On peer-reviewed ground.
The puzzle pieces making our novel 3-D drug building blocks physically real, not just computationally imagined.
From paper to product
Every claim on this page is backed by a paper you can open.
Our platform is not a promise, it is the commercial extension of fundamental chemistry published in the world's most rigorous journals. Here is how each discovery becomes a drug-discovery advantage.
The foundation
Real, reproducible chemistry
Every building block on our platform traces back to a paper in Nature Chemistry, Science or JACS, peer-reviewed and independently reproducible. The synthesis is proven, not promised.
The application
Pharma-ready 3-D matter
Rigid spiro[2.2]pentane and epoxide scaffolds open the saturated, three-dimensional chemical space that flat aromatic libraries cannot reach, directly answering the "escape from flatland" problem in modern drug design.
The leverage
AI-navigable space
Because the route is real, it enumerates into billions of virtual forms that our AI engine pre-filters by ADMET-AI, QED and Lipinski Ro5, turning validated chemistry into a searchable, disease-targeted library.
Isolation and Characterization of Diazoolefins
Landmark paper reporting the first preparative-scale isolation and full characterization of N-heterocyclic diazoolefins, a class of compounds previously observed only as fleeting intermediates. The diazoolefins form through reaction of N-heterocyclic olefins with nitrous oxide, and exhibit strong ylidic character with high charge density at the α-carbon, enabling crystallographic characterization despite harboring a terminal N₂ group.
This Nature Chemistry publication is foundational to DAOdiscovery's entire chemistry platform. Diazoolefins are the reactive building blocks from which the Diazo Ylide reaction generates high-value strained carbocyclic scaffolds. Varava's co-authorship on the paper that established this substance class as isolable entities marks his scientific priority at the origin of our technology.
Synthesis, Structural Characterization, and Coordination Chemistry of Imidazole-Based Alkylidene Ketenes
Imidazole-based diazoolefins react with carbon monoxide to afford thermally stable N-heterocyclic alkylidene ketenes, which were isolated and characterized by single-crystal X-ray diffraction. These heterocumulenes act as C-donor ligands towards both transition metals (Au, Rh, Pd) and main-group metals (Ga), furnishing well-defined coordination complexes and expanding the scope of reactive carbon species available for synthetic applications.
The discovery that imidazole-derived reactive carbon intermediates can be trapped and leveraged as ligands directly informs how DAOdiscovery designs the Diazo Ylide reaction's reactant scope. This expertise in transforming diazo precursors into isolable, functional heterocumulene building blocks is key intellectual capital for expanding the spiropentane scaffold library.
Vanadium Complexes with N-Heterocyclic Vinylidene Ligands
A vanadium(III) complex bearing an imidazole-derived N-heterocyclic vinylidene ligand was synthesized and structurally characterized. The very short V–C bond distance observed by X-ray crystallography confirmed that N-heterocyclic vinylidenes are exceptionally strong σ-donor C-donor ligands, expanding their coordination chemistry beyond precious metals to earth-abundant alternatives.
Establishing N-heterocyclic vinylidenes as powerful C-donor ligands across earth-abundant metals demonstrates the versatility of this ligand class in enabling metal-carbene type reactivity at scale. For DAOdiscovery, this breadth of metal compatibility is important for developing cost-effective and industrially feasible variants of the Diazo Ylide spiropentane synthesis.
Copper Complexes with Diazoolefin Ligands and Their Photochemical Conversion into Alkenylidene Complexes
Copper(I) complexes bearing N-heterocyclic diazoolefin ligands were synthesized and structurally characterized. Upon UV irradiation, these Cu–diazoolefin complexes undergo photochemical dinitrogen extrusion to generate bridging and terminal alkenylidene (Cu=C=CR₂) complexes, with the terminal alkenylidene isolated and structurally characterized for the first time via in crystallo photolysis at low temperature.
This paper directly showcases the generation and trapping of alkenylidene intermediates from diazoolefin precursors under photochemical conditions, a conceptual precedent for the C-atom and carbene transfer chemistry at the core of DAOdiscovery's Diazo Ylide reaction. Varava's role in capturing these elusive intermediates at copper centers demonstrates the practical metal-mediated methods adaptable for spiropentane scaffold construction.
Head-to-Tail Dimerization of N-Heterocyclic Diazoolefins
N-heterocyclic diazoolefins undergo formal (3+3) cycloaddition reactions in a head-to-tail fashion to afford strongly reducing quinoidal tetrazines. Oxidation of these tetrazines proceeds stepwise, enabling isolation of a stable radical cation and a diamagnetic dication, revealing previously unknown reactivity modes for this young class of stabilized diazo compounds.
The discovery of (3+3) cycloaddition reactivity in diazoolefins broadens the synthetic toolkit available for building ring-strained and polyfunctionalized heterocyclic scaffolds, exactly the chemical space DAOdiscovery targets for pharma partners. Varava's command of controlling diazoolefin reactivity pathways is foundational intellectual capital for the Diazo Ylide reaction's design and optimization.
