Redox-neutral organocatalytic Mitsunobu reactions

Abstract

Nucleophilic substitution reactions of alcohols are among the most fundamental and strategically important transformations in organic chemistry. For over half a century, these reactions have been achieved by using stoichiometric, and often hazardous, reagents to activate the otherwise unreactive alcohols. Here, we demonstrate that a specially designed phosphine oxide promotes nucleophilic substitution reactions of primary and secondary alcohols in a redox-neutral catalysis manifold that produces water as the sole by-product. The scope of the catalytic coupling process encompasses a range of acidic pronucleophiles that allow stereospecific construction of carbon-oxygen and carbon-nitrogen bonds.

Dehydration reactions in polyfunctional natural products

“…114,115 The reaction is a powerful tool for stereospecific substitution processes, but side-reactivity observed in substitution reactions, for example in preparation of serine-derived azides, has been observed under the standard displacement conditions. 116 The niche application of various reagent combinations and even catalytic Mitsunobu reactions have been reported, [117][118][119] but the targeted development of Mitsunobu-type elimination has not been investigated thoroughly. Similar sulfonylation and alkyl halide elimination methods, the Mitsunobu elimination requires the absence of nucleophilic moieties that may interfere with the desired elimination reaction pathway by preference of intra-or intermolecular substitution processes.…”

Access to P-chiral sec- and tert-phosphine oxides enabled by Le-Phos-catalyzed asymmetric kinetic resolution

“…18 Then the demethylation of TPO 6 in the presence of BBr 3 furnished the catalyst 7, which has potential application in the asymmetric catalytic Mitsunobu reaction. 19 We also utilized (R)-1a to synthesize chiral pincer-type ligand 8 in 47% yield with 81% ee. Moreover, we demonstrated the utility of these enantioenriched TPOs through further transformations of the P-chiral scaffold.…”

Continuous Flow Organophosphorus Chemistry

“…[116] The reaction usually requires stoichiometric amounts of trialkylphosphine and dialkyl azodicarboxylate, although alternatives do exist such as the organocatalyzed strategy that was recently reported. [117] The procedure relies on an easily accessible phosphine oxide catalyst and leads to water as the sole by-product. Despite the huge synthetic potential of the Mitsunobu reaction, to the best of our knowledge, only one example was reported under continuous flow conditions.…”