Methods for the synthesis of cannabidiol, its derivatives, and other phytocannabinoids

Abstract

Provided herein are synthetic methods for preparing cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), and their derivatives, in racemic mixtures or enantiopure form. Also provided herein are synthetic methods for preparing relevant intermediates in the process.

Description

[Technical field]

[0001] [Related Applications] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 303,614, filed January 27, 2022, which is incorporated by reference in its entirety. [Background technology]

[0002] Over 100 compounds, commonly known as cannabinoids (Hanus, LO et al. 2016), have been found in the Cannabis sativa plant. Among these natural products are cannabidiol (CBD) and delta-9-tetrahydrocannabinol (ΔHTC). 9 -THC). In the United States, the cannabidiol drug Epidiolex® was approved by the Food and Drug Administration in 2018 for the treatment of two rare epilepsy disorders, and the compound is being extensively studied for other illnesses. Dronabinol, the generic name for delta-9-tetrahydrocannabinol, has broad medical utility as an antiemetic (appetite stimulant) and sleep apnea reliever. It has also been approved by the FDA for clinical use in the treatment of HIV / AIDS-induced anorexia, chemotherapy-induced nausea, and glaucoma. Many other cannabinoids are being investigated for various indications, including cannabidivarin for the treatment of epilepsy and tetrahydrocannabidivarin for the treatment of diabetes.

[0003] Many different routes have been reported for producing natural cannabinoids and related compounds (Mechoulam, R., McCallum, N. K., and Burstein, S. 1976; Aguillon, A. R. et al. 2021). The production of CBD on a commercial scale presents many challenges, especially with regard to direct and convergent syntheses that rely on Friedel-Crafts alkylation of olivetol (1,3-dihydroxy-5-pentylbenzene) to construct the central aryl-monoterpenyl C-C bond. In this reaction, it may be impossible to prevent the phenolic hydroxyl group from further cyclizing to the dihydropyran ring of Δ9-THC, as strong Lewis or Brönsted acidic reagents are required to promote terpenylation. Additional isomers such as cis-Δ9-THC (dihydropyran stereoisomer), Δ8-THC (derived from rearrangement of the cyclohexene double bond), and iso-THC (positional isomer resulting from F-C alkylation ortho to the n-pentyl group) forms are time-consuming to separate from the desired product. This adds time and cost to many reported syntheses (Petrzilka, T. et al. 1967; Baek, SH., Srebnik, M., and Mechoulam, R. 1985) and makes it difficult to achieve current purity standards for the active pharmaceutical ingredient. Extraction and purification of natural CBD is economically unattractive and has agricultural constraints. For example, even industrial strains of cannabis specifically bred to contain low amounts of psychotropic Δ9-THC can be found to exceed the legal limit of ≦0.3 dry mass% due to variations in growing or harvesting conditions. Alternative synthetic routes are known that can limit contamination with THC, but they are longer because they rely on protected olivetol intermediates (Aguillon, AR et al. 2021).

[0004] Given fast equipment in which delta-9-tetrahydrocannabinol (Δ9-THC) can undergo acid-catalyzed isomerization, the most efficient chemical syntheses disclosed tend to be based on selective crystallization and isolation of a single Friedel-Crafts product, often resulting in yields of 35–45% or less. Souza et al. (2008) report a Δ9-THC synthesis featuring a late-stage dihydropyran cyclization using mild zinc(II) chloride-promoted conditions (49% yield). The use of cis-menth-1-ene-3,8-diol as the terpene fragment to effectively mask the isopropenyl substituent found in CBD as a tertiary alcohol enables this strategy. By carrying the dihydropyran ring in latent form throughout the synthesis, the authors achieved a 39% yield in the Friedel-Crafts alkylation of olivetol using camphorsulfonic acid (CSA) as a promoter. However, drawbacks exist throughout this route. 10C cis-menth-1-ene-3,8-diol requires six linear steps to prepare from the propargylic alcohol, and resolution is necessary to obtain the optically active material. In an alternative route, Burdick et al. (2012) were also able to develop separate reagents for Friedel-Crafts terpenylation and dihydropyran cyclization. The use of scandium(III) triflate for the condensation of olivetol (and olivetolate esters) with (+)-menthadienol, a more commonly used terpene component, affords crude ethyl cannibidiolate, which undergoes both hydrolysis and decarboxylation upon reflux to yield 44% solid CBD. The second innovation features triisobutylaluminum as a reagent for the selective cyclization of CBD to a mixture of 95.6% Δ9-THC and 1.1% cis-Δ9-THC. However, as previously reported, access to the monoterpene (+)-menthadienol requires a multistep synthesis, typically three to five operations, from (+)-limonene oxide or (R)-limonene itself. Summary of the Invention

[0005] In certain embodiments, the present disclosure provides a process for producing a compound having a structure of formula (±)-(I):

[0006] [ka]

[0007] During the ceremony, R1 is alkyl; The process comprises: (i) reacting citral with a Lewis acid in a suitable solvent under conditions sufficient to produce a compound having the structure of formula (±)-(IIa):

[0008] [ka]

[0009] In certain embodiments, the present disclosure also provides a process for producing a compound having a structure of formula (±)-(Ia):

[0010] [ka]

[0011] During the ceremony, R1 is alkyl; The process comprises: (i) reacting citral with a Lewis acid in a suitable solvent under conditions sufficient to produce a compound having the structure of formula (±)-(IIa):

[0012] [ka]

[0013] In certain embodiments, the disclosure further provides a process for producing a compound having a structure of formula (±)-(IIa):

[0014] [ka]

[0015] The process involves reacting citral with a Lewis acid in a suitable solvent under conditions sufficient to produce the compound.

[0016] In certain embodiments, the disclosure further provides a process for producing a compound having a structure of formula (-)-(I):

[0017] [ka]

[0018] During the ceremony, R1 is alkyl; The process comprises: (i) reacting (R)-limonene with an oxidizing agent in a first suitable solvent under conditions sufficient to produce a compound having a structure of Formula (+)-(IIa);

[0019] [ka]

[0020] (ii) reacting the compound having the structure of Formula (IIa) produced in step (i) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having the structure of Formula (+)-(II') as a single enantiomer or (+)-(II'') as a single enantiomer.

[0021] [ka]

[0022] In certain embodiments, the disclosure further provides a process for producing a compound having a structure of formula (-)-(Ia):

[0023] [ka]

[0024] During the ceremony, R1 is alkyl; The process comprises: (i) reacting (R)-limonene with an oxidizing agent in a first suitable solvent under conditions sufficient to produce a compound having a structure of Formula (+)-(IIa);

[0025] [ka]

[0026] (ii) reacting the compound having the structure of Formula (+)-(IIa) produced in step (i) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having the structure of Formula (+)-(II') as a single enantiomer or Formula (+)-(II'') as a single enantiomer.

[0027] [ka]

[0028] In certain embodiments, the disclosure further provides a process for producing a compound having a structure of formula (+)-(II') or (+)-(II''):

[0029] [ka]

[0030] The process comprises: (i) reacting (R)-limonene with an oxidizing agent in a first suitable solvent under conditions sufficient to produce a compound having a structure of Formula (+)-(IIa);

[0031] [ka]

[0032] (ii) reacting the compound having the structure of Formula (+)-(IIa) produced in step (i) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having the structure of Formula (+)-(II') as a single enantiomer or Formula (+)-(II'') as a single enantiomer.

[0033] In certain embodiments, the disclosure further provides a process for producing a compound having a structure of formula (III):

[0034] [ka]

[0035] During the ceremony, R1 is alkyl; R4 is alkyl; The process comprises: (i) under conditions sufficient to produce a compound having a structure of formula (VIIa);

[0036] [ka]

[0037] The method includes reacting a compound having the structure of Formula (VII) with Br2 in a first suitable solvent.

[0038] [ka]

[0039] In certain embodiments, the disclosure further provides a process for producing a compound having a structure of formula (III):

[0040] [ka]

[0041] During the ceremony, R1 is alkyl; R4 is alkyl; The process comprises: (b) in the presence of a Lewis acid, in a suitable solvent, under conditions sufficient to form a cyclized compound having a structure of formula (III),

[0042] [ka]

[0043] During the ceremony, and X1 is a halide or an activated ester moiety, the compound having the structure of formula (VIc):

[0044] [ka]

[0045] During the ceremony, PG1 and PG2 are each independently a hydroxyl protecting group; R4 is alkyl, which involves reacting with a diene.

[0046] In certain embodiments, the present disclosure further provides a process for producing a compound having a structure of formula (VIII):

[0047] [ka]

[0048] During the ceremony, R1 is alkyl; R4 is alkyl; The process comprises: (i) under conditions sufficient to produce a compound having a structure of formula (VIIIa);

[0049] [ka]

[0050] In a first suitable solvent, in the presence of an acid, a compound having the structure of formula (III)

[0051] [ka]

[0052] with geraniol. [Brief description of the drawings]

[0053] [Figure 1] A common synthetic route to cannabidiol (CBD). [Diagram 2] A general synthetic route to delta-9-tetrahydrocannabinol (Δ9-THC). [Diagram 3] An example of a synthetic pathway to cannabigerolic acid (CBGA). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0054] The present invention aims to overcome the inefficiencies in the preparation of phytocannabinoids. Specifically, methods are disclosed for the preparation of CBD from cannabidiolic acid (CBDA) as the penultimate precursor in a manner that is stereochemically and regiochemically controlled and thus mirrors the way in which the metabolite is biosynthesized in nature. In some embodiments, the synthetic route of the present invention provides stereoenriched monoterpenoids for Friedel-Crafts alkylation in just one or two steps from achiral and highly abundant starting materials. The present invention provides methods for the preparation of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (ΔCBD) in, for example, racemic or enantiopure form. 9Improved synthetic routes to cis-THC are disclosed. Starting from readily available and inexpensive starting materials such as citral and limonene, the routes are scalable and cost-effective. Synthetic routes to key intermediates such as trans-isopiperitenol and methyl olivetolate are also disclosed.

[0055] [process] In certain embodiments, the present invention relates to a process for producing a compound having a structure of formula (±)-(I):

[0056] [ka]

[0057] During the ceremony, R1 is alkyl; The process comprises: (i) reacting citral with a Lewis acid in a suitable solvent under conditions sufficient to produce a compound having the structure of formula (±)-(II'):

[0058] [ka]

[0059] In certain embodiments, the present invention relates to a process for producing a compound having a structure of formula (±)-(I):

[0060] [ka]

[0061] During the ceremony, R1 is alkyl; The process comprises: (i) reacting citral with a Lewis acid in a suitable solvent under conditions sufficient to produce a compound having the structure of formula (±)-(II″).

[0062] [ka]

[0063] In certain embodiments, the present invention relates to a process for producing a compound having a structure of formula (±)-(I):

[0064] [ka]

[0065] During the ceremony, R1 is alkyl; The process comprises: (i) reacting citral with a Lewis acid in a suitable solvent under conditions sufficient to produce a compound having the structure of formula (±)-(IIa):

[0066] [ka]

[0067] In certain embodiments, the citral is a mixture of citral A and citral B. In other embodiments, the citral is citral B.

[0068] In certain embodiments, the Lewis acid comprises an aluminum metal center.

[0069] In certain embodiments, the Lewis acid comprises an aluminum(III) salt.

[0070] In certain embodiments, the Lewis acid is a dialkylaluminum chloride.

[0071] In certain embodiments, the Lewis acid is dimethylaluminum chloride. In other embodiments, the Lewis acid is diethylaluminum chloride.

[0072] In certain embodiments, a solution of citral in a suitable solvent and a solution of Lewis acid in a suitable solvent are slowly mixed for 2-4 hours.

[0073] In certain embodiments, the mixing is performed at a temperature below 0°C.

[0074] In certain embodiments, the mixing is performed at a temperature of about -10° C. In other embodiments, the mixing is performed at a temperature of about -20 to 0° C.

[0075] In certain embodiments, the suitable solvent is dichloromethane, hi some embodiments, the suitable solvent is chloroform.

[0076] In certain embodiments, the process comprises: (ia) reacting the compound having the structure of Formula (±)-(IIa) produced in step (i) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having the structure of Formula (+)-(II″).

[0077] [ka]

[0078] In certain embodiments, the reducing agent comprises lithium metal.

[0079] In certain embodiments, the reducing agent is lithium aluminum hydride.

[0080] In certain embodiments, the second suitable solvent is tetrahydrofuran.

[0081] In certain embodiments, the reaction of step (ii) occurs at a temperature below 0°C.

[0082] In certain embodiments, the process comprises: (ii) under conditions sufficient to produce a compound having the structure of formula (±)-(IV); reacting the compound having the structure of formula (±)-(II) produced in step (i) with a compound having the structure of formula (III) in the presence of an acid in a second suitable solvent,

[0083] [ka]

[0084] wherein R4 is alkyl;

[0085] [ka]

[0086] Further includes:

[0087] In certain embodiments, the acid is an organic acid or a Lewis acid. In certain embodiments, the acid is an organic acid. In certain embodiments, the organic acid is camphorsulfonic acid.

[0088] In certain embodiments, the second suitable solvent is dichloromethane. In some embodiments, the second suitable solvent is chloroform.

[0089] In certain embodiments, the process comprises: (iii) exposing the compound having the structure of Formula (±)-(IV) produced in step (ii) to basic hydrolysis conditions sufficient to produce a compound having the structure of Formula (±)-(V);

[0090] [ka]

[0091] (iv) exposing the compound having the structure of Formula (±)-(V) produced in step (iii) to decarboxylation conditions sufficient to produce a compound having the structure of Formula (±)-(I).

[0092] In certain embodiments, a compound having the structure of formula (III) is (a)

[0093] [ka]

[0094] having the structure of formula (VIb):

[0095] [ka]

[0096] During the ceremony, reacting a compound (VIa) having the structure of formula (VIa) with an activating agent in a first suitable solvent under conditions sufficient to produce a compound where X1 is a halide or an activated ester moiety; (b) under conditions sufficient to form a cyclized compound having a structure of formula (III);

[0097] [ka]

[0098] in a second suitable solvent, in the presence of a Lewis acid, A compound having the structure of formula (VIb) is reacted with a compound having the structure of formula (VIc): wherein PG1 and PG2 are each independently a hydroxyl protecting group; R4 is an alkyl group, and is prepared by a process comprising reacting the group with a diene.

[0099] In certain embodiments, X1 is Cl.

[0100] In certain embodiments, R1 is unsubstituted alkyl. In other embodiments, R1 is substituted alkyl.

[0101] In certain embodiments, R1 is a C4-C6 alkyl.10 It is an alkyl.

[0102] In certain embodiments, R1 is n-pentyl.

[0103] In certain embodiments, the present invention also relates to a process for producing a compound having the structure of formula (±)-(Ia):

[0104] [ka]

[0105] During the ceremony, R1 is alkyl; The process comprises: (i) reacting citral with a Lewis acid in a suitable solvent under conditions sufficient to produce a compound having the structure of formula (±)-(II'):

[0106] [ka]

[0107] In certain embodiments, the present invention relates to a process for producing a compound having a structure of formula (±)-(Ia):

[0108] [ka]

[0109] During the ceremony, R1 is alkyl; The process comprises: (i) reacting citral with a Lewis acid in a suitable solvent under conditions sufficient to produce a compound having the structure of formula (±)-(II″).

[0110] [ka]

[0111] In certain embodiments, the present invention relates to a compound having the structure of formula (±)-(Ia):

[0112] [ka]

[0113] During the ceremony, R1 is alkyl; The process comprises: (i) reacting citral with a Lewis acid in a suitable solvent under conditions sufficient to produce a compound having the structure of formula (±)-(IIa):

[0114] [ka]

[0115] In certain embodiments, the citral is a mixture of citral A and citral B.

[0116] In certain embodiments, the citral is citral B.

