Enantioselective Catalysis • New Reaction Methodology • Natural Product Synthesis
Research in the MacMillan Group is centered on the field of organic synthesis and catalysis. We are inspired by the pursuit of new concepts in synthetic organic chemistry involving organocatalysis, organo-cascade catalysis, metal-mediated catalysis, and total synthesis of natural products and pharmaceuticals. Please visit our Publications page to see our latest work or scroll down to view highlights of the various areas of research we are currently engaged in.
The following four lectures are taken from David MacMillan's one-day short-course on organocatalysis and synthesis; consequently, they highlight our group's contributions to these burgeoning fields of research.
SOMO Catalysis, A New Mode of Organocatalytic Activation
SOMO (Singly Occupied Molecular Orbital) catalysis was developed to allow for π-neutral or π-rich nucleophiles to add to the three-π electron radical cation species at the now electrophilic α-position of an aldehyde (via an umpolung of nucleophilic enamine catalysis). Since its conception, our group has published a variety of unprecedented methods using this approach, including α-carbonyl alkylation, arylation, enolation, vinylation, carbooxidation, chlorination, nitroalkylation, polyene cyclizations, and multi-component cycloadditions.
Merging Photoredox Catalysis and Organocatalysis
Photoredox catalysis and organocatalysis represent two powerful fields of molecular activation that have found widespread application in the areas of inorganic and organic chemistry. Recently, we merged these two fields of catalysis to solve problems in asymmetric chemical synthesis. Specifically, the enantioselective α-alkylation, trifluoromethylation, and benzylation of aldehydes have been accomplished using an interwoven activation pathway that combines an iridium or ruthenium photoredox catalyst with an imidazolidinone organocatalyst. This broadly applicable, yet previously elusive alkylation platform of reactivity provides a highly enantioselective and operationally trivial approach to a range of new transformations.
Mechanistic Investigations on Organocatalysis
An explosion of research interest over the past decade has repeatedly demonstrated that a wide variety of reactions can be rendered asymmetric based on organocatalytic activation. The field has grown at such a rapid pace due, in part, to the firm mechanistic understanding of most organocatalytic reactions. Our lab is focused on deciphering the mechanistic pathways for new transformations that do not otherwise fit established observations. Such explorations have recently led to the development of new, useful techniques for carbonyl and amine functionalizations.
Organocascade Catalysis Directed Towards Total Synthesis
Organocascade catalysis is a new strategy for the rapid construction of molecular complexity that is based on the biochemical blueprints of biosynthesis. The design of new organocascade sequences, based on the successful merger of different reactivity platforms such as enamine, iminium, SOMO, and photoredox activation, can allow access to intricate structural motifs directly applicable to natural product synthesis. Importantly, this concept allows for the straightforward generation of multiple stereocenters in a single operation and thus streamlines synthetic assembly lines. This new strategy is being employed in the construction of the chiral frameworks of the complex natural products: strychnine, akuammicine, aspidospermidine, vincadifformine, kopsinine, kopsanone, ochrosamine B, minovincine, vincorine, minfiensine, indolactam V, and cytoblastin.
Total Synthesis of Complex Natural Products
Application of organocatalytic strategies developed in the our group are being employed toward the development of truncated total syntheses of important and intriguing natural product architectures, such as littoralisone, callipeltoside C, diazonamide A, and capnosenediol.
High-throughput Reaction Development
The Merck Center for Catalysis at Princeton University is a unique state-of-the-art facility that enables the high-throughput discovery and optimization of catalytic reactions. The center houses a Chemspeed Accelerator robotic platform – an automated system used to apply the center’s resources to accelerate challenging, high-value projects for both methodology development and optimization of key steps in total synthesis. Recent advancements in the realms of photoredox, SOMO, enamine, and iminium catalysis have emerged from studies in this facility.
Applications to Drug Discovery
The value of organocatalysis to society is evident as it plays an increasing role in streamlining the process of drug discovery. A highly successful collaboration between the MacMillan Group and Merck has been forged to rapidly synthesize and identify novel drug candidates by combining organocascade catalysis with an affinity screening process.