Rings quinuclidine

The first silica-supported CSP with a cinchona alkaloid-derived chromatographic ligand was described by Rosini et al. [20]. The native cinchona alkaloids quinine and quinidine were immobilized via a spacer at the vinyl group of the quinuclidine ring. A number of distinct cinchona alkaloid-based CSPs were subsequently developed by various groups, including derivatives with free C9-hydroxyl group [17,21-27] or esterified C9-hydroxyl [28,29]. All of these CSPs suffered from low enantiose-lectivities, narrow application spectra, and partly limited stability (e.g., acetylated phases). 

Another issue is validated by the presented X-ray structures This is related to the pseudoenantiomeric character of the tert-butylcarbamates of quinine and quinidine (Figure 1.19a,b). Except for the vinyl on the backside of the quinuclidine ring, both the complexes that are actually diastereomeric to each other actually look like mirror images with regard to conformations and intermolecular interactions as well so that the pseudoenantiomeric experimental chromatographic behavior for DNB-Leu can be rationalized also on the basis of their X-ray crystal structures. 

A cursory examination of the Cinchona catalysts used in O Donnell-type alkylation [90] of methyl (diphenylimino)glycinate (Appendix 7.A) reveals that only minor modifications to the Cinchona scaffold are required for the synthesis of a catalyst the 8-substituent on the quinuclidine core may either be a vinyl group (as in the parent alkaloids, quinine and quinidine) or can be an ethyl substituent, introduced by hydrogenation. The quinoline system at the 2-position ofthe quinuclidine ring can be unsubstituted if the catalyst is derived from quinine or quinidine, but can contain a 6-methoxy group ifit is derived from cinchonine or cinchonidine. The 3-position ofthe quinuclidine ring may contain either a hydroxy group or else a vinyloxy or benzyloxy... 

Quinuclidine (l-azabicyclo[2.2.2]octane) is a heterocyclic system which is part of the structure of a number of natural physiologically active compounds and synthetic drugs.1 Among the natural alkaloids, the following quinoline and indole derivatives contain the quinuclidine ring cinchonine, cinchonamine (alkaloids of Cinchona species),8-12... 

The main attention of the present review is concentrated on the general chemical properties and peculiarities of quinuclidine derivatives, methods for building up quinuclidine systems (methods for quinuclidine ring closure), methods for substituent introduction in quinuclidine molecules, and biological properties of quinuclidine derivatives. 

Quinuclidine (1) is a saturated bicyclic system with a bridgehead nitrogen atom. It has, in contrast to tertiary aliphatic amines and -substituted piperidines, a rigid structure. The atoms forming the quinuclidine ring are incapable of changing their relative positions by rotation around bond axes. These bond axes are included in the bicyclic system with each ring in the boat form. 

Some interesting results were obtained by comparative investigation of the infrared (IR) spectra of quinuclidine, -substituted piperidines, and piperazines.27 Monocyclic compounds gave at 2700-2800 cm-1 characteristic absorption bonds attributable to interaction between the nitrogen lone-pair electrons and the neighboring axial CH bonds. Quinuclidine does not absorb in this region, probably because of the absenceof such interaction in the quinuclidine ring. There are absorption bands characteristic of quinuclidine at 2430, 2915, and 3405 cm"1.28... 

After many years of investigation a great number of quinuclidine derivatives have been synthesized. Synthetic methods described in the literature for the preparation of quinuclidine and its derivatives and methods for building up quinuclidine bicyclic systems are separated in this review from those for substituent introduction into preformed quinuclidine rings. Reactions involving quinuclidine ring expansion with formation of derivatives of other 1-azabicycloalkanes are gathered into a special section. 

Quinuclidine ring formation starting from piperidine derivatives is carried out usually by (a) intramolecular alkylation or acylation or (b) intramolecular Dieckmann condensation. 

Rabe69,70 and others,71-75 carrying out syntheses of quinine analogs and isomers, used this method for building up the quinuclidine ring. In these cases the starting compounds were haloketone deriva-... 

It was found78 that quinuclidine ring closure takes place only if both the 4-bromoacetyl group and the nitrogen lone-pair electrons are in the axial position. Formation of this conformation in a transition state is facilitated by the introduction of bulky substituents at position 4 and at the piperidine nitrogen. Attempts to cyclize compounds without such bulky substituents (e.g., 4-bromoacetyl-piperidine) fail.78... 

In contrast to the cyclization of jV-halogeno-4-(oxoalkyl)-piperidines, closure of the quinuclidine ring starting from 4-alkyl-JV-halogenopiperidines met with difficulties. Application of the Hofmann-Loeffler reaction to 4-alkyl-i r-chloropiperidines by Wawzonek, LukeS, Ferles, and co-workers 83-88 led to a mixture of... 

