Y where Y has the same definition as X and where X and Y may be the same or different.

Preferably, the nucleophiles X and Y are an OR group, where R is as defined above, and the modified catalyst is prepared from the bis (methylether) or bis (benzyl ether) of FgBINOL (i. e. where R2 and R2'are methoxy, or benzyloxy) according to the reaction scheme shown in Figure 1.

More preferably, the nucleophiles X and Y are a methoxy or ethoxy group. It will be understood by those skilled in the art that different catalytic applications will have different preferred substiutents.

While the foregoing describes nucleophilic substitution of BINOL at the 7 and 7'positions, it will be readily appreciated by those skilled in the art that the fluorine atoms at other positions may be additionally or alternately substituted. For example, Figure 7 shows the

selective displacement of fluorine atoms at positions 6 and 6'with the nucleophiles X and Y in a modified F8BINOL containing the ligand A, B or C (where A, B, and C may independently be as previously defined for X) groups at positions 7 and 7'. Figure 8 shows the stereochemistry of a modified F8BINOL containing nucleophiles at the 6,6', 7 and 7'positions.

In this manner, a matrix of different catalysts may be prepared. Such a matrix is useful in determining what combination of substitutions is most useful for any particular catalytic application.

Selective substitution of the fluorine groups at the 7 and 7' positions with the methoxy group takes place in 95% yield with remarkable selectivity. The configuration integrity of the polyfluorobinaphthyl core during the methoxylation process is shown in Figure 2.

Figure 3 is a schematic diagram showing the chemistry of the modified catalyst at the 7 and 7'positions. The favourable conformation of the modified catalyst leads to many improved properties and utilities for the catalyst. For example, facile modification at the 7,7' positions suggests the possibility of placing the catalytic reaction center in that area.

Direct connection of heteroatoms by nucleophilic substitution should lead to novel C2 symmetrical ligands. Their monodentate nature will result from the steric constrains that should defeat chelation. In order to create different bidentate sites at the 7 and 7'positions, linkers of varied lengths may be attached to the 7 and 7'positions. Examples of linkers and their methods of attachment are well known in the art. Examples of linkers include-OCH2CH2NH2,-OCH2CH2OH,-OCH2NH2,-OCH2PH2,- CH2CH2SH, etc.

It will be appreciated by those skilled in the art that the compounds of the present invention may be in racemic or optically pure form. In a preferred embodiment, the compounds are in the optically pure S form.

The examples following particularize the preparation of compounds within the scope of the present invention. Generally

speaking, unsubstituted polyfluorinated compounds may be prepared according to Scheme 1. While reference is made to fluorinated aromatics, it will be appreciated that similar standard processes may be used for other compounds within the scope of the present invention.

Scheme 1a "Key (a) n-BuLi, ether,-78 °C ; (b) 3-methoxythiophene,-78 °C to r. t.: (c) NBS, acetonitrile. r. t. ; (d) Cu°, 175 °C; (e) BBr3, dichloromethane, r t.

Nucleophilic displacement of aromatic fluorine is a well known reaction with a wide scope and utility [Welch, 2000 #14]. The presence of the fluorine atoms in the 2,2' dihydroxy BINOL derivative (compound la in Formula IV) suggests nucleophilic substitution as a potential route to ligand modification. Standard methoxylation with NaOMe of 5,5', 6,6', 7,7', 8,8'-octafluoro-1, 1'-binaphthyl (compound 1b in Formula IV) results in nucleophilic substitution of fluorine, but a complicated mixture of poly (methoxylated) products is obtained, indicating lack of regioselectivity. However, the presence of the methoxy substituents at the 2 and 2'positions in the bis (methyl) ether (compound 1c in Formula IV) is sufficient to secure high regioselectiveity of the methoxylation reaction.

Double substitution proceeds smoothly and results in the 7,7'- bis (methoxy) product in good chemical yield and with high regioselectivity.

Formula IV Other alkoxy nucleophiles behave in a similar manner and may be similarly substituted (See Scheme 2 below). However, subsequent dealkylation with boron tribromide suffers from poor chemoselectivity.

