Novel methods for the asymmetric hydrogenation of cannabinoid compounds

Abstract

Methods for the asymmetric hydrogenation of the trisubstituted olefin in THC are disclosed. The methods disclosed herein can be performed in conventional organic solvents or in water under modified Pickering catalysis conditions. The methods disclosed herein provide improved selectivity over standard industrial conditions with decreased reaction times under ambient conditions.

Description

BACKGROUND OF THE INVENTIONThis application claims benefit of U.S. Provisional Application No. 63 / 679,976, filed August 6, 2024, the contents of which are incorporated herein by reference in its entirety.I. Field of the Invention

[0001] This invention relates to the field of organic chemistry.II. Background

[0002] About 56% of the drugs currently in use are chiral compounds, and 88% of these chiral synthetic drugs are used therapeutically as an equimolar mixture of enantiomers. Although enantiomeric pairs have the same chemical structure, most isomers of chiral drugs exhibit marked differences in biological activities such as pharmacology, toxicology, pharmacokinetics, metabolism etc.

[0003] Thalidomide is a nonaddictive, nonbarbiturate sedative that was used in the 1950s for treating morning sickness in pregnant women. Thalidomide has a chiral center, and a racemic mixture of (R) and (S) enantiomers was used in the pharmaceutical formulation and commercial product. Soon after thalidomide's release, reports surfaced of patients developing peripheral neuropathy after taking the drug. Reports of severe birth defects affecting multiple body systems were also linked to the drug. In 1961, thalidomide was withdrawn due to teratogenicity and neuropathy. Researchers later determined that the (S) enantiomer of thalidomide was responsible for the dangerous side-effects. The lessons learned from the thalidomide fiasco led pharmaceutical producers to study the effects of individual enantiomeric forms in order to eliminate the inactive or dangerous isomers.

[0004] Stereoselectivity in organic chemistry is used to access various enantiomers and diastereomers. Stereoselective chemical reactions provide the opportunity to design synthetic routes to enantiomerically enriched molecules, a feature that is especially important for high- value pharmaceutical applications. Stereoselective drug synthesis can prevent access to undesired compounds, e.g., thalidomide. There remains a need in the pharmaceutical industry for stereoselective chemical reactions that can avoid the synthesis of unwanted or inactive enantiomers.SFWN.P0004WO Patent Application. docx - 1 -SUMMARY OF THE INVENTION

[0005] Hexahydrocannabinol (HHC), a cannabinoid found in small quantities in Cannabis sativa, exists as two diastereomers, (R)-HHC and (S)-HHC. Hexahydrocannabinol has three asymmetric carbon atoms, two carbon atoms with set or non-variable stereochemistry that link the cyclohexyl ring to the aromatic ring of the molecule, and one variable-stereochemistry carbon atom bearing a methyl group. Multiple studies have determined that the (R) diastereomer is more active than the (S) diastereomer.

[0006] A racemic mixture of hexahydrocannabinol can be made through traditional, non- asymmetric hydrogenation of the tri substituted cyclohexyl olefin in tetrahydrocannabinol (THC, FIG. 1). Stereoselective hydrogenation can be used to selectively synthesize the more active (R) diastereomer, however, most stereoselective hydrogenations of HHC suffer from low enantiomeric excess (ee). The present inventors have developed new methods for the stereoselective hydrogenation of THC that provides access to either diastereomer in high enantiomeric excess.

[0007] Some embodiments of the present disclosure are directed to a method for the asymmetric hydrogenation of a tetrahydrocannabinol compound. In some embodiments, the method comprises subjecting the tetrahydrocannabinol compound to hydrogenation in the presence of a hydrogenation catalyst to obtain a hexahydrocannabinol compound. In some embodiments, the tetrahydrocannabinol compound is selected from the group consisting of A8- THC, A9-THC, and A10-THC. In some embodiments, the hydrogenation is performed in the presence of a hydrogen source. In some embodiments, the hydrogen source is hydrogen gas or an in-situ hydrogen source. In some embodiments, the in-situ hydrogen source comprises ammonium formate and / or formic acid. In some embodiments, an amount of ammonium formate ranges from 1 to 40 molar equivalents. In some embodiments, an amount of formic acid ranges from 1 to 40 molar equivalents. In some embodiments, the hydrogen gas is provided in an amount that affords an intra-vessel gas pressure ranging from 20 psi to 500 psi.

[0008] In some embodiments, the catalyst is provided in an amount ranging from 0.01 to 10 molar equivalents. In some embodiments, the catalyst comprises a metal selected from the group consisting of palladium, rhodium, nickel, aluminum, platinum, and iridium. In some embodiments, the catalyst is selected from the group consisting of Pd(dppf)2, Pd G2 Sphos, Pd(OH)2 / C Pd(dba)3, PD(dba)2, Pd(PPhs)4, Pd(OAc)2, Pd / C, Pt / C, Wilkinson's catalyst, Crabtree's catalyst, RuCh, (S,S)-[COD]Ir[cy2PThrePHOX, (R,R)-[COD]Ir[cy2PThrePHOX, HS157, (R,R)-[COD]Ir[Ph2PThrePHOX], (S,S)-[COD]Ir[Ph2PThrePHOX], (S)-2-[2-[Bis(2-SFWN.P0004WO Patent Application. docx - 2 -tolyl)phosphino]phenyl]-4-tert-butyl-2-oxazoline, (A)-2-[2-[Bis(2-tolyl)phosphino]phenyl]-4- ter -butyl-2-oxazoline, (l,5-Cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexafluorophosphate, Europium tris[3-(heptafluoropropylhydroxymethylene)-(+)- camphorate], europium tris[3-(trifluoromethylhydroxymethylene)-(+)-camphorate], palladium(II) trifluoroacetate, (l,5-cyclooctadiene)(pyridine)(tricyclohexylphosphine)- iridium(I) hexafluo-rophosphate, and europium acetate. In some embodiments, the hydrogenation is performed in the presence of a co-catalyst. In some embodiments, the cocatalyst is selected from the group consisting of Eu(OAc)s, Yb(OTf)3, In(OTf)3, TFA, Eu(fod)3, Eu(fcam)3, Eu(hfc)3, and any combination thereof. In some embodiments, the hydrogenation is performed in the presence of an additive. In some embodiments, the additive is selected from the group consisting of EtsN, Hunig’s base, ammonium formate, TPGS, citric acid, propylene gylcol, HCOOH, HCOONa, sodium ascorbate, ascorbic acid, borane- dimethylsulfide, 9-borabicyclo[3.3.1]nonane, BH3-DMSO, BH3-THF, N-methylimidodiacetic (MIDA) boronates, TPGS, Kolliphor REMO, (5)-cA-verbenol, beta-cyclodextrin, and any combination thereof. In some embodiments, the hydrogenation is performed in the presence of a chiral auxiliary or ligand. In some embodiments, the chiral auxiliary or ligand is selected from the group consisting of (R)-alpine borane, (S)-alpine borane, (+)-limonene oxide, (-)- limonene oxide, (S)-cis-verbenol, (R)-cis-verbenol, SPhos, RuPhos, XantPhos, (+)- diethylphosphinoethane, (+)-diethylphosphinoethane, (-)-diisopropylphosphinoethane, (-)- diisopropylphosphinoethane, (+)-diphenylethylenediamine, (-)-diphenylethylenediamine, (+)- l,2-Bis((2S,5S)-2,5-diphenylphospholano)ethane, (-)-l,2-Bis((2R,5R)-2,5- diphenylphospholano) ethane, (R)-BINAP, (S)-BINAP, (R)-BINOL, (S)-BINOL, (-)-tartaric acid, (+)-tartaric acid, (R)-4-(tert-butyl)-2-(2-(diphenylphosphino)phenyl)-4,5- dihydrooxazole, (S)-4-(tert-Butyl)-2-(2-(diphenylphosphino)phenyl)-4,5-dihydrooxazole, a PHOX ligand, a D-amino acid, an L-amino acid, and any combination thereof.