[0117] In certain embodiments, the Lewis acid comprises an aluminum metal center.

[0118] In certain embodiments, the Lewis acid comprises an aluminum(III) salt.

[0119] In certain embodiments, the Lewis acid is a dialkylaluminum chloride.

[0120] In certain embodiments, the Lewis acid is dimethylaluminum chloride. In some embodiments, the Lewis acid is diethylaluminum chloride.

[0121] In certain embodiments, a solution of citral in a suitable solvent and a solution of Lewis acid in a suitable solvent are slowly mixed for 2-4 hours.

[0122] In certain embodiments, the mixing is performed at a temperature below 0°C.

[0123] In certain embodiments, the mixing is performed at a temperature of about -10° C. In some embodiments, the mixing is performed at a temperature of about -20 to 0° C.

[0124] In certain embodiments, the suitable solvent is dichloromethane, hi some embodiments, the suitable solvent is chloroform.

[0125] In certain embodiments, the process comprises: (ia) reacting the compound having the structure of Formula (±)-(IIa) produced in step (i) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having the structure of Formula (+)-(II″).

[0126] [ka]

[0127] In certain embodiments, the reducing agent comprises lithium metal.

[0128] In certain embodiments, the reducing agent is lithium aluminum hydride.

[0129] In certain embodiments, the second suitable solvent is tetrahydrofuran.

[0130] In certain embodiments, the reaction of step (ii) occurs at a temperature below 0° C. In certain embodiments, the process comprises: (ii) reacting the compound having the structure of formula (±)-(II) produced in step (i) with a compound having the structure of formula (IIIa) in a second suitable solvent in the presence of an acid;

[0131] [ka]

[0132] thereby producing a compound having the structure of formula (±)-(Ia).

[0133] In certain embodiments, the acid is an organic acid or a Lewis acid. In certain embodiments, the acid is an organic acid. In certain embodiments, the acid is p-toluenesulfonic acid.

[0134] In certain embodiments, the suitable solvent is dichloromethane.

[0135] In certain embodiments, R1 is unsubstituted alkyl. In other embodiments, R1 is substituted alkyl.

[0136] In certain embodiments, R1 is a C4-C6 alkyl. 10 It is an alkyl.

[0137] In certain embodiments, R1 is n-pentyl.

[0138] In certain embodiments, the present invention further relates to a process for producing a compound having the structure of formula (±)-(IIa):

[0139] [ka]

[0140] The process involves reacting citral with a Lewis acid in a suitable solvent under conditions sufficient to produce the compound.

[0141] In certain embodiments, the citral is a mixture of citral A and citral B.

[0142] In certain embodiments, the citral is citral B.

[0143] In certain embodiments, the Lewis acid comprises an aluminum metal center.

[0144] In certain embodiments, the Lewis acid comprises an aluminum(III) salt.

[0145] In certain embodiments, the Lewis acid is a dialkylaluminum chloride.

[0146] In certain embodiments, the Lewis acid is dimethylaluminum chloride. In some embodiments, the Lewis acid is diethylaluminum chloride.

[0147] In certain embodiments, a solution of citral in a suitable solvent and a solution of Lewis acid in a suitable solvent are slowly mixed for 2-4 hours.

[0148] In certain embodiments, the mixing is performed at a temperature below 0°C.

[0149] In certain embodiments, the mixing is performed at a temperature of about -10° C. In some embodiments, the mixing is performed at a temperature of about -20 to 0° C.

[0150] In certain embodiments, the suitable solvent is dichloromethane, hi some embodiments, the suitable solvent is chloroform.

[0151] In certain embodiments, the present invention relates to a process for producing a compound having a structure of formula (±)-(II″):

[0152] [ka]

[0153] The process includes preparing a compound having a structure of Formula (±)-(IIa) according to a process disclosed herein; and reacting the compound having a structure of Formula (±)-(IIa) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having a structure of Formula (+)-(II″).

[0154] In certain embodiments, the reducing agent comprises lithium metal.

[0155] In certain embodiments, the reducing agent is lithium aluminum hydride.

[0156] In certain embodiments, the second suitable solvent is tetrahydrofuran.

[0157] In certain embodiments, the reaction of step (ii) occurs at a temperature below 0°C.

[0158] In certain embodiments, the present invention further provides a method for producing a compound having a structure of formula (-)-(I):

[0159] [ka]

[0160] During the ceremony, R1 is alkyl; The process comprises: (i) reacting (R)-limonene with an oxidizing agent in a first suitable solvent under conditions sufficient to produce a compound having a structure of Formula (+)-(IIa);

[0161] [ka]

[0162] (ii) reacting the compound having the structure of Formula (+)-(IIa) produced in step (i) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having the structure of Formula (+)-(II') as a single enantiomer.

[0163] [ka]

[0164] In certain embodiments, the present invention provides a method for producing a compound having a structure of formula (-)-(I):

[0165] [ka]

[0166] During the ceremony, R1 is alkyl; The process comprises: (i) reacting (R)-limonene with an oxidizing agent in a first suitable solvent under conditions sufficient to produce a compound having a structure of Formula (+)-(IIa);

[0167] [ka]

[0168] (ii) reacting the compound having the structure of Formula (+)-(IIa) produced in step (i) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having the structure of Formula (+)-(II″) as a single enantiomer.

[0169] [ka]

[0170] In certain embodiments, the oxidizing agent comprises a chromium metal complex or salt.

[0171] In certain embodiments, the oxidizing agent is chromium(VI) oxide.

[0172] In certain embodiments, the first suitable solvent is chloroform.

[0173] In certain embodiments, the reducing agent comprises sodium metal.

[0174] In certain embodiments, the reducing agent is sodium borohydride.

[0175] In certain embodiments, the second suitable solvent is methanol.

[0176] In certain embodiments, the reaction of step (ii) occurs in the presence of cerium(III) chloride or samarium(III) iodide.

[0177] In certain embodiments, the reducing agent comprises lithium metal.

[0178] In certain embodiments, the reducing agent is lithium aluminum hydride.

[0179] In certain embodiments, the second suitable solvent is tetrahydrofuran.

[0180] In certain embodiments, the reaction of step (ii) occurs at a temperature below 0°C.

[0181] In certain embodiments, the process comprises: (iii) reacting the compound having the structure of formula (+)-(II') or (+)-(II'') produced in step (ii) with a compound having the structure of formula (III) in the presence of an acid in a suitable solvent under conditions sufficient to produce a compound having the structure of formula (-)-(IV),

[0182] [ka]

[0183] wherein R4 is alkyl.

[0184] [ka]

[0185] In certain embodiments, the acid is an organic acid or a Lewis acid. In certain embodiments, the acid is an organic acid. In certain embodiments, the acid is camphorsulfonic acid.

[0186] In certain embodiments, the suitable solvent is dichloromethane.

[0187] In certain embodiments, the process comprises: (iv) exposing the compound having the structure of Formula (-)-(IV) produced in step (iii) to basic hydrolysis conditions sufficient to produce a compound having the structure of Formula (-)-(V);

[0188] [ka]

[0189] (v) exposing the compound having the structure of Formula (-)-(V) produced in step (iv) to decarboxylation conditions sufficient to produce a compound having the structure of Formula (-)-(I).

[0190] In certain embodiments, a compound having the structure of formula (III) is (a)

[0191] [ka]

[0192] having the structure of formula (VIb):

[0193] [ka]

[0194] During the ceremony, reacting a compound (VIa) having the structure of formula (VIa) with an activating agent in a first suitable solvent under conditions sufficient to produce an activated ester compound, where X1 is a halide or an activated ester moiety; (b) under conditions sufficient to form a cyclized compound having a structure of formula (III);

[0195] [ka]

[0196] reacting a compound having the structure of Formula (VIb) with a compound having the structure of Formula (II) in the presence of a Lewis acid in a second suitable solvent, wherein PG1 and PG2 are each independently a hydroxyl protecting group; R4 is an alkyl group, and is prepared by a process comprising reacting the group with a diene.

[0197] In certain embodiments, X1 is Cl.

[0198] In certain embodiments, R1 is unsubstituted alkyl. In other embodiments, R1 is substituted alkyl.

[0199] In certain embodiments, R1 is a C4-C6 alkyl. 10 It is an alkyl.

[0200] In certain embodiments, R1 is n-pentyl.

[0201] In certain embodiments, the present invention further provides a process for producing a compound having a structure of formula (-)-(Ia):

[0202] [ka]

[0203] During the ceremony, R1 is alkyl; The process comprises: (i) reacting (R)-limonene with an oxidizing agent in a first suitable solvent under conditions sufficient to produce a compound having a structure of Formula (+)-(IIa);

[0204] [ka]

[0205] (ii) reacting the compound having the structure of Formula (+)-(IIa) produced in step (i) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having the structure of Formula (+)-(II') as a single enantiomer.

[0206] [ka]

[0207] In certain embodiments, the present invention provides a process for producing a compound having a structure of formula (-)-(Ia):

[0208] [ka]

[0209] During the ceremony, R1 is alkyl; The process comprises: (i) reacting (R)-limonene with an oxidizing agent in a first suitable solvent under conditions sufficient to produce a compound having a structure of Formula (+)-(IIa);

[0210] [ka]

[0211] (ii) reacting the compound having the structure of Formula (+)-(IIa) produced in step (i) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having the structure of Formula (+)-(II″) as a single enantiomer.

[0212] [ka]

[0213] In certain embodiments, the oxidizing agent comprises a chromium metal complex or salt.

[0214] In certain embodiments, the oxidizing agent is chromium(VI) oxide.

[0215] In certain embodiments, the first suitable solvent is chloroform.

[0216] In certain embodiments, the reducing agent comprises sodium metal.

[0217] In certain embodiments, the reducing agent is sodium borohydride.

[0218] In certain embodiments, the second suitable solvent is methanol.

[0219] In certain embodiments, the reaction of step (ii) occurs in the presence of cerium(III) chloride or samarium(III) iodide.

[0220] In certain embodiments, the reducing agent comprises lithium metal.

[0221] In certain embodiments, the reducing agent is lithium aluminum hydride.

[0222] In certain embodiments, the second suitable solvent is tetrahydrofuran.

[0223] In certain embodiments, the reaction of step (ii) occurs at a temperature below 0°C.

[0224] In certain embodiments, the process comprises: (iii) reacting the compound having the structure of formula (+)-(II) produced in step (ii) with a compound having the structure of formula (IIIa) in the presence of an organic acid or a Lewis acid in a second suitable solvent;

[0225] [ka]

[0226] thereby producing a compound having the structure of Formula (-)-(Ia).

[0227] In certain embodiments, the acid is an organic acid or a Lewis acid.

[0228] In a particular embodiment, the acid is p-toluenesulfonic acid.

[0229] In certain embodiments, the suitable solvent is dichloromethane.

[0230] In certain embodiments, R1 is unsubstituted alkyl. In other embodiments, R1 is substituted alkyl.

[0231] In certain embodiments, R1 is a C4-C6 alkyl. 10 It is an alkyl.

[0232] In certain embodiments, R1 is n-pentyl.

[0233] In certain embodiments, the present invention further provides a process for producing a compound having a structure of formula (+)-(II'):

[0234] [ka]

[0235] The process comprises: (i) reacting (R)-limonene with an oxidizing agent in a first suitable solvent under conditions sufficient to produce a compound having a structure of Formula (IIa);

[0236] [ka]

[0237] (ii) reacting the compound having the structure of Formula (+)-(IIa) produced in step (i) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having the structure of Formula (+)-(II″) as a single enantiomer.

[0238] In certain embodiments, the present invention provides a process for producing a compound having a structure of formula (+)-(II″):

[0239] [ka]

[0240] The process comprises: (i) reacting (R)-limonene with an oxidizing agent in a first suitable solvent under conditions sufficient to produce a compound having a structure of Formula (+)-(IIa);

[0241] [ka]

[0242] (ii) reacting the compound having the structure of Formula (+)-(IIa) produced in step (i) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having the structure of Formula (+)-(II″) as a single enantiomer.

[0243] In certain embodiments, the oxidizing agent comprises a chromium metal complex or salt.

[0244] In certain embodiments, the oxidizing agent is chromium(VI) oxide.

[0245] In certain embodiments, the first suitable solvent is chloroform.

[0246] In certain embodiments, the reducing agent comprises sodium metal.

[0247] In certain embodiments, the reducing agent is sodium borohydride.

[0248] In certain embodiments, the second suitable solvent is methanol.

[0249] In certain embodiments, the reaction of step (ii) occurs in the presence of cerium(III) chloride or samarium(III) iodide.

[0250] In certain embodiments, the reducing agent comprises lithium metal.

[0251] In certain embodiments, the reducing agent is lithium aluminum hydride.

[0252] In certain embodiments, the second suitable solvent is tetrahydrofuran.

[0253] In certain embodiments, the reaction of step (ii) occurs at a temperature below 0°C.

[0254] In certain embodiments, the present invention further provides a process for producing a compound having a structure of formula (III):

[0255] [ka]

[0256] During the ceremony, R1 is alkyl; R4 is alkyl; The process comprises: (i) under conditions sufficient to produce a compound having a structure of formula (VIIa);

[0257] [ka]

[0258] The method includes reacting a compound (VII) having the structure of formula (VII) with Br2 in a first suitable solvent.

[0259] [ka]

[0260] In certain embodiments, the first suitable solvent is dimethylformamide.

[0261] In certain embodiments, the reaction is carried out at a temperature of -10 to 10°C.

[0262] In certain embodiments, about 1 molar equivalent of Br2 is used in the reaction.

[0263] In certain embodiments, about 1-1.05 molar equivalents of Br2 are used in the reaction.

[0264] In certain embodiments, the process comprises: (ii) refluxing the compound having the structure of Formula (VIIa) produced in step (i) in a second suitable solvent under conditions sufficient to produce a compound having the structure of Formula (III).

[0265] In certain embodiments, the second suitable solvent is toluene.

[0266] In certain embodiments, a compound having the structure of formula (VII) is prepared by a process comprising reacting a dialkyl malonate with trans-3-nonen-2-one in the presence of a base in a third suitable solvent under conditions sufficient to produce a compound having the structure of formula (VII).

[0267] In certain embodiments, the dialkyl malonate is dimethyl malonate.

[0268] In certain embodiments, the base is sodium methoxide. In some embodiments, the base is sodium ethoxide.

[0269] In certain embodiments, the third suitable solvent is methanol, hi some embodiments, the third suitable solvent is ethanol.

[0270] In certain embodiments, the reaction occurs at reflux.

[0271] In certain embodiments, the present invention provides a process for producing a compound having a structure of formula (III):

[0272] [ka]

[0273] During the ceremony, R1 is alkyl; R4 is alkyl; The process comprises: (b) under conditions sufficient to form a cyclized compound having a structure of formula (III);

[0274] [ka]

[0275] In a suitable solvent, in the presence of a Lewis acid, having the structure of formula (VIb): wherein X1 is a halide or an activated ester moiety, having the structure of formula (VIc):

[0276] [ka]

[0277] During the ceremony, PG1 and PG2 are each independently a hydroxyl protecting group; R4 is alkyl, which involves reacting with a diene.

[0278] In certain embodiments, the method comprises: (a)

[0279] [ka]

[0280] Formula (VIb) The structure is

[0281] [ka]

[0282] During the ceremony, The method further includes reacting compound (VIa), having the structure of formula (VIa), with an activating agent in a first suitable solvent under conditions sufficient to produce a compound, where X1 is a halide or an activated ester moiety.

[0283] In certain embodiments, in step (a), the activating agent is oxalyl chloride.

[0284] In certain embodiments, the first suitable solvent is benzene.

[0285] In certain embodiments, in step (b), the Lewis acid is titanium chloride.

[0286] In certain embodiments, the suitable solvent is dichloromethane.

[0287] In certain embodiments, R4 is methyl. In other embodiments, R4 is ethyl.

