Current – 2013 ⋅ 2012 – 2008 ⋅ 2007 – 2002
Rh(III)-Catalyzed C–H Activation-Initiated Directed Cyclopropanation of Allylic Alcohols
Erik J. T. Phipps and Tomislav Rovis
Journal of the American Chemical Society, 2019, 141, 6807-6811
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 alcohol, in directing cyclopropanation to control diastereoselectivity. Allylic alcohols are shown to be highly reactive olefin coupling partners leading to a directed diastereoselective cyclopropanation reaction, providing products not accessible by other routes.
Visible-Light-Controlled Ruthenium-Catalyzed Olefin Metathesis
Cédric Theunissen, Melissa A. Ashley, and Tomislav Rovis
Journal of the American Chemical Society, 2019, 141, 6791-6796
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 increased control over the reaction which is crucial for applications in materials science. Here, we report our work on the development of a new system to achieve visible-light-controlled metathesis by merging olefin metathesis and photoredox catalysis. The combination of a ruthenium metathesis catalyst bearing two N-heterocyclic carbenes with an oxidizing pyrylium photocatalyst affords excellent temporal and spatial resolution using only visible light as stimulus. Applications of this system in synthesis, as well as in polymer patterning and photolithography with spatially resolved ring-opening metathesis polymerization, are described.
Asymmetric δ-Lactam Synthesis with a Monomeric Streptavidin Artificial Metalloenzyme
Isra S. Hassan, Angeline N. Ta, Michael W. Danneman, Natthawat Semakul, Matthew Burns, Corey H. Basch, Vanessa N. Dippon, Brian R. McNaughton, and Tomislav Rovis
Journal of the American Chemical Society, 2019, 141, 4815-4819
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-δ-lactams via a tandem C–H activation and [4+2] annulation reaction. These products are readily derivatized to enantioenriched piperidines, the most common N-heterocycle found in FDA approved pharmaceuticals. Desired δ-lactams are achieved in yields as high as 99% and enantiomeric excess of 97% under aqueous conditions at room temperature. Embedding a Rh cyclopentadienyl (Cp*) catalyst in the active site of mSav results in improved stereocontrol and a 7-fold enhancement in reactivity relative to the isolated biotinylated Rh(III) cofactor. In addition, mSav-Rh outperforms its well-established tetrameric forms, displaying 11–33 times more reactivity.
Photoredox‐Catalyzed Site‐Selective α‐C(sp3)−H Alkylation of Primary Amine Derivatives
Melissa A. Ashley, Dr. Chiaki Yamauchi, Dr. John C. K. Chu, Shinya Otsuka, Hideki Yorimitsu, Tomislav Rovis
Angewandte Chemie Int. Ed. 2019, 58, 4002-4006
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‐light photoredox catalysis, primary sulfonamides are coupled with electron‐deficient alkenes to efficiently and mildly construct C−C bonds. Interestingly, a divergence between intermolecular hydrogen‐atom transfer (HAT) catalysis and intramolecular [1,5] HAT was observed through precise manipulation of the protecting group. This dichotomy was leveraged to achieve excellent α/δ site‐selectivity.
Ir-Catalyzed Intermolecular Branch-Selective Allylic C–H Amidation of Unactivated Terminal Olefins
Honghui Lei and Tomislav Rovis
Journal of the American Chemical Society, 2019, 141, 2268-2273
An efficient method for intermolecular branch-selective allylic C–H amidation has been accomplished via Ir(III) catalysis. The reaction proceeds through initial allylic C–H activation, supported by the isolation and crystallographic characterization of an allyl-Ir(III) intermediate, followed by a subsequent oxidative amidation with readily available dioxazolones as nitrenoid precursors. A diverse range of amides are successfully installed at the branched position of terminal alkenes in good yields and regioselectivities. Importantly, the reaction allows the use of amide-derived nitrenoid precursors avoiding problematic Curtius-type rearrangements.
Photoredox catalysis using infrared light via triplet fusion upconversion
Benjamin D. Ravetz, Andrew B. Pun, Emily M. Churchill, Daniel N. Congreve, Tomislav Rovis & Luis M. Campos
Nature., 2019, 565, 343–346
Recent advances in photoredox catalysis have made it possible to achieve various challenging synthetic transformations, polymerizations and surface modifications. 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 light through most reaction media is very low, leading to problems in large-scale reactions. Moreover, reactants can compete with photocatalysts for the absorption of incident light, limiting the scope of the reactions. These problems can be overcome by the use of near-infrared light, which has a much higher penetration depth through various media, notably biological tissue. Here we demonstrate various photoredox transformations under infrared radiation by utilizing the photophysical process of triplet fusion upconversion, a mechanism by which two low-energy photons are converted into a higher-energy photon. We show that this is a general strategy applicable to a wide range of photoredox reactions. We tune the upconversion components to adjust the output light, accessing both orange light and blue light from low-energy infrared light, by pairwise manipulation of the sensitizer and annihilator. We further demonstrate that the annihilator itself can be used as a photocatalyst, thus simplifying the reaction. This approach enables catalysis of high-energy transformations through several opaque barriers using low-energy infrared light.