[0009] In some embodiments, the hydrogenation comprises heating reaction components to a temperature ranging from 25 °C to 100 °C. In some embodiments, the tetrahydrocannabinol compound comprises a phenolic oxygen protecting group. In some embodiments, the protecting group is selected from the group consisting of methoxymethyl ether, tetrahydropyranyl ether, / -butyl ether, allyl ether, methyl ether, benzyl ether, / - butyldimethylsilyl ether, t-butyldiphenylsilyl ether, acetate ester, pivloyl ester, and benzoic acid ester. In some embodiments, the hexahydrocannabinol compound is produced in an enantiomeric excess of greater than 80%. In some embodiments, the hexahydrocannabinol compound is produced in an enantiomeric excess of greater than 90%. In some embodiments,SFWN.P0004WO Patent Application. docx - 3 -the hexahydrocannabinol compound is produced in an enantiomeric excess of greater than 95%. In some embodiments, the hexahydrocannabinol compound is produced in an enantiomeric excess of greater than 96%. In some embodiments, the hexahydrocannabinol compound is produced in an enantiomeric excess of greater than 97%. In some embodiments, the hydrogenation is carried out in a solvent. In some embodiments, the solvent is selected from the group consisting of DMSO, MeOH, EtOH, TFE, IP A, HFIP, PhMe, DCM, THF, EtOAc, EtsSiH, water, propylene glycol, ethylene glycol, and any combination thereof.

[0010] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the measurement or quantitation method. In some embodiments, the tetrahydrocannabinol compound is selected from the group consisting of A8- THC, A9-THC, and A10-THC.

[0011] The use of the word “a” or “an” when used in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0012] The phrase “and / or” means “and” or “or”. To illustrate, A, B, and / or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C.

[0013] The words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0014] It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention.

[0015] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGSSFWN.P0004WO Patent Application. docx - 4 -

[0016] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

[0017] FIG. l is a general reaction scheme depicting the conversion of A-8 and A-9 THC to a mixture of (R)-HHC and (S)-HHC.

[0018] FIG. 2 includes different catalysts employed in embodiments of the invention.

[0019] FIG. 3 is a table with results of initial hydrogenation catalyst screening. THC was subjected to different catalysts at 20 °C in MeOH to benchmark initial stereoselectivity and reaction times.

[0020] FIGS. 4A-4B. FIG. 4A is a UV-Vis spectrum of a microemulsion of Pd(OH)2 (0.002M Pd2+) and H20 / Me0H with no hydrogen source added. FIG. 4B is a UV-Vis spectrum of a microemulsion of Pd(OH)2 (0.002M Pd2+) and H20 / Me0H with hydrogen added.

[0021] FIGS. 5A-5B. FIG. 5A depicts general reaction times and percentage of THC hydrogenation observed during catalyst screening. Catalyst A - Pd(OH)2 / C; catalyst B - Pd(OAc)2; catalyst C - Pt / C; catalyst D - Pd / C. FIG. 5B depicts catalyst effects on THC hydrogenation under Pickering conditions. Catalyst E - Pd(OH)2, Eu(OAc)3, Me0H,H20, (R / S ratio 1 : 1); catalyst F - Pd(OH)2, Eu(OAc)3, TPGS, H2O / MeOH (10: 1), NH4COOH, (R / S ratio 3.4:1) catalyst G - Pd(OAc)2, Eu(OAc)3,H2O / MeOH (10: 1),NH4COOH, no H2; catalyst H - Pd(OAc)2, EU(OAC)3, TPGS, H2O / MeOH (10: 1), NH4COOH, (R / S ratio 3: 1); catalyst I - HS157, NH4COOH, H2O / MeOH (10: 1), (R / S ratio 1.5: 1); catalyst J - HS157, NH4COOH, H2O / MeOH (10: 1), Eu(OAc)3, (R / S ratio 1: 1); catalyst K - Pd(OH)2, NH4COOH, H2O / MeOH, No H2 (R / S ratio 1.5: 1). All reactions were performed at room temperature with a substrate concentration of 0.05 M at 1 atm.

[0022] FIG. 6 is a table that includes THC hydrogenation results for different catalysts.

[0023] FIG. 7 is a table that includes THC hydrogenation results for different catalyst / co- catalyst combinations.

[0024] FIGS 8A-8B. FIG. 8A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 8B. FIG. 8B is a table that includes results of THC hydrogenation experiments using different Europium co-catalysts and chiral auxiliaries in combination with a Pd(OAc)2 catalyst.SFWN.P0004WO Patent Application. docx - 5 -

[0025] FIGS 9A-9B. FIG. 9A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 9B. FIG. 9B is a table that includes results of THC hydrogenation experiments in different solvents.

[0026] FIGS 10A-10B. FIG. 10A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 10B. FIG. 10B is a table that includes results of hydrogenation experiments using THC methyl ether as a substrate.

[0027] FIGS 11A-11B. FIG. 11A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 1 IB. FIG. 1 IB is a table that includes results of hydrogenation experiments using A9-THC as a substrate.

[0028] FIG. 12 is a table that includes results of THC hydrogenation experiments using an HS157 catalyst in combination with different co-catalysts / chiral auxiliaries.

[0029] FIGS 13A-13B. FIG. 13 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 13B. FIG. 13B is a table that includes results of hydrogenation experiments using an HS157 catalyst with THC methyl ether as a substrate.

[0030] FIGS 14A-14B. FIG. 14A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 14B. FIG. 14B is a table that includes results of hydrogenation experiments using an HS157 catalyst with different THC ether or ester substrates.

[0031] FIGS 15A-15B. FIG. 15A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 15B. FIG. 15B is a table that includes results of hydrogenation experiments using different catalyst / co-catalyst combinations with THC or THC methyl ether substrates.

[0032] FIGS 16A-16B. FIG. 16A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 16B. FIG. 16B is a table that includes results of hydrogenation experiments using different catalyst / additive combinations.

