Spirocyclic Ketones Research Articles

Chiral Auxiliary Approach for Gold(I)‐Catalyzed Cyclizations

AbstractTwo different classes of stereoselective cyclizations have been developed using a chiral auxiliary approach with commercially available [JohnPhosAu(MeCN)SbF6] as catalyst. First, a stereoselective cascade cyclization of 1,5‐enynes was achieved using the Oppolzer camphorsultam as chiral auxiliary. In this case, a one‐pot cyclization‐hydrolysis sequence was developed to directly afford enantioenriched spirocyclic ketones. Then, the stereoselective alkoxycyclization of 1,6‐enynes was mediated by an Evans‐type oxazolidinone. A reduction‐hydrolysis sequence was selected to remove the auxiliary to give enantioenriched β‐tetralones. DFT studies confirmed that the steric clash between the chiral auxiliary and alkene accounts for the experimentally observed diastereoselective cyclization through the Si face.

Convergent Syntheses of Isomeric Imidazolospiroketones as Templates for Acetyl-CoA Carboxylase (ACC) Inhibitors.

The synthesis of imidazole fused spirocyclic ketones as templates for acetyl-CoA carboxylase (ACC) inhibitors is reported. By completing the spirocyclic ring closure via divergent pathways, the synthesis of these regioisomers from common intermediates was developed. Through an aldehyde homologation/transmetalation strategy, one isomer was formed selectively. The second desired isomer was obtained via an intramolecular aromatic homolytic substitution reaction. Preparation of these isomeric spiroketones provided templates which, upon elaboration, led to key structure-activity relationship (SAR) points for delivery of potent ACC inhibitors.

N-heterocyclic carbene-catalyzed enantioselective synthesis of spirocyclic ketones bearing gem-difluoromethylenes

An enantioselective construction of spirocyclic ketones bearing the gem-difluoromethylene group has been accomplished through NHC-catalyzed umpolung [3 + 2] annulation of enals with cyclic gem-difluoroalkyl ketones.

Tropane-Based Dispirocyclic Oxiranes and Spirocyclic Ketones

AbstractThe Prilezhaev epoxidation of N-Boc-protected 3-cyclobutylidenetropane 1a affords a 1:2 mixture of compounds 2a and 2b, in which tropane and cyclobutane fragments are spiro-connected to the oxirane ring in endo- and exo-fashion, respectively. The exo-isomer 2b is obtained in 89% yield and 97% selectivity via the dioxirane oxidation of 1a. BF3-catalyzed isomerization of exo-oxirane 2b results in a 1:1 mixture of the spirocyclic ketones endo 3a and exo 3b containing spiro-connected tropane and cyclopentanone rings, while endo-epoxide 2a gives exclusively endo-ketone 3a. Prilezhaev and dioxirane epoxidations of N-Boc-protected 3-cyclopropylidenetropane 1b affords a mixture of endo- and exo-oxiranes 2c and 2d. Compounds 2c and 2d are not isolated in individual forms since they isomerize into a mixture of spirocyclic ketones endo 3c and exo 3d. Removal of the Boc groups from ketones 3a–d gives the corresponding hydrochlorides of aminoketones 4a–d in quantitative yields. Quantum chemical calculations predict that the rearrangement of endo-epoxides into the corresponding endo-ketones involving BF3-containing intermediates has by 4.4–7.9 kcal/mol lower activation barriers than the respective conversion of the exo-epoxides into exo-ketones. The cyclopropyl-containing dispiroepoxides 2c and 2d are predicted to interconvert faster into the corresponding ketones compared to their less strained cyclobutyl counterparts 2a and 2b.

Iron‐Catalyzed Asymmetric Inter‐ and Intramolecular Aerobic Oxidative Dearomatizing Spirocyclization of 2‐Naphthols

AbstractHighly chemo‐ and enantioselective inter‐ and intra‐molecular oxidative dearomatizing spirocyclization of 1‐alkyl‐2‐naphthols with O2 as the hydrogen acceptor was achieved using an iron catalyst. In the iron complex 1‐catalyzed reaction, 1‐methyl‐2‐naphthols 2 in the presence of phenol derivatives as the nucleophile was selectively oxidized, producing the spirocyclic ketones with good to high enantioselectivities via a tandem strategy. Pre‐synthesized 1,1′‐methylbis(arenol)s 6 and 7, intermediates of the tandem strategy were also converted to the desired products with chemo‐ and enantioselectivity.