[0288] In certain embodiments, R1 is unsubstituted alkyl. In other embodiments, R1 is substituted alkyl.

[0289] In certain embodiments, R1 is a C4-C6 alkyl. 10 It is an alkyl.

[0290] In certain embodiments, R1 is n-pentyl.

[0291] In certain embodiments, the present invention further provides a process for producing a compound having a structure of formula (VIII):

[0292] [ka]

[0293] During the ceremony, R1 is alkyl; R4 is alkyl; The process comprises: (i) under conditions sufficient to produce a compound having the structure of formula (III);

[0294] [ka]

[0295] In a first suitable solvent, in the presence of an acid, a compound (III) having a structure of formula (III) is

[0296] [ka]

[0297] This involves reacting with geraniol.

[0298] In certain embodiments, the compound of formula (III) in the above process is produced according to a process involving intermediates (VII) and (VIIa).

[0299] In certain embodiments, the compound of formula (III) in the above process is produced according to a process involving intermediates (VIb) and (VIc).

[0300] In certain embodiments, the acid is an organic acid or a Lewis acid.

[0301] In certain embodiments, the acid is camphorsulfonic acid.

[0302] In certain embodiments, the first suitable solvent is dichloromethane.

[0303] In certain embodiments, the reaction is carried out at a temperature between 0 and 25°C.

[0304] In certain embodiments, the process comprises: (ii) subjecting the compound having the structure of Formula (VIIIa) prepared in step (i) to decarboxylation conditions sufficient to produce a compound having the structure of Formula (VIII).

[0305] In certain embodiments, R4 is methyl. In certain embodiments, R4 is ethyl.

[0306] In certain embodiments, R1 is unsubstituted alkyl. In other embodiments, R1 is substituted alkyl.

[0307] In certain embodiments, R1 is a C4-C6 alkyl. 10 It is an alkyl.

[0308] In certain embodiments, R1 is n-pentyl.

[0309] In certain embodiments, the compound produced has the following structure:

[0310] [ka]

[0311] In certain embodiments, the compound produced has the following structure:

[0312] [ka]

[0313] In certain embodiments, the compound produced has the following structure:

[0314] [ka]

[0315] In certain embodiments, the compound produced has the following structure:

[0316] [ka]

[0317] In certain embodiments, the compound produced has the following structure:

[0318] [ka]

[0319] In certain embodiments, the present disclosure relates to a process for preparing (±)-cannabidiol (CBD), including the preparation of (±)-isopiperitenone of the present invention.

[0320] In certain embodiments, the present disclosure provides (±)-delta-9-tetrahydrocannabinol (Δ 9 The present invention relates to a process for preparing (±)-isopiperitenone, which comprises the preparation of (±)-isopiperitenone.

[0321] In certain embodiments, the present disclosure relates to a process for preparing (±)-cannabidiol (CBD), including the preparation of (±)-isopipertenol of the present invention.

[0322] In certain embodiments, the present disclosure provides (±)-delta-9-tetrahydrocannabinol (Δ 9The present invention relates to a process for preparing (±)-isopiperthenol (-THC), which comprises the preparation of (±)-isopiperthenol of the present invention.

[0323] In certain embodiments, the present disclosure relates to a process for preparing (-)-cannabidiol (CBD), including the preparation of (+)-trans-isopiperitenol of the present invention.

[0324] In certain embodiments, the present disclosure provides (-)-delta-9-tetrahydrocannabinol (Δ 9 -THC), which includes the preparation of (+)-trans-isopiperitenol of the present invention.

[0325] In certain embodiments, the present disclosure relates to a process for preparing (-)-cannabidiol (CBD), including the preparation of (+)-cis-isopiperitenol of the present invention.

[0326] In certain embodiments, the present disclosure provides (-)-delta-9-tetrahydrocannabinol (Δ 9 -THC), which includes the preparation of (+)-cis isopiperitenol of the present invention.

[0327] In certain embodiments, the present disclosure relates to a pharmaceutical composition comprising (±)-cannabidiol (CBD) and a pharma- ceutically acceptable carrier, wherein the (±)-cannabidiol (CBD) is produced according to the present invention.

[0328] In certain embodiments, the present disclosure provides (±)-delta-9-tetrahydrocannabinol (Δ 9 -THC) and a pharma- ceutically acceptable carrier, 9 -THC) produced according to the present invention.

[0329] In certain embodiments of any of the disclosed compounds, R1 is C4-C6 alkyl. In other embodiments, R1 is C7-C 10 In other embodiments of any of the disclosed compounds, R1 is n-pentyl.

[0330] [Definition] As used herein, the term "citral" refers to the E isomer geranial (trans-citral) or citral A, and / or the Z isomer neral (cis-citral) or citral B. It may refer to a mixture of the two isomers or to each individual isomer. Generally, citral is commercially available as a mixture of the following two isomers:

[0331] [ka]

[0332] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. In general, the terms used in connection with and techniques relating to chemistry, cell and tissue culture, molecular biology, cell and cancer biology, neurobiology, neurochemistry, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein are well known and commonly used in the art.

[0333] The methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references cited and described throughout this specification, unless otherwise indicated. See, for example, "Principles of Neural Science", McGraw-Hill Medical, New York, NY (2000); Motulsky, "Intuitive Biostatistics", Oxford University Press, Inc. (1995); Lodish et al., "Molecular Cell Biology, 4th ed.", WH Freeman & Co., New York (2000); Griffiths et al., "Introduction to Genetic Analysis, 7th ed.", WH Freeman & Co., NY (1999); and Gilbert et al., "Developmental Biology, 6th ed.", Sinauer Associates, Inc., Sunderland, MA (2000).

[0334] As used herein, unless otherwise defined herein, chemical terms are used according to conventional usage in the art, as exemplified in "The McGraw-Hill Dictionary of Chemical Terms", Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0335] Starting materials and reagents used in the synthesis of the compounds described herein are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fisher Scientific (Fisher Chemicals), and Acros Organics.

[0336] All of the above, as well as any other publications, patents, and published patent applications mentioned in this application are specifically incorporated herein by reference. In case of conflict, the present specification, including its specific definitions, will control.

[0337] For convenience, certain terms employed in the specification, examples, and appended claims are collected here.

[0338] As used herein, the articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0339] The definition of each term, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0340] Certain compounds may exist in particular geometric or stereoisomeric forms. In addition, the polymers of the present invention may also be optically active. The present invention contemplates that all such compounds are within the scope of the present invention, including cis and trans isomers, R and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in a substituent, such as an alkyl group. All such isomers, and mixtures thereof, are intended to be included in the present invention.

[0341] For example, if a particular enantiomer of a compound of the invention is desired, it may be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is cleaved to yield the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the formed diastereomers by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0342] For purposes of this invention, the chemical elements are identified according to the Periodic Table of the Elements, CAS version, inside cover of Handbook of Chemistry and Physics, 67th Ed., 1986-87.

[0343] The term "mixing" refers to any method of contacting one component of a mixture with another component of the mixture, including stirring, blending, combining, contacting, grinding, shaking, sonicating, spraying, stirring, and vortexing.

[0344] An "alkyl" group is a fully saturated straight or branched chain non-aromatic hydrocarbon. Typically, a straight or branched chain alkyl group has 1 to about 20 carbon atoms, preferably 1 to about 10, unless otherwise defined. Examples of straight and branched chain alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, and octyl. C1-C6 straight or branched chain alkyl groups are also referred to as "lower alkyl" groups.

[0345] Furthermore, the term "alkyl" (or "lower alkyl"), as used throughout the specification, examples, and claims, is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having a substituent in place of hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, unless otherwise specified, may include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain may themselves be substituted, where appropriate. For example, substituents of substituted alkyls can include amino, azido, imino, amide, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as substituted and unsubstituted forms of ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.

[0346] "C x-y The term "C" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups containing x to y carbons in the chain. For example, the term "C x-y"Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight and branched chain alkyl groups containing x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. CO alkyl refers to hydrogen when the group is in a terminal position and a bond when it is internal. The term "C 2-y Alkenyl" and "C 2-y "Alkynyl" refers to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond respectively.

[0347] The term "carboxy," as used herein, refers to a group represented by the formula -CO2H.

[0348] The term "ester" as used herein refers to the group -C(O)OR 10 In the formula, R 10 represents a hydrocarbyl group.

[0349] As used herein, the terms "halo" and "halogen" mean halogen and include chloro, fluoro, bromo, and iodo.

[0350] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

[0351] The term "lower", when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is meant to include groups in which there are 10 or fewer non-hydrogen atoms in the substituent, preferably 6 or fewer. "Lower alkyl", for example, refers to alkyl groups containing 10 or fewer, preferably 6 or fewer carbon atoms. In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituent as defined herein is, respectively, a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether appearing alone or in combination with other substituents (e.g., when counting the carbon atoms of an alkyl substituent), such as in the descriptions hydroxyalkyl and aralkyl.

[0352] The term "silyl" refers to a silicon moiety having three hydrocarbyl moieties attached thereto.

[0353] The term "silyloxy" refers to a silyl-bonded oxygen moiety.

[0354] As used herein, the term "activated ester moiety" refers to any ester group, i.e., C(O)OY, where OY is an activating group that renders the carbonyl carbon highly susceptible to nucleophilic attack. Activating groups include:

[0355] [ka]

[0356] It can be, but is not limited to,

[0357] "Protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, a protecting group can be selectively removed as desired during the course of a synthesis. Examples of protecting groups are described in Greene and Wuts, Protective Groups in Organic Chemistry, 3 rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("TES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxyl protecting groups include, but are not limited to, those in which the hydroxyl group is acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers (e.g., ethylene glycol and propylene glycol derivatives), and allyl ethers.

[0358] The expression "pharmacologically acceptable" is recognized in the art. In certain embodiments, the term includes compositions, excipients, adjuvants, polymers, and other materials and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0359] "Pharmaceutically acceptable salt" or "salt" is used herein to refer to an acid addition salt or a base addition salt that is suitable or compatible with the treatment of a patient.

[0360] As used herein, the term "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of any basic polypeptide disclosed herein. Examples of inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include mono-, di-, and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, as well as sulfonic acids, such as p-toluenesulfonic acid and methanesulfonic acid. Either mono- or di-acid salts may be formed, and such salts may exist in either hydrated, solvated, or substantially anhydrous form. In general, acid addition salts of polypeptides are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points than their free base forms. The selection of an appropriate salt will be known to one of skill in the art. Other pharma-ceutically unacceptable salts, such as oxalates, may be used, for example, in the isolation of polypeptides for laboratory use or for subsequent conversion to a pharma-ceutically acceptable acid addition salt.

[0361] As used herein, the term "pharmaceutically acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt of any of the acid polypeptides represented by formula I or II. Examples of inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline or ammonia. The selection of suitable salts will be known to those skilled in the art.

[0362] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, useful in formulating a drug for pharmaceutical or therapeutic use.

[0363] Having broadly described the invention, the same will be more readily understood by reference to the following examples, which are included merely for the purpose of illustrating certain aspects and embodiments of the invention and are not intended to be limiting of the invention. EXAMPLES

[0364] The invention is described in more detail in the following examples, which do not limit the scope of the invention described in the claims.

[0365] Example 1: Preliminary synthesis of enantiopure (-)-cannabidiol (CBD) Enantiopure (-)-cannabidiol (CBD) was prepared starting from commercially available (R)-limonene.

[0366] [ka]

[0367] [1. (S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-2-enone: Generic name (+)-(S)-isopiperitenone (Dethe,DHet al.2015)] 40 mL of tert-butanol was syringed into a flame-dried 100 mL round-bottom flask. With vigorous magnetic stirring, 16.0 g (160 mmol, 4.0 equiv.) of powdered chromium(VI) oxide was added in small portions. Initial dissolution of the oxidant results in a bright orange solution, but with continued stirring the solution turns a deep maroon color and slight warming is observed. After 10 min at 25 °C, the solution was cooled to 0 °C, diluted with 40 mL of chloroform, and transferred to a 250 mL separatory funnel. Ice-cold deionized water (50 mL) was added and the mixture was swirled before allowing the phases to separate. The lower organic layer (bright red) was removed and the upper aqueous layer (light brown) was back-extracted with two 20 mL portions of chloroform. The pooled organic layers were dried over sodium sulfate and vacuum filtered through cotton in a coarse porosity fritted funnel and placed directly into a flame-dried 250 mL round-bottom receiving flask. To the resulting deep red filtrate was added 6.50 mL (40.2 mmol, 1.0 equiv.) of (R)-limonene. With continuous stirring, the vessel was fitted with a heating mantle and the solution was brought to gentle reflux. After 1 hour, the reaction mixture became opaque and dark brown in color. The heat source was removed and stirring was continued overnight at 25° C., at which point TLC analysis confirmed the absence of starting material and the formation of two regioisomeric enones. The mixture was directly filtered to remove the insoluble chromium(IV) deposit and the resulting brown filtrate was concentrated on a rotary evaporator in the presence of 10 grams of added silica gel. Purification of the residue by column chromatography using 10:1 petroleum ether:diethyl ether as eluent and KMnO4 stain for spot visualization afforded the major isomer (R f =0.55) (S)-carvone (1.99 g, 33%) and isopiperitenone (R f = 0.40, 1.03 g, 17%) was obtained. [α] 28 D =+27.88(c 0.54,CHCl3);IR(undiluted, cm -1)3076,2927,1667,1435,1379,1201,1087,891; 1 H NMR(CDCl3,400MHz)δ5.89(d,J=1.5Hz,1H),4.94(d,J=1.5Hz,1H),4.75(d,J=1.5Hz,1H),2.94(d d,J=10.5,5.4Hz,1H),2.35-2.31(m,2H),2.11-1.98(m,2H),1.94(s,3H),1.74(d,J=1.5Hz,3H); 13 C NMR (CDCl3, 100MHz) δ199.5, 162.0; 143.4, 126.8, 113.6, 53.9, 30.4, 27.7, 24.3, 20.7; HRMS (ESI+) calcd. 10 H 14 O[M] + :150.1045; measured value 150.1043.

[0368]

change

[0369] [2. (1S,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-2-enol; generic name (+)-cis-isopiperitenol] A flame-dried 100 mL round-bottom flask was charged with 808 mg (5.38 mmol, 1.0 equiv.) of neat (S)-isopiperitenone and 15 mL of anhydrous methanol (0.36 M concentration) as solvent. With magnetic stirring at 25°C, 996 mg (2.67 mmol, 0.50 equiv.) of cerium(III) chloride heptahydrate was added in one portion as a colorless blocky solid, which slowly dissolved to give a homogeneous solution. After 10 min, the solution was cooled (methanol / ice bath) to -10°C and ground sodium borohydride (204 mg, 5.39 mmol, 1.0 equiv.) was added in two portions, resulting in immediate evolution of hydrogen gas in the form of gentle bubbling. The resulting cloudy mixture was stirred for 1 h and the cold bath was removed. After dilution with 40 mL of deionized water, the reaction mixture was transferred to a 125 mL separatory funnel and extracted three times with 30 mL of dichloromethane. Alternative extraction solvents (diethyl ether and ethyl acetate) were tested but resulted in emulsions. Some heterogeneity was observed with dichloromethane, but the bilayer reverted upon standing for 10-15 min. The combined organic layers were dried over MgSO4, filtered through cotton, and concentrated to give 750 mg of an orange liquid. This material was predominantly the 1,4-reduced product (R 2 ) due to steric hindrance associated with the 1,2-reduction. f Purification by flash silica gel chromatography using 3:1 petroleum ether:diethyl ether as eluent and CAM staining afforded 303 mg of (+)-cis-isopiperitenol (R f = 0.25, 37% yield) was obtained as a colorless oil. f = 0.26, <4% yield) was observed eluting just before the product, reflecting a stereoselectivity of > 10:1 when the hydride agent was added at -10°C. The spectral characteristics of this material were identical in all respects to material with 94% ee previously prepared by multi-step asymmetric synthesis (Tomooka, K. et al. 2005).

