A method for synthesizing a cannabinoid, wherein the method comprises:
- (a) reacting an optionally substituted phloroglucinol reactant having the structure
- with an electron-withdrawing hydroxyl-protecting reagent under conditions effective to provide a first intermediate comprising a hydroxyl-protected compound having the structure
- wherein n is zero, 1 or 2;
- R2 is selected from C1-C12 alkyl, C1-C12 alkoxy, C2-C12 alkoxyalkyl, C1-C12 alkylsulfanyl, C2-C12 acyl, C2-C12 acyloxy, C2-C12 alkoxycarbonyl, C6-C18 aryloxycarbonyl, carboxyl, and halo;
- and PR is a hydroxyl-protecting group;
- (b) effecting a cross-coupling reaction between the first intermediate and a reactant R1-M in a solvent in the presence of a cross-coupling catalyst, wherein:
- R1 is selected from C1-C12 alkyl;
- (C1-C8 alkoxy)-substituted C1-C12 alkyl;
- C1-C12 alkyl substituted with N (C1-C8 alkyl)2;
- C1-C12 alkyl substituted with C1-C8 alkylsulfonyl (—SO2-alkyl);
- and C1-C12 alkyl substituted with oxanyl, morpholino, or diazinanyl, and
- M is selected from —Zn—X, —B(OH)2, —B(OR)2, —MgX and —CuLi in which X is halo and R is alkyl, thereby providing a second intermediate in which a protected hydroxyl group has been replaced with R1, the second intermediate having the structure
- (c) hydrolyzing the second intermediate to remove the hydroxyl-protecting groups, thereby providing an R1-substituted deprotected compound as a third intermediate having the
- (d) contacting the R1-substituted deprotected compound with a substituted cyclohexene reactant having the structure
- wherein R5 is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo;
- R8 is methyl, hydroxymethyl, or halomethyl;
- and L is a leaving group, in the presence of a Lewis acid catalyst under reaction conditions effective to result in coupling of the R1-substituted deprotected intermediate and the substituted cyclohexene reactant to provide a reaction product composition comprising a cannabinoid having the structure