Tomislav Rovis

• Colorado State University

A one‐pot photocatalytic method is reported for the generation of dehydroprolines, valuable precursors to 5‐aryl prolines. Imines, obtained via simple condensation of aminocyclopropane carboxylates (ACPC) with a broad range of aldehydes, were employed in this transformation without purification. We demonstrate this energy‐transfer (EnT) enabled Clo...

A one‐pot photocatalytic method is reported for the generation of dehydroprolines, valuable precursors to 5‐aryl prolines. Imines, obtained via simple condensation of aminocyclopropane carboxylates (ACPC) with a broad range of aldehydes, were employed in this transformation without purification. We demonstrate this energy‐transfer (EnT) enabled Clo...

With the advent of photoredox catalysis, new synthetic paradigms have been established with many novel transformations being achieved. Nevertheless, modern photoredox chemistry has several drawbacks, namely, deficiencies in reaction efficiency and scalability. Furthermore, wavelengths of light in excess of the energy required for a chemical reactio...

Herein, we report a simple and noninvasive experimental protocol in which a series of relative reaction rates may be obtained by way of single competition experiments. This approach permits a quantitative comparison of any given number of chiral catalysts relative to a ‘benchmarking’ chiral catalyst – a particularly useful tool since catalyst desig...

A method for the generation of tertiary carbanions via a deaminative radical‐polar crossover is reported using redox active imines from α‐tertiary primary amines. A variety of benzylic amines and amino esters can be used in this approach, with the latter engaging in a novel “aza‐Reformatsky” reaction. Electronic trends correlate the stability of th...

A method for the generation of tertiary carbanions via a deaminative radical‐polar crossover is reported using redox active imines from α‐tertiary primary amines. A variety of benzylic amines and amino esters can be used in this approach, with the latter engaging in a novel “aza‐Reformatsky” reaction. Electronic trends correlate the stability of th...

The absorption of light by photosensitizers has been shown to offer novel reactive pathways through electronic excited state intermediates, complementing ground-state mechanisms. Such strategies have been applied in both photocatalysis and photoredox catalysis, driven by generating reactive intermediates from their long-lived excited states. One de...

State-of-the-art methods in photo-proximity labeling center on the targeted generation and capture of short-lived re-active intermediates to provide a snapshot of local protein environments. Diazirines are the current gold standard for high-resolution proximity labelling, generating short-lived aryl(trifluoromethyl) carbenes. Here, we present a met...

We report the development and characterization of a library of Ir(III) photocatalysts capable of undergoing spin-forbidden excitation (SFE) under orange light irradiation (595 nm). These catalysts were successfully applied to the construction of synthetically valuable C(sp2)-C(sp3) bonds inaccessible with existing methods of low-energy light-driven...

The development of a system to electrochemically control ruthenium-catalyzed olefin metathesis is reported. Catalyzed by a commercially-available bis-NHC Ru complex, this system displays a broad substrate scope with very short reaction times, as well as excellent levels of temporal control over metathesis with only electricity as a stimulus.

Electric field acceleration of alkyl hydroperoxide activation to acylate amines in the scanning tunneling microscope-based break-junction is reported. Alkyl hydroperoxide mixtures, generated from hydrocarbon autoxidation in air, were found to be competent reagents for the functionalization of gold surfaces. Intermolecular coupling on the surface in...

The global plastics problem is a trifecta, greatly affecting environment, energy and climate1–4. Many innovative closed/open-loop plastics recycling or upcycling strategies have been proposed or developed5–16, addressing various aspects of the issues underpinning the achievement of a circular economy17–19. In this context, reusing mixed-plastics wa...

N-Demethylation of trialkylamines is a useful transformation, but typically requires harsh reaction conditions and stepwise procedures, as well as judicious protection of labile functional groups. Herein we report a mild, catalytic approach for the demethylation of trialkylamines by utilizing photoinduced nickel catalysis wherein C(sp2)-bromides se...