Photoinduced Ligand-to-Metal Charge Transfer Enables Photocatalyst-Independent Light-Gated Activation of Co(II)
Benjamin D. Ravetz, Jason Y. Wang, Kyle E. Ruhl, and Tomislav Rovis
ACS Catal., 2019, 9, 200–204
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-acetylides, formed in situ, are photoactive complexes that undergo ligand-to-metal charge transfer using visible light. The net transformation uses air-stable Co(II) complexes as precatalysts and induces Co(I) chemistry. The acetylide is an electron reservoir forming the Co(I) but accepting the electron back at the end of the catalytic cycle. The electronic nature of the acetylide leads to either on–off behavior or simply initiates catalysis, depending on electronics.
The Catalytic Alkylative Desymmetrization of Anhydrides in a Formal Synthesis of Ionomycin
Kevin M. Oberg, Brian M. Cochran, Matthew J. Cook, and Tomislav Rovis
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 at installing the C23 stereocenter, but this stereochemical issue was overcome through a reduction/SN2 approach. In addition to the synthesis of a protected diastereomer of ionomycin, the synthesis of a C17–C32 fragment constitutes a formal total synthesis.
Generation of Phosphoranyl Radicals via Photoredox Catalysis Enables Voltage–Independent Activation of Strong C–O Bonds
Erin E. Stache, Alyssa B. Ertel, Tomislav Rovis, and Abigail G. Doyle
ACS Catal., 2018, 8, 11134–11139
Despite the prevalence of alcohols and carboxylic acids as functional groups in organic molecules and the potential to serve as radical precursors, C–O bonds remain difficult to activate. We report a synthetic strategy for direct access to both alkyl and acyl radicals from these ubiquitous functional groups via photoredox catalysis. This method exploits the unique reactivity of phosphoranyl radicals, generated from a polar/SET crossover between a phosphine radical cation and an oxygen-centered nucleophile. We show the desired reactivity in the reduction of benzylic alcohols to the corresponding benzyl radicals with terminal H atom trapping to afford the deoxygenated products. Using the same method, we demonstrate access to synthetically versatile acyl radicals, which enables the reduction of aromatic and aliphatic carboxylic acids to the corresponding aldehydes with exceptional chemoselectivity. This protocol also transforms carboxylic acids to heterocycles and cyclic ketones via intramolecular acyl radical cyclizations to forge C–O, C–N, and C–C bonds in a single step.
Direct α-alkylation of primary aliphatic amines enabled by CO2 and electrostatics
Juntao Ye, Indrek Kalvet, Franziska Schoenebeck and Tomislav Rovis
Nature Chemistry (2018)
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 transformation of abundant primary aliphatic amines into valuable γ-lactams under photoredox and hydrogen atom transfer (HAT) catalysis. Experimental and computational studies suggest that CO2 not only inhibits undesired N-alkylation of primary amines, but also promotes selective intermolecular HAT by an electrostatically accelerated interaction between the in situ-generated negatively charged carbamate and the positively charged quinuclidinium radical. This electrostatic attraction overwhelms the inherent bond dissociation energies which suggest that HAT should occur unselectively. We anticipate that our findings will open up new avenues for amine functionalizations as well as selectivity control in HAT reactions.
Stereodivergent Rhodium(III)-Catalyzed cis-Cyclopropanation Enabled by Multivariate Optimization
Tiffany Piou, Fedor Romanov-Michailidis, Melissa A. Ashley, Maria Romanova-Michaelides, and Tomislav Rovis
Journal of the American Chemical Society, 2018, 140, 9587-9593
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 cyclopropanation of alkenes with N-enoxyphthalimides through rhodium(III) catalysis. Careful parametrization of catalyst–substrate molecular determinants allowed us to interrogate linear-free energy relationships and establish an intuitive and robust statistical model that correlates an extensive number of data points in high accuracy. Our multivariate correlations-steered mechanistic investigation culminated with a robust and general diastereodivergent cyclopropanation tool where the switch from trans- to cis-diastereoinduction is attributed to a mechanistic dichotomy. Selectivity might be determined by the flexibility of rhodacyclic intermediates derived from ring-opened versus -unopened phthalimides, induced by both their respective ring size and the Sterimol B1 parameter of the CpX ligand on rhodium.
External Regulation of Cobalt-Catalyzed Cycloaddition Polymerization with Visible Light
Benjamin D. Ravetz, Kyle E. Ruhl, and Tomislav Rovis
ACS Catalysis, 2018, 8, 5323-5327
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 temporal and spatial control of catalysis. Recent advances in photoredox catalysis have sparked an emergence of photocontrolled ionic and radical polymerizations; meanwhile, photocontrolled coordination polymerizations remain relatively unexplored. Herein, we report a light-regulated cobalt-catalyzed [2+2+2] cycloaddition polymerization. Using this methodology, block copolymers are generated while regulating their Mn with visible light.
