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1.
J Org Chem ; 87(13): 8437-8444, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-35679839

RESUMEN

An organocatalyzed, formal (3+3) cycloaddition reaction is described for the practical synthesis of substituted pyridines. Starting from readily available enamines and enal/ynal/enone substrates, the protocol affords tri- or tetrasubstituted pyridine scaffolds bearing various functional groups. This method was demonstrated on a 50 g scale, enabling the synthesis of 2-isopropyl-4-methylpyridin-3-amine, a raw material used for the manufacture of sotorasib. Mechanistic analysis using two-dimensional nuclear magnetic resonance (NMR) spectrometry revealed the transformation proceeds through the reversible formation of a stable reaction off-cycle species that precedes pyridine formation. In situ reaction progress kinetic analysis and control NMR studies were employed to better understand the role of FeCl3 and pyrrolidine hydrochloride in promoting the reaction.


Asunto(s)
Aldehídos , Cetonas , Aldehídos/química , Catálisis , Reacción de Cicloadición , Cetonas/química , Cinética , Piridinas/química
2.
J Am Chem Soc ; 138(20): 6372-5, 2016 05 25.
Artículo en Inglés | MEDLINE | ID: mdl-27133576

RESUMEN

A tandem olefin metathesis/oxidative cyclization has been developed to synthesize 2,5-disubstituted tetrahydrofuran (THF) diols in a stereocontrolled fashion from simple olefin precursors. The ruthenium metathesis catalyst is converted into an oxidation catalyst in the second step and is thus responsible for both catalytic steps. The stereochemistry of the 1,5-diene intermediate can be controlled through the choice of catalyst and the type of metathesis conducted. This olefin stereochemistry then controls the THF diol stereochemistry through a highly stereospecific oxidative cyclization.


Asunto(s)
Alquenos/química , Furanos/química , Catálisis , Ciclización , Furanos/síntesis química , Estructura Molecular , Oxidación-Reducción
3.
Angew Chem Int Ed Engl ; 54(24): 7134-8, 2015 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-25914354

RESUMEN

A stereoselective synthesis of anti-1,2-diols has been developed using a multitasking Ru catalyst in an assisted tandem catalysis protocol. A cyclometalated Ru complex catalyzes first a Z-selective cross-metathesis of two terminal olefins, followed by a stereospecific dihydroxylation. Both steps are catalyzed by Ru, as the Ru complex is converted to a dihydroxylation catalyst upon addition of NaIO4. A variety of olefins were transformed into valuable, highly functionalized, and stereodefined molecules. Mechanistic experiments were performed to probe the nature of the oxidation step and catalyst inhibition pathways. These experiments point the way to more broadly applicable tandem catalytic transformations.


Asunto(s)
Alcoholes/química , Alcoholes/síntesis química , Alquenos/química , Catálisis , Complejos de Coordinación/química , Cristalografía por Rayos X , Hidroxilación , Conformación Molecular , Rutenio/química , Estereoisomerismo
4.
J Am Chem Soc ; 136(37): 13029-37, 2014 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-25137310

RESUMEN

The success of enantioselective olefin metathesis relies on the design of enantioenriched alkylidene complexes capable of transferring stereochemical information from the catalyst structure to the reactants. Cyclometalation of the NHC ligand has proven to be a successful strategy to incorporate stereogenic atoms into the catalyst structure. Enantioenriched complexes incorporating this design element catalyze highly Z- and enantioselective asymmetric ring opening/cross metathesis (AROCM) of norbornenes and cyclobutenes, and the difference in ring strain between these two substrates leads to different propagating species in the catalytic cycle. Asymmetric ring closing metathesis (ARCM) of a challenging class of prochiral trienes has also been achieved. The extent of reversibility and effect of reaction setup was also explored. Finally, promising levels of enantioselectivity in an unprecedented Z-selective asymmetric cross metathesis (ACM) of a prochiral 1,4-diene was demonstrated.