Therefore, the use of the bis (benzyl) ether (compound Id in Formula IV) or another selective protective group which benefits from selective deprotection via hydrogenation, is preferable in order to arrive at the final bis-2,2'-hydroxy stage.

No racemization is observed when enantiomerically pure bis (methoxy) derivative (compound Ic in Formula IV) is used in the methoxylation reaction.

Scheme 2 F F III FI w w OR'NaOH, ROH (5 eq) ROt WOR' F _ F F THF, reflux, 24h I--Z-17 /i F F R R'yield (%) <BR> <BR> Me Me 95<BR> <BR> Et Bn 88<BR> <BR> iPr Bn 88<BR> <BR> tBu Bn 88

It will, of course, be appreciated that the nucleophilical substitution process may be utilized with not only the binaphthyl derivatives above described, but with any of the aromatic ring systems previously described.

For example, the selective substitution may be be used on polyfluorinated benzene or polyfluorinated naphthalene systems, or indeed any aromatic ring system having at least one electronegative radical.

Those skilled in the art will understand that the compounds of the present invention have many useful applications. Such applications include asymmetric catalysis with main group elements, transition metal and lanthanide metals; asymmetric reagent with main group elements, transition metal and lanthanide metals; polymer supported catalysis; incorporation of molecules into crown ethers for development of phase transfer catalysts; use of compounds as a monomer for polymerization; asymmetric polymer supported electrochemical oxidation catalysis; as a chiral auxiliary in an asymmetric reaction; as a resolving agent for chiral compounds, including but not limited to amines; asymmetric catalysis (reagent) in fluorous phase reactions; as a chiral stationary phase for HPLC and other chromatographic techniques; phase transfer catalyst between organic, fluorous phase and alkali solutions.

One specific application is to develop combinatorial approaches to catalyst development. It is possible to determine which substitution pattern on the F8BINOL moiety gives optimal catalyst with regard to rate and selectivity in a particular reaction. To address this issue, the dihedral angle and electron distribution in BINOL may be varied by replacing fluorine atoms at the 7,7' positions with a variety of nucleophiles to develop analogs of F8BINOL.

It is also possible to generate libraries of such analogs using solution and solid-phase parallel synthesis. The structure/activity relationships may be deciphered based on screening the resulting catalyst libraries in a variety of reactions including hetero Diels-Alder, aziridination, direct aldol, and imine hydrogenation processes.

A library of compounds may also be generated for any other suitable purpose. For example, it is possible to build a library of compounds for pharmaceutical testing. With the highly selective substitution, it is possible to start with a base compound and develop a number of related but different compounds by selectively substituting different nucleophiles at the same or different locations on the base compound. Pharmacological activity screening may then be done on the library of compounds to determine which compounds have the highest activity.

The highly selective nucleophilic functionalization of the F8BINOL core will allow the attachment of the modified catalysts to an electrode surface or a solid support. Figure 4 shows the attachment of the modified catalyst to an electrode surface and Figure 5 shows experimentally observed cyclic voltammogram for the modified electrode surface.

Figure 6 shows the attachment of the modified catalyst to a solid support. In particular, Figure 6 exemplifies an approach toward libraries of TentaGel S OH resin-linked catalysts. An alternative to this strategy is to introduce functionality X directly onto the ligand-derivatized resin. On bead screening for the catalytic activity will allow the fine-tuning of the ligand's torsion angle using solid-phase chemistry by manipulating the 7,7' substituents. It should be emphasized that established routes to modified BINOL involve rather harsh electrophilic functionalization which puts substituents into the 6,6' positions and necessitates a subsequent resolution step which is not feasible under combinatorial protocols commonly performed on a microgram scale. On the contrary, high configurational stability of F8BINOL under basic conditions will enable the use the homochiral starting material without the loss of enantiomeric purity during the nucleophilic substitution. As well, substituents at the 7,7' positions could have direct steric influence over the dihedral angle which should modulate the catalytic activity, a feature not available for the 6,6' substitution pattern.

Figure 9 shows internal nucleophilic displacement in monoprotected F8BINOL which illustrates that the axial chirality of F8BINOL provides convenient access to ligands with helical chirality.

