Research

Our research over the years has covered many aspects of synthetic organic chemistry. Below is a list of some of the major areas, which we have focused on since the year 2000. Click on the different headings to obtain more information and relevant references on the different subjects of interest.

Palladium-Catalyzed Reactions

Catalysis with Other Metals

Carbon Monoxide Releasing Molecules

Replacing Carbon with Silicon

Synthesis with single electron reducing agents

Other Projects

Palladium-Catalyzed Reactions

We have had a particular interest in palladium-catalyzed transformations for the creation of carbon–carbon and carbon–heteroatom bonds. Our research is broad and spans from 1) the use of aryl and vinyl tosylates/phosphates for a variety of coupling reactions, b) discovery and investigation of the 1,2-migration in the Heck and Negishi reaction, c) application of bulky Pd–H complexes for the selective one-carbon migration of terminal olefins, d) enamide synthesis from the decarbonylation of amino acid and peptidyl thioesters and the intermolecular ene-yne coupling for the synthesis of butadienes.

 

Palladiumcatalysis

 

Catalysis with Vinyl and Aryl Tosylates and Phosphates

 

A. L. Hansen and T. Skrydstrup, “Fast and Regioselective Heck Couplings with N-Acyl-N-vinylamine Derivatives” J. Org. Chem. 2005, 70, 5997.

A. L. Hansen and T. Skrydstrup, “Regioselective Heck Couplings of a,b-Unsaturated Tosylates and Mesylates with Electron Rich Olefins”, Org. Lett. 2005, 7, 5585.

A. L. Hansen, J.-P. Ebran, T. Gøgsig and T. Skrydstrup, “Direct synthesis of 1,1-diaryl alkenes from alkenyl phosphates via nickel(0)-catalysed Suzuki-Miyaura coupling” Chem. Commun. 2006,4137.

A. L. Hansen, J. P. Ebran, T. Gøgsig and T. Skrydstrup, ”Investigations on the Suzuki-Miyaura and Negishi Couplings with Alkenyl Phosphates: Application to the Synthesis of 1,1-Disubstituted Alkenes” J. Org. Chem. 2007, 72, 6464-6472.

T. M. Gøgsig, L. S. Søbjerg, A. T. Lindhardt (né Hansen), K. L. Jensen and T. Skrydstrup, “Direct Vinylation and Difluorovinylation of Arylboronic Acids Using Vinyl- and 2,2-Difluorovinyl Tosylates via the Suzuki-Miyaura Cross Coupling” J. Org. Chem. 2008, 73, 3404.

A. T. Lindhardt and T. Skrydstrup, “Classical Reagents: New Surprises in Palladium-Catalyzed C–C Coupling Reactions” Chem. Eur. J. 2008, 14, 8756.

T. M. Gøgsig, A. T. Lindhardt, M. Dekhane, J. Grouleff and Troels Skrydstrup, “Heteroaromatic Tosylates as Electrophiles in Regioselective Mizoroki-Heck Couplings with Electron Rich Olefins”, Chem. Eur. J. 2009, 15, 5950.

D. Gauthier, S. Beckendorf, T. M. Gøgsig, A. T. Lindhardt and T. Skrydstrup, “A Ligand Free and Room Temperature Protocol for Pd-Catalyzed Kumada-Corriu Couplings of Unactivated Alkenyl Phosphates” J. Org. Chem. 2009, 74, 3536.

M. L. H. Mantel, A. T. Lindhardt, D. Lupp and T. Skrydstrup, “Pd-Catalyzed C–N Bond Formation with Heteroaromatic Tosylates”, Chem. Eur. J. 2010, 16, 5437-5442.

A. T. Lindhardt, T. M. Gøgsig, D. Gauthier, D. Lupp, M. L. H. Mantel, K. M. Bjerglund and T. Skrydstrup, “2-Pyridyl Tosylate Derivatives –Building Blocks for Structural Diversity via Transition Metal Catalysis” Israel J. Chem. 2010, 50, 558-567.

