Mechanism • Catalyst Design • Reaction Development • Complex Molecule Synthesis/Modification
OUR GENERAL APPROACH
We like to learn as much as possible about fundamentals of reactivity and selectivity by designing and developing catalysts that promote high-impact chemical transformations. We usually identify a problem first and then try to solve it. Reaction mechanism is the basis for every project, impacting the way we design and carry out a project.
Achieving high regio-, diastereo-, and/or enantioselectivities is not our only goal. We have a number of requirements for a catalytic process or a synthesis route that we develop. We prefer earth-abundant metals (such as Cu or Mo); we like ligands and catalysts that are derived from renewable resources, such as amino acids. We are partial to catalysts that are easy to prepare and use, are robust and efficient (do not require more than 6-8 hours to deliver complete conversion), and that have as low a molecular weight as possible. Our goal is to develop catalytic protocols that are economical, reliable, and practical. For example, we recently discovered a two-catalyst/four-component process, based on a strategy that we call “delayed catalysis”, to effect sequential additions of different types of nucleophiles to nitriles, an abundant and underexplored class of electrophiles. The reactions generate unprotected and versatile N-H amines with high efficiency, diastereoselectivity and enantioselectivity without any need for oxidation/reduction, or protection/deprotection; the method is stereodivergent too. We were able to use this advance (along with some of our other catalysts) to accomplish a nine-step gram-scale synthesis of a naturally occurring alkaloid (versus 26 steps previously).
Applying our catalysts, methods and strategies to complex molecule synthesis is important to us. Such initiatives show us how effective our catalysts and methods truly are, and what problems we should be focusing on. Our interest in larger molecules extends well beyond natural product synthesis; we are equally keen on introducing catalytic strategies that may be applied to assembling non-natural macromolecules and/or site selectively modifying them.
APRIL 5, 2019
“Delayed Catalyst Function Enables Direct Enantioselective Conversion of Nitriles to NH2-Amines”
Accessing enantiomerically enriched amines often demands oxidation-state adjustments, protection and deprotection processes, and purification procedures that increase cost and waste, limiting applicability. When diastereomers can be formed, one isomer is attainable. Here, we show that nitriles, largely viewed as insufficiently reactive, can be transformed directly to multifunctional unprotected homoallylic amines by enantioselective addition of a carbon-based nucleophile and diastereodivergent reduction of the resulting ketimine. Successful implementation requires that competing copper-based catalysts be present simultaneously and that the slower-forming and less reactive one engages first. This challenge was addressed by incorporation of a nonproductive side cycle, fueled selectively by inexpensive additives, to delay the function of the more active catalyst. The utility of this approach is highlighted by its application to the efficient preparation of the anticancer agent (+)-tangutorine.
APRIL 1, 2019
“E- and Z-, Di- and Tri-Substituted Alkenyl Nitriles Through Catalytic Cross-Metathesis”
Nitriles are found in many bioactive compounds, and are among the most versatile functional groups in organic chemistry. Despite many notable recent advances, however, there are no approaches that may be used for the preparation of di- or tri-substituted alkenyl nitriles. Related approaches that are broad in scope and can deliver the desired products in high stereoisomeric purity are especially scarce. Here, we describe the development of several efficient catalytic cross-metathesis strategies, which provide direct access to a considerable range of Z- or E-di-substituted cyano-substituted alkenes or their corresponding tri-substituted variants. Depending on the reaction type, a molybdenum-based monoaryloxide pyrrolide or chloride (MAC) complex may be the optimal choice. The utility of the approach, enhanced by an easy to apply protocol for utilization of substrates bearing an alcohol or a carboxylic acid moiety, is highlighted in the context of applications to the synthesis of biologically active compounds.
Hoveyda Group Members, Alumni and Friends at 60th Birthday Reception in Honor of Amir Hoveyda.