RESUMO
An early synthetic step in the synthesis of adavosertib, AZD1775, is the SNAr reaction between 4-fluoronitrobenzene and 1-methylpiperazine in acetonitrile. A simple kinetics-based design of four reaction profiling experiments was used to investigate the kinetics of the reaction for the purpose of building a kinetic model. Fitting of the reaction profile data from two experiments conducted at 70 °C with a different excess of 1-methylpiperazine showed the reaction to follow a third-order rate law with a second-order dependence upon 1-methylpiperazine. This was rationalized in terms of the reaction following a rate-limiting proton transfer mechanism (base catalyzed) in which the progress to product is driven by a proton transfer involving a second molecule of 1-methylpiperazine. The experimentally determined entropy of activation of -180 J K-1 is consistent with this mechanism. The formation of a low level impurity was found to be due to the presence of traces of piperazine in the 1-methylpiperazine, which was shown to react approximately 15 times faster than 1-methylpiperazine at 70 °C. The rate constants for the 1-methylpiperazine catalyzed reaction of piperazine, 1-methylpiperazine, and the piperazine derived impurity were found to correlate in a Brønsted type analysis with the pKa's (acetonitrile) of the amine nucleophile.
Assuntos
Aminas , Prótons , Acetonitrilas , CinéticaRESUMO
Route design and proof of concept synthesis was conducted on a synthetically challenging atropisomeric KRASG12C inhibitor to support clinical API manufacture. Improvements to the synthesis of a chiral piperazine fragment gave reduced step count and streamlined protecting group strategy via the formation and methanol ring opening of an N-carboxy-anhydride (NCA). The complex atropisomeric nitroquinoline was accessed via an early stage salt-resolution followed by a formal two-part nitromethane-carbonylation, avoiding a high temperature Gould-Jacobs cyclization that previously led to atropisomer racemization. The substrate scope of the formal nitromethane-carbonylation strategy was further explored for a range of ortho-substituted bromo/iodo unprotected anilines.
Assuntos
Proteínas Proto-Oncogênicas p21(ras) , Metano/análogos & derivados , NitroparafinasRESUMO
A new three-component reductive arylation of amides with stable reactants (iPrOH and arylboronate esters), making use of a 2-pyridinyl (Py) directing group, is described. The N-Py-amide substrates are readily prepared from carboxylic acids and PyNH2 , and the resulting N-Py-1-arylalkanamine reaction products are easily transformed into the corresponding chlorides by substitution of the HN-Py group with HCl. The 1-aryl-1-chloroalkane products allow substitution and cross-coupling reactions. Therefore, a general protocol for the transformation of carboxylic acids into a variety of functionalities is obtained. The Py-NH2 by-product can be recycled.
RESUMO
The first total synthesis of phacelocarpus 2-pyrone A is reported. The original natural compound was tentatively assigned (by NMR spectroscopy) as containing two cis-alkenes and a trans-vinyl ether connected to a 2-pyrone ring motif. Our computational predictions indicated that a cis-vinyl ether motif was equally feasible. Attempts to prepare the trans-vinyl ether were met with no success. The all cis-target compound was synthesised in nine steps, employing key regio- and stereoselective reactions including Au(I)-catalysed vinyl etherification, Wittig alkenylation and end-game Stille macrocyclisation. Analysis of the NMR data enabled identification and confirmation of the correct structure of phacelocarpus 2-pyrone A, containing a cis-vinyl ether. Our studies pave the way for future development of methodologies to these structurally distinct pyrone skipped-polyenyne natural products.
RESUMO
The Baeyer-Villiger monooxygenase (BVMO) 'MO14' from Rhodococcus jostii RHA1, is an enantioselective BVMO that catalyses the resolution of the model ketone substrate bicyclo[3.2.0]hept-2-en-6-one to the (1S,5R)-2-oxa lactone and the residual (1S,5R)-substrate enantiomer. This regio-plus enantioselective behaviour is highly unusual for BVMOs, which often perform enantiodivergent biotransformations of this substrate. The scaleability of the transformation was investigated using fermentor-based experiments, in which variables including gene codon optimisation, temperature and substrate concentration were investigated. E. coli cells expressing MO14 catalysed the resolution of bicyclo[3.2.0]hept-2-en-6-one to yield (1S,5R)-2-oxa lactone of >99% ee and (1S,5R)-ketone of 96% ee after 14 h at a temperature of 16 °C and a substrate concentration of 0.5 g L(-1) (4.5 mM). MO14 is thus a promising biocatalyst for the production of enantio-enriched ketones and lactones derived from the [3.2.0] platform.