[0370] [ka]

[0371] 3. (-)-Cannabidiolic acid methyl ester, generic name methyl cannabiolate: 23.8 mg of methyl 2,4-dihydroxy-6-pentylbenzoate (0.100 mmol, 1.1 equiv.) and 7.2 mg of camphorsulfonic acid (0.031 mmol, 0.34 equiv.) were placed as solids in a flame-dried 1-dram vial in air, then the vial was purged with nitrogen gas before 0.6 mL of anhydrous dichloromethane was added as solvent. To the resulting clear solution, stirred at 0° C., was added dropwise over 1 hour (+)-cis-isopiperitenol 13.8 mg (0.0907 mmol, 0.91 equiv.) in 0.4 mL of dichloromethane. The reaction mixture was stirred at 0° C. for an additional hour, the ice bath was removed, and the reaction mixture was concentrated to a neat oil at 25° C. using a nitrogen gas purge line (and vent needle). The contents of the vial were then resuspended in 1.0 mL of diethyl ether, 1.0 mL of cold saturated sodium bicarbonate was added to quench the acid catalyst, and after agitation by swirling, the organic layer was removed with a Pasteur pipette. The aqueous layer was washed twice with 1.0 mL of diethyl ether, and the extracts were pooled, dried over MgSO4, filtered through cotton, and concentrated to give an oily residue. Purification by silica gel chromatography in 9:1 petroleum ether:diethyl ether afforded the title compound as a yellow oil (21.1 mg, 60%, R f = 0.55, UV active spot or deep blue color against CAM stain). 1H NMR(CDCl3,500MHz)δ12.00(s,1H),6.51(s,1H),6.21(s,1H),5.55(s,1H),4.52(s,1H),4.37(s,1H),4.10(br s,1H),3.90(s,3H),2.87-2.81(m,1H),2.76-2.69(m,1H),2.71-2.65(m,1H),2.42-2.32(m,1H),2.34-2.27(m,1H),2.26-2.17(m, 1H),2.12-2.06(m,1H),1.79(s,3H),1.71(s,3H),1.54-1.46(m,2H),1.35-1.27(m,2H),1.27-1.23(m,2H),0.89(t,J=6.5Hz,3H).

[0372] [ka]

[0373] [4. (-)-Cannabidiol (CBD)] Basic hydrolysis with LiOH (1 equivalent) in THF gives the free acid, which is followed by thermal decarboxylation to give (-)-cannabidiol (CBD).

[0374] Example 2: Preliminary synthesis of racemic (±)-cannabidiol (CBD) The method described in Example 1 was adapted to provide racemic (±)-cannabidiol (CBD). Specifically, the following method was used to obtain (±)-cis-isopiperitenol, which was then subjected to steps 3 and 4 of Example 1.

[0375] [ka]

[0376] [1. Rac-(±)-cis-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enol; generic name cis-isopiperitenol] A 1.75 gram sample of commercial citral (≥96%, a mixture of trans (geranial) and cis (neral)) was filtered through a column (5 cm diameter × 10 cm height) of silica gel slurry packed in benzene containing 3% diethyl ether (R f= 0.54; yellow spot under UV activity or KMnO4 staining). This flash chromatography step serves to remove the yellow impurity eluting at the solvent front and also rigorously dry the substrate by azeotropic removal of traces of water. The pure citral fraction was concentrated on a rotary evaporator, backfilled with an argon balloon, further degassed under high vacuum, and magnetically stirred the undiluted oil to give 1.52 g (10.0 mmol, 1.0 equiv.) of completely colorless citral. The starting material was dissolved in 10.0 mL of anhydrous dichloromethane and the solution was loaded into a 12 mL plastic syringe. A second disposable gas-tight syringe was charged with commercially available dimethylaluminum chloride (10.1 mL of 1.0 M in hexane, 10.1 mmol, 1.01 equiv.) while degassing under positive nitrogen pressure. Finally, another flame-dried, 100 mL round-bottom flask with a 24 / 40 joint equipped with a side-arm stopcock and a hose connector (for nitrogen pressure) was charged with 10.0 mL of dichloromethane and cooled to -10 °C in an ice / methanol bath. The substrate and promoter solutions were added dropwise to the cooled flask over a period of 3 h at equal addition rates using two syringe pumps. The exit needle of the promoter solution was placed below the solvent surface to minimize fume or turbidity in the headspace of the reaction flask. The role of the slow addition is to mimic high dilution and minimize intermolecular reactions. During the course of the addition, the reaction mixture turned light orange and eventually maroon. Stirring was continued while slowly warming to room temperature over the course of 1 h. The mixture was then quenched at 0 °C by sequential addition of 1.0 mL of deionized water, 1.0 mL of 4 M aqueous sodium hydroxide, and an additional 3.0 mL of water. These additions, which mirror the standard workup of the lithium aluminum hydride reaction, caused the evolution of methane gas, the bleaching of the reaction mixture to an orange color, and the formation of a milky precipitate from which the yellow supernatant was easily isolated by decantation. Thus, the mixture was filtered through a cotton pad, the aluminum(III) hydroxide precipitate was washed with additional dichloromethane, and concentrated to reveal primarily unreacted citral (R), with either KMnO4 or cerium ammonium molybdate (CAM) TLC staining.f =0.71) and the product (R f =0.38 in 2:1 heptane:diethyl ether) to give a bronze oil. Purification was carried out by chromatography on silica gel in the same solvent system to give 228 mg (15% yield) of a colorless oil. IR (neat, cm -1 )3352, 3088, 2936, 1676, 1649, 1450, 1379, 1245, 1210, 1176, 1156, 1114, 1069, 1025, 957, 915, 886, 849, 816, 723, 681cm -1 ; 1 H NMR(CDCl3,400MHz)δ5.67(m,1H),4.99(s,1H),4.81(s,1H),4.12(br s,1H),2.17-2.04(m,3H),1.83(s,3H),1.80-1.74(m,1H),1.72(s,3H),1.65-1.55(m,1H),1.48(br s,1H); 13 C NMR(CDCl3,100MHz)δ146.7,139.9,122.5,111.8,63.9,46.2,31.3,23.5,22.7,21.0; HRMS(ESI+) calculated value C 10 H 16 O[M] + :152.1201;actual value 150.1209.

[0377] Example 3: Enantiopure (-)-delta-9-tetrahydrocannabinol (Δ 9 -THC) Enantiopure (-)-delta-9-tetrahydrocannabinol (Δ 9 -THC) was prepared starting from commercially available (R)-limonene.

[0378] [ka]

[0379] [1. (S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-2-enone: Generic name (+)-(S)-isopiperitenone (Dethe,DHet al.2015)] 40 mL of tert-butanol was syringed into a flame-dried 100 mL round-bottom flask. With vigorous magnetic stirring, 16.0 g (160 mmol, 4.0 equiv.) of powdered chromium(VI) oxide was added in small portions. Initial dissolution of the oxidant results in a bright orange solution, but with continued stirring the solution turns a deep maroon color and slight warming is observed. After 10 min at 25 °C, the solution was cooled to 0 °C, diluted with 40 mL of chloroform, and transferred to a 250 mL separatory funnel. Ice-cold deionized water (50 mL) was added and the mixture was swirled before allowing the phases to separate. The lower organic layer (bright red) was removed and the upper aqueous layer (light brown) was back-extracted with two 20 mL portions of chloroform. The pooled organic layers were dried over sodium sulfate and vacuum filtered through cotton in a coarse porosity fritted funnel and placed directly into a flame-dried 250 mL round-bottom receiving flask. To the resulting deep red filtrate was added 6.50 mL (40.2 mmol, 1.0 equiv.) of (R)-limonene. With continuous stirring, the vessel was fitted with a heating mantle and the solution was brought to gentle reflux. After 1 hour, the reaction mixture became opaque and dark brown in color. The heat source was removed and stirring was continued overnight at 25° C., at which point TLC analysis confirmed the absence of starting material and the formation of two regioisomeric enones. The mixture was directly filtered to remove the insoluble chromium(IV) deposit and the resulting brown filtrate was concentrated on a rotary evaporator in the presence of 10 grams of added silica gel. Purification of the residue by column chromatography using 10:1 petroleum ether:diethyl ether as eluent and KMnO4 stain for spot visualization afforded the major isomer (R f =0.55) (S)-carvone (1.99 g, 33%) and isopiperitenone (R f = 0.40, 1.03 g, 17%) was obtained. [α] 28 D =+27.88(c 0.54,CHCl3);IR(undiluted, cm -1)3076,2927,1667,1435,1379,1201,1087,891; 1 H NMR(CDCl3,400MHz)δ5.89(d,J=1.5Hz,1H),4.94(d,J=1.5Hz,1H),4.75(d,J=1.5Hz,1H),2.94(d d,J=10.5,5.4Hz,1H),2.35-2.31(m,2H),2.11-1.98(m,2H),1.94(s,3H),1.74(d,J=1.5Hz,3H); 13 C NMR (CDCl3, 100MHz) δ199.5, 162.0; 143.4, 126.8, 113.6, 53.9, 30.4, 27.7, 24.3, 20.7; HRMS (ESI+) calcd. 10 H 14 O[M] + :150.1045; measured value 150.1043.

[0380]

change

[0381] [2. (1S,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-2-enol; generic name (+)-cis-isopiperitenol] A flame-dried 100 mL round-bottom flask was charged with 808 mg (5.38 mmol, 1.0 equiv.) of neat (S)-isopiperitenone and 15 mL of anhydrous methanol (0.36 M concentration) as solvent. With magnetic stirring at 25°C, 996 mg (2.67 mmol, 0.50 equiv.) of cerium(III) chloride heptahydrate was added in one portion as a colorless blocky solid, which slowly dissolved to give a homogeneous solution. After 10 min, the solution was cooled (methanol / ice bath) to -10°C and ground sodium borohydride (204 mg, 5.39 mmol, 1.0 equiv.) was added in two portions, resulting in immediate evolution of hydrogen gas in the form of gentle bubbling. The resulting cloudy mixture was stirred for 1 h and the cold bath was removed. After dilution with 40 mL of DI water, the reaction mixture was transferred to a 125 mL separatory funnel and extracted three times with 30 mL of dichloromethane. Alternative extraction solvents (diethyl ether and ethyl acetate) were tested but resulted in emulsions. Some heterogeneity was observed with dichloromethane, but the bilayer reverted upon standing for 10-15 min. The combined organic layers were dried over MgSO4, filtered through cotton, and concentrated to give 750 mg of an orange liquid. This material was predominantly the 1,4-reduced product (R 2 ) due to steric hindrance associated with the 1,2-reduction. f Purification by flash silica gel chromatography using 3:1 petroleum ether:diethyl ether as eluent and CAM staining afforded 303 mg of (+)-cis-isopiperitenol (R f = 0.25, 37% yield) was obtained as a colorless oil. f = 0.26, <4% yield) was observed eluting just before the product, reflecting a stereoselectivity of > 10:1 when the hydride agent was added at -10°C. The spectral characteristics of this material were identical in all respects to material with 94% ee previously prepared by multi-step asymmetric synthesis (Tomooka, K. et al. 2005).

[0382] [ka]

[0383] [3. Delta-9-tetrahydrocannabinol (Δ 9 -THC), international non-proprietary name dronabinol] para-toluenesulfonic acid monohydrate was recrystallized (as fine needles) from boiling chloroform, washed with hexane, and dried under vacuum before use. A flame-dried 10 mL round-bottom flask was charged with 20.0 mg olivetol (0.111 mmol, 1.0 equiv.) as a solid and 6.8 mg p-TsOH (0.039 mmol, 0.35 equiv.) and 1.7 mL anhydrous dichloromethane under positive nitrogen pressure. To the resulting clear solution stirred at 25°C, 18.6 mg (+)-cis-isopiperitenol (0.122 mmol, 1.1 equiv.) (Cardillo, B. et al. 1973) in 0.5 mL dichloromethane was added dropwise over 1 h. TLC analysis of the mixture after 2 hours of reaction showed only traces of reactants and a prominent non-polar spot (R in 3:1 hexane:diethyl ether). f =>0.90). The reaction was quenched with 2.0 mL of saturated sodium bicarbonate and the organic layer was removed. The aqueous layer was washed twice with 1.0 mL of dichloromethane and the extracts were combined, dried over MgSO4, filtered through cotton and concentrated to give an oily residue. Purification by passage through silica gel in 50:1 petroleum ether:ethyl acetate gave 12.7 mg (33%) of Δ 9 -THC and Δ 8 A clean 3:1 mixture with -THC (Hively, RLet et al. 1966) was obtained. Separation by HPLC was reported under the following conditions: Sunfire C18 5μ, 4.6×150 mm column, 1 mL / min flow rate, gradient elution from 80% water to 100% acetonitrile in acetonitrile containing 0.5–1% TFA. Synthesis Δ 9 The spectroscopic data collected for -THC is consistent with that of both the natural product (Gaoni, Y. et al. 1964) and the racemic material prepared according to earlier biomimetic synthesis (Taylor, EC et al. 1966).

[0384] [Example 4]: Racemic (±)-delta-9-tetrahydrocannabinol (Δ 9 -THC) The method described in Example 3 was carried out to obtain racemic (±)-delta-9-tetrahydrocannabinol (Δ 9 -THC). Specifically, the following method was used to obtain (±)-cis-isopiperitenol, which is then subjected to Step 3 of Example 3.

[0385] [ka]

[0386] [1. Rac-(±)-cis-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enol; generic name cis-isopiperitenol] A 1.75 gram sample of commercial citral (≥96%, a mixture of trans (geranial) and cis (neral)) was filtered through a column (5 cm diameter × 10 cm height) of silica gel slurry packed in benzene containing 3% diethyl ether (R f= 0.54; yellow spot under UV activity or KMnO4 staining). This flash chromatography step serves to remove the yellow impurity eluting at the solvent front and also rigorously dry the substrate by azeotropic removal of traces of water. The pure citral fraction was concentrated on a rotary evaporator, backfilled with an argon balloon, further degassed under high vacuum, and magnetically stirred the undiluted oil to give 1.52 g (10.0 mmol, 1.0 equiv.) of completely colorless citral. The starting material was dissolved in 10.0 mL of anhydrous dichloromethane and the solution was loaded into a 12 mL plastic syringe. A second disposable gas-tight syringe was charged with commercially available dimethylaluminum chloride (10.1 mL of 1.0 M in hexane, 10.1 mmol, 1.01 equiv.) while degassing under positive nitrogen pressure. Finally, another flame-dried, 100 mL round-bottom flask with a 24 / 40 joint equipped with a side-arm stopcock and a hose connector (for nitrogen pressure) was charged with 10.0 mL of dichloromethane and cooled to -10 °C in an ice / methanol bath. The substrate and promoter solutions were added dropwise to the cooled flask over a period of 3 h at equal addition rates using two syringe pumps. The exit needle of the promoter solution was placed below the solvent surface to minimize fume or turbidity in the headspace of the reaction flask. The role of the slow addition is to mimic high dilution and minimize intermolecular reactions. During the course of the addition, the reaction mixture turned light orange and eventually maroon. Stirring was continued while slowly warming to room temperature over the course of 1 h. The mixture was then quenched at 0 °C by sequential addition of 1.0 mL of deionized water, 1.0 mL of 4 M aqueous sodium hydroxide, and an additional 3.0 mL of water. These additions, which mirror the standard workup of the lithium aluminum hydride reaction, caused the evolution of methane gas, the bleaching of the reaction mixture to an orange color, and the formation of a milky precipitate from which the yellow supernatant was easily isolated by decantation. Thus, the mixture was filtered through a cotton pad, the aluminum(III) hydroxide precipitate was washed with additional dichloromethane, and concentrated to reveal primarily unreacted citral (R), with either KMnO4 or cerium ammonium molybdate (CAM) TLC staining.f =0.71) and the product (R f =0.38 in 2:1 heptane:diethyl ether) to give a bronze oil. Purification was carried out by chromatography on silica gel in the same solvent system to give 228 mg (15% yield) of a colorless oil. IR (neat, cm -1 )3352, 3088, 2936, 1676, 1649, 1450, 1379, 1245, 1210, 1176, 1156, 1114, 1069, 1025, 957, 915, 886, 849, 816, 723, 681cm -1 ; 1 H NMR(CDCl3,400MHz)δ5.67(m,1H),4.99(s,1H),4.81(s,1H),4.12(br s,1H),2.17-2.04(m,3H),1.83(s,3H),1.80-1.74(m,1H),1.72(s,3H),1.65-1.55(m,1H),1.48(br s,1H); 13 C NMR(CDCl3,100MHz)δ146.7,139.9,122.5,111.8,63.9,46.2,31.3,23.5,22.7,21.0, HRMS(ESI+) calculated value C 10 H 16 O [M] + In this case: 152.1201, actual value 150.1209.

