Browse
Submit Data
Databases
API
Help

Dataset Information

27 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Enantioselective synthesis of angularly substituted 1-azabicyclic ring systems: dynamic kinetic resolution using aza-Cope rearrangements.

ABSTRACT: A useful enantioselective synthesis of angularly substituted 1-azabicyclic molecules that delivers the bicyclic amine products in good yield and 99% ee is reported. Angularly substituted cis-octahydrocyclopenta[b]pyrroles, cis-octahydroindoles, cis-decahydrocyclohepta[b]pyrroles, and cis-octahydrocyclopenta[b]pyridine are formed in good yields and 99% ee exclusively as the cis stereoisomers. Decahydroquinolines are generated as mixtures of cis and trans stereoisomers in similarly high ee. The starting materials for this cascade transformation are assembled in five steps from cycloalkanones and enantiomerically pure (R)-2-phenyl-3-butenamine. This enantioselective synthesis introduces a new strategy for dynamic kinetic resolution in which a rapid tautomeric equilibration of diastereomeric iminium cations is combined with a diastereoselective sigmatropic rearrangement.

SUBMITTER: Ito T

PROVIDER: S-EPMC2858009 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Enantioselective synthesis of angularly substituted 1-azabicyclic ring systems: dynamic kinetic resolution using aza-Cope rearrangements.

Ito Tatsuya T Overman Larry E LE Wang Jocelyn J

Journal of the American Chemical Society 20100301 10

A useful enantioselective synthesis of angularly substituted 1-azabicyclic molecules that delivers the bicyclic amine products in good yield and 99% ee is reported. Angularly substituted cis-octahydrocyclopenta[b]pyrroles, cis-octahydroindoles, cis-decahydrocyclohepta[b]pyrroles, and cis-octahydrocyclopenta[b]pyridine are formed in good yields and 99% ee exclusively as the cis stereoisomers. Decahydroquinolines are generated as mixtures of cis and trans stereoisomers in similarly high ee. The st ...[more]

PMID: 20175519

Similar Datasets

Enantioselective synthesis of angularly substituted 1-azabicylic rings: coupled dynamic kinetic epimerization and chirality transfer.

Project description:A new strategy for enantioselective synthesis of azacyclic molecules in which dynamic kinetic equilibration of diastereomeric iminium ions precedes a stereochemistry-determining sigmatropic rearrangement is reported. The method is illustrated by the synthesis, in high enantiomeric purity (generally 95-99% ee), of a variety of 1-azabicyclic molecules containing angular allyl or 3-substituted 2-propenyl side chains adjacent to nitrogen and up to three stereogenic centers. In these products, the size of the carbocyclic ring is varied widely (5-12 membered); however, useful yields are obtained in forming 1-azabicyclic products containing only fused pyrrolidine and piperidine rings. Chirality transfer from substituents at carbons 1 and 2 of the 3-butenylamine fragment of the starting material is investigated, with methyl and phenyl substituents at the allylic position shown to provide exquisite stereocontrol (generally 98-99% chirality transfer). An attractive feature of the method is the ability to carry out the key transformation in the absence of solvent. Illustrated also is the high yielding conversion of four such products to a new family of bicyclic ?-amino acids of high enantiomeric purity.

| S-EPMC3843940 | biostudies-literature

N-heteroatom substitution effect in 3-aza-cope rearrangements.

Project description:BackgroundThe nature of the heteroatom substitution in the nitrogen of a 3-aza-Cope system is explored.ResultsWhile N-propargyl isoxazolin-5-ones suffer 3-aza-Cope rearrangements at 60°C, the corresponding N-propargyl pyrazol-5-ones need a higher temperature of 180°C for the equivalent reaction. When the propargyl group is substituted by an allyl group, the temperature of the rearrangement for both type of compounds is less affected by the nature of the heteroatom present. Treatment with a base, such as ethoxide, facilitates the rearrangement, and in the case of isoxazol-5- ones other ring opening reactions take precedence, involving N-O ring cleavage of the 5-membered ring. However when base-catalysed decomposition is prevented by substituents, products arising from a room temperature aza-Cope rearrangement are isolated. A possible mechanistic pathway based on free energies derived from density functional calculations involving cyclic intermediates is proposed.ConclusionsThe nature of the heteroatom substitution in the nitrogen of a 3-aza-Cope system leads to a remarkable difference in the energy of activation of the reaction.

| S-EPMC3702470 | biostudies-literature

Overcoming Kinetic and Thermodynamic Challenges of Classic Cope Rearrangements.

