A Revised Modular Approach to (–)‐trans‐Δ⁸‐THC and Derivatives Through Late‐Stage Suzuki–Miyaura Cross‐Coupling Reactions

Abstract

A revised modular approach to various synthetic (–)‐ trans ‐Δ 8 ‐THC derivatives through late‐stage Suzuki–Miyaura cross‐coupling reactions is disclosed. Ten derivatives were synthesized allowing both sp 2 ‐ and sp 3 ‐hybridized cross‐coupling partners with minimal β‐hydride elimination. Importantly, we demonstrate that a para ‐bromo‐substituted THC scaffold for Suzuki–Miyaura cross‐coupling reactions has been initially reported incorrectly in recent literature.

Synthesis of CBD and Its Derivatives Bearing Various C4′-Side Chains with a Late-Stage Diversification Method

“…Through retrosynthetic analysis, we proposed our synthetic strategy for (−)-CBD and its C4′-substituted derivatives as outlined in Scheme . Considering that 5-substituted resorcinol displayed poor regioselectivity between the two nucleophilic substitution sites, we selected commercially available symmetric phloroglucinol, which has been used in the synthesis of THC and its analogues − as the starting material, to avoid the generation of positional isomers (abnormal CBDs) during the synthesis of 1 . In addition, the key intermediate 3 could be prepared from 1 in two steps through regioselective triflation and activation/protection.…”

“…The highest yield obtained was about 20% by treating 2 with excess C 5 H 11 ZnCl (10 equiv) in the presence of LiCl and a catalytic amount of Pd­(dppf)­Cl 2 . We presumed that it was difficult to form the organopalladium intermediate state through the oxidative addition of a metal to the electron-rich phenolate state of 2 in the basic environment of the coupling reaction. , Taking into account this problem, we adopted the phenolic hydroxyl protection strategy to investigate whether the Negishi cross-coupling could be influenced by the phenolic protecting groups of 3 (Table ).…”

One-flow synthesis of tetrahydrocannabinol and cannabidiol using homo- and heterogeneous Lewis acids

“…Homogeneous flow synthesis of olivetylverbenyl and Δ 8 -THC Inspired by the chiral pool approach of Mechoulam [16], which we initially used in a batch approach to make THC derivatives, we now set out to use this strategy in a one-flow system to synthesise (−)-trans-Δ 8 -THC [25,26]. Since our group previously investigated such chiral pool approach [27], we were keen to implement the proven batch process into a continuous flow process. In line with our previous batch experiments we initially investigated the flow synthesis of thermodynamically favoured Δ 8 -THC using homogeneous Brønsted catalysts.…”

Synthesis of Cannabinoids: “In Water” and “On Water” Approaches: Influence of SDS Micelles

“…The results obtained when gallium iodide was used as catalysts (Table , entry 5) also deserved to be mentioned. Thus, racemic Δ9-THC ( 17 ) and its isomer Δ8-THC ( 18 ), , the major (psycho-)­active compounds encountered in C. sativa , were obtained as well as tetracyclic 16 . Considering that no CBC is obtained in these cases, the generation of THC ( 17 ) by the Lewis acid-promoted isomerization of the initially generated CBC ( 13 ) should not be completely discarded.…”

“…A fraction containing compound 18 was subjected to HPLC (normal phase, H/MTBE, 9:1) to give pure 18 ( 21 ) ( t R = 6.3 min): 1 H NMR (400 MHz, CDCl 3 ) δ 6.30 (d, J = 1.5 Hz, 1H), 6.13 (d, J = 1.6 Hz, 1H), 5.45 (bd, J = 4.9 Hz, 1H), 4.62 (s, 1H), 3.21 (dd, J = 16.7, 5.9 Hz, 1H), 2.72 (td, J = 10.6, 4.2 Hz, 1H), 2.46 (td, J = 7.3, 2.3 Hz, 2H), 2.20–2.12 (m, 1H), 1.90–1.80 (m, 2H), 1.73 (s, 3H), 1.70–1.57 (m, 3H), 1.43 (s, 3H), 1.37–1.28 (m, 4H), 1.13 (s, 3H), 0.90 (t, J = 7.0 Hz, 3H); HRMS (ESI-TOF) m / z [M + H] + calcd for C 21 H 30 O 2 315.2324, found 315.2315.…”