A Metal-Free Approach for the Synthesis of 2-Tetralones via Carbanion-Induced Ring Transformation of 2H-Pyran-2-ones

A metal-free, ultrasound-assisted approach for the synthesis of highly functionalized 2-tetralones in high yields is described. The process involves ring transformation of 2H-pyran-2-ones with the spirocyclic ketone 1,4-cyclohexandione monoethylene ketal to yield spiro­cyclic ketals and subsequent acid-mediated hydrolysis. This protocol is free from any organometallic reagents, is economical and tolerates a wide range of functional groups.

Enantioselective Copper-Catalyzed Arylation-Driven Semipinacol Rearrangement of Tertiary Allylic Alcohols with Diaryliodonium Salts.

A copper-catalyzed enantioselective arylative semipinacol rearrangement of allylic alcohols using diaryliodonium salts is reported. Chiral Cu(II)-bisoxazoline catalysts initiate an electrophilic alkene arylation, triggering a 1,2-alkyl migration to afford a range of nonracemic spirocyclic ketones with high yields, diastereo- and enantioselectivities.

Oxidative N-Heterocyclic Carbene Catalyzed Dearomatization of Indoles to Spirocyclic Indolenines with a Quaternary Carbon Stereocenter.

An efficient method for the asymmetric intramolecular dearomatization of indoles by using oxidative N-heterocyclic carbene catalysis is demonstrated. Valuable optically active spirocyclic indolenines bearing an all-carbon quaternary stereocenter are obtained in excellent yields and with excellent enantioselectivity. The starting indoles are readily prepared and the reactions proceed through an intramolecular indole 3-acylation with an in situ generated acyl azolium intermediate to form a spirocyclic ketone moiety.

ChemInform Abstract: Pd‐Catalyzed Enantioselective Intramolecular α‐Arylation of α‐Substituted Cyclic Ketones: Facile Synthesis of Functionalized Chiral Spirobicycles.

AbstractVarious chiral spirocyclic ketones are enantioselectively obtained via Pd‐catalyzed intramolecular α‐arylation reactions of cyclic ketones.

Pd-catalyzed enantioselective intramolecular α-arylation of α-substituted cyclic ketones: facile synthesis of functionalized chiral spirobicycles.

Catalytic synthesis of chiral spirocyclic ketones was accomplished via the Pd-catalyzed intramolecular α-arylation of α-substituted cyclic ketones. The obtained spirocyclic ketone could be converted into a bifunctional organocatalyst.

ChemInform Abstract: Propargylic Cation‐Induced Intermolecular Electrophilic Addition—Semipinacol Rearrangement.

AbstractA series of β‐propargyl spirocyclic ketones is prepared by treatment of crude Co‐complexed propargylic acetates with a Lewis acid followed by reaction of resulting intermediate propargylic cations with cyclic allylic silyl ethers and a subsequent decomplexation.

Synthesis of diarylcyclopropyl spirocyclic ketones

A facile one-pot synthetic route for preparing a series of functionalized diarylcyclopropyl spirocyclic ketones 4 is developed. The efficient cyclopropanation route of the conjugated cyclic ketones 2 with sulfones 1 in the presence of NaH shows interesting molecular diversities. The reaction mechanism of the stereocontrolled cyclopropanations has been discussed.

Propargylic cation-induced intermolecular electrophilic addition–semipinacol rearrangement

A novel propargylic electrophile-induced tandem intermolecular addition-semipinacol rearrangement was developed efficiently under mild conditions. Various allylic silylether substrates as well as Co-complexed propargylic species were applicable to this protocol and gave a series of synthetically useful β-propargyl spirocyclic ketones in moderate to good yields. Its synthetic application was also demonstrated by an efficient construction of the key tricyclic moiety of daphlongamine E.

A Natural-Like Synthetic Small Molecule Impairs Bcr-Abl Signaling Cascades and Induces Megakaryocyte Differentiation in Erythroleukemia Cells

Over the past years, we synthesized a series of new molecules that are hybrids of spirocyclic ketones as complexity-bearing cores with bi- and ter-phenyls as privileged fragments. Some of these newly-shaped small molecules showed antiproliferative, pro-apoptotic and differentiating activity in leukemia cell lines. In the present study, to investigate more in depth the mechanisms of action of these molecules, the protein expression profiles of K562 cells treated with or without the compounds IND_S1, MEL_T1, IND_S7 and MEL_S3 were analyzed using two-dimensional gel electrophoresis coupled with mass spectrometry. Proteome comparisons revealed several differentially expressed proteins, mainly related to cellular metabolism, chaperone activity, cytoskeletal organization and RNA biogenesis. The major results were validated by Western blot and qPCR. To attempt integrating findings into a cellular signaling context, proteomic data were explored using MetaCore. Network analysis highlighted relevant relationships between the identified proteins and additional potential effectors. Notably, qPCR validation of central hubs showed that the compound MEL_S3 induced high mRNA levels of the transcriptional factors EGR1 and HNF4-alpha; the latter to our knowledge is reported here for the first time to be present in K562 cells. Consistently with the known EGR1 involvement in the regulation of differentiation along megakaryocyte lineage, MEL_S3-treated leukemia cells showed a marked expression of glycoprotein IIb/IIIa (CD41) and glycoprotein Ib (CD42), two important cell markers in megakaryocytic differentiation, together with morphological aspects of megakaryoblasts and megakaryocytes.

