About

Scott Miller is a Sterling Professor of Chemistry and a member of the Yale faculty since 2006. His research focuses on molecular synthesis, particularly the development of new methods for the synthesis and derivatization of complex structures. His group employs reaction design, development, and application, utilizing principles from biologically relevant structures and processes to discover new reactions and apply new principles to the selective synthesis of complex molecules. Miller's work involves the use of modern synthetic chemistry techniques, rational design, combinatorial screening, and mechanistic analysis to discover new chemical transformations that enable rapid synthesis of stereochemically complex structures and the development of new catalysts for selective functionalization, including the catalytic modification of natural products. His contributions have significantly advanced the field of organic chemistry, earning him international recognition and numerous awards.

Research topics

• Combinatorial chemistry
• Chemistry
• Stereochemistry
• Biochemistry
• Pharmacology
• Computer Science
• Biology
• Biochemical engineering
• Genetics
• Library science
• Organic chemistry
• Computational chemistry
• Computational biology

Selected publications

• Asymmetric Desymmetrizing Sulfonylation of Diarylmethanes via Peptidyl-Cu(I)-Catalysis with Remote Stereocontrol

  Journal of the American Chemical Society · 2026-01-07

  articleOpen accessSenior authorCorresponding

  An asymmetric catalytic desymmetrizing cross-coupling of diarylmethanes with organosulfinates has been developed. Permutations of proteinogenic and noncanonical amino acids allow access to guanidinylated peptide-based ligands that may be tuned for distal stereocontrol under copper catalysis. Noncovalent attractive interactions are likely significant in organizing the geometry of substrate-copper-peptide ternary complexes, modulated by countercation effects, for effective enantioselective oxidative addition; further enantioenrichment of the sulfone products occurs via secondary kinetic resolution, corroborated by mechanistic studies. The mild protocols disclosed herein expand asymmetric and site-selective catalysis mediated by peptides first to enable C-S bond-forming cross-coupling reactions with remote stereocontrol.

  PublisherDOI

• Assessment of Complementary Catalysts in an Uncharted Enantioselective Reaction of Sulfondiimines

  Journal of the American Chemical Society · 2026-05-04

  articleOpen accessSenior authorCorresponding

  Traditionally, many chemists turn to “privileged” catalyst scaffolds, which often demonstrate appreciable performance for a broad range of transformations. However, these structures can be challenging to modify, so complementary catalysts, such as peptides, are of interest. We simultaneously explored both peptidic and privileged cinchona catalysts for the asymmetric trifluoroacetylation of sulfondiimines (SDIs), an unexplored enantioselective reaction. The resultant acylated SDIs can enable access to a broad range of enantioenriched sulfur(VI) products for potential applications as bioisosteres. A significant challenge facing the establishment of an enantioselective variant of this reaction is that the background reaction has a high rate of reactivity, achieving 70% conversion in just 1 h at −78 °C. Nonetheless, we identified both a peptide and a cinchona alkaloid featuring kinetic profiles that outcompete this extremely fast background reactivity by an order of magnitude. Substrate scope was profiled using an algorithmic strategy followed by a comparison of statistical models relating substrate molecular descriptors and ΔΔG‡ to reveal the contrasting nature of each catalyst’s performance.

  PublisherDOI

• Site-Divergent Oxidations within Venerable Macrolide Antibiotic Scaffolds Unveil Compounds with Broad Spectrum and Anti-MRSA Activities

  ACS Central Science · 2026-03-17 · 1 citations

  articleOpen accessSenior authorCorresponding

  The synthesis of bioactive compounds with differential, and ideally enhanced, activities presents persistent and growing challenges for the field of organic synthesis. By leveraging Nature’s ability to build complex, stereochemically rich, and biologically active molecular scaffolds, site-selective modification of natural products can deliver analogs without the need for lengthy de novo syntheses. Yet, achieving selective reactivity at a single desired position is complicated by the presence of multiple iterations of similar reactive functional groups, thus precluding widespread adoption of catalyst-controlled site-selective modification. Herein we describe the development of complementary systems for the oxidation of secondary alcohols on erythromycin A, clarithromycin, and azithromycin using a newly designed azaadamantyl oxoammonium catalyst, wherein different hydroxyl groups show disparate reactivities under the same conditions. The application of this methodology has enabled the generation of a suite of oxidized macrolide antibiotics and derivatives that take advantage of the newly installed carbonyls. Antimicrobial activity testing revealed that multiple compounds retain activity against a broad range of pathogens consistent with erythromycin A coverage. Additionally, three of the compounds reported herein display antibiotic activity against CA-MRSA and MRSA(mph(C)), for which the clinical analogs erythromycin A, clarithromycin, and azithromycin exhibit no activity at tested concentrations.

