22232-64-0Relevant academic research and scientific papers
Transition-Metal-Free Multiple Functionalization of Piperidines to 4-Substituted and 3,4-Disubstituted 2-Piperidinones
Chamorro-Arenas, Delfino,Nolasco-Hernández, Alejandro A.,Fuentes, Lilia,Quintero, Leticia,Sartillo-Piscil, Fernando
, p. 4671 - 4676 (2020/03/10)
Remote and multiple functionalization of piperidines without the use of transition-metal catalysts and elaborate directing groups is one of the major challenges in organic synthesis. Herein is reported an unprecedented two-step protocol that enables the multiple functionalization of piperidines to either 4-substituted or trans-3,4-disubstituted 2-piperidones. First, by exploiting the duality of TEMPO reactivity, which under oxidative and thermal conditions fluctuates between cationic and persistent-radical form, a novel multiple C(sp3)-H oxidation of piperidines to α,β-unsaturated 2-piperidones was developed. Second, the intrinsic low reactivity of the unsaturated piperidones toward conjugated Grignard additions was overcome by using trimethylsilyl chloride (TMSCl) as Lewis acid. Subsequently, conjugated Grignard addition/electrophilic trapping protocol provided substituted 2-piperidone intermediates, some of which were then transformed into pharmaceutical alkaloids.
Direct access to the optically active VAChT inhibitor vesamicol and its analogues via the asymmetric aminolysis of meso-epoxides with secondary aliphatic amines
Sharma, Arun,Agarwal, Jyoti,Peddinti, Rama Krishna
, p. 1913 - 1920 (2017/03/09)
First highly enantioselective synthesis of biologically important vesamicol, benzovesamicol, and their derivatives was achieved via the desymmetrization of meso-epoxides with secondary aliphatic amines (4-phenylpiperidine derivatives) using a chiral [sale
Reactions of nitrogen nucleophiles with enantiopure cyclohexenyl electrophiles: A stereo- and regio- selective study
Boyd, Derek R.,Sharma, Narain D.,Belhocine, Tayeb,Malone, John F.,McGregor, Stuart T.,Atchison, Jordan,McIntyre, Peter A. B.,Stevenson, Paul J.
, p. 997 - 1008 (2014/01/06)
The reactions of enantiopure cyclohexene epoxides and trans-1,2- bromoacetates, derived from the corresponding substituted benzene cis-dihydrodiol metabolites, with nitrogen nucleophiles, were examined and possible mechanisms proposed. An initial objective was the synthesis of new 1,2-aminoalcohol enantiomers as potential chiral ligands and synthetic scaffolds for library generation. These apparently simple substitution reactions proved to be more complex than initially anticipated and were found to involve a combination of different reaction mechanisms. Allylic trans-1,2-azidohydrins were prepared by Lewis acid-catalysed ring-opening of cyclic vinyl epoxides with sodium azide via an SN2 mechanism. On heating, these trans-1,2-azidohydrins isomerized to the corresponding trans-1,4-azidohydrins via a suprafacial allyl azide [3,3]-sigmatropic rearrangement mechanism. Conversion of a 1,2-azidohydrin to a 1,2-azidoacetate moved the equilibrium position in favour of the 1,4-substitution product. Allylic trans-1,2- bromoacetates reacted with sodium azide at room temperature to give C-2 and C-4 substituted products. A clean inversion of configuration at C-2 was found, as expected, from a concerted SN2-pathway. However, substitution at C-4 was not stereoselective and resulted in mixtures of 1,4-cis and 1,4-trans products. This observation can be rationalized in terms of competitive S N2 and SN2′ reactions allied to a [3,3]-sigmatropic rearrangement. cis-1,2-Azidohydrins and cis-1,2-azidoacetates were much more prone to rearrange than the corresponding trans-isomers. Reaction of the softer tosamide nucleophile with trans-1,2-bromoacetates resulted, predominantly, in C-4 substitution via a syn-SN2′ mechanism. One application of the reaction of secondary amines with allylic cyclohexene epoxides, to give trans-1,2-aminoalcohols, is in the synthesis of the anticholinergic drug vesamicol, via an SN2 mechanism. Copyright 2013 John Wiley & Sons, Ltd. Multiple reaction pathways including SN2, S N2′, and [3,3]-sigmatropic rearrangement mechanisms are required to rationalize the formation of products obtained from the reaction of cyclohexene epoxides and trans-bromoacetates with azide and other nitrogen nucleophiles. Copyright
LIGAND FOR VESICULAR ACETYLCHOLINE TRANSPORTER
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Page/Page column 17, (2008/06/13)
The present invention provides a novel compound represented by the formula (I): wherein R1 and R2 are as defined in the specification, or a salt thereof, which is useful as a reagent (radiotracer) for VAChT mapping and the like, and can be used for positron emission tomography (PET), and a production method of the compound. Moreover, the present invention provides a diagnostic reagent for diagnosing cholinergic neurodegenerative disorders (e.g., Alzheimer's disease, memory disorder, learning disorder, schizophrenia, cognitive dysfunction, hyperactivity disorder, anxiety neurosis, depression, analgia, Parkinson's disease and the like) and the like, which contains the aforementioned compound.
In vitro characterization of radioiodinated (+)-2-[4-(4-iodophenyl) piperidino]cyclohexanol [(+)-pIV] as a sigma-1 receptor ligand
Shiba, Kazuhiro,Ogawa, Kazuma,Mori, Hirofumi
, p. 1095 - 1099 (2007/10/03)
We investigated the binding characteristics of a (+)-enantiomer of radioiodinated 2-[4-(4-iodophenyl)piperidino]cyclohexanol [(+)-[ 125I]pIV], radioiodinated at the para-position of the 4-phenylpiperidine moiety, to sigma receptors (σ-1, σ-2) and to vesicular acetylcholine transporters (VAChT) in membranes of the rat brain and liver. In competitive inhibition studies, (+)-pIV (Ki = 1.30 nM) had more than 10 times higher affinity to the sigma-1 (σ-1) receptor than (+)-pentazocine (Ki = 19.9 nM) or haloperidol (Ki = 13.5 nM) known as sigma ligands. Also, the binding affinity of (+)-pIV for the σ-1 receptor (Ki = 1.30 nM), was about 16 times higher than the sigma-2 (σ-2) receptor (Ki = 20.4 nM). (+)-pIV (Ki = 1260 nM) had a much lower affinity for VAChT than (-)-vesamicol (Ki = 13.0 nM) or (-)-pIV (Ki = 412 nM). (+)-[125I]pIV had low affinity for the dopamine, serotonin, adrenaline, and acetylcholine receptors. Furthermore, in a saturation binding study, (+)-[125I]pIV exhibited a Kd of 6.96 nM with a Bmax of 799 fmol/mg of protein. These results showed that (+)-pIV binds to the σ-1 receptor with greater affinity than sigma receptor ligands such as (+)-pentazocine or haloperidol, and that radioiodinated (+)-pIV is suitable as radiotracer for σ-1 receptor studies in vitro.
Chemoenzymatic preparation of optically active β-amino-cyclohexanols and their application in the enantioselective addition of diethylzinc to benzaldehyde
Gonzalez-Sabin, Javier,Gotor, Vicente,Rebolledo, Francisca
, p. 1335 - 1341 (2007/10/03)
Optically active vesamicol and other trans-2-(N,N-dialkylamino) cyclohexanols have been easily prepared in a two step sequence: opening of the oxirane ring of cyclohexene oxide with a secondary amine and subsequent resolution of the resulting racemic amin
Synthesis, in Vitro Acetylcholine-Storage-Blocking Activities, and Biological Properties of Derivatives and Analogues of trans-2-(4-Phenylpiperidino)cyclohexanol (Vesamicol)
Rogers, Gary A.,Parsons, Stanley M.,Anderson, D. C.,Nilsson, Lena M.,Bahr, Ben A.,et al.
, p. 1217 - 1230 (2007/10/02)
Eighty-four analogues and derivatives of the acetylcholine-storage-blocking drug trans-2-(4-phenylpiperidino)cyclohexanol (vesamicol) were synthesized, and their potencies were evaluated with the acetylcholine active-transport assay utilizing purified synaptic vesicles from Torpedo electric organ.The parent drug exhibits enantioselectivity, with (-)-vesamicol being 25-fold more potent than (+)-vesamicol.The atomic structure and absolute configuration of (+)-vesamicol were determined by X-ray crystallography.The absolute configuration of (-)-vesamicol is 1R,2R.Structure-activity evidence indicates that (-)-vesamicol does not act as an acetylcholine analogue.Alterations to all three rings can have large effects on potency.Unexpectedly, analogues locking the alcohol and ammonium groups trans-diequatorial or trans-diaxial both exhibit good potency.A potent benzovesamicol family has been discovered that is suitable for facile elaboration of the sort useful in affinity labeling and affinity chromatography applications.A good correlation was found between potencies as assessed by the acetylcholine transport assay and LD50 values in mouse.