γ-Lactams are prevalent in small-molecule pharmaceuticals and provide useful precursors to highly substituted pyrrolidines. Despite numerous methods for the synthesis of this valuable motif, previous redox approaches to γ-lactam synthesis from α-haloamides and olefins require additional electron withdrawing functionality as well as N-aryl substitut...

Aryl amination is an essential transformation for medicinal, process, and materials chemistry. In addition to classic Buchwald-Hartwig amination conditions, blue-light-driven metallaphotoredox catalysis has emerged as a valuable tool for C-N cross-coupling. However, blue light suffers from low penetration through reaction media, limiting its scalab...

State-of-the-art photoactivation strategies in chemical biology provide spatiotemporal control and visualization of biological processes. However, using high-energy light (λ < 500 nm) for substrate or photocatalyst sensitization can lead to background activation of photoactive small-molecule probes and reduce its efficacy in complex biological envi...

We herein report a modular strategy, which enables Rh(III)-catalyzed diastereoselective 3,4-amino oxygenation and diamination of 1,3-dienes using different O- and N-nucleophiles in combination with readily available 3-substituted 1,4,2-dioxazolones (78 examples, 37-91% yield). Previous attempts to functionalize the internal double bond rested on th...

Catalytic C(sp 3 )H activation has revolutionized approaches in organic synthesis to access molecular complexity. Precise activation of targeted C(sp 3 )H bonds presents fundamental and practical challenges. Over the past few decades, complementary catalytic modes have been developed to selectively activate a C(sp 3 )H bond: (i) insertion of met...

The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds...

The use of low-energy deep-red (DR) and near-infrared (NIR) light to excite chromophores enables catalysis to ensue across barriers such as materials and tissues. Herein, we report the detailed photophysical characterization of a library of OsII polypyridyl photosensitizers that absorb low-energy light. By tuning ligand scaffold and electron densit...

Oximes are valuable synthetic intermediates for the preparation of a variety of functional groups. To date, the stereoselective synthesis of oximes remains a major challenge, as most current synthetic methods either provide mixtures of E and Z isomers or furnish the thermodynamically preferred E isomer. Herein we report a mild and general method to...

We report a method to activate α-3° amines for deaminative arylation via condensation with an electron-rich aldehyde and merge this reactivity with nickel metallaphotoredox to generate benzylic quaternary centers, a common motif in pharmaceuticals and natural products. The reaction is accelerated by added ammonium salts. Evidence is provided in sup...

Photocatalysis driven by visible and ultraviolet irradiation is a fundamental tool for synthetic chemists. Recently, expansion of this tool to near-infrared (NIR) light has gained in popularity. Herein, we report the detailed photophysical characterization of a library of OsII polypyridyl photosensitizers that absorb NIR irradiation. By tuning liga...

Photocatalysis driven by visible and ultraviolet irradiation is a fundamental tool for synthetic chemists. Recently, expansion of this tool to near-infrared (NIR) light has gained in popularity. Herein, we report the detailed photophysical characterization of a library of OsII polypyridyl photosensitizers that absorb NIR irradiation. By tuning liga...

State-of-the art photoactivation strategies in chemical biology provide spatiotemporal control and visualization of biological processes. However, using high energy light (λ < 500 nm) for substrate or photocatalyst sensitization can lead to background activation of photoactive small molecule probes and reduce its efficacy in complex biological envi...

State-of-the art photoactivation strategies in chemical biology provide spatiotemporal control and visualization of biological processes. However, using high energy light (λ < 500 nm) for substrate or photocatalyst sensitization can lead to background activation of photoactive small molecule probes and reduce its efficacy in complex biological envi...

The diversity and wide availability of trialkylamines render them ideal sources for rapid construction of complex amine architectures. Herein, we report that a nickel/photoredox dual catalysis strategy affects site-selective α-arylation of various trialkylamines. Our catalytic system shows exclusive N-Me selectivity with a wide range of trialkylami...