Utility of the poly (alkoxylated) ligands in asymmetric catalysis was illustrated using diethylzinc addition to aldehydes. We observed high levels of enantioselectivity in titanium-catalyzed addition of diethylzinc to aldehydes using x and x under the conditions where the formation of the monomeric catalysts of 1: 1 composition is favored.

All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

The following examples, which are non-limiting, are illustrative of the present invention. The scope of the invention is limited only by the claims.

EXAMPLES 1. FLUORINE SUBSTITUTION OF BINOL (a) 5,5', 6,6', 7,7', Racemic form of the compound 5,5', 6,6', 7,7', 8,8'-octafluoro-2,2'- dihydroxy-1,1'-binaphthyl (compound 2 in Scheme 1) was prepared according to Scheme 1 above. Tetrafluorobenzyne, formed by treating commercially available chloropentafluorobenzene with n-butyllithium at -78°C, was reacted with 3-methoxythiophene, obtained from 3- bromothiophene using a literature procedure (methoxythiophene preparation). Upon the in situ extrusion of sulfur, 2-methoxy-5,6,7,8- tetrafluoronaphthalene (Formula III) was obtained in 52% yield. 5,6,7,8- Tetrafluoro-2-naphthol, prepared from 2-methoxy-5,6,7,8- tetrafluoronaphthalene by demethylation with BBr3, did not undergo the FeCl3-catalyzed oxidative coupling, commonly used for the preparation of BINOL from 2-naphthol (BINOL prep via Fez'3 coupling). Instead,

substitution of hydrogen for chlorine at the 1 position of the aromatic ring took place. Higher oxidation potential of 5,6,7,8-tetrafluoro-2- naphthol (2.07V vs Ag/AgCl compared to 1.47V vs Ag/AgCl for BINOL) is a likely reason for the lack of reactivity in the oxidative coupling.

Therefore, the reductive route through intermediacy of the 1- brominated derivative (compound 4 in Scheme 1), prepared in 52% yield from compound 3 in Scheme 1 by treatment with N-bromosuccinimide in acetonitrile, was utilized. The Ullmann homocoupling of the 1-bromo derivative, facilitated by the presence of aromatic fluorines, gave the desired bis (methoxy) product (compound 5 in Scheme 1) in 85% yield.

Demethylation of the bis (methoxy) derivative with BBr3 furnished F8BINOL (compound 2 in Scheme 1) in 88% yield. Finally, recrystallization from methanol/water gave pure FBINOL as white needles. After several unsuccessful attempts at resolving F8BINOL, the diastereomeric bis (menthyl) carbonates were chromatographically separated by reacting racemic F8BINOL with excess (-)- menthylchloroformate. Treatment of each diastereomer with dilute NaOH followed by extraction with diethyl ether afforded (-)-F8BINOL and (+)-F8BINOL, respectively. The enantiomeric excess, determined using chiral HPLC (Chiralpak AD column), was found to be >99.9% in each case.

(b) 8-tetrafluoro-1-naphthol Replacement of aromatic hydrogens for fluorines is known to substantially increase barriers to axial torsion in substituted biphenyls. For example, fluorination of the 4 and 5 positions of 9,10- dihydrophenanthrene raises the torsion barrier from 4.1 to 10.3 kcal/mol (M. Schlosser, D. Michel Tetrahedron 1996,52,99 and references cited therein). In order to estimate the effect of polyfluorination on atropisomerism in the octafluoro-1,1'-binaphthyl species racemic 5,6,7,8- octafluoro-1,1'-binaphthyl (compound 6 below) was prepared and its X-ray structure determined. Racemic was

prepared from 5,6,7,8-tetrafluoro-1-naphthol (G. W. Gribble, C. G.

LeHoullier, M. P. Sibi, R. W. Allen J. Org. Chem. 1985,50,1611) by Ni (0)- catalyzed homocoupling of its trifluoromethanesulfonate ester in NMP at 100 °C. The torsion angles in the molecular structures of BINOL and F8BINOL were not compared due to the possibility of intramolecular OH- F hydrogen bonding in the crystal lattice that could have complicated direct comparison of geometric parameters. Remarkably, the torsion angle between the two tetrafluorinated naphthyl planes in 5,6,7,8-octafluoro- 1,1'-binaphthyl is only 0.7° larger than in the parent hydrido derivative (70.2° for octafluoro-1,1'-binaphthyl vs 69.5° for 1,1'-binaphthyl (R.