Ir(III)-Catalyzed Carbocarbation of Alkynes through Undirected Double C–H Bond Activation of Anisoles
Dr. Fedor Romanov-Michailidis, Benjamin D. Ravetz, Daniel W. Paley, and Prof. Tomislav Rovis
Journal of the American Chemical Society, 2018, 140, 5370-5374
Electronic and Steric Tuning of a Prototypical Piano Stool Complex: Rh(III) Catalysis for C–H Functionalization
Dr. Tiffany Piou and Prof. Tomislav Rovis
Accounts of Chemical Research, 2018, 51, 170-180
Complementary Strategies for Directed C(sp3)−H Functionalization: A Comparison of Transition‐Metal‐Catalyzed Activation, Hydrogen Atom Transfer, and Carbene/Nitrene Transfer
John C. K. Chu and Prof. Tomislav Rovis
Angewandte Chemie International Edition, 2018, 57, 62-101
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 and weaknesses of three main approaches: transition‐metal‐catalyzed C−H activation, 1,n‐hydrogen atom transfer, and transition‐metal‐catalyzed carbene/nitrene transfer, for the directed functionalization of unactivated C(sp3)−H bonds. For each strategy, the scope, the reactivity of different C−H bonds, the position of the reacting C−H bonds relative to the directing group, and stereochemical outcomes are illustrated with examples in the literature. The aim of this Review is to provide guidance for the use of C−H functionalization reactions and inspire future research in this area.
Cluster Preface: Alkene Halofunctionalization
Jeffrey N. Johnston and Tomislav Rovis
Synlett, 2018, 29, 399-400
It has long been recognized that alkenes react with elemental bromine to give vicinal dibromides. It was not long after that the community noted the presence of water leads to bromohydrin formation, and the halohydrin family of reactions were born. Indeed, the coupling of many other nucleophiles has been developed leading to a general field of alkene halofunctionalization.
Regiodivergent Iridium(III)-Catalyzed Diamination of Alkenyl Amides with Secondary Amines: Complementary Access to γ- or δ-Lactams
John H. Conway Jr. and Prof. Tomislav Rovis
Journal of the American Chemical Society, 2018, 140, 135-138
Alkenyl N-pivaloylhydroxamates undergo an Ir(III)-catalyzed diamination of the alkene with simple exogenous secondary amines under extraordinarily mild reaction conditions. The regioselectivity of the diamination is controlled by the solvent and the electronics of the cyclopentadienyl (Cpx) ligand on Ir. On the basis of a set of mechanistic experiments, we propose that the relative rates of Ir(V)-nitrenoid formation versus attack on the amido-Ir-coordinated alkene by the exogenous amine determine the outcome of the reaction.
Rhodium-Catalyzed Desymmetrization of meso-Glutaric Anhydrides to Access Enantioenriched anti,anti-Polypropionates
Brian M. Cochran, Daniel D. Henderson, Scott M. Thullen and Prof. Tomislav Rovis
Synlett, 2018, 29, 306-309
A Mild Hydroaminoalkylation of Conjugated Dienes Using a Unified Cobalt and Photoredox Catalytic System
Scott M. Thullen and Prof. Tomislav Rovis
Journal of the American Chemical Society, 2017, 139, 15504-15508
Experimental and Computational Gas Phase Acidities of Conjugate Acids of Triazolylidene Carbenes: Rationalizing Subtle Electronic Effects
Yijie Niu, Ning Wang, Alberto Muñoz, Jiahui Xu, Hao Zheng, Prof. Tomislav Rovis and Prof. Jeehuin K. Lee
Journal of the American Chemical Society, 2017, 139, 14917-14930
Directed γ-C(sp3)–H Alkylation of Carboxylic Acid Derivatives through Visible Light Photoredox Catalysis
Dian-Feng Chen, John C. K. Chu, and Prof. Tomislav Rovis
Journal of the American Chemical Society, 2017, 139, 14897-14900
Enantioselective N-heterocyclic carbene-catalyzed nucleophilic dearomatization of alkyl pyridiniums
Darrin M. Flanigan and Prof. Tomislav Rovis
Chemical Science, 2017, 8, 6566-6569
NHC-catalyzed nucleophilic dearomatization of alkyl pyridiniums has been achieved to generate 1,4-dihydropyridines with high enantioselectivity. This is a rare example of catalytic, asymmetric addition of a nucleophile to the activated pyridinium that prefers C-4 functionalization leading to the 1,4-dihydropyridine with high selectivity.
Cluster Preface: Catalytic Aerobic Oxidations
Shannon S. Stahl and Prof. Tomislav Rovis
Synlett, 2017, 28, 1546-1547
These reports describe a subset of the exciting work going on in this field and highlight both the accomplishments as well as some of the challenges. The field is vibrant as it aims to replace all other oxidants with nature’s simplest one.