We report the FeCl3-catalyzed alkylation of nonactivated C(sp3)–H bonds. Photoinduced ligand-to-metal charge transfer at the iron center generates chlorine radicals that then preferentially abstract hydrogen atoms from electron-rich C(sp3)–H bonds distal to electron-withdrawing functional groups. The resultant alkyl radicals are trapped by electron...

Herein we report a Rh(III)-catalyzed three-component carboamination of alkenes from readily available aryl boronic acids as a carbon source and dioxazolones as nitrogen electrophiles. This protocol provides facile access to valuable amine products including α-amino acid derivatives in good yield and regioselectivity without the need for a directing...

We describe a mammalian cell-based assay to identify coronavirus 3CL protease (3CLpro) inhibitors. This assay is based on rescuing protease-mediated cytotoxicity and does not require live virus. By enabling the facile testing of compounds across a range of 15 distantly related coronavirus 3CLpro enzymes, we identify compounds with broad 3CLpro inhi...

The catalytic enantioselective Stetter reaction is the coupling of an aldehyde with an electron-deficient alkene via the conjugate addition of an acyl anion equivalent (Breslow intermediate) generated from the aldehyde and a chiral N-heterocyclic carbene (NHC) catalyst. The process affords 1,4-dicarbonyl compounds and related systems, such as β-nit...

Herein we disclose an iron-catalyzed method to access skeletal rearrangement reactions akin to the Dowd-Beckwith ring expansion from unactivated C(sp3)-H bonds. Photoinduced ligand-to-metal charge transfer at the iron center generates a chlorine radical, which abstracts electron-rich C(sp3)-H bonds. The resulting unstable alkyl radicals can undergo...

p>Herein we report a Rh(III)-catalyzed three-component carboamination of alkenes from readily available aryl boronic acids as a carbon source and dioxazolones as nitrogen electrophiles. This protocol provides facile access to valuable amine products including a -amino acid derivatives in good yield and excellent regioselectivity without the need fo...

Primary amines are often cheap, naturally occurring, and chemically diverse starting materials. For these reasons, deaminative functionalization of amines has emerged as an important area of research. Recent advances in C-N activation transform simple α-1° and α-2° amines into alkylating reagents via Katritzky pyridinium salts. We report a compleme...

Over the past decade, chemists have embraced visible-light photoredox catalysis due to its remarkable ability to activate small molecules. Broadly, these methods employ metal complexes or organic dyes to convert visible light into chemical energy. Unfortunately, the excitation of widely utilized Ru and Ir chromophores is energetically wasteful as ∼...

We describe a mammalian cell-based assay capable of identifying coronavirus 3CL protease (3CLpro) inhibitors without requiring the use of live virus. By enabling the facile testing of compounds across a range of coronavirus 3CLpro enzymes, including the one from SARS-CoV-2, we are able to quickly identify compounds with broad or narrow spectra of a...

C–H activation reactions enable chemists to unveil new retrosynthetic disconnections and streamline conventional synthetic approaches. A long-standing challenge in C–H activation is the inability to distinguish electronically and sterically similar C–H bonds. Although numerous synergistic combinations of transition-metal complexes and chelating dir...

We describe a new family of catalysts that undergo direct ground state singlet to excited state triplet excitation with IR light, leading to photoredox catalysis without the energy waste associated with intersystem crossing. The finding allows a mole scale reaction in batch using infrared irradiation.

Nützliche Lactame: Ungeschützte δ-Lactame lassen sich regio- und diastereoselektiv aus gut zugänglichen Acrylamiden und nichtaktivierten Alkenen synthetisieren. Die Reaktion bietet eine effiziente Methode zur Synthese vielfältiger δ-Lactame in guter Ausbeute und Stereoselektivität, die nützliche Bausteine für substituierte Piperidine sind. Abstrac...

We report a RhIII‐catalyzed regio‐ and diastereoselective synthesis of δ‐lactams from readily available acrylamide derivatives and unactivated alkenes. The reaction provides a rapid route to a diverse set of δ‐lactams in good yield and stereoselectivity, which serve as useful building blocks for substituted piperidines. The regioselectivity of the...

