piperidines and indoline

Optically active alpha,alpha-disubstituted alpha-amino acids belong to an important class of unnatural amino acids. Since the synthesis of such amino acids involves the creation of a quaternary stereocenter, methods for their synthesis have been extensively studied. We have reported that N-t-butoxycarbonyl(Boc)-N-methoxymethyl(MOM)-amino acid derivatives undergo asymmetric alpha-alkylation in up to 93% ee. Original chiral information on an amino acid is preserved in axially chiral enolate intermediates, and thus asymmetric induction is achieved without the aid of external chiral sources (i.e., memory of chirality). Recently, we have reported a new protocol for the asymmetric cyclization of amino acid derivatives, which enables straightforward synthesis of cyclic amino acids with a tetrasubstituted carbon center from the usual alpha-amino acids in up to 98% ee. Here we report the asymmetric construction of highly substituted chiral nitrogen heterocycles via intramolecular conjugate addition of chiral enolates generated from N-Boc-N-alkylylamino acid derivatives. This method is applicable to the asymmetric construction of pyrrolidine, piperidine, tetrahydroisoquinoline, and indoline derivatives with contiguous quaternary and tertiary stereocenters.

Topics: Amino Acids; Heterocyclic Compounds; Indoles; Nitrogen Compounds; Piperidines; Pyrrolidines; Stereoisomerism; Tetrahydroisoquinolines

Solid-state photodecarbonylation is an attractive but underutilized methodology to forge hindered C-C bonds in complex molecules. This study discloses the use of this reaction to assemble the vicinal quaternary stereocenter motif present in bis(cyclotryptamine) alkaloids. Our strategy was enabled by experimental and computational investigations of the role of substrate conformation on the success or failure of the solid-state photodecarbonylation reaction. This informed a crystal engineering strategy to optimize the key step of the total synthesis. Ultimately, this endeavor culminated in the successful synthesis of the bis(cyclotryptamine) alkaloid "psychotriadine," which features the elusive piperidinoindoline framework. Psychotriadine, a previously unknown compound, was identified in the extracts of the flower

Topics: Alkaloids; Carbon; Free Radicals; Indoles; Light; Molecular Conformation; Piperidines; Stereoisomerism

The vesicular acetylcholine transporter (VAChT) is an important target for in vivo imaging of neurodegenerative processes using positron emission tomography (PET). So far the development of VAChT PET radioligands is based on the single known lead compound vesamicol. In this study we investigated a recently published spiroindoline based compound class (Sluder et al., 2012), which was suggested to have potential in the development of VAChT ligands. Therefore, we synthesized a small series of N,N-substituted spiro[indoline-3,4'-piperidine] derivatives and determined their in vitro binding affinities toward the VAChT. In order to investigate the selectivity, the off-target binding toward σ

Topics: Animals; Brain Chemistry; Female; Indoles; Ligands; Liver; PC12 Cells; Piperidines; Positron-Emission Tomography; Radioisotopes; Rats; Rats, Sprague-Dawley; Spiro Compounds; Vesicular Acetylcholine Transport Proteins

Application of indolin-3-one derivatives in a cascade reaction for efficient assembly of complex molecules is a much less explored research area. It is demonstrated that structurally interesting polysubstituted piperidino[1,2-a]indoline compounds containing four contiguous stereocenters including one tetrasubstituted carbon center can be readily obtained with good yields (up to 94% yield) and excellent enantioselectivities (up to >99% ee) by employing indolin-3-one derivatives as substrates via bifunctional catalysis.

Topics: Catalysis; Indoles; Magnetic Resonance Spectroscopy; Molecular Structure; Piperidines; Stereoisomerism

Blockade of the P2Y1 receptor is important to the treatment of thrombosis with potentially improved safety margins compared with P2Y12 receptor antagonists. Investigation of a series of urea surrogates of the diaryl urea lead 3 led to the discovery of 2-amino-1,3,4-thiadiazoles in the 7-hydroxy-N-neopentyl spiropiperidine indolinyl series as potent P2Y1 receptor antagonists, among which compound 5a was the most potent and the first non-urea analog with platelet aggregation (PA) IC50 less than 0.5 μM with 10 μM ADP. Several 2-amino-1,3,4-thiadiazole analogs such as 5b and 5f had a more favorable pharmacokinetic profile, such as higher Ctrough, lower Cl, smaller Vdss, and similar bioavailability compared with 3.

Topics: Animals; Dose-Response Relationship, Drug; Humans; Indoles; Molecular Structure; Piperidines; Rats; Receptors, Purinergic P2Y1; Structure-Activity Relationship; Thiadiazoles

Chiral nonracemic alkynyl(alkoxy)carbene complexes of tungsten(0) undergo the [3 + 2] cyclization toward alpha-methylindoles and 1,6-dimethyl-1,2,3,4-tetrahydropyridine to provide 2,3-indoline-fused cyclopentenone and 2,3-piperidine-fused cyclopentenone skeletons, respectively, with very high enantiomeric purities (96-99% ee).

Topics: Alkynes; Cyclopentanes; Indoles; Piperidines; Pyridines; Stereoisomerism; Tungsten

In both title compounds, C(19)H(24)N(2)O(2), (I), and C(17)H(21)N(3)O(2), (II), respectively, there are two molecules in the asymmetric unit and the pyrrolidine rings adopt envelope conformations. The conformations of the cyclooctane [in (I)] and 1-methylpiperidone [in (II)] rings are boat-chair and chair, respectively. The indolin-2-one group is almost perpendicular to the pyrrolidine ring. Intermolecular C-H...O, N-H...O and N-H...N interactions provide stability to the structures.

Topics: Crystallography, X-Ray; Drug Stability; Hydrogen Bonding; Indoles; Models, Molecular; Molecular Conformation; Piperidines; Pyrrolidines; Spiro Compounds

The present study was designed to investigate which muscarinic receptors the indoline derivatives interact with and also their pharmacological properties. Compounds I and II contracted guinea-pig ileum in a concentration-dependent manner, whereas compounds III-IX behaved as antagonists and Schild plots gave straight lines. 4-DAMP antagonized the contractile responses to compounds I and II, and the pA2 values for 4-DAMP were 8.96 +/- 0.23 and 9.09 +/- 0.06, respectively. In guinea-pig left atrium, compound I partly inhibited twitch responses, whereas compound II did not have any effect. In rabbit vas deferens, compounds I and II produced inhibitory effects on twitch responses evoked by field stimulation. Pirenzepine antagonized the inhibitory responses of compounds I and II, and the pA2 values for pirenzepine were 7.90 +/- 0.13 and 8.12 +/- 0.06, respectively. Compound I has about 150-fold higher affinity to M1 receptors than to M3 receptors, while compound II has about 360-fold higher affinity to M1 receptors. Our results indicate that compounds I and II show 7- and 16-fold higher M1 receptor selectivity than McN-A-343, respectively. Therefore, compound II is selective for M1 receptors over M2 or M3 receptors.

Topics: (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; Animals; Electric Stimulation; Female; Guinea Pigs; Heart Atria; Ileum; In Vitro Techniques; Indoles; Male; Muscarinic Agonists; Muscarinic Antagonists; Muscle, Smooth; Myocardial Contraction; Piperidines; Pirenzepine; Rabbits; Receptors, Muscarinic; Vas Deferens