DESCRIPTION

TRANSITION METAL FREE METHODS OF SYNTHESIS OF BIARYL

COMPOUNDS

This application claims the benefit of U.S. Provisional Application Serial No. 62/255,267, filed on November 13, 2105, the entirety of which is incorporated herein by reference.

BACKGROUND 1. Field

This disclosure relates to the methods of preparing biaryl compounds. In some aspects, the present disclosure provides transition metal free methods of synthesis to join to aryl groups to form biaryl compounds. 2. Related Art

Hindered rotation about the C-C bond in biaryl compounds renders the biaryl axis stereogenic, which is a key structural motif in a large number of natural products, pharmaceuticals, chiral auxiliaries, ligands and catalysts (FIG. 1) ( Bringmann et al., 2005a; Bringmann et al., 2005b; Wolf 2007; Bringmann et al., 2011 and Zask et al, 2013).

In fact, more than 1000 axially chiral natural products have been isolated and many of them exhibit remarkable biological activities (e.g., vancomycin, teicoplanin, streptonigrin, michellamines). Recently it was recognized that controlling the chirality of unsymmetrical biaryl structures will have enormous implications in the future development of pharmaceuticals (Clayden et al., 2009a; Clayden et al., 2009b; LaPlante et al., 2011a; LaPlante et al., 2011b). During the past two decades, both C ₂ - and non-C2-symmetrical axially chiral biaryl compounds (Bringmann et al., 2005a; Bringmann et al., 2005b and Wolf 2007) have played key roles as ligands for transition-metals in the development of catalytic enantioselective transformations, including cross-coupling reactions (Corey and Kiirti, 2010; Ojima, 2010; Busacca et al., 2011 and Magano and Dunetz, 2011). These transformations have revolutionized the synthesis of both structurally simple and complex chiral active pharmaceutical ingredients (APIs, which are the key components of modern medicines) by dramatically improving step-efficiency and reducing waste. Several reactions are even applicable on industrial scales (Chen et al., 2003; Kocovsky et al., 2003; Jacobsen et al., 2004; Akiyama 2007; Blaser and Federsel 2010 and Zhou 2011). Given the abundance of axially chiral biaryl compounds in nature as well as their importance in drug discovery, asymmetric catalysis and materials science, it is not surprising that a number of synthetic approaches have been developed for their construction (Anastasia and Negishi 2002; Hassan et al, 2002; Alberico et al, 2007; Ackermann, 2009; McGlacken and Bateman, 2009; Ashenhurst, 2010; Quideau, et al, 2014; Bencivenni, 2015 and Ma and Sibi, 2015). However, there are a number of biaryl linkages that remain exceedingly difficult to construct in an atom- and step-economical fashion. In particular, 2,2'-di-heteroatom substituted non-C ₂ - symmetrical Ι, -biaryls, such as the highly functionalized 2,2'-aminohydroxy-l, l '-biaryl motif found in TMC-95A and Streptonigrin, (FIG. 1) have not been readily accessible until recently (Gao et al, 2013), however serious challenges remain especially with regard to achieving diverse substitution patterns on the biaryl scaffold. Synthetic access is even more limited for non-C ₂ -symmetrical but configurationally stable biaryldiols (e.g., 2,2'-dihydroxy-l, l '-biaryl motif found in certain chiral phosphoric acids) as no general methods are currently available for their preparation (Dohi et al, 2011 ; Terada and Dan, 2012; Holtz- Mulholland et al., 2013 and Reddy Parumala and Peddinti, 2013). The scarcity of reliable methods is surprising as these atropoisomeric but non-C ₂ -symmetrical biaryldiols have been shown to be excellent ligands or catalysts in many catalytic reactions, especially in those where the C ₂ - symmetrical scaffolds were found to be ineffective (Kocovsky et al., 2003). Therefore, there remain a great need for new methods of preparing biaryl compounds for use as starting materials, building blocks, reaction catalysts, chiral auxiliaries, or as therapeutic agents.

SUMMARY

Thus, the present disclosure provides methods of synthesizing biaryl compounds which do not require transition metal catalysts.

In some aspects, the present disclosure provides methods of preparing a compound of the formula:

wherein:

X3 is -ORd or -NR _e Rf, wherein:

Rd is hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a hydroxy protecting group;

R _e and Rf are each independently hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a monovalent amino protecting group, or R _e and Rf are taken together and are a divalent amino protecting group;

R6 is hydrogen or alkyl(c<8), cycloalkyl(c<8), or a substituted version of either of these groups;

R7, Re, and R9 are each independently hydrogen, halo, or alkyl(c<8), cycloalkyl(c<8), alkoxy(c<8), or a substituted version of any of these groups; or R ₇ and Rs are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8); and

Y3, Y4, Y5, and Υβ are each independently hydrogen, halo, hydroxy, or alkyl(c<8), cycloalkyl(c<8), alkoxy(c<8), or a substituted version of any of these groups; or Y3 and Y4 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Y4 and Y5 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Y5 and Υβ are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8); comprising reacting a compound of the formula:

wherein:

R6, R7, Rs, and R9 are as defined above;

X3 is O or NR _e , wherein:

R _e is hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a monovalent amino protecting group;

Re' is hydrogen or alkyl(c<8), cycloalkyl(c<8), or a substituted version of either of these groups; with a compound of the formula:

wherein:

Y3, Y4, Y5, and Υβ are each independently hydrogen, halo, or alkyl(c<8), cycloalkyl(c<8), alkoxy(c<8), or a substituted version of any of these groups; or Y3 and Y4 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Y4 and Y5 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Y5 and Υβ are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8);

in the presence of an organic solvent and a solution phase acid.

In some embodiments, the solution phase acid is a Br0nsted acid. In some embodiments, the solution phase acid is a Br0nsted acid with a pK _a from about -10 to about 5. In some embodiments, the solution phase acid is a diester phosphoric acid(c<i 8)- In some embodiments, the solution phase acid is a diarylester phosphoric acid(c<i 8) such as diphenyl phosphoric acid. In other embodiments, the solution phase acid is a halocarboxylic acid(c<i2) such as trifluoroacetic acid.

In some embodiments, the organic solvent is a polar protic organic solvent. In some embodiments, the organic solvent is a polar aprotic organic solvent. In some embodiments, the organic solvent is a solvent with a dipole moment of greater than 1.4 debye. In some embodiments, the organic solvent is a solvent with a dipole moment of greater than 1.6 debye. In some embodiments, the organic solvent is a polar hydrocarbon(c<i2) or substituted hydrocarbon(c<i2). In some embodiments, the organic solvent is haloalkane(c<i2) such as dichloromethane. In other embodiments, the organic solvent is an alcohol(c<8) or substituted alcohol(c<8). In some embodiments, the organic solvent is a haloalcohol(c<8) such as fluoroalcohol(c<8). In some embodiments, the organic solvent is 2,2,2-trifluoroethanol. In other embodiments, the organic solvent is an arene(c<i2) or a substituted arene(c<i2). In some embodiments, the organic solvent is an arene(c<i2) such as toluene.

In some embodiments, the amount of the solution phase acid is from about 1 mol% to about

50 mol%. In some embodiments, the amount of the solution phase acid is from about 10 mol% to about 30 mol%. In some embodiments, the amount of the solution phase acid is about 20 mol%. In some embodiments, the ratio of the compound of formula VIII to the compound of formula IX is from about 1 : 1 to about 25: 1. In some embodiments, the ratio is from about 5: 1 to about 20: 1. In some embodiments, the ratio is about 10: 1.

In some embodiments, the methods comprise reacting the compound of formula VIII and the compound of formula IX for a time period from about 4 hours to about 48 hours. In some embodiments, the time period is from about 8 hours to about 36 hours. In some embodiments, the time period is from about 12 hours to about 24 hours. In some embodiments, the methods further comprise reacting the compound of formula VIII and the compound of formula IX at a temperature from about 20 °C to about 150 °C. In some embodiments, the temperature is about 20 °C to about 35 °C. In some embodiments, the temperature is about room temperature. In other embodiments, the temperature is about 80 °C to about 120 °C. In other embodiments, the temperature is about 100 °C. In some embodiments, the temperature is sufficient to cause the organic solvent to reflux.

In some embodiments, the solution phase acid is a diester phosphoric acid(c<i8) and the organic solvent is a haloalcohol(c<i2). In some embodiments, the temperature is about room temperature. In other embodiments, the solution phase acid is a halocarboxylic acid(c<i2) and the organic solvent is an arene(c<i2)- In some embodiments, the temperature is about 100 °C.

In another aspect, the present disclosure provides methods of preparing a compound of the formula:

wherein:

X3 is -ORd or -NR _e Rf, wherein: Rd is hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a hydroxy protecting group;

R _e and Rf are each independently hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a monovalent amino protecting group, or R _e and Rf are taken together and are a divalent amino protecting group;

and Re' are each independently hydrogen or alkyl(c<8), cycloalkyl(c<8), or a substituted version of either of these groups, or a monovalent amino protecting group;

Re, and R9 are each independently hydrogen, halo, or alkyl(c<8), cycloalkyl(c<8), alkoxy(c<8), or a substituted version of any of these groups; or R ₇ and Rs are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8); and

Y4, Y5, and Υβ are each independently hydrogen, halo, hydroxy, or alkyl(c<8), cycloalkyl(c<8), alkoxy(c<8), or a substituted version of any of these groups; or Y3 and Y4 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Y4 and Y5 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Y5 and Υβ are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8); or is a group of the formula:

wherein:

X5 is -ORk or -NRiRm, wherein:

Rk is hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a hydroxy protecting group;

Ri and R _m are each independently hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a monovalent amino protecting group, or R _e and Rf are taken together and are a divalent amino protecting group;

Ri4 and R14' are each independently hydrogen or alkyl(c<8), cycloalkyl(c<8), or a substituted version of either of these groups, or a monovalent amino protecting group;

Ri5, R16, and Rn are each independently hydrogen, halo, or alkyl(c<8), cycloalkyl(c<8), alkoxy(c<8), or a substituted version of any of these groups; or Rn and R12 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8);

comprising reacting a compound of the formula:

wherein:

R6, R7, Rs, and R9 are as defined above;

X3 is O or NR _e , wherein:

R _e is hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a monovalent amino protecting group;

with a compound of the formula:

wherein:

Y3, Y4, Y5, and Υβ are as defined above;

in the presence of an organic solvent and a solution phase acid.

In some embodiments, the solution phase acid is a Br0nsted acid such as a Br0nsted acid with a pK _a from about -10 to about 5. The solution phase acid may be a diester phosphoric acid(c<64)- In some embodiments, the solution phase acid is a diarylester phosphoric acid(c<64) such as:

In some embodiments, organic solvent is a polar protic organic solvent such as a polar aprotic organic solvent or a solvent with a dipole moment of greater than 1.4 debye. The organic solvent may be a solvent with a dipole moment of greater than 1.6 debye. In some embodiments, the organic solvent is a polar hydrocarbon(c<i2) or substituted hydrocarbon(c<i2)- The organic solvent may be haloalkane(c<i2) such as dichloroethane. In other embodiments, the organic solvent is an alcohol(c<8) or substituted alcohol(c<8)- In still other embodiments, the organic solvent is an arene(c<i2) or a substituted arene(c<i2)- In some embodiments, the organic solvent is a substituted arene(c<i2) such as chlorobenzene.

In some embodiments, the amount of the solution phase acid is from about 1 mol% to about 50 mol% or from about 5 mol% to about 25 mol%. The amount of the solution phase acid may be about 10 mol%. In some embodiments, the ratio of the compound of formula VIII to the compound of formula IX is from about 1 :2 to about 10: 1 or from about 1 : 1 to about 5: 1. In some embodiments, the ratio is about 1.5: 1.

In some embodiments, the methods further comprise reacting the compound of formula VIII and the compound of formula IX at a temperature from about 20 °C to about 150 °C. In some embodiments, the temperature is about 20 °C to about 35 °C such as about room temperature, or the temperature is about 40 °C to about 70 °C such as about 50 °C. In some embodiments, the methods comprise adding two compounds of formula VII to the compound of formula VI. In some embodiments, at least one of R7, Rs, and R9 of the compound of formula VI is hydrogen.

In still yet another aspect, the present disclosure provides compounds of the formula:

wherein:

X4 is -ORg or -NRhRj, wherein:

R _g is hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a hydroxy protecting group;

Rh and Rj are each independently hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a monovalent amino protecting group, or R _e and Rf are taken together and are a divalent amino protecting group;

Rio and Rio' are each independently hydrogen or alkyl(c<8), cycloalkyl(c<8), or a substituted version of either of these groups, or a monovalent amino protecting group;

R11, R12, and R are each independently hydrogen, halo, or alkyl(c<8), cycloalkyl(c<8), alkoxy(c<8), or a substituted version of any of these groups; or Rn and R12 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8); and

Y7, Ys, Y9, and Y10 are each independently hydrogen, halo, hydroxy, or alkyl(c<8), cycloalkyl(c<8), alkoxy(c<8), or a substituted version of any of these groups; or Y7 and Ye are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Ys and Y9 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Y9 and Y10 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8); or is a group of the formula:

wherein:

X5 is -ORk or -NRiRm, wherein:

Rk is hydrogen, alkyl(c cycloalkyl(c acyl(c or a substituted version of any of these groups; or a hydroxy protecting group;

Ri and R _m are each independently hydrogen, alkyl(c cycloalkyl(c acyl(c or a substituted version of any of these groups; or a monovalent amino protecting group, or R _e and Rf are taken together and are a divalent amino protecting group;

Ri4 and R ' are each independently hydrogen or alkyl(c cycloalkyl(c or a substituted version of either of these groups, or a monovalent amino protecting group;

Ri5, R16, and Rn are each independently hydrogen, halo, or alkyl(c cycloalkyl(c alkoxy(c or a substituted version of any of these groups; or Rn and R12 are taken together and are alkenediyl(c or substituted alkenediyl(c

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds are further defined as:

wherein:

X4 is -ORg or -NRhRj, wherein:

R _g is hydrogen, alkyl(c cycloalkyl(c acyl(c or a substituted version of any of these groups; or a hydroxy protecting group;

Rh and Rj are each independently hydrogen, alkyl(c cycloalkyl(c acyl(c or a substituted version of any of these groups; or a monovalent amino protecting group, or R _e and R _f are taken together and are a divalent amino protecting group;

Rio and Rio' are each independently hydrogen or alkyl(c cycloalkyl(c or a substituted version of either of these groups, or a monovalent amino protecting group;

Rn, R12, and R13 are each independently hydrogen, halo, or alkyl(c cycloalkyl(c alkoxy(c or a substituted version of any of these groups; or Rn and R12 are taken together and are alkenediyl(c or substituted alkenediyl(c and

Y7, Ye, Y9, and Y10 are each independently hydrogen, halo, hydroxy, or alkyl(c cycloalkyl(c alkoxy(c or a substituted version of any of these groups; or Y7 and Ye are taken together and are alkenediyl(c or substituted alkenediyl(c or Ys and Y9 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Y9 and Y10 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8);

or a pharmaceutically acceptable salt thereof.

In some embodiments, X4 is -OR _g , wherein: R _g is hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups such as -OH. In other embodiments, X4 is -NRhRj, wherein: Rh and Rj are each independently hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a monovalent amino protecting group. In some embodiments, Rh is hydrogen. In other embodiments, Rh is a monovalent amino protecting group such as mesyl or toslyl group. In some embodiments, R _j is hydrogen.

In some embodiments, Rio is hydrogen. In other embodiments, Rio is alkyl(c<8) or substituted alkyl(c<8)- In one example, Rio is alkyl(c<8) such as methyl. In other embodiments, Rio is a monovalent amino protecting group. In some embodiments, Rio' is hydrogen. In other embodiments, Rio' is a monovalent amino protecting group.

In some embodiments, Rn is hydrogen. In other embodiments, Rn is halo such as fluoro, chloro, or bromo. In other embodiments, Rn is alkyl(c<8) or substituted alkyl(c<8)- R11 may be alkyl(c<8) such as methyl. In other embodiments, Rn is alkoxy(c<8) or substituted alkoxy(c<8). R11 is alkoxy(c<8) such as methoxy.

In some embodiments, R12 is hydrogen. In other embodiments, R12 is halo such as fluoro, chloro, or bromo. In other embodiments, R12 is alkyl(c<8) or substituted alkyl(c<8)- R12 may be alkyl(c<8) such as methyl. In other embodiments, R12 is alkoxy(c<8) or substituted alkoxy(c<8)- R12 is alkoxy(c<8) such as methoxy.

In some embodiments, R13 is hydrogen. In other embodiments, R ₁₃ is halo such as fluoro, chloro, or bromo. In other embodiments, R13 is alkyl(c<8) or substituted alkyl(c<8). R13 may be alkyl(c<8) such as methyl. In other embodiments, R13 is alkoxy(c<8) or substituted alkoxy(c<8)- R13 is alkoxy(c<8) such as methoxy.

In some embodiments, Y7 is hydrogen. In other embodiments, Y7 is hydroxy. In other embodiments, Y7 is halo such as fluoro, chloro, or bromo. In other embodiments, Y7 is alkyl(c<8) or substituted alkyl(c<8)- Y7 may be alkyl(c<8) such as methyl. In other embodiments, Y7 is alkoxy(c<8) or substituted alkoxy(c<8)- Y7 may be alkoxy(c<8) such as methoxy.

In some embodiments, Y7 is hydrogen. In other embodiments, Y7 is hydroxy. In other embodiments, Y7 is halo such as fluoro, chloro, or bromo. In other embodiments, Y7 is alkyl(c<8) or substituted alkyl(c<8)- Y7 may be alkyl(c<8) such as methyl. In other embodiments, Y7 is alkoxy(c<8) or substituted alkoxy(c<8)- Y7 may be alkoxy(c<8) such as methoxy.

In some embodiments, Y7 is hydrogen. In other embodiments, Y7 is hydroxy. In other embodiments, Y7 is halo such as fluoro, chloro, or bromo. In other embodiments, Y7 is alkyl(c<8) or substituted alkyl(c<8)- Y7 may be alkyl(c<8) such as methyl. In other embodiments, Y7 is alkoxy(c<8) or substituted alkoxy(c<8)- Y7 may be alkoxy(c<8) such as methoxy. In some embodiments, Y ₇ is hydrogen. In other embodiments, Y ₇ is hydroxy. In other embodiments, Y7 is halo such as fluoro, chloro, or bromo. In other embodiments, Y7 is alkyl(c<8) or substituted alkyl(c<8). Y7 may be alkyl(c<8) such as methyl. In other embodiments, Y7 is alkoxy(c<8) or substituted alkoxy(c<8). Y7 may be alkoxy(c<8) such as methoxy.

In some embodiments the compounds are further defined as:

or a pharmaceutically acceptable salt thereof.

In yet another aspect, the present disclosure provides pharmaceutical compositions comprising:

(a) a compound described herein; and

(b) a pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical compositions are formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in cremes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion. In some embodiments, the pharmaceutical compositions are formulated for intravenous administration, oral administration, topical administration, or administration as an aerosol. In some embodiments, the aerosols are formulated as a dry powder or as a solution. In some embodiments, the compound is formulated using an electrospun membrane. In some embodiments, the compound is encapsulated in a liposome, micelle, or polymeric nanoparticle. In some embodiments, the pharmaceutical composition is formulated as a unit dose.

In still yet another aspect, the present disclosure provides methods of treating a disease or disorder in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound or composition described herein.

In some embodiments, the disease or disorder is a bacterial infection. In some embodiments, the bacterial infection is an infection of gram positive bacterium. In some embodiments, the bacterial infection is an infection of a pathogenic gram positive bacterium. In some embodiments, the pathogenic gram positive bacterium is a plant, animal, or human pathogen.

In some embodiments, the pathogenic gram positive bacterium is an animal or human pathogen. In some embodiments, the pathogenic gram positive bacterium is a Streptococcus, Staphylococcus, Corynebacterium, Listeria, Bacillus, Enterococcus, Nocardia, or Clostridium bacterium. In some embodiments, the Staphylococcus bacterium is Staphylococcus aureus such as methicillin resistant Staphylococcus aureus. In some embodiments, the Enterococcus bacterium is Enterococcus faecalis.

In other embodiments, the pathogenic gram positive bacterium is a plant pathogen. In some embodiments, the pathogenic gram positive bacterium is a Rathybacter, Leifsonia, or Clavibacter bacterium.

In other embodiments, the bacterial infection is an infection of acid fast bacterium. In some embodiments, the acid fast bacterium is a human or animal pathogen such as Mycobacterium or Rhodococcus bacterium. In some embodiments, the Mycobacterium bacterium is Mycobacterium tuberculosis or a non-tuberculous Mycobacterium. In some embodiments, the Rhodococcus bacterium is Rhodococcus equi. In other embodiments, the bacterial infection is an infection of a gram negative bacterium.

In some embodiments, the bacterial infection exhibits resistance to one or more common antibiotics. In some embodiments, the bacterial infection exhibits resistance to multiple different antibiotics. In some embodiments, the method further comprises administering one or more antibiotic agents.

In other embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma. In some embodiments, the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, gastrointestinal tract, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle, or thyroid.

In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is a non-small cell lung cancer. In other embodiments, the lung cancer is a large cell lung cancer. In some embodiments, the method comprises administering a second cancer therapy. In some embodiments, the second cancer therapy is a second chemotherapeutic agent, surgery, a radiotherapy, or an immunotherapy.

In some embodiments, the patient is a plant. In other embodiments, the patient is an animal. In some embodiments, the patient is a mammal such as a human. In some embodiments, the method comprises administering the compound or composition once. In some embodiments, the method comprises administering the compound or composition two or more times. It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein.

The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." The word "about" means plus or minus 5% of the stated number.

Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

FIG. 1 - The axially chiral functionalized biaryl motif in natural products, ligands and catalysts.

FIG. 2 - Schematic of DFT transition states. Bond lengths reported in A.

FIG. 3 - Formation of a mixed-acetal intermediate is not possible with 2-methoxynaphthalene (9), thus coupling with 1 does not occur. Unprotected naphthol (2) undergoes smooth arylation to afford biaryldiol (5a).

FIG. 4 - X-ray crystal structure for compound 5c.

FIG. 5 - Schematic description of the instant catalytic atroposelective direct arylation approach to non-C2-symmetrical BINOL derivatives (A (Gao, et al , 2016) & B). A recent report by Tan et al. (C) (Chen, et al , 2015). FIG. 6 - The symmetry of intermediates in chirality transfer processes has a dramatic impact on the final product's ee.

FIG. 7 - The case is made for the aminal-formation/[3, 3] -rearrangement sequence as opposed to a 1,4-direct addition.