1,2-Migration

A. L. Hansen, J.-P. Ebran, M. Ahlquist, P.-O. Norrby and T. Skrydstrup, ”Heck Coupling with Nonactivated Alkenyl Tosylates and Phosphates. Examples of Effective 1,2-Migrations of the Alkenyl Palladium(II) Intermediates” Angew. Chem. Int. Ed. 2006, 45, 3349.

J. P. Ebran, A. L. Hansen, T. Gøgsig and T. Skrydstrup, ”Studies on the Heck Reaction with Alkenyl Phosphates: Can the 1,2-Migration Be Controlled? Scope and Limitations”, J. Am. Chem. Soc. 2007, 129, 6931-6942.

A. T. Lindhardt, T. M. Gøgsig and T. Skrydstrup, “Studies on the 1,2-Migrations in Pd-Catalyzed Negishi Couplingswith JosiPhos Ligands” J. Org. Chem. 2009, 74, 135.

Intermolecular Ene-Yne Reaction

A. T. Lindhardt (né Hansen), M. L. H. Mantel and T. Skrydstrup, “Intermolecular Enyne Isomerization: Development of an Atom Efficient Mizoroki-Heck Type Coupling” Angew. Chem. Int. Ed. 2008, 47, 2668.

S. T. Henriksen, D. Tanner, T. Skrydstrup and P.-O. Norrby, “DFT Investigation of the Palladium-Catalyzed Ene–Yne Coupling” Chem. Eur. J. 2010, 16, 9494-9501.

Selective Isomerization of Olefins

D. Gauthier, A. T. Lindhardt, E. P. K. Olsen, J. Overgaard, T. Skrydstrup, “In Situ Generated Bulky Palladium Hydride Complexes as Catalysts for the Efficient Isomerization of Olefins. Selective

Transformation of Terminal Alkenes to 2-Alkenes”J. Am. Chem. Soc. 2010, 132, 7998-8009.

Enamide Synthesis

G. K. Min, D. Hernandez, A. T. Lindhardt and T. Skrydstrup, ”Enamides Accessed from Aminothioesters via a Pd(0)-Catalyzed Decarbonylative/β-Hydride Elimination Sequence” Org. Lett. 2010, 12, 4716-4719.

Catalysis with Other Metals

Our research interests have also focused on the use of other transition metals in organic synthesis. This includes a) the development of Ni-catalyzed Heck reactions under relatively mild reaction conditions, which parallel those catalyzed by Pd, and b) Fe-catalyzed cross couplings of heterocyclic tosylates/phosphates with Grignard reagents. Furthermore, we have developed a series of Au-catalyzed ring formations such as indoles, pyrroles, furans and multicyclic systems.

 

Other Metals

 

Ni-Catalyzed Heck Reactions

T. M. Gøgsig, J. Kleimark, S. O. Nilsson Lill, S. Korsager, A. T. Lindhardt, P.-O. Norrby and T. Skrydstrup, ”Mild and Efficient Nickel-Catalyzed Heck Reactions with Electron-Rich Olefins” J. Am. Chem. Soc. 2012, 134, 443-452.

Fe-Catalyzed Cross Couplings

T. M. Gøgsig, A. T. Lindhardt, and T. Skrydstrup, “Heteroaromatic Tosylates as Electrophiles in Iron Catalyzed Cross-Couplings” Org. Lett. 2009, 11, 4886.

Au(I)-Catalyzed C–C and C–Heteroatom Bond Formation

S. Kramer, K. Dooleweerdt, A. T. Lindhardt, M. Rottländer and T. Skrydstrup, “Highly Regioselective Au(I)-Catalyzed Hydroamination of Ynamides and Propiolic Acid Derivatives with Anilines” Org. Lett. 2009, 11, 4208.

S. Kramer, J. L. H. Madsen, M. Rottländer, T. Skrydstrup, “Access to 2,5-Diamidopyrroles and 2,5-Diamidofurans by Au(I)-Catalyzed Double Hydroamination or Hydration of 1,3-Diynes” Org. Lett. 2010, 12, 2758-2761.

