WO2025006693A1 - Cannabidiol-like compounds and methods for the selective preparation of the same - Google Patents

Abstract

In one aspect, the disclosure relates to new cannabidiol (CBD) analogs produced from allylic monoterpene alcohols and substituted resorcinols in the presence of aryl boronic acids, efficient and mild synthetic methods of making the new CBD analogs, and improved methods of making known CBD analogs. In one aspect, the methods produce low amounts of tetrahydrocannabinol (THC)-like compounds, low amounts of abnormal cannabidiol (abn-CBD) analogs, and higher amounts of CBD analogs, greatly simplifying purification. The methods can be tailored further to produce low amounts of CBD analogs and higher amounts abn-CBD analogs. In the disclosed methods, synthesis parameters can be varied in order to selectively produce a desired normal or abnormal regioisomer.

Description

CANNABIDIOL-LIKE COMPOUNDS AND METHODS FOR THE SELECTIVE PREPARATION OF THE SAME

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No. 63/511 ,207 filed on June 30, 2023, which is incorporated herein by reference in its entirety.

BACKGROUND

[0002] Cannabidiol (CBD) and A⁹-tetrahydrocannabinol (THC) are the principal and therapeutically relevant constituents in Cannabis sativa. Unlike THC, CBD is non-psychoactive and is increasingly gaining popularity among researchers. CBD's poly-pharmacological effects include the treatment of inflammatory and neurodegenerative diseases ranging from epilepsy and cancer to autoimmune disorders like multiple sclerosis and arthritis. In June 2018, Epidiolex, a cannabis extraction product containing 99% CBD, was approved to treat severe forms of childonset epilepsy. This multi-target molecule interacts with non-endocannabinoid signaling systems, but its exact mechanism of action is not fully known. However, these effects are not just limited to only CBD. CBD analog cannabidivarin (CBDV) exerts antiepileptic effects by targeting ion channels involved in the onset and progression of several types of epilepsy. Cannabidiolic acid (CBDA), a natural precursor of CBD, inhibits the migration of highly invasive MDA-MB-231 human breast cancer cells. Synthetic derivatives of CBD like KLS-13019, a neuroprotective agent, and H4-CBD, an anti-inflammatory agent, have been developed to address the shortcomings of CBD in terms of efficacy or pharmacokinetic properties.

[0003] Several strategies have been reported for synthesizing cannabidiol (CBD) or its derivatives. The Friedel-Crafts alkylation reaction between commercially available olivetol and p- mentha-2,8-dien-1-ol or frans-isopiperitenol is the most popular one-step strategy to get access to cannabidiol. This strategy furnishes both the regioisomers of CBD (C2 linkage and C4 linkage) simultaneously. The regioselectivity, which is governed by steric crowding and probability, favors nucleophilic attack at the C4 position rather than the C2 position, generating the C4 isomer as the major product.

C2 regioisomer C4 regioisomer

[0004] This approach is also very sensitive to operational variables, like the strength of the acid, and reaction time. In the presence of weak acids (e.g., oxalic acid, camphor sulfonic acid (CSA), p-toluene sulfonic acid (pTSA)), or Lewis acids (e.g. BF3-Et2O in the presence or absence of alumina), intramolecular cyclization of CBD generates controlled substances and renders the purification step difficult. Monitoring the progress of the acid-catalyzed reactions is crucial to check the formation of unwanted products. Thus, there is an unmet need for efficient catalysts and synthetic methods that circumvent these limitations and improve the yield of the cannabidiol (CBD) and CBD-like products. These needs and other needs are satisfied by the present disclosure.

SUMMARY

[0005] In accordance with the purpose(s) of the present disclosure, as embodied and broadly described herein, the disclosure, in one aspect, relates to new CBD analogs produced from allylic monoterpene alcohols and substituted resorcinols in the presence of aryl boronic acids, efficient and mild synthetic methods of making the new CBD analogs, and improved methods of making known CBD analogs. In one aspect, the methods produce low amounts of tetrahydrocannabinol (THC)-like, low amounts abnormal-CBD (abn-CBD)-like and higher amounts of CBD-like compounds, greatly simplifying purification. The methods can be tailored further to produce low amounts of CBD-like and higher amounts abn-CBD-like compounds. In the disclosed methods, synthesis parameters can be varied in order to selectively produce a desired normal or abnormal regioisomer.

[0006] Other systems, methods, features, and advantages of the present disclosure will be or become apparent to one with skill in the art upon examination of the following drawings and detailed description. It is intended that all such additional systems, methods, features, and advantages be included within this description, be within the scope of the present disclosure, and be protected by the accompanying claims. In addition, all optional and preferred features and modifications of the described embodiments are usable in all aspects of the disclosure taught herein. Furthermore, the individual features of the dependent claims, as well as all optional and preferred features and modifications of the described embodiments are combinable and interchangeable with one another.

DETAILED DESCRIPTION

[0007] Friedel-Crafts reaction or any of its variants generally used for the preparation of cannabidiols result in several unwanted, tetrahydrocannabinol-like, regulated entities. In addition, the classical Friedel-Crafts alkylation of substituted resorcinols often results in abnormal cannabidiol-like compounds as the major products. Moreover, the Brbnsted or Lewis acids used to carry out this transformation often lead to unwanted cyclization of the product, further decreasing the overall yield of the desired cannabidiol-like entities. It was hypothesized that fluorinated solvents having hydrogen-bonding ability with substituted resorcinols might improve the yields of the desired isomer by decreasing the electron density at the unwanted site of the resorcinol. In one aspect, the use of milder boronic acids was additionally expected to eliminate the formation of unwanted cyclization products. In a further aspect, boronic acids are established catalysts for Friedel-Crafts reactions between allylic alcohols and electron-rich arenes and heteroarenes. Thus, herein is disclosed a Friedel-Crafts reaction between allylic alcohols and electron-rich phenols in a fluorinated/non-fluorinated solvent/s in the presence/absence of aryl boronic acid that gives cannabidiol or cannabidiol-like isomers as major products while substantially suppressing/minimizing the formation of the unwanted THC-like compounds and/or abnormal cannabidiol-like compounds. In any of these aspects, few side products are produced, leading to easy product purification. In one aspect, the reaction parameters can be varied in order to selectively produce the abnormal-CBD or abnormal-CBD like regioisomer while minimizing the THC or CBD-like isomers.

[0008] In one aspect, disclosed herein is a method for synthesizing a cannabidiol (CBD) analogs or abnormal cannabidiol (abn-CBD) analogs while minimizing the formation of THC-like products. In a further aspect, the method includes at least the following steps:

(a) contacting an allylic monoterpene alcohol having a structure according to Formula la, Formula lb, or Formula Ic with an aryl boronic acid to form a first admixture; and

(+/-) (+/-) (+/-)

Formula la Formula lb Formula ic

(b) contacting the first admixture with a substituted resorcinol having Formula II

Formula II; wherein X is selected from H, OH or alkyl; wherein Y is selected from linear or branched alkyl, linear or branched alkenyl, cycloalkyl, cycloalkenyl, alkyl aryl, or alkenyl aryl; and wherein R is selected from C1-C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; substituted aryl or heteroaryl, alkylaryl, or alkyl heteroaryl.

[0009] In another aspect, the aryl boronic acid can be selected from pentafluorophenylboronic acid (PFBA), 2,3,4,5-tetrafluorophenylboronic acid, 3,4,5-triflulrophenylboronic acid, 2,4,6- trifluorophenylboronic acid, or any combination thereof. In one aspect, the aryl boronic acid can be present in an amount of from about 0 mol% to about 100 mol% relative to the amount of allylic monoterpene alcohol, or from about 5 mol% to about 100 mol%, or from about 50 mol% to about 100 mol%, or about 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mol%, or a combination of any of the foregoing values, or a range encompassing any of the foregoing values.

[0010] In another aspect, the aryl boronic acid can be present in a molar ratio of from about 0.05:3 to about 1 :1.5 relative to the amount of substituted resorcinol, or of from about 0.05:3 to about 1 :1 , or in an amount of 0.05:3, 0.1:3, 0.25:3, 0.5:3, 1 :3, 1 :2, or about 1 :1.5, or a combination of any of the foregoing values, or a range encompassing any of the foregoing values.

[0011] In one aspect, the method can be conducted in a solvent such as, for example, dichloromethane, acetonitrile, nitromethane, 1 ,1 ,1 ,3,3,3-hexafluoroisopropanol (HFIP), 2,2,2- trifluoroethanol (TFE), 2,2,3,3,4,4,5-heptafluoro-5-(1 ,1 ,2,2,3,3,4,4,4-nonafluorobutyl)oxolane, hexafluorobenzene, or any combination thereof. In one aspect, the solvent is HFIP.

