Synthesis of Functionalized Cannabilactones

Abstract

A new approach to synthesize cannabilactones using Suzuki cross-coupling reaction followed by one-step demethylation-cyclization is presented. The two key cannabilactone prototypes AM1710 and AM1714 were obtained selectively in high overall yields and in a lesser number of synthetic steps when compared to our earlier synthesis. The new approach expedited the synthesis of cannabilactone analogs with structural modifications at the four potential pharmacophoric regions.

Keywords: CB2 selective ligands; Suzuki cross-coupling; cannabilactones; cannabinoids.

Figure 1

(A), structures of AM1710 and AM1714 and potential pharmacophores of the cannabilactone template. (B), representative tetrahydrocannabinol (THC) and hexahydrocannabinol (HHC) analogs with the well-defined pharmacophoric regions.

Scheme 1

Earlier synthesis of AM1710 and AM1714 (6–7 steps, 27–38% overall yields) ^a. ^a Reagents and conditions: (a) Diisopropylamine, Et₃N, CH₂Cl₂, rt, 2 h, 75% [26]; (b) i. sec-BuLi, N,N,N′,N′-tetramethylethylenediamine (TMEDA), THF, −78 °C, 1 h; ii. B(OCH₃)₃, −78 °C to rt, 12 h; iii. 5% aq. HCl, 96%; (c) Br₂, CCl₄, 0 °C, 20 min, 85%; (d) Pd(Ph₃P)₄, Ba(OH)₂, DME/H₂O, 110 °C, microwave irradiation, 15 min, 83%; (e) 9-iodo-9-BBN, CH₂Cl₂, 0 °C, 4 h; (f) AcOH, reflux, 5 h, 76% from 8; (g) BBr₃, CH₂Cl₂, reflux, 12 h, 72%.

Scheme 2

New synthesis of functionalized cannabilactones.

Scheme 3

Synthesis of AM1710, AM1714, and C3 side chain modified cannabilactones (a–g) ^a. ^a Reagents and conditions: (a) i. n-BuLi, THF, −78 °C, 45 min, 10 °C, 1.5 h, −78 °C 30 min; ii. B(OMe)₃, −78 °C to rt, overnight; iii. 5% aq. HCl, 88% for 13, 65% for 17, 80% for 21, 73% for 25, 61% for 30, and 61% for 35; (b) Cs₂CO₃, DME/H₂O, Pd(Ph₃P)₄, 110 °C, microwave irradiation, 45 min, 84% for 15, 69% for 18, 81% for 22, 76% for 26, 84% for 31, and 83% for 38; (c) 9-iodo-9-BBN, CH₂Cl₂, 0 °C to rt, overnight, 78% for AM1710, 75% for 19, 70% for 23, 67% for 27, 68% for 32, and 73% for 39; (d) BBr₃, CH₂Cl₂, 2 days, reflux, 74% for AM1714; (e) NaCN, DMSO, rt, overnight, 90%; (f) AgNO₃, CH₃CN, rt, 5 h, 91%; (g) TIPSOTf, 2,6-lutidine, DCM, 0 °C to rt, 2 h, 89% (h) TBAF, THF, rt, 2 h, 90%; (i) 1-adamantanol, MeSO₃H, 50 °C, 3 h, 58%; (j) Tf₂NPh, Et₃N, 4-(dimethylamino)pyridine (DMAP), CH₂Cl₂, reflux, 18 h, 95%; (k) PdCl₂(Ph₃P)₂, dppp, n-Bu₃N, HCOOH, polymethylhydrosiloxan (PMHS), DMF, reflux, 19 h, 92%.

Scheme 4

Synthesis of C9/C11 and C1 modified cannabilactones (a–e) ^a. ^a Reagents and conditions: (a) Cs₂CO₃, DME/H₂O, Pd(Ph₃P)₄, 110 °C, microwave irradiation, 45 min, 82% for 45, 81% for 48, 80% for 50, 62% for 54, 86% for 59; (b) 9-iodo-9-BBN, DCM, 0°C to rt, overnight, 65% for 46, 75% for 49, 73% for 55, 60% for 60; (c) K₂CO₃, CD₃I, DMF, 0 °C to rt, 3 h, 86%; (d) BBr₃, CH₂Cl₂, −78 °C to rt, overnight, 68%; (e) FeSO₄·7H₂O, CH₂Cl₂, MeOH, EtOH, or propan-2-ol, 130 °C, microwave, 1 h, 97–99% for 52a–52c; (f) n-Bu₄N⁺N₃⁻, CH₂Cl₂, rt, 2 days, 96% for 52d; (g) MOMCl, DIPEA, CH₂Cl₂, 0 °C to rt, 1 h, 92%; (h) DABSO, PdCl₂(Amphos)₂, Et₃N, propan-2-ol, 75 °C, 24 h, then NFSI, rt, 3 h, 71%; (i) Sc(OTf)₃, EtOH/CH₃CN, rt, 8 h, 91%; (j) MOMCl, DIPEA, CH₂Cl₂, 0 °C to rt, overnight, 98%; (k) TBAF, THF, 0 °C to rt, 30 min, 97%.

Scheme 5

Synthesis of AM4089 and thiocannabilactone (a,b) ^a. ^a Reagents and conditions: (a) CH₃MgBr, Et₂O/THF, reflux, 2 h; p-TsOH·H₂O, CHCl₃, rt, 12 h, 65% from 39; (b) TIPSOTf, 2,6-lutidine, CH₂Cl₂, 0 °C to rt, 2 h, 89%; (c) Lawesson reagent, toluene, reflux, 24 h, 76%; (d) TBAF, THF, −40 °C, 30 min, 82%.