Ambiphilic Reactivity of Iridium Complexes with N-Heterocyclic Vinylidene Ligands
Cationic iridium complexes bearing terminal N-heterocyclic vinylidene ligands were synthesized by reacting (Cp*IrCl₂)₂ with an N-heterocyclic diazoolefin followed by chloride abstraction. The vinylidene ligands display ambiphilic reactivity: cationic forms covalent adducts with halides and pseudohalides while neutral forms react with electrophiles. Crystallographic analysis revealed unusually short Ir–C bonds indicating partial carbyne character.
This work demonstrates deep expertise in reactive organometallic intermediates and novel ligand architectures, directly relevant to designing the metal-carbene chemistry underpinning the Diazo Ylide reaction platform. Ambiphilic reactivity and short M–C bonds are hallmarks of the strained, high-energy intermediates that DAOdiscovery harnesses to build spiropentane scaffolds with unique 3D pharmacophoric profiles.
Isolation and Reactivity of an Elusive Diazoalkene
Diazoalkenes (R₂C=C=N₂) had long been postulated as reactive intermediates but had never been isolated. The Hansmann group demonstrated that N-heterocyclic backbone stabilization enables their isolation and full structural/spectroscopic characterization. The compound displays dual-site nucleophilicity at both C and N atoms, a bent C–C–N geometry (124°), and an unusually low IR absorption at 1,944 cm⁻¹.
Directly mirroring Varava's concurrent Nature Chemistry publication on diazoolefins, this paper establishes the founding intellectual basis for DAOdiscovery's Diazo Ylide reaction chemistry. Hansmann's co-founder role is rooted in this breakthrough, signalling to partners that DAOdiscovery's platform emerges from independently validated, world-class fundamental science.
N₂/CO Exchange at a Vinylidene Carbon Center: Stable Alkylidene Ketenes and Alkylidene Thioketenes from Diazoalkenes
Room-temperature-stable diazoalkenes based on a 1,2,3-triazole backbone undergo a novel dinitrogen-for-CO/isocyanide ligand exchange at the vinylidene carbon center, affording isolable alkylidene ketenes and alkylidene thioketenes. This work, highlighted in a JACS Spotlights editorial, demonstrates clean functional-group interconversion at an otherwise inaccessible reactive carbon site.
The demonstration that diazoalkene-derived vinylidenes can be cleanly converted into diverse hetero-cumulene building blocks shows the broad functional group diversity accessible from this reactive intermediate class. This versatility is directly applicable to DAOdiscovery's strategy of diversifying its spiropentane scaffold library through post-cyclization modification.
Characterization of a Triplet Vinylidene
Triplet vinylidenes, monosubstituted carbon-centered diradicals with two unpaired electrons, had been predicted but were entirely uncharacterized experimentally. By photochemical liberation of N₂ from a stable diazoalkene precursor, the Hansmann group generated and characterized a triplet vinylidene using EPR and ENDOR spectroscopy at low temperatures, opening a new chapter on carbon-centered diradicals.
The ability to generate and characterize high-energy vinylidene intermediates on demand from stable diazoalkene precursors is mechanistically central to understanding how the Diazo Ylide reaction creates strained spiropentane ring systems. This work demonstrates the exquisite control over reactive carbon species that is the scientific foundation for designing selective and efficient spirocyclization reactions.
Room-Temperature-Stable Diazoalkenes by Diazo Transfer from Azides: Pyridine-Derived Diazoalkenes
A Regitz-type diazo transfer from azide reagents to weakly polarized 2-pyridine-derived olefins yields room-temperature-stable pyridine-backbone diazoalkenes. This strategy extends accessible backbone diversity beyond imidazole and triazole systems to include pyridine heterocycles, broadening the practical synthetic toolkit for preparing this emerging class of reactive intermediates.
By introducing pyridine-backbone diazoalkenes via a scalable azide-based diazo transfer, this paper expands the substrate scope of the diazoalkene platform underlying the Diazo Ylide reaction, offering DAOdiscovery access to nitrogen-containing spiropentane scaffold variants. Pyridine motifs are highly prevalent in FDA-approved drugs, making this synthetic extension directly valuable for medicinal chemistry programs.
Diazoalkenes: From an Elusive Intermediate to a Stable Substance Class in Organic Chemistry
This invited solo minireview by Hansmann surveys the emergence of stable diazoalkenes since their 2021 isolation, covering early mechanistic postulations, the discovery of N-heterocyclic stabilization strategies, and the rapidly diversifying reactivity profile now known for this class. It contextualizes diazoalkenes as synthetically versatile building blocks at the frontier of organic chemistry.
As the definitive expert minireview by DAOdiscovery's scientific co-founder, this paper serves as an authoritative reference document for the core technology area, providing the scientific community with context for the novelty and potential of diazoalkene-based synthetic methods. For pharma partners and investors, it functions as independent confirmation that Diazo Ylide chemistry occupies a genuinely frontier position.