[0012] In any of these aspects, R can be selected from

wherein Z is selected from F, Cl, Br, CN, or NO2; and wherein Q is selected from NH, O, or S.

[0013] In one aspect, the disclosed method yields less than 15 mol% THC, less than 15% abn- CBD, greater than 60% CBD, or any combination thereof. In an alternative aspect, the disclosed method yields less than 15 mol% THC, less than 15% CBD, greater than 60% abn-CBD, or any combination thereof.

[0014] In some aspects, the CBD analog or abn-CBD analog has Formula III:

Formula III; wherein two of Ri_a, Ri_b, and Ri_c are OH, and wherein the Ri_a, Rw, or Ri_c that is not OH is R; wherein a carbon atom indicated by * has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof; and wherein a carbon atom indicated by ** has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof.

[0015] In one aspect, the method produces an abn-CBD analog wherein Ri_c and Rw are OH and Ri_a is R. In another aspect, the method yields at least about 80% of an abn-CBD analog, or at least about 80, 85, 90, 95, or 99% of the abn-CBD analog. In an alternative aspect, the method produces a CBD analog, wherein Ri_a and Ri_c are OH and Ri_b is R. Further in this aspect, the method yields at least about 80% of the CBD analog, or at least about 80, 85, 90, 95, or 99% of the CBD analog.

[0016] Also disclosed herein are CBD analogs or abn-CBD analogs having a structure according to Formula III:

wherein two of Ri_a, Ri_b, and Ri_c are OH, and wherein the Ri_a, Ri_b, or Ri_c that is not OH is selected from C1-C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; or substituted aryl or heteroaryl; or alkylaryl or alkyl heteroaryl; wherein a carbon atom indicated by * has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof; and wherein a carbon atom indicated by ** has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof. provided that the CBD analog is not CBD or abn-CBD; and provided that when Ri_a and Ri_c are OH, Rw is not linear alkyl.

In one aspect, the compound is an abn-CBD analog, wherein Ri_c and Ru are OH and Ri_a is selected from C1-C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N- alkylamide; or substituted aryl or heteroaryl; alkylaryl or alkyl heteroaryl. In another aspect, the compound is a CBD analog, wherein Ri_a and Ru are OH and Rw is selected from C1-C9 branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; or substituted aryl or heteroaryl; alkylaryl or alkyl heteroaryl. In any of these aspects, the Ri_a, Ri_b, or Ri_c that is not OH is:

wherein Z is selected from F, Cl, Br, CN, or NO2; and wherein Q is selected from NH, O, or S. [0017] In one aspect, the CBD analog or abn-CBD analog is selected from

combination thereof.

[0018] Many modifications and other embodiments disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein.

[0019] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0020] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure.

[0021] Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0022] All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation.

[0023] While aspects of the present disclosure can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present disclosure can be described and claimed in any statutory class.

[0024] It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein.

[0025] Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure.

Definitions

[0026] As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to, but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by”, “comprising,” “comprises”, “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of.

[0027] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, references to “a CBD analog,” “a catalyst,” or “an acid,” including, but are not limited to, mixtures or combinations of two or more such CBD analogs, catalysts, or acids, and the like.

[0028] It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed.

[0029] When a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g. the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g. 'about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘less than x’, less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x’, ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x’, greater than y’, and ‘greater than z’. In addition, the phrase “about ‘x’ to ‘y’”, where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’”.

[0030] It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub- ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a numerical range of “about 0.1 % to 5%” should be interpreted to include not only the explicitly recited values of about 0.1 % to about 5%, but also include individual values (e.g., about 1 %, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range.

[0031] As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about,” “approximate,” or “at or about” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0032] As used herein, the term “effective amount” refers to an amount that is sufficient to achieve the desired modification of a physical property of the composition or material. For example, an “effective amount” of a CBD analog refers to an amount that is sufficient to achieve the desired improvement in the property modulated by the formulation component, e.g. achieving the desired level of symptom reduction for a disease or condition for which the CBD analog is used for treatment. The specific level in terms of wt% in a composition required as an effective amount will depend upon a variety of factors including the chemical identity of the CBD analog, condition being treated, concurrent treatments being administered, method of administration, and the presence of any additional active ingredients in pharmaceutical compositions comprising the CBD analog. [0033] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0034] Unless otherwise specified, temperatures referred to herein are based on atmospheric pressure (i.e. one atmosphere).

Chemical and Synthesis Definitions

[0035] A residue of a chemical species, as used in the specification and concluding claims, refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species. Thus, an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester. Similarly, a sebacic acid residue in a polyester refers to one or more - CO(CH₂)SCO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.

[0036] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (J.e., further substituted or unsubstituted).

[0037] In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0038] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (7.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0039] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.

[0040] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0041] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0042] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0043] The term “alkanediyl” as used herein, 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, cyclo, cyclic or acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups, — CH₂ — (methylene), — CH₂CH₂ — , — CH₂C(CH₃)2CH₂ — , and — CH₂CH₂CH₂ — are non-limiting examples of alkanediyl groups.

[0044] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as — OA¹ where A¹ is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as — OA¹ — OA² or — OA¹ — (OA²)_a — OA³, where “a” is an integer of from 1 to 200 and A¹, A², and A³ are alkyl and/or cycloalkyl groups.

[0045] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A¹A²)C=C(A³A⁴) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0046] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0047] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0048] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0049] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized TT electrons above and below the plane of the molecule, where the rr clouds contain (4n+2) TT electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “ Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0050] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, — NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl to two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0051] The term “aldehyde” as used herein is represented by the formula — C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O.

[0052] The terms “amine” or “amino” as used herein are represented by the formula — NA¹A², where A¹ and A² can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is — NH₂.

[0053] The term “alkylamino” as used herein is represented by the formula — NH(-alkyl) and — N (-alkyl)₂, where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

[0054] The term “carboxylic acid” as used herein is represented by the formula — C(O)OH.

[0055] The term “ester” as used herein is represented by the formula — OC(O)A¹ or — C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula — (A¹O(O)C-A²-C(O)O)_a — or — (A¹O(O)C-A²-OC(O))_a — , where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0056] The term “ether” as used herein is represented by the formula A¹OA², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula — (A¹O-A²O)_a — , where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0057] The terms “halo,” “halogen” or “halide,” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0058] The terms “pseudohalide,” “pseudohalogen” or “pseudohalo,” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

[0059] The term “heteroalkyl” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0060] The term “heteroaryl” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[cf]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1 ,2- b]pyridazinyl, imidazo[1 ,2-a]pyrazinyl, benzo[c][1 ,2,5]thiadiazolyl, benzo[c][1 ,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0061] The terms “heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocycle,” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1 ,2,3-oxadiazole, 1 ,2,5-oxadiazole and 1 ,3,4-oxadiazole, thiadiazole, including, 1 ,2,3-thiadiazole, 1,2,5-thiadiazole, and 1 ,3,4-thiadiazole, triazole, including, 1,2,3-triazole, 1, 3, 4-triazole, tetrazole, including 1 ,2,3,4-tetrazole and 1 ,2, 4, 5- tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1 ,3,5-triazine, tetrazine, including 1 ,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetra hydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. For example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0062] The term “bicyclic heterocycle” or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1 , 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1 ,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1 ,3-benzodioxolyl, 2,3-dihydro- 1 ,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1 H-pyrazolo[4,3-c]pyridin-3-yl; 1 H-pyrrolo[3,2- b]pyridin-3-yl; and 1 H-pyrazolo[3,2-b]pyridin-3-yl.

[0063] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0064] The term “hydroxyl” or “hydroxy” as used herein is represented by the formula — OH.

[0065] The term “ketone” as used herein is represented by the formula A¹C(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0066] The term “azide” or “azido” as used herein is represented by the formula — N₃.

[0067] The term “nitro” as used herein is represented by the formula — NO2.

[0068] The term “nitrile” or “cyano” as used herein is represented by the formula — CN.

[0069] The term “silyl” as used herein is represented by the formula — SiA¹A²A³, where A¹, A², and A³ can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. [0070] The term “sulfo-oxo” as used herein is represented by the formulas — S(O)A¹, — S(O)2A¹, — OS(O)2A¹, or — OS(O)2OA¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula — S(O)2A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A¹S(O)2A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A¹S(O)A², where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0071] The term “thiol” as used herein is represented by the formula — SH.

[0072] “R¹,” “R²,” “R³,”... “Rⁿ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R¹ is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (/.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0073] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (/.e., further substituted or unsubstituted).

