Generation of Axially Chiral Fluoroallenes through a Copper-Catalyzed Enantioselective β-Fluoride Elimination

Abstract

Herein we report the copper-catalyzed silylation of propargylic difluorides to generate axially chiral, tetrasubstituted monofluoroallenes in both good yields (27 examples >80%) and enantioselectivities (82–98% ee). Compared to previously reported synthetic routes to axially chiral allenes (ACAs) from prochiral substrates, a mechanistically distinct reaction has been developed: the enantiodiscrimination between enantiotopic fluorides to set an axial stereocenter. DFT calculations and vibrational circular dichroism (VCD) suggest that β-fluoride elimination from an alkenyl copper intermediate likely proceeds through a syn-β-fluoride elimination pathway rather than an anti-elimination pathway. The effects of the C1-symmetric Josiphos-derived ligand on reactivity and enantioselectivity were investigated. Not only does this report showcase that alkenyl copper species (like their alkyl counterparts) can undergo β-fluoride elimination, but this elimination can be achieved in an enantioselective fashion.

Recent advances in the metal-catalyzed asymmetric synthesis of chiral allenes

“…A copper-catalyzed enantioselective β-fluoride elimination of propargylic difluorides to access chiral fluoroallenes was demonstrated by Toste and coworkers in 2021. 33 This transformation gave rise to a wide range of tetrasubstituted monofluoroallenes in good yields with high enantioselectivities. Based on DFT calculations and vibrational circular dichroism, a mechanism was proposed, as presented in Scheme 18.…”

“…32 A copper-catalyzed enantioselective β-fluoride elimination of propargylic difluorides to access chiral fluoroallenes was demonstrated by Toste and coworkers in 2021. 33 This transformation gave rise to a wide range of tetrasubstituted mono-Scheme 15 The Cu-catalyzed asymmetric silylation of propargyl dichlorides.…”

Recent Advances in Non-Precious Metal Catalysis

“…Notably, the Liu and Toste groups reported Cu catalysis to synthesize axially chiral fluoroallenes through silylation of propargylic difluorides. 43 The catalytic cycle starts from the formation of Cu−Si species, which regioselectively undergo syn-1,2-addition to an alkyne. The resulting vinyl copper releases the product through 1,2-fluoride elimination.…”

Photo and copper dual catalysis for allene syntheses from propargylic derivatives via one-electron process

“…A few strategies such as allenylic substitution with 2-halo-1,3-butadienes 12 , 13 or allenyl esters 14 – 18 , 1,4-difunctionalization of 1,3-enynes 19 – 32 , allenation of the terminal alkynes (ATA) reaction 33 , 34 , and coupling reactions involving propargylic substrates 35 – 53 , have been extensively and well established. For the last reaction, in addition to the S N 2′-type substitution of propargylic substrates 38 – 46 , transition metal-catalyzed coupling reaction of propargylic alcohol derivatives with organometallic reagents 47 – 53 involves a two-electron oxidative addition-transmetalation-reductive elimination process (Fig. 1a ).…”