Kuroda, S. F. Martin J. Chem. Soc. Perkin Trans II 1981,167)).

To further understand atropisomerism in BINOL acid-promoted racemization of its (-) enantiomer was investigated. This process is known to operate for BINOL. Remarkably, BINOL remains optically active (99.9% e. e) after 24 hours in boiling THF/HCl mixture, whereas BINOL rapidly racemizes under these conditions! Polyfluorination of aromatic nuclei is also known to decrease pKa's of bound heteroatoms (B. E. Smart, in: Organofluorine compounds: Principles and Commercial Applications (R. E. Banks, ed.), Chapter 3, Plenum Press: New York, 1994). For example, incorporation of four fluorine atoms into the aromatic skeleton of tyrosine results in the pKa' decrease of the ring-bound hydroxyl group by 5 units (K. Kim, P. A. Cole J.

Am. Chem. Soc. 1998,120,6851). It was determined that the pKa'of the hydroxyl group in F8BINOL decreases by 1 unit upon octafluorination (BINOL: pKa'10.28; F8BINOL: pKa'9.29). Another important consequence of fluorination is anodic shift in the oxidation potential of BINOL, which was found to be more positive than that of binaphthyl by 0.6 V, a useful property for applications in oxidation catalysis.

These results lead to the conclusion that the effect of fluorine on the reactivity of F8BINOL is primarily electronic in nature. The desired conformational flexibility, one of the most important characteristics of BINOL allowing it to coordinate a wide variety of metals, should be preserved. Remarkable configurational stability of either enantiomer of BINOL is perhaps its most valuable property.

II. NUCLEOPHILIC SUBSTITUTION General: Anhydrous THF was obtained by distillation over sodium benzophenone ketyl under nitrogen. 2,2'-dimethoxy-5,5', 6,6', 7,7', 8,8'- octafluoro-1,1'-binaphthyl and 6,6', 7,7', 8,8'-octafluoro- 1,1'-binaphthyl were prepared according to literature procedures. Column chromatography was carried out using 230-400 mesh silica gel.

(a) 2,2', 7,7'-tetramethoxy-5,5', 6, 6', 8, 8'-hexafluoro-1, 1'-binaphthyl (1) To a solution of 6,6', 7,7', binaphthyl (91.7mg, 0.2mmol) in anhydrous THF (lOmL) was added 81RI (2.0mmol) methanol and 112mg (2.0mmol) KOH. The mixture was stirred and refluxed for 12hrs. The reaction mixture was diluted with ether and washed with aqueous HCl (5%). The result organic extract was dried over MgSO4 and concentrated. Purification of the residue by chromatography over silica afforded pure (1) (91. Omg, 84%) as white solid.

'HNMR (400 MHz, CDCl3) : 88.10 (d, J=9.2Hz, 2H), 7.42 (d, J=9.2Hz, 2H), 3.91 (S, 6H), 3.75 (S, 6H). 19FNMR (400MHz, CDCl3): # -148.93 (d, J=16.8Hz),- 152.65 (dd, J=16.8Hz, 3.2Hz),-158.80 (d, J=19.6Hz). 13CNMR (100MHz, CDCl3) : 8155.6 (s), 147.2 (dt, J=249.2Hz, 3.8Hz), 142.4 (ddd, J=249. 0Hz, 6. 1Hz, 4.6Hz), 139.9 (ddd, J=250. 0Hz, 9.2Hz, 4.5Hz), 135.9 (m), 121.6 (m), 120.9 (m), 117.2 (s), 116.0 (dd, J=9.9Hz, 4.5Hz), 114.3 (s), 62.5 (s), 56.9 (s). HREI-MS, m/z: Calcd for C24Hl6F604 482.0953; found, 482.0958.