[0074] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0075] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH₂)o-4R°; -(CH₂)o-40R°; -O(CH₂)₀-4R°, -O- (CH₂)O-4C(0)OR°; -(CH₂)O-4CH(OR°)₂; -(CH₂)O-4SR°; -(CH₂)o-4Ph, which may be substituted with R°; -(CH₂)o-40(CH₂)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH₂)o-40(CH₂)o-i-pyridyl which may be substituted with R°; -NO₂; -CN; - N₃; -(CH₂)O-₄N(R⁰)₂; -(CH₂)O-4N(R°)C(0)R°; -N(R°)C(S)R°; -(CH₂)₀-

₄N(R°)C(O)NR^O ₂; -N(R^O)C(S)NR°₂; -(CH₂)₀-4N(R^O)C(O)OR°;

N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°₂; -N(R°)N(R°)C(O)OR°; -(CH₂)o-₄C(0)R°; -C(S)R°; - (CH₂)O-4C(0)OR°; -(CH₂)O-₄C(0)SR°; -(CH₂)₀-4C(O)OSiR°₃; -(CH₂)_0-4OC(O)R^o; -OC(O)(CH₂)₀- ₄SR-, SC(S)SR°; -(CH₂)O-₄SC(0)R°; -(CH₂)_0-4C(O)NR^O ₂; -C(S)NR^O ₂; -C(S)SR°; -(CH₂)₀- ₄OC(O)NR^O ₂; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH₂C(O)R^O; -C(NOR°)R°; -(CH₂)O-₄SSR°; - (CH₂)O_4S(0)₂R°; -(CH₂)O_₄S(0)₂OR⁰; -(CH₂)O-₄OS(0)₂R⁰; -S(O)₂NR^O ₂; -(CH₂)_O_

₄S(O)R^O; -N(R^O)S(O)₂NR°₂; -N(R^O)S(O)₂R°; -N(OR°)R°; -C(NH)NR^O ₂;

P(O)₂R^O; -P(O)R°₂; -OP(O)R°₂; -OP(O)(OR°)₂; SiR°₃; -(C1-4 straight or branched alkylene)O- N(R°)₂; or -(C1-4 straight or branched alkylene)C(O)O-N(R°)₂, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH₂Ph, -O(CH₂)₀- 1 Ph, -CH₂-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0076] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH₂)o-2R*, -(haloR*), -(CH₂)O_₂OH, -(CH₂)O-₂OR*, -(CH₂)O-2CH(OR*)₂; -O(haloR’), -CN, -N₃, -(CH₂)o- ₂C(O)R‘, -(CH₂)O-₂C(0)OH, -(CH₂)O-₂C(0)OR*, -(CH₂)O-₂SR*, -(CH₂)_O-2SH, -(CH₂)O-₂NH₂, - (CH₂)_0-2NHR‘, -(CH₂)O-2NR*₂, -NO2, -SiR*₃, -OSiR*₃, -C(O)SR* -(C1-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, - CH₂Ph, -0(CH₂)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0077] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*₂, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)₂R*, =NR*, =NOR*, -O(C(R*₂))₂-3O-, or -S(C(R*₂))₂_3S-, wherein each independent occurrence of R* is selected from hydrogen, Ci_₆ aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*₂)₂-3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0078] Suitable substituents on the aliphatic group of R* include halogen, -R* -(haloR*), -OH, - OR*, -O(haloR’), -CN, -C(O)OH, -C(O)OR‘, -NH₂, -NHR®, -NR*₂, or -NO₂, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH₂Ph, -0(CH₂)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0079] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -C(O)CH₂C(O)R^t, - S(O)₂Rt,

wherein each R^f is independently hydrogen, Ci_₆ aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0- 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^f, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0080] Suitable substituents on the aliphatic group of Rt are independently halogen, - R’, -(haloR*), -OH, -OR*, -O(haloR’), -CN, -C(O)OH, -C(O)OR’, -NH₂, -NHR’, -NR*₂, or - NO₂, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH₂Ph, -O(CH₂)₀-iPh, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0081] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.

[0082] The terms “hydrolyzable group” and “hydrolyzable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolyzable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-lnterscience, 1999).

[0083] The term “organic residue” defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0084] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure:

regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (/.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0085] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosubstituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[0086] “Inorganic radicals,” as the term is defined and used herein, contain no carbon atoms and therefore comprise only atoms other than carbon. Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations. Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals. The inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical. Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.

[0087] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[0088] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

[0089] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and I or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-lngold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0090] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, and ³⁶CI, respectively. Compounds further comprise prodrugs thereof and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., ²H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0091] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0092] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0093] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.

keto form enol form amide form imidic acid form

Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, the invention includes all such possible tautomers.

[0094] It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0095] In some aspects, a structure of a compound can be represented by a formula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R" is understood to represent five independent substituents, R^n(a), R^n(b), R^n(c), R^n(d), and R^n(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance R^n(a) is halogen, then R^n(b) is not necessarily halogen in that instance.

[0096] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0097] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible nonexpress basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0098] Now having described the aspects of the present disclosure, in general, the following Examples describe some additional aspects of the present disclosure. While aspects of the present disclosure are described in connection with the following examples and the corresponding text and figures, there is no intent to limit aspects of the present disclosure to this description. On the contrary, the intent is to cover all alternatives, modifications, and equivalents included within the spirit and scope of the present disclosure. ASPECTS

[0099] The present disclosure can be described in accordance with the following numbered aspects, which should not be confused with the claims.

[0100] Aspect 1. A method for synthesizing a cannabidiol (CBD) analog or abnormal cannabidiol

(abn-CBD) analog, the method comprising

(a) contacting an allylic monoterpene alcohol having a structure according to Formula la, Formula lb, or Formula Ic with an aryl boronic acid to form a first admixture; and

(+/-) (+/-) (+/-)

Formula la Formula lb Formula Ic

(b) contacting the first admixture with a substituted resorcinol having Formula II

Formula II; wherein X is selected from H, OH or alkyl; wherein Y is selected from linear or branched alkyl, linear or branched alkenyl, cycloalkyl, cycloalkenyl, alkyl aryl, or alkenyl aryl; and wherein R is selected from C1-C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; substituted aryl or heteroaryl, alkylaryl, or alkyl heteroaryl.

[0101] Aspect 2. The method of aspect 1 , wherein the aryl boronic acid comprises pentafluorophenylboronic acid (PFBA), 2,3,4,5-tetrafluorophenylboronic acid, 3,4,5- triflulrophenylboronic acid, 2,4,6-trifluorophenylboronic acid, or any combination thereof.

[0102] Aspect 3. The method of aspect 1 or 2, wherein the aryl boronic acid is present in an amount of from about 0 mol% to about 100 mol% relative to an amount of allylic monoterpene alcohol. [0103] Aspect 4. The method of aspect 3, wherein the aryl boronic acid is present in an amount of about 5 mol% relative to an amount of allylic monoterpene alcohol.

[0104] Aspect 5. The method of any one of aspects 1-4, wherein the aryl boronic acid is present in a molar ratio of from about 0.05:3 to about 1 :1.5 relative to an amount of substituted resorcinol. [0105] Aspect 6. The method of aspect 5, wherein the aryl boronic acid is present in a molar ratio of about 0.05:3 relative to an amount of substituted resorcinol.

[0106] Aspect 7. The method of any one of aspects 1-6, wherein the method is conducted in a solvent.

[0107] Aspect 8. The method of aspect 7, wherein the solvent comprises dichloromethane, acetonitrile, nitromethane, 1,1 ,1 ,3,3,3-hexafluoroisopropanol (HFIP), 2,2,2-trifluoroethanol (TFE), 2,2,3,3,4,4,5-heptafluoro-5-(1 , 1 ,2,2,3,3,4,4,4-nonafluorobutyl)oxolane, hexafluorobenzene, or any combination thereof.

[0108] Aspect 9. The method of aspect 8, wherein the solvent is HFIP.

[0109] Aspect 10. The method of any one of aspects 1-9, wherein R is selected from:

wherein Z is selected from F, Cl, Br, CN, or NO2; and wherein Q is selected from NH, O, or S.

[0110] Aspect 11. The method of any one of aspects 1-10, wherein the method yields less than 15 mol% THC, less than 15% abn-CBD, greater than 60% CBD, or any combination thereof.

[0111] Aspect 12. The method of any one of aspects 1-10, wherein the method yields less than 15 mol% THC, less than 15% CBD, greater than 60% abn-CBD, or any combination thereof. [0112] Aspect 13. The method of any one of aspects 1-12, wherein the CBD analog or abn-CBD analog has Formula III:

Formula III; wherein two of Ri_a, Rib, and Ri_c are OH, and wherein the Ri_a, Rit, or Ri_c that is not OH is R; wherein a carbon atom indicated by * has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof; and wherein a carbon atom indicated by ** has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof.

