David MacMillan

Research in the MacMillan Group is focused on organic synthesis, catalysis, and chemical biology. We aim to pursue new concepts in synthetic organic chemistry that allow access to structural motifs not readily available via conventional methods. In this endeavor, we target the development of general strategies—organocatalysis, cascade, synergistic, photoredox, and metallaphotoredox catalysis—that can be implemented in a wide spectrum of chemical processes, and we place particular emphasis on the synthesis of moieties prevalent in medicinal agents, agrochemicals, and natural products. Our emerging chemical biology research program leverages photocatalysis to investigate complex biological environments.

Areas of active research include:

Photoredox catalysis. Since its early beginnings, the field of photoredox catalysis has undergone substantial expansion. Today, photoredox catalysis serves as a focus of research for more than 300 academic groups, and thousands of manuscripts have been published in this area. This notable growth can be attributed to the fact that photoredox: (1) selectively delivers ~60 kcal/mol of energy in the form of visible light to a photocatalyst, enabling the generation of highly reactive free radicals at room temperature and resulting in exquisite functional group tolerance; (2) utilizes feedstock chemical functionalities such as alcohols, olefins, carboxylic acids, and C-H bonds as radical precursors; and (3) has a mild, yet robust nature, allowing for merger with other catalytic approaches, including organocatalysis, NHC, hydrogen-atom-transfer (HAT), Lewis acids, and transition-metal catalysis.

Our laboratory has played a part in the development of photoredox catalysis over the last 17 years, with more than 100 published works, of which more than 20 have been featured in Science or Nature. We aspire to continue to grow the chemist’s synthetic toolbox of transformations that are novel yet highly adaptable across the many fields of science that rely upon molecule construction.

Metallaphotoredox catalysis. In a 2014 collaboration with the Doyle group, we reported one of the first examples of merging transition metal catalysis and photoredox catalysis to access novel reactivity that cannot be achieved by either catalytic system individually. Over the past decade, this new field of catalysis has delivered a host of highly enabling C–C and C–X bond-forming reactions that reveal previously elusive synthetic disconnections. Our group’s research in this area of metallaphotoredox catalysis is primarily focused on two metals: nickel and copper. By combining the fundamental mechanistic steps of nickel catalysis, such as oxidative addition and reductive elimination, with high-energy radicals generated through photoredox catalysis, we have been able to develop a broad range of novel C(sp²)–C(sp³) and C(sp³)–C(sp³) bond forming reactions. More recently, we demonstrated that copper catalysis could be successfully merged with photoredox catalysis, establishing a new catalytic platform with orthogonal reactivity to previous metallaphotoredox systems. The ability to access elusive high-energy copper intermediates under exceedingly mild conditions has unlocked new synthetic transformations, including C–CF₃, C–X, C–N, and C–C bond formations. Our metallaphotoredox research program continues to focus on the development of new methods that accelerate the synthesis of complex organic molecules.

Radical sorting. In 2021, we disclosed one of the first applications of S_H2 radical sorting to chemical methodology. Previously, the bimolecular homolytic substitution (S_H2) mechanism had been well-known in biological systems but had not yet been harnessed as a general platform for cross-coupling reactions in the laboratory. We showed that this platform could be used to enable previously inaccessible disconnections. Traditional inner sphere bond-forming mechanisms proceed through the intermediacy of unstable dialkyl metal complexes that are prone to decomposition. By contrast, the innate outer sphere nature of bond formation via S_H2 radical sorting circumvents this requirement, enabling the synthesis of historically challenging motifs such as all-aliphatic quaternary carbons. In principle, any two radical precursors might be used to form a new C–C bond within this paradigm, underscoring the immense synthetic potential for this platform. Indeed, the overarching goal for our radical sorting platform is to view any two functional groups as precursors to C(sp3)–C(sp3) bonds.

Chemical Biology. A current focus of the MacMillan group is the development and application of synthetic tools to address outstanding questions in chemical biology. In a 2020 Science paper, we introduced a new photocatalytic proximity labeling platform capable of elucidating interactions between proteins in biological systems with significantly enhanced spatial resolution compared to traditional methods. Application of this platform, which we term micromap (µ-map), has enabled us to make key discoveries in the areas of glycoprotein and chromatin biology. In 2023, we demonstrated that the exquisite special resolution inherent to µ-map allows for the identification of small molecule binding sites, circumventing the need for labor-intensive protein crystallization. We continue to refine and apply the µ-map technology with the goal of leveraging µ-map to investigate diverse facets of biology at the sub-cellular levels.

In our efforts to rapidly discover and optimize new reaction methodologies, we have capitalized on the capabilities of the Merck Center for Catalysis at Princeton University, which is a unique state-of-the-art facility that enables the high-throughput execution and analysis 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.