3-Lithioquinuclidin-2-ene: A novel intermediate for the synthesis of muscarinic agonists and antagonists

Nordvall, Gunnar; Sundquist, Staffan; Nilvebrant, Lisbeth; Hacksell, Uli

doi:10.1016/s0960-894x(01)80824-6

Cited by 14 publications

(5 citation statements)

References 15 publications

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“…Substituted quinuclidines possess interesting and diverse pharmacological activities as the quinuclidine nucleus has been found to be a good mimic for the quaternary nitrogen in acetylcholine [1], The synthetic methods most frequently used for the preparation of quinuclidine-based pharmaceutical lead structures have started from quinuclidin-3-one [2,3]. In the course of our investigations on the synthesis of chiral quinuclidinone analogs the title compound has been prepared from Quincoridine® [4] in enantiopure form following an eight step pathway [5].…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of (1S,2R,4S)-2-bromomethyl-1-azabicyclo[2.2.2]·octan-5-one, C8H12BrNO

Wartchow

Frackenpohl

Hoffmann

2000

Zeitschrift Für Kristallographie - New Crystal Structures

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C 8 Hi 2 BrNO, orthorhombic, P2\2\2] (No. 19), a = 7.002(1) Ä, b = 7.432(1) Ä, c = 16.762(2) Ä, V=872.3 Ä 3 ,Z = 4, R & (F) = 0.031, wR m (F 2 ) = 0.050, T= 300 K. Source of materialMethanesulfonyl chloride (0.39 ml, 5.0 mmol) was added to (lS,2Ä,4S)-2-hydroxymethyl-l-azabicyclo[2.2.2]octan-5-one (600 mg, 3.9 mmol) and Et3N (1.08 ml, 7.7 mmol) in absolute CH2CI2 (10 ml) at 273 K. The reaction mixture was stirred for 10 h at room temperature, diluted with CH2CI2 and extracted with saturated aqueous NaHC03. The organic layer was dried, the solvent evaporated and the crude product (83 %,748 mg,3.21 mmol) dissolved in abs. dioxan (5 ml). Powdered lithium bromide (838 mg, 9.64 mmol, 3.0 eq) was added and the mixture was refluxed for 24 h at 383 K. After addition of saturated aqueous NaHCC>3 the aqueous layer was extracted with CH2CI2, and the combined organic layer dried (MgSCU) and evaporated. Purification by chromatography (EtOAc / MeOH 20:1) furnished the desired brominated ketone which was recrystallized from MTBE / acetone. Experimental detailsCompleteness of Laue data set in class mmm 100%, but Friedel pairs kept separate in the refinement. The empirical absorption corerection was based on a function of the mean intensity of the imaging plate versus angle φ improving the Rint from 0.201 to 0.076. A spherical absorption correction with μ-r = 0.34 was applied too. The Flack parameter was found to be -0.01(2). DiscussionSubstituted quinuclidines possess interesting and diverse pharmacological activities as the quinuclidine nucleus has been found to be a good mimic for the quaternary nitrogen in acetylcholine [1], The synthetic methods most frequently used for the preparation of quinuclidine-based pharmaceutical lead structures have started from quinuclidin-3-one [2, 3]. In the course of our investigations on the synthesis of chiral quinuclidinone analogs the title compound has been prepared from Quincoridine® [4] in enantiopure form following an eight step pathway [5]. Because of their low molecular weight and their compact azabicyclic structure quincoridine-derivatives are of general interest [6,7]. Oxidative degradation of the vinylic side chain of quincoridine was carried out by double bond shift, 1,2-dihydroxylation and subsequent diol cleavage. O-Mesylation of resulting (15,2/f,4S)-2-hydroxymethyl-l-azabicyclo[2.2.2]octan-5-one followed by LiBr-promoted SN2 displacement furnished the desired γ-amino δ-bromo ketone of which we present the crystal structure. (15,2if,45)-2-Bromomethyl-l-azabicyclo[2.2.2]-octan-5-one contains a prochiral carbonyl group and three stereogenic centres including the chiral 5-configurated bridgehead nitrogen. The analysis of N,C-bond angles shows a less developed pyramidalization of the bridgehead nitrogen than in 10,11-didehydroquincorine and -quincoridine [8,9,10]. Table 1. Data collection and handling. Crystal: Wavelength: μ: Diffractometer, scan mode: 20max: N(hkl)measured, N(hkl)u"ique: Criterion for I 0 bs, N(hkljp;. N(param) rermed: Programs: colourless plate II (100), size 0.06...