[0113] Aspect 14. The method of aspect 13, wherein the method produces an abn-CBD analog wherein Ri_c and Rw are OH and Ri_a is R.

[0114] Aspect 15. The method of aspect 14, wherein the method yields at least about 80% of an abn-CBD analog.

[0115] Aspect 16. The method of aspect 13, wherein the method produces a CBD analog, wherein Ri_a and Ri_c are OH and Rw is R.

[0116] Aspect 17. The method of aspect 16, wherein the method yields at least about 80% of a CBD analog.

[0117] Aspect 18. A cannabidiol (CBD) analog or abnormal cannabidiol (abn-CBD) analog having a structure according to Formula III;

wherein two of Ri_a, Ri_b, and Ri_c are OH, and wherein the Ri_a, Ri_b, or Ri_c that is not OH is selected from C1-C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; or substituted aryl or heteroaryl; or alkylaryl or alkyl heteroaryl; wherein a carbon atom indicated by * has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof; and wherein a carbon atom indicated by ** has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof. provided that the CBD analog is not CBD or abn-CBD; and provided that when Ri_a and Ri_c are OH, Rw is not linear alkyl.

[0118] Aspect 19. The abn-CBD analog of aspect 18, wherein Ri_c and Ri_b are OH and Ri_a is selected from C1-C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N- alkylamide; or substituted aryl or heteroaryl; alkylaryl or alkyl heteroaryl.

[0119] Aspect 20. The CBD analog of aspect 18, wherein Ri_a and Ru are OH and Rw is selected from C1-C9 branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; or substituted aryl or heteroaryl; alkylaryl or alkyl heteroaryl.

[0120] Aspect 21. The CBD analog or abn-CBD analog of any one of aspects 18-20, wherein the Ria, Rw, or Ric that is not OH is:

wherein Z is selected from F, Cl, Br, CN, or NO2; and wherein Q is selected from NH, O, or S.. [0121] Aspect 22. The CBD analog or abn-CBD analog of any one of aspects 18-21, wherein the CBD analog or abn-CBD analog is selected from:

combination thereof.

EXAMPLES

[0122] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure. Efforts have been made to ensure accuracy with respect to numbers (e.gr, amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

Example 1 : General Synthetic Scheme and Compound Characterization X OH R .

R

Y = linear or branched alk(en)yl or cycloalk(en)yl, or alk(en)yl aryl OH [0123] A representative example include an aryl boronic acid (1.0 equiv) wa

tion of appropriate allylic monoterpene alcohol (1.0 equiv) in a combination of organic and fluorinated solvents at room temperature followed by the dropwise addition of substituted resorcinol (1.5 equiv) over 1.0 h. After the addition was complete, the reaction mixture was heated until the starting material was completely consumed (monitored by TLC). After the reaction mixture had cooled down to room temperature, the solvent was removed under a vacuum and the residue was purified by column chromatography to obtain the desired compound. OH [0124] (1'R,2'R)-5'-methyl-4-pent

y- - p p- - - -y - , ,3',4'-tetrahydro-[1,1'-biphenyl]-2,6- diol.¹H NMR (400 MHz, CDCl₃) δ 6.36 – 6.08 (m, 2H), 5.99 (s, 1H), 5.60 – 5.53 (m, 1H), 4.79 (s, 1H), 4.65 (t, J = 1.8 Hz, 1H), 4.55 (s, 1H), 3.86 (ddd, J = 10.2, 4.1, 2.2 Hz, 1H), 2.48 – 2.33 (m, 3H), 2.30 – 2.16 (m, 1H), 2.14 – 2.03 (m, 1H), 1.85 – 1.74 (m, 5H), 1.65 (s, 3H), 1.55 (p, J = 7.3 Hz, 2H), 1.35 – 1.23 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 156.2, 154.1, 149.4, 143.1, 140.1, 124.3, 113.9, 111.0, 109.9, 108.1, 46.3, 37.3, 35.6, 31.6, 30.8, 30.5, 28.5, 23.8, 22.7, 20.5, 14.2. HRMS (ESI) m/z calcd for C₂₁H₃₁O₂ [M + H]⁺, 315.2324, found 315.2337. ^H [0125] (1'R,2'R)-5'-methyl-6-pentyl-2

',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4- diol.¹H NMR (400 MHz, CDCl₃) δ 6.20 (q, J = 2.7 Hz, 2H), 6.06 (s, 1H), 5.59 – 5.47 (m, 1H), 4.83 (s, 1H), 4.64 (s, 1H), 4.49 – 4.42 (m, 1H), 3.59 – 3.48 (m, 1H), 2.59 (ddd, J = 13.9, 8.7, 6.7 Hz, 1H), 2.48 (ddd, J = 11.7, 9.9, 3.4 Hz, 1H), 2.32 – 2.15 (m, 2H), 2.15 – 2.03 (m, 1H), 1.88 – 1.71 (m, 5H), 1.53 (s, 3H), 1.52 – 1.40 (m, 2H), 1.31 (tt, J = 9.1, 3.2 Hz, 4H), 0.89 (t, J = 7.0 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 156.6, 154.7, 147.8, 144.1, 140.0, 124.9, 120.1, 111.6, 108.7, 102.3, 45.1, 40.2, 34.1, 32.0, 31.2, 30.4, 28.3, 23.8, 22.7, 21.5, 14.2. HRMS (ESI) m/z calcd for C₂₁H₃₁O₂ [M + H]⁺, 315.2324, found 315.2322. OH [0126] (1'R,2'R)-4-heptyl-5'-me

, , ,4'-tetrahydro-[1,1'-biphenyl]-2,6- diol.¹H NMR (500 MHz, DMSO) δ 8.64 (s, 2H), 6.01 (s, 2H), 5.08 (s, 1H), 4.48 (d, J = 2.8 Hz, 1H), 4.44 – 4.36 (m, 1H), 3.82 (ddd, J = 10.5, 4.2, 2.2 Hz, 1H), 3.02 (ddd, J = 13.1, 10.5, 2.8 Hz, 1H), 2.29 (t, J = 7.6 Hz, 2H), 2.16 – 2.00 (m, 1H), 1.91 (dd, J = 16.9, 5.0 Hz, 1H), 1.72 – 1.65 (m, 1H), 1.65 – 1.54 (m, 7H), 1.51 – 1.40 (m, 2H), 1.30 – 1.21 (m, 8H), 0.85 (t, J = 6.8 Hz, 3H).¹³C NMR (126 MHz, DMSO) δ 156.2, 149.1, 140.2, 130.0, 126.9, 114.1, 109.7, 106.6, 43.7, 35.5, 34.9, 31.3, 30.6, 30.3, 29.5, 28.7, 28.6, 23.3, 22.1, 19.3, 14.0. HRMS (ESI) m/z calcd for C₂₃H₃₅O₂ [M + H]⁺, 343.2637, found 343.2636.

[0127] (1'R,2'R)-6-heptyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,4- diol.¹H NMR (400 MHz, CDCl₃) δ 6.20 (q, J = 2.7 Hz, 2H), 6.06 (s, 1H), 5.59 – 5.49 (m, 1H), 5.35 (s, 1H), 4.66 – 4.63 (m, 1H), 4.52 – 4.39 (m, 1H), 3.53 (d, J = 9.6 Hz, 1H), 2.64 – 2.54 (m, 1H), 2.47 (ddd, J = 13.1, 10.1, 3.4 Hz, 1H), 2.32 – 2.15 (m, 2H), 2.15 – 2.02 (m, 1H), 1.85 – 1.73 (m, 5H), 1.53 (s, 3H), 1.50 – 1.40 (m, 2H), 1.32 – 1.26 (m, 8H), 0.90 – 0.87 (m, 3H).¹³C NMR (101 MHz, CDCl₃) δ 156.6, 154.6, 147.8, 144.2, 140.0, 124.8, 120.2, 111.6, 108.7, 102.3, 45.1, 40.2, 34.2, 32.0, 31.6, 30.4, 29.8, 29.3, 28.3, 23.8, 22.8, 21.5, 14.2. HRMS (ESI) m/z calcd for C₂₃H₃₅O₂ [M + H]⁺, 343.2637, found 343.2636. OH [0128] (1'R,2'R)-5'-methyl-4-(2-met