FIG. 8— Table describing the substrate scope by coupling 6a with structurally diverse hydroxyarenes and the X-ray crystal structure for compound 9ea'.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

In some aspects, the present disclosure provides methods of preparing biaryl compounds from two aryl components without a transition metal catalyst. In some embodiments, these methods may be used to prepare compounds which are useful as chiral auxiliaries, as therapeutic agents, or as building blocks for other compounds. I. Compounds and Formulations Thereof

A. Compounds

In one aspect, the present disclosure provides compounds of the formula:

wherein:

Xi is amino or alkylaminO(c<8), dialkylaminO(c<8), amidols), or a substituted version of any of these groups; or -N(R _a )Rb, wherein:

R _a is a monovalent amino protecting group or is taken together with R _b and form a divalent amino protecting group; and

R _b is hydrogen, a monovalent amino protecting group; or is taken together with R _a and form a divalent amino protecting group;

X2 is hydroxy or alkoxy(c<8), acyloxy(c<8), or a substituted version of any of these groups; or -OR _c wherein:

R _c is a hydroxy protecting group;

Yi is halo;

Y2 is hydrogen or halo;

Ai and A2 are each independently hydrogen, halo, alkyl(c<8), substituted alkyl(c<8), cycloalkyl(c<8), substituted cycloalkyl(c<8), alkoxy(c<8), or substituted alkoxy(c<8);

Ri and R2 are each independently hydrogen, halo, alkyl(c<8), substituted alkyl(c<8), cycloalkyl(c<8), substituted cycloalkyl(c<8), alkoxy(c<8), or substituted alkoxy(c<8); or Ri and R2 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8); and

R3 and R4 are each independently hydrogen, halo, alkyl(c<8), substituted alkyl(c<8), cycloalkyl(c<8), substituted cycloalkyl(c<8), alkoxy(c<8), or substituted alkoxy(c<8); or R3 and R4 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8); or a compound of the formula:

wherein:

X3 is -ORd or -NR _e Rf, wherein:

Rd is hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a hydroxy protecting group;

R _e and Rf are each independently hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a monovalent amino protecting group, or R _e and R _f are taken together and are a divalent amino protecting group;

R6 is hydrogen or alkyl(c<8), cycloalkyl(c<8), or a substituted version of either of these groups;

R7, Rs, and R9 are each independently hydrogen, halo, or alkyl(c<8), cycloalkyl(c<8), alkoxy(c<8), or a substituted version of any of these groups; or R ₇ and Rs are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8); and

Y3, Y4, Y5, and Υβ are each independently hydrogen, halo, hydroxy, or alkyl(c<8), cycloalkyl(c<8), alkoxy(c<8), or a substituted version of any of these groups; or Y3 and Y4 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Y4 and Y5 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Y5 and Υβ are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8); or a compound of the formula:

wherein:

X3 is -ORd or -NR _e Rf, wherein: Rd is hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a hydroxy protecting group;

R _e and Rf are each independently hydrogen, alkyl(c<8), cycloalkyl(c<8), acyl(c<8), or a substituted version of any of these groups; or a monovalent amino protecting group, or R _e and Rf are taken together and are a divalent amino protecting group;

R6 and Re' are each independently hydrogen or alkyl(c<8), cycloalkyl(c<8), or a substituted version of either of these groups, or a monovalent amino protecting group;

R7, Re, and R9 are each independently hydrogen, halo, or alkyl(c<8), cycloalkyl(c<8), alkoxy(c<8), or a substituted version of any of these groups; or R7 and Rs are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8); and

Y3, Y4, Y5, and Υβ are each independently hydrogen, halo, hydroxy, or alkyl(c<8), cycloalkyl(c<8), alkoxy(c<8), or a substituted version of any of these groups; or Y3 and Y4 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Y4 and Y5 are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8), or Y5 and Υβ are taken together and are alkenediyl(c<8) or substituted alkenediyl(c<8);

or a pharmaceutically acceptable salt thereof. These compounds may be used in the treatment of cancer or in the treatment of a microbial infection.

Additionally, the compounds provided by the present disclosure are shown, for example, above in the summary section and in the examples and claims below. They may be made using the methods outlined in the Examples section. The biaryl compounds can be synthesized according to the methods described, for example, in the Examples section below. These methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007), which is incorporated by reference herein.

The biaryl compounds of the disclosure may contain one or more asymmetrically-substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present disclosure can have the S or the R configuration.

Chemical formulas used to represent the biaryl compounds of the present disclosure will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended.

In addition, atoms making up the biaryl compounds of the present disclosure are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³ C and ¹⁴ C.

It should be recognized that the particular anion or cation forming a part of any salt form of a compound provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference.

Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates." For example, a complex with water is known as a "hydrate." Solvates of the biaryl compounds provided herein are within the scope of the disclosure. It will also be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary from solvate to solvate. Thus, all crystalline forms of the biaryl compounds or the pharmaceutically acceptable solvates thereof are within the scope of the present disclosure. II. Synthetic Methods

In some aspects, the compounds of this disclosure can be synthesized using the methods of organic chemistry as described in this application. These methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (2007), which is incorporated by reference herein.

A. Process Scale-Up

The synthetic methods described herein can be further modified and optimized for preparative, pilot- or large-scale production, either batch of continuous, using the principles and techniques of process chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Practical Process Research & Development (2000), which is incorporated by reference herein. The synthetic method described herein may be used to produce preparative scale amounts of the biaryl compounds. B. Chemical Definitions

When used in the context of a chemical group: "hydrogen" means -H; "hydroxy" means -OH; "oxo" means =0; "carbonyl" means -C(=0)-; "carboxy" means -C(=0)OH (also written as -COOH or -CO2H); "halo" means independently -F, -CI, -Br or -I; "amino" means -NH2; "hydroxyamino" means -NHOH; "nitro" means -NO2; imino means =NH; "cyano" means -CN; "isocyanate" means -N=C=0; "azido" means -N3; in a monovalent context "phosphate" means -OP(0)(OH)2 or a deprotonated form thereof; in a divalent context "phosphate" means -OP(0)(OH)0- or a deprotonated form thereof; "mercapto" means -SH; and "thio" means =S; "sulfato" means -SO3H, "sulfamido" means -S(0)2NH2, "sulfonyl" means -S(0)2-; and "sulfinyl" means -S(O)-.

In the context of chemical formulas, the symbol "-" means a single bond, "=" means a double bond, and "≡" means triple bond. The symbol " " represents an optional bond, which if present is either single or double. The symbol " ==" represents a single bond or a double bond. Thus, for example, the formula understood that no one such ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol when connecting one or two stereogenic atoms, does not indicate any preferred stereochemistry. Instead, it covers all stereoisomers as well as mixtures thereof. The symbol ' ^{ί ιΛΛΛ} ", when drawn perpendicularly across a bond — CH ₃ for methyl) indicates a point of attachment of the group. It is noted that the point of attachment is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment. The symbol " "^· " means a single bond where the group attached to the thick end of the wedge is "out of the page." The symbol " ""HI " means a single bond where the group attached to the thick end of the wedge is "into the page". The symbol " ^« ΛΛΛ " means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper. When a group "R" is depicted as a "floating group" on a ring system, for example, in the formula:

then R may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed. When a group "R" is depicted as a "floating group" on a fused ring system, as for example in the formula:

then R may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise. Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals -CH-), so long as a stable structure is formed. In the example depicted, R may reside on either the 5- membered or the 6-membered ring of the fused ring system. In the formula above, the subscript letter "y" immediately following the group "R" enclosed in parentheses, represents a numeric variable. Unless specified otherwise, this variable can be 0, 1, 2, or any integer greater than 2, only limited by the maximum number of replaceable hydrogen atoms of the ring or ring system.

For the groups and classes below, the following parenthetical subscripts further define the group/class as follows: "(Cn)" defines the exact number (n) of carbon atoms in the group/class. "(C<n)" defines the maximum number (n) of carbon atoms that can be in the group/class, with the minimum number as small as possible for the group in question, e.g., it is understood that the minimum number of carbon atoms in the group "alkenyl(c<8)" or the class "alkene(c<8)" is two. For example, "alkoxy(c<io)" designates those alkoxy groups having from 1 to 10 carbon atoms. (Cn-n') defines both the minimum (n) and maximum number (η') of carbon atoms in the group. Similarly, "alkyl(C2 io)" designates those alkyl groups having from 2 to 10 carbon atoms.

The term "saturated" as used herein means the compound or group so modified has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below. In the case of substituted versions of saturated groups, one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto-enol tautomerism or imine/enamine tautomerism are not precluded.

The term "aliphatic" when used without the "substituted" modifier signifies that the compound/group so modified is an acyclic or cyclic, but non-aromatic hydrocarbon compound or group. In aliphatic compounds/groups, the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds/groups can be saturated, that is joined by single bonds (alkanes/alkyl), or unsaturated, with one or more double bonds (alkenes/alkenyl) or with one or more triple bonds (alkynes/alkynyl).

The term "alkyl" when used without the "substituted" modifier refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen. The groups -C¾ (Me), -CH2CH ₃ (Et), -CH2CH2CH3 (ra-Pr or propyl), -CH(CH ₃ ) ₂ (i-Pr, 'Pr or isopropyl), -CH2CH2CH2CH3 (ra-Bu), -CH(CH ₃ )CH ₂ CH ₃ (sec-butyl), -CH ₂ CH(CH ₃ ) ₂ (isobutyl), -C(CH ₃ ) ₃ (tert-butyl, f-butyl, f-Bu or ¾u), and -CH ₂ C(CH ₃ ) ₃ (reeo-pentyl) are non-limiting examples of alkyl groups. The term "alkanediyl" when used without the "substituted" modifier refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups, -CH ₂ - (methylene), -CH ₂ CH ₂ - -CH ₂ C(CH ₃ ) ₂ CH ₂ - and -CH ₂ CH ₂ CH ₂ - , are non-limiting examples of alkanediyl groups. The term "alkylidene" when used without the "substituted" modifier refers to the divalent group =CRR' in which R and R' are independently hydrogen or alkyl. Non- limiting examples of alkylidene groups include: =CH ₂ , =CH(CH ₂ CH ₃ ), and =C(CH ₃ ) ₂ . An "alkane" refers to the compound H-R, wherein R is alkyl as this term is defined above. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -N0 ₂ , -C0 ₂ H, -C0 ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -C(0)NH ₂ , -OC(0)CH ₃ , or -S(0) ₂ NH ₂ . The following groups are non-limiting examples of substituted alkyl groups: -CH ₂ OH, -CH ₂ C1, -CF ₃ , -CH ₂ CN, -CH ₂ C(0)OH, -CH ₂ C(0)OCH ₃ , -CH ₂ C(0)NH ₂ , -CH ₂ C(0)CH ₃ , -CH ₂ OCH ₃ , -CH ₂ OC(0)CH ₃ , -CH ₂ NH ₂ , -CH ₂ N(CH ₃ ) ₂ , and -CH ₂ CH ₂ C1. The term "haloalkyl" is a subset of substituted alkyl, in which one or more hydrogen atoms has been substituted with a halo group and no other atoms aside from carbon, hydrogen and halogen are present. The group, -CH ₂ C1 is a non- limiting example of a haloalkyl. The term "fluoroalkyl" is a subset of substituted alkyl, in which one or more hydrogen has been substituted with a fluoro group and no other atoms aside from carbon, hydrogen and fluorine are present. The groups, -CH ₂ F, -CF ₃ , and -CH ₂ CF ₃ are non-limiting examples of fluoroalkyl groups.

The term "cycloalkyl" when used without the "substituted" modifier refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forms part of one or more non-aromatic ring structures, a cyclo or cyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples of cycloalkyl groups include: -CH(CH ₂ ) ₂ (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl. The term "cycloalkanediyl" when used without the "substituted" modifier refers to a divalent saturated aliphatic group with one or two carbon atom as the point(s) of attachment, said carbon atom(s) forms part of one or more non-aromatic ring structures, a cyclo or cyclic structure, no carbon-carbon double or

triple bonds, and no atoms other than carbon and hydi

limiting examples of cycloalkanediyl groups. A "cycloalkane' refers to the compound H-R, wherein R is cycloalkyl as this term is defined above. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -N0 ₂ , -N ₃ , -C0 ₂ H, -C0 ₂ CH ₃ , -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH ₃ , -NHCH3, -NHCH2CH3, -N(CH ₃ ) ₂ , -C(0)NH ₂ , -OC(0)CH ₃ , or -S(0) ₂ NH ₂ . The following groups are non-limiting examples of substituted cycloalkyl groups:

The term "alkenyl" when used without the "substituted" modifier refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples of alkenyl groups include: -CH=CH ₂ (vinyl), -CH=CHCH ₃ , -CH=CHCH ₂ CH ₃ , -CH ₂ CH=CH ₂ (allyl), -CH ₂ CH=CHCH ₃ , and -CH=CHCH=CH ₂ . The term "alkenediyl" when used without the "substituted" modifier refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched, cyclo, cyclic or acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups, -CH=CH-, -CH=C(CH ₃ )CH ₂ -, and -CH=CHCH ₂ -, are non-limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure. The terms "alkene" and refer to a compound having the formula H-R, wherein R is alkenyl as this term is defined above. A "terminal alkene" refers to an alkene having just one carbon-carbon double bond, wherein that bond forms a vinyl group at one end of the molecule. When any of these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -N0 ₂ , -N ₃ , -C0 ₂ H, -C0 ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -C(0)NH ₂ , -OC(0)CH ₃ , or -S(0) ₂ NH ₂ . The groups, -CH=CHF, -CH=CHC1 and -CH=CHBr, are non-limiting examples of substituted alkenyl groups.

The term "aryl" when used without the "substituted" modifier refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more six-membered aromatic ring structure, wherein the ring atoms are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. As used herein, the term does not preclude the presence of one or more alkyl or aralkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, -CeH4CH ₂ CH ₃ (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl. The term "arenediyl" when used without the "substituted" modifier refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six-membered aromatic ring structure(s) wherein the ring atoms are all carbon, and wherein the monovalent group consists of no atoms other than carbon and hydrogen. As used herein, the term does not preclude the presence of one or more alkyl, aryl or aralkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings may be connected via one or more of the following: a covalent bond, alkanediyl, or alkenediyl groups (carbon number limitation permitting). Non-limiting examples of arenediyl groups include:

An "arene" refers to the compound H-R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes. When any of these terms are used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -NO2, -N ₃ , -C0 ₂ H, -CO2CH3, -CN, -SH, -OCH3, -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH3, -NHCH2CH3, -N(CH ₃ ) ₂ , -C(0)NH ₂ , -OC(0)CH ₃ , or -S(0) ₂ NH ₂ .

The term "aralkyl" when used without the "substituted" modifier refers to the monovalent group -alkanediyl-aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples of aralkyls are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. When the term aralkyl is used with the "substituted" modifier one or more hydrogen atom from the alkanediyl and/or the aryl group has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -N0 ₂ , -N ₃ , -C0 ₂ H, -C0 ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -C(0)NH ₂ , -OC(0)CH ₃ , or -S(0) ₂ NH ₂ . Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-l-yl.

The term "acyl" when used without the "substituted" modifier refers to the group -C(0)R, in which R is a hydrogen, alkyl, cycloalkyl, aryl, aralkyl or heteroaryl, as those terms are defined above. The groups, -CHO, -C(0)CH ₃ (acetyl, Ac), -C(0)CH ₂ CH ₃ , -C(0)CH ₂ CH ₂ CH ₃ , -C(0)CH(CH ₃ ) ₂ , -C(0)CH(CH ₂ ) ₂ , -C(0)C ₆ H ₅ , -C(0)C ₆ H ₄ CH ₃ , -C(0)CH ₂ C ₆ H ₅ , -C(0)(imidazolyl) are non-limiting examples of acyl groups. A "thioacyl" is defined in an analogous manner, except that the oxygen atom of the group -C(0)R has been replaced with a sulfur atom, -C(S)R. The term "aldehyde" corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a -CHO group. When any of these terms are used with the "substituted" modifier one or more hydrogen atom (including a hydrogen atom directly attached the carbonyl or thiocarbonyl group, if any) has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -N0 ₂ , -N ₃ , -C0 ₂ H, -CO2CH3, -CN, -SH, -OCH3, -OCH2CH3, -C(0)CH ₃ , -NHCH3, -NHCH2CH3, -N(CH ₃ ) ₂ , -C(0)NH ₂ , -OC(0)CH ₃ , or -S(0) ₂ NH ₂ . The groups, -C(0)CH ₂ CF ₃ , -C0 ₂ H (carboxyl), -C0 ₂ CH ₃ (methylcarboxyl), -C0 ₂ CH ₂ CH ₃ , -C(0)NH ₂ (carbamoyl), and -CON(CH ₃ ) ₂ , are non-limiting examples of substituted acyl groups.

The term "alkylamino" when used without the "substituted" modifier refers to the group

-NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples of alkylamino groups include: -NHCH ₃ and -NHCH ₂ CH ₃ . The term "dialkylamino" when used without the "substituted" modifier refers to the group -NRR', in which R and R' can each independently be the same or different alkyl groups, or R and R' can be taken together to represent an alkanediyl. Non- limiting examples of dialkylamino groups include: -N(CH3) ₂ , -N(CH3)(CH ₂ CH3), and -pyrrolidinyl. The terms "alkoxyamino", "cycloalkylamino", "alkenylamino", "cycloalkenylamino", "alkynylamino", "arylamino", "aralkylamino", "heteroarylamino", "heterocycloalkylamino" and "alkylsulfonylamino" when used without the "substituted" modifier, refers to groups, defined as -NHR, in which R is alkoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and alkylsulfonyl, respectively. A non-limiting example of an arylamino group is -NHC6H5. The term "amido" (acylamino), when used without the "substituted" modifier, refers to the group -NHR, in which R is acyl, as that term is defined above. A non-limiting example of an amido group is -NHC(0)CH3. The term "alkylimino" when used without the "substituted" modifier refers to the divalent group =NR, in which R is an alkyl, as that term is defined above. The term "alkylaminodiyl" refers to the divalent group -NH-alkanediyl-, -NH-alkanediyl-NH-, or -alkanediyl-NH-alkanediyl-. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -N0 ₂ , -N ₃ , -C0 ₂ H, -C0 ₂ CH ₃ , -CN, -SH, -OCH3, -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -C(0)NH ₂ , -OC(0)CH ₃ , or -S(0) ₂ NH ₂ . The groups -NHC(0)OCH ₃ and -NHC(0)NHCH3 are non-limiting examples of substituted amido groups.

The term "alkoxy" when used without the "substituted" modifier refers to the group -OR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: -OCH3 (methoxy), -OCH ₂ CH ₃ (ethoxy), -OCH ₂ CH ₂ CH ₃ , -OCH(CH ₃ ) ₂ (isopropoxy), and -OC(CH ₃ ) ₃ (tert- butoxy). The terms "cycloalkoxy", "alkenyloxy", "alkynyloxy", "aryloxy", "aralkoxy", "heteroaryloxy", "heterocycloalkoxy", and "acyloxy", when used without the "substituted" modifier, refers to groups, defined as -OR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The term "alkoxydiyl" refers to the divalent group -O-alkanediyl-, -O-alkanediyl-O-, or -alkanediyl-O-alkanediyl-. The term "alkylthio" and "acylthio" when used without the "substituted" modifier refers to the group -SR, in which R is an alkyl and acyl, respectively. The term "alcohol" corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term "ether" corresponds to an alkane or cycloalkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy or cycloalkoxy group. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -NO2, -N ₃ , -C0 ₂ H, -CO2CH3, -CN, -SH, -OCH3, -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH3, -NHCH2CH3, -N(CH ₃ ) ₂ , -C(0)NH ₂ , -OC(0)CH ₃ , or -S(0) ₂ NH ₂ .

The term "diester phosphoric acid" when used without the "substituted" modifier refers to the group P(0)OROR'OR", in which R, R', and R" are each independently hydrogen or an alkyl, cycloalkyl, alkenyl, aryl, or aralkyl group as those terms are defined above. Non-limiting examples include: dimethyl phosphoric acid or diphenyl phosphoric acid. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -N0 ₂ , -N ₃ , -C0 ₂ H, -C0 ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -C(0)NH ₂ , -OC(0)CH ₃ , or -S(0) ₂ NH ₂ .

The term "halocarboxylic acid" when used without the "substituted" modifier refers to the group RC0 ₂ R', in which R is a haloalkyl and R is hydrogen or alkyl, as those terms is defined above. Non-limiting examples include: trifluoro acetic acid or 2,2,2-trifluoropropionic acid. When any of these terms is used with the "substituted" modifier one or more hydrogen atom has been independently replaced by -OH, -F, -CI, -Br, -I, -NH ₂ , -N0 ₂ , -N ₃ , -C0 ₂ H, -C0 ₂ CH ₃ , -CN, -SH, -OCH ₃ , -OCH ₂ CH ₃ , -C(0)CH ₃ , -NHCH ₃ , -NHCH ₂ CH ₃ , -N(CH ₃ ) ₂ , -C(0)NH ₂ , -OC(0)CH ₃ , or -S(0) ₂ NH ₂ .

An "amine protecting group" is well understood in the art. An amine protecting group is a group which prevents the reactivity of the amine group during a reaction which modifies some other portion of the molecule and can be easily removed to generate the desired amine. Amine protecting groups can be found at least in Greene and Wuts, 1999, which is incorporated herein by reference. Some non-limiting examples of amino protecting groups include formyl, acetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a- chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxycarbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5- dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2- nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 -(p-biphenylyl)- 1 - methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t- butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2- trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9- methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Additionally, the "amine protecting group" can be a divalent protecting group such that both hydrogen atoms on a primary amine are replaced with a single protecting group. In such a situation the amine protecting group can be phthalimide (phth) or a substituted derivative thereof wherein the term "substituted" is as defined above. In some embodiments, the halogenated phthalimide derivative may be tetrachlorophthalimide (TCphth).

A "hydroxyl protecting group" is well understood in the art. A hydroxyl protecting group is a group which prevents the reactivity of the hydroxyl group during a reaction which modifies some other portion of the molecule and can be easily removed to generate the desired hydroxyl. Hydroxyl protecting groups can be found at least in Greene and Wuts, 1999, which is incorporated herein by reference. Some non-limiting examples of hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4- nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p- methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p- bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l- methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t- butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2- trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9- methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.

A "stereoisomer" or "optical isomer" is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. "Enantiomers" are stereoisomers of a given compound that are mirror images of each other, like left and right hands. "Diastereomers" are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), the total number of hypothetically possible stereoisomers will not exceed 2", where n is the number of tetrahedral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase "substantially free from other stereoisomers" means that the composition contains < 15%, more preferably < 10%, even more preferably < 5%, or most preferably < 1% of another stereoisomer(s).

III. Examples

The following examples are included to demonstrate preferred embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

EXAMPLE 1 - Synthesis of Biaryl Compounds and Reaction Optmization

Direct arylation of 2-naphthols via Br0nsted acid-catalyzed tandem mixed acetal formation/[3,3]-sigmatropic rearrangement sequence was proposed as shown in Scheme 1 below. It was proposed that if quinone monoacetals (1) were reacted with unprotected naphthols (2) in the presence of a strong Br0nsted acid catalyst, an acetal exchange would afford the corresponding mixed-acetals (3). The mixed-acetal (3) then would undergo a /3,3/-sigmatropic rearrangement (i.e., Claisen rearrangement) to afford a doubly de-aromatized intermediate (4) which, upon rapid re- aromatization, is expected to furnish the corresponding functionalized biaryls (5).