Asunto(s)
Alquenos/química , Complejos de Coordinación/química , Rutenio/química , Ciclización , Ciclobutanos/química , Modelos Moleculares , Norbornanos/química , Estereoisomerismo
5.
J Am Chem Soc ; 136(1): 291-8, 2014 Jan 08.
Artículo en Inglés | MEDLINE | ID: mdl-24350903

RESUMEN

A dynamic kinetic resolution (DKR) of allylic sulfoxides has been demonstrated by combining the Mislow [2,3]-sigmatropic rearrangement with catalytic asymmetric hydrogenation. The efficiency of our DKR was optimized by using low pressures of hydrogen gas to decrease the rate of hydrogenation relative to the rate of sigmatropic rearrangement. Kinetic studies reveal that the rhodium complex acts as a dual-role catalyst and accelerates the substrate racemization while catalyzing olefin hydrogenation. Scrambling experiments and theoretical modeling support a novel mode of sulfoxide racemization which occurs via a rhodium π-allyl intermediate in polar solvents. In nonpolar solvents, however, the substrate racemization is primarily uncatalyzed. Computational studies suggest that the sulfoxide binds to rhodium via O-coordination throughout the catalytic cycle for hydrogenation.


Asunto(s)
Simulación por Computador , Rodio/química , Sulfóxidos/química , Catálisis , Hidrogenación , Cinética , Cloruro de Metileno/química , Estereoisomerismo
6.
J Am Chem Soc ; 131(20): 6932-3, 2009 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-19415904

RESUMEN

This communication describes the first rhodium-catalyzed intramolecular olefin hydroacylation to produce medium-sized heterocyclic ketones with high regio- and enantiocontrol. Both alpha- and beta-substituted ketones can be produced, depending on catalyst choice and substrate structure. In this stereoselective C-H bond functionalization, ethers, sulfides, and sulfoxides function as effective directing groups. Results from an isotopic labeling study suggest reductive elimination is not the turnover-limiting step in this olefin hydroacylation; thus, the proposed mechanism is distinct from those previously reported.


Asunto(s)
Alquenos/química , Compuestos Heterocíclicos/síntesis química , Acilación , Aldehídos/química , Benzaldehídos/química , Catálisis , Ciclización , Cetonas/síntesis química , Rodio/química , Estereoisomerismo
7.
J Am Chem Soc ; 131(3): 1077-91, 2009 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-19128061

RESUMEN

[Rh((R)-DTBM-SEGPHOS)]BF(4) catalyzes the intramolecular hydroacylation of ketones to afford seven-membered lactones in large enantiomeric excess. Herein, we present a combined experimental and theoretical study to elucidate the mechanism and origin of selectivity in this C-H bond activation process. Evidence is presented for a mechanistic pathway involving three key steps: (1) rhodium(I) oxidative addition into the aldehyde C-H bond, (2) insertion of the ketone CO double bond into the rhodium hydride, and (3) C-O bond-forming reductive elimination. Kinetic isotope effects and Hammett plot studies support that ketone insertion is the turnover-limiting step. Detailed kinetic experiments were performed using both 1,3-bis(diphenylphosphino)propane (dppp) and (R)-DTBM-SEGPHOS as ligands. With dppp, the keto-aldehyde substrate assists in dissociating a dimeric precatalyst 8 and binds an active monomeric catalyst 9. With [Rh((R)-DTBM-SEGPHOS)]BF(4), there is no induction period and both substrate and product inhibition are observed. In addition, competitive decarbonylation produces a catalytically inactive rhodium carbonyl species that accumulates over the course of the reaction. Both mechanisms were modeled with a kinetics simulation program, and the models were consistent with the experimental data. Density functional theory calculations were performed to understand more elusive details of this transformation. These simulations support that the ketone insertion step has the highest energy transition state and reveal an unexpected interaction between the carbonyl-oxygen lone pair and a Rh d-orbital in this transition state structure. Finally, a model based on the calculated transition-state geometry is proposed to rationalize the absolute sense of enantioinduction observed using (R)-DTBM-SEGPHOS as the chiral ligand.