[0033] FIGS 17A-17B. FIG. 17A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 17B. FIG. 17B is a table that includes results of hydrogenation experiments using a THC methyl ether substrate.

[0034] FIGS 18A-18B. FIG. 18A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 18B. FIG. 18B is a table that includes results of hydrogenation experiments using different co-catalysts in combination with a Pd(OH)2 / C catalyst.SFWN.P0004WO Patent Application. docx - 6 -

[0035] FIGS 19A-19B. FIG. 19A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 19B. FIG. 19B is a table that includes results of hydrogenation experiments using different catalysts combinations.

[0036] FIGS 20A-20B. FIG. 20 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 20B. FIG. 20B is a table that includes results of hydrogenation experiments using different catalysts combinations.

[0037] FIGS 21A-21B. FIG. 21A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 21B. FIG. 21B is a table that includes results of hydrogenation experiments using different solvent / additive combinations.

[0038] FIGS 22A-22B. FIG. 22 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 22B. FIG. 22B is a table that includes results of hydrogenation experiments using different catalyst / additive combinations at different temperatures.

[0039] FIGS 23A-23B. FIG. 23 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 23B. FIG. 23B is a table that includes results of hydrogenation experiments of a THC pivaloyl ester substrate using different catalyst / additive combinations at different temperatures.

[0040] FIGS 24A-24B. FIG. 24 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 24B. FIG. 24B is a table that includes results of hydrogenation experiments of a THC-OTBS ether substrate using different catalyst / additive combinations at different temperatures.

[0041] FIGS 25A-25B. FIG. 25 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 25B. FIG. 25B is a table that includes results of hydrogenation experiments of a THC acetate ester substrate using different catalyst / additive combinations.

[0042] FIGS 26A-26B. FIG. 26 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 26B. FIG. 26B is a table that includes results of hydrogenation experiments using different ruthenium or rhodium catalysts.

[0043] FIGS 27A-27B. FIG. 27 A is a reaction scheme depicting general reaction conditions and catalyst ligands used for the experiments included in FIG. 27B. FIG. 27B is a table that includes results of hydrogenation experiments using different catalyst / ligand combinations.

[0044] FIGS 28A-28B. FIG. 28 A is a reaction scheme depicting general reaction conditions and catalysts employed in the experiments included in FIG. 28B. FIG. 28B is a tableSFWN.P0004WO Patent Application. docx - 7 -that includes results of hydrogenation experiments of a THC acetate ester substrate using different catalyst / ligand combinations.

[0045] FIGS 29A-29B. FIG. 29 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 29B. FIG. 29B is a table that includes results of hydrogenation experiments of a THC pivaloyl ester substrate using different catalyst / ligand combinations at different temperatures.

[0046] FIGS 30A-30B. FIG. 30A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 30B. FIG. 30B is a table that includes results of hydrogenation experiments using different catalysts.

[0047] FIGS 31A-31B. FIG. 31A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 3 IB. FIG. 3 IB is a table that includes results of hydrogenation experiments using different catalysts.

[0048] FIGS 32A-32B. FIG. 32A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 32B. FIG. 32B is a table that includes results of A9 hydrogenation experiments using different catalysts.

[0049] FIGS 33A-33B. FIG. 33A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 33B. FIG. 33B is a table that includes results of A8-OMe hydrogenation experiments using different catalysts.

[0050] FIGS 34A-34B. FIG. 34A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 34B. FIG. 34B is a table that includes results of A9-OTBS hydrogenation experiments using different catalysts.

[0051] FIGS 35A-35B. FIG. 35 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 35B. FIG. 35B is a table that includes results of A8 or A9 hydrogenation experiments using different catalysts.

[0052] FIGS 36A-36B. FIG. 36A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 36B. FIG. 36B is a table that includes results of A8 hydrogenation experiments using different catalysts. D / R-dry reduced, AP- alumina powder, CP- carbon powder, M / R-moist reduced, M / UR-moist unreduced, numbers represent catalyst identification code.

[0053] FIGS 37A-37B. FIG. 37A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 37B. FIG. 37B is a table that includes results of A9 hydrogenation experiments using different catalysts.SFWN.P0004WO Patent Application. docx - 8 -

[0054] FIGS 38A-38B. FIG. 38A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 38B. FIG. 38B is a table that includes results of A9 hydrogenation experiments using different catalysts.

[0055] FIGS 39A-39B. FIG. 39A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 39B. FIG. 39B is a table that includes results of hydrogenation of A8 or A9 phenoxy-protected substrates using different catalysts.

[0056] FIGS 40A-40B. FIG. 40 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 40B. FIG. 40B is a table that includes results of A8-OMe hydrogenation experiments using different catalysts.

[0057] FIGS 41A-41B. FIG. 41A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 41B. FIG. 41B is a table that includes results of A8-OMe hydrogenation experiments using different catalysts.

[0058] FIGS 42A-42B. FIG. 42 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 42B. FIG. 42B is a table that includes results of A8 hydrogenation experiments using different catalysts.

[0059] FIGS 43A-43B. FIG. 43 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 43B. FIG. 43B is a table that includes results of hydrogenation of A8 phenoxy-protected substrates using different catalysts.

[0060] FIGS 44A-44B. FIG. 44 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 44B. The reaction conditions illustrated provide the highest conversion and selectivity for R-HHC. FIG. 44B is a table that includes results of hydrogenation of A8 phenoxy-protected substrates using different catalysts.

[0061] FIGS 45A-45B. FIG. 45 A is a reaction scheme depicting general reaction conditions for the experiments included in FIG. 45B. The reaction conditions illustrated provide the highest conversion and selectivity for S-HHC. FIG. 45B is a table that includes results of hydrogenation of A8 phenoxy-protected substrates using different catalysts.DETAILED DESCRIPTION OF THE INVENTION

[0062] A standard hydrogenation technique for the transformation of THC to produce the biologically relevant Hexahydrocannabinol (HHC) involves the use of Pd / C with hydrogen gas bubbled in an ethanolic solution at standard pressure. Various changes to the catalyst type / loading, solvent, and additives, can provide diastereoselective results through hydrogen atom transfers (HAT), although without regard to green principles or scalability. HydrogenSFWN.P0004WO Patent Application. docx - 9 -transfer (HT) process, which include reagents like formic acid, sodium formate, ammonium formate, silanes, and quaternary ammonium halides can fall within the guidelines of a green hydrogenative additive and or reagent, depending on concentration and choice of solvent. The importance of performing hydrogenation under green principles is pertinent for reduction of waste and environmental impacts.Chemical Definitions

[0063] The terms delta-8 tetrahydrocannabinol, delta-8 THC, D8 THC, A8- tetrahydrocannabinol, and A8-THC are used interchangeably herein. The terms delta-9 tetrahydrocannabinol, delta-9 THC, D9 THC, A9-tetrahydrocannabinol, A9-THC, and THC are used interchangeably herein. The terms hexahydrocannabinol and HHC are used interchangeably herein.