Project description:Systematic evaluation of 1,5-dienes bearing 3,3-electron-withdrawing groups and 4-methylation results in the discovery of a Cope rearrangement for Meldrum's acid-containing substrates that have unexpectedly favorable kinetic and thermodynamic profiles. The protocol is quite general due to a concise and convergent synthesis from abundant starting materials. Furthermore, products with an embedded Meldrum's acid moiety are prepared, which, in turn, can yield complex amides under neutral conditions. We have now expanded the scope of the reductive Cope rearrangement, which, via chemoselective reduction, can promote thermodynamically unfavorable [3,3] sigmatropic rearrangements of 3,3-dicyano-1,5-dienes to form reduced Cope rearrangement products. The Cope rearrangement is found to be stereospecific and can yield enantioenriched building blocks when chiral, nonracemic 1,3-disubstituted allylic electrophiles are utilized. We expand further the use of Cope rearrangements for the synthesis of highly valuable building blocks for complex- and drug-like molecular synthesis.

| S-EPMC8195263 | biostudies-literature

Kinetic Resolution of Racemic Mixtures via Enantioselective Photocatalysis.

Project description:Despite the increasing demand for enantiopure drugs in the pharmaceutical industry, currently available chiral separation technologies are still lagging behind, whether due to throughput or to operability considerations. This paper presents a new kinetic resolution method, based on the specific adsorption of a target enantiomer onto a molecularly imprinted surface of a photocatalyst and its subsequent degradation through a photocatalytic mechanism. The current model system is composed of an active TiO2 layer, on which the target enantiomer is adsorbed. A photocatalytic suppression layer of Al2O3 is then grown around the adsorbed target molecules by atomic layer deposition. Following the removal of the templating molecules, molecularly imprinted cavities that correspond to the adsorbed species are formed. The stereospecific nature of these pores encourages enantioselective degradation of the undesired species through its enhanced adsorption on the photocatalyst surface, while dampening nonselective photocatalytic activity around the imprinted sites. The method, demonstrated with the dipeptide leucylglycine as a model system, revealed a selectivity factor of up to 7 and an enrichment of a single enantiomer to 85% from an initially racemic mixture. The wide range of parameters that can be optimized (photocatalyst, concentration of imprinted sites, type of passivating layer, etc.) points to the great potential of this method for obtaining enantiomerically pure compounds, beginning from racemic mixtures.

| S-EPMC8397234 | biostudies-literature

Revisiting ring-degenerate rearrangements of 1-substituted-4-imino-1,2,3-triazoles.

Project description:The 1-substituted-4-imino-1,2,3-triazole motif is an established component of coordination compounds and bioactive molecules, but depending on the substituent identity, it can be inherently unstable due to Dimroth rearrangements. This study examined parameters governing the ring-degenerate rearrangement reactions of 1-substituted-4-imino-1,2,3-triazoles, expanding on trends first observed by L'abbé et al. The efficiency of condensation between 4-formyltriazole and amine reactants as well as the propensity of imine products towards rearrangement was each strongly influenced by the substituent identity. It was observed that unsymmetrical condensation reactions conducted at 70 °C produced up to four imine products via a dynamic equilibrium of condensation, rearrangement and hydrolysis steps. Kinetic studies utilizing 1-(4-nitrophenyl)-1H-1,2,3-triazole-4-carbaldehyde with varying amines showed rearrangement rates sensitive to both steric and electronic factors. Such measurements were facilitated by a high throughput colorimetric assay to directly monitor the generation of a 4-nitroaniline byproduct.

| S-EPMC6122373 | biostudies-literature

Room-temperature enantioselective C-H iodination via kinetic resolution.

