| 1. |
- Ankner, Tobias, et al.
(författare)
-
Palladium- and Nickel-Catalyzed Alkenylation of Enolates
- 2013
-
Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 19:6, s. 1858-1871
-
Forskningsöversikt (refereegranskat)abstract
- Transition-metal-catalyzed alkenylation of enolates provides a direct method to synthesize broadly useful ,-unsaturated carbonyl compounds from the corresponding carbonyl compound and alkenyl halides. Despite being reported in the early seventies, this reaction class saw little development for many years. In the past decade, however, efforts to develop this reaction further have increased considerably, and many research groups have reported efficient coupling protocols, including enantioselective versions. These reactions most commonly employ palladium catalysts, but there are also some important reports using nickel. There are many examples of this powerful transformation being used in the synthesis of complex natural products.
|
|
| 2. |
- Bengtsson, Christoffer, 1979-
(författare)
-
Synthesis of substituted Ring-Fused 2-Pyridones and applications in chemical biology
- 2013
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Antibiotics have been extensively used to treat bacterial infections since Alexander Fleming’s discovery of penicillin 1928. Disease causing microbes that have become resistant to antibiotic drug therapy are an increasing public health problem. According to the world health organization (WHO) there are about 440 000 new cases of multidrug-resistant tuberculosis emerging annually, causing at least 150 000 deaths. Consequently there is an immense need to develop new types of compounds with new modes of action for the treatment of bacterial infections.Presented herein is a class of antibacterial ring-fused 2-pyridones, which exhibit inhibitory effects against both the pili assembly system in uropathogenic Escherichia coli (UPEC), named the chaperone usher pathway, as well as polymerization of the major curli subunit protein CsgA, into a functional amyloid fibre. A pilus is an organelle that is vital for the bacteria to adhere to and infect host cells, as well as establish biofilms. Inhibition of the chaperone usher pathway disables the pili assembly machinery, and consequently renders the bacteria avirulent.The focus of this work has been to develop synthetic strategies to more efficiently alter the substitution pattern of the aforementioned ring-fused 2-pyridones. In addition, asymmetric routes to enantiomerically enriched key compounds and routes to compounds containing BODIPY and coumarin fluorophores as tools to study bacterial virulence mechanisms have been developed. Several of the new compounds have successfully been evaluated as antibacterial agents. In parallel with this research, manipulations of the core structure to create new heterocycle based central fragments for applications in medicinal chemistry have also been performed.
|
|
| 3. |
- Cosner, Casey C., et al.
(författare)
-
Evolution of Concise and Flexible Synthetic Strategies for Trichostatic Acid and the Potent Histone Deacetylase Inhibitor Trichostatin A
- 2013
-
Ingår i: European Journal of Organic Chemistry. - : Wiley. - 1434-193X .- 1099-0690. ; :1, s. 162-172
-
Tidskriftsartikel (refereegranskat)abstract
- (R)-(+)-Trichostatic acid and (R)-(+)-trichostatin A (TSA) are natural products that have attracted considerable attention in the field of epigenetic therapies. TSA in particular is a naturally occurring hydroxamic acid having potent activity as a histone deacetylase inhibitor (HDACi) and having significant potential for treatment of a myriad of genetically based diseases. Development of TSA and other trichostatic acid derivatives into useful small-molecule therapies has been hindered by the low natural abundance and high cost associated with these compounds. We report herein our collective efforts towards the development of concise and scalable routes for the synthesis of trichostatic acid and TSA in both racemic and enantioenriched forms. Three independent synthetic pathways were developed with varying degrees of efficiency and convergency. In the first synthesis, the key step was a vinylogous Horner-Wadsworth-Emmons condensation. A Marshall propargylation reaction was used as the key step in the second synthesis, and Pd-catalyzed a-alkenylation of a ketone zinc enolate by using various functionalized alkenyl or dienyl halides was developed for the third synthesis. The second pathway proved to be readily amenable to an enantioselective modification, and both the second and third pathways were straightforwardly adapted for the facile preparation of new analogues of trichostatic acid and TSA.
|
|
| 4. |
- Donoghue, Patricks J, et al.
(författare)
-
Development of a Q2MM Force Field for the Asymmetric Rhodium Catalyzed Hydrogenation of Enamides
- 2008
-
Ingår i: J.Chem.Theory Comput. - : American Chemical Society (ACS). ; 4, s. 1313-1323
-
Tidskriftsartikel (refereegranskat)abstract
- The rhodium catalyzed asymmetric hydrogenation of enamides to generate amino acid products and derivatives is a widely used method to generate unnatural amino acids. The choice of a chiral ligand is of utmost importance in this reaction and is often based on high throughput screening or simply trial and error. A virtual screening method can greatly increase the speed of the ligand screening process by calculating expected enantiomeric excesses from relative energies of diastereomeric transition states. Utilizing the Q2MM method, new molecular mechanics parameters are derived to model the hydride transfer transition state in the reaction. The new parameters were based off of structures calculated at the B3LYP/LACVP** level of theory and added to the MM3* force field. The new parameters were validated against a test set of experimental data utilizing a wide range of bis-phosphine ligands. The computational model agreed with experimental data well overall, with an unsigned mean error of 0.6 kcal/mol against a set of 18 data points from experiment. The major errors in the computational model were due either to large energetic errors at high e.e., still resulting in qualitative agreement, or cases where large steric interactions prevent the reaction from proceeding as expected.
|
|
| 5. |
- Donoghue, Patrick J, et al.