A Photochemical Two-Step Formal [5+2] Cycloaddition: A Condensation–Ring-Expansion Approach to Substituted Azepanes
Scott M. Thullen, David M. Rubush, and Prof. Tomislav Rovis
Synlett, 2017, 28, 2755-2758
Dual Nickel- and Photoredox-Catalyzed Enantioselective Desymmetrization of Cyclic meso-Anhydrides
Erin E. Stache, Prof. Tomislav Rovis and Prof. Abigail G. Doyle
Angewandte Chemie International Edition, 2017, 56, 3679-3683
Correlating Reactivity and Selectivity to Cyclopentadienyl Ligand Properties in Rh(III)-Catalyzed C–H Activation Reactions: An Experimental and Computational Study
Tiffany Piou, Fedor Romanov-Michailidis, Maria Romanova-Michaelides, Kelvin E. Jackson, Natthawat Semakul, Trevor D. Taggart, Brian S. Newell, Christopher D. Rithner, Robert S. Paton, and Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2017, 139, 1296-1310
CpXRh(III)-catalyzed C–H functionalization reactions are a proven method for the efficient assembly of small molecules. However, rationalization of the effects of cyclopentadienyl (CpX) 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 of these reactions is challenging because subtle variations in ligand structure can cause notable changes in reaction behavior. A predictive tool is, nonetheless, of considerable value to the community as it would greatly accelerate reaction development. Designing a data set in which the steric and electronic properties of the CpXRh(III) catalysts were systematically varied allowed us to apply multivariate linear regression algorithms to establish correlations between these catalyst-based descriptors and the regio-, diastereoselectivity, and rate of model reactions. This, in turn, led to the development of quantitative predictive models that describe catalyst performance. Our newly described cone angles and Sterimol parameters for CpX ligands served as highly correlative steric descriptors in the regression models. Through rational design of training and validation sets, key diastereoselectivity outliers were identified. Computations reveal the origins of the outstanding stereoinduction displayed by these outliers. The results are consistent with partial η5–η3 ligand slippage that occurs in the transition state of the selectivity-determining step. In addition to the instructive value of our study, we believe that the insights gained are transposable to other group 9 transition metals and pave the way toward rational design of C–H functionalization catalysts.
Heptamethylindenyl (Ind*) enables diastereoselective benzamidation of cyclopropenes via Rh(III)-catalyzed C–H activation
Natthawat Semakul, Kelvin E. Jackson, Robert S. Paton, and Tomislav Rovis
Chemical Science, 2016, 8, 1015-1020
The diastereoselective coupling of O-substituted arylhydroxamates and cyclopropenes mediated by Rh(III) catalysis was successfully developed. Through ligand development, the diastereoselectivity of this reaction was improved using a heptamethylindenyl (Ind*) ligand, which has been rationalized using quantum chemical calculations. In addition, the nature of the O-substituted ester of benzhydroxamic acid proved important for high diastereoselectivity. This transformation tolerates a variety of benzamides and cyclopropenes that furnish cyclopropa[c]dihydroisoquinolones with high diastereocontrol, which could then be easily transformed into synthetically useful building blocks for pharmaceuticals and bio-active molecules.
N-Heterocyclic Carbene and Chiral Brønsted Acid Cooperative Catalysis for a Highly Enantioselective [4+2] Annulation
Dian-Feng Chen and Tomislav Rovis
Synthesis, 2016, 49, 293-298
A chiral NHC/Brønsted acid cooperative catalysis system has been developed for the asymmetric annulation of functionalized benzaldehydes and activated ketones, through dearomative generation of dienolate, to give 3-aryl-3-(perfluoroalkyl)isochroman-1-ones.
Visible Light-Gated Cobalt Catalysis for a Spatially and Temporally Resolved [2+2+2] Cycloaddition
Kyle E. Ruhl and Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2015, 138, 15527-15530
The ability to exert spatial and temporal control over a transition-metal catalyst offers diverse opportunities for the fabrication of functional materials. Using an external stimulus such as visible light to toggle a catalyst between an active and dormant state has proven to be an effective approach for controlled, radical methodologies. Outside of radical bond formation, there is a dearth of evidence that suggests traditional transition metal catalysis can similarly be controlled with visible light energy. Many cobalt complexes that catalyze the [2+2+2] cycloaddition are assisted by UV photolysis, but strict photocontrolled methods are unattainable due to high levels of thermally driven reactivity. Herein, we disclose the first light-controlled, cobalt-catalyzed [2+2+2] cycloaddition via a dual cobalt and photoredox catalyst manifold. We demonstrate the power of this method with a spatially and temporally resolved technique for arene formation using photolithography.
Amide-directed photoredox-catalysed C–C bond formation at unactivated sp3 C–H bonds
John C.K. Chu and Tomislav Rovis
NATURE, 2016, 539, 272-275
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) bonds enable access to molecules that would otherwise be inaccessible and the development of more efficient syntheses of complex molecules. Here we report a method for the formation of C–C bonds by directed cleavage of traditionally non-reactive C–H bonds and their subsequent coupling with readily available alkenes. Our methodology allows for amide-directed selective C–C bond formation at unactivated sp3 C–H bonds in molecules that contain many such bonds that are seemingly indistinguishable. Selectivity arises through a relayed photoredox-catalysed oxidation of a nitrogen–hydrogen bond. We anticipate that our findings will serve as a starting point for functionalization at inert C–H bonds through a strategy involving hydrogen-atom transfer.
Rhodium-catalysed syn-carboamination of alkenes via a transient directing group
Tiffany Piou and Tomislav Rovis
NATURE, 2015, 527, 86-90
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 produce highly complex molecular architectures. Stereoselective oxidation reactions, including dihydroxylation, aminohydroxylation and halogenation, are well established methods for functionalizing alkenes. However, the intermolecular incorporation of both carbon- and nitrogen-based functionalities stereoselectively across an alkene has not been reported. Here we describe the rhodium-catalysed carboamination of alkenes at the same (syn) face of a double bond, initiated by a carbon–hydrogen activation event that uses enoxyphthalimides as the source of both the carbon and the nitrogen functionalities.