Scheme 1 :

Im inoquinone 2-Naphthols O or NHR

Table 1 (below) shows possible combinations of strong organic acids (i.e., Br0nsted acids) and solvents. Quinone monoacetal la and 2-naphthol 2a were chosen as coupling partners. In the highly polar solvent of 2,2,2-trifluoroethanol (TFE), very strong Br0nsted acids (e.g., triflic acid, methansulfonic acid, hydrochloric acid; Table 1, entries 1-3) gave poor results, however, the somewhat weaker acids such as p-toluenesulfonic acid, trifluoroacetic acid and diphenylphosphoric acid (i.e., p-TSA, TFA & DPA) furnished the desired functionalized biaryl product 5a in moderate to excellent yields at room temperature (Table 1, entries 4-6). In order to achieve the highest isolated yield of 5a in the shortest possible time, it was found that the use of 2 equivalents of 2a and 20 mol% of the organic acid catalyst were necessary (Table 1, entries 7-10). When the weakly polar solvent dichloromethane was utilized along with catalytic amounts of DPA and TFA, the direct arylation of 2a did not proceed at 25 °C, however, moderate yield of 5a was obtained at reflux temperature (Table 1, entries 11-14). After screening a series of different combinations of acid and solvent at various temperatures, it was found that the combination of TFA and toluene at 100 °C afforded 5a in 85% isolated yield in 16 hours (Table 1, entry 17; More detailed optimization study, see Table 4 in Example 2).

Table 1. Optimization of the reaction conditions for the conversion of la + 2a— > 5a. [a] la (0.2 mmol), 2a (2.0 equiv), 20 mol% of acid and 2 mL solvent were employed - unreacted 2a can be recovered via flash chromatography and reused; [b] Isolated yield; [c] 1.5 equiv of 2a was used; [d] 1.2 equiv of 2a was used; [e] 10 mol% of acid was used; [f] 5 mol% of acid was used; [g] N.R. = No Reaction.

Entry ^[a] Acid Solvent Temp. Time Yield ^M

(°C) (h) (%)

1 TfOH CF ₃ CH ₂ OH 25 16 < 5

2 MsOH CF ₃ CH ₂ OH 25 16 < 5

3 HC1 CF ₃ CH ₂ OH 25 16 48

4 TsOH H ₂ 0 CF ₃ CH ₂ OH 25 16 52

5 TFA CF ₃ CH ₂ OH 25 16 59

6 (PhO) ₂ P0 ₂ H CF ₃ CH ₂ OH 25 16 85

₇ M (PhO) ₂ P0 ₂ H CF ₃ CH ₂ OH 25 18 75 g[d] (PhO) ₂ P0 ₂ H CF ₃ CH ₂ OH 25 18 65

9M (PhO) ₂ P0 ₂ H CF ₃ CH ₂ OH 25 24 83

10 ^ra (PhO) ₂ P0 ₂ H CF ₃ CH ₂ OH 25 24 78

11 (PhO) ₂ P0 ₂ H CH ₂ C1 ₂ 25 16 N.R. ^[g]

12 (PhO) ₂ P0 ₂ H CH ₂ C1 ₂ reflux 16 42

13 TFA CH ₂ C1 ₂ 25 24 N.R.

14 TFA CH ₂ C1 ₂ reflux 24 60

15 TFA Toluene 25 16 N.R.

16 TFA Toluene 50 18 64

17 TFA Toluene 100 16 84

Two suitable reaction conditions were chosen (A: 20 mol% of TFA in toluene at 100 °C and B: 20 mol% of DPA in TFE at 25 °C) and an extensive study was initiated to determine the scope of substrates. Diversely substituted 2-naphthols (Table 2, entries 1-8) that range from strongly electron rich to weakly electron-poor rings were studied first. For this series reaction condition A seemed to work the best as isolated yields of the product biaryldiols ranged between good to excellent. Only in the case of product 5e (entry 5) was reaction condition B superior. Several of these reactions could be readily scaled up; biaryldiol 5c was prepared on a 26 gram scale (starting from 98 mmols of la) which is particularly well-suited for ligand/catalyst synthesis. The structure of biaryl 5c was confirmed using single crystal X-ray crystallography. Table 2. Preparation of non-C2-symmetrical atropoisomeric 2,2' -dihydroxy-l, l' -biaryls (i.e., BINOL- type) from phenols and naphthols (5a-r). [a] Reactions were performed on 0.2 or 0.3 mmol scale (0.1 M solution); [b] Isolated yield after column chromatography.

(98 mmol scale)

(4): 5d (5): 5e (6): 5f (7):5g A, 75% B, 70% A, 60%; B, 55% A, 70%; B, 60%

A, 68% (1 mmol scale)

(8): 5h (9): 5i (10): 5j, (1 1): 5k A, 90% yield A, 15%; B, 68% yield A, 72%; A, 60% A, 64%

B, 60% yield (5 mmol) (40 mmol scale)

(12): 5I (13): 5m (14) : 5m' (15): 5n

Varying the structure of the quinone monoacetal coupling partner (entries 9-12, Table 2) did not cause any issues and an electron-poor 2-naphthol could be coupled with an electron poor quinone monoacetal to afford functionalized biaryldiol 5j (entry 10). The presence of the Br substituent in the 6-position will allow further elaboration of the naphthalene nucleus (e.g., via TM-catalyzed cross- coupling reactions). When 1-naphthol was used in the transformation (entries 13 & 14), the regioselectivity of the direct arylation reaction (i.e., 2- versus 4-position) could be controlled by switching between conditions A and B. Monocyclic phenols (entries 15 -18) were found to be equally suitable substrates for this transformation as substituted 1- or 2-naphthols, allowing the preparation of biaryldiols that have hindered rotation about their chiral axis (i.e., configurationally stable functionalized biaryls).

Finally, 2,3-dihydroxynaphthalene can be coupled twice with quinone monoacetal la to afford a functionalized terphenyl 5r in good isolated yield (Table 2, entry 19). Terphenyls such as 5r hold the promise of becoming multifaceted ligands for one or more transition metals and in turn could potentially be utilized as catalysts for cascade reactions. Nearly all of the biaryldiols shown in Table 2 are brand new compounds/structures, previously not accessible in an operationally simple and scalable process.

Next, three iminoquinone monoacetals (6a-c) were prepared and successfully coupled with nine different naphthols (Table 3, entries 20-28 & 31-38) and four different phenols (entries 29, 30, 39 & 40) under the previously optimized reactions conditions A or B. The presence of the sulfonyl group (Ts = p-toluenesulfonyl & Ms = methanesulfonyl) on the nitrogen atom was necessary to impart sufficient reactivity for the system. The resulting -sulfonyl substituted 2-amino-2' -hydroxy- 1, 1' - biaryls are of the NOBIN-type and completely novel structures. The .V-sulfonyl group can be efficiently removed using a previously published protocol (Ito et ah, 2013).

Table 3. Preparation of non-C2-symmetrical atropoisomeric 2-amino-2'-hydroxy-l,l'-biaryls (i.e. , NOBIN-type) from phenols and naphthols (7a-u). [a] Reactions were performed on 0.2 or 0.3 mmol scale (0.1 M solution); [b] Isolated yield after column chromatography.

(20): 7a (21 ): 7b (22): 7c (23): 7d

A, 84%; B, 92% A, 84% ; B, 60% A, 89% ; B, 64% A, 90%; B, 57%

(24): 7e (25): 7f (26): 7g (27): 7h

A, 71 % ; B, 84% A, 94% ; B, 58% A, 58% A, 82%

(28): 7i (29): 7j (30): 7k (31 ): 7I

A, 76%, B, 59% A, 69% A, 80% A, 85% ; B, 82%

(32): 7m (33): 7n (34): 7o (35): 7p

M06-2X/6-31+G(d,p)[SMD toluene] density functional calculations (See Example 2 for details) were used to examine intermediates and transition states (Frisch et ai, 2009: Zhao and Truhlar, 2008a; Zhao and Truhlar, 2008b; Marenich et ai, 2009). The reaction between 2-naphthol and a simplified quinone acetal (R ³ = H for 1) catalyzed by TFA in toluene solvent was examined.

Assuming a relatively fast exchange of an acetal methoxy group for O-naphthyl to form the mixed actetal intermediate 3, the barrier was calculated for the subsequent concerted [3,3]- sigmatropic rearrangement via TS1 shown in FIG. 2. ^[16] The AH ⁱ for TS1 is 15.6 kcal/mol. ^[17] Subsequent re-aromatization of this endothermic intermediate generates the corresponding biaryl. The barrier for this Claisen rearrangement can be significantly lowered by TFA/MeOH catalysis. FIG. 2 shows TS2 where TFA and MeOH hydrogen bonding result in a more polarized and asynchronous ¹¹⁸³ /3,3/-sigmatropic transition-state structure. ^[19] The AH ⁱ for TS2 is 8.9 kcal/mol relative to the corresponding ground state with hydrogen bonding interactions. This low barrier suggests that once the mixed acetal is formed the Claisen rearrangement and the subsequent re-aromatization are very fast. This mixed acetal//3,3/-sigmatropic rearrangement reaction pathway is also consistent with the nonreactivity of 2-methoxynaphfhalene since it cannot generate the mixed acetal intermediate. (FIG. 2).

Alternative to Claisen type reaction pathways, it was also examined if 2-naphthol nucleophilicly captures the oxocarbenium intermediate (10, FIG. 3) that is required for acetal group exchange. This pathway would directly form the C-C (i.e., aryl-aryl) bond through transition state TS3 shown in FIG. 2. Direct comparison of the enthalpy values of TS2 and TS3 indicates that TS2 is several kcal/mol lower in enthalpy than TS3. However, the AH ⁱ for TS3 relative to 2-naphthol and the oxocarbenium intermediate/TFA-MeOH is 7.3 kcal/mol and close to the barrier height for the [3,3]- sigmatropic rearrangement. However, this reaction pathway cannot account for the non-reactivity of 2-methoxynaphthalene.

And last, the possibility that there could be TFA-catalyzed C-C bond formation between 2- naphthol and the quinone monoacetal in an S _N 2' type reaction pathway was examined. However, despite extensive transition state searching (i.e., starting from -1000 structures), no concerted SN2' transition state was located. EXAMPLE 2 - General Methods and Materials

All reactions were carried out in oven-dried glassware under air with magnetic stirring. All phenol and naphthol compounds were purchased from Sigma- Aldrich Co. and used without further purification. All reactions were monitored by thin-layer chromatography (TLC) with E. Merck silica gel 60 F254 pre-coated plates (0.25 mm). Silica gel (particle size 0.032-0.063 mm) purchased from SiliCycle was used for flash chromatography. Proton (Ή) and carbon ( ¹³ C) NMR spectra were recorded on a Bruker AV-400 (or a Bruker DRX-600) spectrometer operating at 400 MHz (or 600 MHz) for proton and 100 MHz (or 151 MHz) for carbon nuclei using CDC1 ₃ [or (CD ₃ ) ₂ CO] as solvent, respectively. Chemical shifts are expressed as parts per million (δ, ppm) and are referenced to 7.26 (CDCls) or 2.05 (CD ₃ ) ₂ CO for Ή NMR and 77.00 (CDCI3) or 206.26 (CD ₃ ) ₂ CO for ¹³ C NMR. Proton signal data uses the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and J = coupling constant. High Resolution Mass Spectrometry was performed on a Shimadzu LCMS-IT-TOF under the conditions of electrospray ionization (ESI) in both positive and negative mode.

X-ray Diffraction Experiment data were measured at 100(2) K on a SMART APEX II CCD area detector system equipped with a Oxford Cryosystems 700 series cooler, a graphite monochromator, and a Mo Ka fine-focus sealed tube (λ = 0.71073 A). Intensity data were processed using the Saint Plus program. All the calculations for the structure determination were carried out using the SHELXTL package (version 6.14). Initial atomic positions were located by using XT, and the structures of the compounds were refined by the least-squares method using XL. Absorption corrections were applied by using SADABS. Hydrogen atoms were placed at calculated positions and refined riding on the corresponding carbons. The X-ray diffraction pattern is shown in FIG. 4.

Synthesis of quinone monk tals (Zhang et at, 2013; Dohi et at, 2011; Okuma et at, 2012 and Ito et al, 2013)

4,4-dimethoxy-3,5-dimethylcyclohexa-2,5-dienone (la)

1a

To a solution of 3,5-dimethylphenol (1.22 g, 10 mmol, 1.0 equiv) in distilled MeOH (20 mL) was added phenyliodoso diacetate (PIDA) (7.08 g, 22 mmol, 2.2 equiv) and the mixture was stirred at room temperature, and monitored by TLC analysis, which indicated the reaction was complete in 30 min. The reaction was quenched with sat. NaHCC (50 mL) and then extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2S04 and the solvent was removed in vacuo to give the crude product which was purified by flash column chromatography (S1O ₂ , 20: 1 to 10: 1, ra-Hexane: EtOAc) to give the desired product la (1.10 g, 60% yield) as a yellow solid, R _f = 0.50 (4: 1, ra-Hexane: EtOAc). ¾ NMR (400 MHz, CDCI ₃ ): δ 6.27 (s,

2H), 3.02 (s, 6H), 1.89 (s, 6H).

2,5-dichloro-4,4-dimethoxycyclohexa-2,5-dien-l-one (lb)

1 b

The procedure of preparation was used as above. The crude product which was purified by flash column chromatography (S1O ₂ , 10: 1 to 5: 1, ra-Hexane: EtOAc) to produce the desired product lb as a light yellow solid, 40% yield, R _f 0.50 (5: 1, ra-Hexane: EtOAc). ¾ NMR (600 MHz, CDCI3): δ 6.98 (s, 1H), 6.67 (s, 1H), 3.32 (s, 6H); ¹³ C NMR (151 MHz, CDCI3): δ 176.1, 153.3, 139.6, 134.9, 129.8, 96.2, 51.6. 4,4-dimethoxy-3-mefhylnaphfhalen- 1 (4H)-one (lc)

The procedure of preparation was used as above. The crude product which was purified by flash column chromatography (S1O ₂ , 15:1 to 10: 1, ra-Hexane: EtOAc) to produce the desired product as a light yellow solid, 60% yield, R _f 0.40 (5: 1, ra-Hexane: EtOAc). ¾ NMR (400 MHz, CDCI3): δ 8.05 (d, / = 8.0 Hz, 1H), 7.71 (d, / = 7.6 Hz, 1H), 7.67-7.61 (m, 1H), 7.48 (t, / = 7.6 Hz, 1H), 6.53 (s, 1H), 2.89 (s, 6H), 2.02 (s, 3H); ¹³ C NMR (100 MHz, CDCI3): δ 183.3, 155.7, 139.3, 133.4, 132.9, 132.5, 129.3, 126.6, 125.9, 97.9, 51.2, 51.1, 16.5.

A ⁱ -(4,4-dimethoxy-3,5-dimethylcyclohexa-2,5-dien- 1 -ylidene)methanesulfonamide (6a)

To a solution of -^S-dimethylpheny^methanesulfonamide (1.99 g, 10 mmol, 1.0 equiv) in distilled MeOH (20 mL) was added phenyliodoso diacetate (PIDA) (3.94 g, 12 mmol, 1.2 equiv) and the mixture was stirred at room temperature, and monitored by TLC analysis, which indicated the reaction was complete in 30 min. The reaction was quenched with sat. NaHC(¾ (50 mL) and then extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (50 mL), dried with anhydrous Na2S04 and the solvent was removed in vacuo to give the crude product which was purified by flash column chromatography (S1O ₂ , 5: 1 to 3: 1, ra-Hexane: EtOAc) to give the desired product 6a (2.08 g, 80% yield) as a yellow solid, R _f 0.30 (4: 1, ra-Hexane: EtOAc). ¾ NMR (400 MHz, CDCI ₃ ): δ 7.37 (s, 1H), 6.35 (s, 1H), 3.14 (s, 3H), 3.00 (s, 6H), 1.97 (s, 3H), 1.94 (s, 3H); ¹³ C NMR (100 MHz, CDCI3): δ 163.5, 156.7, 154.7, 131.5, 125.2, 97.3, 50.9, 43.0, 17.1, 16.6.

A ⁱ -(4,4-dimethoxy-3,5-dimethylcyclohexa-2,5-dien- 1 -ylidene)-4-methylbenzenesulfonamide (6b)

6b The procedure of preparation was used as 6a. The crude product which was purified by flash column chromatography (Si0 ₂ , 5: 1 to 3: 1, ra-Hexane: EtOAc) to produce the desired product as a light yellow solid, 60% yield, R _f 0.30 (4: 1, ra-Hexane: EtOAc). ¾ NMR (400 MHz, CDCI3): δ 7.87 (d, / = 5.6 Hz, 2H), 7.63 (s, 1H), 7.33 (d, / = 5.2 Hz, 2H), 6.37 (s, 1H), 3.03 (s, 6H), 2.44 (s, 3H), 2.03 (s, 3H), 1.93 (s, 3H); ¹³ C NMR (100 MHz, CDC1 ₃ ): δ 163.3, 156.8, 154.4, 143.7, 138.4, 132.0, 129.5, 127.1, 125.3, 97.5, 50.9, 21.6, 17.3, 16.6.

A ⁱ -(3,4,4,5-tetramethoxycyclohexa-2,5-dien- 1 -ylidene)methanesulfonamide (6c)

The procedure of preparation was used as 6a. The crude product which was purified by flash column chromatography (Si0 ₂ , 3: 1 to 1 : 1, ra-Hexane: EtOAc) to produce the desired product as a light yellow solid, 72% yield, R _f 0.30 (1 : 1, ra-Hexane: EtOAc). ¾ NMR (600 MHz, CDCI3): δ 6,71 (s, 1H), 5.64 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.26 (s, 6H), 3.13 (s, 3H); ¹³ C NMR (151 MHz, CDC1 ₃ ): δ 166.8, 166.7, 165.3, 103.8, 98.1, 94.8, 56.8, 56.5, 52.3, 43.1.

Optimization of the reaction conditions for the conversion of la + 2a→ 5a (see Table 1 )

Table 4 below shows the further detailed optimization study referenced in Example 1.

Table 4. [a] la (0.3 mmol), 2a (2.0 equiv), 20 mol% of acid and 3 mL solvent were employed; [b] Isolated yield; [c] 1.5 equiv of 2a was used; [d] 1.2 equiv of 2a was used; [e] 10 mol% of acid was used; [f] 5 mol% of acid was used; [g] N.R. = No Reaction; [h] N.P. = No Target Product.

Entry" Acid Solvent Temp. (°C) Time (h) Yield* (%)

1 TfOH CF ₃ CH ₂ OH 25 16 < 5

2 MsOH CF ₃ CH ₂ OH 25 16 < 5

3 HC1 CF ₃ CH ₂ OH 25 16 48

4 TsOH HzO CF ₃ CH ₂ OH 25 16 52

5 TFA CF ₃ CH ₂ OH 25 16 59

6 TFA CF ₃ CH ₂ OH 50 16 65

7 (PhO) ₂ P0 ₂ H CF ₃ CH ₂ OH 25 16 85

8 ^C (PhO) ₂ P0 ₂ H CF ₃ CH ₂ OH 25 18 75 gd (PhO) ₂ P0 ₂ H CF ₃ CH ₂ OH 25 18 65

10 ^e (PhO) ₂ P0 ₂ H CF ₃ CH ₂ OH 25 24 83

11' (PhO) ₂ P0 ₂ H CF ₃ CH ₂ OH 25 24 78

12 (PhO) ₂ P0 ₂ H CH ₂ C1 ₂ 25 16 N.R/

13 (PhO) ₂ P0 ₂ H CH3CN 25 30 62

14 (PhO) ₂ P0 ₂ H CH ₂ C1 ₂ reflux 16 42

15 (PhO) ₂ P0 ₂ H CHCI3 50 16 35

16 (PhO) ₂ P0 ₂ H THF 50 30 N.R.

17 (PhO) ₂ P0 ₂ H EtOH 50 30 < 5 18 (PhO) ₂ P0 ₂ H Toluene 50 30 80

20 TFA CH2CI2 reflux 24 60

21 TFA DMF 25 16 N.R.

22 TFA DMF 100 16 N.P. ^A

23 TFA DMSO 25 16 N.R.

24 TFA DMSO 100 16 N.P.

25 TFA Acetone 25 16 N.R.

26 TFA Acetone 50 16 N.P.

27 TFA Toluene 25 16 N.R.

28 TFA Toluene 50 18 64

29 TFA Toluene 100 16 84

General Procedure for the Synthesis ofBiaryls

Procedure A: To a stirred solution of la (55 mg, 0.30 mmol) and 2a (88 mg, 0.60 mmol) in toluene (3 mL), TFA (6.9 mg, 4.6 uL, 0.06 mmol) was added in one portion at room temperature, and it was stirred at 100 °C for 16 hours. Solvent was removed under reduced pressure and the crude residue was purified by column chromatography on silica- gel (hexane/ethyl acetate = 20: 1 to 5: 1) to give pure product 5a (73.9 mg, 84% yield).

Procedure B: To a stirred solution of la (36.5 mg, 0.20 mmol) and 2a (58 mg, 0.40 mmol) in CF3CH2OH (2 mL), (PhO)2P02H (10 mg, 0.04 mmol) was added in one portion at room temperature, and it was stirred at room temperature for 16 hours. Solvent was removed under reduced pressure and the crude residue was purified by column chromatography on silica-gel (hexane/ethyl acetate = 20: 1 to 5:1) to give pure product 5a (50.2 mg, 85% yield).

EXAMPLE 3 - Compound Characterization

l-(6-hydroxy-3-methoxy-2,4-dimethylphenyl)naphthalen-2-ol (5a)

5a, white solid, m.p. 190-191 °C; R _f 0.50 (3: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, Acetone-d ⁶ ): δ 7.84-7.80 (m, 3H), 7.31-7.21 (m, 4H), 7.13 (s, 1H), 6.70 (s, 1H), 3.69 (s, 3H), 2.30 (s, 3H), 1.84 (s, 3H); ¹³ C NMR (100 MHz, Acetone-d ⁶ ): δ 153.5, 152.4, 151.3, 134.9, 132.5, 131.7, 130.0, 129.9, 128.8, 127.0, 125.1, 123.6, 120.9, 119.3, 116.8, 116.0, 60.1, 16.4, 13.4; HRMS (ESI): Exact mass calcd. for Ci ₉ Hi ₈ 0 ₃ [M-H] ^" : 293.1183, Found: 293.1175. 3-bromo-l-(6-hydroxy-3-methoxy-2,4-dimethylphenyl)naphtliale ri-2-ol (5b)

For 0.2 mmol scale, the standard procedure A was followed to provide 5b (48.5 mg, 65% yield); the standard procedure B was followed to provide 5b (8.9 mg, 12% yield).

5b, white solid, m.p. 208-210 °C; R _f 0.50 (3: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, Acetone-d ⁶ ): δ 8.20 (s, IH), 8.04 (br s, IH), 7.84-7.81 (m, IH), 7.53 (br s, IH), 7.35-7.32 (m, 2H), 7.20-7.17 (m, IH), 6.72 (s, IH), 3.69 (s, 3H), 2.31 (s, 3H), 1.83 (s, 3H); ¹³ C NMR (100 MHz, Acetone-d ⁶ ): δ 152.5, 151.3, 149.8, 133.9, 132.6, 132.5, 130.4, 128.0, 127.4, 125.2, 124.8, 119.9, 119.0, 116.32, 116.27, 113.6, 60.1, 16.4, 13.3; HRMS (ESI): Exact mass calcd. for Ci ₉ Hi ₇ 0 ₃ Br [M-H] ^" : 371.0288, Found: 371.0301.