ChemInform Abstract: Novel Nucleophilic Rearrangement of 1‐Substituted Isoquinolines Using an Alcoholic Sodium Hydroxide Solution.

The reactions of 1-substituted isoquinolinium salts have been studied in the cases of the 1-isopropyl-2-methyl- and 2-methyl-1-cyclohexylisoquinolinium iodides using an alcoholic solution of sodium hydroxide. The possibility of preparing a wide range of spirocyclic ketones, alcohols, amino alcohols, and isochroman-3-ones has been demonstrated.

Novel nucleophilic rearrangement of 1-substituted isoquinolines using an alcoholic sodium hydroxide solution

The reactions of 1-substituted isoquinolinium salts have been studied in the cases of the 1-isopropyl-2-methyl- and 2-methyl-1-cyclohexylisoquinolinium iodides using an alcoholic solution of sodium hydroxide. The possibility of preparing a wide range of spirocyclic ketones, alcohols, amino alcohols, and isochroman-3-ones has been demonstrated.

Synthesis of spirocyclic carbazole- and acridine-lactams

Spirocyclic carbazole- and acridine-lactams were prepared by Fischer-indole or Friedländer-quinoline synthesis starting from spirocyclic ketones with a lactam ring. All annulation products were obtained as mixtures of separable regioisomers, which differ only in the position of one methyl group. The starting materials were prepared from 2-pyrrolidone and 2-piperidone by a sequence of protection (by N-allylation), alpha-acylation, iron-catalyzed Michael reaction followed by Robinson-annulation, palladium-catalyzed N-deprotection and catalytic hydrogenation. The overall yields of this six-step sequence are 13 and 17%, respectively, and the racemic ketones are obtained as single diastereoisomers.

Facile Synthesis of Spirocyclic Ketones via Gold(I)-Catalyzed Claisen-Type Rearrangement of Cyclic 8-Aryl-2,7-enyn-1-ols

The gold(I)-catalyzed Claisen-type rearrangement of cyclic 8-aryl-2,7-enyn-1-ols proceeds via a cationic allylic vinyl ether gold intermediate to give spirocyclic ketones. The reaction proceeded via attack of the hydroxyl group onto the gold-activated alkynes followed by [3,3]-sigmatropic rearrangement to generate the spirocyclic ketones. This transformation can be applied to the synthesis of aza- and oxaspirocyclic ketones from cyclic 8-aryl-2,7-enyn-1-ols bearing an N-sulfonamide or an oxygen atom linkage in the tether and the gold(I) catalyst.

Identification of Biphenyl-Based Hybrid Molecules Able To Decrease the Intracellular Level of Bcl-2 Protein in Bcl-2 Overexpressing Leukemia Cells

With the aim of enhancing the structural complexity and diversity of an existing collection of bi- and terphenyl compounds, we synthesized hybrid molecules comprising of spirocyclic ketones (a complexity-bearing core) and bi/terphenyls (privileged fragments). Compounds 1, 3, 4, and 6 showed well-defined activity on apoptosis and differentiation, making them potential leads for development as new anticancer agents and chemical probes to study signaling networks in neoplastic cells.

Stable Ion and Electrophilic Chemistry of the Sterically Crowded Stilbene 1,1′-Bi(benzocyclobutenylidene) and Its Derivatives

Generation and NMR studies of novel carbocations and carboxonium ions are reported from sterically hindered stilbene 1,1'-bi(benzocyclobutenylidene) 1, its dimethoxy derivative 5, and from their skeletally rearranged derivatives, namely, the spirocyclic ketone 6, diastereomeric alcohols 7 and isomeric diols 8. Quenching experiments on the carbocations under various conditions resulted in the formation/isolation of several novel covalent adducts. Acid-catalyzed isomerization of the diols 8 produced a remarkable dimeric molecule, whose structure was confirmed by X-ray analysis. Reactions of hindered stilbenes 1 and 5 with Br 2/CDCl 3 were examined via NMR experiments. The experimentally observed carbocations were also studied computationally by GIAO-DFT and by NICS.