[0387] [Example 5]: Preliminary synthesis of cannabigerolic acid (CBGA) and cannabigerol (CBG) Cannabigerolic acid (CBGA) and cannabigerol (CBG) were prepared starting from commercially available geraniol and synthetic methyl olivetolate (see Example 6 below).

[0388] [ka]

[0389] [1. (E)-3-(3,7-dimethylocta-2,6-dien-1-yl)-2,4-dihydroxy-6-pentylbenzoate methyl] Cannabigerolic acid methyl ester, CBGA methyl ester. A flame-dried 10 mL round bottom flask was charged in air with 125 mg of methyl 2,4-dihydroxy-6-pentylbenzoate (0.525 mmol, 1.0 equiv.) and recrystallized para-toluenesulfonic acid monohydrate (fine needle from chloroform, 20 mg, 0.11 mmol, 0.21 equiv.) as solids, then 2.25 mL of anhydrous dichloromethane was added as solvent after purging the vial with nitrogen gas. To the resulting pale yellow solution, stirring at 0° C., was added 80.9 mg (0.524 mmol, 0.998 equiv.) of geraniol in 3.0 mL of dichloromethane dropwise over 15 min. The reaction mixture was stirred at 0° C. for an additional hour, the ice bath was removed, and the reaction mixture was concentrated to a neat oil at 25° C. using a nitrogen gas purge line (and vent needle). The contents of the flask were suspended in 20 mL of diethyl ether and the reaction was quenched by pouring it into 20 mL of cold saturated aqueous sodium bicarbonate. The aqueous layer was washed twice with 5 mL of diethyl ether and the extracts were pooled, dried over MgSO4, filtered through cotton and concentrated to give an oily residue. Purification by silica gel chromatography in 3:1 petroleum ether:ethyl acetate afforded the title compound as an off-white solid (118 mg, 60%, R f = 0.30, a deep blue color to UV-active spots or CAM stains. The spectroscopic data of this material were consistent with those reported in the literature (Mechoulam, R. et al. 1965).

[0390] [ka]

[0391] Basic hydrolysis with LiOH in THF gives the free acid (CBGA) (Mechoulam, R. et al. 1965).

[0392] [ka]

[0393] Hydrolysis by thermal decarboxylation yields cannabigerol (CBG) (Mechoulam, R. et al. 1965).

[0394] [Example 6]: Synthesis of methyl olivetolate Methyl olivetolate (compound (III) where R1 is pentyl and R4 is methyl) was prepared by two different methods.

[0395] [Multi-step method] [1.3-Oxo-Ethyl Octanoate] A 250 mL round-bottom flask equipped with a Teflon-coated spin bar and a wide 24 / 40 ground glass joint was flame-dried under vacuum and backfilled with nitrogen. Anhydrous tin(II) chloride (1.5 g, 7.9 mmol, 0.099 equiv.) was ground with a mortar and pestle, weighed in air, and added to the flask, where the vacuum drying procedure was repeated in the presence of the solid and gently agitated by magnetic stirring. Under positive nitrogen pressure, the rigorously dried catalyst was suspended in 110 mL of dichloromethane obtained from a solvent purification system, and 12.5 g of ethyl diazoacetate (80.1 mmol, 1.00 equiv.) was added via syringe while stirring as a solution in 50 mL of dichloromethane (Womack, EB and Nelson, AB, 1944). To the resulting cloudy yellow mixture at ambient temperature, 9.8 mL of distilled hexanal (80 mmol, 1.0 equiv.) was added dropwise over 15 min, and vigorous nitrogen evolution was observed. After stirring for 1 h, effervescence ceased and the mixture became homogeneous. The reaction was transferred to a 500 mL separatory funnel containing 100 mL of saturated sodium chloride and extracted twice with 200 mL of diethyl ether. The organic layers were pooled, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. The resulting liquid was passed through a cotton plug and all remaining volatiles were removed under reduced pressure to give 15.0 g (quantitative yield) of a colorless, translucent oil that was found to be a single spot by TLC analysis (R in 4:1 petroleum ether:diethyl ether with KMnO4 stain). f =0.55). IR (undiluted, cm -1)2933, 1741, 1716, 1647, 1466, 1411, 1368, 1308, 1233, 1152, 1096, 1029, 847cm -1 ; 1 H NMR(CDCl3,500MHz)δ4.19(q,J=7.3Hz,2H),3.43(s,2H),2.53(t,J=7.3Hz,1H),1.60(quartet, J=6.9Hz,2H),1.33-1.24(m,7H),0.88(t,J=6.9Hz,3H); 13 C NMR(CDCl3,125MHz)δ203.2,167.4,61.5,49.5,43.2,31.3,23.3,22.5,14.2,14.0; HRMS(ESI+) calculated value C 10 H 18 O3Na[M+Na] + :209.1154;actual value 209.1155.

[0396] [2.2-(2-Pentyl-1,3-dioxolan-2-yl)ethyl acetate] To a solution of 5.70 g (30.6 mmol, 1.0 equiv.) of ethyl 3-oxooctanoate in 2-ethyl-2-methyl-1,3-dioxolane (9.0 mL, 72 mmol, 2.4 equiv.) in a flame-dried 100 mL round-bottom flask was added 1.75 g of para-toluenesulfonic acid hydrate (9.20 mmol, 0.30 equiv.) as a solid in one portion. The acid catalyst dissolved rapidly and the colorless solution was stirred at 25 °C for 12 h. The reaction mixture was quenched with 60 mL of saturated aqueous sodium bicarbonate, transferred to a 125 mL separatory funnel and washed three times with 50 mL of diethyl ether. The combined organic layers were dried over MgSO4 and concentrated to give the crude ethylene ketal as a yellow oil. Purification was achieved by flash chromatography on silica gel in 4:1 cyclohexane:diethyl ether as eluent using KMnO4 as stain. The product was purified by filtration using a small amount of recovered starting material (R f = 0.38, 210 mg, 3.7%) along with a colorless, free-flowing oil (R f = 0.50, 5.64 g, 80%). IR (undiluted, cm -1)2933, 1735, 1628, 1466, 1369, 1199, 1095, 1031, 949, 855cm -1 ; 1 H NMR(CDCl3,500MHz)δ4.15(q,J=7.3Hz,2H),4.01-3.94(m,4H),2.64(s,2H),1.79(ddd,J=5.4,2. 9,1.0Hz,2H),1.42-1.36(m,2H),1.33-1.27(m,4H),1.26(t,J=7.3Hz,3H),0.88(t,J=7.3Hz,3H); 13 C NMR (CDCl3, 125MHz) δ169.8, 109.6, 65.2, 60.6, 42.7, 37.9, 32.0, 23.3, 22.7, 14.3, 14.2; HRMS (ESI+) calcd. 12 H 22 O4Na[M+Na] + :253.1416; measured value 253.1413. C 12 H 22 Calculated value of O4's anus: C, 62.58; H, 9.63. Test value: C, 63.35; H, 9.55.

[0397] [3. 2-(2-Pentyl-1,3-dioxolan-2-yl)acetic acid] A 200 mL round bottom flask was charged with 2.31 g (10.0 mmol, 1.0 equiv.) of 2-(2-pentyl-1,3-dioxolan-2-yl)ethyl acetate in air and the oil was dissolved in 30 mL of absolute ethanol. With magnetic stirring at 25°C, 20.5 mL of 0.5 N standardized sodium hydroxide solution (10.3 mmol, 1.03 equiv.) was added via syringe, causing the solution to turn slightly opaque yellow. The flask was placed in an oil bath preheated to 80°C and the reaction mixture was refluxed for 2 hours, at which point the mixture became homogeneous. Stirring was continued for 12 hours at 25°C and the solution was briefly concentrated by rotary evaporation to remove the ethanol. The reaction mixture was then quenched at 0°C by the addition of 15 mL of saturated aqueous ammonium chloride, diluted with 20 mL of cold diethyl ether, and transferred to a 125 mL separatory funnel to separate the layers. The organic layer was isolated and the aqueous layer was treated with an additional 30 mL of ammonium chloride, resulting in visible turbidity. The mixture was extracted again with 30 mL of cold ether. A routine litmus paper test indicated that the aqueous layer was pH 6-7. Therefore, the acidification was repeated, this time with formic acid (300 μL) to reach a final pH of 5. A third 30 mL ether extract was collected and all organic layers were pooled, dried over MgSO4, and filtered through cotton. Concentration gave a colorless oil, which was purified by filtration through a short but wide pad of silica gel in 4:1:1 diethyl ether:dichloromethane:petroleum ether to remove traces of starting material (R f =0.80). Gradient elution with 100% diethyl ether and KMnO visualization revealed the acid product (R f =0.45) was obtained as a colorless oil which was stored under nitrogen at -20°C (1.54g, 76%). 1 H NMR(CDCl3,500MHz)δ4.04-3.98(m,4H),2.70(s,3H),1.78(ddd,J=5.4,2.9,1.0Hz,2H),1.42-1.36(m,2H),1.32-1.23(m,4H),0.88(t,J=6.8Hz,3H); 13C NMR(CDCl3,125MHz)δ175.3,109.5,65.2,42.4,37.7,31.9,23.3,22.7,14.2,14.1.HRMS(ESI+) Calculated value C 10 H 18 O4Na[M+Na] + :225.1097;actual value 225.1099.

[0398] [4. Methyl 2,4-dihydroxy-6-pentylbenzoate] A flame-dried 100 mL round-bottom flask equipped with a Teflon-coated spin bar was charged with 1.54 g (7.61 mmol, 1.0 equiv.) of 2-(2-pentyl-1,3-dioxolan-2-yl)acetic acid followed by 30 mL of dry benzene. After the solution was stirred at 25° C. for 5 min, oxalyl chloride (0.64 mL, 7.6 mmol, 0.99 equiv.) was added dropwise via syringe under positive nitrogen pressure. After placing a heating mantle under the vessel, the reaction mixture was refluxed for 2 h with continuous stirring. The flask was then cooled to 25° C., the stir bar was removed, and the benzene was removed by rotary evaporation. Heating was avoided during solvent removal as the acid chloride product decomposes on standing at room temperature. The resulting pale yellow oil, obtained in >98% yield based on mass difference, was used immediately without purification in the subsequent cycloaddition.

[0399] Thus, a second flame-dried 100 mL round-bottom flask equipped with a Teflon-coated spin bar was charged with 1.96 g (7.52 mmol, 1.0 equiv.) of (E)-1,3-bis(trimethylsiloxy)-1-methoxybuta-diene prepared by the procedure of Chan and Brownbridge (Chan, T.H., Brownbridge, PA, 1980).

[0400] The 2-(2-pentyl-1,3-dioxolan-2-yl)acetyl chloride (1.66 g, 7.52 mmol, 1.0 equiv.) prepared above was dissolved in 30 mL of dry dichloromethane and added to the flask containing the bis(silyl enol ether) via a steel cannula under positive nitrogen pressure. With continuous stirring, the resulting yellow-orange mixture was treated with a solution of titanium tetrachloride (1.65 mL, 15.0 mmol, 2.0 equiv.) in 8.0 mL of dichloromethane (final concentration 0.20 M). After stirring for 24 h at 25° C., the reaction mixture was poured into 50 mL of cold saturated aqueous sodium bicarbonate in a 125 mL separatory funnel and extracted three times with 30 mL of diethyl ether. The combined organic layers were dried over MgSO4, filtered, and concentrated by rotary evaporation. The crude product was purified by HPLC using a 4:1 mixture of benzene:diethyl ether (R 2 ) and 1:1 benzene:diethyl ether (R 2 ). f The crude product was purified by flash chromatography on silica gel using KMnO4 stain for spot visualization, with 100% NaOH (molecular weight, 1000 g) as the eluent. Concentration of the pure product fractions afforded the spontaneous deposition of methyl olivetolate as a yellow solid (986 mg, 55%). Mp=77-78 °C; IR (neat, cm -1 ) 3600, 3400 (phenol OH band), 1660 (ester); 1 H NMR(CDCl3,500MHz)δ11.68(s,1H),6.28(d,J=2.9Hz,1H),6.23(d,J=2.5Hz,1H),5.26(br s,1H),3.92(s,3H),2.83(t,J=7.8Hz,2H),1.56-1.49(m,2H),1.36-1.30(m,4H),0.90(t,J=6.8Hz,3H); 13 C NMR(CDCl3,125MHz)δ172.1,165.4,160.4,149.1,110.9,104.8,101.5,52.1,37.0,32.2,31.6,22.7,14.2.HRMS(ESI+) calculated value C 13 H 19 O4Na[M+H] + :239.1283;actual value 239.1279.

[0401] [One-step method] [1. Methyl 2,4-dihydroxy-6-pentylbenzoate] Methyl 6-n-pentyl-2-hydroxy-4-oxo-cyclohex-2-ene-1-carboxylate (2.62 g, 10.9 mmol), prepared as a white flaky solid by literature procedures (Focella, A. et al. 1977), was added to a 100 mL round-bottom flask containing a Teflon-coated spin bar and dissolved in 10 mL of anhydrous DMF at 25° C. to give a viscous yellow solution. Into a separate flame-dried 50 mL round-bottom flask, under positive nitrogen pressure, was charged by syringe with 10 mL of anhydrous DMF followed by 0.56 mL (11 mmol, 1.0 equiv.) of bromine. The reaction mixture was then cooled to -10 °C in an ice / methanol bath, and the bright red oxidant stock solution was drawn into a degassed 12 mL disposable gas-tight syringe and added dropwise to the substrate automatically over 90 min from a Ryzel syringe pump. At the end of the addition, the reaction mixture was successively diluted with 50 mL ice-cold deionized water and 75 mL diethyl ether, the former resulting in a dark brown bleaching of the solution. The resulting bilayer was transferred to a 125 mL separatory funnel and, after mixing, the yellow organic layer was removed. The aqueous layer, neutral to litmus paper, was washed twice with 30 mL portions of diethyl ether. In a 250 mL separatory funnel, the combined organic layers were washed three times with 100 mL portions of saturated aqueous sodium chloride to remove traces of DMF. The extract was dried over MgSO4 and filtered directly into a 250 mL round-bottom flask through a medium porosity glass frit in preparation for the thermal rearomatization step. Concentration by rotary evaporation gave a yellow solid which was immediately redissolved in toluene (55 mL) and the flask was fitted with a reflux condenser and a heating mantle. After stirring at reflux under air for 1 h, the solvent was removed by rotary evaporation. The crude methyl olivetolate was dissolved in 5:1 petroleum ether:diethyl ether (R f =0.35) as eluent and KMnO4 stain for spot visualization. Concentration of the pure product fractions led to spontaneous crystallization of methyl olivetolate as a yellow solid (2.08 g, 80%), which was further dried under high vacuum. Mp=77-78 °C; IR (neat, cm -1) 3600, 3400 (phenol OH band), 1660 (ester); 1 H NMR(CDCl3,500MHz)δ11.68(s,1H),6.28(d,J=2.9Hz,1H),6.23(d,J=2.5Hz,1H),5.26(br s,1H),3.92(s,3H),2.83(t,J=7.8Hz,2H),1.56-1.49(m,2H),1.36-1.30(m,4H),0.90(t,J=6.8Hz,3H); 13 C NMR(CDCl3,125MHz)δ172.1,165.4,160.4,149.1,110.9,104.8,101.5,52.1,37.0,32.2,31.6,22.7,14.2.HRMS(ESI+) calculated value C 13 H 19 O4Na[M+H] + :239.1283;actual value 239.1280.