6-bromo- 1 -(6-hydroxy-3-methoxy-2,4-dimethylphenyl)naphthalen-2-ol (5c)

For 0.2 mmol scale, the standard procedure A was followed to provide 5c (56.8 mg, 76% yield); the standard procedure B was followed to provide 5c (35.7 mg, 48% yield); For 98 mmol scale, the standard procedure A was followed to provide 5c (25.64 g, 70% yield).

5c, white solid, m.p. 217-218 °C; R _f 0.50 (3: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, Acetone-d ⁶ ): δ 8.05-8.03 (m, 2H), 7.80 (d, / = 8.8 Hz, IH), 7.41 (dd, / = 2.0, 9.2 Hz, IH), 7.33-7.30 (m, 2H), 7.16 (d, J = 8.8 Hz, IH), 6.70 (s, IH), 3.69 (s, 3H), 2.30 (s, 3H), 1.84 (s, 3H); ¹³ C NMR (100 MHz, Acetone-d ⁶ ): δ 154.0, 152.4, 151.2, 133.5, 132.4, 132.0, 131.0, 130.6, 129.9, 129.2, 127.4, 120.6, 117.4, 116.7, 116.08, 116.05, 60.1, 16.4, 13.3; HRMS (ESI): Exact mass calcd. for Ci ₉ Hi ₇ 0 ₃ Br [M- H] ^" : 371.0288, Found: 371.0299. 7-bromo-l-(6-hydroxy-3-methoxy-2,4-dimethylphenyl)naplitlial eri-2-ol (5d)

For 0.2 mmol scale, the standard procedure A was followed to provide 5d (55.8 mg, 75% yield).

5d, white solid, m.p. 76-78 °C; R _f 0.50 (3: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, Acetone-d ⁶ ): δ 8.13 (br s, 1H), 7.84 (d, J = 9.2 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.39-7.36 (m, 3H), 7.31 (d, J = 8.4 Hz, 1H), 6.71 (s, 1H), 3.69 (s, 3H), 2.30 (s, 3H), 1.86 (s, 3H); ¹³ C NMR (100 MHz, Acetone-d ⁶ ): δ 154.4, 152.3, 151.2, 136.2, 132.4, 132.1, 130.9, 130.0, 128.2, 126.9, 126.5, 121.0, 120.1, 119.9, 116.5, 116.1, 60.1, 16.3, 13.3; HRMS (ESI): Exact mass calcd. for Ci ₉ Hi ₇ 0 ₃ Br [M-H] ^" : 371.0288, Found: 371.0298.

l-(6-hydroxy-3-methoxy-2,4-dimethylphenyl)-3-methoxynaphthal en-2-ol (5e)

For 0.2 mmol scale, the standard procedure B was followed to provide 5e (45.6 mg, 70% yield).

5e, white solid, m.p. 241-242 °C; R _f 0.50 (2: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, Acetone-d ⁶ ): δ 7.75 (d, / = 8.4 Hz, 1H), 7.74 (br s, 1H), 7.33 (s, 1H), 7.28-7.17 (m, 4H), 6.68 (s, 1H), 4.02 (s, 3H), 3.68 (s, 3H), 2.30 (s, 3H), 1.84 (s, 3H); ¹³ C NMR (100 MHz, Acetone-d ⁶ ) δ: 152.0, 151.1, 149.3, 145.5, 132.0, 131.3, 130.1, 130.0, 127.7, 124.9, 124.7, 124.2, 121.7, 117.4, 115.9, 106.6, 60.2, 56.1, 16.4, 13.5; HRMS (ESI): Exact mass calcd. for C20H20O4 [M-H] ^" : 323.1289, Found: 323.1294. l-(6-hydroxy-3-methoxy-2,4-dimethylphenyl)-7-methoxynaphmale n-2-ol (5f)

5f

For 0.2 mmol scale, the standard procedure A was followed to provide 5f (38.8 mg, 60% yield); the standard procedure B was followed to provide 5f (35.7 mg, 55% yield).

5f, white solid, m.p. 166-167 °C; R _f 0.50 (2: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, Acetone-d ⁶ ): δ 7.76 (d, J = 7.6 Hz, 1H), 7.74-7.71 (m, 2H), 7.09 (d, J = 8.0 Hz, 1H), 7.06 (s, 1H), 6.95 (dd, J = 2.4, 9.2 Hz, 1H), 6.70 (s, 1H), 6.59 (d, / = 2.0 Hz, 1H), 3.69 (s, 3H), 3.64 (s, 3H), 2.30 (s, 3H), 1.86 (s, 3H); ¹³ C NMR (100 MHz, Acetone-d ⁶ ): δ 159.3, 154.1, 152.3, 151.3, 136.3, 132.4, 131.7, 130.4, 129.8, 125.2, 121.0, 116.7, 116.1, 116.0, 115.4, 104.2, 60.1, 55.2, 16.4, 13.4; HRMS (ESI): Exact mass calcd. for C20H20O4 [M-H] ^" : 323.1289, Found: 323.1296.

l-(6-hydroxy-3-methoxy-2,4-dimethylphenyl)naphthalene-2,3-di ol (5g)

For 0.2 mmol scale, the standard procedure A was followed to provide 5g (43.6 mg, 70% yield); the standard procedure B was followed to provide 5g (37.3 mg, 60% yield); For 1 mmol scale, the standard procedure A was followed to provide 5g (210 mg, 68% yield).

5g, white solid, m.p. 197-198 °C; R _f 0.40 (1 : 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, Acetone-d ⁶ ): δ 7.84 (br s, 3H), 7.65 (d, / = 8.0 Hz, 1H), 7.26 (s, 1H), 7.25-7.20 (m, 1H), 7.13 (d, / = 8.0 Hz, 1H), 6.69 (s, 1H), 3.69 (s, 3H), 2.30 (s, 3H), 1.85 (s, 3H); ¹³ C NMR (100 MHz, Acetone-d ⁶ ): δ 152.1, 151.0, 146.9, 144.8, 132.2, 131.6, 130.4, 129.4, 127.0, 124.8, 124.0, 120.9, 117.3, 115.9, 115.8, 109.9, 60.0, 16.3, 13.3; HRMS (ESI): Exact mass calcd. for Ci ₉ Hi ₈ 0 ₄ [M-H] ^" : 309.1132, Found: 309.1144. Methyl 6-hydroxy-5-(6-hydroxy-3-methoxy-2,4-dimethylphenyl)-2-napht hoate (5h)

For 0.2 mmol scale, the standard procedure A was followed to provide 5h (63.6 mg, 90% yield).

5h, white solid, m.p. 226-227 °C; R _f 0.35 (2: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, Acetone-d ⁶ ) δ 8.56 (s, 1H), 8.00 (d, / = 8.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.76 (br s, 2H), 7.36 (d, J = 9.2 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 6.71 (s, 1H), 3.90 (s, 3H), 3.69 (s, 3H), 2.30 (s, 3H), 1.84 (s, 3H); ¹³ C NMR (100 MHz, Acetone-d ⁶ ) δ 167.5, 155.8, 152.4, 151.2, 137.3, 132.4, 132.0, 131.8, 131.6, 128.7, 126.2, 125.4, 125.3, 120.4, 120.3, 116.10, 116.07, 60.1, 52.2, 16.4, 13.3; HRMS (ESI): Exact mass calcd. for C21H20O5 [M-H] ^" : 351.1238, Found: 351.1248.

l-(2,5-dichloro-6-hydroxy-3-methoxyphenyl)naphthalen-2-ol (5i)

5i

For 0.2 mmol scale, the standard procedure A was followed to provide 5i (10.3 mg, 15% yield); the standard procedure B was followed to provide 5i (45.6 mg, 68% yield); For 5 mmol scale, the standard procedure B was followed to provide 5i (l.Olg, 60% yield).

5i, yellow oil; R _f 0.50 (2: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, CDCI ₃ ): δ 7.89-7.82 (m, 2H), 7.42-7.34 (m, 2H), 7.27-7.20 (m, 2H), 7.12 (s, 1H), 5.20 (br s, 2H), 3.92 (s, 3H); ¹³ C NMR (100 MHz, CDCI3): δ 151.3, 149.7, 144.8, 132.3, 131.3, 129.0, 128.3, 127.3, 123.9, 123.5, 123.1, 122.1, 118.9, 117.8, 113.7, 112.3, 56.8; HRMS (ESI): Exact mass calcd. for C17H12O3CI2 [M-H] ^" : 333.0091, Found: 333.0091. 6-bromo- 1 -(2,5-dichloro-6-hydroxy-3-methoxyphenyl)naphtlialen-2-ol (5j)

For 0.2 mmol scale, the standard procedure A was followed to provide 5j (60.1 mg, 72% yield); For 40 mmol scale, the standard procedure A was followed to provide 5j (9.95g, 60% yield).

5j, yellow oil; R _f 0.50 (2: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.98 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 2.0, 8.8 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 7.13 (s, 1H), 7.08 (d, J = 8.8 Hz, 1H), 5.31 (br s, 1H), 5.19 (br s, 1H), 3.93 (s, 3H); ¹³ C NMR (100 MHz, CDCI3): δ 151.5, 149.8, 144.7, 130.9, 130.5, 130.3, 130.2, 125.5, 123.2, 121.6, 119.0, 118.9, 117.6, 113.71, 113.68, 113.0, 56.9; HRMS (ESI): Exact mass calcd. for CnHnOsBrCh [M-H] ^" : 410.9196, Found: 410.9195.

Methyl 5-(2,5-dichloro-6-hydroxy-3-methoxyphenyl)-6-hydroxy-2-napht hoate (5k)

For 0.3 mmol scale, the standard procedure A was followed to provide 5k (75 mg, 64% yield).

5k, white solid, m.p. 205-206 °C; R _f 0.30 (2: 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, Acetone-d ⁶ ): δ 8.91 (s, 1H), 8.59 (d, J = 1.2 Hz, 1H), 8.07 (d, J = 9.0 Hz, 1H), 7.92 (dd, J = 8.4, 1.8 Hz, 1H), 7.81 (s, 1H), 7.41 (d, / = 8.4 Hz, 1H), 7.29 (s, 1H), 7.28 (d, / = 8.4 Hz, 1H), 3.96 (s, 3H), 3.93 (s, 3H); ¹³ C NMR (151 MHz, Acetone-d ⁶ ): δ 166.6, 155.3, 149.3, 146.1, 136.0, 131.8, 131.0, 127.8, 125.8, 124.7, 124.6, 124.0, 122.7, 119.5, 119.2, 114.4, 113.4, 56.3, 51.4; HRMS (ESI): Exact mass calcd. for C19H14O5CI2 [M-H]- _: 391.0146, Found: 391.0145.

4 ^, -methoxy-3'-methyl-[l,2'-binaphthalene]-r,2-diol (51)

51 For 0.2 mmol scale, the standard procedure A was followed to provide 51 (46 mg, 70% yield).

51, white solid, m.p. 202-203 °C; R _f 0.45 (2: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, CDC1 ₃ ): δ 8.27 (d, / = 8.0 Hz, IH), 8.15 (d, J = 8.4 Hz, IH), 7.93 (d, J = 9.2 Hz, IH), 7.89-7.86 (m, IH), 7.65- 7.61 (m, IH), 7.55-7.51 (m, IH), 7.39-7.34 (m, 3H), 7.26-7.24 (m, IH), 5.17 (br s, IH), 5.12 (br s, IH), 3.94 (s, 3H), 2.03 (s, 3H); ¹³ C NMR (100 MHz, CDC1 ₃ ): δ 152.2, 147.9, 146.9, 133.1, 131.2, 129.4, 129.1, 128.4, 127.5, 127.3, 126.6, 125.2, 124.0, 123.8, 123.6, 123.0, 121.7, 1 17.6, 1 12.4, 112.2, 61.6, 13.1; HRMS (ESI): Exact mass calcd. for C ₂ 2Hi ₈ 0 ₃ [M-H] ^" : 329.1183, Found: 329.1195.

2-(6-hydroxy-3-methoxy-2,4-dimethylphenyl)naphthalen-l-ol (5m)

For 0.2 mmol scale, the standard procedure A was followed to provide 5m (40.5 mg, 69% yield).

5m, white solid, m.p. 125-127 °C; R _f 0.50 (4: 1, ra-Hexane: EtOAc); Ή NMR (400 MHz, Acetone-d ⁶ ): δ 8.34-8.29 (m, IH), 7.88-7.83 (m, 2H), 7.53-7.42 (m, 4H), 7.15 (d, J = 8.8 Hz, IH), 6.67 (s, IH), 3.68 (s, 3H), 2.26 (s, 3H), 1.99 (s, 3H); ¹³ C NMR (100 MHz, Acetone-d ⁶ ): δ 152.1, 151.3, 150.8, 135.4, 132.2, 131.8, 130.4, 128.3, 126.8, 126.3, 125.6, 123.4, 123.3, 120.1, 117.8, 116.1, 60.0, 16.3, 13.8; HRMS (ESI): Exact mass calcd. for C19H18O3 [M-H] ^" : 293.1 183, Found: 293.1 185.

4-(6-hydroxy-3-methoxy-2,4-dimethylphenyl)naphthalen-l-ol (5m')

5m"

For 0.2 mmol scale, the standard procedure B was followed to provide 5m' (47.2 mg, 80% yield).

5m', white solid; m.p. 190-191 °C; R _f 0.50 (3: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, Acetone- d ⁶ ): δ 9.1 1 (s, IH), 8.31 (d, / = 8.4 Hz, IH), 7.49-7.34 (m, 3H), 7.13 (d, / = 8.0 Hz, IH), 6.99 (d, / = 8.0 Hz, IH), 6.96 (s, IH), 6.69 (s, IH), 3.68 (s, 3H), 2.30 (s, 3H), 1.81 (s, 3H); ¹³ C NMR (100 MHz, Acetone-d ⁶ ): δ 153.6, 151.9, 151.0, 134.6, 131.7, 131.2, 129.3, 127.0, 126.7, 126.23, 126.18, 125.3, 123.2, 1 15.73, 1 15.69, 108.9, 60.1, 16.3, 13.8; HRMS (ESI): Exact mass calcd. for Ci ₉ Hi ₈ 0 ₃ [M-H] ^" : 293.1 183, Found: 293.1186. 5-methoxy-4,4',6,6'-tetramethyl- [1,1 '-biphenyl] -2,2'-diol (5n)

For 0.3 mmol scale, the standard procedure A was followed to provide 5n (44 mg, 54% yield).

5n, white solid, m.p. 128-129 °C; R _f 0.55 (3: 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, CDC1 ₃ ): δ 6.74 (s, IH), 6.712 (s, IH), 6.706 (s, IH), 4.71 (br s, IH), 4.55 (br s, IH), 3.70 (s, 3H), 2.33 (s, 3H), 2.31 (s, 3H), 1.96 (s, 3H), 1.94 (s, 3H); ¹³ C NMR (151 MHz, CDCI3): δ 153.7, 151.0, 149.7, 140.2, 138.7, 132.9, 131.3, 123.5, 118.1, 116.7, 115.1, 113.7, 60.1, 21.3, 19.4, 16.3, 13.0; HRMS (ESI): Exact mass calcd. for G7H20O3 [M-H] ^" : 271.1340, Found: 271.1339.

4',5,6'-trimethoxy-4,6-dimethyl- [1,1 '-biphenyl]-2,2'-diol (5o)

For 0.3 mmol scale, the standard procedure A was followed to provide 5o (59 mg, 65% yield).

5o, brown solid, m.p. 146-148 °C; R _f 0.30 (3: 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, CDCI3): δ 6.70 (s, IH), 6.25 (d, J = 2.4 Hz, IH), 6.18 (d, / = 2.4 Hz, IH), 5.02 (br s, IH), 4.77 (br s, IH), 3.82 (s, 3H), 3.701 (s, 3H), 3.695 (s, 3H), 2.29 (s, 3H), 1.97 (s, 3H); ¹³ C NMR (151 MHz, CDCI3): δ 162.1, 158.9, 155.5, 150.9, 150.3, 132.8, 132.4, 115.5, 115.0, 101.4, 93.0, 91.9, 60.0, 55.7, 55.4, 16.3, 13.1; HRMS (ESI): Exact mass calcd. for C17H20O5 [M-H] ^" : 303.1238, Found: 303.1240. 4^6'-dichloro-5-methoxy-4,6-dimethyl-[l, r-biphenyl]-2,2 ^, -diol (5p)

For 0.3 mmol scale, the standard procedure A was followed to provide 5p (71.5 mg, 76% yield).

5p, white solid, m.p. 144-146 °C; R _f 0.50 (3: 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, Acetone-d ⁶ ): δ 8.54 (s, 1H), 7.68 (s, 1H), 7.08 (d, / = 1.8 Hz, 1H), 6.97 (d, J = 2.4 Hz, 1H), 6.63 (s, 1H), 3.66 (s, 3H), 2.25 (s, 3H), 1.95 (s, 3H); ¹³ C NMR (151 MHz, Acetone-d ⁶ ): δ 157.1, 150.8, 150.1, 136.0, 133.3, 131.3, 130.8, 123.1, 119.9, 119.4, 115.1, 114.5, 59.3, 15.5, 12.4; HRMS (ESI): Exact mass calcd. for C15H14CI2O3 [M-H] ^" : 311.0247, Found: 311.0247.

4',6'-dibromo-5-methoxy-4,6-dimethyl-[l,l'-biphenyl]-2,2'-di ol (5q)

For 0.3 mmol scale, the standard procedure A was followed to provide 5q (83.2 mg, 69% yield).

5q, brown solid, m.p. 147-149 °C; R _f 0.50 (3: 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, CDCI3): δ 7.46 (d, / = 1.8 Hz, 1H), 7.17 (d, / = 1.8 Hz, 1H), 6.68 (s, 1H), 5.16 (br s, 1H), 4.60 (br s, 1H), 3.70 (s, 3H), 2.30 (s, 3H), 1.95 (s, 3H); ¹³ C NMR (151 MHz, CDCI3): δ 155.2, 151.2, 149.2, 134.1, 131.5, 127.6, 125.9, 123.6, 122.0, 118.3, 117.9, 115.9, 60.2, 16.4, 13.0; HRMS (ESI): Exact mass calcd. for Ci ₅ Hi ₄ Br ₂ 03 [M-H]- _: 398.9237, Found: 398.9233. l,4-bis(6-hydroxy-3-methoxy-2,4-dimethylphenyl)naplitlialene -2,3-diol (5r)

For 0.2 mmol scale, the standard procedure A was followed to provide 5r (50 mg, 54% yield); For 8 mmol scale, the standard procedure A was followed to provide 5r (1.85g, 50% yield).

5r, white solid, m.p. 263-264 °C; R _f 0.30 (1 : 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, CDC1 ₃ ) δ 7.31-7.24 (m, 4H), 6.77 (s, 2H), 6.02 (br s, 2H), 4.64 (br s, 2H), 3.75 (s, 6H), 2.36 (s, 6H), 1.94 (s, 6H); ¹³ C NMR (100 MHz, CDCI3) δ 151.0, 149.7, 142.4, 132.9, 131.8, 128.2, 125.3, 124.4, 117.8, 115.4, 115.0, 60.2, 16.3, 13.4; HRMS (ESI): Exact mass calcd. for C28H28O6 [M-H] ^" : 459.1813, Found: 459.1816.

A ⁱ -(2-(2-hydroxynaphthalen-l-yl)-4-methoxy-3,5-dimethylp henyl)methanesulfonamide (7a)

For 0.2 mmol scale, the standard procedure A was followed to provide 7a (62.5 mg, 84%yield); the standard procedure B was followed to provide 7a (68 mg, 92% yield).

7a, white solid, m.p. 187-188 °C; R _f 0.50 (2: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, CDCI3): δ 7.87-7.83 (m, 2H), 7.48 (s, 1H), 7.37-7.24 (m, 2H), 7.24 (d, / = 8.8 Hz, 1H), 7.12-7.09 (m, 1H), 5.85 (s, 1H), 5.80 (br s, 1H), 3.76 (s, 3H), 2.66 (s, 3H), 2.40 (s, 3H), 1.87 (s, 3H); ¹³ C NMR (100 MHz, CDCI3): δ 154.9, 151.0, 132.8, 132.7, 132.5, 131.7, 130.9, 129.2, 128.6, 127.5, 124.3, 124.0, 123.1, 121.6, 117.8, 114.1, 60.0, 39.4, 16.4, 13.3; HRMS (ESI): Exact mass calcd. for C20H21NO4S [M-H] ^" : 370.1119, Found: 370.1119. A ⁱ -(2-(3-bromo-2-hydroxynaphthalen-l-yl)-4-methoxy-3,5-d imethylphenyl)methan (7b)

For 0.2 mmol scale, the standard procedure A was followed to provide 7b (76.1 mg, 84% yield); the standard procedure B was followed to provide 7b (53.8 mg, 60% yield).

7b, white solid, m.p. 157-159 °C; R _f 0.50 (2: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, CDC1 ₃ ): δ 8.18 (s, 1H), 7.79-7.77 (m, 1H), 7.49 (s, 1H), 7.42-7.36 (m, 2H), 7.13-7.10 (m, 1H), 5.76 (br s, 1H), 5.74 (br s, 1H), 3.76 (s, 3H), 2.68 (s, 3H), 2.41 (s, 3H), 1.85 (s, 3H); ¹³ C NMR (100 MHz, CDCI3): δ 154.9, 147.0, 132.8, 132.6, 132.1, 132.0, 131.1, 129.8, 128.0, 127.7, 125.2, 124.9, 123.6, 121.7, 116.2, 112.4, 60.0, 39.4, 16.5, 13.3; HRMS (ESI): Exact mass calcd. for C2oH ₂ oN0 ₄ SBr [M-H] ^" : 448.0224, Found: 448.0234.

A ⁱ -(2-(6-bromo-2-hydroxynaphthalen- 1 -yl)-4-methoxy-3,5-dimethylphenyl)methanesulfonamide (7c)

For 0.2 mmol scale, the standard procedure A was followed to provide 7c (80.1 mg, 89% yield); the standard procedure B was followed to provide 7c (57.5 mg, 64% yield); For 2 mmol scale, the standard procedure A was followed to provide 7c (785 mg, 87% yield).

7c, white solid, m.p. 199-200 °C; R _f 0.50 (2: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, CDCI3): δ 8.00 (d, / = 1.6 Hz, 1H), 7.77 (d, / = 8.4 Hz, 1H), 7.46 (s, 1H), 7.41 (dd, / = 9.2, 2.0 Hz, 1H), 7.27 (d, / = 9.2 Hz, 1H), 6.98 (d, / = 8.8 Hz, 1H), 5.79 (s, 1H), 5.72 (br s, 1H), 3.76 (s, 3H), 2.71 (s, 3H), 2.39 (s, 3H), 1.84 (s, 3H); ¹³ C NMR (100 MHz, CDCI3): δ 154.9, 151.4, 133.3, 132.8, 131.8, 131.1, 130.7, 130.6, 130.4, 130.1, 125.0, 123.4, 121.5, 119.1, 117.8, 114.5, 60.1, 39.7, 16.5, 13.3; HRMS (ESI): Exact mass calcd. for C ₂ oH ₂ oN0 ₄ SBr [M-H] ^" : 448.0224, Found: 448.0232. A ⁱ -(2-(7-bromo-2-hydroxynaphthalen-l-yl)-4-methoxy-3,5-d imethylphenyl)methan (7d)

For 0.2 mmol scale, the standard procedure A was followed to provide 7d (81.1 mg, 90% yield); the standard procedure B was followed to provide 7d (51.5 mg, 57% yield).

