Revisiting the Peer-Nagata Reaction:
A Catalytic Effort toward a Ortho-Regiospecific Dehydrative Aldol Reaction of Phenols
|Goal: Methodology Development for catalytic ortho-regiospecific Aldol reaction of phenols. Catalytic formation of ortho-quinone methides for an application to the Total Synthesis of bruceol Natural Product||Students: Tanya Kelley, Miran Mavlan
UG Students: Laurine Guillaume
Collaborator: Prof. James Inglese (NIH; NCATS) for biological testing
Funding: The project is not advanced enough yet.
Background. Regioselective and regiospecific reactions are crucial in the toolbox of synthetic chemists. Many systems have been reported either using substrate, reagent or catalyst control to achieve regioselective transformations, which can translate into powerful maneuvers for the synthesis of complex molecules. One important method yet to be developed in a catalytic manner is the ortho-regiospecific Aldol Reaction of phenols also called the Peer-Nagata reaction.
Goals. In our effort to develop a method for the preparation of ortho-quinone methides (o-QMs) we decided to deeply examine this Peer-Nagata reaction. The Peer-Nagata reaction has been developed in the early 70’s and proved to be useful transformation to produce benzodioxaborins xx which are versatile precursors for numerous scaffolds via the transient formation of extremely reactive ortho-quinone methides. This unique transformation combines high atom economy and regio-specificity in its chemical reactivity. For instance, o-QMs can be reduced to give o-alkylphenols, can be trapped by alcohols/thiols and carbon nucleophiles to generate substituted phenol derivatives or react with different dienophiles inter- and intramolecularly to deliver the Diels–Alder cycloadducts.
Of interest, the Nagata reaction presents several advantages: 1) great stereoelectronic tolerance for the phenolic and aldehydic substrates (EWG/EDG) and 2) ortho-regiospecificity due to the proposed cyclic transition state 4, a [3,3] sigmatropic rearrangement delivering benzodioxaborin 5 in good yields. The importance of this procedure lies in the C-C bond formation at the ortho-position and the possible creation of a chiral hydroxyl stereocenter at the benzylic position (ortho-Aldol reaction)
Our goal is to revisit the Peer-Nagata reaction by establishing a catalytic and more general version of this reaction while preserving the ortho-specificity of the reaction. We envision that such method will demonstrate its efficiency and significance to synthesize useful styrene, chroman and chromene building blocks in a single step. By doing so, the catalytic peer-Nagata reaction will most likely become a more useful tool to the organic synthesis community and find application in complex natural product synthesis.
Publications. Kelley, T.; Mavlan, M.; Roche, S. P. (preparation for Org. Lett. or Tetrahedron Lett. 2015-2016) Revisiting the Peer-Nagata Reaction: A Catalytic Ortho-Regiospecific dehydrative Aldol Reaction of Phenols for the synthesis of styrenes.