Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Strain-Release Driven Spirocyclization of Azabicyclo[1.1.0]butyl Ketones.

ABSTRACT: Due to their intrinsic rigidity, three-dimensionality and structural novelty, spirocyclic molecules have become increasingly sought-after moieties in drug discovery. Herein, we report a strain-release driven synthesis of azetidine-containing spirocycles by harnessing the inherent ring strain of the azabicyclo[1.1.0]butane (ABB) fragment. Novel ABB-ketone precursors bearing silyl-protected alcohols were synthesized in a single step and shown to engage in electrophile-induced spirocyclization-desilylation reactions. Primary, secondary and tertiary silyl ethers were effectively transformed into a library of new spiro-azetidines, with a range of substituents and ring sizes. In addition, the products are generated with synthetically useful ketone and protected-amine functional groups, which provides the potential for further elaboration and for this chemistry to be utilized in the rapid assembly of medicinally relevant compounds.

SUBMITTER: Tyler JL

PROVIDER: S-EPMC8251566 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Strain-Release Driven Spirocyclization of Azabicyclo[1.1.0]butyl Ketones.

Tyler Jasper L JL Noble Adam A Aggarwal Varinder K VK

Angewandte Chemie (International ed. in English) 20210416 21

Due to their intrinsic rigidity, three-dimensionality and structural novelty, spirocyclic molecules have become increasingly sought-after moieties in drug discovery. Herein, we report a strain-release driven synthesis of azetidine-containing spirocycles by harnessing the inherent ring strain of the azabicyclo[1.1.0]butane (ABB) fragment. Novel ABB-ketone precursors bearing silyl-protected alcohols were synthesized in a single step and shown to engage in electrophile-induced spirocyclization-desi ...[more]

PMID: 33754432

Similar Datasets

Strain-Release-Driven Friedel-Crafts Spirocyclization of Azabicyclo[1.1.0]butanes.

Project description:The identification of spiro N-heterocycles as scaffolds that display structural novelty, three-dimensionality, beneficial physicochemical properties, and enable the controlled spatial disposition of substituents has led to a surge of interest in utilizing these compounds in drug discovery programs. Herein, we report the strain-release-driven Friedel-Crafts spirocyclization of azabicyclo[1.1.0]butane-tethered (hetero)aryls for the synthesis of a unique library of azetidine spiro-tetralins. The reaction was discovered to proceed through an unexpected interrupted Friedel-Crafts mechanism, generating a highly complex azabicyclo[2.1.1]hexane scaffold. This dearomatized intermediate, formed exclusively as a single diastereomer, can be subsequently converted to the Friedel-Crafts product upon electrophilic activation of the tertiary amine, or trapped as a Diels-Alder adduct in one-pot. The rapid assembly of molecular complexity demonstrated in these reactions highlights the potential of the strain-release-driven spirocyclization strategy to be utilized in the synthesis of medicinally relevant scaffolds.

| S-EPMC9299780 | biostudies-literature

Divergent, Strain-Release Reactions of Azabicyclo[1.1.0]butyl Carbinols: Semipinacol or Spiroepoxy Azetidine Formation.

Project description:The azetidine moiety is a privileged motif in medicinal chemistry and new methods that access them efficiently are highly sought after. Towards this goal, we have found that azabicyclo[1.1.0]butyl carbinols, readily obtained from the highly strained azabicyclo[1.1.0]butane (ABB), can undergo divergent strain-release reactions upon N-activation. Treatment with trifluoroacetic anhydride or triflic anhydride triggered a semipinacol rearrangement to give keto 1,3,3-substituted azetidines. More than 20 examples were explored, enabling us to evaluate selectivity and the migratory aptitude of different groups. Alternatively, treatment of the same alcohols with benzyl chloroformate in the presence of NaI led to iodohydrin intermediates which gave spiroepoxy azetidines upon treatment with base. The electronic nature of the activating agent dictates which pathway operates.

| S-EPMC8247891 | biostudies-literature

Strain-Release Driven Epoxidation and Aziridination of Bicyclo[1.1.0]butanes via Palladium Catalyzed σ-Bond Nucleopalladation.

Project description:The development of preparative methods for the synthesis of four-membered carbocycles is gaining increasing importance due to the widespread utility of cyclic compounds in medicinal chemistry. Herein, we report the development of a new methodology for the production of spirocyclic epoxides and aziridines containing a cyclobutane motif. In a two-step one-pot process, a bicyclo[1.1.0]butyl sulfoxide is lithiated and added to a ketone, aldehyde or imine, and the resulting intermediate is cross-coupled with an aryl triflate through C-C σ-bond alkoxy- or aminopalladation with concomitant epoxide or aziridine formation. After careful optimization, a remarkably efficient reaction was conceived that tolerated a broad variety of both aromatic and aliphatic substrates. Lastly, through several high yielding ring-opening reactions, we demonstrated the excellent applicability of the products as modular building blocks for the introduction of three-dimensional structures into target molecules.

| S-EPMC10107310 | biostudies-literature

Strain‐Release Driven Epoxidation and Aziridination of Bicyclo[1.1.0]butanes via Palladium Catalyzed σ‐Bond Nucleopalladation

Project description: Not available

| S-EPMC10952369 | biostudies-literature

Four-Component Strain-Release-Driven Synthesis of Functionalized Azetidines.