7d, white solid, m.p. 190-191 °C; R _f 0.50 (2: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.83 (d, / = 9.2 Hz, 1H), 7.72 (d, / = 8.4 Hz, 1H), 7.49 (s, 1H), 7.44 (dd, / = 2.0, 8.4 Hz, 1H), 7.26 (d, / = 8.4 Hz, 1H), 7.21 (d, / = 1.6 Hz, 1H), 5.75 (s, 1H), 5.61 (br s, 1H), 3.77 (s, 3H), 2.75 (s, 3H), 2.41 (s, 3H), 1.86 (s, 3H); ¹³ C NMR (100 MHz, CDC1 ₃ ): δ 154.9, 152.1, 133.8, 133.5, 132.9, 131.9, 131.0, 130.4, 127.7, 127.5, 125.2, 122.8, 122.2, 121.2, 118.3, 113.4, 60.1, 39.6, 16.6, 13.3; HRMS (ESI): Exact mass calcd. for C2oH ₂ oN0 ₄ SBr [M-H] ^" : 448.0224, Found: 448.0232.

A ⁱ -(2-(2-hydroxy-3-methoxynaphthalen-l-yl)-4-methoxy-3,5 -dimethylphenyl)methanesulfonamide

(7e)

For 0.2 mmol scale, the standard procedure A was followed to provide 7e (57.1 mg, 71% yield); the standard procedure B was followed to provide 7e (67.6 mg, 84% yield).

7e, white solid, m.p. 220-222 °C; R _f 0.35 (2: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, CDCI3): δ 7.76 (d, / = 8.0 Hz, 1H), 7.50 (s, 1H), 7.38-7.33 (m, 1H), 7.27-7.23 (m, 2H), 7.11 (d, / = 8.0 Hz, 1H), 6.17 (s, 1H), 5.87 (s, 1H), 4.08 (s, 3H), 3.77 (s, 3H), 2.62 (s, 3H), 2.41 (s, 3H), 1.87 (s, 3H); ¹³ C NMR (100 MHz, CDCI3): δ 154.8, 146.8, 142.9, 132.0, 130.9, 129.2, 127.8, 127.3, 125.8, 125.3, 124.7, 123.4, 121.7, 114.8, 106.6, 60.0, 56.0, 16.4, 13.4; HRMS (ESI): Exact mass calcd. for C21H23NO5S [M-H] ^" : 400.1224, Found: 400.1231. A ⁱ -(2-(2-hydroxy-7-methoxynaphthalen- 1 -yl)-4-methoxy-3,5-dimethylphenyl)methanesulfonamide (7f)

For 0.2 mmol scale, the standard procedure A was followed to provide 7f (75.6 mg, 94% yield); the standard procedure B was followed to provide 7f (46.6 mg, 58% yield).

7f, white solid, m.p. 188-190 °C; R _f 0.35 (2: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.75 (t, J = 8.8 Hz, 2H), 7.47 (s, 1H), 7.08 (d, J = 8.8 Hz, 1H), 7.02 (dd, J = 2.4, 8.8 Hz, 1H), 6.38 (d, / = 2.4 Hz, 1H), 5.87 (s, 1H), 5.68 (br s, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 2.70 (s, 3H), 2.39 (s, 3H), 1.90 (s, 3H); ¹³ C NMR (100 MHz, CDC1 ₃ ): δ 159.1, 154.9, 151.6, 133.9, 132.8, 132.7, 131.7, 130.7, 130.3, 124.6, 124.4, 121.8, 115.6, 115.1, 113.3, 102.4, 60.0, 55.2, 39.4, 16.5, 13.2; HRMS (ESI): Exact mass calcd. for C21H23NO5S [M-H] ^" : 400.1224, Found: 400.1231.

A ⁱ -(2-(2,3-dihydroxynaphthalen- 1 -yl)-4-methoxy-3,5-dimethylphenyl)methane-sulfonamide (7g)

For 0.2 mmol scale, the standard procedure A was followed to provide 7g (44.8 mg, 58% yield).

7g, white solid, m.p. 87-88 °C; R _f 0.35 (1: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, CDCI3): δ 7.69 (d, / = 8.4 Hz, 1H), 7.44 (s, 1H), 7.35-7.31 (m, 2H), 7.23-7.19 (m, 1H), 7.03 (d, / = 8.0 Hz, 1H), 6.47 (br s, 1H), 5.89 (br s, 1H), 5.85 (s, 1H), 3.77 (s, 3H), 2.69 (s, 3H), 2.40 (s, 3H), 1.87 (s, 3H); ¹³ C NMR (100 MHz, CDCI3): δ 155.1, 144.3, 141.9, 132.8, 132.7, 131.4, 129.8, 127.4, 127.2, 125.2, 125.0, 124.8, 123.2, 122.1, 115.5, 111.0, 60.1, 39.7, 16.5, 13.4; HRMS (ESI): Exact mass calcd. for C20H21NO5S [M-H]- _: 386.1068, Found: 386.1081. Methyl 6-hydroxy-5-(3-methoxy-2,4-dimethyl-6-(methylsulfonamido)phe nyl)-2-naphthoate (7h)

For 0.2 mmol scale, the standard procedure A was followed to provide 7h (70.6 mg, 82% yield).

7h, white solid, m.p. 178-179 °C; R _f 0.30 (1: 1, ra-Hexane: EtOAc); ¾ NMR (400 MHz, CDC1 ₃ ): δ 7.84-7.80 (m, 3H), 7.31-7.21 (m, 4H), 7.13 (s, 1H), 6.70 (s, 1H), 3.69 (s, 3H), 2.30 (s, 3H), 1.84 (s, 3H); ¹³ C NMR (100 MHz, CDC1 ₃ ): δ 153.5, 152.4, 151.3, 134.9, 132.5, 131.7, 130.0, 129.9, 128.8, 127.0, 125.1, 123.6, 120.9, 119.3, 116.8, 116.0, 60.1, 16.4, 13.4; HRMS (ESI): Exact mass calcd. for C22H2 ₃ NO6S [M-H] ^" : 428.1173, Found: 428.1174.

A ⁱ -(2-(l-hydroxynaphthalen-2-yl)-4-methoxy-3,5-dimethylp henyl)methane-sulfonamide (7i)

For 0.3 mmol scale, the standard procedure A was followed to provide 7i (85 mg, 76% yield); the standard procedure B was followed to provide 7i (66 mg, 59% yield);

7i, white solid, m.p. 135-137 °C; R _f 0.40 (1 : 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, CDCI3): δ 8.24 (d, / = 8.4 Hz, 1H), 8.14 (d, / = 8.4 Hz, 1H), 7.60-7.55 (m, 1H), 7.47-7.40 (m, 2H), 7.22 (s, 2H), 6.49 (d, J = 8.4 Hz, 1H), 3.65 (s, 3H), 3.22 (s, 3H), 2.23 (s, 6H); ¹³ C NMR (151 MHz, CDCI3): δ 155.5, 152.8, 136.6, 133.0, 131.9, 128.8, 128.1, 127.7, 126.3, 125.5, 123.2, 122.5, 108.0, 59.6, 39.8, 16.2; HRMS (ESI): Exact mass calcd. for C20H2 ₁ NO4S [M-H] ^" : 370.1119, Found: 370.1112. A ⁱ -(2'-hydroxy-5-methoxy-4,4',6,6'-tetramethyl-[l ,l'-biphenyl]-2-yl)methane- sulfonamide (7j)

For 0.3 mmol scale, the standard procedure A was followed to provide 7j (72.2 mg, 69% yield).

7j, white solid, m.p. 216-218 °C; R _f 0.50 (2: 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, CDC1 ₃ ): δ 6.85 (s, 2H), 6.50 (s, 2H), 3.69 (s, 3H), 3.25 (s, 3H), 2.22 (s, 6H), 2.21 (s, 6H); ¹³ C NMR (151 MHz, CDCI3): δ 155.7, 153.2, 140.2, 136.3, 131.8, 129.8, 119.7, 115.8, 59.7, 39.9, 19.2, 16.4; HRMS (ESI): Exact mass calcd. for C ₁ 8H2 ₃ NO4S [M-H] ^" : 348.1275, Found: 378.1268.

A ⁱ -(2'-hydroxy-4^5,6'-trimethoxy-4,6-dimethyl-[l,r-biphe nyl]-2-yl)methane-sulfonamide (7k)

For 0.3 mmol scale, the standard procedure A was followed to provide 7k (92 mg, 80% yield).

7k, white solid, m.p. 209-210 °C; R _f 0.50 (1 : 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, CDCI3): δ 7.38 (s, IH), 6.23 (s, IH), 6.19 (s, IH), 6.05 (s, IH), 4.87 (br s, IH), 3.83 (s, 3H), 3.74 (s, 3H), 3.69 (s, 3H), 2.76 (s, 3H), 2.34 (s, 3H), 1.98 (s, 3H); ¹³ C NMR (151 MHz, CDC1 ₃ ): δ 162.1, 158.0, 155.1, 154.6, 132.9, 132.6, 132.0, 123.1, 122.6, 103.1, 93.6, 92.1, 59.9, 55.7, 55.4, 39.1, 16.4, 13.3; HRMS (ESI): Exact mass calcd. for Ci ₈ H ₂₃ N06S [M-H] ^" : 380.1173, Found: 380.1176.

A ⁱ -(2-(2-hydroxynaphthalen- 1 -yl)-4-methoxy-3,5-dimethylphenyl)-4-methylbenzene- sulfonamide (71)

For 0.3 mmol scale, the standard procedure A was followed to provide 71 (114 mg, 85% yield); the standard procedure B was followed to provide 71 (110 mg, 82% yield).

71, white solid, m.p. 194-195 °C; R _f 0.50 (2: 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, Acetone-d ⁶ ): δ 8.48 (s, 1H), 7.90 (d, / = 8.4 Hz, 1H), 7.85 (d, / = 7.8 Hz, 1H), 7.47 (s, 1H), 7.35 (d, / = 9.6 Hz, 1H), 7.33-7.27 (m, 3H), 7.16-7.12 (m, 1H), 7.00 (d, / = 8.4 Hz, 2H), 6.86 (s, 1H), 6.67 (d, / = 8.4 Hz, 1H), 3.70 (s, 3H), 2.36 (s, 3H), 2.30 (s, 3H), 1.74 (s, 3H); ¹³ C NMR (151 MHz, Acetone-d ⁶ ): δ 154.4, 152.1, 143.2, 137.1, 133.2, 131.8, 131.7, 130.8, 130.3, 129.3, 128.9, 128.1, 126.9, 126.8, 126.6, 123.5, 123.0, 121.2, 118.3, 114.9, 59.2, 20.6, 15.7, 12.9; HRMS (ESI): Exact mass calcd. for C26H25NO4S [M-H] ^" : 446.1432, Found: 446.1430.

N-(2-(2 -hydro xy-7-methoxynaphthalen- 1 -yl)-4-methoxy-3,5-dimethylphenyl)-4- methylbenzenesulfonamide (7m)

For 0.3 mmol scale, the standard procedure A was followed to provide 7m (125 mg, 87% yield).

7m, white solid, m.p. 163-165 °C; R _f 0.40 (3: 1, ra-Hexane: EtOAc); Ή NMR (600 MHz, Acetone-d ⁶ ): δ 8.61 (s, 1H), 7.81 (d, / = 9.0 Hz, 1H), 7.74 (d, / = 9.0 Hz, 1H), 7.50 (s, 1H), 7.21 (d, / = 9.0 Hz, 1H), 7.17 (d, J = 7.8 Hz, 2H), 6.95 (dd, J = 9.0, 2.4 Hz, 1H), 6.90-6.86 (m, 3H), 5.92 (d, J = 2.4 Hz, 1H), 3.71 (s, 3H), 3.47 (s, 3H), 2.37 (s, 3H), 2.25 (s, 3H), 1.79 (s, 3H); ¹³ C NMR (151 MHz, Acetone-d ⁶ ): δ 158.4, 154.8, 152.4, 143.1, 137.0, 134.8, 131.6, 131.3, 130.7, 130.0, 129.6, 129.1, 127.6, 126.7, 124.2, 122.4, 115.35, 115.33, 114.4, 102.3, 59.3, 54.1, 20.6, 15.8, 13.1; HRMS (ESI): Exact mass calcd. for C2 ₇ H2 ₇ NO5S [M-H] ^" : 476.1537, Found: 476.1541.

A ⁱ -(2-(6-bromo-2-hydroxynaphthalen-l-yl)-4-methoxy-3,5-d imethylphenyl)-4- methylbenzenesulfonamide (7n)

For 0.3 mmol scale, the standard procedure A was followed to provide 7n (139 mg, 88% yield). 7n, white solid, m.p. 204-206 °C; R _f 0.40 (3: 1, ra-Hexane: EtOAc); Ή NMR (600 MHz, Acetone-d ⁶ ): δ 8.03 (d, / = 1.8 Hz, 1H), 7.87 (d, 7 = 9.0 Hz, 1H), 7.48 (s, 1H), 7.39 (d, 7 = 9.0 Hz, 1H), 7.22 (d, / = 8.4 Hz, 2H), 7.17 (dd, / = 9.0, 2.4 Hz, 1H), 6.96 (d, / = 8.4 Hz, 2H), 6.53 (d, / = 9.0 Hz, 1H), 3.71 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H), 1.71 (s, 3H); ¹³ C NMR (151 MHz, Acetone-d ⁶ ): δ 154.7, 152.5, 143.2, 137.3, 132.0, 131.62, 131.57, 131.1, 130.0, 129.8, 129.6, 129.4, 129.1, 126.8, 126.6, 125.8, 122.8, 119.5, 116.2, 115.5, 59.2, 20.8, 15.7, 13.0.

methyl-6-hydroxy-5-(3-methoxy-2,4-dimethyl-6-((4-methylpheny l)sulfonamido)- phenyl)- 2- naphthoate (7o)

For 0.3 mmol scale, the standard procedure A was followed to provide 7o (142 mg, 94% yield).

7m, white solid, m.p. 209-210 °C; R _f 0.30 (2:1, ra-Hexane: EtOAc); Ή NMR (600 MHz, Acetone-d ⁶ ): δ 8.93 (s, 1H), 8.54 (d, / = 1.8 Hz, 1H), 8.06 (d, / = 9.0 Hz, 1H), 7.60 (dd, / = 9.0, 1.8 Hz, 1H), 7.50 (s, 1H), 7.45-7.40 (m, 1H), 7.22 (dd, / = 8.4, 1.8 Hz, 2H), 6.99 (s, 1H), 6.94 (d, / = 7.8 Hz, 2H), 6.65 (d, J = 9.0 Hz, 1H), 3.96 (s, 3H), 3.72 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H), 1.71 (s, 3H); ¹³ C NMR (151 MHz, Acetone-d ⁶ ): δ 166.6, 154.7, 154.4, 143.2, 137.3, 135.8, 131.8, 131.7, 131.6, 131.0, 130.9, 129.2, 127.8, 126.7, 126.6, 126.0, 124.6, 123.8, 122.5, 119.2, 115.5, 59.3, 51.4, 20.5, 15.7, 12.9; HRMS (ESI): Exact mass calcd. for C28H27NO6S [M-H] ^" : 504.1486, Found: 504.1490.

A ⁱ -(2-(2-hydroxynaphthalen- 1 -yl)-3,4,5-trimethoxyphenyl)methanesulfonamide (7p)

For 0.3 mmol scale, the standard procedure A was followed to provide 7p (78 mg, 64% yield).

7p, white solid, m.p. 241-242 °C; R _f 0.50 (1: 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, Acetone-d ⁶ ): δ 8.59 (s, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.40-7.32 (m, 3H), 7.29 (d, J = 8.4 Hz, 1H), 7.22 (s, 1H), 6.61 (s, 1H), 3.96 (s, 3H), 3.87 (s, 3H), 3.52 (s, 3H), 2.72 (s, 3H); ¹³ C NMR (151 MHz, Acetone-d ⁶ ): δ 154.0, 153.0, 152.8, 140.0, 134.3, 132.4, 130.3, 129.0, 128.2, 126.7, 124.1, 123.2, 118.3, 114.4, 112.6, 101.6, 60.2, 60.1, 55.5, 38.9; HRMS (ESI): Exact mass calcd. for C20H2 ₁ NO6S [M-H] ^" : 402.1017, Found: 402.1019.

A ⁱ -(2-(6-bromo-2-hydroxynaphthalen-l-yl)-3,4,5-trimethox yphenyl)methariesulforiamide (7q)

For 0.3 mmol scale, the standard procedure A was followed to provide 7q (108 mg, 74% yield).

7q, white solid, m.p. 236-237 °C; R _f 0.40 (1: 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, Acetone-d ⁶ ): δ 8.08 (d, / = 2.4 Hz, 1H), 7.89 (d, / = 9.0 Hz, 1H), 7.48 (dd, / = 9.0, 2.4 Hz, 1H), 7.39 (d, / = 8.4 Hz, lH),7.26-7.22 (m, 2H), 3.96 (s, 3H), 3.87 (s, 3H), 3.52 (s, 3H), 2.75 (s, 3H); ¹³ C NMR (151 MHz, Acetone-d ⁶ ): δ 154.1, 153.5, 152.7, 140.0, 133.1, 132.6, 130.2, 130.0, 129.5, 129.4, 126.5, 119.6, 116.3, 113.9, 113.1, 101.9, 60.19, 60.15, 55.5, 39.1.

A ⁱ -(2-(2,3-dihydroxynaphthalen- 1 -yl)-3,4,5-trimethoxyphenyl)methanesulfonamide (7r)

For 0.3 mmol scale, the standard procedure A was followed to provide 7r (84 mg, 67% yield).

7r, white solid, m.p. 216-217 °C; R _f 0.30 (1: 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, Acetone-d ⁶ ): δ 7.69 (d, / = 7.8 Hz, 1H), 7.35 (s, 1H), 7.30-7.25 (m, 1H), 7.24 (s, 1H), 7.23-7.17 (m, 2H), 3.96 (s, 3H), 3.87 (s, 3H), 3.53 (s, 3H), 2.74 (s, 3H); ¹³ C NMR (151 MHz, Acetone-d ⁶ ): δ 154.0, 152.8, 145.8, 144.8, 140.0, 132.4, 129.6, 128.8, 126.4, 123.9, 123.8, 123.7, 114.4, 113.2, 110.1, 101.6, 60.21, 60.17, 55.5, 38.9; HRMS (ESI): Exact mass calcd. for C20H21NO7S [M-H] ^" : 418.0966, Found: 418.0970. Methyl 6-hydroxy-5-(2 ,4-trimethoxy-6-(methylsulfonamido)phenyl)-2-naphthoate (7s)

For 0.3 mmol scale, the standard procedure A was followed to provide 7s (91 mg, 66% yield).

7s, white solid, m.p. 183-184 °C; R _f 0.50 (1 : 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, Acetone-d ⁶ ): δ 8.96 (s, 1H), 8.58 (d, / = 1.8 Hz, lH), 8.08 (d, 7 = 9.0 Hz, 1H), 7.93 (dd, / = 9.0, 1.8 Hz, 1H), 7.44 (d, / = 8.4 Hz, 1H), 7.38 (d, / = 8.4 Hz, 1H), 7.25 (s, 1H), 6.84 (s, 1H), 3.96 (s, 3H), 3.92 (s, 3H), 3.88 (s, 3H), 3.53 (s, 3H), 2.75 (s, 3H); ¹³ C NMR (151 MHz, Acetone-d ⁶ ): δ 166.6, 155.3, 154.1, 152.7, 140.0, 136.9, 132.6, 131.8, 131.1, 128.0, 125.8, 124.9, 124.6, 119.4, 113.9, 113.1, 101.9, 60.20, 60.17, 55.5, 51.4, 39.1; HRMS (ESI): Exact mass calcd. for C22H2 ₃ NO8S [M+Na] ⁺ : 484.1037, Found: 484.1045.

A ⁱ -(2',4'-dichloro-6'-hydroxy-4,5,6-trimethoxy-[l,r-biph enyl]-2-yl)methane- sulfonamide (7t)

7t

For 0.3 mmol scale, the standard procedure A was followed to provide 7t (65.8 mg, 52% yield).

7t, white solid, m.p. 195-197 °C; R _f 0.50 (2: 1, ra-Hexane: EtOAc); ¾ NMR (600 MHz, Acetone-d ⁶ ): δ 9.11 (s, 1H), 7.22 (s, 1H), 7.16 (s, 1H), 7.10 (d, / = 1.8 Hz, 1H), 7.01 (d, / = 1.8 Hz, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 3.70 (s, 3H), 2.92 (s, 3H); ¹³ C NMR (151 MHz, Acetone-d ⁶ ): δ 157.5, 154.2, 152.0, 139.6, 136.7, 134.3, 132.0, 120.4, 119.6, 114.8, 113.7, 102.0, 60.3, 60.1, 55.5, 39.2; HRMS (ESI): Exact mass calcd. for QeHnCkNOeS [M-H] ^" : 420.0081, Found: 420.0085. A ⁱ -(2',4'-dibromo-6'-hydroxy-4,5,6-trimethoxy-[l ,l'-biphenyl]-2-yl)metliane- sulfonamide (7u)

7u

For 0.3 mmol scale, the standard procedure A was followed to provide 7u (73.5 mg, 48% yield).

7u, white solid, m.p. 209-210 °C; R _f 0.50 (2: 1, re-Hexane: EtOAc); ¾ NMR (600 MHz, Acetone-d ⁶ ): δ 9.10 (s, 1H), 7.40 (d, / = 2.4 Hz, 1H), 7.20 (d, / = 1.8 Hz, 2H), 7.17 (s, 1H), 3.91 (s, 3H), 3.83 (s, 3H), 3.71 (s, 3H), 2.95 (s, 3H); ¹³ C NMR (151 MHz, Acetone-d ⁶ ): δ 157.5, 154.2, 151.8, 139.5, 131.8, 127.3, 126.1, 122.3, 122.0, 118.2, 115.5, 101.5, 60.3, 60.1, 55.5, 39.4; HRMS (ESI): Exact mass calcd. for QeHnB^NOeS [M-H] ^" : 507.9071, Found: 507.9070.

Deprotection of the Mesyl (Ms) Group (Ito, et at, 2013)

To a stirred solution of 7a (150 mg, 0.40 mmol) and Boc ₂ 0 (210 mg, 0.96 mmol) in CH ₂ C1 ₂ (10 mL), DMAP (20 mg) was added at room temperature under air, and it was stirred for 1 h. Solvent was removed under reduced pressure. The crude residue was dissolved in THF (10 mL) under Argon atmosphere and ra-BuLi (1.6 M in hexane, 0.75 mL, 1.2 mmol) was added dropwise at 0 °C. After stirring 20 min., Argon balloon was replaced by dry O ₂ balloon and then stirred for 1 h at room temperature. Water was added to the reaction mixture and the aqueous phase was extracted with EtOAc three times. The combined extract was dried over anhydrous Na ₂ S04 and then evaporated to dryness. The crude residue was dissolved to CH2CI2 (5 mL) and then TFA (0.6 mL) was added at room temperature. After reaction completion was confirmed by TLC, solvent was removed under vacuum and crude product was purified by column chromatography on S1O ₂ (hexane/ethyl acetate = 3: 1) to give pure amine 8a (88 mg, 75% yield).