(b) 6', 8, 8'-hexafluoro-1, 1'- binaphthyl (2) In accordance to the general procedure described above, but 116gel (2. 0mmol) ethanol was used instead of methanol. A total of 78. lmg (77%) of 2 was obtained as white solid.

'HNMR (400MHz, CDCl3) : 8 8.09 (d, J=9.2Hz, 2H), 7.38 (d, J=9.6Hz, 2H), 4.11 (q, J=6.8Hz, 4H), 3.73 (S, 6H), 1.29 (t, J= 6.8Hz, 6H).'9FNMR (400MHz, CDcl3) : 8-139.91 (d, J=16.8Hz),-152.68 (dd, J=16.8Hz, 2.8Hz),-158.08 (d, J=19.6Hz). 13CNMR (100MHz, CDCl3): 8155.6 (s), 147.6 (dt, J=249.3Hz, 3.8Hz), 142.3 (ddd, J=247. 0Hz, 6. 0Hz, 4.6Hz), 140.2 (ddd, J=246.0Hz, 9.2Hz, 4.5Hz), 134.8 (m), 121.5 (m), 120.9 (m), 117.2 (s), 116.1 (dd, J=9.8Hz, 3.8Hz), 114.2 (s), 71.0 (s), 56.9 (s), 15.5 (s). HREI-MS, m/z: Calcd for C26H20F604,510.1255; found, 510.1266.

(c) 6, 6', 8, 8'-hexafluoro-1, 1'- binaphthyl (3) In accordance to the general procedure described above, but 154R1 (2. 0mmol) iso-propanol was used instead of methanol. A total of 87.9mg (89%) of 3 was obtained as white foam.

'HNMR (400MHz, CDCl3) : 88.08 (d, J=9.2Hz, 2H), 7.38 (d, J=9.2Hz, 2H), 4.36 (sep, J=6. 0Hz, 2H), 3.71 (s, 6H), 1.23 (dd, J=6. 0Hz, 3.2Hz, 12H).

l9FNMR (400MHz, CDC13): 8-157.19 (d, J=19.6Hz),-152.81 (dd, J=16.8Hz, 2.8Hz),-138.60 (d, J=16.8Hz). 13CNMR (100MHz, CDC13): 8 155.6 (s), 148.2 (dt, J=250.0Hz, 3.8Hz), 142.3 (ddd, J=247.0Hz, 6.0Hz, 4.6Hz), 140.6 (ddd, J=245. 0Hz, 9.2Hz, 3.8Hz), 133.8 (m), 121.5 (m), 120.9 (m), 117.3 (s), 116.2 (dd, J=10.6Hz, 3.8Hz), 114.2 (s), 77.7 (s), 56.8 (s), 22.4 (s). HREI-MS m/z: Calcd for C28H24F604 538.1583; found, 538.1579.

(d) 2,2'-dimethoxy-7,7'-dibenzyloxy-5,5', 6,6', 8, 8'-hexafluoro-1, 1'- binaphthyl (4) In accordance to the general procedure described above, but 207tl (2.0mmol) benzyl alcohol was uesd instead of methanol. A total of 98.6mg (78%) of 4 was obtained as white foam.'HNMR (400MHz, CDCl3): 88.07 (d, J=9.2Hz, 2H), 7.37-7.22 (m, 12H), 5.06 (s, 4H), 3.68 (s, 6H).

"FNMR (400MHz, CDCl3) : 8-138.78 (d, J=16.8Hz),-152.49 (dd, J=16.8Hz, 2.8Hz),-157.48 (d, J=20.8Hz)."CNMR (100MHz, CDCl3) : 8155.6 (s), 147.6 (dt, J=250. 0Hz, 3.8Hz), 142.3 (ddd, J=247. 0Hz, 6.8Hz, 4.6Hz), 140.1 (ddd, J=246. 0Hz, 9. 1Hz, 3.8Hz), 136.3 (s), 134.4 (m), 128.7 (d, J=3.1HZ), 128.6 (d, J=4.6Hz), 128.5 (s), 121.6 (m), 120.9 (m), 117.2 (s), 116.2 (dd, J=9.8Hz, 4.6Hz), 114.3 (s), 76.5 (s), 56.9 (s). HREI-MS, m/z: Calcd for C36H24F604,634.1560; found, 634.1579.