  PublisherDOI

• Peptidyl Glycosyl Thiols and Disulfides for Enantioselective Hydrogen Atom Transfer (HAT) and Thiyl Radical Catalysis

  The Journal of Organic Chemistry · 2025-10-20 · 1 citations

  articleOpen accessSenior authorCorresponding

  A novel class of peptidyl glycosyl disulfide and thiol catalysts is developed. The thiols are found to catalyze enantioselective olefin hydrosilylation up to 5:95 er. The disulfide catalysts are competent in an enantioselective thiyl-catalyzed cycloaddition reaction, yielding product with complementary selectivity to that previously reported with cystine-based catalysts. The modular nature of these catalysts provides new opportunities for asymmetric thiyl and thiol HAT catalysis.

  PublisherOA PDFDOI

• Catalyst-Controlled Site-Selective and Epimer-Selective Hydrogenations of Thiostrepton

  Journal of the American Chemical Society · 2025-05-13 · 1 citations

  articleOpen accessSenior authorCorresponding

  The hydrogenation of the antibiotic thiostrepton with control over the site- and stereoselectivity of reduction is reported. Studies on model substrates designed to mimic aspects of the consecutive dimeric dehydroalanine (Dha) tail of thiostrepton first culminate in the development of an asymmetric hydrogenation method for a diverse set of bis(Dha) compounds. Monodentate phosphoramidite ligands (e.g., MonoPhos) are optimal and allow for selectivity of up to a 96:2:2:<1 ratio for doubly hydrogenated products. Subsequently, the protecting-group free, diastereomer-selective hydrogenation of the tail fragment of thiostrepton (Dha16 and Dha17) under mild conditions is presented with >80% selectivity for a single stereoisomer, relative to the sum of other detectable products. Opposite MonoPhos chirality results in alternative selectivity for the hydrogenated tail product, establishing ligand-controlled hydrogenation. The further study of ligands enabled hydrogenation of the internal dehydroalanine residue (Dha3), using sterically attenuated phosphoramidite ligands. Strikingly, ligand chirality dictates the stereochemical outcome at the sterically occluded Dha3, allowing for the synthesis of distinct stereoisomers, culminating in two distinct bis-hydrogenated isomers and two distinct tris-hydrogenated stereoisomers. Finally, hydrogenation with yet another phosphine ligand scaffold, a bidentate bisphosphine, results in the controlled formation of a single tetra-hydrogenated product. The structures and stereochemistry of the products are identified using multidimensional nuclear magnetic resonance methods, X-ray crystallography, and comparison to model substrates with confirmed absolute stereochemistry. The new thiostrepton derivatives are benchmarked for their antibiotic activity against representative antibiotic-resistant bacterial strains, revealing significant effects of Dha hydrogenation, and a number of new insights, most notably about the significance of Dha3 for antibiotic activity.

  PublisherOA PDFDOI

• Thioesters Support Efficient Protein Biosynthesis by the Ribosome

  ACS Central Science · 2025-01-30 · 4 citations

  articleOpen accessCorresponding

  Thioesters are critical chemical intermediates in numerous extant biochemical reactions and are invoked as key reagents during prebiotic peptide synthesis on an evolving Earth. Here we asked if a thioester could replace the native oxo-ester in acyl-tRNA substrates during protein biosynthesis by the ribosome. We prepared 3′-thio-3′-deoxyadenosine triphosphate in 10 steps from xylose and demonstrated that it is an effective substrate for the Escherichia coli CCA-adding enzyme, which appends 3′-thio-3′-deoxyadenosine to truncated tRNAs ending with 3′-CC. Using a variety of aminoacyl-tRNA synthetases, flexizymes, or a direct thioester exchange reaction, we prepared a suite of 3′-thio-tRNAs acylated with α- and non-α-amino acids. All were recognized and utilized by wild-type E. coli ribosomes during in vitro translation reactions to generate oligopeptides in yields commensurate with native oxo-ester tRNAs. These results indicate that thioester intermediates widely used in Nature can be co-opted to support the incorporation of natural α-amino acids as well as noncanonical monomers by the extant translational machinery for sequence-defined polymer synthesis.

