The development of an asymmetric morita-baylis-hillman reaction and application toward the total synthesis of pycnanthuquinone A

• Main Author: Wensley, Allison M.
• Language: en_US
• Published: Boston University 2015
• Online Access: https://hdl.handle.net/2144/12887

Thesis (Ph.D.)--Boston University PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at [e-mail]. Thank you. === In an effort to discover novel treatments for type 2 diabetes, pycnanthuquinone A was isolated from the leaves of a West African tree. The compound demonstrated excellent antihyperglycemic activity in diabetes model mice. However, the biological target remains unknown and no chemical synthesis of the natural product has been reported. We sought to complete an enantioselective route by developing and implementing an asymmetric Morita-Baylis-Hillman (MBH) reaction of cyclopentenone with aryl aldehydes. The MBH reaction is a carbon-carbon bond forming reaction defined as the condensation of activated alkenes with aldehydes via tertiary amine or phosphine promoters. An enantioselective Brønsted acid-catalyzed method was developed using BINOL derivatives that induced high levels of enantioinduction. Kinetics were investigated via in situ IR monitoring, and the reaction was found to have a first order dependence with respect to catalyst. Additionally, a linear relationship between catalyst and product enantioratios was observed. 31P-NMR and direct inject mass spectral studies provided further evidence for the reaction mechanism. Based on these results, the catalyst is proposed to be intimately involved in the catalytic cycle and play several roles, including: activation of the ketone toward conjugate addition, stabilization of the zwitterionic intermediate, activation of the aldehyde toward aldol addition and assistance in proton transfer. The application of this methodology was investigated in synthetic studies of pycnanthuquinone A. Conjugate addition to the MBH adduct resulted in elimination of the alcohol stereocenter, through a rapid addition-Elcb sequence. Functional group transformation of the cyclopentenone carbonyl to a leaving group allowed for addition of nucleophiles via allylic substitution, however, subsequent attempts at ring closure were unsuccessful. Ring closure through reaction at the β-position of the enone was also explored. Development of a novel method for coupling benzyne precursors with aldimines generated benzaldehyde derivatives with methylene ester substituents at the ortho-position. These substrates underwent successful reaction with phosphine to form the MBH adducts. Reaction with base deprotonated the benzylic position and generated the desired tricyclic pycnanthuquinone core via two routes: conjugate addition-elimination as observed in the intermolecular case, or, under suppressed temperatures, aldol addition formed the [6,6,5] tricycle with the sensitive secondary alcohol still intact.