-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'- biphenyl]-2,6-diol.¹H NMR (500 MHz, DMSO) δ 8.57 (s, 2H), 6.15 (s, 2H), 5.09 (s, 1H), 4.49 (s, 1H), 4.40 (s, 1H), 3.87 – 3.73 (m, 1H), 3.01 (ddd, J = 13.2, 10.6, 2.8 Hz, 1H), 2.15 – 2.04 (m, 1H), 1.96 – 1.87 (m, 1H), 1.67 (dt, J = 5.2, 2.0 Hz, 1H), 1.62 – 1.56 (m, 7H), 1.45 – 1.40 (m, 2H), 1.20 ^{– 1.12 (m, 12H), 1.02 – 0.96 (m, 2H), 0.81 (t, J = 6.9 Hz, 3H). 13} _{C NMR (126 MHz, DMSO) δ} 155.9, 149.2, 147.3, 130.0, 126.8, 113.8, 109.5, 104.2, 44.2, 43.6, 36.7, 35.6, 31.3, 30.3, 29.5, 29.4, 28.7, 28.6, 24.2, 23.3, 22.0, 19.4, 13.9. HRMS (ESI) m/z calcd for C₂₅H₃₉O₂ [M + H]⁺, 371.295, found 371.2934. [0129] (1'R,2'R)-4,5'-dimethyl-2'-(prop

-1-en-2-yl)-1,2,3',4'-tetrahydro-[1,1'-biphenyl]-2,6-diol. ¹H NMR (400 MHz, CDCl₃) δ 6.39 – 6.07 (m, 2H), 5.97 (s, 1H), 5.55 (s, 1H), 4.78 – 4.61 (m, 2H), 4.56 (s, 1H), 3.93 – 3.79 (m, 1H), 2.40 (td, J = 10.8, 3.7 Hz, 1H), 2.30 – 2.14 (m, 4H), 2.14 – 2.04 (m, 1H), 1.86 – 1.74 (m, 5H), 1.66 (s, 3H).¹³C NMR (101 MHz, CDCl₃) δ 154.0, 149.4, 140.2, 138.0, 124.3, 113.7, 111.0, 110.7, 108.4, 46.3, 37.2, 30.5, 28.6, 23.8, 21.2, 20.5. HRMS (ESI) m/z calcd for C₁₇H₂₃O₂ [M + H]⁺, 259.1698, found 259.17. ^H [0130] (1'R,2'R)-5',6-dimethyl-2'-(pro ,4'-t ¹

etrahydro-[1,1'-biphenyl]-2,4-diol. H NMR (400 MHz, CDCl₃) δ 6.25 – 6.15 (m, 2H), 6.12 (s, 1H), 5.54 (s, 1H), 5.05 (s, 1H), 4.65 (t, J = 1.7 Hz, 1H), 4.46 (s, 1H), 3.55 (ddd, J = 9.7, 4.1, 2.2 Hz, 1H), 2.45 (ddd, J = 11.5, 9.8, 3.4 Hz, 1H), 2.29 – 2.04 (m, 5H), 1.87 – 1.74 (m, 5H), 1.56 (s, 3H).¹³C NMR (101 MHz, CDCl₃) δ 156.4, 154.6, 147.7, 140.0, 139.1, 124.7, 120.6, 111.6, 109.7, 102.3, 45.2, 40.4, 30.3, 28.2, 23.7, 21.2, 21.0. HRMS (ESI) m/z calcd for C₁₇H₂₃O₂ [M + H]⁺, 259.1698, found 259.1715. H OH [0131] (1'R,2'R)-4-cyclohexyl-5'-meth

-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]- 2,6-diol.¹H NMR (400 MHz, CDCl₃) δ 6.40 – 6.10 (m, 2H), 5.98 (s, 1H), 5.57 (s, 1H), 4.70 – 4.63 (m, 1H), 4.57 (s, 1H), 3.92 – 3.78 (m, 1H), 2.44 – 2.16 (m, 3H), 2.14 – 2.04 (m, 1H), 1.85 – 1.75 (m, 9H), 1.74 – 1.68 (m, 1H), 1.65 (s, 3H), 1.38 – 1.21 (m, 5H).¹³C NMR (101 MHz, CDCl₃) δ 156.3, 154.0, 149.5, 148.5, 140.2, 124.3, 114.0, 111.0, 108.3, 106.6, 46.2, 44.2, 37.4, 34.4, 34.3, 30.5, 28.5, 26.98, 26.97, 26.3, 23.8, 20.7. HRMS (ESI) m/z calcd for C₂₂H₃₁O₂ [M + H]⁺, 327.2324, found 327.2333. H [0132] (1'R,2'R)-4-(2-ethoxyethyl)-

5-methyl-2-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'- biphenyl]-2,6-diol.¹H NMR (500 MHz, CDCl₃) δ 6.40 – 6.14 (m, 2H), 5.98 (s, 1H), 5.61 – 5.41 (m, 2H), 4.61 (s, 1H), 4.52 (d, J = 2.1 Hz, 1H), 3.89 (ddd, J = 10.1, 4.3, 2.2 Hz, 1H), 3.60 (t, J = 7.4 Hz, 2H), 3.50 (q, J = 7.0 Hz, 2H), 2.73 (t, J = 7.4 Hz, 2H), 2.41 (td, J = 10.9, 3.6 Hz, 1H), 2.29 – 2.17 (m, 1H), 2.14 – 2.03 (m, 1H), 1.86 – 1.75 (m, 5H), 1.67 (s, 3H), 1.19 (t, J = 7.0 Hz, 3H).¹³C NMR (126 MHz, CDCl₃) δ 156.4, 154.5, 149.0, 140.0, 138.8, 124.3, 114.5, 111.1, 109.9, 108.5, 71.5, 66.4, 46.3, 36.9, 36.1, 30.5, 28.5, 23.8, 20.2, 15.3. HRMS (ESI) m/z calcd for C₂₀H₂₉O₃ [M + H]⁺, 317.2117, found 317.2145. O O^H [0133] (1'R,2'R)-6-(2-ethoxyethyl)-5'-m

-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'- biphenyl]-2,4-diol.¹H NMR (500 MHz, CDCl₃) δ 6.28 – 6.19 (m, 2H), 6.04 (s, 1H), 5.99 (s, 1H), 5.51 (s, 1H), 4.65 (t, J = 1.7 Hz, 1H), 4.50 – 4.45 (m, 1H), 3.56 (ddd, J = 9.9, 4.1, 2.1 Hz, 1H), 3.52 – 3.44 (m, 4H), 2.91 (dt, J = 13.5, 7.7 Hz, 1H), 2.59 (dt, J = 13.6, 7.6 Hz, 1H), 2.48 (ddd, J = 11.8, 10.0, 3.3 Hz, 1H), 2.28 – 2.16 (m, 1H), 2.14 – 2.03 (m, 1H), 1.84 – 1.75 (m, 5H), 1.52 (s, 3H), 1.20 (t, J = 7.0 Hz, 3H).¹³C NMR (126 MHz, CDCl₃) δ 156.6, 155.3, 147.9, 139.8, 139.5, 124.9, 120.3, 111.6, 109.4, 103.0, 71.7, 66.4, 45.0, 40.5, 34.4, 30.5, 28.3, 23.8, 21.6, 15.3. HRMS (ESI) m/z calcd for C₂₀H₂₉O₃ [M + H]⁺, 317.2117, found 317.2146. OH [0134] 2-((1'R,2'R)-2,6-dihydroxy

yl)-1',2',3',4'-tetrahydro-[1,1'- biphenyl]-4-yl)ethyl propionate.¹H NMR (500 MHz, CDCl₃) δ 6.25 (d, J = 48.8 H 2H), 6.02 (s, 1H), 5.55 (s, 1H), 5.05 (s, 1H), 4.63 (s, 1H), 4.53 (s, 1H), 4.24 (td, J = 7.3, 1.4 Hz,

), 3.88 (ddd, J = 9.2, 4.2, 2.1 Hz, 1H), 2.77 (t, J = 7.2 Hz, 2H), 2.40 (td, J = 11.0, 3.5 Hz, 1H), 2.31 (q, J = 7.6 Hz, 2H), 2.28 – 2.18 (m, 1H), 2.14 – 2.05 (m, 1H), 1.87 – 1.73 (m, 5H), 1.65 (s, 3H), 1.12 (t, J = 7.6 Hz, 3H).¹³C NMR (126 MHz, CDCl₃) δ 174.8, 156.5, 154.4, 149.2, 140.3, 137.8, 124.1, 114.9, 111.1, 110.3, 108.3, 64.8, 46.3, 37.1, 34.8, 30.5, 28.5, 27.8, 23.8, 20.4, 9.2. HRMS (ESI) m/z calcd for C₂₁H₂₉O₄ [M + H]⁺, 345.2066, found 345.2089.