[0064] The term “alkyl” includes straight-chain alkyl, branched-chain alkyl, cycloalkyl (alicyclic), heteroatom -unsubstituted alkyl, heteroatom-substituted alkyl, heteroatom- unsubstituted Cn-alkyl, and heteroatom-substituted Cn-alkyl. In certain embodiments, lower alkyls are contemplated. The term “lower alkyl” refers to alkyls of 1-6 carbon atoms (that is, 1, 2, 3, 4, 5 or 6 carbon atoms). The term “heteroatom -unsubstituted Cn-alkyl” refers to a radical, having a linear or branched, cyclic or acyclic structure, further having no carboncarbon double or triple bonds, further having a total of n carbon atoms, all of which are nonaromatic, 3 or more hydrogen atoms, and no heteroatoms. For example, a heteroatom- unsubstituted Ci-Cio-alkyl has 1 to 10 carbon atoms. The groups, — CH3 (Me), — CH2CH3 (Et), — CH2CH2CH3 (n-Pr), — CH(CH3)2(iso-Pr), — CH(CH2)2(cyclopropyl), — CH2CH2CH2CH3 (n-Bu), — CH(CH3)CH2CH3 (sec-butyl), — CH2CH(CH3)2 (iso-butyl), — C(CHs)3 (tent-butyl), — CH2C(CH3)3 (neo-pentyl), cyclobutyl, cyclopentyl, and cyclohexyl, are all non-limiting examples of heteroatom -unsubstituted alkyl groups. The term “heteroatom-substituted Cn- alkyl” refers to a radical, having a single saturated carbon atom as the point of attachment, no carbon-carbon double or triple bonds, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, all of which are nonaromatic, 0, 1, or more than one hydrogen atom, at least one heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom- substituted Ci-Cio-alkyl has 1 to 10 carbon atoms. The following groups are all non-limiting examples of heteroatom-substituted alkyl groups: trifluoromethyl, — CH2F, — CH2CI, — CH2Br, piperidinyl, — CH2OH, — CH2OCH3, — CH2OCH2CF3, — CH2OC(O)CH3, —SFWN.P0004WO Patent Application. docx - 10 -CH2NH2, — CH2NHCH3, — CH2N(CH3)2, — CH2CH2CI, — CH2CH2OH, CH2CH2OC(O)CH3, — CH2CH2NHCO2C(CH3)3, and — CH2Si(CH3)3.

[0065] The term “alkenyl” includes straight-chain alkenyl, branched-chain alkenyl, cycloalkenyl, cyclic alkenyl, heteroatom -unsubstituted alkenyl, heteroatom-substituted alkenyl, heteroatom -unsubstituted Cn-alkenyl, and heteroatom-substituted Cn-alkenyl. In certain embodiments, lower alkenyls are contemplated. The term “lower alkenyl” refers to alkenyls of 1-6 carbon atoms (that is, 1, 2, 3, 4, 5 or 6 carbon atoms). The term “heteroatom- unsubstituted Cn-alkenyl” refers to a radical, having a linear or branched, cyclic or acyclic structure, further having at least one nonaromatic carbon-carbon double bond, but no carboncarbon triple bonds, a total of n carbon atoms, three or more hydrogen atoms, and no heteroatoms. For example, a heteroatom-unsubstituted C2-Cio-alkenyl has 2 to 10 carbon atoms. Heteroatom -unsubstituted alkenyl groups include: — CH=CH2 (vinyl), — CH=CHCH3, — CH=CHCH2CH3, — CH2CH=CH2(allyl), — CH2CH=CHCH3, and — CH=CH— C6H5. The term “heteroatom-substituted Cn-alkenyl” refers to a radical, having a single nonaromatic carbon atom as the point of attachment and at least one nonaromatic carbon-carbon double bond, but no carbon-carbon triple bonds, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 0, 1, or more than one hydrogen atom, and at least one heteroatom, wherein each heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. For example, a heteroatom-substituted C2-C10- alkenyl has 2 to 10 carbon atoms. The groups, dihydrofuranyl, — CH=CHF, — CH=CHC1 and — CH=CHBr, are non-limiting examples of heteroatom-substituted alkenyl groups. In some embodiments, a continuous flow process as disclosed herein is employed to reduce an alkenyl group and provide the corresponding alkyl group.

[0066] 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, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture.

[0067] The term “protecting group” refers to chemical moieties that block some or all reactive moieties and prevent such groups from participating in chemical reactions until the protective group is removed. In some embodiments, a protecting group used in the context of the present invention is selected from the group consisting of methoxymethyl ether, tetrahydropyranyl ether, / -butyl ether, allyl ether, methyl ether, benzyl ether, / - butyldimethylsilyl ether, t-butyldiphenylsilyl ether, acetate ester, pivloyl ester, and benzoic acid ester. The protecting groups disclosed herein can be used to protect theSFWN.P0004WO Patent Application. docx - 11 -tetrahydrocannabinol phenolic hydroxyl group. In some embodiments, a protecting group can be employed to increase the enantioselectivity of an asymmetric hydrogenation reaction.

[0068] The claimed invention is also intended to encompass salts of any of the compounds of the present invention. The term “salt(s)” as used herein, is understood as being acidic and / or basic salts formed with inorganic and / or organic acids and bases. Zwitterions (internal or inner salts) are understood as being included within the term “salt(s)” as used herein, as are quaternary ammonium salts such as alkylammonium salts. Nontoxic, pharmaceutically acceptable salts are preferred, although other salts may be useful, as for example in isolation or purification steps during synthesis. Salts include, but are not limited to, sodium, lithium, potassium, amines, tartrates, citrates, hydrohalides, phosphates and the like. A salt may be a pharmaceutically acceptable salt, for example. Thus, pharmaceutically acceptable salts of compounds of the present invention are contemplated.

[0069] The term "pharmaceutically acceptable salts," as used herein, refers to salts of compounds of this invention that are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of a compound of this invention with an inorganic or organic acid, or an organic base, depending on the substituents present on the compounds of the invention.

[0070] Compounds employed in methods of the invention may contain one or more asymmetrically-substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present invention can have the S- or the R-configuration, as defined by the IUPAC 1974 Recommendations. Compounds may be of the D- or L-form, for example. It is well known in the art how to prepare and isolate such optically active forms. For example, mixtures of stereoisomers may be separated by standard techniques including, but not limited to, resolution of racemic form, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers.

[0071] In addition, atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and withoutSFWN.P0004WO Patent Application. docx - 12 -limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0072] Various catalysts useful for hydrogenation reactions are discussed by Blaser et. al., Supported palladium catalysts for fine chemicals synthesis in Journal of Molecular Catalysis A: Chemical, 2001, v. 172, p. 3-18, the entirety of which is incorporated by reference.