S. Kramer, Y. Odabachian, J. Overgaard, M. Rottländer, F. Gagosz and T. Skrydstrup, ”Taking Advantage of the Ambivalent Reactivity of Ynamides in Gold Catalysis: A Rare Case of Alkyne Dimerization” Angew. Chem. Int Ed. 2011, 50, 5090-5094.

S. Kramer and T. Skrydstrup, ”Gold-Catalyzed Transfer to Alkynes: Novel Access to 2,4-Disubstituted Furans” Angew. Chem. Int. Ed. 2012, 51, 4681

Carbon Monoxide Releasing Molecules

We have a high interest in developing new techniques for running a variety of transition metal catalyzed reactions with low molecular weight gasses. For example, carbon monoxide is extensively used for the introduction of a carbonyl group. However, there is a reluctance to use this reagent, due to its high toxicity. We have recently developed two carbon monoxide releasing molecules, which upon activation effectively liberate carbon monoxide. Applying a double reactor set-up with a CO-producing chamber and a CO-consuming chamber, we have successfully performed a number of known and new carbonylation reactions with stoichiometric carbon monoxide. This technique has been demonstrated to be ideal for 13C- and 14C-carbon labeling.

 

CO releasing molecules

 

Relevant References

P. Hermange, A. T. Lindhardt, R. Taaning, K. Bjerglund, D. Lupp and T. Skrydstrup, ”Ex Situ Generation of Stoichiometric and Substoichiometric 12CO and 13CO and its Efficient Incorporation in Palladium Catalyzed Aminocarbonylations” J. Am. Chem. Soc. 2011, 133, 6061-6071.

P. Hermange, T. M. Gøgsig, A. T. Lindhardt, R. Taaning and T. Skrydstrup, ”Carbonylative Heck Reactions Using CO Generated ex Situ in a Two-Chamber System” Org. Lett. 2011, 13, 2444-2447.

D. U. Nielsen, R. Taaning, A. T. Lindhardt, T. M. Gøgsig and T. Skrydstrup, ”Palladium-Catalyzed Approach to Primary Amides Using Nongaseous Precursors” Org. Lett. 2011, 13, 4454-4457.

S. Friis, R. Taaning, A. T. Lindhardt and T. Skrydstrup, ”Silacarboxylic Acids as Efficient Carbon Monoxide Releasing Molecules: Synthesis and Application in Palladium-Catalyzed Carbonylation Reactions” J. Am. Chem. Soc. 2011, 133, 18114-18117.

T. M. Gøgsig, R. H. Taaning, A. T. Lindhardt and T. Skrydstrup, ”Palladium-Catalyzed Carbonylative alpha-Arylation for Accessing 1,3-Diketones” Angew. Chem. Int. Ed. 2012, 51, 798-801.

Z. Xin, T. M. Gøgsig, A. T. Lindhardt and T. Skrydstrup, ”An Efficient Method for the Preparation of Tertiary Esters by Palladium-Catalyzed Alkoxycarbonylation of Arylbromides” Org. Lett. 2012, 14, 284-287.

K. M. Bjerglund, A. T. Lindhardt and T. Skrydstrup, “Palladium-Catalyzed N-Acylation of Mono-Substituted Ureas Using Near-Stoichiometric Carbon Monoxide” J. Org. Chem. 2012, 77, 3793.

T. M. Gøgsig, D. U. Nielsen, A. T. Lindhardt, and T. Skrydstrup, ”Palladium-Catalyzed Carbonylative Heck Reaction Affording Monoprotected 1,3-Ketoaldedydes” Org. Lett. 2012, 14, 2536.

M. N. Burhardt, R. Taaning, N. C. Nielsen and T. Skrydstrup, “Isotope-Labeling of the Fibril Binding Compound FSB via a Pd-Catalyzed Double Alkoxycarbonylation” J. Org. Chem. 2012, 77, 5357.

D. U. Nielsen, K. Neumann, R. H. Taaning, A. T. Lindhardt, A. Modvig and T. Skrydstrup, “Palladium-Catalyzed Double Carbonylation Using Near Stoichiometric Carbon Monoxide: Expedient Access to Substituted 13C2-Labeled Phenethylamines” J. Org. Chem. 2012, 77, 6155.