O O [0135] 2-((1'R,2'R)-4,6-dihydroxy-5'-

n-2-yl)-1',2',3',4'-tetrahydro-[1,1'- biphenyl]-2-yl)ethyl propionate.¹H NMR (500 MHz, CDCl₃) δ 6.26 (d, J = 2.6 Hz, 1H), 6.22 (d, J = 2.7 Hz, 1H), 6.09 (s, 1H), 5.52 (s, 1H), 4.90 (s, 1H), 4.66 (s, 1H), 4.46 (s, 1H), 4.14 (qdd, J = 10.8, 8.5, 6.4 Hz, 2H), 3.58 (ddd, J = 9.8, 4.2, 2.2 Hz, 1H), 2.96 (ddd, J = 14.4, 8.5, 6.4 Hz, 1H), 2.61 (ddd, J = 13.8, 8.6, 6.5 Hz, 1H), 2.47 (ddd, J = 11.7, 10.1, 3.5 Hz, 1H), 2.32 (q, J = 7.5 Hz, 2H), 2.28 – 2.18 (m, 1H), 2.15 – 2.05 (m, 1H), 1.89 – 1.75 (m, 5H), 1.53 (s, 3H), 1.13 (t, J = 7.6 Hz, 3H).¹³C NMR (126 MHz, CDCl₃) δ 174.8, 156.8, 155.0, 147.8, 140.3, 138.6, 124.5, 120.8, 111.8, 109.3, 103.3, 64.9, 45.1, 40.5, 33.2, 30.5, 28.3, 27.7, 23.8, 21.5, 9.2. HRMS (ESI) m/z calcd for C₂₁H₂₈NaO₄ [M + H]⁺, 367.1885, found 367.1902. OH [0136] (1R,2R)-4''-(tert-butyl)-5-m

,2,3,4-tetrahydro-[1,1':4',1''- terphenyl]-2',6'-diol.¹H NMR (500 MHz, CDCl₃) δ 6.74 (s, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 6.59 (s, 1H), 6.15 (s, 1H), 5.61 (s, 1H), 4.99 (s, 1H), 4.68 (s, 1H), 4.59 (s, 1H), 3.94 (ddt, J = 10.4, 4.2, 2.2 Hz, 1H), 2.46 (td, J = 11.0, 3.4 Hz, 1H), 2.30 – 2.21 (m, 1H), 2.16 – 2.09 (m, 1H), 1.90 – 1.77 (m, 5H), 1.70 (s, 3H), 1.35 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 156.6, 154.5, 150.5, 149.2, 140.7, 140.6, 137.4, 126.5, 125.7, 123.9, 115.6, 111.2, 108.5, 106.6, 46.3, 37.4, 34.6, 31.5, 30.5, 28.5, 23.9, 20.6. HRMS (ESI) m/z calcd for C₂₆H₃₃O₂ [M + H]⁺, 377.2481, found 377.2466. ^H [0137] (1''R,2''R)-4-(tert-butyl)-5''-met

2-yl)-1'',2'',3'',4''-tetrahydro-[1,1':2',1''- terphenyl]-3',5'-diol. ¹H NMR (400 MHz, CDCl₃) δ 7.38 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 6.39 (d, J = 2.7 Hz, 1H), 6.28 (d, J = 2.7 Hz, 1H), 6.19 (s, 1H), 5.75 (s, 1H), 4.73 (s, 1H), 4.41 (t, J = 2.0 Hz, 1H), 4.22 – 4.11 (m, 1H), 3.71 – 3.56 (m, 1H), 2.48 (ddd, J = 13.1, 10.3, 3.0 Hz, 1H), 2.30 – 2.12 (m, 1H), 2.11 – 1.97 (m, 1H), 1.83 (s, 3H), 1.73 – 1.59 (m, 1H), 1.59 – 1.45 (m, 1H), 1.36 (s, 9H), 0.95 (s, 3H).¹³C NMR (101 MHz, CDCl₃) δ 156.7, 154.4, 149.7, 146.5, 145.3, 140.1, 139.0, 124.8, 120.0, 112.1, 109.4, 103.3, 46.2, 39.6, 34.6, 31.5, 30.4, 28.0, 23.9, 18.5. HRMS (ESI) m/z calcd for C₂₆H₃₃O₂ [M + H]⁺, 377.2481, found 377.247. OH F₃ [0138] (1R,2R)-5-methyl-2-(prop-

hyl)-1,2,3,4-tetrahydro-[1,1':4',1''- terphen l 2'6'-diol.¹H NMR (500 MHz, CDCl₃) δ 7.72 – 7.58 (m, 4H), 6.80 – 6.49 (m, 2H), 6.17 (s, 1H),

. (dt, J = 2.8, 1.7 Hz, 1H), 4.69 (t, J = 1.8 Hz, 1H), 4.59 (d, J = 2.0 Hz, 1H), 3.99 – 3.89 (m, 1H), 2.45 (ddd, J = 11.7, 10.3, 3.3 Hz, 1H), 2.34 – 2.21 (m, 1H), 2.13 (ddt, J = 17.9, 4.9, 2.4 Hz, 1H), 1.87 – 1.79 (m, 5H), 1.70 (t, J = 1.1 Hz, 3H).¹³C NMR (126 MHz, CDCl₃) δ 156.9, 154.8, 149.2, 144.0, 140.9, 139.4, 129.5 (q, J = 32.5 Hz), 127.2, 125.7 (q, J = 3.7 Hz), 125.5, 123.6, 123.3, 116.9, 111.3, 108.9, 106.9, 46.3, 37.4, 30.5, 28.5, 23.9, 20.5. HRMS (ESI) m/z calcd for C₂₃H₂₂F₃O₂ [M - H]-, 387.1572, found 387.1569. CF₃ H [0139] (1''R,2''R)-5''-methyl-2''-(prop-

romethyl)-1'',2'',3'',4''-tetrahydro- [1,1':2',1''-terphenyl]-3',5'-diol.¹H NMR (500 MHz, CDCl₃) δ 7.68 – 7.51 (m, 2H), 7.30 (s, 2H), 6.40 (d, J = 2.6 Hz, 1H), 6.21 (d, J = 2.6 Hz, 1H), 6.17 (s, 1H), 5.69 (s, 1H), 4.87 (s, 1H), 4.49 – 4.37 (m, 1H), 4.14 (d, J = 2.1 Hz, 1H), 3.48 – 3.37 (m, 1H), 2.46 (ddd, J = 13.1, 10.3, 2.9 Hz, 1H), 2.26 – 2.13 (m, 1H), 2.08 – 1.99 (m, 1H), 1.81 (s, 3H), 1.66 – 1.63 (m, 1H), 1.52 – 1.44 (m, 1H), 0.98 (s, 3H).¹³C NMR (126 MHz, CDCl₃) δ 156.9, 154.6, 146.3, 145.8, 143.8, 140.7, 130.0, 129.1 (q, J = 32.4 Hz), 125.5, 124.1, 123.3, 119.8, 112.4, 109.2, 104.1, 45.9, 40.0, 30.4, 28.0, 23.9, 19.1. HRMS (ESI) m/z calcd for C₂₃H₂₂F₃O₂ [M - H]-, 387.1572, found 387.1578. OH [0140] N-(2-((1'R,2'R)-2,6-dihy

2-yl)-1',2',3',4'-tetrahydro-[1,1'- biphenyl]-4-yl)ethyl)-N-methylacetamide.¹H NMR (500 MHz, CDCl₃) δ 6.44 – 5.91 (m, 4H), 5.54 (dd, J = 13.5, 2.7 Hz, 1H), 4.54 (dt, J = 7.3, 2.0 Hz, 1H), 4.43 (s, 1H), 3.95 (dddd, J = 12.7, 10.5, 4.4, 2.3 Hz, 1H), 3.73 – 3.39 (m, 2H), 2.87 (d, 3H), 2.67 (q, 2H), 2.49 – 2.32 (m, 1H), 2.33 – 2.17 (m, 1H), 2.14 – 2.02 (m, 3H), 1.88 – 1.72 (m, 6H), 1.66 (d, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 172.1, 171.7, 156.5, 155.5, 148.6, 148.5, 140.2, 139.8, 138.6, 137.9, 124.5, 124.2, 115.4, 114.8, 111.2, 111.0, 109.4, 108.5, 52.6, 50.1, 46.6, 46.6, 37.3, 36.5, 36.4, 34.4, 33.9, 33.5, 30.6, 28.5, 28.4, 23.8, 21.7, 21.0, 19.6. HRMS (ESI) m/z calcd for C₂₁H₂₉NNaO₃ [M + Na]⁺, 366.2045, found 366.2067. OH [0141] N-(2-((1'R,2'R)-2,6-dihy

