Concise synthesis of new bridged-nicotine analogues

Crestey, François; Hooyberghs, Geert; Kristensen, Jesper L.

doi:10.1016/j.tet.2011.12.029

Cited by 11 publications

(8 citation statements)

References 31 publications

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“…It is well-known that strong bases such as lithium amide − or organolithium − abstract protons from azines to give the corresponding organolithium species. It is notable that C–H acidity was calculated and the relationship with regioselectivity was nicely summarized. − For example, Quéguiner and co-workers reported C3-lithiation of 2-methoxypyridine in the presence of a catalytic amount of secondary amine (Scheme ).…”

Section: Deprotonative Metalation Of Azines −mentioning

confidence: 99%

C–H Functionalization of Azines

et al. 2017

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Azines, which are six-membered aromatic compounds containing one or more nitrogen atoms, serve as ubiquitous structural cores of aromatic species with important applications in biological and materials sciences. Among a variety of synthetic approaches toward azines, C-H functionalization represents the most rapid and atom-economical transformation, and it is advantageous for the late-stage functionalization of azine-containing functional molecules. Since azines have several C-H bonds with different reactivities, the development of new reactions that allow for the functionalization of azines in a regioselective fashion has comprised a central issue. This review describes recent advances in the C-H functionalization of azines categorized as follows: (1) SAr reactions, (2) radical reactions, (3) deprotonation/functionalization, and (4) metal-catalyzed reactions.

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Section: Deprotonative Metalation Of Azines −mentioning

confidence: 99%

C–H Functionalization of Azines

et al. 2017

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“…In continuation of that line of thinking we recently reported the synthesis of new bridged-nicotine analogues locked in the “up” position, i.e., compounds rac - 4 and rac - 5 …”

mentioning

confidence: 87%

“…This required an enantioselective Negishi cross-coupling reaction with a 3-bromo-4-chloropyridine giving an enantioenriched version of known intermediate in our previous synthesis of rac-4. 12 The synthesis of (R)-4 using this approach is depicted in Scheme 1. Stoichiometric lithiation of N-Boc-protected pyrrolidine 6 using (−)-sparteine/s-BuLi, subsequent transmetalation with ZnCl 2 , and palladium-catalyzed cross-coupling reaction with 3-bromo-4-chloropyridine at 65°C gave α-arylpyrrolidine 7 in 58% yield.…”

Section: T He Neuronal Nicotinic Acetylcholine Receptors (Nachrs)mentioning

confidence: 99%

“…12 Rigid nicotine analogue 1 was previously shown to be a selective partial agonist of rat α7 receptor, while 3 had no agonist activity at any nAChR of the investigated subtypes, whereas conformational restriction in 2 was reported to attenuate nicotinic activity.…”

mentioning

confidence: 96%

“…Eventually a strategy based on the enantioselective metalation of N -Boc-pyrrolidines − (which has been demonstrated to proceed with a predictable stereo chemical outcome) proved to be fruitful. This required an enantioselective Negishi cross-coupling reaction with a 3-bromo-4-chloropyridine giving an enantioenriched version of known intermediate in our previous synthesis of rac- 4 …”

mentioning

confidence: 99%

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Tying up Nicotine: New Selective Competitive Antagonist of the Neuronal Nicotinic Acetylcholine Receptors

Petersen

Crestey

Jensen

et al. 2015

ACS Med. Chem. Lett.

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Conformational restriction of the pyrrolidine nitrogen in nicotine by the introduction of an ethylene bridge provided a potent and selective antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors. Resolution by chiral SFC, pharmacological characterization of the two enantiomers, and determination of absolute configuration via enantioselective synthesis showed that the pharmacological activity resided almost exclusively in the (R)-enantiomer.KEYWORDS: Bridged-nicotine analogue, nAChRs, selective antagonist, Negishi cross-coupling reaction, oocyte T he neuronal nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop receptor family of ligandgated ion channels. They are assembled by either α-subunits or a combination of α-and β-subunits and play an important role in the peripheral and central nervous systems where they mediate neurotransmission in response to acetylcholine (ACh). 1,2 The involvement of nAChRs in a wide range of disease states as well as psychiatric and neurodegenerative disorders (such as depression, schizophrenia, attention deficit hyperactivity disorder, Alzheimer's and Parkinson's diseases, substance abuse, and pain) has made this class of receptors a highly pursued target for drug discovery. 3−6 Nicotine is the principal psychoactive ingredient in tobacco and acts as a potent agonist of the nAChRs. Structural modifications of nicotine have been the starting point for many drug discovery programs, and the introduction of conformational restraint as in compounds 1, 7,8 2, 9 and 3 10,11 has previously been investigated to probe the different possible conformations of nicotine (see Figure 1). Ligands 1 and 2 lock the pyrrolidine nitrogen in nicotine in the "down" position, whereas compound 3 locks it in the "up" position.In continuation of that line of thinking we recently reported the synthesis of new bridged-nicotine analogues locked in the "up" position, i.e., compounds rac-4 and rac-5. 12 Rigid nicotine analogue 1 was previously shown to be a selective partial agonist of rat α7 receptor, while 3 had no agonist activity at any nAChR of the investigated subtypes, whereas conformational restriction in 2 was reported to attenuate nicotinic activity.Herein we report the pharmacological characterization of the racemic compounds rac-4 and rac-5 at several nAChR subtypes. Furthermore, we describe the resolution of rac-4 by chiral supercritical fluid chromatography (SFC on chiral phase) and determination of absolute configuration of the most potent enantiomer via enantioselective synthesis.As depicted in Table 1, compound rac-5 exhibited low binding affinity at α4β2 nAChRs (K i = 13 μM), while its affinity for other nAChR subtypes was negligible. In contrast, the direct analogue of nicotine, rac-4, was a potent and highly subtype selective ligand for α4β2 receptors in terms of affinity. Compound rac-4 displayed nanomolar affinity (K i = 71 nM) toward the α4β2 nAChR with more than 100-fold selectivity over α4β4, α3β4, and α7 (K i values of 7.2, ∼100, and ∼50...

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A Predictive Model Towards Site‐Selective Metalations of Functionalized Heterocycles, Arenes, Olefins, and Alkanes using TMPZnCl⋅LiCl

et al. 2020

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The development of a predictive model towards site‐selective deprotometalation reactions using TMPZnCl⋅LiCl is reported (TMP=2,2,6,6‐tetramethylpiperidinyl). The pKa values of functionalized N‐, S‐, and O‐heterocycles, arenes, alkenes, or alkanes were calculated and compared to the experimental deprotonation sites. Large overlap (>80 %) between the calculated and empirical deprotonation sites was observed, showing that thermodynamic factors strongly govern the metalation regioselectivity. In the case of olefins, calculated frozen state energies of the deprotonated substrates allowed a more accurate prediction. Additionally, various new N‐heterocycles were analyzed and the metalation regioselectivities rationalized using the predictive model.

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Concise synthesis of new bridged-nicotine analogues

Cited by 11 publications

References 31 publications

C–H Functionalization of Azines

C–H Functionalization of Azines

Tying up Nicotine: New Selective Competitive Antagonist of the Neuronal Nicotinic Acetylcholine Receptors

A Predictive Model Towards Site‐Selective Metalations of Functionalized Heterocycles, Arenes, Olefins, and Alkanes using TMPZnCl⋅LiCl

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