[0402] Example 7: Synthesis of enantiopure (-)-cannabidiol (CBD) via LAH reduction Enantiopure (-)-cannabidiol (CBD) was prepared starting from commercially available (R)-limonene.

[0403] [1. (S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-2-enone: Generic name (+)-(S)-isopiperitenone (Dethe,DHet al.2015)] A flame-dried 100 mL round-bottom flask was syringed with 40 mL of tert-butanol. With vigorous magnetic stirring, 16.0 g (160 mmol, 4.0 equiv.) of powdered chromium(VI) oxide was added in portions. Initial dissolution of the oxidant results in a bright orange solution, but with continued stirring the solution turns a deep maroon color and slight warming is observed. After 10 min at 25 °C, the solution was cooled to 0 °C, diluted with 40 mL of chloroform, and transferred to a 250 mL separatory funnel. Ice-cold DI water (50 mL) was added and the mixture was swirled before allowing the phases to separate. The lower organic layer (bright red) was removed and the upper aqueous layer (light brown) was back-extracted with two 20 mL portions of chloroform. The pooled organic layers were dried over sodium sulfate and vacuum filtered through cotton in a coarse porosity fritted funnel and placed directly into a flame-dried 250 mL round-bottom receiving flask. To the resulting deep red filtrate was added 6.50 mL (40.2 mmol, 1.0 equiv.) of (R)-limonene. With continuous stirring, the vessel was fitted with a heating mantle and the solution was brought to gentle reflux. After 1 hour, the reaction mixture became opaque and dark brown in color. The heat source was removed and stirring was continued overnight at 25° C., at which point TLC analysis confirmed the absence of starting material and the formation of two regioisomeric enones. The mixture was directly filtered to remove the insoluble Cr(IV) deposit and the resulting brown filtrate was concentrated on a rotary evaporator in the presence of 10 grams of added silica gel. Purification of the residue by column chromatography using 10:1 petroleum ether:diethyl ether as eluent and KMnO4 stain for spot visualization afforded the major isomer (R f =0.55) (S)-carvone (1.99 g, 33%) and isopiperitenone (R f = 0.40, 1.03 g, 17%) was obtained. [α] 22 D =+27.88(c 0.54,CHCl3);IR(undiluted, cm -1)3076, 2927, 1667, 1435, 1379, 1201, 1087, 891; 1 H NMR(CDCl3,500MHz)δ5.89(d,J=1.5Hz,1H),4.94(d,J=1.5Hz,1H),4.75(d,J=1.5Hz,1H),2.94(d d,J=10.5,5.4Hz,1H),2.35-2.31(m,2H),2.11-1.98(m,2H),1.94(s,3H),1.74(d,J=1.5Hz,3H); 13 C NMR (CDCl3, 125MHz) δ199.5, 162.0; 143.4, 126.8, 113.6, 53.9, 30.4, 27.7, 24.3, 20.7; HRMS (ESI+) calcd. 10 H 14 O[M] + :150.1045; measured value 150.1043.

[0404] [2. (1R,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-2-enol, common name (+)-trans-isopiperitenol] In a flame-dried 100 mL round-bottom flask, in air, 227 mg (5.98 mmol, 1.8 equiv.) of lithium aluminum hydride (LAH) was placed as a moisture-sensitive gray powder. With magnetic stirring, 3.0 mL of anhydrous THF (distributed from a solvent purification system) was added via syringe under positive nitrogen pressure. The resulting heterogeneous suspension of reducing agent (concentration 2.0 M) was cooled to -78 °C in a dry ice / acetone bath in a Dewar. In a separate flame-dried 50 mL pear-shaped flask, undiluted (+)-(S)-isopiperitenone (500 mg, 3.33 mmol, 1.0 equiv.) was placed and the ketone was dissolved in 10 mL of additional anhydrous THF. The resulting pale yellow-orange solution of substrate was transferred to the LAH suspension down the wall of the receiving flask (for precooling) using a 12 mL degassed syringe. The rate of addition was controlled to offset the small amount of foaming observed in the reaction mixture, and the temperature of the Dewar bath was maintained at -78 °C by supplementing with additional dry ice. After stirring for 30 min after addition, the reaction mixture was slowly warmed to 0 °C and then held at that temperature using an ice bath for quenching. The reaction mixture was then treated successively with 0.23 mL of deionized water, 0.23 mL of 10% aqueous sodium hydroxide, and finally 0.69 mL of deionized water. The triple addition is a convenient protocol for quenching n grams of LAH with n mL of H2O, n mL of dilute NaOH, and 3n mL of H2O to obtain a granular precipitate of Al(OH)3 salt that is easily removed by filtration, but should be performed with caution due to the initial vigorous evolution of hydrogen gas. After continued stirring for 30 min, the reaction mixture was filtered through a crude fritted funnel and the precipitate and original vessel were washed twice with 5 mL of diethyl ether. The combined filtrate was concentrated to give a colorless liquid. 1H NMR analysis confirmed the presence of the 1,2-reduction products (+)-(1R,6S)-isopiperitenol and (+)-(1S,6S)-isopiperitenol in a 5:1 (trans:cis) ratio with no detectable 1,4-reduction. Some separation of the major isomers is possible by flash chromatography in 5:1 petroleum ether:ethyl acetate using CAM stain for spot visualization. In that case, a 4 cm wide x 16 cm high silica gel column was used to elucidate 42.2 mg of (+)-trans-isopiperitenol (R f =0.32) and 376 mg of the diastereomeric mixture (R f = 0.36, 83% total yield. Spectroscopic data for the minor (+)-cis-isopiperitenol were identical to material previously prepared by multi-step asymmetric synthesis with 94% ee enriched in the (1R,6R) enantiomer (Tomooka, K. et al. 2005): IR (undiluted, cm -1 )3352, 3088, 2936, 1676, 1649, 1450, 1379, 1245, 1210, 1176, 1156, 1114, 1069, 1025, 957, 915, 886, 849, 816, 723, 681cm -1 ; 1 H NMR(CDCl3,500MHz)δ5.67(m,1H),4.99(s,1H),4.81(s,1H),4.12(br s,1H),2.17-2.04(m,3H),1.83(s,3H),1.80-1.74(m,1H),1.72(s,3H),1.65-1.55(m,1H),1.48(br s,1H); 13 C NMR (CDCl3, 125 MHz) δ 146.7, 139.9, 122.5, 111.8, 63.9, 46.2, 31.3, 23.5, 22.7, 21.0. Characterization of the major diastereomers is as follows: IR (neat, cm -1 ) 3396, 2925, 2854, 1453, 1375, 1035, 887; 1H NMR(CDCl3,500MHz)δ5.45-5.44(m,1H),4.89-4.88(m,1H),4.85-4.84(m,1H),4.13-4.10(m, 1H),2.10-2.04(m,2H),1.95-1.93(m,1H),1.73-1.72(s,3H),1.69(m,3H),1.65-1.56(m,2H); 13 C NMR(CDCl3,125MHz)δ146.4,136.6;124.3,112.2,68.6,50.8,30.1,26.1,23.0,19.3;HRMS(ESI+) calculated value C 10 H 16 O[M] + :152.1201;actual value 152.1209.

[0405] 3. (-)-Cannabidiolic acid methyl ester, generic name methyl cannabiolate: 23.8 mg of methyl 2,4-dihydroxy-6-pentylbenzoate (0.100 mmol, 1.1 equiv.) and 7.2 mg of camphorsulfonic acid (0.031 mmol, 0.34 equiv.) were placed as solids in a flame-dried 1-dram vial in air, then the vial was purged with nitrogen gas before 0.6 mL of anhydrous dichloromethane was added as solvent. To the resulting clear solution, stirred at 0° C., 13.8 mg of (+)-trans-isopiperitenol (0.0907 mmol, 0.91 equiv.) in 0.4 mL of dichloromethane was added dropwise over 1 hour. The reaction mixture was stirred at 0° C. for an additional hour, the ice bath was removed, and the reaction mixture was concentrated to a neat oil at 25° C. using a nitrogen gas purge line (and vent needle). The contents of the vial were then resuspended in 1.0 mL of diethyl ether, and 1.0 mL of cold saturated aqueous sodium bicarbonate was added to quench the acid catalyst and agitated by stirring, after which the organic layer was removed with a Pasteur pipette. The aqueous layer was washed twice with 1.0 mL of diethyl ether, and the extracts were pooled, dried over MgSO4, filtered through cotton, and concentrated to give an oily residue. Purification by silica gel chromatography in 9:1 petroleum ether:diethyl ether afforded the title compound as a yellow oil (21.1 mg, 60%, R f= 0.55, UV active spot or deep blue color against CAM stain). 1 H NMR(CDCl3,500MHz)δ12.00(s,1H),6.51(s,1H),6.21(s,1H),5.55(s,1H),4.52(s,1H),4.37(s,1H),4.10(br s,1H), 3.90(s,3H), 2.87-2.81(m,1H), 2.76-2.69(m,1H), 2.71-2.65(m,1H), 2.42-2.32(m,1H), 2.34-2.27(m,1H), 2.26-2.17(m,1H), 2.12-2.06(m,1H), 1.79(s,3H), 1.71(s,3H), 1.54-1.46(m,2H), 1.35-1.27(m,2H), 1.27-1.23(m,2H), 0.89(t,J=6.5Hz,3H).When the above protocol is carried out with a >4:1 trans:cis mixture of (+)-isopiperitenol, a similar yield is obtained with a smaller amount of the diastereomer consumed.

[0406] [4. (-)-Cannabidiol (CBD)] The above methyl cannabiolate (21.1 mg, 0.0566 mmol, 1.0 equiv.) was dissolved in 0.28 mL of methanol in a 1-dram vial containing a Teflon-coated flea stir bar. With magnetic stirring and under positive nitrogen pressure, the solution was treated with 0.22 mL of 0.5 N standardized sodium hydroxide solution by syringe through a rubber septum. The septum was removed, the opening was sealed with a Teflon-lined screw cap closure, and the vial was immersed in an oil bath heated to 65°C. The reaction mixture was stirred continuously under gentle reflux for 3 hours and then cooled to 25°C, at which point TLC analysis confirmed the absence of starting ester. The mixture was acidified by adding 1.0 mL of a 30% solution of citric acid in deionized water, and the contents were washed three times with 0.5 mL volumes of diethyl ether. Liquid-liquid extraction was conveniently performed in the same vial by capping and shaking the two phases. The combined organic washes were siphoned, dried over MgSO4, filtered through cotton, and concentrated to give the title compound CBD as an off-white solid (16 mg, 90%). [α] 22 D =‐122(c 1.0,EtOH);IR(undiluted, cm -1 )3513, 3401, 2914, 1621, 1438, 1216; 1 H NMR(CDCl3,500MHz)δ6.40-6.10(br s,2H),6.10-5.80(br s,1H),5.57(s,1H),4.90-4.60(br s,1H),4.64(m,1H),4.54(m,1H),3.90-3.80(dm,J=11.8Hz,1H),2.50-2.40(m,3H),2.30-2.00(m,2H),1 .90-1.75(m,2H),1.82(s,3H),1.67(s,3H),1.65-1.50(m,2H),1.40-1.20(m,4H),0.90(t,J=6.5Hz,3H); 13C NMR(DMSO-d6,125MHz)δ156.7,149.6;140.6,130.5,127.3,114.6,110.1,107. 1,44.1,36.0,35.4,31.5,30.8,30.0,23.8,22.5,19.7,14.4;HRMS(ESI+) calculation value C 21 H 29 O2[M-H] - :313.2173;Actual value 313.2170.

[0407] [Example 8]: Synthesis of racemic (±)-cannabidiol (CBD) via (±)-trans-isopiperitenol The method described in Example 1 was adapted to provide racemic (±)-cannabidiol (CBD). Specifically, the following method was used to obtain (±)-trans-isopiperitenol in >5:1dr, which was then subjected to steps 3 and 4 of Example 7.

[0408] [1.Rac-(±)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-2-enone, common name (±)-isopiperitenone] A 1.75 gram sample of commercial citral (≥96%, a mixture of trans (geranial) and cis (neral)) was filtered through a column (5 cm diameter × 10 cm height) of silica gel slurry packed in benzene containing 3% diethyl ether (R f= 0.54; yellow spot under UV activity or KMnO4 staining). This flash chromatography step serves to remove the yellow impurity eluting at the solvent front and also rigorously dry the substrate by azeotropic removal of traces of water. The pure citral fraction was concentrated on a rotary evaporator, backfilled with an argon balloon, further degassed under high vacuum, and magnetically stirred the undiluted oil to give 1.52 g (10.0 mmol, 1.0 equiv.) of completely colorless citral. The starting material was dissolved in 10.0 mL of anhydrous dichloromethane and the solution was loaded into a 12 mL plastic syringe. A second disposable gas-tight syringe was charged with commercially available dimethylaluminum chloride (10.1 mL of 1.0 M in hexane, 10.1 mmol, 1.01 equiv.) while degassing under positive nitrogen pressure. Finally, a separate, flame-dried, 100 mL round-bottom flask with a 24 / 40 joint equipped with a side-arm stopcock and hose connector (for nitrogen pressure) was charged with 10.0 mL of dichloromethane and cooled to -10 °C in an ice / methanol bath. The substrate and promoter solutions were added dropwise to the cooled flask over a period of 3 h at equal addition rates using two syringe pumps. The exit needle of the promoter solution was placed below the solvent surface to minimize fume or turbidity in the headspace of the reaction flask. The role of the slow addition is to mimic high dilution and minimize intermolecular reactions. Over the course of the addition, the reaction mixture turns light orange and eventually maroon. Stirring was continued while slowly warming to room temperature over the course of 1 h. The mixture was then quenched at 0 °C by sequential addition of 1.0 mL of DI water, 1.0 mL of 4 M aqueous sodium hydroxide, and an additional 3.0 mL of water. These additions, which mirror the standard workup of lithium aluminum hydride reactions, caused the evolution of methane gas, the bleaching of the reaction mixture to an orange color, and the formation of a milky white precipitate from which the yellow supernatant was easily isolated by decantation. Thus, the mixture was filtered through a cotton pad, the Al(III) hydroxide precipitate was washed with additional dichloromethane, and concentrated to give a bronze-colored oil. 1H NMR analysis indicated 30% conversion of citral to a product mixture consisting of a 2.5:1 ratio of (±)-isopiperitenone to (±)-isopiperitenol (the latter present at a dr of >10:1) relative to the predicted trans-selective carbonyl ene reaction promoted by the Al reagent. However, mechanistic considerations suggest that, following the designed pericyclic process, the electron-rich dimethylaluminum(III) alkoxide undergoes an internal Oppenauer oxidation (via transfer of Meerwein-Ponndorf-Burley hydride to unreacted citral) to yield a ketone as the major product. The desired polar fraction (R in 2:1 heptane:diethyl ether) was then reacted with 1H NMR to obtain 1H NMR. f =0.38) was separated from unreacted citral by flash filtration through silica gel in the same eluent with either KMnO4 or cerium ammonium molybdate (CAM) TLC staining. This provided >60% citral (R f =0.90) and 228 mg (15% yield) of a 2.5:1 mixture of (±)-isopiperitenone:(±)-isopiperitenol as a colorless oil. This mixture was subjected to the 1,2-reduction protocol exactly as reported above (Example 7, step 1), allowing the blocking of the asymmetric pathway to CBD. Spectroscopic and TLC analytical data for (±)-isopiperitenone, (±)-trans-isopiperitenol, and (±)-cis-isopiperitenol were consistent with those of the optically active standards (+)-(S)-isopiperitenone, (+)-(1R,6S)-isopiperitenol, and (+)-(1S,6S)-isopiperitenol, as reported in steps 1 and 2 of Example 7 above.