1 -(6-amino-3-methoxy-2,4-dimethylphenyl)naphthalen-2-ol (8a)

8a, 75% yield (3 steps), yellow amorphous; R _f 0.45 (2: 1, re-Hexane: EtOAc); Ή NMR (400 MHz, CDC1 ₃ ): δ 7.83 (d, / = 8.8 Hz, 2H), 7.35-7.26 (m, 4H), 6.56 (s, 1H), 4.02 (br s, 3H), 3.71 (s, 3H), 2.32 (s, 6H), 1.84 (s, 3H); ¹³ C NMR (100 MHz, CDCI ₃ ): δ 151.1, 150.2, 141.1, 132.7, 132.4, 132.2, 129.9, 129.3, 128.3, 126.9, 123.9, 123.5, 117.7, 116.7, 115.80, 115.76, 60.2, 16.3, 13.1.

EXAMPLE 4 - Crystal Structure and Transition State Data

The x-ray crystal structure for compound 5c is shown in FIG. 4. Additional crystal data are listed below.

Table 5. Crystal data and structure refinement for CwHnBrOs

Identification code laszlol6_0m_a

Empirical formula CioHivBrOs

Formula weight 373.23

Temperature 100(2) K

Wavelength 0.71073 A

Crystal system Monoclinic

Space group P 21/n

Unit cell dimensions a = 7.7304(3) A = 90°.

b = 19.0967(8) A β= 92.8390(10)°.

c = 11.0245(4) A γ= 90°.

Volume 1625.50(11) A ³

Z 4

Density (calculated) 1.525 Mg/m ³

Absorption coefficient 2.541 mm ^"1

F(000) 760

Crystal size 0.372 x 0.258 x 0.174 mm ³

Theta range for data collection 3.147 to 36.317°.

Index ranges -12<=h<=12, -31<=k<=31, -18<=1<=18

Reflections collected 33843

Independent reflections 7865 [R(int) = 0.0261]

Completeness to theta = 25.000' 99.8 %

Absorption correction Numerical

Max. and min. transmission 0.748 and 0.643

Refinement method Full-matrix least- squares on F ²

Data / restraints / parameters 7865 / 0 / 213

Goodness-of-fit on F ² 1.031

Final R indices [I>2sigma(I)] Rl = 0.0357, wR2 = 0.0823

R indices (all data) Rl = 0.0489, wR2 = 0.0873

Extinction coefficient n/a

Largest diff. peak and hole 1.816 and -0.594 e.A ^"3

Table 6. Atomic coordinates (x 10 ⁴ ) and equivalent isotropic displacement parameters (A ² x 10 ³ ) for Ci9HnBr03. U(eq) is defined as one third of the trace of the orthogonalized U ^lj tensor. X y z U(eq)

Br(l) 3404(1) 7437(1) 1724(1) 23(1)

O(l) 683(1) 9696(1) 7706(1) 20(1)

0(2) 2945(1) 7863(1) 8073(1) 21(1)

0(3) 7579(1) 10059(1) 8468(1) 17(1)

C(l) 3044(2) 7948(1) 3169(1) 17(1)

C(2) 1485(2) 8262(1) 3339(1) 16(1)

C(3) 1224(1) 8617(1) 4451(1) 14(1)

C(4) -378(1) 8940(1) 4699(1) 16(1)

C(5) -580(1) 9290(1) 5766(1) 16(1)

C(6) 806(1) 9334(1) 6655(1) 14(1)

C(7) 2368(1) 9007(1) 6467(1) 13(1)

C(8) 2597(1) 8646(1) 5355(1) 13(1)

C(9) 4190(1) 8311(1) 5129(1) 16(1)

C(10) 4415(2) 7965(1) 4057(1) 18(1)

C(l l) 3801(1) 9015(1) 7420(1) 12(1)

C(12) 4043(1) 8428(1) 8169(1) 14(1)

C(13) 5416(2) 8390(1) 9026(1) 16(1)

C(14) 6607(1) 8938(1) 9149(1) 16(1)

C(15) 6352(1) 9522(1) 8403(1) 14(1)

C(16) 4969(1) 9575(1) 7542(1) 13(1)

C(17) 8132(2) 8892(1) 10050(1) 25(1)

C(18) 7134(2) 10625(1) 9257(1) 20(1)

C(19) 4740(2) 10218(1) 6761(1) 18(1)

Table 7. Bond lengths [A] and angles [°] for CwHnBrCb.

Br(l)-C(l) 1.9011(11)

0(1)-C(6) 1.3561(14)

0(1)-H(1) 0.8400

0(2)-C(12) 1.3741(14)

0(2)-H(2) 0.8400

0(3)-C(15) 1.3965(13)

0(3)-C(18) 1.4389(14)

C(l)-C(2) 1.3674(16)

C(l)-C(10) 1.4067(17)

C(2)-C(3) 1.4241(16)

C(2)-H(2A) 0.9500

C(3)-C(8) 1.4212(15) C(3)-C(4) 1.4220(15)

C(4)-C(5) 1.3689(16)

C(4)-H(4) 0.9500

C(5)-C(6) 1.4180(15)

5 C(5)-H(5) 0.9500

C(6)-C(7) 1.3837(14)

C(7)-C(8) 1.4256(15)

C(7)-C(l l) 1.4888(15)

C(8)-C(9) 1.4204(15)

10 C(9)-C(10) 1.3718(16)

C(9)-H(9) 0.9500

C(10)-H(10) 0.9500

C(l l)-C(12) 1.3992(15)

C(l l)-C(16) 1.4022(15)

15 C(12)-C(13) 1.3872(16)

C(13)-C(14) 1.3956(17)

C(13)-H(13) 0.9500

C(14)-C(15) 1.3946(16)

C(14)-C(17) 1.5060(16)

20 C(15)-C(16) 1.3978(15)

C(16)-C(19) 1.5039(16)

C(17)-H(17A) 0.9800

C(17)-H(17B) 0.9800

C(17)-H(17C) 0.9800

25 C(18)-H(18A) 0.9800

C(18)-H(18B) 0.9800

C(18)-H(18C) 0.9800

C(19)-H(19A) 0.9800

C(19)-H(19B) 0.9800

30 C(19)-H(19C) 0.9800

C(6)-0(1)-H(l) 109.5

C(12)-0(2)-H(2) 109.5

C(15)-0(3)-C(18) 113.61(9)

C(2)-C(l)-C(10) 122.21(10)

35 C(2)-C(l)-Br(l) 120.43(9)

C(10)-C(l)-Br(l) 117.32(9)

C(l)-C(2)-C(3) 119.35(10)

C(1)-C(2)-H(2A) 120.3 C(3)-C(2)-H(2A) 120.3 C(8)-C(3)-C(4) 118.40(10) C(8)-C(3)-C(2) 119.30(10) C(4)-C(3)-C(2) 122.29(10) C(5)-C(4)-C(3) 120.96(10) C(5)-C(4)-H(4) 119.5 C(3)-C(4)-H(4) 119.5 C(4)-C(5)-C(6) 120.57(10) C(4)-C(5)-H(5) 119.7 C(6)-C(5)-H(5) 119.7 0(1)-C(6)-C(7) 117.14(10) 0(1)-C(6)-C(5) 122.54(10) C(7)-C(6)-C(5) 120.31(10) C(6)-C(7)-C(8) 119.59(10) C(6)-C(7)-C(l l) 120.97(9) C(8)-C(7)-C(l l) 119.44(9) C(9)-C(8)-C(3) 118.90(10) C(9)-C(8)-C(7) 121.00(10) C(3)-C(8)-C(7) 120.10(9) C(10)-C(9)-C(8) 121.05(10) C(10)-C(9)-H(9) 119.5 C(8)-C(9)-H(9) 119.5 C(9)-C(10)-C(l) 119.18(11) C(9)-C(10)-H(10) 120.4 C(l)-C(10)-H(10) 120.4 C(12)-C(l l)-C(16) 119.22(10) C(12)-C(l l)-C(7) 118.77(9) C(16)-C(l l)-C(7) 121.91(9) 0(2)-C(12)-C(13) 117.39(10) 0(2)-C(12)-C(l l) 121.31(10) C(13)-C(12)-C(l l) 121.29(10) C(12)-C(13)-C(14) 120.37(11) C(12)-C(13)-H(13) 119.8 C(14)-C(13)-H(13) 119.8 C(15)-C(14)-C(13) 117.97(10) C(15)-C(14)-C(17) 121.26(11) C(13)-C(14)-C(17) 120.76(11) C(14)-C(15)-0(3) 118.78(10) C(14)-C(15)-C(16) 122.68(10)

0(3)-C(15)-C(16) 118.44(10)

C(15)-C(16)-C(l l) 118.45(10)

C(15)-C(16)-C(19) 120.84(10)

C(l l)-C(16)-C(19) 120.70(9)

C(14)-C(17)-H(17A) 109.5

C(14)-C(17)-H(17B) 109.5

H(17A)-C(17)-H(17B) 109.5

C(14)-C(17)-H(17C) 109.5

H(17A)-C(17)-H(17C) 109.5

H(17B)-C(17)-H(17C) 109.5

0(3)-C(18)-H(18A) 109.5

0(3)-C(18)-H(18B) 109.5

H(18A)-C(18)-H(18B) 109.5

0(3)-C(18)-H(18C) 109.5

H(18A)-C(18)-H(18C) 109.5

H(18B)-C(18)-H(18C) 109.5

C(16)-C(19)-H(19A) 109.5

C(16)-C(19)-H(19B) 109.5

H(19A)-C(19)-H(19B) 109.5

C(16)-C(19)-H(19C) 109.5

H(19A)-C(19)-H(19C) 109.5

H(19B)-C(19)-H(19C) 109.5

Symmetry transformations were used to generate equivalent atoms.

Table 8. Anisotropic displacement parameters (A ² xl0 ³ ) for Ci9Hi7Br(¾. The anisotropic displacement factor exponent takes the form: -2π ² [1ι ² a* ² U ⁿ + . . + 2 h k a* b* U ¹² ].

U ¹¹ u ²² U ³³ U ²³ U ¹³ U ¹²

Br(l) 26(1) 25(1) 19(1) -10(1) 4(1) -3(1)

O(l) 13(1) 27(1) 21(1) -9(1) 3(1) 4(1)

0(2) 22(1) 17(1) 23(1) 3(1) -1(1) -6(1)

0(3) 11(1) 18(1) 21(1) -7(1) 3(1) -2(1)

C(l) 21(1) 16(1) 15(1) -3(1) 3(1) -2(1)

C(2) 18(1) 16(1) 15(1) -1(1) 0(1) -3(1)

C(3) 14(1) 13(1) 14(1) 0(1) 0(1) -1(1)

C(4) 12(1) 16(1) 18(1) 2(1) -2(1) 0(1)

C(5) 11(1) 16(1) 20(1) 1(1) 1(1) 1(1) C(6) 12(1) 14(1) 16(1) -1(1) 2(1) 0(1)

C(7) 10(1) 14(1) 14(1) -1(1) 1(1) 0(1)

C(8) 12(1) 13(1) 13(1) -1(1) 1(1) 0(1)

C(9) 14(1) 18(1) 15(1) -2(1) 0(1) 3(1)

C(10) 18(1) 19(1) 17(1) -4(1) 3(1) 3(1)

C(l l) 11(1) 14(1) 12(1) -1(1) 2(1) 1(1)

C(12) 14(1) 15(1) 14(1) -1(1) 2(1) 0(1)

C(13) 19(1) 17(1) 14(1) 0(1) 1(1) 3(1)

C(14) 15(1) 18(1) 14(1) -3(1) 0(1) 3(1)

C(15) 10(1) 16(1) 15(1) -4(1) 2(1) 1(1)

C(16) 11(1) 14(1) 14(1) -2(1) 3(1) 1(1)

C(17) 22(1) 29(1) 23(1) -1(1) -8(1) 4(1)

C(18) 19(1) 19(1) 22(1) -8(1) 2(1) 0(1)

C(19) 17(1) 16(1) 20(1) 2(1) -1(1) -2(1)

Table 9. Hydrogen coordinates (x 10 ⁴ ) and isotropic displacement parameters (A ² x 10 ³ ) for CioHivBrOs.

x y z U(eq)

H(l) -349 9820 7779 30

H(2) 2211 7928 7496 31

H(2A) 586 8244 2720 20

H(4) -1323 8912 4116 19

H(5) -1657 9506 5913 19

H(9) 5114 8327 5729 19

H(10) 5483 7741 3916 21

H(13) 5545 7989 9533 20

H(17A) 9208 8895 9616 37

H(17B) 8061 8457 10516 37

H(17C) 8119 9293 10603 37

H(18A) 5999 10814 8991 30

H(18B) 8010 10994 9226 30

H(18C) 7090 10451 10091 30

H(19A) 3989 10552 7156 27

H(19B) 4210 10086 5968 27

H(19C) 5872 10433 6650 27

Computational details All optimizations were performed in Gaussian 09 with the M06-2X density functional and 6- 31+G(d,p) basis set (Frisch, et al. 2009). Geometries presented were confirmed as minima or saddle points by optimization to a stationary point and then full calculation of the Hessian and vibrational analysis. Transition-state structures were also examined using intrinsic reaction coordinate calculations to verify the connection to proposed intermediates. The M06-2X density functional was chosen because it provides the best expected accuracy for main-group organic species and reactive intermediates. All optimizations and energy evaluations were carried out in the implicit SMD toluene solvent model. Enthalpies and free energies are reported at 298 K. Enthalpies reported are the sum of AE + AGsoiv + ΛΕΖΡΕ + AU + nRT.

xyz coordinates

TSl

Lowest Frequency Vibration = -190.1998 cm**-l

Temperature = 298.150 K

Pressure = 1.00000 Atm

Electronic Energy = -881.532407780

Electronic and Zero-Point Energy = -881.263611

Enthalpy = -881.246935

Free Energy = -881.305843

C -2.0772990 -0.9323790 1.0170890

C -0.8378630 -0.6393580 1.5040830 c -0.3213010 0.7494630 1.5348560 c -1.2202060 1.7927150 0.9959150 c -2.4060920 1.4686680 0.4468690

H -0.2306970 -1.3871690 2.0056560

H -0.8774150 2.8200930 1.0699560

O 0.7800340 1.0196470 2.0004780

C -2.7892780 0.0775130 0.3085040

O -3.9868540 -0.1036630 -0.2277200

C -4.3933180 -1.4365750 -0.5387740

H -5.2837250 -1.3355870 -1.1578080

H -3.6032190 -1.9449090 -1.0974260

H -4.6459990 -1.9867670 0.3729090

C 3.9783030 -1.5119840 0.4084970

C 2.6638020 -1.7831270 0.1149590

C 1.8195290 -0.7776400 -0.4302600

C 2.3572530 0.5193160 -0.6692210 c 3.7151340 0.7693660 -0.3595080 c 4.5096030 -0.2218860 0.1699170

H 0.0518590 -2.0255980 -0.5943650

H 4.6149160 -2.2859290 0.8262370

5 H 2.2484800 -2.7716140 0.2963850

C 0.4530730 -1.0226710 -0.7059300

C 1.5153880 1.5262880 -1.2429840

H 4.1200890 1.7615870 -0.5411400

H 5.5485900 -0.0159960 0.4084460

10 C 0.2063110 1.2795430 -1.5232730

C -0.3848500 -0.0266360 -1.2782320

H 1.9456220 2.5054640 -1.4394860

H -0.4376180 2.0404490 -1.9547170

O -1.6251290 -0.2429980 -1.4930120

H -2.4477700 -1.9505820 1.0306260

H -3.0766700 2.2089690 0.0217160

TS2

Lowest Frequency Vibration = -146.3237 cm**-l

Temperature = 298.150 K

Pressure = 1.00000 Atm

Electronic Energy = -1523.88659866 Electronic and Zero-Point Energy = -1523.523845

Enthalpy = -1523.494835

Free Energy = -1523.585683 c 0.0410770 2.6315610 1.0861870 c -1.2575120 2.2893770 1.2312410 c -1.6543850 0.9301280 1.6705140 c -0.5662580 0.0078210 2.0681420

30 c 0.7203120 0.3551250 1.8951760

H -2.0623320 2.9990460 1.0645230

H -0.8600090 -0.9509770 2.4879150

O -2.8350080 0.5972120 1.7187460

C 1.0479160 1.6046800 1.2297090

O 2.3397830 1.8374610 1.1394630

C 2.7958860 3.0062090 0.4451410

H 3.8675780 2.8667170 0.3141300 H 2.3046730 3.0784420 -0.5284720

H 2.6100360 3.8997720 1.0472860

C -5.1823070 0.8689000 -1.9178640

C -3.9329180 1.4300080 -1.8251200

C -2.8071450 0.6382680 -1.4641870

C -2.9944930 -0.7501980 -1.1991810

C -4.2953380 -1.3026020 -1.3145680

C -5.3653880 -0.5125850 -1.6622800

H -1.3505930 2.2481920 -1.5545340

H -6.0360850 1.4814210 -2.1904300

H -3.7850960 2.4885640 -2.0237160

C -1.5168570 1.1989690 -1.3288200

C -1.8647410 -1.5477510 -0.8431860

H -4.4337400 -2.3637780 -1.1256690

H -6.3569930 -0.9465780 -1.7453340

C -0.6229940 -0.9952980 -0.7115640

C -0.4208600 0.4098020 -0.9531920

H -2.0125640 -2.6082420 -0.6557630

H 0.2379470 -1.5880050 -0.4136720

O 0.7503870 0.9632450 -0.7523250

H 0.3266490 3.6208940 0.7482990

H 1.5453350 -0.3057970 2.1378500

C 3.4042530 -0.8738380 -0.4235240

O 2.7637730 -1.4857010 0.3993690

O 3.0035430 0.0630810 -1.2286830

H 2.0135420 0.3457100 -1.0255670

C 4.9155160 -1.1400120 -0.6028260

F 5.2430720 -1.2834970 -1.8923270

F 5.6191400 -0.1026750 -0.1162580

F 5.2963100 -2.2367120 0.0478840

O -2.9149400 -2.1644550 2.4165540

H -3.0774720 -1.2805460 2.0486700

C -3.8992990 -3.0642190 1.9530930

H -3.8671480 -3.9513610 2.5909920

H -4.9081320 -2.6362890 2.0082200

H -3.7093900 -3.3840580 0.9192210 TS3

Lowest Frequency Vibration = -350.9512 cm**-l

Temperature = 298.150 K Pressure = 1.00000 Atm Electronic Energy = -1523.84972876 Electronic and Zero-Point Energy = -1523.485251

Enthalpy = -1523.456234 Free Energy = -1523.545709 c 0.1416850 1.5594850 -0.4160800 c 0.3496490 0.3168120 0.2414720 c -0.6267980 -0.0961770 1.3240550 c -1.5373570 0.9424600 1.8357560 c -1.6124380 2.1398160 1.2342880

H 0.6928740 -0.5249370 -0.3561340

H -2.1555990 0.6782960 2.6874490

O -0.6246940 -1.2292030 1.7703230

C -0.7935800 2.4433950 0.0546510

O -0.9263880 3.5937310 -0.5959190

C -2.0238830 4.4692660 -0.3180740

H -1.9691560 5.2435770 -1.0825930

H -2.9654760 3.9236340 -0.4054850

H -1.9102360 4.9292820 0.6684190

C -4.5509240 1.4684790 -0.1658800

H -4.3065590 0.9036180 0.7437660

H -5.0255510 2.4149140 0.1200550

H -5.2794870 0.8784520 -0.7361870

H -2.8949930 0.9206000 -1.0345430

O -3.4020580 1.7639100 -0.9301100

O -1.9566770 -0.5035750 -1.0029450

C 4.1517340 1.9180990 -1.5571990

C 3.3225870 1.8694750 -0.4484820

C 3.0231100 0.6367470 0.1519280

C 3.5729490 -0.5505150 -0.3895140

C 4.4066130 -0.4803660 -1.5262450

C 4.6929830 0.7404610 -2.1034060

H 1.8533960 1.4325710 1.8309660

H 4.3841340 2.8764180 -2.0114360 H 2.9030840 2.7821100 -0.0342980

C 2.1004350 0.5327050 1.2723510

C 3.2981780 -1.7988870 0.2575040

H 4.8187100 -1.3984790 -1.9357610

H 5.3354510 0.7938190 -2.9759660

C 2.5913000 -1.8758320 1.4274500

C 2.0884790 -0.6839800 2.0002450

H 3.6970140 -2.7080480 -0.1851770

H 2.4342090 -2.8251490 1.9308750

O 1.5312010 -0.6555360 3.1996100

H 1.3040660 -1.5470200 3.5106770

C -2.5056620 -1.5649300 -0.6003160

O -3.5811350 -1.7515970 -0.0363920

C -1.6757590 -2.8454880 -0.9239900

F -0.3450780 -2.6182850 -0.9622240

F -1.8719810 -3.8390970 -0.0455850

F -2.0145090 -3.3254570 -2.1411970

H 0.6738470 1.7948540 -1.3303810

H -2.3073860 2.8890640 1.5971850

EXAMPLE 5 - Coupling of Iminoquinones with Naphthols

The quinone monoacetal coupling partner was developed in a way to avoid the generation of a proton source (e.g., MeOH) and thereby remove this potentially detrimental factor from the catalytic cycle (Intriguingly, when the coupling between 2a and 6a to form biaryl 9a was conducted in the presence of catalyst 7c ( 10 mol%) and 1 equivalent of MeOH (in DCE as the solvent), no detrimental impact on either the isolated yield (97%) or the enantiomeric excess (86% ee) was observed. However, when 20 equivalents of MeOH were added, the reaction slowed down dramatically while the isolated yield and ee also dropped to 35% and 62%, respectively (at 50% conversion).). The readily available -sulfonyl-protected iminoquinones was selected as substrates as these were expected to undergo acid-catalyzed in-situ aminal-formation (Li, et al., 2008) and subsequent /3,3/-rearrangement/rearomatization (FIG. 5B). In contrast, a 1,4-addition mechanism has been proposed recently by Tan et al. for a related reaction (FIG. 5C) (Chen, et al., 2015). With 10 mol% of chiral phosphoric acid 7b the reaction was catalyzed the coupling of 6a with 2a under mild conditions and led to the formation of functionalized biaryl 9a in excellent isolated yield and with 49% ee. Encouraged by this initial result, a survey of structurally diverse BINOL-derived chiral phosphoric acid catalysts (Akiyama, 2007; Kampen, et al., 2010; Terada, 2010; Parmar, et al., 2014) was conducted and solvents to find the optimum conditions that maximizes the enantiomeric excess of the product (Tables 10 and 11).

Table 10: Catal st Screen for the Atroposelective Synthesis of 9a from 6a and 2a.

