Stephen L. Buchwald

Transition-metal-catalyzed C–O coupling reactions of aryl halides and alcohols represent a useful alternative to classical aromatic substitution methods due to their improved functional group tolerance and substrate scope. Despite these benefits, many existing protocols rely on harsh reaction conditions or necessitate the use of a significant molar excess of alcohol to facilitate efficient C–O bond formation, thereby limiting their utility with complex substrates. Herein, we disclose the development of a Cu-catalyzed C–O coupling method utilizing a new N1,N2-diarylbenzene-1,2-diamine ligand, L8. Under optimized reaction conditions, a structurally diverse set of aryl and heteroaryl bromides underwent efficient coupling with a variety of alcohols at room temperature using an L8-based catalyst. Notably, the L8-derived catalyst exhibited enhanced activity when compared to the L4-based system previously disclosed for C–N coupling, most notably including the ability to functionalize aryl bromides containing acidic functional groups. Mechanistic studies demonstrate that C–O coupling utilizing the catalyst derived from L8 involves rate-limiting alkoxide transmetallation, resulting in a mechanism of C–O bond formation that is distinct from previously described Pd-, Cu-, or Ni-based systems. Consequently, this lower energy pathway leads to rapid C–O bond formation; a 7-fold increase relative to what it seen with other ligands. The results presented in this report overcome limitations in previously described transition-metal-catalyzed C–O coupling methods, expand the utility of this ligand family, and introduce a new ligand that we anticipate may be useful in …

I first met Miquel Pericàs when he came to MIT to visit in the mid-1990s and to check on the progress of his student, Xevi Verdaguer, who was a postdoc with me. Little did I know that this would be the beginning of a close personal and professional relationship that has now gone on for over 25 years. When Miquel founded the ICIQ, I was very pleased to be appointed as a member of the Scientific Advisory Board (in 2002), which I ultimately led for almost nine years. I watched Miquel build the ICIQ into an international chemistry powerhouse during this time. He was able to attract outstanding colleagues and build an infrastructure that was the envy of others. He maintained a vigorous research program in organic synthesis, asymmetric catalysis, flow chemistry, and immobilized catalysts. I was fortunate enough to visit “Casa Pericas” in Barcelona many times, where I enjoyed the tremendous hospitality of Miquel and his …

We disclose the development of a Cu‐catalyzed C−O coupling method utilizing a new N1,N2‐diarylbenzene‐1,2‐diamine ligand, L8. Under optimized reaction conditions, structurally diverse aryl and heteroaryl bromides underwent efficient coupling with a variety of alcohols at room temperature using an L8‐based catalyst. Notably, the L8‐derived catalyst exhibited enhanced activity when compared to the L4‐based system previously disclosed for C−N coupling, namely the ability to functionalize aryl bromides containing acidic functional groups. Mechanistic studies demonstrate that C−O coupling utilizing L8 ⋅ Cu involves rate‐limiting alkoxide transmetallation, resulting in a mechanism of C−O bond formation that is distinct from previously described Pd‐, Cu‐, or Ni‐based systems. This lower energy pathway leads to rapid C−O bond formation; a 7‐fold increase relative to what is seen with other ligands. The …

Ullmann-type C–N coupling reactions represent an important alternative to well-established Pd-catalyzed approaches due to the differing reactivity and the lower cost of Cu. While the design of anionic Cu ligands, particularly those by Ma, has enabled the coupling of various classes of aryl halides and alkyl amines, most methods require conditions that can limit their utility on complex substrates. Herein, we disclose the development of anionic N1,N2-diarylbenzene-1,2-diamine ligands that promote the Cu-catalyzed amination of aryl bromides under mild conditions. Guided by DFT calculations, these ligands were designed to (1) increase the electron density on Cu, thereby increasing the rate of oxidative addition of aryl bromides, and (2) stabilize the active anionic CuI complex via a π-interaction. Under optimized conditions, structurally diverse aryl and heteroaryl bromides and a broad range of alkyl amine …

Encoding small-molecule information in DNA has been leveraged to accelerate the discovery of ligands for therapeutic targets such as proteins. However, oligonucleotide-based encoding is hampered by inherent limitations of information stability and density. In this study, we establish abiotic peptides for next-generation information storage and apply them for the encoding of diverse small-molecule synthesis. The chemical stability of the peptide-based tag allows the use of palladium-mediated reactions to efficiently synthesize peptide-encoded libraries (PELs) with broad chemical diversity and high purity. We demonstrate the successful de novo discovery of small-molecule protein ligands from PELs by affinity selection against carbonic anhydrase IX and the oncogenic protein targets BRD4(1) and MDM2. Collectively, this work establishes abiotic peptides as carriers of information for the encoding of small-molecule …

The utility of antibody therapeutics is hampered by potential cross-reactivity with healthy tissue. Over the past decade, significant advances have been made in the design of activatable antibodies which increase, or create altogether, the therapeutic window of a parent antibody. Of these, antibody prodrugs (pro-antibodies) are masked antibodies that have advanced the most for therapeutic use. They are designed to reveal the active, parent antibody only when encountering proteases upregulated in the microenvironment of the targeted disease tissue, thereby minimizing off-target activity. However, current pro-antibody designs are relegated to fusion proteins that append masking groups restricted to the use of only canonical amino acids, offering excellent control of the site of introduction, but with no authority over where the masking group is installed other than the N-terminus of the antibody. Here, we present a palladium-based bioconjugation approach for the site-specific introduction of a masked tyrosine mimic in the complementary determining region of the FDA approved antibody therapeutic Ipilimumab used as a model system. The approach enables the introduction of a protease cleavable group tethered to non-canonical polymers (poly-ethylene glycol, PEG) resulting in 47-fold weaker binding to cells expressing CTLA-4, the target antigen of Ipilimumab. Upon exposure to tumor-associated proteases, the masking group is cleaved unveiling a tyrosine-mimic (dubbed a hydroxyphenyl cysteine, HPC) that restores (>90% restoration) binding affinity to its target antigen.

We report a versatile and functional-group-tolerant method for the Pd-catalyzed C–N cross-coupling of five-membered heteroaryl halides with primary and secondary amines, an important but underexplored transformation. Coupling reactions of challenging, pharmaceutically relevant heteroarenes, such as 2-H-1,3-azoles, are reported in good-to-excellent yields. High-yielding coupling reactions of a wide set of five-membered heteroaryl halides with sterically demanding α-branched cyclic amines and acyclic secondary amines are reported for the first time. The key to the broad applicability of this method is the synergistic combination of (1) the moderate-strength base NaOTMS, which limits base-mediated decomposition of sensitive five-membered heteroarenes that ultimately leads to catalyst deactivation, and (2) the use of a GPhos-supported Pd catalyst, which effectively resists heteroarene-induced catalyst …

Protein–protein interactions (PPIs) are intriguing targets in drug discovery and development. Peptides are well suited to target PPIs, which typically present with large surface areas lacking distinct features and deep binding pockets. To improve binding interactions with these topologies and advance the development of PPI-focused therapeutics, potential ligands can be equipped with electrophilic groups to enable binding through covalent mechanisms of action. We report a strategy termed electrophile scanning to identify reactivity hotspots in a known peptide ligand and demonstrate its application in a model PPI. Cysteine mutants of a known ligand are used to install protein-reactive modifiers via a palladium oxidative addition complex (Pd-OAC). Reactivity hotspots are revealed by cross-linking reactions with the target protein under physiological conditions. In a model PPI with the 9-mer peptide antigen VL9 and …