Project description:Asymmetric carbon-hydrogen (C-H) activation reactions often rely on desymmetrization of prochiral C-H bonds on the same achiral molecule, using a chiral catalyst. Here, we report a kinetic resolution via palladium-catalyzed enantioselective C-H iodination in which one of the enantiomers of a racemic benzylic amine substrates undergoes faster aryl C-H insertion with the chiral catalysts than the other. The resulting enantioenriched C-H functionalization products would not be accessible through desymmetrization of prochiral C-H bonds. The exceedingly high relative rate ratio (k(fast)/k(slow) up to 244), coupled with the subsequent iodination of the remaining enantiomerically enriched starting material using a chiral ligand with the opposite configuration, enables conversion of both substrate enantiomers into enantiomerically pure iodinated products.

| S-EPMC4382011 | biostudies-literature

Enantioselective Copper Catalyzed Alkyne-Azide Cycloaddition by Dynamic Kinetic Resolution.

Project description:The copper(I) catalyzed alkyne-azide cycloaddition (CuAAC), a click reaction, is one of the most powerful catalytic reactions developed during the last two decades. Conducting CuAAC enantioselectively would add a third dimension to this reaction and would enable the direct synthesis of α-chiral triazoles. Doing so is demanding because the two precursors have linear geometries, and the triazole product is a flat heterocycle. Designing a chiral catalyst is further complicated by the complex mechanism of CuAAC. We report an enantioselective CuAAC (E-CuAAC), enabled by dynamic kinetic resolution (DKR). The E-CuAAC is high yielding and affords up to 99:1 er. The E-CuAAC can directly generate α-chiral triazoles in a complex molecular environment.

| S-EPMC6594181 | biostudies-literature

Enantioselective Nickel-Catalyzed Alkyne-Azide Cycloaddition by Dynamic Kinetic Resolution.

Project description:The triazole heterocycle has been widely adopted as an isostere for the amide bond. Many native amides are α-chiral, being derived from amino acids. This makes α-N-chiral triazoles attractive building blocks. This report describes the first enantioselective triazole synthesis that proceeds via nickel-catalyzed alkyne-azide cycloaddition (NiAAC). This dynamic kinetic resolution is enabled by a spontaneous [3,3]-sigmatropic rearrangement of the allylic azide. The 1,4,5-trisubstituted triazole products, derived from internal alkynes, are complementary to those commonly obtained by the related CuAAC reaction. Initial mechanistic experiments indicate that the NiAAC reaction proceeds through a monometallic Ni complex, which is distinct from the CuAAC manifold.

| S-EPMC8130861 | biostudies-literature

Substituted Imidazoline Synthesis: A Diastereo- and Enantioselective aza-Henry Route to a Human Proteasome Modulator.

Project description:The first enantio- and diastereoselective synthesis of Tepe's human proteasome modulator is described. Routes to this and other highly substituted chiral imidazolines generally produce racemic material. Key to the route disclosed here is a gram-scale anti-selective aza-Henry reaction of an α-alkyl α-nitro ester nucleophile, catalyzed by a Bis(Amidine) [BAM] chiral proton complex, delivering the key intermediate in high yield as a single stereoisomer. The adduct is reduced to the amino ester and converted to an imidazoline.

| S-EPMC8627105 | biostudies-literature

Enantioselective preparation of mechanically planar chiral rotaxanes by kinetic resolution strategy.

Project description:Asymmetric synthesis of mechanically planar chiral rotaxanes and topologically chiral catenanes has been a long-standing challenge in organic synthesis. Recently, an excellent strategy was developed based on diastereomeric synthesis of rotaxanes and catenanes with mechanical chirality followed by removal of the chiral auxiliary. On the other hand, its enantioselective approach has been quite limited. Here, we report enantioselective preparation of mechanically planar chiral rotaxanes by kinetic resolution of the racemates via remote asymmetric acylation of a hydroxy group in the axis component, which provides an unreacted enantiomer in up to >99.9% ee in 29% yield (the theoretical maximum yield of kinetic resolution of racemate is 50%). While the rotaxane molecules are expected to have conformational complexity, our original catalysts enabled to discriminate the mechanical chirality of the rotaxanes efficiently with the selectivity factors in up to 16.

| S-EPMC7811017 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data