1 CH2CI2 48 88.5:1 1.5 77

2 toluene 48 86:14 72

3 1 ,2-dichloroethane (DCE) 48 94:6 88

4 CHCI3 48 90.5:9.5 81

5 chlorobenzene 84 97:3 94

6 1 ,3-di-CF ₃ -benzene 60 93:7 86

7 ^C 1 ,2-dichloroethane (DCE) 24 94:6 88

8 ^C chlorobenzene 48 96:4 92

9 ^d 1 ,2-dichloroethane (DCE) 8 91 :9 82

10 ^{c e} 1 ,2-dichloroethane (DCE) 100 88.5:11.5 77 aReaction conditions: 2a (0.075 mmol), 6a (0.05 mmol), cat. (10 mol%), solvent (1 ml_). Reactions were stopped when all of 6a was consumed. ''Enantiomeric ratio was determined by HPLC analysis. ^c Reacted at 50 °C. ^d Reacted at 80 °C. ^e Using 5 mol% 7c.

Table 11: .

entry cat. solvent time (h) ee (%) *

entry cat. solvent time (h) ee (%) *

9 7c CH ₃ CN 48 53

10 7c toluene 48 72

11 7c DCE 48 88

12 7c THF 48 5

14 7c chlorobenzene 84 94

15 7c l,3-di-CF ₃ - 60 86

benzene

16 ^c 7c DCE 24 88

17 ^c 7c chlorobenzene 48 92

I8 ^d 7c DCE 8 82

19 ^{c e} 7c DCE 100 77 ^a Reaction conditions: 2a (0.075 mmol), 6a (0.05 mmol), cat. (10 mol%), solvent (1 mL). *

Determined by HPLC analysis. ^c Reacted at 50 °C. ^d Reacted at 80 °C. ^e Using 5 mol% 7c.

Based on the optimization studies (described in Tables 10 and 11), DCE as the preferred solvent, chiral phosphoric acid 7c (at 10 mol% loading) as the preferred catalyst and either 25 °C or 50 °C as the optimum reaction temperature were selected. At first, the coupling of iminoquinone 6a was evaluated with fourteen (14) structurally different hydroxyarenes that included eleven (11) naphthols (FIG. 8, entries 1-11) and three (3) monocyclic phenols (FIG. 8, entries 12-14).

For 2-naphthols the biaryl products were formed in good to excellent yield and the observed enantioselectivities ranged between 78-96% ee. There is no clear pattern that can be discerned how electron- withdrawing and electron-donating groups on the naphthalene ring influence the level of enantio-induction.

The nearly perfect enantioselectivity (99% ee) obtained during the formation of terphenyl compound 9ea' from 2,3-dihydroxynapthalene (FIG. 8, entry 15) is remarkable and suggests that significant substrate stereocontrol occurs as the second biaryl linkage is established (see discussion in Example 7).

With one exception (FIG. 8, entry 14), the use of monocyclic phenols resulted in good levels of enantio-induction (entries 12 & 13). In a few cases (FIG. 8, entries 1 & 5) the use of chlorobenzene as the solvent instead of DCE improved the enantioselectivities.

Next, the effects of structural changes (e.g., symmetry as well as size and nature of the substituents) were explored in the iminoquinones (6b-j) influence the yields and enantioselectivities of the biaryl products (Table 13).

Among the unsymmetrical iminoquinones 6b-e that were coupled with 2,3- dihydroxynaphthalene (2e), the presence of a large alkyl substituent in the ortho position of the N-Ts imine moiety led to somewhat lower the isolated yield and ee of 9ed (entry 18) compared to the isomeric 9eb and 9ec (entries 16 & 17) in which a smaller methyl (Me) substituent is in the ortho position. Without wishing to be bound by any theory, it is believed that the larger i-Pr group slows down aminal formation and also lowers the enantioselectivity of this step. Additionall, without wishing to be bound by any theory, it is believed that the nature of the acyl/sulfonyl group on the N atom also appears to be important - enantioselectivities increase as more electron withdrawing groups are used (e.g., Ts≥ Ms > Ac > p-NC -benzoyl; compare 9aa in Table 10 with entries 16, 23 & 24 in FIG. 8).

The most dramatic drop in the level of enantio-induction occurred when symmetrical (6f) and pseudosymmetrical (6g) iminoquinones were utilized as coupling partners (Table 13, entries 20 & 21). In fact, the poor ee' s observed for biaryls 9ef and 9eg provided a clue that helped establish if indeed aminal-formation versus 1,4-addition is involved in the key stereochemistry-determining step.

Table 13: Expansion of the Substrate Scope by Coupling Structurall Diverse Iminoquinones

ol Non-C ₂ -Symmetrical BINO

Based on several experimental findings (FIG. 6), it appears that in catalytic enantioselective processes where sequential chirality-transfer steps are involved, the highest level of enantio-induction will most likely take place in those cases where the catalyst does not "miss/ skip" an opportunity to transfer chiral information. One way to "lose" or "skip" an opportunity for chirality-transfer is when one or more symmetrical intermediates are formed along the pathway (see FIG. 6A & 6C). Naturally, symmetrical (e.g., prochiral) intermediates can be desymmetrized using chiral catalysts, however, the level of enantio-induction in these desymmetrizations must be very high which is often difficult to achieve. In particular, organocatalytic asymmetric versions of the Claisen rearrangement are challenging and there are only a few highly enantioselective examples in the literature (Uyeda, et al. , 2010; Rodrigues, et al., 2015).

In light of the enantio-induction levels for biaryls 9ea (96% ee) and 9eg (21% ee), we can make a convincing mechanistic case for the involvement of sequential aminal-formation//3,3 - rearrangement. FIG. 7 clearly shows that if a direct 1,4-addition was operational, the influence of the highlighted extra methyl group could not account for the dramatic loss of enantioselectivity.

EXAMPLE 6 - Characterization of Iminoquinone Coupled Compounds A. General Methods

All reactions were carried out in oven-dried glassware under air with magnetic stirring. All naphthol compounds were purchased from Sigma-Aldrich Co. and used without further purification. Reactions were monitored by TLC on silica gel 60 F254 plates Column chromatography was carried out on silica gel (200-300 mesh). Proton (Ή) and carbon ( ¹³ C) NMR spectra were recorded on an ACF* 300Q Bruker spectrometer operating at 300 MHz (or 500 MHz) for proton and 75 MHz (or 151 MHz) for carbon nuclei using CDCI ₃ [or (CD ₃ ) ₂ SO] as solvent, respectively. Chemical shifts are expressed as parts per million (δ, ppm) and are referenced to 7.26 (CDCh) or 2.50 (CD ₃ ) ₂ SO for Ή NMR and 77.23 (CDCh) or 39.51 (CD ₃ ) ₂ SO for ^{1 3} C NMR. Data for Ή NMR are recorded as follows: chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet or unresolved, br s = broad singlet, coupling constant (s) in Hz, integration). Data for ^{1 3} C NMR are reported in terms of chemical shift (δ, ppm). High Resolution Mass Spectrometry was performed on a Agilent Technologies 6230 TOF LC/MS under the conditions of electrospray ionization (ESI) in both positive and negative mode. Optical rotations were measured using a 2-mL cell with a 10-cm path length on Rudolph Autopol® IV automatic polarimeter, and concentrations (c) were reported in gx(100 mL) ¹ . Analytical HPLC was recorded on a HPLC machine equipped with SHIMADZU LC-20AT HPLC Pump and SHIMADZU SPD-20A Photodiode Array Detector (SHIMADZU HPLC machine). The chiral stationary phase was Daicel Chiralpak AD-H or IA, IA-3 column (0 = 0.46 cm, length = 25.0 cm). Melting points were recorded on Tianjin Analysis Instrument Factory RY-1.

B. Characterization

The phenol (50.0 mmol) was dissolved in HC1 (33 mL, 12 mol/L) and 95% ethanol (30 mL). NaNO ₂ (5.0 g) was slowly added at 0 °C (5 min) maintaining the stirring for 1 h at 0 °C. Ethanol (10 mL) was then added and the stirring was matintained for a further hour at room temperature. The reaction mixture was diluted with water (300 mL) and extracted with ethyl ether. The organic phase was extracted with 10% aqueous Na ₂ CC>3 solution. The carbonate solution on acidification with HCl (3 mol/L) yielded a precipitate, wash the precipitate with hexane to eliminate soluble impurities.

To an eggplant shaped bottle para-benzoquinone mono-oxime (10.0 mmol) was dissolved in CH ₂ CI ₂ (100 mL), then concentrated HCl (2 mL) was added. The solution was heated to reflux, then SnCh (5.7 g, 30.0 mmol) was added. The mixture was heated to reflux for 24 h. Then remove the CH2CI2 under reduced pressure, and the residue was dissolved in ethyl acetate and washed with concentrated aqueous NaHCC>3. Filter off the precipitate and the organic layer was dried over anhydrous Na ₂ S0 ₄ and the filtrate was concentrated under reduced pressure to afford the solid amino phenols.

Then the para-amino-phenol (5.0 mmol) was dissolved in dry pyridine (6 mL) and cooled to 0 °C. Para-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was added in small portions. The mixture was warmed to room temperature and stirred under nitrogen for 24 h. The reaction mixture was diluted with EtOAc and washed with HCl (10 mol/L), the organic layer was dried over anhydrous MgSC^, filtered, and concentrated to yield the crude sulfonamide.

The N-tosyl-para-aminophenol (4.0 mmol) was dissolved in dry CH ₂ CI ₂ (15 mL) and Ag ₂ 0 (8.0 mmol) was added, and stirred. The reaction was monitored by TLC. When the reaction was completed, the solution was filtered through celatom. The organic layer was concentrated to yield the crude product. The product 6 was purified by silica gel column using petroleum ether/ acetone (20: 1) as eluent. 35-45% yields (4 steps).

6a, yellow solid (920 mg, 45% yield). Ή NMR (500 MHz, DMSO-ife) δ 7.91 (d, J = 8.2 Hz, 2H), 7.83 (s, 1H), 7.51 (d, / = 8.2 Hz, 2H), 6.75 (s, 1H), 2.46 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H).

6b, brown solid (620 mg, 40% yield). ¾ NMR (500 MHz, DMSO-ife) δ 7.64 (s, 1H), 6.75 (s, 1H), 3.40 (s, 3H), 2.10 (s, 3H), 2.03 (s, 3H).

6c, yellow solid (420 mg, 35% yield). ¾ NMR (500 MHz, DMSO-ife) δ 7.90 (d, J = 8.0 Hz, 2H), 7.74 (s, IH), 7.51 (d, / = 7.6 Hz, 2H), 6.74 (s, IH), 3.02-2.97 (m, IH), 2.45 (s, 3H), 2.01 (s, 3H), 1.11 (d, / = 6.8 Hz, 6H).

6d, yellow solid (470 mg, 38% 00 MHz, DMSO-ife) δ 7.92-7.85 (m, 3H), 7.51 (d, / = 7.2 Hz, 2H), 6.60 (s, IH), 3.00-2.92 (m, IH), 2.45 (s, 3H), 2.07 (s, 3H), 1.05 (d, / = 7.2 Hz, 6H).

6e, brown solid (350 mg, 36% yield). ¾ NMR (300 MHz, CDC1 ₃ ) δ 7.92-7.89 (m, 3H), 7.39 (d, / = 8.0 Hz, 2H), 6.60-6.57 (m, IH), 2.48 (s, 3H), 2.11 (s, 3H).

6f, orange solid (210 mg, 18% yield). ¾ NMR (300 MHz, CDCI3) δ 7.80 (s, / = 8.3 Hz, 2H), 7.28 (d, / = 8.2 Hz, 2H), 6.42 (s, 2H), 2.39 (s, 3H), 2.25 (s, 6H).

6g, orange solid (235 mg, 22% yield). ¾ NMR (300 MHz, CDCI3) δ 7.88 (d, / = 8.1 Hz, 2H),

7.35 (d, / = 8.0 Hz, 2H), 6.48 (s, IH), 2.47 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H), 2.05 (s, 3H).

6h, yellow solid (450 mg, 40% yield). ¾ NMR (500 MHz, DMSO-*) δ 6.88 (s, IH), 6.62 (s, IH ), 2.30 (s, 3H), 2.09 (s, 3H), 1.95 (s, 3H).

6i, yellow solid (380 mg, 38% yield). ¾ NMR (500 MHz, DMSO-ife) δ 8.38 (d , / = 8.4 Hz, 2H), 8.17 (d, / = 8.4 Hz, 2H ), 6.85 (s, 1H), 6.75 (s, 1H), 2.25 (s, 3H), 1.91 (s, 3H).

6j, brown solid (280 mg, 34% yield) 300 MHz, CDC1 ₃ ) δ 8.19-8.15 (m, 1H), 7.89 (d, / = 7.9 Hz 2H), 7.36 (d, / = 8.0 Hz, 2H), 6.63-6.55 (m, 2H), 2.48 (s, 3H), 2.06 (s, 3H).

1. General procedure for the enantioselective synthesis of biaryls.

To a stirred solution of 2a (32.5 mg, 0.225 mmol) and 6a (43.5 mg, 0.15 mmol) in DCE or chlorobenzene (3 mL), cat. CPA 7c (11.2 mg, 10 mol%) was added in one portion at room temperature, and it was stirred at rt or 50 °C until the reaction was completed. Solvent was removed under reduced pressure and the crude residue was purified by column chromatography on silica-gel (petroleum ether/acetone = 8: 1 to 1 : 1) to give pure product 9aa (63.0 mg, 97% yield).

9aa, white solid, 97% yield (63.0 mg), 88% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); ra-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 15.32 (minor), 50.88 (major) min]. [a] _D ²⁰ = -82.7 (c = 0.3, CH ₃ OH). ¾ NMR (500 MHz, DMSO-*) δ 9.22 (br s, 1H), 9.14 (br s, 1H), 7.77 (d, / = 7.9 Hz, 1H), 7.73 (d, / = 8.8 Hz, 1H), 7.50 (d, / = 6.4 Hz, 2H), 7.49 (s, 1H), 7.32 (d, / = 8.0 Hz, 2H), 7.29-7.19 (m, 3H), 6.88 (s, 1H), 6.83 (d, / = 8.2 Hz, 1H), 2.31 (s, 3H), 2.12 (s, 3H), 1.21 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ife) δ 152.45, 151.96, 142.45,

137.76, 133.50, 133.32, 131.54, 129.56, 129.41, 128.67, 128.08, 127.84, 126.67, 125.94, 125.86,

123.77, 122.26, 121.52, 118.51, 116.09, 21.00, 16.55, 14.36. HRMS (ESI-TOF): Exact mass calcd. for C25H23NO4S [M+Na] ⁺ 456.1240, Found: 456.1240. MP 139-141 °C.

9ba, brown solid, 87% yield (66.9 mg), 92% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 11.38 (major), 16.62 (minor) min]. [a] _D ²⁰ = -56.0 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 9.19 (br s, 1H), 8.39 (br s, 1H), 8.17 (s, 1H), 7.78 (dd, / = 3.5, 6.2 Hz, 1H), 7.50 (d, / = 8.2 Hz, 2H), 7.38-7.25 (m, 4H), 6.95 (s, 1H), 6.80-6.73 (m, 1H), 2.30 (s, 3H), 2.14 (s, 3H), 1.18 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ife) δ 152.66, 148.98, 142.85, 138.05, 133.68, 132.86, 131.56, 130.70, 129.80, 129.35, 127.42, 127.09, 126.80, 126.50, 124.39, 123.94, 122.83, 122.39, 119.60, 114.23, 21.39, 16.99, 14.74. HRMS (ESI-TOF): Exact mass calcd. for C25H ₂ 2BrN0 ₄ S [M+Na] ⁺ 534.0345, Found: 534.0360. MP 113- 115 °C.

9ca, Brown solid, 88% yield (67.6 mg), 78% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 11.53 (major), 14.36 (minor) min]. [a] _D ²⁰ = -71.0 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 9.41 (br s, 1H), 9.16 (br s, 1H), 8.03 (s, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 8.0 Hz, 2H), 7.41 (dd, J = 1.6, 8.8 Hz, 1H), 7.34 (d, / = 8.1 Hz, 2H), 7.24 (d, J = 8.9 Hz, 1H), 6.91 (s, 1H), 6.74 (d, J = 8.9 Hz, 1H), 2.32 (s, 3H), 2.12 (s, 3H), 1.16 (s, 3H). ¹³ C NMR (75 MHz, DMSO-i _s ) δ 153.39, 152.33, 142.82, 138.09, 133.62, 132.57, 130.18, 129.89, 129.83, 129.69, 129.20, 128.34, 127.08, 126.51, 126.29, 123.58, 122.09, 120.11, 116.91, 115.49, 21.37, 16.93, 14.67. HRMS (ESI-TOF): Exact mass calcd. for C2 ₅ H ₂ 2BrN0 S [M+Na] ⁺ 534.0345, Found: 534.0351. MP 113-115 °C.

9da, brown solid, 84% yield (64.6 mg), 81 % ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); ra-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 11.60 (minor), 21.28 (major) min]. [a] _D ²⁰ = -52.0 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, CDCI3) δ 7.83 (d, / = 8.9 Hz, 1H), 7.69 (d, / = 8.7 Hz, 1H), 7.60 (d, / = 8.3 Hz, 2H), 7.44 (dd, / = 1.9, 11.2 Hz, 1H), 7.36 (s, 1H), 7.28 (d, / = 8.2 Hz, 2H), 7.25 (s, 1H), 7.16 (d, / = 1.7 Hz, 1H), 6.14 (br s, 1H), 4.99 (br s, 1H), 4.60 (br s, 1H), 2.39 (s, 3H), 2.29 (s, 3H), 1.37 (s, 3H). ¹³ C NMR (75 MHz, CDCI3) δ 153.49, 151.86, 142.45, 137.84, 134.93, 133.23, 130.25, 129.86, 129.28, 128.79, 126.49, 126.00, 125.17, 125.08, 123.06, 121.74, 119.69, 119.09, 115.68, 20.92, 16.47, 14.27. HRMS (ESI-TOF): Exact mass calcd. for C25H ₂ 2BrN0 ₄ S [M+Na] ⁺ 534.0345, Found: 534.0340. MP 129-131 °C.

9ea, white solid, 80% yield (54.0 mg), 96% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 25.50 (minor), 43.86 (major) min]. [a] _D ²⁰ = -86.3 (c = 0.3 CH ₃ OH). ¾ NMR (300 MHz, CD ₃ OD) δ 7.60-7.55 (m, 3H), 7.29 (d, J = 7.9 Hz, 2H), 7.23-7.18 (m, 2H), 7.10 (t, J = 7.3 Hz, 1H), 7.00 (s, 1H), 6.85 (d, J = 8.2 Hz, 1H), 2.35 (s, 3H), 2.18 (s, 3H), 1.33 (s, 3H). ¹³ C NMR (75 MHz, CD ₃ OD) δ 153.47, 147.47, 145.79, 144.75, 138.97, 135.39, 131.59, 131.19, 130.66, 129.70, 128.45, 127.80, 127.37, 125.00, 124.65, 124.58, 124.02, 123.79, 117.09, 110.65, 21.63, 16.55, 15.00. HRMS (ESI- TOF): Exact mass calcd. for C25H23NO5 ⁺ 472.1189, Found: 472.1197. MP 138-140 °C.

9fa, white solid, 89% yield (61.9 mg), 85% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); ra-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 31.69 (major), 35.00 (minor) min]. [a] _D ²⁰ = -58.3 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 9.15 (br s, 1H), 8.58 (br s, 1H), 7.72 (d, / = 7.8 Hz, 1H), 7.50 (br s, 1H), 7.48 (d, / = 7.9 Hz, 2H), 7.34 (s, 1H), 7.30 (d, J = 7.9 Hz, 2H), 7.24 (t, J = 1.1 Hz, 1H), 7.15 (t, J = 1.1 Hz, 1H), 6.88 (s, 1H), 6.75(d, J = 8.0 Hz, 1H), 3.95 (s, 3H), 2.31 (s, 3H), 2.11 (s, 3H), 1.20 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ife) δ 151.79, 148.41, 144.17, 142.35, 137.71, 133.14, 129.51, 129.32, 128.47, 128.37, 126.57, 126.51, 125.75, 123.49, 123.42, 122.83, 121.44, 116.79, 105.68, 55.51, 20.95, 16.46, 14.29. HRMS (ESI-TOF): Exact mass calcd. for C ₂₆ H ₂₅ NO ₅ S [M+Na] ⁺ 486.1347. Found: 486.1352. MP 129-131 °C.

9ga, brown solid, 78% yield (52.6 mg), 85% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); ra-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 16.30 (minor), 25.72 (major) min]. [a] _D ²⁰ = +105.3 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 9.40 (s, 1H), 9.12 (s, 1H), 9.05 (s, 1H), 7.59 (t, J = 8.3 Hz, 2H), 7.50 (d, / = 8.1 Hz, 2H), 7.41 (s, 1H), 7.30 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 8.8 Hz, 1H), 8.86 (s, 1H), 6.80 (dd, J = 1.8, 8.8 Hz, 1H), 6.23 (d, / = 1.7 Hz, 1H), 2.27 (s, 3H), 2.12 (s, 3H), 1.15 (s, 3H). ¹³ C NMR (125 MHz, DMSO-ife) δ 155.52, 152.72, 151.83, 142.29, 137.94, 135.28, 133.39, 129.61, 129.32, 128.44, 126.58, 125.92, 124.12, 122.84, 121.32, 115.04, 114.74, 114.34, 105.49, 20.91, 16.47, 14.07. HRMS (ESI-TOF): Exact mass calcd. for C25H23NO5S [M+Na] ⁺ 472.1189, Found: 472.1186. MP 128-130 °C.

9ha, brown solid, 87% yield (60.5 mg), 89% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 11.92 (minor), 22.11 (major) min]. [a] _D ²⁰ = -25.0 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 9.21 (br s, 1H), 9.16 (br s, 1H), 7.72 (d, / = 8.8 Hz, 1H), 7.67 (d, / = 8.8 Hz, 1H), 7.52 (br s, 1H), 7.50 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.8 Hz, 1H), 6.94 (dd, / = 2.1, 8.8 Hz, 1H), 6.70 (s, 1H), 6.28 (s, 1H), 3.64 (s, 3H), 2.32 (s, 3H), 2.07 (s, 3H), 1.39 (s, 3H). ¹³ C NMR (75 MHz, CDCI3) δ 159.34, 152.73, 151.90, 144.14, 136.91, 134.36, 133.15, 131.19, 130.97, 130.25, 129.75, 127.43, 127.33, 124.84, 123.75, 118.80, 115.66, 115.23, 111.33, 103.45, 55.46, 21.75, 16.16, 14.60. HRMS (ESI-TOF): Exact mass calcd. for C ₂₆ H ₂₅ NO ₅ S [M+Na] ⁺ 486.1346, Found: 486.1339. MP 124-126 °C.