We report a three-component diamination of simple unactivated alkenes using an electrophilic nitrene source and amine nucleo­philes. The reaction provides rapid access to 1,2-vicinal diamines from terminal alkenes through a one-pot protocol. The transformation proceeds smoothly with excellent tolerance for a broad array of primary and secondary ami...

C−H activation reactions enable chemists to unveil new retrosynthetic disconnections and streamline conventional synthetic approaches. A longstanding challenge in C−H activation is the inability to distinguish electronically and sterically similar C–H bonds. Although numerous synergistic combinations of transition-metal complexes and chelating dire...

We have developed a rhodium(III)-catalyzed cyclopropanation of unactivated olefins initiated by an alkenyl C–H activation. A variety of 1,1-disubstituted olefins undergo efficient cyclopropanation with a slight excess of alkene stoichiometry. A series of mechanistic interrogations implicate a metal carbene as an intermediate.

In Fig. 1c of this Letter, the orange axis label of the graph should have read ‘FDPP upconversion photoluminescence (AU)’ instead of ‘TTBP upconversion photoluminescence (AU)’. This has been corrected online.

Olefin metathesis is now one of the most efficient ways to create new carbon-carbon bonds. While most efforts focused on the development of ever-more efficient catalysts, a particular attention has recently been devoted to developing latent metathesis catalysts, inactive species that need an external stimulus to become active. This furnishes an inc...

We have developed a Rh(III)-catalyzed diastereoselective [2+1] annulation onto allylic alcohols initiated by alkenyl C-H activation of N-enoxyphthalimides to furnish substituted cyclopropyl-ketones. Notably, the traceless oxyphthalimide handle serves three functions: Directing C-H activation, oxidation of Rh(III), and, collectively with the allylic...

Reliable design of artificial metalloenzymes (ArMs) to access transformations not observed in nature remains a long-standing and important challenge. We report that a monomeric streptavidin (mSav) Rh(III) ArM permits asymmetric synthesis of α,β-unsaturated-Î-lactams via a tandem C-H activation and [4+2] annulation reaction. These products are readi...

The synthetic utility of tertiary amines to oxidatively generate α‐amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site‐selective α‐functionalization of primary amine derivatives through the generation of α‐amino radical intermediates. Employing visible‐...

The synthetic utility of tertiary amines to oxidatively generate α‐amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site‐selective α‐functionalization of primary amine derivatives through the generation of α‐amino radical intermediates. Employing visible‐...

Recent advances in photoredox catalysis have made it possible to achieve various challenging synthetic transformations, polymerizations and surface modifications1–3. All of these reactions require ultraviolet- or visible-light stimuli; however, the use of visible-light irradiation has intrinsic challenges. For example, the penetration of visible li...

This chapter describes the evolution of achiral cyclopentadienyl ligands in rhodium(III) C‐H activation catalysis. Emphasis is placed on the improvement of reactivity and/or selectivity with tailored ligands and mechanistic insights aimed at explaining why one ligand outperforms another. A sampled collection of recently described sterically and ele...

Photoredox catalysis can be used to manipulate the redox state of a transition metal complex leading to the desired reactivity. While powerful, obviating the role of the second catalyst would be attractive from the perspective of simplifying the protocol and using visible light to uncover unexpected, enabling reactivity. Herein we report that Co-ac...

Correction for ‘Ligand design for Rh( iii )-catalyzed C–H activation: an unsymmetrical cyclopentadienyl group enables a regioselective synthesis of dihydroisoquinolones’ by Todd K. Hyster et al. , Chem. Sci. , 2015, 6 , 254–258.

Primary aliphatic amines are important building blocks in organic synthesis due to the presence of a synthetically versatile NH2 group. N-functionalization of primary amines is well established, but selective C-functionalization of unprotected primary amines remains challenging. Here, we report the use of CO2 as an activator for the direct transfor...

