Synthesis of novel 3-heterospiro[5.5]undecanes

Fröhlich, Johannes; Sauter, F.; Hametner, Christian; Pfalz, Monika

doi:10.3998/ark.5550190.0010.629

Cited by 5 publications

(4 citation statements)

References 9 publications

(11 reference statements)

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“…Aldehyde 3 (Scheme 3) was synthesized according to a published two-step sequence: [42] a Wittig reaction between 1methylpiperidin-4-one and (methoxymethyl)triphenylphosphonium chloride, followed by acidic hydrolysis of the resulting vinyl ether 2.…”

Section: Synthesismentioning

confidence: 99%

“…For the synthesis of compound 14 b, primary amine 8 was reductively alkylated with aldehyde 10 [42] by using a pyridine-borane complex as reducing agent. [32] The resulting secondary amine 11 [32] was acylated with 4-(4-fluorobutoxy)butanoic acid (7 b), and the trifluoroborate moiety was finally converted into a boronic acid by treatment with trimethylsilyl chloride in aqueous acetonitrile, yielding 14 b.…”

Section: Synthesismentioning

confidence: 99%

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Ligand‐Biased and Probe‐Dependent Modulation of Chemokine Receptor CXCR3 Signaling by Negative Allosteric Modulators

et al. 2015

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Over the last decade, functional selectivity (or ligand bias) has evolved from being a peculiar phenomenon to being recognized as an essential feature of synthetic ligands that target G protein-coupled receptors (GPCRs). The CXC chemokine receptor 3 (CXCR3) is an outstanding platform to study various aspects of biased signaling, because nature itself uses functional selectivity to manipulate receptor signaling. At the same time, CXCR3 is an attractive therapeutic target in the treatment of autoimmune diseases and cancer. Herein we report the discovery of an 8-azaquinazolinone derivative (N-{1-[3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]ethyl}-4-(4-fluorobutoxy)-N-[(1-methylpiperidin-4-yl)methyl]butanamide, 1 b) that can inhibit CXC chemokine 11 (CXCL11)-dependent G protein activation over β-arrestin recruitment with 187-fold selectivity. This compound also demonstrates probe-dependent activity, that is, it inhibits CXCL11- over CXCL10-mediated G protein activation with 12-fold selectivity. Together with a previously reported biased negative allosteric modulator from our group, the present study provides additional information on the molecular requirements for allosteric modulation of CXCR3.

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Section: Synthesismentioning

confidence: 99%

Section: Synthesismentioning

confidence: 99%

Ligand‐Biased and Probe‐Dependent Modulation of Chemokine Receptor CXCR3 Signaling by Negative Allosteric Modulators

et al. 2015

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“…Scheme S1, Supporting Information). This was accomplished efficiently using a two-step, one-pot Wittig hydrolysis reaction . The resulting endo -bicyclo[2.2.2]oct-5-en-2-ylacetaldehyde ( 11 ) was photolyzed with UV light to effect [2 + 2] cycloaddition of its formyl and vinylene groups (i.e., Paternò–Büchi cyclization) − to give the expected oxetane 2 …”

Section: Resultsmentioning

confidence: 99%

Bromination and Accompanying Rearrangement of the Polycyclic Oxetane 2,4-Oxytwistane

et al. 2014

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Bromination of the polycyclic oxetane 2,4-oxytwistane (rac-(1R,3S,4R,7S,9R,11S)-2-oxatetracyclo[5.3.1.0(3,11).0(4,9)]undecane) was undertaken in order to form 2,4-dibromotwistane. The oxetane was subjected to the mild reagent combination CBr4/Ph3P in a fashion similar to that for the Appel and Corey-Fuchs reactions. NMR spectroscopy revealed that the isomeric dibromo compound 2,8-dibromoisotwistane (2,8-dibromotricyclo[4.3.1.0(3,7)]decane) was inadvertently formed. The conversion was prevented by migration of a C-C bond within the geometrically stressed C10 framework. Computational chemistry was used to model the structure of the polycyclic oxetane and to assess the component of total ring strain energy due to the four-membered heterocycle. Mechanistic aspects behind the skeletal rearrangement are also discussed.

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“…Our next step was to evaluate each of these steps to maximize yields and practicality on larger scale. For the synthesis of the N 1 i- propyl-substituted amine 21 , we discovered that a switch to BOC protected spiroenone 29 offered multiple improvements. The CBZ protected spiroenone 13 , a thick, viscous oil, is difficult to handle whereas 29 is a free-flowing solid.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors

et al. 2012

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Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2-substituted spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50-75 g scale with minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors.

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Synthesis of novel 3-heterospiro[5.5]undecanes

Cited by 5 publications

References 9 publications

Ligand‐Biased and Probe‐Dependent Modulation of Chemokine Receptor CXCR3 Signaling by Negative Allosteric Modulators

Ligand‐Biased and Probe‐Dependent Modulation of Chemokine Receptor CXCR3 Signaling by Negative Allosteric Modulators

Bromination and Accompanying Rearrangement of the Polycyclic Oxetane 2,4-Oxytwistane

Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-CoA Carboxylase Inhibitors

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