Assuntos
Reatores Biológicos , Escherichia coli/genética , Cetonas/metabolismo , Oxigenases/genética , Rhodococcus/enzimologia , Biocatálise , Escherichia coli/citologia , Escherichia coli/metabolismo , Regulação Enzimológica da Expressão Gênica/genética , Cetonas/química , Conformação Molecular , Oxigenases/química , Oxigenases/metabolismo , Rhodococcus/metabolismo , Especificidade por SubstratoRESUMO
Two mild and efficient strategies have been developed for the O-functionalisation of 4-hydroxy-6-alkyl-2-pyrones, by using them as nucleophilic partners in oxa-Michael additions and the Mitsunobu reaction. The reactions proceed in moderate to excellent yields on a range of substrates containing useful functionality. The reactions serve as practical and valuable synthetic methods to construct complex 2-pyronyl ethers, which are found embedded in a number of natural products.
RESUMO
The reactions of dppf-nickel(0) with alkyl halides proceed via three-coordinate nickel(0) intermediates of the form [Ni(dppf)(L)]. The effects of the identity of the added ligand (L) on catalyst speciation and the rates of reactions of [Ni(COD)(dppf)] with alkyl halides have been investigated using kinetic experiments and density functional theory calculations. A series of monodentate ligands have been investigated in attempts to identify trends in reactivity. Sterically bulky and electron-donating ligands are found to decrease the reaction rate. It was found that (i) the halide abstraction step is not always irreversible and the subsequent recombination of a nickel(I) complex with an alkyl halide can have a significant effect on the overall rate of the reaction and (ii) some ligands lead to very stable [Ni(dppf)(L)2] species. The yields of prototypical (dppf)nickel-catalyzed Kumada cross-coupling reactions of alkyl halides are significantly improved by the addition of free ligands, which provides another important variable to consider when optimizing nickel-catalyzed reactions of alkyl halides.
RESUMO
A nickel/dppf catalyst system was found to successfully achieve the Suzuki-Miyaura cross-coupling reactions of 3- and 4-chloropyridine and of 6-chloroquinoline but not of 2-chloropyridine or of other α-halo-N-heterocycles. Further investigations revealed that chloropyridines undergo rapid oxidative addition to [Ni(COD)(dppf)] but that α-halo-N-heterocycles lead to the formation of stable dimeric nickel species that are catalytically inactive in Suzuki-Miyaura cross-coupling reactions. However, the corresponding Kumada-Tamao-Corriu reactions all proceed readily, which is attributed to more rapid transmetalation of Grignard reagents.
RESUMO
The mechanism of the reactions between dppf-Ni0 complexes and alkyl halides has been investigated using kinetic and mechanistic experiments and DFT calculations. The active species is [Ni(κ2-dppf)(κ1-dppf)], which undergoes a halide abstraction reaction with alkyl halides and rapidly captures the alkyl radical that is formed. The rates of the reactions of [Ni(COD)(dppf)] with alkyl halides and the yields of prototypical nickel-catalyzed Kumada cross-coupling reactions of alkyl halides are shown to be significantly improved by the addition of free dppf ligand.
RESUMO
The stereoselective synthesis of a challenging macrocyclic polyene scaffold, containing a sensitive vinyl ether motif, has been accomplished using O,C-dilithiation/selective C-alkylation, Pd-catalysed etherification and Wittig reactions as key steps. An end-game macrocyclisation strategy employed a regio- and stereoselective Stille cross-coupling using Pd(Br)(N-Succ)(AsPh3)2 (AsCat) as the precatalyst.
Assuntos
Alcadienos/química , Alcinos/química , Éteres/química , Compostos Macrocíclicos/química , Compostos Policíclicos/química , Compostos de Vinila/química , Catálise , Estrutura Molecular , Compostos Organometálicos/química , EstereoisomerismoRESUMO
Two novel succinimide-based palladium complexes, AsCat and FurCat, are highly efficient catalysts for room-temperature Stille cross-coupling of organostannanes with benzyl chlorides. The air- and moisture-stable catalysts are prepared in one step, and the coupling reactions proceed with a high selectivity for the benzyl position under mild conditions without the need for additives.
RESUMO
Aziridines formed upon treatment of allylic carbamates and homoallylic sulfamates with Rh(II) carboxylate catalysts under oxidative conditions are trapped by suitably-disposed hydroxyl groups to give functionalised tetrahydrofurans.