[0409] Example 9: Enantiopure (-)-delta-9-tetrahydrocannabinol (Δ 9 -THC) Enantiopure (-)-delta-9-tetrahydrocannabinol (Δ 9 -THC) was prepared starting from commercially available (R)-limonene.

[0410] [1. (S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-2-enone; generic name (+)-(S)-isopiperitenone (Dethe,DHet al. 2015)] 40 mL of tert-butanol was syringed into a flame-dried 100 mL round-bottom flask. With vigorous magnetic stirring, 16.0 g (160 mmol, 4.0 equiv.) of powdered chromium(VI) oxide was added in small portions. Initial dissolution of the oxidant results in a bright orange solution, but with continued stirring the solution turns a deep maroon color and slight warming is observed. After 10 min at 25 °C, the solution was cooled to 0 °C, diluted with 40 mL of chloroform, and transferred to a 250 mL separatory funnel. Ice-cold DI water (50 mL) was added and the mixture was swirled before allowing the phases to separate. The lower organic layer (bright red) was removed and the upper aqueous layer (light brown) was back-extracted with two 20 mL portions of chloroform. The pooled organic layers were dried over sodium sulfate and vacuum filtered through cotton in a coarse porosity fritted funnel and placed directly into a flame-dried 250 mL round-bottom receiving flask. To the resulting deep red filtrate was added 6.50 mL (40.2 mmol, 1.0 equiv.) of (R)-limonene. With continuous stirring, the vessel was fitted with a heating mantle and the solution was brought to gentle reflux. After 1 hour, the reaction mixture became opaque and dark brown in color. The heat source was removed and stirring was continued overnight at 25° C., at which point TLC analysis confirmed the absence of starting material and the formation of two regioisomeric enones. The mixture was directly filtered to remove the insoluble Cr(IV) deposit and the resulting brown filtrate was concentrated on a rotary evaporator in the presence of 10 grams of added silica gel. Purification of the residue by column chromatography using 10:1 petroleum ether:diethyl ether as eluent and KMnO4 stain for spot visualization afforded the major isomer (R f =0.55) (S)-carvone (1.99 g, 33%) and isopiperitenone (R f = 0.40, 1.03 g, 17%) was obtained. [α] 22 D =+27.88(c 0.54, CHCl3);IR(undiluted, cm -1)3076,2927,1667,1435,1379,1201,1087,891; 1 H NMR(CDCl3,500MHz)δ5.89(d,J=1.5Hz,1H),4.94(d,J=1.5Hz,1H),4.75(d,J=1.5Hz,1H),2.94(d d,J=10.5,5.4Hz,1H),2.35-2.31(m,2H),2.11-1.98(m,2H),1.94(s,3H),1.74(d,J=1.5Hz,3H); 13 C NMR (CDCl3, 125MHz) δ199.5, 162.0; 143.4, 126.8, 113.6, 53.9, 30.4, 27.7, 24.3, 20.7; HRMS (ESI+) calcd. 10 H 14 O[M] + :150.1045; measured value 150.1043.

[0411] [2. (1R,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-2-enol, common name (+)-trans-isopiperitenol] In a flame-dried 100 mL round-bottom flask, in air, 227 mg (5.98 mmol, 1.8 equiv.) of lithium aluminum hydride (LAH) was placed as a moisture-sensitive gray powder. With magnetic stirring, 3.0 mL of anhydrous THF (distributed from a solvent purification system) was added via syringe under positive nitrogen pressure. The resulting heterogeneous suspension of reducing agent (concentration 2.0 M) was cooled to -78 °C in a dry ice / acetone bath in a Dewar. In a separate flame-dried 50 mL pear-shaped flask, undiluted (+)-(S)-isopiperitenone (500 mg, 3.33 mmol, 1.0 equiv.) was placed and the ketone was dissolved in 10 mL of additional anhydrous THF. The resulting pale yellow-orange solution of substrate was transferred to the LAH suspension down the wall of the receiving flask (for precooling) using a 12 mL degassed syringe. The rate of addition was controlled to offset the small amount of foaming observed in the reaction mixture, and the temperature of the Dewar bath was maintained at -78 °C by supplementing with additional dry ice. After stirring for 30 min after addition, the reaction mixture was slowly warmed to 0 °C and then held at that temperature using an ice bath for quenching. The reaction mixture was then treated successively with 0.23 mL of deionized water, 0.23 mL of 10% aqueous sodium hydroxide, and finally 0.69 mL of deionized water. The triple addition is a convenient protocol for quenching n grams of LAH with n mL of H2O, n mL of dilute NaOH, and 3n mL of H2O to obtain a granular precipitate of Al(OH)3 salt that is easily removed by filtration, but should be performed with caution due to the initial vigorous evolution of hydrogen gas. After continued stirring for 30 min, the reaction mixture was filtered through a crude fritted funnel and the precipitate and original vessel were washed twice with 5 mL of diethyl ether. The combined filtrate was concentrated to give a colorless liquid. 1H NMR analysis confirmed the presence of the 1,2-reduction products (+)-(1R,6S)-isopiperitenol and (+)-(1S,6S)-isopiperitenol in a 5:1 (trans:cis) ratio with no detectable 1,4-reduction. Some separation of the major isomers is possible by flash chromatography in 5:1 petroleum ether:ethyl acetate using CAM stain for spot visualization. In that case, a 4 cm wide x 16 cm high silica gel column was used to elucidate 42.2 mg of (+)-trans-isopiperitenol (R f =0.32) and 376 mg of the diastereomeric mixture (R f = 0.36, 83% total yield. Spectroscopic data for the minor (+)-cis-isopiperitenol were identical to material previously prepared by multi-step asymmetric synthesis with 94% ee enriched in the (1R,6R) enantiomer (Tomooka, K. et al. 2005): IR (undiluted, cm -1 )3352, 3088, 2936, 1676, 1649, 1450, 1379, 1245, 1210, 1176, 1156, 1114, 1069, 1025, 957, 915, 886, 849, 816, 723, 681cm -1 ; 1 H NMR(CDCl3,500MHz)δ5.67(m,1H),4.99(s,1H),4.81(s,1H),4.12(br s,1H),2.17-2.04(m,3H),1.83(s,3H),1.80-1.74(m,1H),1.72(s,3H),1.65-1.55(m,1H),1.48(br s,1H); 13 C NMR (CDCl3, 125 MHz) δ 146.7, 139.9, 122.5, 111.8, 63.9, 46.2, 31.3, 23.5, 22.7, 21.0. Characterization of the major diastereomers is as follows: IR (neat, cm -1 ) 3396, 2925, 2854, 1453, 1375, 1035, 887; 1H NMR(CDCl3,500MHz)δ5.45-5.44(m,1H),4.89-4.88(m,1H),4.85-4.84(m,1H),4.13-4.10(m, 1H),2.10-2.04(m,2H),1.95-1.93(m,1H),1.73-1.72(s,3H),1.69(m,3H),1.65-1.56(m,2H); 13 C NMR(CDCl3,125MHz)δ146.4,136.6;124.3,112.2,68.6,50.8,30.1,26.1,23.0,19.3;HRMS(ESI+) calculated value C 10 H 16 O[M] + :152.1201;actual value 152.1209.

[0412] [3. (-)-Delta-9-tetrahydrocannabinol (Δ 9 [-THC, International Non-Proprietary Name Dronabinol] para-toluenesulfonic acid monohydrate was recrystallized (as fine needles) from boiling chloroform, washed with hexane, and dried under vacuum before use. A flame-dried 10 mL round-bottom flask was charged under positive nitrogen pressure with 20.0 mg of commercial olivetol (0.111 mmol, 1.0 equiv.) as a solid and 6.8 mg of p-TsOH (0.039 mmol, 0.35 equiv.), as well as 1.7 mL of anhydrous dichloromethane. To the resulting clear solution, stirred at 25°C, was added dropwise over 1 h 18.6 mg (0.122 mmol, 1.1 equiv.) of (+)-trans-isopiperitenol (Cardillo, B. et al. 1973) in 0.5 mL of dichloromethane. TLC analysis of the mixture after 2 hours of reaction showed only traces of reactants and a prominent non-polar spot (R in 3:1 hexane:diethyl ether). f =>0.90). The reaction was quenched with 2.0 mL of saturated sodium bicarbonate and the organic layer was removed. The aqueous layer was washed twice with 1.0 mL of dichloromethane and the extracts were combined, dried over MgSO4, filtered through cotton and concentrated to give an oily residue. Purification by passage through silica gel in 50:1 petroleum ether:ethyl acetate gave 12.7 mg (33%) of Δ 9 -THC and Δ8 A clean 3:1 mixture with -THC (Hively, RLet et al. 1966) was obtained. Separation by HPLC was reported under the following conditions: Sunfire C18 5μ, 4.6×150 mm column, 1 mL / min flow rate, gradient elution from 80% water to 100% acetonitrile in acetonitrile containing 0.5–1% TFA. Synthesis Δ 9 The spectroscopic and analytical data for -THC are consistent with that of both the natural product (Gaoni, Y. et al. 1964) and the racemic material prepared according to earlier biomimetic synthesis (Taylor, EC et al. 1966).

[0413] [Example 10]: Racemic (±)-delta-9-tetrahydrocannabinol (Δ) via (±)-trans-isopiperitenol 9 -THC) The method described in Example 9 was carried out to obtain racemic (±)-delta-9-tetrahydrocannabinol (Δ 9 -THC). Specifically, the following method was used to obtain (±)-trans-isopiperitenol in >5:1dr, which was then subjected to step 3 of Example 9.

[0414] [1.Rac-(±)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-2-enone, common name (±)-isopiperitenone] A 1.75 gram sample of commercial citral (≥96%, a mixture of trans (geranial) and cis (neral)) was filtered through a column (5 cm diameter × 10 cm height) of silica gel slurry packed in benzene containing 3% diethyl ether (R f= 0.54; yellow spot under UV activity or KMnO4 staining). This flash chromatography step serves to remove the yellow impurity eluting at the solvent front and also rigorously dry the substrate by azeotropic removal of traces of water. The pure citral fraction was concentrated on a rotary evaporator, backfilled with an argon balloon, further degassed under high vacuum, and magnetically stirred the undiluted oil to give 1.52 g (10.0 mmol, 1.0 equiv.) of completely colorless citral. The starting material was dissolved in 10.0 mL of anhydrous dichloromethane and the solution was loaded into a 12 mL plastic syringe. A second disposable gas-tight syringe was charged with commercially available dimethylaluminum chloride (10.1 mL of 1.0 M in hexane, 10.1 mmol, 1.01 equiv.) while degassing under positive nitrogen pressure. Finally, a separate, flame-dried, 100 mL round-bottom flask with a 24 / 40 joint equipped with a side-arm stopcock and hose connector (for nitrogen pressure) was charged with 10.0 mL of dichloromethane and cooled to -10 °C in an ice / methanol bath. The substrate and promoter solutions were added dropwise to the cooled flask over a period of 3 h at equal addition rates using two syringe pumps. The exit needle of the promoter solution was placed below the solvent surface to minimize fume or turbidity in the headspace of the reaction flask. The role of the slow addition is to mimic high dilution and minimize intermolecular reactions. Over the course of the addition, the reaction mixture turns light orange and eventually maroon. Stirring was continued while slowly warming to room temperature over the course of 1 h. The mixture was then quenched at 0 °C by sequential addition of 1.0 mL of DI water, 1.0 mL of 4 M aqueous sodium hydroxide, and an additional 3.0 mL of water. These additions, which mirror the standard workup of lithium aluminum hydride reactions, caused the evolution of methane gas, the bleaching of the reaction mixture to an orange color, and the formation of a milky white precipitate from which the yellow supernatant was easily isolated by decantation. Thus, the mixture was filtered through a cotton pad, the Al(III) hydroxide precipitate was washed with additional dichloromethane, and concentrated to give a bronze-colored oil. 1H NMR analysis indicated 30% conversion of citral to a product mixture consisting of a 2.5:1 ratio of (±)-isopiperitenone to (±)-isopiperitenol (the latter present at a dr of >10:1) relative to the predicted trans-selective carbonyl ene reaction promoted by the Al reagent. However, mechanistic considerations suggest that, following the designed pericyclic process, the electron-rich dimethylaluminum(III) alkoxide undergoes an internal Oppenauer oxidation (via transfer of Meerwein-Ponndorf-Burley hydride to unreacted citral) to yield a ketone as the major product. The desired polar fraction (R in 2:1 heptane:diethyl ether) f =0.38) was separated from unreacted citral by flash filtration through silica gel in the same eluent with either KMnO4 or cerium ammonium molybdate (CAM) TLC staining. This provided >60% citral (R f =0.90) and 228 mg (15% yield) of a 2.5:1 (±)-isopiperitenone:(±)-isopiperitenol mixture as a colorless oil. This mixture was subjected to the 1,2-reduction protocol exactly as reported above (Example 1, step 1), allowing for the blocking of the asymmetric pathway to CBD. Spectroscopic and TLC analytical data for (±)-isopiperitenone, (±)-trans-isopiperitenol, and (±)-cis-isopiperitenol were consistent with those of the optically active standards (+)-(S)-isopiperitenone, (+)-(1R,6S)-isopiperitenol, and (+)-(1S,6S)-isopiperitenol, as reported in Example 7, steps 1 and 2 above.

[0415] [Consideration] Cannabidiol is a well-known phytocannabinoid produced as a major constituent in both marijuana and cannabis plants, Cannabis sativa and Cannabis indica. Over the decades, the endocannabinoid receptor system (ECS), which underlies the physiological effects of the cannabis plant in humans, has emerged as a major target for pharmacological therapy (Mechoulam, R. et al. 2014). ECS proteins include the cannabinoid receptors CB1 and CB2, as well as endogenous ligands called endocannabinoids (Morales, P. et al. 2017). CB1 receptors are abundant in the brain and to a lesser extent in peripheral tissues, while CB2 is mainly expressed on the surface of circulating immune cells. Currently, cannabidiol (CBD) has attracted increasing medical interest due to its demonstrated antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, and neuroprotective properties. However, the production of CBD on a commercial scale presents many challenges due to the common preparative approach that relies on Friedel-Crafts alkylation of olivetol (1,3-dihydroxy-5-pentylbenzene) to introduce the key aryl-monoterpenyl C-C bond. One of the significant issues that plagues many syntheses is the need for strong Lewis or Brönsted acidic reagents to promote terpenylation, making it impossible due to acidic conditions to terminate the further cyclization of the phenolic group to the dihydropyran ring of (-)-trans-delta-9-tetrahydrocannabinol (THC), a Schedule 1 federally controlled substance. 9 -THC (dihydropyran stereoisomers), Δ 8 Additional isomers such as -THC (derived from rearrangement of the cyclohexene double bond) and iso-THC (positional isomeric material resulting from F-C alkylation in the ortho position relative to the 5C n-amyl substituent) are time-consuming to separate from the desired product, increasing time and cost and making it difficult for the active pharmaceutical ingredient to achieve current purity standards. Extraction and purification of natural CBD is economically unattractive and suffers from similar drawbacks. For example, the psychoactive Δ 9Even industrial strains of cannabis that are specifically bred to have low amounts of THC often exceed the legal limit of 0.3% or less by dry weight.