  PublisherDOI

• Additively Printed Circuit Performance of Thermoformed In-Mold Electronics for Automotive Applications

  Journal of Electronic Packaging · 2025-11-29

  articleOpen accessSenior author

  Abstract The use of in-mold Electronics has the potential for transforming design and production of automotive systems through greater integration of form and function and lightweighting achieved by elimination of wire harnesses and connectors. IME can facilitate the smooth integration of electronic circuits into intricate three-dimensional surfaces. Nevertheless, despite the potential for providing numerous benefits, the technology transition of additive IME circuits is still lacking. It is still unclear how important manufacturing factors, such as substrate deformation, ink conductivity, and mechanical stress, affect circuit performance. The purpose of this study is to look into how the electrical performance of IME circuits made for automotive applications is affected by screen-printing and thermoforming settings. This study offers important insights into the viability and dependability of IME technology in actual automotive settings by examining resistance fluctuations, capacitance stability, and overall circuit performance both before and after thermoforming. The results facilitate IME's wider implementation in next-generation vehicle electronics by advancing our understanding of its design and optimization.

  PublisherOA PDFDOI

• A New Methodology for Preparing Benzylated Aminopyridines Yields Previously Inaccessible Organocatalysts

  European Journal of Organic Chemistry · 2025-10-05

  article

  p ‐Dialkylaminopyridines represent a key class of nucleophilic organocatalysts, widely used in alcohol‐modifying reactions, among other applications. However, access to certain variants of these catalysts, particularly those with sterically congested secondary sphere, remains challenging or even unfeasible using previously established synthetic routes. Lewis acid‐promoted benzylation or cyclative dibenzylation of simple aminopyridines with corresponding alcohols effectively overcomes these shortcomings. This innovative approach enables the synthesis of previously inaccessible (2,5‐diarylpyrrolidino)pyridines and novel ( N ‐benzyl‐ N ‐methylamino)pyridines bearing extended ortho ‐alkoxy tails on the aryl substituents. The new catalysts, characterized by their bulky secondary sphere, exhibit outstanding activity and high site‐selectivity in the phosphorylation of a model diol amphiphile.

  PublisherDOI

• Beyond Ranked Lists: The SARAL Framework for Cross-Lingual Document Set Retrieval

  ArXiv.org · 2025-11-05

  preprintOpen accessSenior author

  Machine Translation for English Retrieval of Information in Any Language (MATERIAL) is an IARPA initiative targeted to advance the state of cross-lingual information retrieval (CLIR). This report provides a detailed description of Information Sciences Institute's (ISI's) Summarization and domain-Adaptive Retrieval Across Language's (SARAL's) effort for MATERIAL. Specifically, we outline our team's novel approach to handle CLIR with emphasis in developing an approach amenable to retrieve a query-relevant document \textit{set}, and not just a ranked document-list. In MATERIAL's Phase-3 evaluations, SARAL exceeded the performance of other teams in five out of six evaluation conditions spanning three different languages (Farsi, Kazakh, and Georgian).

  PublisherOA PDFDOI

• Chemical and ribosomal synthesis of atropisomeric and macrocyclic peptides with embedded quinolines

  Nature Chemistry · 2025-09-17 · 6 citations

  articleSenior author
  PublisherDOI

Recent grants

• Minimal Peptide Catalysts for Asymmetric Synthesis

  NSF · $424k · 2006–2009

• Site-Selective Catalysis for Organic Synthesis

  NIH · $2.7M · 2003–2021

• Site-Selective Catalysis for Bioactive Scaffold Diversification

  NIH · $5.5M · 2019–2029

• Selective Peptide-Based Oxidation Catalysts for Bioactive Molecule Synthesis

  NIH · $2.4M · 2010–2019

• NIH Grant R01GM068649

  NIH · $2.3M · 2011

Frequent coauthors

• Alanna Schepartz

  Arc Research Institute

  118 shared

• Paul J. Chirik

  105 shared

• Brandon Q. Mercado

  Yale University

  98 shared

• Kai Rossen

  96 shared

• Bryan W. Brooks

  Baylor University

  94 shared

• Krishna N. Ganesh

  Jawaharlal Nehru Centre for Advanced Scientific Research

  94 shared

• David T. Allen

  Center for Environmental Health

  94 shared

• Phillip E. Savage

  Pennsylvania State University

  94 shared

Education

• National Science Foundation Postdoctoral Fellow, Department of Chemistry

  California Institute of Technology

  1996

• Ph.D., Department of Chemistry

  Harvard University

  1994

• B.A. and M.A., Department of Chemistry

  Harvard University

  1989

Awards & honors

• Research Innovation Award, Research Corporation (1998)
• NSF CAREER Award (1999)
• Cottrell Scholar Award of Research Corporation (1999)
• Eli Lilly Grantee (1999)
• Novartis Chemistry Lectureship Award (1999)