Rhodium(III)-Catalyzed Allylic C(sp3)–H Activation of Alkenyl Sulfonamides: Unexpected Formation of Azabicycles
Alexis Archambeau, Tomislav Rovis
Angewandte Chemie International Edition, 2015, 54, 13337-13340
Unsaturated N-sulfonamides undergo a RhIII– catalyzed allylic C(sp3)H activation followed by insertion with an exogenous internal alkyne. The reaction generates [3.3.0], [4.3.0], and [5.3.0] azabicyclic structures with excellent diastereoselectivity. Deuterium labeling experiments implicate a 1,3-Rh shift as a key step in the mechanism.
Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes
Darrin M. Flanigan, Fedor Romanov-Michailidis, Nicholas A. White, and Tomislav Rovis
CHEMICAL REVIEWS, 2015, 15, 9307-9387
The field has periodically been reviewed, with the most recent such comprehensive review appearing in this journal in 2007. This review will thus focus on developments since the last review with the caveat that seminal contributions are acknowledged.
Oxidatively Initiated NHC-Catalyzed Enantioselective Synthesis of 3,4-Disubstituted Cyclopentanones from Enals
Nicholas A. White and Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2015, 137, 10112-10115
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 substituted cyclopentanones. Mechanistically, the reaction is thought to proceed through radical intermediates, further establishing the synthetic utility of this class of reactivity.
Organic chemistry: Natural polarity inverted
Fedor Romanov-Michailidis, Tomislav Rovis
NATURE, 2015, 523, 417-418
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.
Expedient Access to 2,3-Dihydropyridines from Unsaturated Oximes by Rh(III)-Catalyzed C–H Activation
Fedor Romanov-Michailidis, Kassandra F. Sedillo, Jamie M. Neely, and Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2015, 137, 8892-8895
α,β-Unsaturated oxime pivalates are proposed to undergo reversible C(sp2)–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. Catalytic hydrogenation can then be used to convert these molecules into piperidines, which are important structural components of numerous pharmaceuticals.
Influence of Electronic Effects on the Reactivity of Triazolylidene-Boryl Radicals: Consequences for the use of N-Heterocyclic Carbene Boranes in Organic and Polymer Synthesis
Sofia Telitel, Anne-Laure Vallet, Darrin M. Flanigan, Dr. Bernadette Graff, Dr. Fabrice Morlet-Savary, Prof. Tomislav Rovis, Prof. Jacques Lalevée and Dr. Emmanuel Lacôte
CHEMISTRY – A EUROPEAN JOURNAL, 2015, 21, 13772-13777
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 orbital calculations, and ESR spin-trapping experiments, and benchmarked relative to the already known dimethyltriazolylidene-borane. The new NHC-boranes were also used as co-initiators for the Type I photopolymerization of acrylates. This allowed a structure–reactivity relationship with regard to the substitution pattern of the NHC to be established and the role of electronic effects in the reactivity of NHC-boryl radicals to be probed. Although their rate of addition to methyl acrylate depends on their electronegativity, the radicals are all nucleophilic and good initiators for photopolymerization reactions.
Rhodium(III)-Catalyzed C–H Activation: An Oxidative Intramolecular Heck-Type Reaction Directed by a Carboxylate
Tyler A. Davis, Chuanqi Wang, Tomislav Rovis
SYNLETT, 2015, 26, 1520-1524
Carboxylates effectively direct C–H activation for rhodium(III)-catalyzed intramolecular Heck-type reactions. A catalytic amount of Cu(OAc)2 is used as the external oxidant with oxygen likely acting as the terminal oxidant. Additionally, a novel electron-deficient rhodium(III) catalyst was found to be more effective than [RhCp*Cl2]2 with some substrates. A wide variety of complex dihydrobenzofurans, dihydrobenzopyrans, and other bicycles that can be easily further functionalized are now accessible through relatively mild reaction conditions.
Zn-Catalyzed Enantio- and Diastereoselective Formal [4 + 2] Cycloaddition Involving Two Electron-Deficient Partners: Asymmetric Synthesis of Piperidines from 1-Azadienes and Nitro-Alkenes
John C. K. Chu, Derek M. Dalton, and Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2015, 137, 445-4452
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 arenes adjacent to the bis(oxazolines) was found to be particularly impactful, due to limiting the undesired coordination of 1-azadiene to the Lewis acid and thus allowing the reaction to be carried out at lower temperature. A series of secondary kinetic isotope effect studies using a range of ligands implicates a stepwise mechanism for the transformation, involving an initial Michael-type addition of the imine to the nitro-alkene followed by a cyclization event. The stepwise mechanism obviates the electronic requirement inherent to a concerted mechanism, explaining the successful cycloaddition between two electron-deficient partners.
Cluster Preface: Catalysis Using Sustainable Metals – Part II
SYNLETT, 2015, 26, 306
The discovery of new catalytic reactions involving the use of abundant, inexpensive, and sustainable metal complexes has enjoyed a resurgence of activities in recent years. This Cluster, the second of a two-part series, continues the update of this important field, communicating a variety of approaches that address this important challenge.
Enantioselective Rhodium-Catalyzed Isomerization of 4-Iminocrotonates: Asymmetric Synthesis of a Unique Chiral Synthon
Wen-Zhen Zhang, John C. K. Chu, Kevin M. Oberg, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2015, 137, 553-555
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 remains unclear, both Rh and the phosphoramidite play a central role.