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Section: Discussionmentioning

confidence: 99%

Crystal structure of (1S,2R,4S)-2-bromomethyl-1-azabicyclo[2.2.2]·octan-5-one, C8H12BrNO

Wartchow

Frackenpohl

Hoffmann

2000

Zeitschrift Für Kristallographie - New Crystal Structures

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“…A mixture of 5-bromo-3-furancarbonitrile (13) (105 mg, 0.61 mmol) and Pd(PPh3)4 (70 mg, 0.061 mmol) in DMF (3 mL) was stirred at 100 °C. A solution of 3-(tributylstannyl)quinuclidin-2-ene ( 19) 18 (403 mg, 1.01 mmol) in DMF (1 mL) was added to the reaction mixture after 5 min. The mixture was heated at 100 °C for 48 h in a sealed flask, diluted with dioxane, filtered through a pad of Celite, and concentrated in vacuo.…”

Section: Methods Iiib 3-(5-methylfuran-2-yl)quinuclidin-3-ol Fumarate...mentioning

confidence: 99%

“…i Prepared according the literature procedure, ref 7. j Lit. 7 18 and the appropriate bromofuran derivatives produced amides (37)(38)(39), esters (40)(41)(42), and nitriles (44 and 45) (method VA-C; Scheme 5). In certain reactions, addition of silver(I) oxide (40) 19,20 or cupric oxide 20 (method VB) increased the yields and slightly reduced the reaction times of the cross-coupling reactions.…”

Section: Chemistrymentioning

confidence: 99%

Antimuscarinic 3-(2-Furanyl)quinuclidin-2-ene Derivatives: Synthesis and Structure−Activity Relationships

et al. 1997

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A series of 25 derivatives of the muscarinic antagonist 3-(2-furanyl)quinuclidin-2-ene (4) was synthesized and evaluated for muscarinic and antimuscarinic properties. Substitution at all three positions of the furan ring has been investigated. The affinities of the new compounds were determined by competition experiments in homogenates of cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs using (-)-[3H]-3-quinuclidinyl benzilate as the radioligand, and the antimuscarinic potency was determined in a functional assay on isolated guinea pig urinary bladder using carbachol as the agonist. Several of the novel derivatives displayed high muscarinic affinities. Whereas the affinity of lead compound 4 for cortical muscarinic receptors is moderate (Ki = 300 nM), it is much higher for the 5-methyl (48; Ki = 12 nM), 5-ethyl (52; Ki = 7.4 nM), 5-bromo (33; Ki = 6.4 nM), and 3-phenyl (49; Ki = 2.8 nM) substituted derivatives. The substituent-induced increases in affinity do not appear to be additive as a 5-bromo-3-phenyl (54), and a 5-methyl-3-phenyl (55) substitution pattern only slightly increases affinity (Ki = 1.55 and 2.39 nM, respectively). The conformational preferences of the 3-phenyl (49) and 5-phenyl (51) derivatives were studied by X-ray crystallography and molecular mechanics calculations. Because of the observed high affinity of 49, a series of 16 meta- and para-substituted analogues of 49 was synthesized and tested. The m-hydroxy derivative (68) exhibited more than 10-fold improvement in affinity as compared to 49. The structure-activity relationships of the new series are well described with QSAR and CoMFA models.

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“…3-Lithioquinuclidin-2ene was generated as a novel nucleophilic intermediate for the synthesis of muscarinic agonists and antagonists, which were trapped with aldehydes and ketones (5 examples). 101 The synthesized compounds together with 149 were screened for their affinities against muscarinic receptors and low affinities were identified.…”

Section: Scheme 24 Synthesis Of L-cysteine Derivativesmentioning

confidence: 99%

The Dibenzosuberenone Scaffold as a Privileged Substructure: From Synthesis to Application

2017

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Numerous studies on dibenzosuberenones, especially on 5-dibenzosuberenones, have emerged in recent years. This review focuses on the chemistry of dibenzosuberenones, including their synthesis and applications, which are currently used as tools by the synthetic and biological communities.1 Introduction2 5-Dibenzosuberenone (5H-Dibenzo[a,d]cyclohepten-5-one)2.1 Synthesis of 5-Dibenzosuberenone2.2 Reactions of 5-Dibenzosuberenone3 5H-Dibenzo[a,c]cyclohepten-5-one3.1 Synthesis of 5H-Dibenzo[a,c]cyclohepten-5-one3.2 Reactions of 5H-Dibenzo[a,c]cyclohepten-5-one4 6H-Dibenzo[a,c]cyclohepten-6-one and 10H-Dibenzo[a,d]cyclohepten-10-one4.1 Generation and Trapping of 6H-Dibenzo[a,c]cyclohepten-6-one and 10H-Dibenzo[a,d]cyclohepten-10-one5 Dibenzocycloheptenediones5.1 Synthesis of Dibenzocycloheptenediones5.2 Reactions of Dibenzocycloheptenediones6 Conclusion

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3-Lithioquinuclidin-2-ene: A novel intermediate for the synthesis of muscarinic agonists and antagonists

Cited by 14 publications

References 15 publications

Crystal structure of (1S,2R,4S)-2-bromomethyl-1-azabicyclo[2.2.2]·octan-5-one, C8H12BrNO

Crystal structure of (1S,2R,4S)-2-bromomethyl-1-azabicyclo[2.2.2]·octan-5-one, C8H12BrNO

Antimuscarinic 3-(2-Furanyl)quinuclidin-2-ene Derivatives: Synthesis and Structure−Activity Relationships

The Dibenzosuberenone Scaffold as a Privileged Substructure: From Synthesis to Application

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