Koenigs method for quinuclidine ring closure was applied by Rubtsov90,91 and Grob 92,93 to the intramolecular alkylation of a-halogeno acids and esters of piperidines. Rubtsov and Dorokhova 90 developed a simple five-step method for the synthesis of quinuclidine-2-carboxylic acid (39). 

Intramolecular acylation in piperidines also is used to build up a quinuclidine ring. By this method Yakhontov and Rubtsov,43 and later Pracejus,44,45,101 synthesized quinuclidin-2-one (3) and its 6,6-dimethyl and 6,6,7-trimethyl derivatives, starting from the corresponding acid chlorides, by the action of potassium carbonate or tertiary amines. 

A special case in quinuclidine ring closure is the synthesis of quinuclidine compounds by intramolecular aldol condensation used for the preparation of 4-acetylquinuclidin-3-ol (53) from 4-acetyl-l-(2, 2 -diethoxyethyl)piperidine (54).77... 

These methods were used for the preparation of quinuclidine,301114 117 2-,23,24 g 24 ancj 4-alkylquinuclidines,25 and quinuclidine-2-carboxylic acid.118 Prelog s attempts to prepare quinine analogs by quinuclidine ring closure starting from the tribromoalkyl derivative (57) failed.119... 

B. Methods op Introducing Substituents into the Quinuclidine Ring... 

For this reason reactive groups are usually introduced before quinuclidine ring closure and various transformations are effected afterward. The carboxyl and carbonyl derivatives, e.g., quinuclidine-2-carboxylic acid, quinuclidin-3-one, and so on, are useful compounds containing such functional groups. Nearly all substituted quinuclidines were obtained from their carboxylic acids and carbonyl derivatives by common synthetic methods. 

At the present time quinuclidine 2-,90,118 3-,121 122 and 4-mono-carboxylic acids 97,100 are known as well as quinuclidine-2- carboxylic acids with various substituents at positions 395,108 or 5 99,110 and quinuclidine-3-carboxylic acids substituted at positions 2123 or 6.U1 Only one compound with two carboxylic groups in the quinuclidine ring, the 2,3-dicarboxylic acid, has been described.109 Homologs of many quinuclidinecarboxylic acids have been prepared, among which quinuclidine-3-acetic124-127 and 3-carboxymethylquinuclidine-2-carboxylic acids94 are interesting for subsequent transformations. 

An interesting method for the introduction of substituents into the 2-position of the quinuclidine ring starting from 3-substituted A2-dehydroquinuclidines (126) has been described.47 By the reaction of methyl J2-dehydroquinuclidine-3-carboxylate (130) with iso-propylmagnesium bromide, 1,4-addition with formation of 2-iso-propyl-3-methoxycarbonylquinuclidine (131) took place instead of a sterically hindered Grignard reaction at the alkoxycarbonyl group. 

Condensed heterocyclic systems containing a quinuclidine ring have been synthesized from ethyl 3-oxoquinuclidine-2-carboxylate (99), A 2-dehydroquinuclidine (4), and methyl J2-dehydroquinuclidine-3-carboxylate pyrazolo-, oxazolo-, triazolo-, pyrimido-, andpyridazino-quinuclidines have been made171 (Scheme 6). 

Investigation of the biological properties of quinuclidine derivatives has proceeded mainly in two directions (1) natural alkaloids, their synthetic analogs, and reaction products and (2) the pharmacological actions of compounds containing a quinuclidine ring. This review deals with the second aspect only reference has already been made to several reviews devoted to the quinuclidine alkaloids. 

It should be noticed that the activity of secondary amines like 2-benzylaminomethyl-3-(j8-benzylaminoethyl)quinuclidine (151) depends on the presence of the bicyclic quinuclidine system, in contrast to the similar action of aminoalkyl quinuclidinecarboxylate quaternary salts. In this case transition to compounds without a quinuclidine ring removes their action on ganglions of the sympathetic and parasympathetic nervous systems. 

Cinchonine contains five chirality centres. Note that because of the rigid structure of the molecule, the nitrogen atom in the quinuclidine ring is also a chirality centre and has the S configuration because the group of lowest priority (the unshared electron pair) is directed towards the observer. 

Dehydrogenation of cinchonamine with selenium or palladium-charcoal resulted in fission of the quinuclidine ring and the isolation of dehydrocinchonamine (V), mp 203°, whose spectral characteristics and p/fa were in agreement with its formulation. From the selenium dehydrogenation products, a trace of a crystalline compound was also obtained which, from a single ultimate analysis and UV-spectrum, is considered to be IV (10). 

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