Activation of Marginally Reactive Boron Enolates by MeLi for the Formation of Enol Phosphates and Synthesis of the Δ⁹-THC Intermediate

Abstract

The addition of MeLi to boron enolates produced by the 1,4-addition of Ar2Cu(CN)Li2 to BF3·OEt2-activated enones was followed by the reaction with ClP(O)(OEt)2 to afford the corresponding enol phosphates in moderate to good yields. The scope of this method was examined with sterically hindered or electronically biased enones and/or reagents. This activation of boron enolates was successfully applied to the synthesis of the methyl ether of Δ(9)-tetrahydrocannabinol.

Synthesis of (−)-Piperitylmagnolol Featuring ortho-Selective Deiodination and Pd-Catalyzed Allylation

“…Although the 1,4-addition of sterically bulky copper reagents to BF 3 ·OEt 2 -activated enones produces only marginally reactive boron enolates, we recently developed a method to activate such enolates using MeLi, which allows phosphorylation to furnish enol phosphates . This method was successfully utilized for the synthesis of tetrahydro­cannabinol ( 2 ), which has analgesic effects.…”

Cannabidiol Discovery and Synthesis—a Target‐Oriented Analysis in Drug Production Processes

“…Then, the 1,4-addition of bulky diaryl cuprate 66,p repared in situ from 21, [179] Some authors have expanded the scope of this methodology with variations to afford cannabinoid compoundss uch as 8 and (À)-1. [180][181][182]…”

“…Some authors have expanded the scope of this methodology with variations to afford cannabinoid compounds such as 8 and (−)‐ 1 [180–182] …”

Synthetic pathways to tetrahydrocannabinol (THC): an overview

“…The same group also published direct 1,4-arylation of diaryl cuprates onto non-iodinated cyclohexenones, promoted solely by boron trifluoride. 50 This direct approach is considered advantageous for organic synthesis, but synthetically challenging because of the strongly stabilised boron enolate. To circumvent the low reactivity, MeLi was used to create the lithio enolate intermediates which are more reactive towards electrophiles.…”