59th Annual Report on Research 2014

Over the past 12 months, PRF funding has enabled our group to further our studies on the synthetic applications of proton-coupled electron transfer (PCET) reactions. PCET mechanisms are unconventional redox processes in which chemically independent electrons and protons are simultaneously exchanged in a single elementary step, often through the agency of hydrogen–bonded complexes, to afford neutral free radical products. Strong energetic coupling between the transfer events often gives rise to surprising kinetic features, with the concerted mechanisms often proceeding at rates significantly fast than either competing stepwise pathway. These processes are now recognized to be an integral part of biological redox processes ranging from photosynthetic water oxidation to natural product biosynthesis, but to date their deliberate applications in organic synthesis remain rare.

Our group has begun to investigate the potential of these mechanisms to address two long-standing challenges in organic free radical chemistry and asymmetric catalysis. Foremost, this work aims to establish concerted PCET as a general strategy for the rational design of catalyst systems competent to homolytically break unusually strong bonds sigma (>100 kcal/mol) or to form extremely weak sigma bonds from p precursors (<20 kcal/mol), enabling the activation of common functional groups that are energetically inaccessible using conventional hydrogen atom transfer technologies. Key to the success of this idea was the recognition that the rates of PCET mechanisms, like those of electron transfer and H-atom transfer, are intimately coupled to reaction thermodynamics. Combined with Mayer’s effective bond strength formalism, this insight provides a straightforward design principle to identify effective base/oxidant or acid/reductant combinations that are energetically matched for specific bond activations.

Secondly, we hypothesized that concerted PCET could present novel opportunities for controlling enantioselectivity in the reactions of neutral free radical intermediates. PCET reactions typically occur through the intermediacy of a hydrogen-bond complex between the substrate and a proton donor/acceptor. These H-bonding interactions kinetically gate the electron transfer steps, ensuring that radical intermediates are only generated when the substrate is bound to the proton donor catalyst. We have found that these H-bond interfaces often remain intact following the PCET event, and can result in the formation of strongly stabilized non-covalent complexes of neutral radical intermediates. When chiral proton donors/acceptors are employed, we have shown that this association can provide a basis for asymmetric induction in subsequent bond forming events.

 We have leveraged this finding to develop a number of new catalytic enantioselective reactions of neutral ketyl radicals. Aided by PRF support, we reported in late 2013 the first catalytic asymmetric azapinacol reaction. These classical reductive couplings of ketones and imine derivatives are a direct way to access vicinal amino alcohols, a motif commonly found in natural products, pharmaceuticals and popular ligand scaffolds. Over the past years extensive kinetic and mechanistic studies have shed light on the inner working of this process. The studies are consistent with ketyl formation via concerted PCET and a rate and enantioselectivity C-C bond formation involving a phosphate-bound neutral ketyl. These results are significant in representing a rare examples of asymmetric catalysis in which induction is transduced through non-covalent association of chiral catalyst with a neutral free radical.

In seeking to expand the scope of this work, we have found that this reaction manifold can be extended to asymmetric intermolecular reductive couplings. Specifically, acetophenone derivatives can be asymmetrically coupled with a variety of acrylate derivatives to form substituted butanolide adducts directly from simple starting materials with promising levels of enantioselectivity. Excitingly, novel amino acid derivatives can also be accessed in excellent yield by addition of phosphate bound ketyls to a-amino acrylate acceptors. Work to render these reactions highly enantioselective is ongoing in our labs, as are extensions and applications to related systems. A central goal of these studies is aid our understanding of how conventional non-covalent interactions that have large dispersion components are impacted by a radical substrates that are significantly more polarizable than their closed shell analogs.

Beyond the specific chemistries developed, PRF funding has allowed us to an opportunity to build and test a set of hypotheses that we believe will enable us to significantly expand the scope of catalytic and enantioselective radical chemistries enabled by PCET. In particular, the design principles resulting from our PRF-supported work on reductive PCET reactions have enabled us to design novel oxidative PCET processes which break strong sigma bonds that are often energetically inaccessible using conventional technologies, such as the N-H bonds in amides and indoles. This work is currently a focus of research in our labs, providing catalytic access to useful radical intermediates directly from native functional group precursors under mild catalytic conditions. In analogy to the reductive work, preliminary studies suggest that these oxidative processes can also be rendered enantioselective through specific hydrogen bonding interactions with the resulting radical intermediates, a finding that we think will have a significant impact on the further development of both catalytic enantioselective radical chemistries and our understanding of the non-covalent interactions of free radical intermediates.