Jon Ellman
· Eugene Higgins Professor of Chemistry and Professor of PharmacologyVerifiedYale University · Department of Chemistry
Active 1978–2026
About
Jon Ellman is the Eugene Higgins Professor of Chemistry and Professor of Pharmacology at Yale University, and has been a member of the Yale faculty since 2010. His research focuses on the rapid and efficient synthesis of new chemical matter, aiming to discover and develop compounds with diverse properties and applications. His laboratory has pioneered the development of tert-butanesulfinamide chemistry, which is extensively used for the asymmetric synthesis of amine-containing compounds prevalent in pharmaceuticals. Additionally, his work involves the catalytic conversion of C-H to C-C bonds, enabling the direct preparation of complex structures from simple precursors. Ellman's research also includes designing and synthesizing structures that interact with biological systems, developing tools to understand enzyme function, and creating compounds to interact with biomolecular targets for potential drug development.
Research topics
- Chemistry
- Stereochemistry
- Organic chemistry
- Biology
- Biophysics
- Medicine
- Combinatorial chemistry
- Photochemistry
- Computational biology
- Computational chemistry
- Biochemistry
- Pharmacology
Selected publications
CCDC 2453740: Experimental Crystal Structure Determination
The Cambridge Structural Database · 2026-01-05
datasetOpen accessSenior authorAn entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Asymmetric Synthesis of <i>S</i> -Trifluoromethyl Sulfoxide and Sulfoximine Pharmacophores
Journal of the American Chemical Society · 2026-04-27
articleOpen accessSenior authorCorrespondingChiral sulfoxides and sulfoximines are present in many approved drugs and clinical candidates, and as predicated by the extensive use of the trifluoromethyl group in medicinal chemistry, S-trifluoromethyl derivatives with potent biological activity have been reported. However, chiral S-trifluoromethyl sulfoxides and sulfoximines are underexplored, perhaps because the only published routes for their preparation proceed by racemic synthesis followed by chiral separation. Here we report the asymmetric syntheses of S-trifluoromethyl sulfoxides and sulfoximines utilizing highly enantioenriched S-trifluoromethyl sulfilimines as common intermediates, obtained by the enantioselective copper-catalyzed S-trifluoromethylation of a wide range of sulfenamides, including complex drug and natural product derivatives. Methods were developed for the efficient conversion of the S-trifluoromethyl sulfilimines to sulfoxides via hydrolysis with inversion and sulfoximines via oxidation with retention. Mechanistic studies of the conversion of S-trifluoromethyl sulfilimines to sulfoxides reveal that the sulfilimine N-acyl group is first cleaved to give the free-NH sulfilimine that then undergoes hydrolysis by backside displacement of the amine to give the sulfoxide with inversion of stereochemistry.
Journal of the American Chemical Society · 2025-04-28 · 33 citations
articleOpen accessSenior authorCorrespondingSulfoximines are increasingly utilized in pharmaceuticals and agrochemicals with all sulfoximine clinical candidates incorporating either an S-methyl or an S-cyclopropyl substituent. Here, we report on a general and efficient sequence for the asymmetric synthesis of both of these sulfoximine substitution patterns. The asymmetric synthesis of sulfilimine intermediates by the first Ru-catalyzed enantioselective alkylation of sulfenamides enables the first examples of enantioselective S-alkylation with monosubstituted diazo compounds. The reaction proceeds at ≤1 mol % Ru-catalyst loading, and for tert-butyl diazoacetate, high yields and ≥98:2 er are achieved for an exceedingly broad range of sulfenamides, including with S-(hetero)aryl, -alkenyl, -methyl, -benzyl, -branched alkyl, and -tert-butyl substituents and for sterically and electronically diverse N-acyl groups. Sulfenamides derived from densely functionalized advanced drug intermediates also alkylated with 99:1 er. After oxidation of an N-pivaloyl S-tert-butyl acetate substituted sulfilimine to the corresponding sulfoximine, treatment with trifluoracetic acid in an aprotic solvent resulted in decarboxylation to the S-methyl N-pivaloyl sulfoximine, while aqueous HCl resulted in both decarboxylation and cleavage of the N-acyl group to give the S-methyl NH sulfoximine. Alternatively, sulfoximine alkylation with dibromoethane followed by acid-mediated decarboxylation provided the S-cyclopropyl sulfoximine. The efficient asymmetric synthesis of the preclinical candidate LTGO-33 and the formal asymmetric synthesis of the phase II clinical candidate ART0380 demonstrate the utility of the disclosed approach.