[0073] Abbreviations used: ee = enantiomeric excess; HS157 = Bis(l,5- cyclooctadiene)diiridium(I) dichloride; R-BINAP = (R)-(+)-2,2'-Bis(diphenylphosphino)- l,l'-binaphthalene; S-BINAP = (S)-(+)-2,2'-Bis(diphenylphosphino)-l,l '-binaphthalene; R- BINOL = (+)-2,2'-Dihydroxy-l,l'-dinaphthyl; S-BINOL = (-)-2, 2 '-Dihydroxy- 1,1 '- dinaphthyl; dEtpe = 1,2 di-(o-l-ethyltrizene-l-ethyltrazene-l-oxide-3 -phenoxy) ethane; idPrpe = 1,2-Bis(diisopropylphosphino)ethane; hped = N,N'-di(o-hydroxyphenyl)ethylenediamine- N,N'-diacetic acid; (+)-Ph-Bpe = (+)-l,2-Bis((2S,5S)-2,5-diphenylphospholano)ethane; (-)- Ph-Bpe = (-)-l,2-Bis((2R,5R)-2,5-diphenylphospholano)ethane; SPhos = 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl; XPhos = 2-Dicyclohexylphosphino-2',4',6'- triisopropylbiphenyl; RuPhos = 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; TPGS = tocopherol polyethylene glycol succinate; Eu(fod)s = EufOCCfCJEhCHCOCMTh; Pd G2 Sphos = [Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-l, 1 '-biphenyl)[2-(2'-amino-l, 1 biphenyl)]palladium (II)]; TPGS = 2,2,7-trimethyl-guanosine-5'-triphosphate-5'-guanosine; TFE - trifluoroethanol; HFIP = hexafluoroisopropanol; IP A = isopropanol; THF = tetrahydrofuran; DCM = dichloromethane; PhMe = toluene; EtOAc = ethyl acetate; EtsSiH = triethylsilane; AcOH = acetic acid.EXAMPLES

[0074] The following examples are included to demonstrate preferred embodiments of the invention. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the invention, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the invention.EXAMPLE 1 HYDROGENATION REACTION

[0075] A water microemulsion was prepared by mixing 100 mg of THC in 0.5 mL MeOH (0.06 M), adding the solubilized material into a 40 mL scintillation vial containing 3.5 mg ofSFWN.P0004WO Patent Application. docx - 13 -Pd(OH)2 (~10 mol%), and adding 6 mL of deionized (DI) H2O. MeOH (1 mL) was added to loosen catalyst and cannabinoid off the wall of the vial, resulting in an effective cannabinoid concentration of -0.04 M. A small PTFE coated stir bar (10 mm) was placed in the scintillation vial, the scintillation vial was fitted with septum, and the septum was taped to ensure no leakage. A double ballooned syringe equipped with a 5-inch spinal needle was filled with hydrogen gas and submerged into the solution to allow bubbling of hydrogen to occur. No heat or pressure was applied, and the reaction was carried out under ambient conditions.

[0076] The reaction mixture appeared milky white in color while stirring. Over time, the reaction color changed to dark gray, indicating reaction progression. Small aliquots (0.1 mL) were taken throughout a 24 hr time period and transferred to sample scintillation vials. Samples were extracted with small amounts of toluene to ensure maximum extraction of cannabinoids from water emulsion. The reaction was monitored at T=0 hr and T=8 hrs using UV-VIS as shown in FIGS. 3A and 3B, respectively.

[0077] UV-Vis can be used to observe Pd2+ions in solution, and their absorbance can change according to absorption of hydrogen and their redox state. UV-Vis was conducted at T=0 (unreacted THC), and a broad absorbance was visible at 270 nm (Fig. 3A). At the 8 hr time point of the reaction, absorbance changes and the 270 nm starting point peak shifts by about 4 nm to 266 nm (FIG. 3B). The 8 hr time point peak is broader and indicates the presence of activated palladium. Because the cannabinoid forms an emulsion and the Pd(OH)2 / C catalyst is a fine powder, the formation of pseudo-micelles can be observed.EXAMPLE 2 GENERAL HYDROGENATION UNDER PICKERING CONDITIONS

[0078] To a 10 mL scintillation vial was added D8-THC (100 mg, 0.318 mmol, 1 equiv.) and methanol (2 mL), followed by addition of catalyst (10 mol %) and co-catalyst (0.1 mol %). Water (2 mL) was added, followed by addition of hydrogen (1 bar), and the reaction was stirred at 25 °C for 16 hr. Upon completion, the reaction mixture was filtered using a 22-micron filter, then sampled on HPLC. HPLC: (S)-HHC: 7.086 min (R)-HHC: 7.257 min.EXAMPLE 3 EXAMINATION OF HYDROGENATION REACTION CONDITIONS

[0079] To a 10 mL scintillation vial, D8-THC (100 mg, 0.318 mmol, 1 equiv.) was added and dissolved in methanol (2 mL) followed by addition of catalyst (10 mol %). Several catalysts were screened (FIG. 4A), and the catalysts that performed best were selected to be pushed forward for subsequent reactions. An atmosphere of hydrogen (1 bar) was added, and theSFWN.P0004WO Patent Application. docx - 14 -reaction was stirred at 25 °C for up to 16 hr. Upon completion, the reaction mixture was filtered using a 22-micron filter and sampled on HPLC. HPLC: (S)-HHC: 7.086 min (R)-HHC: 7.257 min.EXAMPLE 4 EXAMINATION OF HYDROGENATION UNDER PICKERING CONDITIONS

[0080] Hydrogenation of THC to HHC catalyzed by a microemulsion of Pd(OH)2 / C formed micelle was initially performed in a 10: 1 H2O / MeOH mixture at room temperature (20 °C). Several catalysts were screened (FIG. 4B), and the catalysts that performed best were selected to be pushed forward for subsequent aqueous solvent reactions. Pd(OH)2 and Pd(OAc)2 performed best in initial screenings.EXAMPLE 5 EXAMINATION OF CATALYSTS, CO-CATALYSTS, ADDITIVES, SOLVENTS, REACTION TIMES, AND TEMPERATURES

[0081] A general screening of traditional hydrogenation catalysts under standard conditions was performed to observe changes in selectivity and reaction times, and provide a benchmark of the HHC output (FIG. 3). Hydrogen gas and ammonium formate were employed as sources of hydrogen. Unless indicated otherwise, hydrogen gas (1 atm) was used as a hydrogen source.

[0082] Hydrogenation of A8-THC was carried out using various transition metal catalysts, and Pd(OH)2 / C and Pd(OAc)2 provided the highest stereoselectivities (FIG. 6). Hydrogenation of A8-THC was then carried out using different combinations of co-catalyst / ligand and catalyst combinations. Of these, Pd(OAc)2 in combination with SPhos or Eu(OAc)s provided the highest conversions (FIG. 7). Based on these results, hydrogenation of A8-THC using was examined using various chiral auxiliaries in combination with a Pd(OAc)2 / Eu(OAc)3 catalyst system (FIG. 8). Pinacol provided the highest conversion (>98%), however, selectivity was low. A similar experiment using Pd(OAc) in combination with (+)-dEtpe provided complete conversion, however, selectivity was low. Hydrogenation was then examined using a combination of Pd(OAc)2 with chiral Europium auxiliaries, and the chiral auxiliary Eu(fod)s provided the highest (S) / (R) selectivity (FIG. 8).