Replacing Carbon with Silicon

We have a keen interest in the development of new methods for the efficient creation of carbon–silicon bonds with the purpose of synthesizing silicon-containing bioactive molecules. This includes silicon-containing nitrogen heterocycles and silanediol isosteres of peptides as potent protease inhibitors.

 

Silicon

 

Relevant References

L. Nielsen, K. B. Lindsay, J. B. Faber, N. Chr. Nielsen and Troels Skrydstrup, ”Stereocontrolled Synthesis of Methyl Silanediol Peptide Mimics” J. Org. Chem. 2007, 72, 10035-10044.

L. Nielsen and T. Skrydstrup, “Sequential C–Si Bond Formations from Diphenylsilane: Application to Silanediol Peptide Isostere Precursors” J. Am. Chem. Soc. 2008, 130, 13145.

D. Hernández, K. B. Lindsay, L. Nielsen, T. Mittag, K. Bjerglund, S. Friis, R. Mose, T. Skrydstrup, “Further Studies Towards the Stereocontrolled Synthesis of Silicon-Containing Peptide Mimics” J. Org. Chem. 2010, 75, 3283-3293.

D. Hernandez, L. Nielsen, K. B. Lindsay, M. A. Lopez-Garca, K. Bjerglund and T. Skrydstrup, “Stereocontrolled Synthesis of 2-Substituted-1,3-Azasilaheterocycles” Org. Lett. 2010, 12, 3528-3531.

D. Hernandez, R. Mose and T. Skrydstrup, ”Reductive Lithiation of Methyl Substituted Diarylmethylsilanes: Application to Silanediol Peptide Precursors” Org. Lett. 2011, 13, 732-735.

G. K. Min and T. Skrydstrup, “Regioselective Rh(1)-Catalyzed Sequential Hydrosilylation towards the Assembly of Silicon-Based Peptidomimetic Analogs” J. Org. Chem. 2012, 77, 5894 (Featured article).

Synthesis with Single Electron Reducing Agents

A major theme for many years of our research has been directed to exploring the use of single electron reducing agents, such as samarium diiodide for the creation of C–C bonds in a variety of systems. We have developed a variety of different methodologies including a) the introduction of side chains directly on to small peptides, b) ketyl-like radical additions from nitrones for the synthesis of gamma-amino acids and cyclic diamines; and c) acyl-like radical addition reactions for the rapid synthesis of ketoethylene and hydroxyethylene isosteres of peptides.

 

Samarium

 

Side Chain Introduction

M. Ricci, L. Madariaga and T. Skrydstrup, “Application of Reductive Samariation to the Synthesis of Small Unnatural Peptides” Angew. Chem. Int. Ed. Engl. 2000, 39, 242.

M. Ricci, P. Blakskjær and T. Skrydstrup, “Selective Side Chain Introduction onto Small Peptides Mediated by Samarium Diiodide: A Potential Route to Peptide Libraries” J. Am. Chem. Soc. 2000, 122, 12414.

P. Blakskjær, A. Gavrila, L. Andersen and T. Skrydstrup, “An improved protocol for the SmI2-promoted C-alkylation of peptides: degradation and functionalization of serine residues in linear and cyclic peptides” Tetrahedron Lett. 2004, 45, 9091.

Proline Derivative Synthesis

M. F. Jacobsen, M. Turks, R. G. Hazell and T. Skrydstrup, “SmI2-Mediated Cyclizations of Derivatized b-Lactams for the Highly Diastereoselective Construction of Functionalized Prolines” J. Org. Chem. 2002, 67, 2411.

C–C Peptide Ligation

P. Blakskjær, B. Høj, D. Riber and T. Skrydstrup, “SmI2 Reduced Thioesters as Synthons of Unstable Acyl Radical: Direct Synthesis of Potential Protease Inhibitors Via Intermolecular Radical Addition” J. Am. Chem. Soc. 2003, 125, 4030.