8.
Chem Commun (Camb) ; (31): 3645-7, 2008 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-18665286

RESUMEN

A novel method for the cyclotrimerization of dimethylcyanamide to form hexamethylmelamine has been developed using an aluminium amide catalyst; detailed DFT modelling of the catalytic cycle supports a triple insertion, nucleophilic ring closure, deinsertion mechanism.


Asunto(s)
Aluminio/química , Cianamida/síntesis química , Altretamina/química , Catálisis , Cristalografía por Rayos X , Cianamida/química , Ciclización , Conformación Molecular , Termodinámica
9.
Chemphyschem ; 9(6): 911-9, 2008 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-18386265

RESUMEN

Nonspherical cages in inclusion compounds can result in non-uniform motion of guest species in these cages and anisotropic lineshapes in NMR spectra of the guest. Herein, we develop a methodology to calculate lineshape anisotropy of guest species in cages based on molecular dynamics simulations of the inclusion compound. The methodology is valid for guest atoms with spin 1/2 nuclei and does not depend on the temperature and type of inclusion compound or guest species studied. As an example, the nonspherical shape of the structure I (sI) clathrate hydrate large cages leads to preferential alignment of linear CO(2) molecules in directions parallel to the two hexagonal faces of the cages. The angular distribution of the CO(2) guests in terms of a polar angle theta and azimuth angle phi and small amplitude vibrational motions in the large cage are characterized by molecular dynamics simulations at different temperatures in the stability range of the CO(2) sI clathrate. The experimental (13)C NMR lineshapes of CO(2) guests in the large cages show a reversal of the skew between the low temperature (77 K) and the high temperature (238 K) limits of the stability of the clathrate. We determine the angular distributions of the guests in the cages by classical MD simulations of the sI clathrate and calculate the (13)C NMR lineshapes over a range of temperatures. Good agreement between experimental lineshapes and calculated lineshapes is obtained. No assumptions regarding the nature of the guest motions in the cages are required.

10.
J Chem Phys ; 127(12): 124510, 2007 Sep 28.
Artículo en Inglés | MEDLINE | ID: mdl-17902924

RESUMEN

Classical molecular dynamics simulations are used to compare the stability of methane, carbon dioxide, nitrogen, and mixed CO(2)N(2) structure I (sI) clathrates under deep ocean seafloor temperature and pressure conditions (275 K and 30 MPa) which were considered suitable for CO(2) sequestration. Substitution of methane guests in both the small and large sI cages by CO(2) and N(2) fluids are considered separately to determine the separate contributions to the overall free energy of substitution. The structure I clathrate with methane in small cages and carbon dioxide in large cages is determined to be the most stable. Substitutions of methane in the small cages with CO(2) and N(2) have positive free energies. Substitution of methane with CO(2) in the large cages has a large negative free energy and substitution of the methane in the large cages with N(2) has a small positive free energy. The calculations show that under conditions where storage is being considered, carbon dioxide spontaneously replaces methane from sI clathrates, causing the release of methane. This process must be considered if there are methane clathrates present where CO(2) sequestration is to be attempted. The calculations also indicate that N(2) does not directly compete with CO(2) during methane substitution or clathrate formation and therefore can be used as a carrier gas or may be present as an impurity. Simulations further reveal that the replacement of methane with CO(2) in structure II (sII) cages also has a negative free energy. In cases where sII CO(2) clathrates are formed, only single occupancy of the large cages will be observed.

11.
Org Lett ; 9(20): 3893-6, 2007 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-17784766

RESUMEN

UVA irradiation (ca. 350 nm) of a mixture of cyclic enones and nitrogen heterocycles leads to efficient formation of the 1,4-adducts in a variety of solvents, at room temperature. These reactions likely proceed through strained E-cycloalkenone intermediates, as suggested by low-temperature generation/trapping experiments monitored by 1H NMR. These results demonstrate that E-cycloalkenones are good electrophiles despite their known tendency to favor a conformation in which the carbonyl is not fully conjugated with the double bond.

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