Organic Letters · 2025-12-19
articleOpen accessSenior authorCorrespondingEnantioenriched sulfinamides serve as key intermediates for the asymmetric synthesis of sulfoximines and other S(VI) pharmacophores. Enantioselective biocatalytic oxidation of an S-methyl sulfenamide to the corresponding S-methyl sulfinamide proceeds in good yield and >99:1 er. Its utility as a key chiral intermediate was demonstrated by stereoretentive S-arylation and S-alkylation as well as by the asymmetric synthesis of two S-methyl sulfoximine drug candidates, with S-methyl substitution notably present in most sulfoximine clinical candidates.
bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-14 · 2 citations
preprintOpen accessAbstract Large library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving many interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration and targeted docking of isoquinuclidines. These “natural-product-like” molecules are rare in the current libraries and are functionally congested, making them interesting as receptor probes. Using a modular, four-component reaction scheme, we built and docked a virtual library of over 14.6 million isoquinuclidines against both the µ- and κ -opioid receptors (MOR and KOR, respectively). Synthesis and experimental testing of 18 prioritized compounds found nine ligands with low µM affinities. Structure-based optimization revealed low- and sub- nM antagonists and inverse agonists targeting both receptors. Cryo-electron microscopy (cryoEM) structures illuminate the origins of activity on each target. In mouse behavioral studies, a potent member of the series with joint MOR-antagonist and KOR-inverse-agonist activity reversed morphine-induced analgesia, phenocopying the MOR-selective anti-overdose agent naloxone. Encouragingly, the new molecule induced less severe opioid-induced withdrawal symptoms compared to naloxone during withdrawal precipitation, and did not induce conditioned-place aversion, likely reflecting a reduction of dysphoria due to the compound’s KOR-inverse agonism. The strengths and weaknesses of bespoke library docking, and of docking for opioid receptor polypharmacology, will be considered.
ACS Central Science · 2025-04-29 · 8 citations
articleOpen accessCorrespondingLarge library docking of tangible molecules has revealed potent ligands across many targets. While make-on-demand libraries now exceed 75 billion enumerated molecules, their synthetic routes are dominated by a few reaction types, reducing diversity and inevitably leaving many interesting bioactive-like chemotypes unexplored. Here, we investigate the large-scale enumeration and targeted docking of isoquinuclidines. These "natural-product-like" molecules are rare in current libraries and are functionally congested, making them interesting as receptor probes. Using a modular, four-component reaction scheme, we built and docked a virtual library of over 14.6 million isoquinuclidines against both the μ- and κ-opioid receptors (MOR and KOR, respectively). Synthesis and experimental testing of 18 prioritized compounds found nine ligands with low μM affinities. Structure-based optimization revealed low- and sub-nM antagonists and inverse agonists targeting both receptors. Cryo-electron microscopy structures illuminate the origins of activity on each target. In mouse behavioral studies, a potent joint MOR-antagonist and KOR-inverse-agonist reversed morphine-induced analgesia, phenocopying the MOR-selective antioverdose agent naloxone. Encouragingly, the isoquinuclidine induced less severe opioid-withdrawal symptoms versus naloxone and did not induce conditioned-place aversion, reflecting reduced dysphoria, consistent with its KOR-inverse agonism. The strengths and weaknesses of bespoke library docking and of docking for opioid receptor polypharmacology will be considered.
Journal of Medicinal Chemistry · 2025-01-09 · 40 citations
articleOpen accessCorrespondingWhile sulfoximines are nowadays a well established functional group for medicinal chemistry, the properties of sulfilimines are significantly less well studied, and no sulfilimine has progressed to the clinic to date. In this account, the physicochemical and in vitro properties of sulfilimines are reported and compared to those of sulfoximines and other more traditional functional groups. Furthermore, the impact on the physicochemical and in vitro properties of real drug scaffolds is studied in two series of sulfilimine-containing analogs of imatinib and hNE inhibitors. We show that sulfilimines can be chemically and configurationally stable under physiologically relevant conditions and that they are basic and highly polar and thus are often beneficial for solubility and metabolic stability, although at the cost of reduced permeability. We conclude that S-cyclopropyl,S-(hetero)aryl and S,S-di(hetero)aryl sulfilimines are so far neglected but potentially valuable S(IV) based pharmacophores that deserve to be considered as part of the medicinal chemistry toolbox.