Ligand design for Rh(III)-catalyzed C–H activation: an unsymmetrical cyclopentadienyl group enables a regioselective synthesis of dihydroisoquinolones
Todd K. Hyster, Derek M. Dalton, Tomislav Rovis
CHEMICAL SCIENCE, 2015, 6, 254-258
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 of benzhydroxamic acids and alkenes. Crystallographic evidence offers insight as to the source of the increased regioselectivity.
Rh(I)–Bisphosphine-Catalyzed Asymmetric, Intermolecular Hydroheteroarylation of α-Substituted Acrylate Derivatives
Claire M. Filloux, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2014, 137, 508-517
Asymmetric hydroheteroarylation of alkenes represents a convenient entry to elaborated heterocyclic motifs. While chiral acids are known to mediate asymmetric addition of electron-rich heteroarenes to Michael acceptors, very few methods exploit transition metals to catalyze alkylation of heterocycles with olefins via a C–H activation, migratory insertion sequence. Herein, we describe the development of an asymmetric, intermolecular hydroheteroarylation reaction of α-substituted acrylates with benzoxazoles. The reaction provides 2-substitued benzoxazoles in moderate to excellent yields and good to excellent enantioselectivities. Notably, a series of mechanistic studies appears to contradict a pathway involving enantioselective protonation of a Rh(I)–enolate, despite the fact that such a mechanism is invoked almost unanimously in the related addition of aryl boronic acids to methacrylate derivatives. Evidence suggests instead that migratory insertion or beta-hydride elimination is enantiodetermining and that isomerization of a Rh(I)–enolate to a Rh(I)–heterobenzyl species insulates the resultant α-stereocenter from epimerization. A bulky ligand, CTH-(R)-Xylyl-P-Phos, is crucial for reactivity and enantioselectivity, as it likely discourages undesired ligation of benzoxazole substrates or intermediates to on- or off-cycle rhodium complexes and attenuates coordination-promoted product epimerization.
Catalysis Using Sustainable Metals – Part I
Matthew Gaunt, Tomislav Rovis, Hak-Fun Chow
SYNLETT, 2014, 25, 2715-2716
The discovery of new catalytic reactions involving the use of abundant, inexpensive and sustainable metal complexes has enjoyed a resurgence of activities in recent years. This Cluster, Part I of a two-part series, focuses on new research findings from several prominent research groups, highlighting the rich diversities of new chemistry that can be originated from the use of sustainable metals in catalytic reactions.
Enantioselective N-Heterocyclic Carbene-Catalyzed β-Hydroxylation of Enals Using Nitroarenes: An Atom Transfer Reaction That Proceeds via Single Electron Transfer
Nicholas A. White, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2014, 136, 14674-14677 (2014)
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 reaction followed by radical recombination. This represents a profound mechanistic departure from the established two-electron disconnects in NHC catalysis.
Rh(III)-Catalyzed Cyclopropanation Initiated by C–H Activation: Ligand Development Enables a Diastereoselective [2 + 1] Annulation of N-Enoxyphthalimides and Alkenes
Tiffany Piou, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2014, 136, 11292-11295
N-Enoxyphthalimides undergo a Rh(III)-catalyzed C–H activation initiated cyclopropanation of electron deficient alkenes. The reaction is proposed to proceed via a directed activation of the olefinic C–H bond followed by two migratory insertions, first across the electron-deficient alkene and then by cyclization back onto the enol moiety. A newly designed isopropylcyclopentadienyl ligand drastically improves yield and diastereoselectivity.
Stereoelectronic Basis for the Kinetic Resolution of N-Heterocycles with Chiral Acylating Reagents
Sheng-Ying Hsieh, Benedikt Wanner, Philip Wheeler, André M. Beauchemin, Tomislav Rovis, Jeffrey W. Bode
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2014, 20, 7228-7231
The kinetic resolution of N-heterocycles with chiral acylating agents reveals a previously unrecognized stereoelectronic effect in amine acylation. Combined with a new achiral hydroxamate, this effect makes possible the resolution of various N-heterocycles by using easily prepared reagents. A transition-state model to rationalize the stereochemical outcome of this kinetic resolution is also proposed.
Cobaltate Anion Couples Terminal Dienes with Trifluoroacetic Anhydride: A Direct Fluoroacylation of 1,3-Diene
Benjamin L. Kohn, Tomislav Rovis
CHEMICAL SCIENCE, 2014, 5, 2889-2892
Perfluoroketones are useful products and intermediates in medicinal chemistry. Herein, cobalt-mediated fluoroacylation of 1,3-dienes is described using perfluorinated anhydrides such as TFAA. The reaction is thought to proceed through a fluoroacylcobalt reagent formed in situ. Perfluoroacylation of 1,3-dienes can also be performed to attain longer chain perfluorinated ketones.
A Late-Stage Strategy for the Functionalization of Triazolium-Based NHC Catalysts
Kerem E. Ozboya, Tomislav Rovis
SYNLETT, 2014, 25, 2665-2668
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.