The design of stereodivergent transformations is of great interest to the synthetic community as it allows funneling of a given reaction pathway toward one stereochemical outcome or another by only minor adjustments of the reaction setup. Herein, we present a physical organic approach to invert the sense of induction in diastereoselective cycloprop...

The catalytic desymmetrization of anhydrides with zinc reagents provides access to deoxypolypropionate and polypropionate synthons. A synthesis of ionomycin was pursued in which three of the four fragments were assembled using this methodology. Two of the strategies (enol silane/oxocarbenium coupling and reductive cyclization) were not successful a...

Coordination polymerizations have been extensively used in commercial plastic and rubber industries since 1956, because of their ability to produce polymeric material with well-defined structure, tunable molecular weight (Mn), narrow dispersity (Đ), and useful chain ends. Typically, these processes are initiated by chemical reagents that sacrifice...

A novel, electron-deficient cyclopentadienyl iridium(III) catalyst enables sequential cleavage of arene C(sp²)–H and methoxy C(sp³)–H bonds of anisoles, generating reactive metalacycles that insert difluoroalkynes to afford chromenes under mild reaction conditions. This transformation is an arylalkylation of an alkyne–a carbocarbation–via a nonchel...

The history of transition metal catalysis is heavily steeped in ligand design, clearly demonstrating the importance of this approach. The intimate relationship between metal and ligand can profoundly affect the outcome of a reaction, often impacting selectivity, physical properties, and the lifetime of a catalyst. Importantly, this metal–ligand rel...

Funktionalisierungen von C(sp3)-H-Bindungen verkürzen und vereinfachen chemische Synthesen, indem sie die Verwendung einfacher Moleküle ermöglichen und neuartige Retrosynthesen bereitstellen. Intensive Forschungen, die auf die Entwicklung neuer Reaktionen basierend auf dem Ansatz der C-H-Funktionalisierung abzielten, haben zur weiten Verbreitung di...

The functionalization of C(sp3)−H bonds streamlines chemical synthesis by allowing the use of simple molecules and providing novel synthetic disconnections. Intensive recent efforts in the development of new reactions based on C−H functionalization have led to its wider adoption across a range of research areas. This Review discusses the strengths...

NHC-catalyzed nucleophilic dearomatization of alkyl pyridiniums has been achieved to generate 1,4-dihydropyridines with high enantioselectivity.

Cp(X)Rh(III)-catalyzed C-H functionalization reactions are a proven method for the efficient assembly of small molecules. However, rationalization of the effects of cyclopentadienyl (Cp(X)) ligand structure on reaction rate and selectivity has been viewed as a black box, and a truly systematic study is lacking. Consequently, predicting the outcomes...

Correction for ‘Ligand design for Rh(III)-catalyzed C–H activation: an unsymmetrical cyclopentadienyl group enables a regioselective synthesis of dihydroisoquinolones’ by Todd K. Hyster et al., Chem. Sci., 2015, 6, 254–258.

Carbon-carbon (C-C) bond formation is paramount in the synthesis of biologically relevant molecules, modern synthetic materials and commodity chemicals such as fuels and lubricants. Traditionally, the presence of a functional group is required at the site of C-C bond formation. Strategies that allow C-C bond formation at inert carbon-hydrogen (C-H)...

This chapter focuses on the numerous ways N-heterocyclic carbene (NHCs) catalyze organic transformations, and highlights examples of new reactivity and mechanisms. The rapid expansion of NHC-catalyzed reactions has led to an increasing interest in evaluating the intrinsic chemical properties of NHCs. The chapter presents the many modes of reactivit...

Alkenes are the most ubiquitous prochiral functional groups-those that can be converted from achiral to chiral in a single step-that are accessible to synthetic chemists. For this reason, difunctionalization reactions of alkenes (whereby two functional groups are added to the same double bond) are particularly important, as they can be used to prod...