Project description:Despite the favorable properties that azetidine rings can engender on drug-compounds, methods for the diversity-oriented synthesis of azetidine-based structures are significantly underdeveloped. Herein, we report the successful realization of a multicomponent [1,2]-Brook rearrangement/strain-release-driven anion relay sequence and its application to the modular synthesis of substituted azetidines. The rapidity of the reaction, as confirmed by in situ infra-red spectroscopy, leverages the strain-release ring-opening of azabicyclo[1.1.0]butane to drive the equilibrium of the Brook rearrangement. The three electrophilic coupling partners, added sequentially to azabicyclo[1.1.0]butyl-lithium, could be individually varied to access a diverse compound library. The utility of this methodology was demonstrated in a 4-step synthesis of the EP2 receptor antagonist PF-04418948.

| S-EPMC10099845 | biostudies-literature

Synthetic studies toward longeracemine: a SmI<sub>2</sub>-mediated spirocyclization and rearrangement cascade to construct the 2-azabicyclo[2.2.1]heptane framework.

Project description:Longeracemine, a member of the Daphniphyllum family of alkaloids contains a novel carbon framework featuring a highly functionalized 2-azabicyclo[2.2.1]heptane core as part of an overall 5/6/5/5/6/5 skeleton. A synthetic intermediate containing the core of longeracemine has been efficiently prepared by employing a stereoselective SmI2-mediated cascade reaction to advance a 7-azabicyclo[2.2.1]heptadiene to a 2-azabicyclo[2.2.1]heptene that is functionally poised for conversion to the natural product.

| S-EPMC8162136 | biostudies-literature

Visible-light-driven spirocyclization of epoxides <i>via</i> dual titanocene and photoredox catalysis.

Project description:We describe the synergistic utilization of titanocene/photoredox dual catalysis driven by visible light for the radical opening/spirocyclization of easily accessible epoxyalkynes. This environmentally benign process uses the organic donor-acceptor fluorophore 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) as a photocatalyst and Hantzsch ester (HE) as an electron donor instead of stoichiometric metallic reductants. The photocatalytic conditions showed exceptionally high reactivity for the synthesis of privileged and synthetically challenging spirocycles featuring a spiro all-carbon quaternary stereocenter. Cyclic voltammetry (CV) studies suggest that Cp2TiIIICl is the catalytically active species.

| S-EPMC8146098 | biostudies-literature

Dearomative spirocyclization of ynamides.

Project description:Spiro N-heterocycles, particularly aza-spiro piperidines, have shown significant promise in pharmaceutical applications due to their ability to enhance physicochemical properties. Despite their potential, the preparation of these complex structures poses significant challenges. To address this, we propose a one-pot dearomative spirocyclization reaction of ynamides. This method involves a copper-catalyzed carbomagnesiation reaction, achieving chemo-, regio-, and stereoselective formation of vinyl metal intermediates. Upon the addition of a Lewis acid, these intermediates undergo a regioselective nucleophilic dearomatization event, facilitating the synthesis of diverse aza-spiro dihydropyridine scaffolds with multiple functional handles. Various Grignard reagents, diverse ynamides, and acylating reagents have been explored. A subsequent hydrogenation reaction provides access to both partially and fully reduced spirocyclic frameworks, broadening the scope of spirocyclic structures with potential medicinal applications.

| S-EPMC11533057 | biostudies-literature

Synthesis of ?-halo-?,?-difluoromethyl ketones by a trifluoroacetate release/halogenation protocol.

Project description:Three series of ?-halo-?,?-difluoromethyl ketones are prepared from highly ?-fluorinated gem-diols by exploiting the facile release of trifluoroacetate, followed by immediate trapping of the liberated ?,?-difluoroenolate with an electrophilic chlorine, bromine, or iodine source. The products are typically isolated in good yields, even in the case of sensitive, ?-iodo-?,?-difluoromethyl ketones. Also, we demonstrate that an ?-iodo-?,?-difluoromethyl ketone will participate in a copper-promoted reaction to forge a new carbon-carbon bond.

| S-EPMC3227119 | biostudies-literature

Bridge Cross-Coupling of Bicyclo[1.1.0]butanes.

Project description:Bicyclo[1.1.0]butanes (BCBs) have gained growing popularity in "strain release" chemistry for the synthesis of four-membered-ring systems and para- and meta-disubstituted arene bioisosteres as well as applications in chemoselective bioconjugation. However, functionalization of the bridge position of BCBs can be challenging due to the inherent strain of the ring system and reactivity of the central C-C bond. Here we report the first late-stage bridge cross-coupling of BCBs, mediated by directed metalation/palladium catalysis.

| S-EPMC10789093 | 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