-yl)-1',2',3',4'-tetrahydro-[1,1'- biphenyl]-4-yl)propan-2-yl)propionamide.¹H NMR (400 MHz, CDCl₃) δ 6.54 – 6.29 (m, 3H), 5.80 (s, 1H), 5.52 (q, J = 1.9 Hz, 1H), 4.59 (t, J = 1.8 Hz, 1H), 4.51 (d, J = 2.1 Hz, 1H), 3.91 (ddd, J = 10.1, 3.9, 2.2 Hz, 1H), 2.40 (td, J = 10.5, 3.8 Hz, 1H), 2.27 – 2.04 (m, 5H), 1.83 – 1.73 (m, 5H), 1.68 – 1.60 (m, 10H), 1.11 (t, J = 7.5 Hz, 3H).¹³C NMR (101 MHz, CDCl₃) δ 173.8, 148.8, 147.0, 140.1, 124.2, 115.3, 111.1, 56.0, 46.3, 36.8, 30.7, 30.5, 28.6, 28.4, 28.3, 23.8, 20.1, 10.0. HRMS (ESI) m/z calcd for C₂₂H₃₁NNaO₃ [M + Na]⁺, 380.2202, found 380.2219. HO [0142] (1'S,2'S)-5'-(hydroxymet

yl)-1',2',3',4'-tetrahydro-[1,1'- biphenyl]-2,6-diol.¹H NMR (400 MHz, CDCl₃) δ 6.21 (s, 2H), 5.83 (d, J = 2.1 Hz, 1H), 4.64 (t, J = 1.8 Hz, 1H), 4.55 (d, J = 2.1 Hz, 1H), 4.19 – 4.00 (m, 2H), 4.00 – 3.85 (m, 1H), 2.50 (ddd, J = 13.1, 10.6, 2.9 Hz, 1H), 2.43 (dd, J = 8.8, 6.7 Hz, 2H), 2.30 – 2.17 (m, 2H), 1.89 (ddt, J = 10.8, 5.1, 2.9 Hz, 1H), 1.85 – 1.74 (m, 1H), 1.74 – 1.63 (m, 4H), 1.61 – 1.49 (q, 2H), 1.38 – 1.21 (m, 4H), 0.88 (t, J = 6.9 Hz, 3H). ¹³C NMR (101 MHz, CDCl₃) δ 149.0, 143.3, 142.0, 125.5, 113.6, 111.2, 66.6, 46.6, 36.8, 35.6, 31.6, 30.8, 28.4, 26.1, 22.7, 20.3, 14.2. HRMS (ESI) m/z calcd for C₂₁H₃₁O₃ [M + H]⁺, 331.2273, found 331.2269.

[0143] (1'S,2'S)-5'-methyl-2'-(prop-1-en-2-yl)-4-((E)-styryl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]- 2,6-diol. [ ^^^^]² ^_^^^ ^2.8 = +128.8 (c 0.24, CH2Cl2); ¹H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.6 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 – 7.26 (m, 1H), 7.03 (d, J = 16.3 Hz, 1H), 6.95 (d, J = 16.2 Hz, 1H), 6.70 – 6.49 (m, 2H), 6.19 – 6.06 (m, 1H), 5.61 (s, 1H), 5.00 (s, 1H), 4.70 (s, 1H), 4.61 (s, 1H), 3.99 – 3.92 (m, 1H), 2.48 (td, J = 11.0, 3.3 Hz, 1H), 2.33 – 2.24 (m, 1H), 2.18 – 2.12 (m, 1H), 1.90 – 1.81 (m, 5H), 1.72 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 156.6, 154.5, 149.1, 140.6, 137.4, 137.19, 128.76, 128.23, 127.68, 126.62, 123.82, 116.60, 111.26, 108.22, 106.15, 46.31, 37.37, 30.53, 28.47, 23.83, 20.38. HRMS (ESI) m/z calcd for C₂₄H₂₇O₂ [M + H]⁺, 347.2011, found 347.2009. H [0144] (1'S,2'S)-5'-methyl-2'-(prop-1

yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]- 2,4-diol. [ ^^^^]² ^_^^^ ^4.2 = -6.65 (c 0.14, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.46 – 7.38 (m, 2H), 7.38 – 7.30 (m, 2H), 7.28 – 7.21 (m, 2H), 6.76 (d, J = 16.0 Hz, 1H), 6.57 (d, J = 2.6 Hz, 1H), 6.34 (d, J = 2.6 Hz, 1H), 6.22 (s, 1H), 5.59 (s, 1H), 5.09 (s, 1H), 4.71 – 4.57 (m, 1H), 4.57 – 4.45 (m, 1H), 3.84 – 3.68 (m, 1H), 2.49 (td, J = 10.6, 9.9, 3.4 Hz, 1H), 2.29 – 2.15 (m, 1H), 2.15 – 2.07 (m, 1H), 1.89 – 1.67 (m, 5H), 1.53 (s, 3H).¹³C NMR (101 MHz, CDCl₃) δ 156.6, 155.0, 147.4, 140.5, 139.9, 138.0, 131.6, 128.8, 127.9, 127.7, 126.6, 124.3, 120.3, 111.9, 106.0, 104.1, 45.7, 40.1, 30.3, 28.1, 23.8, 21.0. HRMS (ESI) m/z calcd for C₂₄H₂₇O₂ [M + H]⁺ 347.2011, found 347.2014. [0145] (1'S,2'S)-4-(benzofuran-2-y

l)-5-methyl-2-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'- biphenyl]-24,6-diol. [ ^^^^]² ^_^^^ ^4.2 = +110.67 (c 0.18, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 7.57 (dd, J = 7.7, 1.3 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.31 – 7.27 (m, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.07 – 6.80 (m, 3H), 6.20 (s, 1H), 5.62 (s, 1H), 5.14 – 5.02 (m, 1H), 4.69 (s, 1H), 4.60 (s, 1H), 3.99 (ddq, J = 10.8, 4.5, 2.3 Hz, 1H), 2.50 (td, J = 11.0, 3.4 Hz, 1H), 2.34 – 2.26 (m, 1H), 2.19 – 2.12 (m, 1H), 1.93 – 1.77 (m, 5H), 1.73 (s, 3H).13C NMR (126 MHz, CDCl3) δ 156.8, 155.6, 154.9, 148.9, 140.8, 130.1, 129.3, 124.3, 123.6, 123.0, 121.0, 117.6, 111.4, 111.2, 106.7, 104.6, 101.5, 46.3, 37.3, 30.6, 28.4, 23.9, 20.3. HRMS (ESI): m/z (M + H)+ calcd. for C₂₄H₂₅O₃, 361.1804; found, 361.1813. H [0146] (1'S,2'S)-6-(benzofuran-2-yl)-5 en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-

biphenyl]-2,4-diol. [ ^^^^]² ^_^^^ ⁵ = -45.81 (c 0.20, CH₂Cl₂); ¹H NMR (400 MHz, CDCl₃) δ 7.57 (ddd, J = 7.4, 1.6, 0.7 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.32 – 7.20 (m, 2H), 6.65 (d, J = 1.0 Hz, 1H), 6.57 (d, J = 2.7 Hz, 1H), 6.45 (d, J = 2.7 Hz, 1H), 6.28 (s, 1H), 5.77 (s, 1H), 4.93 (s, 1H), 4.44 (s, 1H), 4.22 (s, 1H), 4.05 – 3.91 (m, 1H), 2.51 (t, J = 11.2 Hz, 1H), 2.28 – 2.16 (m, 1H), 2.16 – 1.99 (m, 1H), 1.83 (s, 3H), 1.76 – 1.68 (m, 1H), 1.59 (dq, J = 17.6, 6.1, 5.2 Hz, 1H), 1.14 (s, 3H).¹³C NMR (101 MHz, CDCl₃) δ 157.2, 156.5, 154.8, 146.9, 140.5, 133.2, 128.9, 124.2, 122.9, 121.1, 121.0, 111.9, 111.4, 109.4, 105.7, 105.4, 46.1, 40.5, 30.5, 28.1, 23.9, 19.4. HRMS (ESI) m/z calcd for C₂₄H₂₅O₃ [M + H]⁺ 361.1804, found 361.1807. Example 2: Results and Discussion [0147] Several solvents were evaluated in the Friedel-Crafts alkylation of olivetol with allylic monoterpene alcohol in the presence of 1.0 equivalent of arylboronic acid. Satisfactory yields (54% – 35%) of abn-CBD were obtained using various conventional organic solvents like dichloromethane, acetonitrile, nitromethane, trifluoroethanol (TFE) or combination of these solvents at temperatures ranging from 30 °C - 60 °C . [0148] Use of a combination of fluorinated solvents like trifluoroethanol (TFE), 1,1,1,3,3,3- hexafluoroisopropanol (HFIP), 2,2,3,3,4,4,5-heptafluoro-5-(1,1,2,2,3,3,4,4,4- nonafluorobutyl)oxolane or hexafluorobenzene, steered the regioselectivity towards the regioselective formation of CBD. A Friedel-Crafts reaction between 1.0 equivalent of allylic monoterpene alcohol and 1.5 equivalents of olivetol in presence of 1.0 equivalent of arylboronic acid in the presence of a mixture of fluorinated solvents yielded 48 - 32% of CBD, along with THC, at temperatures ranging from 30 °C - 60 °C. Increasing the equivalence of olivetol increased the yield up to 68%. While the optimized method helped enhance the regioselectivity towards the formation of CBD, it was not sufficient to eliminate the production of tetrahydrocannabinol. Reducing the equivalence of PFBA to 5 mol% brought down the amount of THC formed to below 5% at the expense of longer reaction times.