L. M. Mikkelsen, C. M. Jensen, B. Høj, P. Blakskjær and T. Skrydstrup, ” Further studies in the acyl-type radical additions promoted by SmI2: mechanistic implications and stereoselective reduction of the keto-functionality” Tetrahedron 2003, 59, 10541.

C. M. Jensen, K. B. Lindsay, R. H. Taaning, J. Karaffa, A. M. Hansen and T. Skrydstrup, “Can Decarbonylation of Acyl Radicals Be Overcome in Radical Addition Reactions? En Route to a Solution Employing N-Acyl Oxazolidinones and SmI2/H2O ” J. Am. Chem. Soc. 2005, 127, 6544.

C. M. Jensen, K. B. Lindsay, P. Andreasen and T. Skrydstrup, “Synthesis of a Hydroxyethylene Isostere of the Tripeptide Arg-Gly-Leu via a Convergent Acyl-like Radical Addition Strategy” J. Org. Chem. 2005, 70, 7512.

A. M. Hansen, K. B. Lindsay, P. K. Sudhadevi Antharjanam, J. Karaffa, R. A. Flowers II, and T. Skrydstrup, “Mechanistic Evidence for Intermolecular Radical Carbonyl Additions Promoted by Samarium Diiodide” J. Am. Chem. Soc. 2006, 128, 9616.

K. B. Lindsay and T. Skrydstrup, “Formal Total Synthesis of the Potent Renin Inhibitor, Aliskiren: Application of a SmI2-Promoted Acyl-like Radical Coupling” J. Org. Chem. 2006, 71, 4766.

J. Karaffa, K. B. Lindsay and T. Skrydstrup, “Expanding the Scope of the Acyl-type Radical Addition Reactions Promoted by SmI2” J. Org. Chem. 2006, 71, 8219.

T. Mittag, K. L. Christensen, K. B. Lindsay, N. C. Nielsen and T. Skrydstrup, “Direct Entry to Peptidyl Ketones via SmI2-Mediated C-C Bond Formation with Readily Accessible N-Peptidyl Oxazoldinones”, J. Org. Chem. 2008, 73, 1088.

R. H. Taaning, L. Thim, J. Karaffa, A. G. Campaña, A,-M. Hansen and T. Skrydstrup, “SmI2-promoted intra- and intermolecular C–C bond formation with chiral N-acyl oxazolidinones” Tetrahedron 2008, 64, 11884.

A. K. Croft, K. B. Lindsay, P. Renaud, T. Skrydstrup, “Radicals by Design” Chimia 2008, 62, 735.

R. H. Taaning, K. B. Lindsay, B. Schiøtt, K. Daasbjerg, T. Skrydstrup, “Importance of C-N Bond Rotation in N-Acyl Oxazolidinones in their SmI2-Promoted Coupling to Acrylamides” J. Am. Chem. Soc. 2009, 131, 10253.

T. Mittag, D. E. Otzen, N. C. Nielsen and T. Skrydstrup, “Synthesis of a Ketomethylene Isostere of the Fibrillating Peptide SNNFGAILSS” J. Org. Chem. 2009, 74, 7955.

R. H. Taaning, K. B. Lindsay and T. Skrydstrup, “Some unusual reactivities in the SmI2-mediated reductive coupling of acrylamides and acrylates with imides” Tetrahedron 2009, 65, 10908.

C–C Bond Formation with Nitrones

D. Riber and T. Skrydstrup, “SmI2-Promoted intermolecular radical addition of nitrones to acrylamides and acrylates: A novel route to g-amino acids” Org. Lett. 2003, 5, 229.

S. A. Johannesen, S. Albu, R. G. Hazell and T. Skrydstrup, “Radical addition of nitrones to acrylates mediated by SmI2: asymmetric synthesis of g-amino acids employing carbohydrate-based chiral auxiliaries” Chem. Commun. 2004,1962.

J.-P. Ebran, R. G. Hazell and T. Skrydstrup, “Samarium diiodide-induced intramolecular pinacol coupling of dinitrones: Synthesis of cyclic cis-vicinal diamines” Chem. Commun. 2005,5402.