(författare)
-
Prediction of enantioselectivity in rhodium catalyzed hydrogenations.
- 2009
-
Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 131:2, s. 410-1
-
Tidskriftsartikel (refereegranskat)abstract
- Using the Q2MM method, new molecular mechanics parameters were developed to perform initial screening of a chiral library to focus the experimental screening for the rhodium catalyzed hydrogenation of enamides. Computational predictions agree very well with experimental data.
|
|
| 6. |
- Grigalunas, Michael, et al.
(författare)
-
Ni-Catalyzed Alkenylation of Ketone Enolates under Mild Conditions : Catalyst Identification and Optimization
- 2015
-
Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 137:22, s. 7019-7022
-
Tidskriftsartikel (refereegranskat)abstract
- A procedure for Ni-catalyzed cross-coupling of ketone enolates with alkenyl halides has been developed. Intermolecular coupling of aromatic and aliphatic ketone lithium enolates with a variety of alkenyl halides is achieved in the presence of Ni(cod)(2) catalyst (5 mol %), an N-heterocyclic carbene (NHC) ligand, and LiI (10 mol %) at 6-22 degrees C for 0.5-12 h with yields of up to 90%. During the initial development of this reaction, a misleading result with respect to the actual active catalyst was obtained using commercially available Q:Phos ligand, which was found to contain a trace of Pd metal contaminant sufficient to catalyze the reaction. However, under the final conditions optimized for Ni(cod)(2) in the presence of an NHC ligand, Pd was incompetent as a catalyst.
|
|
| 7. |
- Limé, Elaine, et al.
(författare)
-
Stereoselectivity in Asymmetric Catalysis: The Case of Ruthenium-Catalyzed Ketone Hydrogenation
- 2014
-
Ingår i: Journal of Chemical Theory and Computation. - : American Chemical Society (ACS). - 1549-9618 .- 1549-9626. ; 10:6, s. 2427-2435
-
Tidskriftsartikel (refereegranskat)abstract
- The ruthenium-catalyzed asymmetric hydrogenation of simple ketones to generate enantiopure alcohols is an important process widely used in the fine chemical, pharmaceutical, fragrance, and flavor industries. Chiral diphosphine–RuCl2–1,2-diamine complexes are effective catalysts for the reaction giving high chemo- and enantioselectivity. However, no diphosphine–RuCl2–1,2-diamine complex has yet been discovered that is universal for all kinds of ketone substrates, and the ligands must be carefully chosen for each substrate. The procedure of finding the best ligands for a specific substrate can be facilitated by using virtual screening as a complement to the traditional experimental screening of catalyst libraries. We have generated a transition state force field (TSFF) for the ruthenium-catalyzed asymmetric hydrogenation of simple ketones using an improved Q2MM method. The developed TSFF can predict the enantioselectivity for 13 catalytic systems taken from the literature, with a mean unsigned error of 2.7 kJ/mol.
|
|
| 8. |
|
|
| 9. |
- Tutkowski, Brandon, et al.
(författare)
-
Revisiting the Stereodetermining Step in Enantioselective Iridium-Catalyzed Imine Hydrogenation
- 2018
-
Ingår i: ACS Catalysis. - : American Chemical Society (ACS). - 2155-5435. ; 8:1, s. 615-623
-
Tidskriftsartikel (refereegranskat)abstract
- The mechanism for the iridium-catalyzed asymmetric hydrogenation of prochiral imines has been investigated for an experimentally relevant ligand substrate combination using DFT calculations. The possible stereoisomers of the stereodetermining hydride transfer transition state were considered for four possible hydrogenation mechanisms starting from the recently disclosed active catalyst consisting of iridium phosphine-oxazoline with cyclometalated imine substrate. The hydrogenation was found to proceed via an outer sphere pathway. The transition state accurately describes the experimental observations of the active catalyst and provides a structural rationale for the high stereoinduction despite the lack of direct interaction points in the outer-sphere mechanism. The predicted enantioselectivity was consistent with experimental observations. Experimental studies support the hypothesis that the iridacycle forms spontaneously and functions as the active catalyst in the hydrogenation.
|
|
| 10. |
- Verdolino, Vincenzo, et al.
(författare)
-
On the mechanism of the rhodium catalyzed acrylamide hydrogenation
- 2010
-
Ingår i: Journal of Molecular Catalysis A: Chemical. - : Elsevier BV. - 1381-1169. ; 324:1-2, s. 9-13
-
Tidskriftsartikel (refereegranskat)abstract
- The hydrogenation of acrylamides using chiral Rh(I) complexes is an attractive method for the enantioselective synthesis of highly functionalized intermediates. It has been employed less frequently than the related Rh(I) catalyzed hydrogenation of enamides and the mechanism of the reaction is not well understood. The parent reaction of acrylamide with a simple Rh(I) bisphosphine complex was studied at the B3LYP/LanL2TZ(f)/6–31++G** level of theory and shows a number of interesting differences compared to the mechanism of the enamide reaction. The minimum energy reaction pathway was found to involve attack of the molecular hydrogen parallel to the C–Rh–P bond, followed by an isomerization at the stage of the dihydride complex to give an altered orientation of the hydride, which is then transferred to the β-carbon.
|
|
| 11. |
- Wiest, Olaf, et al.
(författare)
-
Chemistry. Striking a balance to control stereochemistry.
- 2011
-
Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 333:6051, s. 1831-2
-
Tidskriftsartikel (refereegranskat)abstract
- A method predicts the success of catalysts for the preferential synthesis of one chiral form of a molecule.
|
|