[0149] Several substrates were investigated utilizing the optimized reaction conditions employed in the synthesis of CBD. With R = Heptyl (Table 1, entry 1), the regioselectivity was almost similar to olivetol but with orcinol (R = methyl, entry 2) no appreciable regioselectivity was observed. Substrates possessing branching at the T position exhibited exceptional regioselectivity, as they produced an insignificant amount of the other regioisomer (Table 1 , entries 3 and 4).

[0150] The substrate scope was even extended to alkyl chains containing functional groups like ester, ether, and amides. 3,5-dihydroxyphenethyl propionate (entry 5) and 5-(2- ethoxyethyl)benzene-1 ,3-diol (entry 6) were individually subjected to a mixture of organic and fluorinated solvents. Entry 5, containing ester functionality, was obtained in a slightly lower yield, most probably because of the poor solubility. N-(3,5-dihydroxyphenethyl)-N-methylacetamide, which contains an amide functionality (entry 7), exhibits poor solubility in traditional solvents. However, when subjected to optimized reaction conditions, the CBD-like (C-2 isomer) product was obtained in 24% yield. However, substrate 8 with increased steric bulk at the T position, gave the CBD-like isomer in appreciable yield (entry 8, Table 1).

[0151] Substrates containing an aromatic ring instead of an alkyl chain were also investigated (entries 9 and 10, Table 3). Due to their poor solubility, they were subjected to a mixture of fluorinated and conventional organic solvents. Compared to the alkyl analogs, substrate 9 exhibited inferior regioselectivity. With substrate 10, the reaction did not terminate at the intended cannabidiol stage under the optimized set of conditions but instead proceeded to form the corresponding tetrahydrocannabinol. In the absence of boronic acid, the C2 isomer was obtained in 27% yield.

Conclusion

[0152] Clinical and preclinical studies of cannabinoids have provided scientific evidence for the efficacy of cannabinoids which has led to the current resurgence in medicinal applications. Thus, there is a growing interest in the development of efficient methodologies for obtaining it through synthetic pathways. The existing synthetic routes are often low yielding due to the formation of undesired regioisomer and controlled substances as side products. The reaction needs to be monitored frequently, to stop the formation of unwanted side products and would often be accompanied by a complex purification step. Furthermore, the major regioisomer of classical Friedel-Crafts alkylation on resorcinol is often undesired. To address these issues, a mild and efficient synthetic strategy has been developed that delivers the desired regioisomer as a major product while suppressing the concomitant conversion to corresponding tetrahydrocannabinols. The current method is tolerant of multiple functional groups and can therefore be used to synthesize various cannabidiol derivatives that could help enhance understanding of their chemical and medicinal properties.

[0153] It should be emphasized that the above-described embodiments of the present disclosure are merely possible examples of implementations set forth for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the abovedescribed embodiment(s) without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.

Claims

CLAIMS What is claimed is:

1. A method for synthesizing a cannabidiol (CBD) analog or abnormal cannabidiol (abn-CBD) analog, the method comprising

(a) contacting an allylic monoterpene alcohol having a structure according to Formula la, Formula lb, or Formula Ic with an aryl boronic acid to form a first admixture; and

(+/-) (+/-) (+/-)

Formula la Formula lb Formula Ic

(b) contacting the first admixture with a substituted resorcinol having Formula II

Formula II; wherein X is selected from H, OH or alkyl; wherein Y is selected from linear or branched alkyl, linear or branched alkenyl, cycloalkyl, cycloalkenyl, alkyl aryl, or alkenyl aryl; and wherein R is selected from C1-C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; substituted aryl or heteroaryl, alkylaryl, or alkyl heteroaryl.

2. The method of claim 1 , wherein the aryl boronic acid comprises pentafluorophenylboronic acid

(PFBA), 2,3,4,5-tetrafluorophenylboronic acid, 3,4,5-triflulrophenylboronic acid, 2,4,6- trifluorophenylboronic acid, or any combination thereof.

3. The method of claim 1 , wherein the aryl boronic acid is present in an amount of from about 0 mol% to about 100 mol% relative to an amount of allylic monoterpene alcohol.

4. The method of claim 3, wherein the aryl boronic acid is present in an amount of about 5 mol% relative to an amount of allylic monoterpene alcohol.

5. The method of claim 1 , wherein the aryl boronic acid is present in a molar ratio of from about

0.05:3 to about 1 :1.5 relative to an amount of substituted resorcinol.

6. The method of claim 5, wherein the aryl boronic acid is present in a molar ratio of about 0.05:3 relative to an amount of substituted resorcinol.

7. The method of claim 1 , wherein the method is conducted in a solvent.

8. The method of claim 7, wherein the solvent comprises dichloromethane, acetonitrile, nitromethane, 1 ,1 ,1 ,3,3,3-hexafluoroisopropanol (HFIP), 2,2,2-trifluoroethanol (TFE), 2,2,3,3,4,4,5-heptafluoro-5-(1 , 1 ,2,2,3,3,4,4,4-nonafluorobutyl)oxolane, hexafluorobenzene, or any combination thereof.

9. The method of claim 8, wherein the solvent is HFIP.

10. The method of claim 1 , wherein R is selected from:

wherein Z is selected from F, Cl, Br, CN, or NO2; and wherein Q is selected from NH, O, or S.

11. The method of claim 1 , wherein the method yields less than 15 mol% THC, less than 15% abn-CBD, greater than 60% CBD, or any combination thereof.

12. The method of claim 1 , wherein the method yields less than 15 mol% THC, less than 15% CBD, greater than 60% abn-CBD, or any combination thereof.

13. The method of claim 1 , wherein the CBD analog or abn-CBD analog has Formula III:

Formula III; wherein two of Ri_a, Ri_b, and Ri_c are OH, and wherein the Ri_a, Rw, or Ri_c that is not OH is R; wherein a carbon atom indicated by * has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof; and wherein a carbon atom indicated by ** has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof.

14. The method of claim 13, wherein the method produces an abn-CBD analog wherein Ri_c and Rw are OH and Ri_a is R.

15. The method of claim 14, wherein the method yields at least about 80% of an abn-CBD analog.

16. The method of claim 13, wherein the method produces a CBD analog, wherein Ri_a and Ri_c are OH and Rw is R.

17. The method of claim 16, wherein the method yields at least about 80% of a CBD analog.

18. A cannabidiol (CBD) analog or abnormal cannabidiol (abn-CBD) analog having a structure according to Formula III;

Formula III; wherein two of Ri_a, Rw, and Ri_c are OH, and wherein the Ri_a, Rib, or Ri_c that is not OH is selected from C1-C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; or substituted aryl or heteroaryl; or alkylaryl or alkyl heteroaryl; wherein a carbon atom indicated by * has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof; and wherein a carbon atom indicated by ** has substantially (R) stereochemistry, substantially (S) stereochemistry, or any combination thereof. provided that the CBD analog is not CBD or abn-CBD; and provided that when R_1a and Ru are OH, Rw is not linear alkyl.

19. The abn-CBD analog of claim 18, wherein Ri_c and Rn, are OH and Ri_a is selected from C1- C9 linear or branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; or substituted aryl or heteroaryl; alkylaryl or alkyl heteroaryl.

20. The CBD analog of claim 18, wherein Ri_a and Ri_c are OH and Rw is selected from C1-C9 branched alkyl or cycloalkyl; C2-C6 ether, ester, amide, or N-alkylamide; or substituted aryl or heteroaryl; alkylaryl or alkyl heteroaryl.

21. The CBD analog or abn-CBD analog of claim 18, wherein the Ri_a, Ri_b, or Ri_c that is not OH is:

wherein Z is selected from F, Cl, Br, CN, or NO2; and wherein Q is selected from NH, O, or S..

22. The CBD analog or abn-CBD analog of claim 18, wherein the CBD analog or abn-CBD analog is selected from: