Six-membered Piperidine Ring Research Articles

The crystal structures and Hirshfeld surface analysis of 6-(naphthalen-1-yl)-6a-nitro-6,6a,6b,7,9,11a-hexa-hydro-spiro-[chromeno[3',4':3,4]pyrrolo-[1,2-c]thia-zole-11,11'-indeno-[1,2-b]quinoxaline] and 6'-(naphthalen-1-yl)-6a'-nitro-6',6a',6b',7',8',9',10',12a'-octa-hydro-2H-spiro-[ace-naphthyl-ene-1,12'-chromeno[3,4-a]indolizin]-2-one.

The title compounds, 6-(naphthalen-1-yl)-6a-nitro-6,6a,6 b,7,9,11a-hexa-hydro-spiro-[chromeno[3',4':3,4]pyrrolo-[1,2-c]thia-zole-11,11'-indeno-[1,2-b]quinoxaline], C37H26N4O3S, (I), and 6'-(naphthalen-1-yl)-6a'-nitro-6',6a',6b',7',8',9',10',12a'-octa-hydro-2H-spiro-[ace-naphthyl-ene-1,12'-chromeno[3,4-a]indolizin]-2-one, C36H28N2O4, (II), are new spiro derivatives, in which both the pyrrolidine rings adopt twisted conformations. In (I), the five-membered thia-zole ring adopts an envelope conformation, while the eight-membered pyrrolidine-thia-zole ring adopts a boat conformation. An intra-molecular C-H⋯N hydrogen bond occurs, involving a C atom of the pyran ring and an N atom of the pyrazine ring. In (II), the six-membered piperidine ring adopts a chair conformation. An intra-molecular C-H⋯O hydrogen bond occurs, involving a C atom of the pyrrolidine ring and the keto O atom. For both compounds, the crystal structure is stabilized by inter-molecular C-H⋯O hydrogen bonds. In (I), the C-H⋯O hydrogen bonds link adjacent mol-ecules, forming R 2 2(16) loops propagating along the b-axis direction, while in (II) they form zigzag chains along the b-axis direction. In both compounds, C-H⋯π inter-actions help to consolidate the structure, but no significant π-π inter-actions with centroid-centroid distances of less than 4 Å are observed.

Synthesis of Aminoalkylated Aziridines from (+)-3-Carene

Aminoalkylated carane-type aziridines were synthesized via epoxidation of (+)-3-carene by H2O2 solution (7%) in EtOAc catalyzed by α-Al2O3 nanoparticles, opening of the epoxide by NaN3, and cyclization of the azidoalcohol by Ph3P followed by condensation of the resulting aziridines with formalin and secondary amines. The cytotoxicity of the aminoalkylated aziridines with heteroorganic substituents increased on going from a five-membered pyrrolidine ring substituent to a six-membered piperidine ring and decreased sharply upon replacing a piperidine by a morpholine ring or increased on going to a piperazine ring. The structures of products were established using IR and NMR spectroscopy and an X-ray crystal structure analysis.

Crystal structure and Hirshfeld surface analysis of dimethyl (3aS,6R,6aS,7S)-2-(2,2,2-tri-fluoro-acet-yl)-2,3-di-hydro-1H,6H,7H-3a,6:7,9a-di-epoxy-benzo[de]iso-quinoline-3a1,6a-di-carboxyl-ate.

The title mol-ecule, C18H16F3NO7, comprises a fused cyclic system containing four five-membered (two di-hydro-furan and two tetra-hydro-furan) rings and one six-membered (piperidine) ring. The five-membered di-hydro-furan and tetra-hydro-furan rings adopt envelope conformations, and the six-membered piperidine ring adopts a distorted chair conformation. Intra-molecular O⋯F inter-actions help to stabilize the conformational arrangement. In the crystal structure, mol-ecules are linked by weak C-H⋯O and C-H⋯F hydrogen bonds, forming a three-dimensional network. The Hirshfeld surface analysis confirms the dominant role of H⋯H contacts in establishing the packing.

Unusual thermolysis of aza-cyclic allene under microwave conditions: crystal structure of (3RS,3aSR,8RS,8aRS)-methyl 5,6-dimeth-oxy-3a,10-dimethyl-1-phenyl-3,3a,8,8a-tetra-hydro-3,8-(epimino-methano)-cyclo-penta-[a]indene-2-carboxyl-ate from synchrotron X-ray diffraction.

The title compound, C25H27NO4 (I), the product of the unusual thermolysis of aza-cyclic allene methyl 10,11-dimeth-oxy-3,8-dimethyl-6-phenyl-3-aza-benzo[d]cyclo-deca-4,6,7-triene-5-carboxyl-ate, represents a bicyclic heterosystem and crystallizes in the monoclinic space group P21/c with three crystallographically independent mol-ecules in the unit cell. These independent mol-ecules adopt very similar geometries and differ only in the conformations of the two meth-oxy substituents on the benzene ring. In two of the three independent mol-ecules, both meth-oxy groups are almost coplanar with the benzene ring [the C-C-O-Me torsion angles are 10.8 (2), 12.3 (2), 9.1 (2) and 13.6 (3)°], whereas in the third mol-ecule, one of the meth-oxy groups is practically coplanar to and the other meth-oxy group is roughly perpendicular to the benzene ring, the C-C-O-Me torsion angles being 14.1 (2) and 76.5 (2)°. The mol-ecule of (I) comprises a fused tetra-cyclic system containing two five-membered rings (cyclo-pentenes) and two six-membered rings (piperidine and benzene). The five-membered rings have the usual envelope conformation, with the methyl-subsituted C atom as the flap in each molecule, and the six-membered piperidine ring has a chair conformation. The methyl substituent at the N atom occupies the sterically favourable equatorial position. The carboxyl-ate group lies almost within the basal plane of the parent cyclo-pentene ring [making dihedral angle of 11.68 (8), 18.94 (9) and 15.16 (9)° in the three independent mol-ecules], while the phenyl substituent is twisted by 48.26 (6), 42.04 (6) and 41.28 (6)° (for the three independent mol-ecules) relative to this plane. In the crystal, mol-ecules of (I) form stacks along the b-axis direction. The mol-ecules are arranged at van der Waals distances.

5′′-(2-Fluorobenzylidene)-1′-(2-fluorophenyl)-1′′-methyl-1′,2′,3′,5′,6′,7′,8′,8a'-octahydrodispiro[acenaphthylene-1,3′-indolizine-2′,3′′-piperidine]-2,4′′(1H)-dione

In the title compound, C37H32F2N2O2, the central six-membered piperidine ring adopts a twisted half-chair conformation, with the N and methyl­ene C atoms deviating by −0.2875 (16) and 0.4965 (15) Å, respectively, from the mean plane defined by the other four atoms. The piperidine connected to the octa­hydro­indolizine ring is in a half-chair conformation. The five-membered pyrrole ring adopts a slightly twisted envelope conformation with the piperidine C atom as the flap atom. The F and H atoms of both fluoro­benzene rings are disordered, with occupancy factors of 0.941 (3):0.059 (3) and 0.863 (3):0.137 (3). The mol­ecular structure features some intra­molecular C—H⋯O inter­actions. In the crystal, a supra­molecular zigzag chain sustained by C—H⋯F inter­actions parallel to the c axis is formed, generating a C(12) graph-set motif.

Intermolecular C—H...O and C—H...Xinteractions in substituted spiroacenaphthylene structures

In the three spiroacenaphthylene structures 5''-[(E)-2,3-dichlorobenzylidene]-7'-(2,3-dichlorophenyl)-1''-methyldispiro[acenaphthylene-1,5'-pyrrolo[1,2-c][1,3]thiazole-6',3''-piperidine]-2,4''-dione, C(35)H(26)Cl(4)N(2)O(2)S, (I), 5''-[(E)-4-fluorobenzylidene]-7'-(4-fluorophenyl)-1''-methyldispiro[acenaphthylene-1,5'-pyrrolo[1,2-c][1,3]thiazole-6',3''-piperidine]-2,4''-dione, C(35)H(28)F(2)N(2)O(2)S, (II), and 5''-[(E)-4-bromobenzylidene]-7'-(4-bromophenyl)-1''-methyldispiro[acenaphthylene-1,5'-pyrrolo[1,2-c][1,3]thiazole-6',3''-piperidine]-2,4''-dione, C(35)H(28)Br(2)N(2)O(2)S, (III), the substituted aryl groups are 2,3-dichloro-, 4-fluoro- and 4-bromophenyl, respectively. The six-membered piperidine ring in all three structures adopts a half-chair conformation, the thiazolidine ring adopts a slightly twisted envelope and the pyrrolidine ring an envelope conformation; in each case, the C atom linking the rings is the flap atom. In all three structures, weak intramolecular C-H···O interactions are present. The crystal packing is stabilized through a number of intermolecular C-H···O and C-H···X interactions, where X = Cl in (I) and F or S in (II), and C-H···O interactions are observed predominantly in (III). In all three structures, molecules are linked through centrosymmetric ring motifs, further tailored through a relay of C-H···X [Cl in (I), Br in (II) and O in (III)] interactions.

7′-(Naphthalen-1-yl)-5′′-[(naphthalen-2-yl)methylidene]-1′,3′,5′,6′,7′,7a′-hexahydrodispiro[acenaphthene-1,5′-pyrrolo[1,2-c]thiazole-6′,3′′-piperidine]-2(1H),4′′-dione

In the title compound, C43H34N2O2S, the six-membered piperidine ring adopts a half-chair conformation. The five-membered thia­zole ring adopts a slightly twisted envelope conformation and the pyrrole ring adopts an envelope conformation; in each case, the C atom linking the rings is the flap atom. The mol­ecular structure features inter- and intra­molecular C—H⋯O inter­actions. Furthermore, the crystal packing is stabilized by four inter­molecular C—H⋯π inter­actions.

An Analog of BIX-01294 Selectively Inhibits a Family of Histone H3 Lysine 9 Jumonji Demethylases

BIX-01294 and its analogs were originally identified and subsequently designed as potent inhibitors against histone H3 lysine 9 (H3K9) methyltransferases G9a and G9a-like protein. Here, we show that BIX-01294 and its analog E67 can also inhibit H3K9 Jumonji demethylase KIAA1718 with half-maximal inhibitory concentrations in low micromolar range. Crystallographic analysis of KIAA1718 Jumonji domain in complex with E67 indicated that the benzylated six-membered piperidine ring was disordered and exposed to solvent. Removing the moiety (generating compound E67-2) has no effect on the potency against KIAA1718 but, unexpectedly, lost inhibition against G9a-like protein by a factor of 1500. Furthermore, E67 and E67-2 have no effect on the activity against histone H3 lysine 4 (H3K4) demethylase JARID1C. Thus, our study provides a new avenue for designing and improving the potency and selectivity of inhibitors against H3K9 Jumonji demethylases over H3K9 methyltransferases and H3K4 demethylases.

Racemic methyl 3,10-dioxa-2-azatricyclo[6.2.1.02,6]undecane-4-carboxylate

The structure of the racemic title compound, C10H15NO4, consists of a tricyclic skeleton comprising a six-membered piperidine ring and five-membered isoxazolidine and tetra­hydro­furan rings. The piperidine ring adopts a distorted chair conformation, while the isoxazolidine and tetra­hydro­furan rings have envelope conformations.

Conformational Preferences of Proline Analogues with Different Ring Size

The conformational study on L-azetidine-2-carboxylic acid (Ac-Aze-NHMe, the Aze dipeptide) and (S)-piperidine-2-carboxylic acid (Ac-Pip-NHMe, the Pip dipeptide) is carried out using ab initio HF and density functional methods with the self-consistent reaction field method to explore the differences in conformational preferences and cis-trans isomerization for proline residue and its analogues with different ring size in the gas phase and in solution (chloroform and water). The change of ring size by deleting a CH2 group from or adding a CH2 group to the prolyl ring results the remarkable changes in backbone and ring structures compared with those of the Pro dipeptide, especially in the C'-N imide bond length and the bond angles around the N-C(alpha) bond. The four-membered azetidine ring can have either puckered structure depending on the backbone structure because of the less puckered structure. The six-membered piperidine ring can adopt chair and boat conformations, but the chair conformation is more preferred than the boat conformation. These calculated preferences for puckering are consistent with experimental results from analysis of X-ray structures of Aze- and Pip-containing peptides. On going from Pro to Aze to Pip, the axiality (i.e., a tendency to adopt the axial orientation) of the NHMe group becomes stronger, which can be ascribed to reduce the steric hindrances between 1,2-substituted Ac and NHMe groups. As the solvent polarity increases, the polyproline II-like conformation becomes more populated and the relative stability of conformation tC with a C7 hydrogen bond between C'=O of the amino group and N-H of the carboxyl group decreases for both the Aze and Pip dipeptides, as seen for the Pro dipeptide. The cis population and rotational barriers for the imide bond increase with the increase of solvent polarity for both the Aze and Pip dipeptides, as seen for the Pro dipeptide. In particular, the cis-trans isomerization proceeds in common through only the clockwise rotation with omega' approximately +120 degrees about azetyl and piperidyl peptide bonds in the gas phase and in solution, as seen for alanyl and prolyl peptide bonds. The pertinent distance d(N...H-N(NHMe)) and the pyramidality of imide nitrogen can describe the role of this hydrogen bond in stabilizing the transition state structure, but the lower rotational barriers for the Aze and Pip dipeptides than those for the Pro dipeptide, which is observed from experiments, cannot be rationalized.

2,2-Dichloro-1-(4-ethoxyphenyl)cyclopropanyl piperidin-1-yl ketone

The title compound, C17H21Cl2NO2, a cyclo­propane derivative related to the insecticide cyclo­prothrin, was prepared from piperidine and 2,2-dichloro-1-(4-ethoxy­phen­yl)cyclo­propane­carbonyl chloride. The six-membered piperidine ring has a chair conformation. The orientation of the carbonyl group relative to the cyclo­propane ring may be described by the torsion angle X—C—C=O of −98.3°, where X is the centroid of the cyclo­propane ring.

(2 S,5 R/2 R,5 S)-Aminoethylpipecolyl aepip-aegPNA chimera: synthesis and duplex/triplex stability

This article reports the design and facile synthesis of novel chiral six-membered PNA analogues (2 S,5 R/2 R,5 S)-1-( N-Boc-aminoethyl)-5-(thymin-1-yl)pipecolic acid, aepipPNA IV that upon incorporation into standard aegPNA sequences effected stabilization of complexes with complementary target DNA. Substitution of aegPNA unit by the designed monomer at the C-terminus was more effective than substitution at N-terminus. The stabilizing behaviour improved with degree of substitution and was found to be dependent on their relative positions in the sequence. The six-membered piperidine ring in the design may freeze the rigid chair conformations and the relative stereochemistry of the substituents may in effect direct the complex formation with DNA/RNA by sequence-specific nucleobase recognition. In the present aepipPNA analogues, the l- trans stereochemical disposition of the substituents seems to lead to the favorable pre-organization of the PNA oligomers for complex formation with DNA. The results reported here further expand the repertoire of cyclic PNA analogues.

Head-to-head dimers in the zwitterion of 1-hydroxy-1-phosphono-3-(1-piperidino)propylidene-1-phosphonate (PHPBP).

The title compound, C(8)H(19)NO(7)P(2), is a member of the bisphosphonate family of therapeutic compounds. PHPBP has inner-salt character, consisting of a negatively charged PO(3) group and a positively charged N atom. The six-membered piperidine ring adopts an almost-perfect chair conformation. The hydroxyl group and the N atom have gauche and trans conformations in relation to the O-C-C-C-N backbone, respectively. Hydrogen bonding is the main contributor to the packing in the crystal, which consists of head-to-head dimers formed through phosphonyl-phosphonyl hydrogen bonds, while O-H.O and N-H.O interactions join the dimers into a plane parallel to crystallographic b and c axes.

Chloral adduct ofN-hydroxypiperidine

The title compound, N-(2,2,2–tri­chloro-1-hydroxy­ethoxy)­piperidine, C7H12Cl3­NO2, contains a six-membered piperidine ring with a chair conformation. The triclinic unit cell contains two independent pairs of mol­ecules, with the mol­ecules in each pair linked about centres of symmetry by O—H⋯N hydrogen bonds.

Intramolecular N—H...π(phenyl) and intermolecular C—H...π(phenyl) interactions in 5-amino-4-(4-methoxyphenyl)-2-phenyl-7-piperidino-1,6-naphthyridine-8-carbonitrile--benzene(2/1)

The structure of the title compound, C 27 H 25 N 5 O-0.5C 6 H 6 , has been determined from X-ray diffraction data. The compound crystallizes from benzene in the triclinic system, space group P1, with two molecules in the asymmetric unit. The naphthyridine ring system is almost planar and the six-membered piperidine ring adopts a chair conformation. Intramolecular N-H interactions are observed in the system with an N...π(phenyl centroid) distance of 3.619 (3) A, and C-H...π interactions between the naphthyridine molecule and the solvent are also observed.