[0416] Despite its high potential for abuse and its notorious status as a federally controlled substance, trans-Δ 9 -THC has broad medical utility as an antiemetic (appetite stimulant) and sleep apnea reliever. It has also been approved by the FDA for clinical use in the treatment of HIV / AIDS-induced anorexia, chemotherapy-induced nausea, and glaucoma. A further feature that further speaks to regulatory and agricultural issues in the cannabis industry is the Δ 9 - Both THC and CBD are converted into the corresponding carboxylic acids (Δ 9 The differences in the amount of cannabidiol (TCA) and cannabidiol (CBDA) derived from the fact that they are biosynthesized in the plant along completely parallel but independent pathways (i.e., THC acid and cannabidiol acid, CBDA). The exact environmental (harvesting of the crop) and physiological conditions that allow for spontaneous decarboxylation (loss of carbon dioxide) from each endogenous precursor are not fully understood. At the same time, it is recognized that these variables may contribute to differences in biological effects depending on how the therapeutic is formulated and ingested. For example, mature flowers of female cannabis plants produce Δ 9 -Concentrates both THC acid and CBDA in varying amounts, but how quickly these molecules are converted to THC and CBD depends on exposure to sunlight and time at ambient temperature. When the plant buds are ingested, the human patient experiences a specific duration and intensity of pharmacological effects. In contrast, when the plant material is smoked or volatilized, immediate decarboxylation occurs due to the higher temperatures, and the patient's experience results from inhalation and more rapid absorption of THC and CBD into the bloodstream in the lungs.

[0417] The present invention is directed to overcoming many inefficiencies associated with the cost, availability, and composition of these pharmaceuticals, as well as standardized or controlled modes of administration to patients seeking various medical benefits. Specifically, preferred embodiments of the present invention provide a novel process for synthesizing CBD in a stereochemically and regiochemically controlled manner using CBD acid as a direct synthetic precursor, just as it does in nature. Alongside CBD, CBDA may be tested and promoted as a valuable prodrug, expected to have better water solubility (compared to CBD), for formulating topical creams and lotions in health and beauty products, as well as for dietary supplements, foods, and beverages. Furthermore, the process reported herein establishes a clean and reliable conversion of synthetic CBDA to CBD at a scale and purity level that facilitates a safer and more uniform supply of this increasingly popular dietary supplement.

[0418] [References] Aguillon, AR, Leao, RAC, Miranda, LSM, de Souza, ROMACannabidiol Discovery and Synthesis-A Target-Oriented Analysis in Drug Production Processes.Chem.Eur.J.2021,27,5577-5600. Baek, S.H., Srebnik, M., Mechoulam, R. Tetrahedron Lett. 1985, 26, 1083-1086. Burdick, DC, Collier, SJ, Biolatto, B., Mecklar, H. Process for Production of Delta-9-Tetrahydrocannibinol. U.S. Patent No. 8,106,244 B2 (January 31, 2012). Cardillo, B., Merlini, L., Servi, S. Alkylation of Resorcinols with Monoterpenoid Allylic Alcohols in Aqueous Acid. Synthesis of New Cannabinoid Derivatives. Gazz. Chim. Ital. 1973, 103, 127. To the best of our knowledge, this reference contains the earliest example of the terpenylation of olivetol with p-mentha-1,8-dien-3-ol, which was carried out using aqueous acid. The preparation of the monoterpenoid starting material involved several steps. The cis / trans mixture of isopiperitenol was also produced using boron trifluoride diethyl ether and olivetol, but not Δ 9 -THC, but in our hands, Lewis acid catalysis affords competitive amounts of the Friedel-Crafts regioisomer iso-Δ 9 -THC is provided. Chan, TH., Brownbridge, PA Novel Cycloaromatization Reaction. Regiocontrolled Synthesis of Substituted Methyl Salicylates. J. Am. Chem. Soc. 1980, 102, 3534-3538. Dethe, DH, Erande, RD, Mahapatra, S., Das, S., Kumar, KBProtecting Group Free Enantiospecific Total Syntheses of Structurally Diverse Natural Products of the Tetrahydrocannabinoid Family.Chem.Comm.2015,51,2871-2873. Focella, A., Teitel, S., Brossi, AA Simple and Practical Synthesis of Olivetol. J. Org. Chem. 1977, 42, 3456-3457. Gaoni,Y.,Mechoulam,R.Isolation,Structure,and Partial Synthesis of an Active Constituent of Hashish.J.Am.Chem.Soc.1964,86,1646-1647. Hanus,L.O.,Meyer,S.M.,Munoz,E.,Taglialatela-Scafati,O.,Appendino,G.Phytocannabinoids:A Critical Inventory.Nat.Prod.Rep.2016,33,1357-1392. Hively,R.L.,Mosher,W.A.,Hoffmann,F.W.Isolation of Δ 6 -Tetrahydrocannabinol from Marijuana.J.Am.Chem.Soc.1966,88,1832-1833.Named Δ 6 -3,4-trans-THC under an alternative numbering scheme,double bond isomerization to the thermodynamic Δ 8 -position is precedented in acidic conditions,and it can also occur through physiology or in isolation work. Mechoulam,R.,Gaoni,Y.Hashish.IV.The Isolation and Structure of Cannabinolic,Cannabidiolic,and Cannabigerolic Acids.Tetrahedron 1965,21,1223-1229. Mechoulam,R.;Hanus,L.O.;Pertwee,R.;Howlett,A.C.“Early Phytocannabinoid Chemistry to Endocannabinoids and Beyond,”Nat.Rev.Neurosci.2014,15,757-764. Morales,P.;Reggio,PH;Jagerovic,N.“An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol,”Front.Pharmacol.2017,8,422-450. Petrzilka,T.,Haefliger,W.,Sikemeier,G.,Ohloff,G.,Eschenmoser,A.Synthesis and Chirality of Intermediates of(-)-Cannabidiols.Helv.Chim.Acta 1967,50,719-723. Souza, FES, Field, JE, Pan, M., Ramjit, NJ, Tharmanathan, T., Jende-Tindall, T. Synthetic Route to Dronabinol. Taylor,EC,Lenard,K.,Shvo,Y.Active Constituents of Hashish.Synthesis of dl-Δ 6 -3,4-trans-Tetrahydrocannabinol.J.Am.Chem.Soc.1966,88,367-369. Planar Chiral Cyclic Ether: Asymmetric Resolution and Chirality Transformation.J.Am.Chem.Soc.2005,127,12182-12183. Womack, EB, Nelson, ABEthyl Diazoacetate.Org.Synth.1944,24,56.

Claims

1. A process for producing a compound having the structure of formula (-)-(I): 【Chemistry 1】 During the ceremony, R １ It is alkyl, The aforementioned process, (i) Reacting (R)-limonene with an oxidizing agent in a first suitable solvent under conditions sufficient to produce a compound having the structure of formula (+)-(IIa), 【Chemistry 2】 (ii) Reacting the compound having the structure of formula (+)-(IIa) produced in step (i) with a reducing agent in a second preferred solvent under conditions sufficient to produce a compound having the structure of formula (+)-(II') as a single enantiomer or the structure of formula (+)-(II'') as a single enantiomer, 【Transformation 3】 The process including the process described above.

2. The process according to claim 1, wherein the oxidizing agent comprises a chromium metal complex or a salt.

3. The process according to claim 1, wherein the reducing agent is lithium aluminum hydride or sodium borohydride.

4. (iii) Under conditions sufficient to produce a compound having the structure of formula (-)-(IV), in a suitable solvent, in the presence of an acid, the compound having the structure of formula (+)-(II') or (+)-(II'') produced in step (ii) has the structure of formula (III), 【Chemistry 4】 In the formula, R4 further comprises reacting with an alkyl compound. 【Transformation 5】 The process according to claim 1.

5. The process according to claim 4, wherein the acid is an organic acid or Lewis acid selected from camphor sulfonic acid and p-toluenesulfonic acid.

6. (iv) Exposing the compound having the structure of formula (-)-(IV) produced in step (iii) to basic hydrolysis conditions sufficient to produce a compound having the structure of formula (-)-(V), 【Transformation 6】 The process according to claim 4, further comprising: (v) exposing the compound having the structure of formula (-)-(V) produced in step (iv) to decarboxylation conditions sufficient to produce a compound having the structure of formula (-)-(I).

7. A method for producing a compound having the structure of formula trans-(±)-(I), 【Transformation 7】 During the ceremony, R1 is alkyl, The method comprises (i) reacting citral with a Lewis acid in a suitable solvent under conditions sufficient to produce a compound having the structure of formula (±)-(IIa). 【Transformation 8】

8. The method according to claim 7, wherein the Lewis acid is dimethylaluminum chloride or diethylaluminum chloride.

9. The method according to claim 7, further comprising the step of (ia) reacting a compound having the structure of formula (±)-(IIa) produced in step (i) with a reducing agent in a second suitable solvent under conditions sufficient to produce a compound having the structure of formula trans-(±)-(II''). 【Chemistry 9】

10. The method according to claim 9, wherein the reducing agent is lithium aluminum hydride or sodium borohydride.

11. The method according to claim 9, further comprising the step of reacting a compound having the structure of formula trans-(±)-(II'') produced in step (ia) with a compound having the structure of formula (III) in a second suitable solvent in the presence of an acid. 【Chemistry 10】 In the formula, R4 is an alkyl group, and the reaction is carried out under conditions sufficient to produce a compound having the trans-(±)-(IV) structure. 【Chemistry 11】

12. The method according to claim 11, wherein the acid is an organic acid or Lewis acid selected from camphor sulfonic acid and p-toluenesulfonic acid.

13. (iii) A step of subjecting a compound having the structure of formula trans-(±)-(IV) produced in step (ii) to basic hydrolysis conditions sufficient to produce a compound having the structure of formula trans-(±)-(V), 【Chemistry 12】 and (iv) A step of subjecting the compound having the structure of formula trans-(±)-(V) produced in step (iii) to decarboxylation conditions sufficient to produce a compound having the structure of formula trans-(±)-(I), The method according to claim 11, further comprising:

14. A process for producing a compound having the structure of formula (-)-(Ia): 【Chemistry 13】 During the ceremony, R1 is alkyl, The aforementioned process, (i) Reacting (R)-limonene with an oxidizing agent in a first suitable solvent under conditions sufficient to produce a compound having the structure of formula (+)-(IIa), 【Chemistry 14】 The process comprises (ii) reacting the compound having the structure of formula (+)-(IIa) produced in step (i) with a reducing agent in a second preferred solvent under conditions sufficient to produce a compound having the structure of formula (+)-(II') as a single enantiomer or of formula (+)-(II'') as a single enantiomer. 【Chemistry 15】

15. The process according to claim 14, wherein the oxidizing agent comprises a chromium metal complex or a salt.

16. The process according to claim 14, wherein the reducing agent is lithium aluminum hydride or sodium borohydride.

17. (iii) The compound having the structure of formula (+)-(II') or (+)-(II'') produced in step (ii) is reacted with a compound having the structure of formula (IIIa) in a second preferred solvent in the presence of an organic acid or a Lewis acid. 【Chemistry 16】 The process according to claim 14, further comprising generating the compound having the structure of formula (-)-(Ia).

18. The process according to claim 17, wherein the organic acid is selected from camphor sulfonic acid and p-toluenesulfonic acid.

19. The process according to claim 14, wherein R1 is n-pentyl.

20. A process for producing a compound having the structure of formula trans-(±)-(Ia): 【Chemistry 17】 During the ceremony, R1 is alkyl, The aforementioned process, (i) React citral with a Lewis acid in a suitable solvent under conditions sufficient to produce a compound having the structure of formula (±)-(IIa). [Chemistry 18] The process including the process described above.

21. The process according to claim 20, wherein the Lewis acid is diethylaluminum chloride or dimethylaluminum chloride.

22. The process according to claim 20, further comprising reacting the compound having the structure of formula (±)-(IIa) produced in step (i) with a reducing agent in a second preferred solvent under conditions sufficient to produce a compound having the structure of formula (ia) trans-(±)-(II''). 【Chemistry 19】

23. The process according to claim 22, wherein the reducing agent is lithium aluminum hydride or sodium borohydride.

24. (ii) The compound having the structure of formula trans-(±)-(II'') produced in step (ia) is reacted with a compound having the structure of formula (IIIa) in a second preferred solvent in the presence of an acid. 【Chemistry 20】 The process according to claim 22, further comprising generating the compound having the structure of formula trans-(±)-(Ia).

25. The process according to claim 24, wherein the acid is an organic acid or Lewis acid selected from camphor sulfonic acid and p-toluenesulfonic acid.

26. The process according to claim 20, wherein R1 is n-pentyl.

27. ​​A process for producing a compound having the structure of formula (±)-(IIa): 【Chemistry 21】 The process comprises reacting citral with a Lewis acid in a suitable solvent under conditions sufficient to produce the compound.

28. The process according to claim 27, wherein the Lewis acid is diethylaluminum chloride or dimethylaluminum chloride.

29. A process for producing a compound having the structure of formula (+)-(II') or (+)-(II''): 【Chemistry 22】 The aforementioned process, (i) Reacting (R)-limonene with an oxidizing agent in a first suitable solvent under conditions sufficient to produce a compound having the structure of formula (+)-(IIa), 【Chemistry 23】 The process comprises (ii) reacting the compound having the structure of formula (+)-(IIa) produced in step (i) with a reducing agent in a second preferred solvent under conditions sufficient to produce a compound having the structure of formula (+)-(II') as a single enantiomer or formula (+)-(II'') as a single enantiomer.

30. The process according to claim 29, wherein the oxidizing agent comprises a chromium metal complex or a salt.

31. The process according to claim 29, wherein the reducing agent is lithium aluminum hydride or sodium borohydride.

32. A process for producing a compound having the structure of formula (III): 【Chemistry 24】 During the ceremony, R1 is alkyl, R4 is an alkyl group, The aforementioned process, (i) Under conditions sufficient to produce a compound having the structure of formula (VIIa), 【Chemistry 25】 The method involves reacting a compound having the structure of formula (VIIa) with Br2 in a first preferred solvent. 【Chemistry 26】 The aforementioned process.

33. The process according to claim 32, further comprising refluxing the compound having the structure of formula (VIIa) produced in step (i) in a second preferred solvent under conditions sufficient to produce the compound having the structure of formula (III).

34. A process for producing a compound having the structure of formula (VIII): 【Chemistry 27】 During the ceremony, R1 is alkyl, R4 is an alkyl group, The aforementioned process, (i) Under conditions sufficient to produce a compound having the structure of formula (VIIIIa), 【Chemistry 28】 The method involves reacting a compound having the structure of formula (III) with geraniol in a first preferred solvent in the presence of an acid. 【Chemistry 29】 The aforementioned process.

35. The process according to claim 34, wherein the acid is an organic acid or Lewis acid selected from camphor sulfonic acid or p-toluenesulfonic acid.

36. The process according to claim 34, further comprising (ii) exposing the compound having the structure of formula (VIIIa) prepared in step (i) to basic hydrolysis conditions sufficient to produce the compound having the structure of formula (VIII).

37. The process according to claim 34, wherein R4 is methyl.

38. The process according to claim 34, wherein R1 is n-pentyl.

39. The process according to any one of claims 7 to 13, wherein the compound produced is a racemic mixture of trans isomers having the following structures. 【Transformation 30】

40. The process according to any one of claims 20 to 26, wherein the compound produced is a racemic mixture of trans isomers having the following structures. 【Chemistry 31】

41. The process according to any one of claims 1 to 6, wherein the compound produced has the following structure. 【Chemistry 32】

42. The process according to any one of claims 14 to 19, wherein the compound produced has the following structure. 【Transformation 33】

43. The process according to any one of claims 34 to 38, wherein the compound produced has the following structure. 【Transformation 34】

Images