An unprecedented N-heterocyclic carbene (NHC)-catalyzed annulation of enals to form 3,4-disubstituted cyclopentanones has been discovered. Aryl enals undergo dimerization in the presence of a single-electron oxidant to form C2 symmetric cyclopentanones. A cross-reaction has also been developed, allowing for the synthesis of differentially substitut...

A small library of triazolylidene-boranes that differ only in the nature of the aryl group on the external nitrogen atom was prepared. Their reactivity as hydrogen-atom donors, as well as that of the corresponding N-heterocyclic carbene (NHC)-boryl radicals toward methyl acrylate and oxygen, was investigated by laser flash photolysis, molecular orb...

The concept of umpolung describes the reversal of the naturally occurring electrostatic polarization of chemical groups. It has now been used to make single mirror-image isomers of nitrogen-containing molecules. See Letter p.445

α,β-Unsaturated oxime pivalates are proposed to undergo reversible C(sp(2))-H insertion with cationic Rh(III) complexes to furnish five-membered metallacycles. In the presence of 1,1-disubstituted olefins, these species participate in irreversible migratory insertion to give, after reductive elimination, 2,3-dihydropyridine products in good yields....

N-heterocyclic carbenes (NHC) have had a broad impact on the field of organic chemistry, often allowing for the mild construction of complex molecules from simple starting materials. The most widely used approach for the synthesis of imidazolium and imidazolinium salts is the introduction of the precarbenic carbon in the cyclization step. Using thi...

We report a catalytic asymmetric synthesis of piperidines through [4 + 2] cycloaddition of 1-azadienes and nitro-alkenes. The reaction uses earth abundant Zn as catalyst and is highly diastereo- and regioselective. A novel BOPA ligand (F-BOPA) confers high reactivity and enantioselectivity in the process. The presence of ortho substitution on the a...

Cyclopentadienyl Rhodium(III) complexes are effective catalysts for C- H activation, providing access to various nitrogen contg. heterocycles. However, limited studies exist on the ligand effect. Recently, we discovered N- enoxyphthalimides participate in a [2+1] annulation with electron deficient alkenes to form trans- disubstituted cyclopropanes....

An enantioselective isomerization of 4-iminocrotonates catalyzed by a rhodium(I)/phosphoramidite complex is described. This reaction uses widely available amines to couple with 4-oxocrotonate to provide a convenient access to a central chiral building block in good yield and high enantioselectivity. Although the mechanism of this new transformation...

A concise enantioselective synthesis of (−)-paroxetine (Paxil) and (−)-femoxetine has been achieved. Key to these syntheses is an N-heterocyclic carbene catalyzed homoenolate addition to a nitroalkene followed by in situ reduction of the nitro group to rapidly access δ-lactams.

Caution, alkyl acyl azides can rapidly decompose with heat to release large amounts of nitrogen. Care should be taken during handling: do not attempt to convert neat and avoid handling neat.

A novel oxidative N-heterocyclic carbene-catalyzed reaction pathway has been discovered. Alkyl and aryl enals undergo β-hydroxylation via oxygen atom transfer from electron-deficient nitrobenzenes, followed by trapping of the resultant acyl azolium by the solvent. The proposed mechanism involves a single electron transfer event to initiate the reac...

We report the regioselective synthesis of dihydroisoquinolones from aliphatic alkenes and O-pivaloyl benzhydroxamic acids mediated by a Rh(III) precatalyst bearing sterically bulky substituents. While the prototypical Cp* ligand provides product with low selectivity, sterically bulky Cpt affords product with excellent regioselectivity for a range o...

A strategy for the diversification of triazolium-based catalysts is presented. This method is based on the reduction to the triazoline, which serves as a suitable and stable substrate for palladium-mediated cross-coupling, followed by trityl cation mediated reoxidation to the triazolium.

Cycloaddition reactions are powerful tools in synthetic chemistry. Incorporation of a nitrogen-containing component via cycloaddition represents an attractive strategy for assembling aza-heterocycles. One approach takes advantage of [4 + 2] cycloaddition reactions of 1-azadiene derivatives and 2-carbon π-components to access pyridines, a particular...