Rapid Construction of (-)-Paroxetine and (-)-Femoxetine via an N-Heterocylic Carbene Catalyzed Homoenolate Addition to Nitroalkanes
Nicholas A. White, Kerem E. Ozboya, Darrin M. Flanigan, Tomislav Rovis
ASIAN JOURNAL OF ORGANIC CHEMISTRY, 2014, 3, 442-444 (2014)
A concise enantionselective 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.
Stereoselective Synthesis of Dioxolanes and Oxazolidines via a Desymmetrization Acetalization/Michael Cascade
David M. Rubush, Tomislav Rovis
SYNLETT, 2014, 25, 713-717
The desymmetrization of p-quinols using a Brønsted acid catalyzed acetalization/Michael cascade was achieved in high yields and diastereoselectivities for aldehydes and imines. Use of a chiral Brønsted acid allowed for the synthesis of 1,3-dioxolane and 1,3-oxazolidine products in modest enantioselectivity.
Rh(III)-Catalyzed Decarboxylative Coupling of Acrylic Acids with Unsaturated Oxime Esters: Carboxylic Acids Serve as Traceless Activators
Jamie M. Neely, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2014, 136, 2735-2738
α,β-Unsaturated carboxylic acids undergo Rh(III)-catalyzed decarboxylative coupling with α,β-unsaturated O-pivaloyl oximes to provide substituted pyridines in good yield. The carboxylic acid, which is removed by decarboxylation, serves as a traceless activating group, giving 5-substituted pyridines with very high levels of regioselectivity. Mechanistic studies rule out a picolinic acid intermediate, and an isolable rhodium complex sheds further light on the reaction mechanism.
Rhodium(III)-Catalyzed Intramolecular Hydroarylation, Amidoarylation, and Heck-type Reaction: Three Distinct Pathways Determined by an Amide Directing Group
Tyler A. Davis, Todd K. Hyster, Tomislav Rovis
ANGEWANDTE CHEMIE INTERNATIONAL EDITION, 2013, 52, 14181-14185
The amide decides: Three different rhodium(III)-catalyzed reaction pathways of a wide variety of tethered alkenes can be accessed through changing the amide directing group. This provides an efficient route to a myriad of complex polycyclic products, many containing newly formed all-carbon quaternary centers. Amidoarylations can diastereoselectively deliver products with up to three contiguous stereocenters.
Rhodium(III)-Catalyzed C-H Activation Mediated Synthesis of Isoquinolones from Amides and Cyclopropenes
Todd K. Hyster, Tomislav Rovis
SYNLETT, 2013, 24, 1842-1844
We have developed a synthesis of 4-substituted isoquinolones from the rhodium(III)-catalyzed, C–H activation mediated coupling of O-pivaloyl benzhydroxamic acids and 3,3-disubstituted cyclopropenes. Experiments suggest the formation of a [4.1.0] bicyclic system, which can open under acidic conditions to generate the desired isoquinolone.
SNAr-Derived Decomposition By-products Involving Pentafluorophenyl Triazolium Carbenes
Xiaodan Zhao, Garrett S. Glover, Kevin M. Oberg, Derek M. Dalton, Tomislav Rovis
SYNLETT, 2013, 24, 1229-1232
Pentafluorophenyl triazolium carbenes, widely used in NHC catalysis, can decompose by several mechanisms. Under high concentration conditions, the azolium may undergo a pentafluorophenyl exchange by a proposed SNAr mechanism to give an inactive salt. In the presence of appropriate substrates, cyclization on the ortho-position of the arene can occur, also by SNAr. These adducts provide a potential pathway for catalyst decomposition and serve as a caveat to the development of new reactions and catalysts.
Asymmetric N-Heterocyclic Carbene Catalyzed Addition of Enals to Nitroalkenes: Controlling Stereochemistry via the Homoenolate Reactivity Pathway To Access δ-Lactams
Nicholas A. White, Daniel A. DiRocco, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2013, 135, 8504-8507
An asymmetric intermolecular reaction between enals and nitroalkenes to yield δ-nitroesters has been developed, catalyzed by a novel chiral N-heterocyclic carbene. Key to this work was the development of a catalyst that favors the δ-nitroester pathway over the established Stetter pathway. The reaction proceeds in high stereoselectivity and affords the previously unreported syn diastereomer. We also report an operationally facile two-step, one-pot procedure for the synthesis of δ-lactams.
Catalytic, Asymmetric Indolizidinone Aza-Quaternary Stereocenter Synthesis: Expedient Synthesis of the Cylindricine Alkaloid Core
Derek M. Dalton, Tomislav Rovis
ORGANIC LETTERS, 2013, 15, 2346-2349
The Rh(I)•CKphos catalyzed [2 + 2 + 2] cycloaddition of 1,1-disubstituted alkenyl isocyanates and alkyl alkynes selectively forms previously inaccessible vinylogous amide indolizidinone cycloadducts, establishing an aza-quaternery stereocenter with excellent enantioselectivities (up to 98% ee). This advance enables a seven step catalytic, asymmetric synthesis of the tricyclic core of the cylindricine alkaloids with excellent control of product selectivity as well as regio- and enantioselectivity.