Indole Dimerization

K. B. Lindsay, F. Ferrando, K. L. Christensen, J. Overgaard, M.-L. Bennasar and T. Skrydstrup, “SmI2-Promoted Radical Addition Reactions with N-(2-Indolylacyl)oxazolidinones: Synthesis of Bisindole Compounds” J. Org. Chem. 2007, 72, 4181-4188.

Other Projects

We also have an interest in other projects including a) the scaffolding of antimicrobial peptides with cyclodextrin to develop more stable membrane spanning ion channels, b) the use of bacteria to recover heavy metals from wastes, and c) the synthesis and subsequent isotope labelling of fibril binding compounds as diagnostic tools for Alzheimer’s disease.

Alamethicin Conjugation

C. U. Hjørringgaard, B. S. Vad, S. B. Nielsen, V. Matchkov, T. Vosegaard, N. C. Nielsen, D. E. Otzen and T. Skrydstrup, “Cyclodextrin Scaffolded Alamethicin with Highly Efficient Channel-Forming Properties” J. Pept. Sci. 2010, 16, 148, Suppl 1.

C. Hjørringgaard, B. Vad, V. Machkov, S. B. Nielsen, T. Vosegaard, N. C. Nielsen, D. E. Otzen and T. Skrydstrup “Cyclodextrin-Scaffolded Alamethicin with Remarkably Efficient Membrane Permeabilizing Properties and Membrane Current Conductance” J. Phys. Chem. B, 2012, 116, 7652.

Pd-Recovery on Bacterial Surface

L. S. Søbjerg, D. Gauthier, A. T. Lindhardt, M. Bunge,K. Finster, R. L. Meyer and T. Skrydstrup, “Bio-Supported Palladium Nanoparticles as a Catalyst for Suzuki-Miyaura and Mizoroki-Heck Reactions“ Green Chem. 2009, 11, 2041.

D. Gauthier, L. S. Søbjerg, K. M. Jensen, A. T. Lindhardt, M. Bunge, K. Finster, R. L. Meyer and T. Skrydstrup, “Environmentally Benign Recovery and Reactivation of Palladium from Industrial Waste by Using Gram-Negative Bacteria” ChemSusChem 2010, 3, 1036-1039.

M. Bunge, L. S. Søbjerg, A. E. Rotaru, D. Gauthier, A. T. Lindhardt, G. Hause, K. Finster, P. Kingshott, T. Skrydstrup and R. L. Meyer, “Formation of Palladium(0) Nanoparticles at Microbial Surfaces” Biotechnol. Bioeng. 2010, 107, 206-215.

L. S. Søbjerg, A. T. Lindhardt, T. Skrydstrup, K. Finster, R. L. Meyer, ”Size control and catalytic activity of bio-supported palladium nanoparticles” Colloids and Surface B 2011, 85, 373-378.

B. Hosseinkhani, L. S. Søbjerg, A.-E. Rotaru, G. Emtiazi, T. Skrydstrup, R. L. Meyer, ”Microbially supported synthesis of catalytically active bimetallic Pd-Au nanoparticles” Biotechnol. Bioeng. 2012, 109, 45-52.

Synthesis of Fibril Binding Compounds

M. L. H. Mantel, L. S. Søbjerg, T. H. V. Huynh, J.-P. Ebran, A. T. Lindhardt (neé Hansen), N. C. Nielsen and T. Skrydstrup, “An Expedient Synthesis of the Fibril Binding Compound FSB Via Sequential Pd-Catalyzed Coupling Reactions”, J. Org. Chem. 2008, 73, 3570.

T. H. V. Huynh, M. L. H. Mantel, K. Mikkelsen, A.T. Lindhardt, N. C. Nielsen, D. Otzen and T. Skrydstrup, “A Versatile Approach to b-Amyloid Fibril-Binding CompoundsExploiting the Shirakawa/Hayashi Protocol for trans-Alkene Synthesis” Org. Lett. 2009, 11, 999.