[0083] The Pd(OAc)2 / Eu(OAc)3 catalyst system was then examined in different solvents (FIG. 9). Hydrogenation in methanol provided complete conversion, albeit with low selectivity. Conversions of >99% were observed when using trifluoroethanol or HFIP as solvents, and trifluoroethanol yielded an (R):(S) ratio of almost 2: 1.SFWN.P0004WO Patent Application. docx - 15 -

[0084] HS157 was examined alone and in combination with different co-catalysts and chiral auxiliaries (FIG. 12). HS157 provided a 70:30 ratio of (S)-HHC to (R)-HHC with complete conversion.

[0085] Subsequent experiments focused on hydrogenation of A8-THC substrates where the phenolic hydroxyl group was protected using different ethers and esters. Hydrogenation of the methyl ether using the Pd(OAc)2 / Eu(OAc)3 catalyst system led to a 65% conversion with a (S):(R) ratio of greater than 2:1 (FIG. 10). Hydrogenation of the methyl ether using Pd(OAc)2 alone resulted in 90% conversion with an (S):(R) ratio of greater than 2.5: 1. The methyl ether was then hydrogenated using an HS157 catalyst. As seen in the table in FIG. 13, there was a correlation between degree of conversion and reaction time using the HS157 catalyst. The HS157 catalyst also provided high (R):(S) ratios ranging from 3.5: 1 to 4.7: 1. The HS157 catalyst was then examined on different protected ethers and esters. As seen in the table in FIG. 14, hydrogenation the methyl ether let to a 3.8: 1 (R):(S) ratio, with a conversion of greater than 99%. The acetate ester gave an (S):(R) ratio of 4.2: 1, albeit with a lower conversion (83%). The HS157 catalyst and the Pd(OAc)2 / Eu(OAc)3 catalyst system were then compared using either A8-THC or the methyl ether as a substrate in the presence of H2 (FIG. 15). The methyl ether substrate resulted in higher conversions (>98%) using both catalysts, and higher selectivity was observed using the HS157 catalyst.

[0086] Pickering catalysis is a technique that employs microemulsions of solid supported catalysts in a biphasic system to hydrogenate or conduct synthesis in a greener manner in the absence of harsh organic solvents. Bi-component solvent systems, including but not limited to water / methanol, water / isopropanol, water / ethanol, can lead to the formation of micelles due to solvent incompatibilities and liophphilicity of THC. Hydrogenation of A8-THC was then examined using water and / or methanol, or other organic solvents, with either Pd(OAc)2, Pd(OH)2, or HS157 in combination with different additives (FIG. 16). Complete conversion was observed using Pd(OH)2 / C with either MeOH or IPA as a co-solvent. Using a combination of HS157 and Eu(OAc)3 catalysts provided a 60:40 ratio of (R)-HHC to (S)-HHC. Replacing water with IPA and propylene glycol yielded a 36:63 ratio of (R)-HHC to (S)-HHC. Using a combination of Pd(OH)2 and Eu(OAc)3 catalysts in methanol / water on a methyl ether substrate resulted in 2.5: 1 (S):(R) selectivity, along with approximately 46% of an unknown product (FIG. 17). Pd(OH)2 / C was then examined in combination with Europium chiral auxiliaries (FIG. 18). When Eu(fod)3 was employed as a chiral auxiliary with ammonium formate as an additive, a 3: 1 (R):(S) ratio was obtained.SFWN.P0004WO Patent Application. docx - 16 -

[0087] Subsequent experiments were performed in the presence of hydrogen gas at high pressures. Palladium and platinum catalysts were employed in the presence of hydrogen gas (400 psi) in methanol (FIG. 19). Pd / C and Pd-AhCh provided complete conversion, however, selectivities were low. Experiments were then performed using the same conditions with 10 mol% of EU(OAC)3 included as an additive (FIG. 20). Both conversion and selectivities were comparable to the results obtained without the Eu(OAc)s additive. Iridium catalysts were then examined using acetic acid as an additive at different temperatures and in different solvents (FIG. 21). When used in combination with 500 psi of EE gas, iridium catalysts provided quantitative conversion and good selectivities (~3:1). Similar experiments using rhodium catalysts also provided quantitative conversion with lower selectivities (FIG. 22). Iridium and rhodium catalysts were then examined using a pivaloyl THC ester substrate (FIG. 23). Quantitative conversion was achieved with significantly higher selectivities (~6:1 to 10: 1). Similar experiments were then performed using iridium and rhodium catalysts with an -OTB S THC ether substrate (FIG. 24). Both quantitative conversion and high selectivities (about 9: 1) were achieved under these conditions. When iridium and rhodium catalysts were used on an - OAc THC ester substrate, conversion remained quantitative and selectivities were good (~3:1 to 5:1), however, deprotection of the -OAc ester group was observed (FIG. 25). Rhodium catalysts were then examined with various ligands and lower hydrogen pressure (300 psi), however, conversion was low (FIG. 26). Similar results were observed when using various asymmetric ligands in combination with HS157 (FIG. 27) and other iridium catalysts (FIG. 28). When the iridium catalyst (S,S)-[COD]Ir[cy2PThrePHOX was employed on a pivaloyl THC ester substrate, an (S):(R) ratio of >99.9 was achieved. Additional experiments using iridium and rhodium catalysts on a pivaloyl THC ester led to no or low conversion (FIG. 29), albeit at very high ee using 5 mol% of the catalyst (S,S)-[COD]Ir[cy2PThrePHOX. Further studies using this type of catalyst on D8 gave mixed conversion results and high enantiomeric excess (FIGS. 30 and 31), where selectivity for the (S) or (R) product was based on the selected stereochemistry of the catalyst. The [COD]Ir[cy2PThrePHOX catalysts gave mixed results using D9 as a substrate, and the [COD]Ir[cy2PThrePHOX] catalysts led to high conversion rates (FIG. 32). When using D8-THC-OMe as a substrate, high selectivity was observed using the [COD]Ir[cy2PThrePHOX and [COD]Ir[cy2PThrePHOX] catalysts (FIG. 33). When using D8-THC-OTBS as a substrate, complete conversion to the deprotected product and very high selectivity was observed using the [COD]Ir[cy2PThrePHOX and [COD]Ir[cy2PThrePHOX] catalysts (FIG. 34). Complete conversion was also observed with D8 or D9 substrates when using [IrCODCl]2 and Rh(nbd)2BF4 catalysts, in the presence or absence of the additive aceticSFWN.P0004WO Patent Application. docx - 17 -acid (FIG. 35). Pd(OH)2 provided complete conversion and high selectivity when using TBS- protected D8 and D9 and unprotected D9 (FIG. 39). HS157 was employed at different reaction durations and a 10 mol% concentration, and essentially complete conversion was achieved when using reaction times of 6 hours or longer on a D8-THC-OMe substrate (FIG. 40). The same catalyst at 2.5 mol% resulted in complete conversion of the methyl ether substrate when using trifluoroethanol as a solvent (FIG. 41). The Fe(acac)3 was examined using different additives and mid to high conversion rates were observed with high enantiomeric excess. The same catalyst was employed using different phenoxy-protected D8 substrates and complete conversion with high enantiomeric excess was observed for every substrate.EXAMPLE 6 SYNTHESIS OF D8-THC-AC