A Catalytic Asymmetric Synthesis of Polysubstituted Piperidines Using a Rhodium(I)-Catalyzed [2+2+2] Cycloaddition Employing a Cleavable Tether
Timothy J. Martin, Tomislav Rovis
ANGEWANDTE CHEMIE INTERNATIONAL EDITION, 2013, 52, 5368-5371
Break the cycle: The title reaction proceeds with a variety of alkyne substrates in good yield and high enantioselectivity. Upon reduction of the vinylogous amide in high diastereoselectivity (>19:1) and cleavage of the tether, N-methylpiperidine products with functional group handles can be accessed.
A Coupling of Benzamides and Donor/Acceptor Diazo Compounds To Form γ-Lactams via Rh(III)-Catalyzed C–H Activation
Todd K. Hyster, Kyle E. Ruhl, Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2013, 135, 5364-5367
The coupling of O-pivaloyl benzhydroxamic acids with donor/acceptor diazo compounds provides isoindolones in high yield. The reaction tolerates a broad range of benzhydroxamic acids and diazo compounds, including substituted 2,2,2-trifluorodiazoethanes. Mechanistic experiments suggested that C–H activation is turnover-limiting and irreversible and that insertion of the diazo compound favors electron-deficient substrates.
Enantioselective Synthesis of the Tricyclic Core of FR901483 Featuring a Rhodium-Catalyzed [2+2+2] Cycloaddition
Stéphane Perreault; Tomislav Rovis
SYNTHESIS, 2013, 45, 719-728
An efficient approach to the tricyclic framework of FR901483 is described. The sequence features a [3,3]-sigmatropic rearrangement of a cyanate to an isocyanate, followed by its subsequent asymmetric rhodium-catalyzed [2+2+2] cycloaddition with a terminal alkyne for the synthesis of the indolizidine core. The aza-tricyclic core is completed using an intramolecular benzoin reaction to close the last ring of the natural product. Through a model study of the key cycloaddition, we evaluated the impact of different substituents on the tether of the alkenyl isocyanate.
Perfluorinated Taddol phosphoramidite as an L,Z-ligand on Rh(I) and Co(−I): evidence for bidentate coordination via metal–C6F5 interaction
Derek M. Dalton; Anthony K. Rappé; Tomislav Rovis
CHEMICAL SCIENCE, 2013, 4, 2062-2070
Perfluorinated Taddol-based phosphoramidite, CKphos, is a highly selective ligand for formation of vinylogous amide cycloadducts in the Rh(I) catalyzed [2 + 2 + 2] cycloaddition of alkenyl isocyanates and alkynes. CKphos overrides substrate bias of product selectivity in the cycloaddition, providing indolizidinones in excellent yields and enantioselectivities. The excellent selectivities are attributed to a shortened Rh–P bond and coordination of one C6F5 to rhodium via a Z-type interaction, making the phosphoramidite a bidentate L,Z-ligand on rhodium. Evidence for the shortened Rh–P and C6F5 coordination is provided by X-ray, NMR and DFT computational analyses. Additionally, an anionic cobalt complex with CKphos was synthesized and two Co–C6F5 interactions are seen. The Rh(C2H4)Cl·CKphos catalyst in the [2 + 2 + 2] cycloaddition of alkenyl isocyanates and alkynes represents a rare example of metal–C6F5 Z-type interaction affecting selectivity in transition metal catalysis.
A photoisomerization-coupled asymmetric Stetter reaction: application to the total synthesis of three diastereomers of (−)-cephalimysin A
Stephen P. Lathrop; Tomislav Rovis
CHEMICAL SCIENCE, 2013, 4, 1668-1673
The total synthesis of 8-epi, 8,9-epi, and 9-epi-(−)-cephalimysin A is described. Our catalytic enantioselective synthesis takes advantage of a novel tandem photoisomerization/Stetter reaction. The approach provides rapid access to the desired spirofuranone lactam core in good yield and excellent enantioselectivity. A late stage oxidation strategy allows for flexible access to three of the four diastereomers of cephalimysin A. Access to the epimers provides further support for the correction of the initially proposed relative stereochemistry of cephalimysin A.
Asymmetric NHC-Catalyzed Synthesis of a-Fluoroamides From Readily Accessible a-Fluoroenals
Philip Wheeler; Harit U. Vora; Tomislav Rovis
CHEMICAL SCIENCE, 2013, 4, 1674-1679
The scope of the NHC-redox amidation has been expanded to include a variety of α,β-unsaturated aldehydes, including α-fluoro α,β-unsaturated aldehydes which give rise to enantioenriched α-fluoroamides in good to excellent yield and enantioselectivity (up to 97% ee). Enantioenriched amines may be elaborated to either diastereomer of the product in high diastereoselectivity (up to 99:1). Functionalization of the amide products to amines and fluorohydrins is also demonstrated with retention of enantioenrichment at the fluorine stereocenter.
Rh(III)-Catalyzed Regioselective Synthesis of Pyridines from Alkenes and α,β-Unsaturated Oxime Esters
Jamie M. Neely; Tomislav Rovis
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2013, 135, 66-69
α,β-Unsaturated O-pivaloyl oximes are coupled to alkenes by Rh(III) catalysis to afford substituted pyridines. The reaction with activated alkenes is exceptionally regioselective and high-yielding. Mechanistic studies suggest that heterocycle formation proceeds via reversible C-H activation, alkene insertion, and a C-N bond formation/N-O bond cleavage process.
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