Cycloadditions of Diazoalkenes with P₄ and tBuCP: Access to Diazaphospholes
Stable diazoalkenes react readily with white phosphorus (P₄) and tert-butylphosphaalkyne via cycloaddition reactions, affording novel phosphorus heterocycles, specifically 3H-1,2,4-diazamonophospholes and 1,2,3,4-diazadiphospholes. Both products represent rare examples of neutral heterophospholes, expanding the chemistry of low-valent phosphorus compounds.
The discovery that diazoalkenes partner in cycloadditions with phosphorus reagents to generate novel polycyclic scaffolds demonstrates the same synthetic logic DAOdiscovery applies in the Diazo Ylide spiropentane synthesis. Phosphorus-containing heterocycles are high-value pharmacophores increasingly sought in drug discovery, suggesting future directions for DAOdiscovery's scaffold library.
Ph₃PCN₂: A Stable Reagent for Carbon-Atom Transfer
A crystalline, isolable diazophosphorus ylide (Ph₃PCN₂) was synthesized and found to act as a versatile C-atom transfer agent: the Ph₃PC fragment delivers phosphorus-terminated heterocumulenes while the CN₂ fragment reacts with aldehydes and ketones to generate vinylidenes en route to alkynes and butatrienes. The reagent also enables selective carbon-atom transfer to white phosphorus to produce spiropentane-containing frameworks.
This Science paper is the direct published precursor to DAOdiscovery's Diazo Ylide platform: it demonstrates for the first time that a diazophosphorus ylide can transfer a single carbon atom to create strained spiropentane-containing ring systems, the foundational transformation that DAOdiscovery has now patented and scaled. Publication in Science validates the exceptional novelty of Hansmann's carbon-atom transfer chemistry at the highest level of peer review.
Cleavage of Carbodicarbenes with N₂O for Accessing Stable Diazoalkenes: Two-Fold Ligand Exchange at a C(0)-Atom
Carbodicarbenes (C(NHC)₂) activate nitrous oxide (N₂O) via NHC/N₂ ligand exchange at the central carbon atom, yielding stable diazoalkenes and a urea byproduct. This approach provides access to previously inaccessible benzimidazole- and benzothiazole-derived diazoalkenes. The paper was selected as a VIP paper and featured on the front cover of Angewandte Chemie.
Using abundant N₂O as a diazo-transfer reagent opens a green-chemistry-compatible route to a structurally diverse palette of stable diazoalkenes for use in the Diazo Ylide reaction. Access to benzimidazole- and benzothiazole-derived diazoalkenes significantly extends the nitrogen-rich scaffold space available to DAOdiscovery, particularly in kinase inhibitor and CNS drug discovery programs.
Spiro-C(sp³)-Atom Transfer: Creating Rigid Three-Dimensional Structures with Ph₂SCN₂
The diazosulfur ylide Ph₂SCN₂ was synthesized and deployed as a reagent for spiro-C(sp³)-atom transfer, creating carbon atoms bearing four σ-C–C bonds in one or two steps without transition metal catalysis. The method generates (oxa)spiro[2.2]pentanes, cyclopropyl spiro compounds, and tricyclic spiro frameworks from simple olefin starting materials by combining the reactivity of sulfur ylides and diazo compounds in a single reagent.
This Science paper describes the direct scientific basis for DAOdiscovery's Diazo Ylide spiropentane synthesis, the core of our patented technology, published in one of the world's most prestigious journals. The ability to create rigid, three-dimensional spiro[2.2]pentane frameworks from simple precursors directly validates DAOdiscovery's central value proposition to the pharmaceutical industry.
Triplet Vinylidenes Based on (Benz)imidazole and 1,2,3-Triazole N-Heterocycles
A series of triplet vinylidenes based on five-membered N-heterocyclic backbones, 2- and 4-imidazole, benzimidazole, and 1,2,3-triazole, were generated by UV-photolysis of stable diazoalkene precursors and characterized by EPR spectroscopy. The work systematically maps how the electronic character of the heterocyclic backbone tunes spin-state, zero-field splitting, and reactivity of the resulting triplet carbene/vinylidene species.
Understanding the electronic tuning of vinylidene intermediates across a range of N-heterocyclic scaffolds is mechanistically crucial for optimizing the Diazo Ylide reaction's selectivity and yield across diverse substrate classes. This systematic study gives DAOdiscovery's team a rational design framework for selecting which diazoalkene backbone delivers the desired spiropentane product with the best efficiency.
Diazo Transfer from Nitrous Oxide Employing Phosphorus Ylides
A diazo transfer strategy in which nitrous oxide (N₂O) is fixed at a phosphorus ylide enables efficient, hydrazine-free diazo transfer to a broad range of organic substrates. The method provides access to diverse dinitrogen-containing building blocks including 1,2,3-triazolo heterocycles, macrocyclic aldazines, and a new class of phthalazine heterocycles under mild conditions using a green feedstock.
A hydrazine-free, N₂O-based diazo transfer substantially improves the safety and sustainability profile of the precursor synthesis routes that feed into the Diazo Ylide spiropentane reaction platform. For DAOdiscovery's scale-up ambitions and future GMP-compatible manufacturing, access to greener, milder diazo-forming reactions is operationally and regulatorily advantageous.