(e) 2,2'-dibenzyloxy-5,5', 6, 6', 7,7', 8, 8'-octafluoro-1, 1'-binaphthyl (5) To a solution of 2,2'-dihydroxy-5,5', 6,6', 7,7', binaphthyl (215.2mg, 0.5mmol) and potassium carbonate (691mg, 5mmol) in THF (15mL) was added benzyl bromide (0.6mL, 5mmol). The mixture was stirred and refluxed for 20hrs. The reaction mixture was diluted with ether and washed with aqueous HCl (5%). The solvent and excess benzyl bromide were removed under reduced pressure. Recrystallization from a Hexanes and dichloromethane mixture gave white solid (224.2mg, 80%).

'HNMR (400MHz, CDC13): 88.16 (d, J=9.6Hz, 2H), 7.50 (d, J=9.6Hz, 2H), 7.23- 7.16 (m, 6H), 6.98-6.96 (m, 4H), 5.12 (s, 4H)."FNMR (300MHz, CDCl3): 8- 146.72 (t, J=17.7Hz),-150.55 (dd, J=16.2Hz, (t, J=20.1Hz),- 163.22 (t, J=20.1Hz).

(e) 5', 6, 6', 8, 8'-hexafluoro-1, 1'- binaphthyl (6) To a solution of 2,2'-dibenzyloxy-5,5', 6,6', 7,7', 8, 8'-octafluoro-1, 1'- binaphthyl (5) (224.2mg, 0.4mmol) and potassium hydroxide (224mg, 4. 0mmol) in THF (20mL) was added methanol (162µl, 4.0mmol). The mixture was stirred and refluxed for 12hrs. The reaction mixture was diluted with ether and washed with aqueous HCl (5%). The result organic extract was dried over MgSO4 and concentrated. Purification of the residue by chromatography over silica afforded pure (6) as white foam (197.9mg, 78%). lHNMR (400MHz, CDCl3): 87.93 (d, J=9.2Hz, 2H), 7.24 (d, J=9.6Hz, 2H), 7.01-6.96 (m, 6H), 6.76 (d, J=7.2Hz, 4H), 4.90 (s, 4H), 3.74 (s, 6H).

19FNMR (300MHz, CDcl3) : 8-140.18 (d, J=17.3Hz),-152.35 (dd, J=16.7Hz, 3. 1Hz), -158. 30 (d, J=21.5Hz).

(f) 2,2'-dihydroxy-7,7'-dimethoxy-5,5', 6, 6', 8, 8'-hexafluoro-1, 1'- binaphthyl (7) To a solution of 5', 6,6', 8,8'- hexafluoro-1,1'-binaphthyl (6) (126.5mg, 0.2mmol) was added Pd/C (85.2mg, 10%) under a hydrogen atmosphere at room temperature.

After being stirred at the same temperature for 10hrs, the reaction mixture was filtered and concentrated. Purification of the residue by chromatography over silica afforded pure (7) (quantitatively) as white <BR> <BR> <BR> <BR> foam.'HNMR (400MHz, CDCl3): 88.06 (d, J=8.8Hz, 2H), 7.30 (d, J=9.2Hz, 2H), 5.39 (s, 2H), 3.92 (s, 6H)."FNMR (400MHz, CDCl3): 8-142.14 (d, J=15.2Hz),-

151.24 (dd, J=16.8Hz, 2.8Hz),-157.16 (d, J=19. 6Hz). l3CNMR (100MHz, CDCl3) : 5 153.2 (s), 146.6 (dt, J=248.5Hz, 3.8Hz), 142.7 (ddd, J=248. 0Hz, 6. 0Hz, 4.6Hz), 140.3 (ddd, J=248. 0Hz, 8.3Hz, 4.6Hz), 136.7 (m), 123.5 (m), 120.5 (m), 118.5 (s), 115.9 (dd, J=10.6Hz, 3.8Hz), 108.6 (s), 62.5 (m). HREI-MS: m/z: calcd for C22H12F6O4 454. 0642; found, 454.0640.