9ia, white solid, 90% yield (69.0 mg), 87% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); ra-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 14.11 (minor), 33.44 (major) min]. [a] _D ²⁰ = -110.33 (c = 0.3, CH3OH). ¾ NMR (300 MHz, DMSO- d ₆ ) δ 9.40 (br s, 1H), 9.24 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.67 (br s, 1H), 7.60-7.45 (m, 5H), 7.43-7.35 (m, 3H). 7.23 (d, / = 8.9 Hz, 1H), 7.13 (s, 1H), 6.93 (d, / = 8.1 Hz, 2H), 6.78 (s, 1H), 2.14 (s, 3H), 2.11 (s, 3H), 1.30 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ife) δ 152.86, 152.02, 142.28, 140.93, 137.88, 137.64, 133.79, 133.58, 129.74, 129.02, 128.98, 128.66, 128.38, 127.40, 127.34, 126.77, 126.44, 125.89, 123.71, 121.57, 121.53, 121.35, 118.70, 116.54, 20.82, 16.49, 14.62. HRMS (ESI-TOF): Exact mass calcd. for C ₃₁ H ₂₇ NO ₄ S [M+Na] ⁺ 532.1553, Found: 532.1543. MP 86- 88 °C.

9ja, white solid, 62% yield (45.7 mg), 85% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 11.44 (major), 16.66 (minor) min]. [a] _D ²⁰ = -92.3 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 9.79 (br s, 1H), 9.17 (s, 1H), 8.50 (s, 1H), 7.96 (d, / = 8.9 Hz, 1H), 7.77 (dd, / = 1.4, 8.9 Hz, 1H), 7.49 (d, / = 8.1 Hz, 2H), 7.33 (d, / = 8.1 Hz, 2H), 7.29 (d, / = 9.0 Hz, 1H), 6.92 (s, 1H), 6.86 (d, / = 8.9 Hz, 1H), 3.89 (s, 3H), 2.31 (s, 3H), 2.13 (s, 3H), 1.16 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ife) δ 166.98, 155.41, 152.35, 142.85, 138.06, 136.44, 133.56, 131.19, 130.87, 130.18, 129.81, 127.37, 127.10, 126.29, 125.36, 124.55, 123.65, 123.56, 122.13, 119.89, 116.94, 52.36, 21.35, 16.94, 14.71. HRMS (ESI-TOF): Exact mass calcd. for C ₂₇ H ₂₅ NO ₆ S [M+Na] ⁺ 514.1295, Found: 514.1291. MP 119-121 °C.

9ka, white solid, 99% yield (69.2 mg), 83% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); ra-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 14.64 (major), 17.57 (minor) min]. [a] _D ²⁰ = -63.7 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 9.21 (s, 1H), 9.06 (s, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.56 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.9 Hz, 2H), 7.21-7.16 (m, 2H), 6.99 (d, / = 7.6 Hz, 1H), 6.92 (s, 1H), 6.73 (d, / = 9.1 Hz, 1H), 3.82 (s, 3H), 2.31 (s, 3H), 2.13 (s, 3H), 1.18 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ifc) δ 154.86, 151.85, 150.67, 142.38, 137.67, 133.19, 129.46, 129.37, 128.82, 128.65, 127.37, 126.62, 125.76, 125.29, 123.86, 121.45, 118.83, 118.18, 116.30, 106.47, 55.08, 21.00, 16.54, 14.31. HRMS (ESI-TOF): Exact mass calcd. for C26H25NO5S [M+Na] ⁺ 486.1346, Found: 486.1340. MP 200-202 °C.

91a, brown solid, 64% yield (42.6 mg), 76% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); ra-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 50.36 (minor), 55.42 (major) min]. [a] _D ²⁰ = -7.7 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-ife) δ 9.07 (s, 1H), 9.04 (s, 1H), 7.48 (d, / = 8.3 Hz, 2H), 7.32-7.28 (m, 3H), 6.58 (s, 1H), 6.06 (dd, / = 2.2, 8.3 Hz, 2H), 3.69 (s, 3H), 3.52 (s, 3H), 2.34 (s, 3H), 1.99 (s, 3H), 1.37 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ife) δ 160.10, 158.67, 156.25, 151.81, 142.27, 138.30, 133.84, 129.24, 128.67, 126.59, 125.40, 122.46, 120.63, 104.68, 93.72, 89.86, 55.20, 54.80, 20.94, 16.40, 14.59. HRMS (ESI-TOF): Exact mass calcd. for C23H25NO6S [M+Na] ⁺ 466.1295, Found: 466.129. MP 97-98 °C.

9ma, brown solid, 49% yield (30.0 mg), 75% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 9.42 (minor), 77.47 (major) min]. [a] _D ²⁰ = +12.67 (c = 0.3, CH3OH). ¾ NMR (300 MHz, DMSO-ifc) δ 9.09 (s, IH), 9.72 (s, IH), 7.45-7.41 (m, 3H), 7.29 (d, / = 8.1 Hz, 2H), 6.71 (s, IH), 6.49 (s, 2H), 2.35 (s, 3H), 2.18 (s, 3H), 2.06 (s, 3H), 1.66 (s, 3H), 1.30 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ife) δ 154.63, 151.18, 142.51, 136.81, 129.39, 128.98, 125.80, 121.34, 120.75, 113.46, 21.00, 20.93, 19.27, 16.50, 14.34. HRMS (ESI-TOF): Exact mass calcd. for C23H25NO4S [M+Na] ⁺ 434.1367, Found: 434.1395. MP 119-121 °C.

9na, brown solid, 97% yield (69.4 mg), 21% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 10.10 (minor), 54.73 (major), min]. [a] _D ²⁰ = +5.7 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 9.07 (s, IH), 8.86 (br s, IH), 7.49 (br s, IH), 7.49 (d, J = 7.8 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.64 (s, IH), 6.31 (s, IH), 3.74 (s, 3H), 3.64 (s, 3H), 3.35 (s, 3H), 2.34 (s, 3H), 2.04 (s, 3H), 1.48 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ife) δ 152.59, 151.90, 151.83, 151.09, 142.41, 138.09, 134.53, 133.57, 129.31, 128.99, 126.66, 125.45, 122.51, 120.85, 109.82, 95.76, 60.43, 59.82, 55.39, 20.96, 16.50, 14.92. HRMS (ESI-TOF): Exact mass calcd. for C ₂₄ H ₂₇ NO ₇ S [M+Na] ⁺ 496.1400, Found: 496.1403. MP 58-60 °C.

9ea', white solid, 90% yield (100.0 mg), 99% ee. [Daicel CHIRALPAK IC (0.46 cm x 25 cm); re-hexane/2-propanol = 60/40; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 29.12 (major), 55.25 (minor) min]. [a] _D ²⁰ = +85.0 (c = 0.3, CH ₃ OH). ¾ NMR (500 MHz, DMSO-i¾ δ 9.18 (s, 2H), 8.41 (br s, 2H), 7.65-7.56 (m, 6H), 7.36-7.38 (m, 4H), 7.09-7.00 (m, 4H), 6.74 (s, 2H), 2.35 (s, 6H), 2.18 (s, 6H), 1.34 (s, 6H). ¹³ C NMR (75 MHz, DMSO-ife) δ 152.05, 143.80, 142.33, 137.88, 133.70, 129.60, 129.32, 128.10, 126.59, 125.88, 123.69, 123.21, 122.42, 121.41, 116.25, 20.99, 16.46, 14.56. HRMS (ESI-TOF): Exact mass calcd. for C40H38N2O8S2 [M+Na] ⁺ 761.1962, Found: 761.1975. MP 251-253 °C.

9eb, white solid, 98% yield (54.9 mg), 87% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 16.45 (minor), 22.31 (major), min]. [a] _D ²⁰ = -2.3 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 8.75 (br s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.19-7.14 (m, 2H), 7.07-7.03 (m, 2H), 6.89 (d, J = 8.3 Hz, 1H), 2.92 (s, 3H), 2.18 (s, 3H), 1.73 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ife) δ 152.40, 146.74, 144.89, 134.08, 129.61, 129.29, 128.35, 126.82, 126.32, 124.25, 123.86, 123.25, 123.09, 122.10, 117.40, 109.16, 40.24, 16.89, 15.64. HRMS (ESI-TOF): Exact mass calcd. for C ₁₉ H ₁₉ NO ₅ S [M+Na] ⁺ 396.0876, Found: 396.0860. MP 127-129 °C.

9ec, brown solid, 68% yield (48.7 mg), 91% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); ra-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 17.88 (major), 20.24 (minor) min]. [a] _D ²⁰ = -32.3 (c = 0.3, CH3OH). ¾ NMR (300 MHz, DMSO-ife) δ 10.07 (br s, 1H), 9.07 (s, 1H), 8.45 (br s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.5 l(d, J = 8.0 Hz, 2H), 7.35 (d, / = 8.0 Hz, 2H), 7.27 (s, 1H), 7.20-7.06 (m, 3H), 6.73 (d, / = 8.2 Hz, 1H), 6.64 (s, 1H), 3.15-3.08 (m, 1H), 2.34 (s, 3H), 1.40 (s, 3H), 1.02 (d, J = 6.7 Hz, 6H). ¹³ C NMR (125 MHz, DMSO-ife) δ 150.47, 146.13, 144.57, 142.38, 137.51, 133.39, 131.66, 129.23, 128.80, 127.90, 126.80, 126.06, 125.75, 124.51, 123.59, 123.32, 122.73, 122.55, 116.43, 108.72, 25.71, 22.51, 22.41, 20.87, 14.53. HRMS (ESI-TOF): Exact mass calcd. for C ₂₇ H ₂₇ NO ₅ S [M+Na] ⁺ 500.1502, Found: 500.1482. MP 159-161 °C.

9ed, brown solid, 63% yield (45.1 mg), 73% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 11.98 (minor), 18.16 (major) min]. [a] _D ²⁰ = -17.7 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 10.07 (br s, 1H), 8.94 (s, 1H), 8.41 (br s, 1H), 7.71 (d, J = 8.2 Hz, 2H), 7.58 (d, / = 8.1 Hz, 1H), 7.43 (d, / = 8.1 Hz, 2H), 7.30 (s, 1H), 7.18-7.14 (m, 2H), 7.05 (t, / = 8.2 Hz, 1H), 6.84 (d, / = 8.3 Hz, 1H), 6.40 (s, 1H), 2.73-2.68 (m, 1H), 2.41 (s, 3H), 1.94 (s, 3H), 0.88 (d, / = 7.1 Hz, 3H), 0.77 (d, / = 6.9 Hz, 3H). ¹³ C NMR (125 MHz, DMSO-ife) δ 157.06, 151.14, 149.78, 148.86, 147.43, 144.48, 134.93, 134.41, 133.93, 133.62, 131.82, 130.96, 130.69, 129.06, 128.50, 127.60, 127.38, 126.08, 122.17, 113.67, 34.67, 26.93, 26.83, 25.98, 21.30. HRMS (ESI-TOF): Exact mass calcd. for C2 ₇ H2 ₇ NO5S [M+Na] ⁺ 500.1502, Found: 500.1483. MP 115-117 °C.

9ee, yellow solid, 56% yield (38.1 mg), 78% ee. [Daicel CHIRALPAK IA-3 (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 17.85 (minor), 33.92 (major) min]. [a] _D ²⁰ = -42.33 (c = 0.3, CH ₃ OH). Ή NMR (300 MHz, DMSO-i¾ δ 10.02 (s, 1H), 9.37 (s, 1H), 8.95 (s, 1H), 8.48 (s, 1H), 7.56 (d, / = 7.6 Hz, 1H), 7.48 (d, / = 8.0 Hz, 2H), 7.33 (d, / = 7.8 Hz, 2H), 7.18-7.04 (m, 3H), 6.88 (d, / = 11.8 Hz, 1H), 6.65 (d, / = 8.1 Hz, 1H), 2.30 (s, 3H), 1.21 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ife) δ 150.39, 147.25, 146.10, 143.94, 142.71, 141.66, 137.25, 131.36, 129.49, 128.57, 127.41, 126.56, 125.79, 125.41, 123.19, 122.80 (d, / = 12.0 Hz), 114.25, 114.03 (d, J = 6.0 Hz), 108.62, 20.96, 13.99. HRMS (ESI-TOF): Exact mass calcd. for C24H20FNO5S [M+Na] ⁺ 476.0938, Found: 476.0918. MP 109-111 °C.

9ef, white solid, 31% yield (21.0 mg), 4% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 1) ; ra-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = .42 (minor), 31.95 (major) min]. [a] _D ²⁰ = +1.0 (c = 0.1, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 10.07 (br s, 1H), 8.98 (s, 1H), 8.82 (br s, 1H), 8.28 (br s, 1H), 7.57-7.52 (m, 3H), 7.32 (d, / = 8.1 Hz, 2H), 7.09-7.18 (m, 3H), 6.87 (d, / = 1.9 Hz, 1H), 6.62 (s, 1H), 2.30 (s, 3H), 2.08 (s, 3H), 1.26 (s, 3H). ¹³ C NMR (75 MHz, OMSO-de) δ 154.08, 146.14, 143.79, 142.26, 138.85, 138.30, 137.54, 129.44, 128.58, 127.82, 126.52, 125.67, 124.48, 123.71, 122.55, 121.28, 117.88, 114.63, 108.23, 20.92, 18.95, 15.42. HRMS (ESI-TOF): Exact mass calcd. for C ₂₅ H ₂₃ NO ₅ S [M+Na] ⁺ 472.1189, Found: 472.0672. MP 167- 169 °C.

9eg, yellow solid, 68% yield (47.3 mg), 21 % ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 19.42 (major), 21.77 (minor) min]. [a] _D ²⁰ = +14.7 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 9.94 (br s, 1H), 9.03 (s, 1H), 8.35 (br s, 1H), 7.58 (d, / = 8.2 Hz, 1H), 7.52 (d, / = 8.0 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.12 (s, 2H), 6.85 (d, J = 7.8 Hz, 1H), 2.29 (s, 3H), 2.09 (s, 3H), 1.18 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ifc) δ 151.55, 146.17, 142.13, 136.59, 134.66, 134.38, 129.40, 128.78, 127.99, 126.55, 125.75, 124.93, 123.62, 122.72, 122.58, 121.09, 120.70, 116.82, 108.62, 20.92, 16.33, 15.37, 12.97. HRMS (ESI-TOF): Exact mass calcd. for C ₂₆ H ₂₅ NO ₅ S [M+Na] ⁺ 486.1346, Found: 486.1334. MP 134- 136 °C.

91c, brown solid, 48% yield (34.0 mg), 83% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 13.93 (minor), 47.81 (major), min]. [a] _D ²⁰ = -6.0 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 9.08 (br s, 1H), 8.97 (s, 1H), 7.54 (d, / = 7.7 Hz, 2H), 7.35 (d, / = 7.7 Hz, 2H), 7.02 (br s, 1H), 6.36 (s, 1H), 6.11 (d, / = 7.2 Hz, 2H), 3.73 (s, 3H), 3.57 (s, 3H), 3.08-3.04 (m, 1H), 2.38 (s, 3H), 1.63 (s, 3H), 0.93 (m, 6H). ¹³ C NMR (75 MHz, DMSO-i _s ) δ 160.75, 159.34, 156.90, 151.10, 142.87, 138.60, 134.68, 131.37, 129.72, 127.39, 126.25, 124.27, 122.95, 104.91, 94.33, 90.56, 55.78, 55.31, 26.17, 23.00, 22.91, 21.41, 15.39. HRMS (ESI-TOF): Exact mass calcd. for C25H29NO6S [M+Na] ⁺ 494.1608, Found: 494.1593. MP 206-208 °C.

9eh, white solid, 98% yield (49.6 mg), 76% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 80/20; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 8.64 (minor), 12.96 (major), min]. [a] _D ²⁰ = -3.7 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-ife) δ 9.09 (s, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.20-7.15 (m, 2H), 7.08-7.04 (m, 2H), 6.93 (d, J = 8.4 Hz, 1H), 2.17 (s, 3H), 2.00 (s, 3H), 1.62 (s, 3H). ¹³ C NMR (75 MHz, DMSO-i¾ δ 167.98, 150.56, 146.24, 144.44, 130.41, 128.78, 128.04, 127.88, 127.44, 125.81, 123.64, 123.25, 122.61, 120.97, 117.19, 108.55, 23.03, 16.49, 14.73. HRMS (ESI-TOF): Exact mass calcd. for C20H19NO4 [M+H] ⁺ 338.1387, Found:

-131 °C.

9ei, yellow solid, 69% yield (45.7 mg), 58% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); ra-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; IR = 6.57 (minor), 11.19 (major) min]. [a] _D ²⁰ = +1.0 (c = 0.3, CH ₃ OH). ¾ NMR (300 MHz, DMSO-i¾ δ 10.07 (s, 1H), 8.35 (d, / = 8.6 Hz, 2H), 8.21 (d, / = 8.5 Hz, 2H), 7.63 (d, / = 7.9 Hz, 1H), 7.21-7.07 (m, 4H), 6.99 (d, / = 8.2 Hz, 1H), 2.24 (s, 3H), 1.68 (s, 3H). ¹³ C NMR (75 MHz, DMSO-ifc) δ 163.71, 151.47, 149.00, 146.23, 144.55, 140.56, 131.87, 128.95, 128.80, 128.23, 128.04, 127.08, 125.85, 123.61, 123.56, 123.49, 122.71, 122.64, 121.36, 116.98, 108.64, 16.45, 14.85. HRMS (ESI-TOF): Exact mass calcd. for C25H20N2O6 [M+Na] ⁺ 467.1214, Found: 467.1204. MP 103-105 °C.

9aj and 9aj', white solid, 99% yield (63 mg), 82% ee for 9aj. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); ra-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; t _R = 19.59 (minor), 30.77 (major) min]. [a] _D ²⁰ = -42.7 (c = 0.3, CH ₃ OH). Ή NMR (300 MHz, DMSO-ife) δ 9.16 (br s, 1H), 8.92 (br s, 1H), 7.75-7.68 (m, 2H), 7.51 (d, / = 7.9 Hz, 2H), 7.32-7.15 (m, 6H), 6.70 (s, 1H), 6.42 (s, 1H), 2.21 (s, 3H), 2.08 (s, 3H). HRMS (ESI-TOF): Exact mass calcd. for C24H21NO4S [M+Na] ⁺ 442.1084, Found: 442.1089. MP 89-91 °C.

2. General procedure for synthesis of chiral CPA 7i and used as a catalyst.

The 9aa (0.15 mmol, 87% ee) was dissolved in dry pyridine in a three-necked flask. Under the argon condition, POCI ₃ (0.3 mmol) was added dropwise. The mixture was allowed to stir at room temperature for 3 h and the reaction. Then the mixture was cooled to 0 °C, add water (0.5 mL) slowly and stirred at room temperature for 30 min. Add CH ₂ CI ₂ to dissolve the mixture completely, wash the organic phase using IN HCl. Then the organic phase was dried over anhydrous Na2S04 and the filtrate was concentrated under reduced pressure. The product was purified column chromatography on silica- gel (AcOEt:MeOH = 25: 1 to 7: 1) to give the white solid. Dissolved the solid to CH ₂ CI ₂ and washed with IN HCl, The organic phase was dried over anhydrous Na ₂ S0 ₄ and the filtrate was concentrated under reduced pressure. 7i, white solid, 50% yield (74 mg). Ή NMR (300 MHz, DMSO-ifc) δ 9.46 (s, 1H), 7.89 (d, / = 8.4 Hz, 2H), 7.61 (d, / = 8.1 Hz, 2H), 7.43-7.30 (m, 5H), 6.70-6.96 (m, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 1.42 (s, 3H). ³¹ P NMR (75 MHz, DMSO-ife) δ 2.74. HRMS (ESI-TOF): Exact mass calcd. for C25H22NO6PS [M+Na] ⁺ 518.0798, Found: 518.0794.

. equ v. (0.15 mmoD

The non-C ₂ -symmetrical CPA 7i proved to be a viable catalyst for the coupling of 2a and 6a and afforded functionalized biaryl 9aa in 88% isolated yield. The level of enantio-induction was poor (-20%, giving rise to the (5)-enantiomer) which was not surprising as no steric modifier is present in 7i in the 2 '-position of the naphthalene nucleus that plays a role in determining the stereoselectivity of the reactions.

3. General procedure for synthesis of compound 9ea*.

To a stirred solution of 9ea (45 mg, 0.1 mmol) and 6k (27 mg, 0.15 mmol) in toluene or DCE (3 mL), TFA (1.2 mg, 0.8 μί, 0.01 mmol) or (PhO^PC^H was added in one portion at room temperature, and it was stirred at 100 °C for 3-8 hours. Solvent was removed under reduced pressure and the crude residue was purified by column chromatography on silica-gel (hexane/ethyl acetate = 5: 1 to 1: 1) to give pure product 9ea* (48 mg, 80% yield), 83% ee. [Daicel CHIRALPAK AD-H (0.46 cm x 25 cm); re-hexane/2-propanol = 70/30; flow rate = 1.0 mL/min; detection wavelength = 230 nm; tR = 9.73 (minor), 46.05 (major) min]. ¾ NMR (300 MHz, DMSO-ife) δ 9.18 (s, 1H), 8.38 (br s, 3H), 7.65 (br s, 1H), 7.53 (d, / = 8.1 Hz, 2H), 7.34 (d, / = 8.1 Hz, 2H), 7.07-7.03 (m, 2H), 7.02-6.97 (m, 2H), 6.76-6.73 (m, 2H), 6.64 (s, 1H), 3.65 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H), 2.16 (s, 3H), 1.82 (s, 3H), 1.31 (s, 3H). ¹³ C NMR (75 MHz, DMSO-*) δ 152.97, 152.25, 150.16, 144.75, 144.27, 143.31, 138.75, 134.36, 132.24, 130.26, 130.37, 130.25, 129.04, 128.85, 127.49, 126.79, 124.94, 124.59, 124.47, 123.33, 123.26, 122.38, 121.68, 118.15, 116.88, 115.54, 60.34, 21.90, 17.38, 16.89, 15.50, 14.11. MP 165-167 °C. HRMS (ESI-TOF): Exact mass calcd. for C34H33NO7S [M+Na] ⁺ 622.1870, Found: 622.1862.

EXAMPLE 7 - Substrate Stereocontrol

The description about 9ea' refers to the possibility that once the first axis of chirality was established in position #1 of the 2,3-dihydroxynaphthalene nucleus, the now existing axially chiral stereocenter would exert significant influence over the stereroselectivity of the second aryl-aryl bond- forming step in position #4. To demonstrate that this substrate control is truly operational and completely independent of the chirality of the acid catalyst, we conducted a control experiment (Scheme 2) in which enantiomerically pure biaryl 9ea was reacted with slight excess of iminoquinone 6a (1.5 equivalents) at 50 °C in DCE using 10 mol% of the achiral diphenylphosphoric acid as catalyst. Indeed the product 9ea' was obtained in excellent isolated yield and also as a single enantiomer (99% ee; the stereochemistry at the two chiral axes were determined to be R,R using X-ray crystallography). No traces of the meso diastereomer (R,S) were observed using LC/MS analysis. Scheme 2: Addition of a second phenol group

Moreover, the coupling reaction between symmetrical quinone monoacetal la and enantiomerically pure biaryl 9ea was also successful (see Scheme 3) and gave rise to enantiomerically enriched terphenyl 9ea* in 83% ee. Clearly substrate stereocontrol was operational in this case but to a lesser extent than during the formation of terphenyl 9ea' . Since only a symmetrical acetal intermediate could be formed the system "missed an opportunity " to transfer chirality in the first step and the stereoselectivity of the second ary-aryl bond-forming step (i.e., via the /3,3/-sigmatropic rearrangement) could not be perfectly controlled by the substrate. Scheme 3: Comparison of acetal and aminal intermediates

All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims.

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