The Journal of Organic Chemistry · 2025-07-31 · 2 citations
articleOpen accessSenior authorCorrespondingN-Acylsulfenamides can be efficiently prepared by a one-pot synthetic sequence via S-functionalization of N-acyl S-phenethyl sulfenamides, utilizing diverse (hetero)aryl and alkenyl iodide and boronic acid inputs to give sulfilimines that then undergo concerted elimination of styrene. To probe the mechanism of styrene elimination from sulfilimines, a Hammett analysis was performed with substituents placed on both the S-aryl and S-phenethyl groups. Positive Hammett ρ values established a modest negative charge build up at both positions, with greater charge buildup at the phenethyl site. A primary isotope effect of 5.4 at the benzyl site was also determined through the synthesis of a deuterated sulfilimine and is consistent with significant C–H bond cleavage at the benzylic carbon in the transition state. Computation provides strong support for the proposed concerted elimination mechanism.
ACS Catalysis · 2025-12-25
articleOpen accessSenior authorCorrespondingCp*Co(III)-catalyzed sequential addition of alkenyl C(sp2)–H bonds to dienes and aldehydes provides products with two additional C–C σ bonds with the simultaneous introduction of contiguous stereogenic centers with high selectivity. Blue LED irradiation is essential for achieving high reaction yields, and under optimized conditions, a broad scope of aromatic and aliphatic aldehydes is observed, including sequential C–H bond additions to chiral aldehydes using acyclic stereocontrol without any epimerization at the racemization prone stereogenic center α to the aldehyde carbonyl. The sequential addition products have carbon frameworks relevant to natural product synthesis applications and can readily be elaborated as demonstrated by the preparation of an intermediate to the macrolide nannocystin Ax and by the efficient asymmetric synthesis of an enantiomerically pure compound incorporating six stereogenic centers. Investigations of the structure and reactivity of allyl cobaltacycle intermediates established pronounced mechanistic differences for the sequential addition of alkenyl versus aromatic C(sp2)–H bonds to dienes and aldehydes. In particular, for alkenyl C–H bond reactants, cobaltacycle intermediates are formed that have different bonding interactions than for aromatic reactants. Moreover, a facile cobaltacycle isomerization pathway to a more stable, less reactive species can occur that is not possible for aromatic reactants. Characterization of a key unstable cobaltacycle intermediate could only be achieved by structural analysis of microcrystals by MicroEd, highlighting the utility of this method for structural analysis.
Organic Letters · 2024-07-15 · 27 citations
articleOpen accessSenior authorCorrespondingThe Rh(II)-catalyzed enantioselective S-alkylation of sulfenamides with α-amide diazoacetates at 1 mol % catalyst loading to obtain sulfilimines in high yields and enantiomeric ratios of up to 99:1 is reported. The enantioenriched sulfilimine products incorporate versatile amide functionality poised for further elaboration to diverse sulfoximines with multiple stereogenic centers, including by highly diastereoselective sulfilimine and sulfoximine α-alkylation with alkylating agents and epoxides and by interconversion of the amide to N-tert-butanesulfinyl aldimines, followed by diastereoselective additions.
Recent grants
Application of Sulfinamides in Synthesis and Catalysis
NSF · $480k · 2011–2014
NIH · $6.7M · 2002
Asymmetric Synthesis Using tert-Butanesulfinamide
NSF · $390k · 2005–2008
Asymmetric Synthesis of Amines
NSF · $88k · 2010–2011
C-H Functionalization for the Synthesis of Amines and Nitrogen Heterocycles
NIH · $5.4M · 2004–2019
Frequent coauthors
- 252 shared
Robert G. Bergman
Lawrence Berkeley National Laboratory
- 75 shared
Bruce H. Lipshutz
University of California, Santa Barbara
- 75 shared
Nicholas E. Leadbeater
University of Connecticut
- 66 shared
Brandon Q. Mercado
Yale University
- 65 shared
Margaret M. Faul
Washington University in St. Louis
- 65 shared
Mark Lautens
- 64 shared
Brianna Lucas
University of Florida
- 64 shared
Julia B. Scheerer
William & Mary
Labs
Education
- 1992
National Science Foundation Postdoctoral Fellow, Department of Chemistry
University of California, Berkeley
- 1989
Ph.D., Department of Chemistry
Harvard University
- 1984
B.S., Department of Chemistry
Massachusetts Institute of Technology
Awards & honors
- NSF Predoctoral Fellowship (1984)
- NSF Postdoctoral Fellowship (1989)
- NSF Young Investigator Award (1993)
- Arnold and Mabel Beckman Foundation Young Investigator Award…
- Burroughs Wellcome Fund Hitchings Award for Drug Design and…
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