[0088] To a flask containing D8-THC (2.5 g, 3.50 mmol, 1.0 equiv) and DCM (25 mL) was added triethylamine (0.33 mL, 7 mmol, 2.0 eq) at 25 °C followed by DMAP and acetic anhydride (1.15 mL, 5.25 mmol, 1.5 eq). The reaction mixture was stirred at rt for 12 hours. Upon completion, the reaction mixture was quenched with water and the aqueous phase was extracted with CH2CI2 (10 mL><3). The combined organic phase was dried with Na2SO4, concentrated under pressure and purified by column chromatography on SiCh (10% ethyl acetate / hexanes) to obtain the product as oil (2.3 g, 83% yield).1H NMR (400 MHz, CDCI3) 5 6.56 (d, J= 1.7 Hz, 1H), 6.41 (d, J= 1.7 Hz, 1H), 5.46 - 5.41 (m, 1H), 2.74 (dd, J= 17.0, 4.5 Hz, 1H), 2.65 - 2.57 (m, 1H), 2.51 (dd, J= 8.7, 6.6 Hz, 2H), 2.28 (s, 3H), 2.18 - 2.10 (m, 1H), 1.97 - 1.86 (m, 1H), 1.83 - 1.75 (m, 2H), 1.70 (s, 3H), 1.63 - 1.56 (m, 2H), 1.38 (s, 3H), 1.35 - 1.28 (m, 4H), 1.10 (s, 3H), 0.89 (dd, J= 8.9, 5.2 Hz, 3H).EXAMPLE 7 GENERAL PROCEDURE FOR THE SYNTHESIS OF HHC

[0089] To a stirring solution of Fe(acac)3 (396 mg, 1.12 mmol, 40 mol%) and thiophenol (118 pL, 1.12 mmol, 40 mol%), in n-propanol (0.5 M) at room temperature, under N2 was added a solution of D8-THC-Ac (1.0 g, 2.80 mmol) in EtOH (2.8 mL) followed by phenylsilane (697 pL, 5.62 mmol, 2 eq). The mixture was purged with N2 for 10 min and stirred for 17 h at 23 °C. Upon completion of the reaction (monitored by HPLC), the mixture was quenched with a solution of IM NaOH (aq) and extracted with CH2CI2 (10 mU3). The combined organics were filtered through a plug of celite, dried over Na2SO4, concentrated and the resulting crude was purified by chromatography on SiCh (5% Ethyl Acetate / Hexane) to obtain the product as orange oil (80% yield, 13.3: 1 dr favoring R-HHC-Ac).SFWN.P0004WO Patent Application. docx - 18 -EXAMPLE 8 ACETATE DEPROTECTION

[0090] Dissolve the HHC-Ac (500 mg) in 5 ml of methanol and add potassium hydroxide (112 mg, 42.52 mmol, 4.0 eq) and water (5 ml). Heat the reaction mixture for 8 h at 80 °C. Upon completion, remove the solvent under reduced pressure and add 10 ml of water. Acidify the solution using 1 M HC1 until the pH reach approximately 3.0 and extract with CH2CI2 (3x 10 ml). Organic phases were combined and washed with brine, dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain HHC favoring R-isomer in 93:7 ratio.EXAMPLE 9 SYNTHESIS OF D8-THC-TBS

[0091] To a flask containing D8-THC (1.1 g, 3.50 mmol, 1.0 equiv) and CH2CI2 (10 mL) was added 2,6-lutidine (0.33 mL, 7 mmol, 2.0 eq) at O °C followed by TBSOTf (1.15 mL, 5.25 mmol, 1,5 eq). The reaction mixture was stirred at rt for 12 h. Upon completion, the reaction mixture was quenched with water and the aqueous phase was extracted with CH2CI2 (10 mL x 3). The combined organic phase was dried with Na2SO4, concentrated under pressure and purified by column chromatography on SiCh (5% ethyl acetate / hexane) to obtain the product as oil (1.40 g, 93% yield). 'HNMR (400 MHz, CDCh) 56.30 (s, 1H), 6.20 (d, J= 0.6 Hz, 1H), 5.41 (d, J= 3.5 Hz, 1H), 3.24 (dd, J= 17.0, 3.4 Hz, 1H), 2.58 (td, J= 10.8, 4.3 Hz, 1H), 2.45 (td, = 7.3, 2.4 Hz, 2H), 2.13 (d, J = 3.5 Hz, 1H), 1.79 (dd, J= 13.1, 6.1 Hz, 3H), 1.69 (s, 3H), 1.62 - 1.52 (m, 3H), 1.39 - 1.26 (m, 8H), 1.08 (s, 3H), 0.99 (d, J= 10.6 Hz, 9H), 0.92 - 0.84 (m, 6H), 0.26 (s, 3H), 0.14 (s, 3H).

[0092] To solution of D8-THC-TBS (30 mg, 96.5 mmol) in MeOH (0.1M) was added (R,R)-[COD]Ir[Ph2PThrePHOX] (8.21 mg, 4.7 mmol, 5 mol%) or (R,R)- [COD]Ir[cy2PThrePHOX] (8.27 mg, 4.7 mmol, 5 mol%) was added inside the glove box. The reactor was sparged with nitrogen three times and then sparged with hydrogen three times. Then the reaction was stirred under hydrogen at 500 psi for 16 h at 23 °C. After completion, the reaction mixture was concentrated under reduced pressure and purified via chromatography on SiCh (5% Ethyl Acetate / Hexane) to obtain the product as an oil (90% yield, 32.3:1 dr favoring S-HHC-TBS).EXAMPLE 10 TBS DEPROTECTION

[0093] HHC-TBS (500 mg, 1.16 mmol) was dissolved in THF (5 mL) and TBAF (1.01 mL, 3.48 mmol, 3 eq) was added at 0 °C. The reaction was stirred for 2 h (0 °C-rt). UponSFWN.P0004WO Patent Application. docx - 19 -completion of the reaction, THF was evaporated under reduced pressure and the residue was dissolved in CH2CI2, washed with H2O. The organic phase was washed with brine, dried over Na2SO4 and passed through a plug of SiCh to obtain the product as an oil (92% yield, 32.3 : 1 dr favoring S-HHC)

[0094] Through the use of Pickering conditions, the low solubility of hydrogen in water (1.6 mg / L) was identified as a restriction on total conversion. Using a proton transfer reagent, such as ammonium formate, helped increase available hydrogen within the reaction mixture. The addition of minimal amounts of methanol also helped create a hyper-saturated biphasic system that increased the amount of available hydrogen. Solid supported catalyst require additional synthetic and purification steps, and the formation of surfactant-induced micelles in- situ is possibly cleaner and faster, especially in a system with extreme lipophilic compound creating micelles within a biphasic solvent system. The modified Pickering reaction conditions employed herein can be used to improve hydrogenation rates of lipophilic cannabinoid compounds. The modified Pickering reaction conditions employed herein provide a diastereomeric ratio of >13: 1 by employing different phenolic oxygen protecting groups, like acetyl and pivaloyl.* * *

[0095] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.SFWN.P0004WO Patent Application. docx - 20 -

Claims

WHAT IS CLAIMED IS:

1. A method for the asymmetric hydrogenation of a tetrahydrocannabinol compound, comprising subjecting the tetrahydrocannabinol compound to hydrogenation in the presence of a hydrogenation catalyst to obtain a hexahydrocannabinol compound.

