Catalytic Enantioselective Carbon–Oxygen Bond Formation: Phosphine-Catalyzed Synthesis of Benzylic Ethers via the Oxidation of Benzylic C–H Bonds

Abstract

Benzylic alcohols and ethers are common subunits in bioactive molecules, as well as useful intermediates in organic chemistry. In this report, we describe a new approach to the enantioselective synthesis of benzylic ethers, through the chiral phosphine-catalyzed coupling of two readily available partners, γ-aryl-substituted alkynoates and alcohols, under mild conditions. In this process, the alkynoate partner undergoes an internal redox reaction, specifically, the benzylic position is oxidized with good enantioselectivity, and the alkyne is reduced to the alkene.

Phosphine Organocatalysis

“…Using alcohols as pronucleophiles, Fu achieved phosphine-catalyzed enantioselective γ -additions to γ -aryl alkynoates (Scheme 144). 219 In the presence of the chiral spirophosphine P32 (5 mol %), a series of γ -aryl (including heteroaryl) alkynoates reacted with various alcohols to provide the corresponding benzylic ethers in moderate to excellent yields and with good to excellent enantioselectivities. Furthermore, the author proposed a mechanism for the reaction, involving, as a key step, nucleophilic addition of the alkoxide anion to the γ -position of the typical zwitterionic intermediate.…”

Enantioselective Synthesis of Alkyl Allyl Ethers via Palladium‐Catalyzed Redox‐Relay Heck Alkenylation of O‐Alkyl Enol Ethers

“…[5] Alternatively, chiral allylic ethers have been synthesized via phosphine-catalyzed γoxidation of alkynoates. [6] Despite noteworthy progress, the scope of these transformations has remained limited due to the nature of suitable electrophiles.…”

“…Traditionally, chiral allylic ethers have been prepared via the reaction of symmetric π‐allyl complexes of Ir, Rh, and Pd with exogenous alcohol nucleophiles, or by enantioselective catalytic S N 2’ reactions with allylic trichloroacetimidates . Alternatively, chiral allylic ethers have been synthesized via phosphine‐catalyzed γ‐oxidation of alkynoates . Despite noteworthy progress, the scope of these transformations has remained limited due to the nature of suitable electrophiles.…”

Enantioselective Synthesis of Isatin‐Derived α‐(Trifluoromethyl)imine Derivatives: Phosphine‐Catalyzed γ‐Addition of α‐(Trifluoromethyl)imines and Allenoates

“…Pioneering phosphine‐mediated/catalyzed γ‐addition reactions can be dated back to the 1990s, when Trost and Lu independently reported umpolung addition reactions of allenoates and alkynoates with pronucleophiles . Besides carbon pronucleophiles, oxygen‐, sulfur‐, or nitrogen‐atom‐containing pronucleophiles have also been reported in γ‐addition reactions by Fu's group and Jacobsen's group . These reactions provide efficient methods for the enantioselective construction of carbon–heteroatom bonds and further functionalized enantiomerically enriched products (Scheme b).…”

“…In recent years, prochiral fluorinated synthons have also been included in organocatalytic reactions, giving rise to many useful organofluorine compounds . Only one report has been published on the umpolung addition reactions of secondary carbon pronucleophiles,[12f] and no reports on trifluoromethyl‐containing secondary carbon pronucleophiles have been published. Inspired by this previous work, in this paper we describe the asymmetric umpolung γ‐addition reaction of allenoates with α‐(trifluoromethyl)imines as pronucleophiles (Scheme f).…”