Synthesis of Functionalized Cyclobutenes and Spirocycles via Asymmetric P(III)/P(V) Redox Catalysis

Abstract

An enantioselective phosphine‐catalyzed transformation has been developed for the synthesis of chiral cyclobutene triesters and fluorinated spirocyclic compounds. The strategy involved a P(III)/P(V) redox cycling process, via in situ reduction of phosphine oxide with phenylsilane. This catalytic methodology has enabled the enantioselective synthesis of functionalized cyclobutenes (24 examples, up to 94% ee). On the occasion of the extension of this study to α‐ketoester indenone substrates, a surprising reactivity has been discovered for the synthesis of spiro‐indenone products.

Progress of Catalytic Mitsunobu Reaction in the Two Decades

“…This new strategy to induce redox events has been employed in the Wittig, Appel, and Staudinger as well as other reactions that are thermodynamically driven by the formation of phosphine oxide, [44–94] we also reported the catalytic Wittig reaction [41] and catalytic asymmetric Staudinger‐aza‐Wittig reaction [95] applying the similar strategy. The initial attempt to conduct this approach in the Mitsunobu reaction was disclosed by O'Brien and co‐workers, however, only one example was shown in the patent (Scheme 10).…”

Recent Advances in Asymmetric Synthesis of Chiral Cyclobutenes

“…Afterward, the same group further explored the generality of this reaction by choosing 2,4-dioxo-4-arylbutanoates 129 and α-ketoester indenones 130 as the substrates under catalysis of chiral phosphine 131. [33] Generally, the reaction proceeded smoothly with a broad substrate scope to deliver chiral cyclobutene triesters 132, spiro(cyclopentane)indenones 133 in decent yields with moderate enantioselectivities (Scheme 20). Remarkably, simple triphenylphosphine could sufficiently catalyze the racemic reaction between trifluoroacetyl-dihydro-1Hindenones or α-ketoester indenones with diethyl acetylenedicarboxylate.…”

“…Afterward, the same group further explored the generality of this reaction by choosing 2,4‐dioxo‐4‐arylbutanoates 129 and α‐ketoester indenones 130 as the substrates under catalysis of chiral phosphine 131 [33] . Generally, the reaction proceeded smoothly with a broad substrate scope to deliver chiral cyclobutene triesters 132 , spiro(cyclopentane)indenones 133 in decent yields with moderate enantioselectivities (Scheme 20).…”

Organocatalytic Stereospecific Appel Reaction

“…In recent years, P­(III)/P­(V) redox cycle catalysis has shown wide applicability in many phosphine-mediated reactions, leading to simplified purifications and less waste. , Here, an in situ reduction of the formed phosphine oxides to the active phosphine species is accomplished by organosilanes. This catalysis technique of phosphorus redox cycling was further developed and applied to multiple reactions, among others the (base-free) Wittig and Staudinger reactions, reductive C–N and N–N couplings, olefin reduction, and the synthesis of (hetero)­cycles by Michael/Wittig tandem reaction. − …”