2. The method of claim 1, wherein the hydrogenation is performed in a solvent.

3. The method of claim 1, wherein the tetrahydrocannabinol compound is selected from the group consisting of A8-THC, A9-THC, and A10-THC.

4. The method of claim 1, wherein the hydrogenation is performed in the presence of a hydrogen source.

5. The method of claim 4, wherein the hydrogen source is hydrogen gas or an in-situ hydrogen source.

6. The method of claim 5, wherein the hydrogen gas is provided in an amount that affords an intra-vessel gas pressure ranging from 20 psi to 500 psi.

7. The method of claim 5, wherein the in-situ hydrogen source comprises ammonium formate and formic acid.

8. The method of claim 7, wherein an amount of ammonium formate ranges from 1 to 40 molar equivalents.

9. The method of claim 6, wherein an amount of formic acid ranges from 1 to 40 molar equivalents.

10. The method of claim 1 , wherein the catalyst is provided in an amount ranging from 0.01 to 10 molar equivalents.

11. The method of claim 10, wherein the catalyst comprises a metal selected from the group consisting of palladium, rhodium, nickel, aluminum, platinum, and iridium.

12. The method of claim 11, wherein the catalyst is selected from the group consisting of Pd(dppf)2, Pd G2 Sphos, Pd(OH)2 / C Pd(dba)3, PD(dba)2, Pd(PPh3)4, Pd(OAc)2, Pd / C, Pt / C, Wilkinson's catalyst, Crabtree's catalyst, RUC13, (S,S)-[COD]Ir[cy2PThrePHOX, (R,R)- [COD]Ir[cy2PThrePHOX, HS157, (R,R)-[COD]Ir[Ph2PThrePHOX], (S,S)-SFWN.P0004WO Patent Application. docx - 21 -[COD]Ir[Ph2PThrePHOX], (5)-2-[2-[Bis(2-tolyl)phosphino]phenyl]-4-tert-butyl-2-oxazoline, (A)-2-[2-[Bis(2-tolyl)phosphino]phenyl]-4-tert-butyl-2-oxazoline, (1,5-Cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexafluorophosphate, Europium tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorate], europium tris[3 - (trifluoromethylhydroxymethylene)-(+)-camphorate], palladium(II) trifluoroacetate, (1,5- cyclooctadiene)(pyridine)(tricyclohexylphosphine)-iridium(I) hexafluorophosphate, and europium acetate.

13. The method of claim 1, wherein the hydrogenation is performed in the presence of a co-catalyst.

14. The method of claim 13, wherein the co-catalyst is selected from the group consisting of EU(0AC)3, Yb(OTf)3, In(OTf)3, TFA, Eu(fod)3, Eu(fcam)3, Eu(hfc)3, and any combination thereof.

15. The method of claim 1, wherein the hydrogenation is performed in the presence of an additive.

16. The method of claim 15, wherein the additive is selected from the group consisting of EtsN, Hunig’s base, ammonium formate, TPGS, citric acid, propylene gylcol, HCOOH, HCOONa, sodium ascorbate, ascorbic acid, borane-dimethylsulfide, 9- borabicyclo[3.

3. l]nonane, BH3-DMSO, BH3-THF, N-methylimidodiacetic (MID A) boronates, TPGS, Kolliphor REEK), (A' -cv.s-verbenol, beta-cyclodextrin, and any combination thereof.

17. The method of claim 1, wherein the hydrogenation is performed in the presence of a chiral auxiliary or ligand.

18. The method of claim 17, wherein the chiral auxiliary or ligand is selected from the group consisting of (R)-alpine borane, (S)-alpine borane, (+)-limonene oxide, (-)-limonene oxide, (S)-cis-verbenol, (R)-cis-verbenol, SPhos, RuPhos, XantPhos, (+)- diethylphosphinoethane, (+)-diethylphosphinoethane, (-)-diisopropylphosphinoethane, (-)- diisopropylphosphinoethane, (+)-diphenylethylenediamine, (-)-diphenylethylenediamine, (+)- l,2-Bis((2S,5S)-2,5-diphenylphospholano)ethane, (-)-l,2-Bis((2R,5R)-2,5- diphenylphospholano) ethane, (R)-BINAP, (S)-BINAP, (R)-BINOL, (S)-BINOL, (-)-tartaric acid, (+)-tartaric acid, (R)-4-(tert-butyl)-2-(2-(diphenylphosphino)phenyl)-4,5-SFWN.P0004WO Patent Application. docx - 22 -dihydrooxazole, (S)-4-(tert-Butyl)-2-(2-(diphenylphosphino)phenyl)-4,5-dihydrooxazole, a PHOX ligand, a D-amino acid, an L-amino acid, and any combination thereof.

19. The method of claim 1, wherein the hydrogenation comprises heating reaction components to a temperature ranging from 25 °C to 100 °C.

20. The method of claim 1, wherein the tetrahydrocannabinol compound comprises a phenolic oxygen protecting group.

21. The method of claim 20, wherein the protecting group is selected from the group consisting of methoxymethyl ether, tetrahydropyranyl ether, / -butyl ether, allyl ether, methyl ether, benzyl ether, / -butyldimethylsilyl ether, t-butyldiphenylsilyl ether, acetate ester, pivloyl ester, and benzoic acid ester.

22. The method of claim 1, wherein the hexahydrocannabinol compound is produced in an enantiomeric excess of greater than 80%.

23. The method of claim 1, wherein the hexahydrocannabinol compound is produced in an enantiomeric excess of greater than 90%.

24. The method of claim 1, wherein the hexahydrocannabinol compound is produced in an enantiomeric excess of greater than 95%.

25. The method of claim 1, wherein the hydrogenation is carried out in a solvent.

26. The method of claim 25, wherein the solvent is selected from the group consisting of DMSO, MeOH, EtOH, TFE, IP A, HFIP, PhMe, DCM, THF, EtOAc, EtsSiH, water, propylene glycol, ethylene glycol, and any combination thereof.SFWN.P0004WO Patent Application. docx - 23 -

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