Enantiospecific Synthesis of (−)-Slaframine and Related Hydroxylated Indolizidines. Utilization of a Nucleophilic Alaninol Synthon Derived from Serine1

A general methodology for the synthesis of indolizidine alkaloids δ-coniceine (12), 1-hydroxyindolizidine (20), desacetoxy slaframine (24), slaframine (34), and an analogue (37) has been developed. This convergent approach utilizes the available chirality in proline and serine and is conceptually different from other approaches. A highly stereoselective coupling of the prolinals with a nucleophilic alaninol synthon provides the precursors for the key cyclization. A novel thermolytic annulation of an oxazolidinone is the key step in the formation of the six-membered piperidine ring. Further elaboration provides the target natural products 24, 34, and 37 in good overall yields.

5,6,7,8,9,10-Hexahydro-10-hydroxy-5,9-methano-4H-thieno[3,2-c]azonine

The title molecule, C11H15NOS, consists of a seven-membered azepine ring fused to both a five-membered thiophene ring and a six-membered piperidine ring so that a methylene bridge links positions 5 and 9. The thiophene ring is planar, while the azepine ring adopts a pseudo-chair conformation with a pseudo-equatorial hydroxy group at C10. The 1,3-fused piperidine ring also possesses a chair conformation.

4,6,7,8,9,9a-Hexahydro-11H-pyrido[1,2-a]thieno[2,3-e][1,3]diazepin-11(10H)-one

The title molecule (C 11 H 14 N 2 OS) consists of a seven-membered diazepine ring fused to a five-membered thiophene ring and a six-membered piperidine ring. The thiophene ring is planar while the diazepine moiety adopts a half-chair conformation; the cis-fused piperidine ring possesses a chair conformation. The least-squares plane of the thiophene and the diazepine rings makes an angle of about 102° with the best plane of the piperidine moiety

A novel spin probe with long life in vivo for ESR imaging.

A dextran-bonded nitroxide radical (TEMPO-DX) was synthesized to obtain a radical with long life in vivo for ESR imaging. TEMPO-DX was injected intravenously into a rat tail vein and the decrease in ESR intensity in the collected, circulating blood was followed. The result showed that the half life of TEMPO-DX in vivo was 30 min, the longest value reported so far and more than 30 times longer than the corresponding radicals of the six-membered piperidine ring, which means that the bonding of a radical to the polymer greatly prolonged life. The stabilities of TEMPO-DX against the reduction with L-ascorbic acid and the rat liver homogenate were also examined and compared with those of the 3-carbamoyl-2,2,5,5-tetramethylpyrolidin-1-yloxy (CPROXYL) known as a radical stable in vivo. TEMPO-DX was shown not to be as stable as CPROXYL, thus in vivo stability of TEMPO-DX arises from the fact that it is slowly absorbed into the tissues where the radicals are quenched. An ESR image of the mouse head domain was obtained only by an intravenous injection of TEMPO-DX solution into the tail vein.

Crystal and molecular structure of methylene bis(piperidine-dithiocarbamate), C13H22N2S4

Reaction of anhydrous sodium piperidine dithiocarbamate with methylene chloride yields methylene bis(piperidine dithiocarbamate). The crystals, C13H22N2S4 (M=334.57), are monoclinic with space group $${{P_{2_| } } \mathord{\left/ {\vphantom {{P_{2_| } } n}} \right. \kern-\nulldelimiterspace} n}$$ ,a=6.421(3),b=29.321(7),c=9.022(4)A,β=109.05(3)°,V=1605.6 A3,Z=4,D c =1.384 g cm−3,F(000)=712,T=295°K λ(Mo-Kα)=0.71069 A,μ=5.62 cm−1 andR=0.032 for 1734 reflections. The molecular structure shows that the methylenic group is bonded to two planar moieties at distances of 1.782(3) and 1.803(3)A with an S-CH2-S angle of 114.7(2)°. The configuration about each N atom is planar rather than pyramidal. The two C-N bond lengths adjacent to the C=S bonds are both very short 1.330(4) and 1.336(4) A indicating the influence of the C=S bond on C-N bond lengths. The six-membered piperidine ring has a classical chair conformation with average C-C distance of 1.511 (5)A.