Quinuclidine derivatives

A -bromo derivative (37.1.1.45), which is reacted with sodium ethoxide realizing the key moment of the synthesis—the transformation of the piperidine derivative to a quinuclidine derivative (37.1.1.46). Reducing the keto group in this molecule with lithium aluminum hydride gives the desired quinine (37.1.1.47) [17-22]. 

Figure 6.9 Bifunctional 3-amino quinuclidine derivatives 30 and 31 and DABCO probed in the MBH reaction between methyl acrylate and o-chlorobenzaldehyde.

Pilocarpine has long been used to increase salivary secretion. Cevimeline, a quinuclidine derivative of acetylcholine, is a new direct-acting muscarinic agonist used for the treatment of dry mouth associated with Sjogren s syndrome and that caused by radiation damage of the salivary glands. 

The increase in heart muscle excitability induced by some natural quinuclidine derivatives (quinidine, ajmaline), suggesting pharmacological activity of some synthetic quinuclidine compounds and the possibility of using quinuclidines as catalysts for production of polymers,17 stimulated further interest in the ring system. 

There are several specialized reviews8-12,21 pertaining to the natural quinuclidine derivatives, in particular to the history of their discovery, practical uses, natural sources, methods of analysis, extraction and isolation, and structural determination, as well as their stereochemistry and chemical reactions. Such material is therefore excluded from this chapter. 

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. 

Unsaturated quinuclidine derivatives, e.g., A 2-dehydroquinuclidine (4)47,48 an(j its 2-substituted derivatives,40 and quinuclidines with a semicyclic double bond at position 2 (5),49 also display some unusual properties, behaving differently from common tertiary enamines. For example, dehydroquinuclidine does not have the characteristic absorption for enamines at 230 mp, and is not hydrolyzed under mild conditions by dilute acids. 

Fragmentation of quinuclidine derivatives,50-57 in contrast to the same process with aliphatic and bicyclic compounds without nitrogen, gives only one product. The solvolysis of 2-bromo-2-(quinuclidin-3-yl)propane (6) has a stepwise mechanism,50-57 and the degradation of 4-bromoquinuclidine (7) is synchronous.50 53... 

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. 

Quinotoxine (31) yielded A7-bromoquinotoxine (32), on treatment with sodium hypobromite, which by reaction with alkoxide was converted into the corresponding quinuclidine derivative—quininone... 

Comparison of the synthetic methods for the preparation of quinuclidine derivative starting from piperidines and tribromo-alkanes and dibromoalkylamines shows that in some cases Prelog s scheme gives better results, while in others intramolecular alkylation, acylation, or Dieckmann cyclization are more useful. For example, the best yield (37%) of 2-methylquinuclidine (12)23 and the only known 3,5-disubstituted quinuclidine, 3,5-dimethylquinuclidine,120 (58) were synthesized by Prelog s method. 

However, the preparation of quinuclidine derivatives starting from tribromoalkanes and dibromoalkylamines may be difficult because the starting compounds require multistage syntheses resulting in poor yields. Prelog s scheme is also less useful for the formation of quinuclidine derivatives with functional groups, e.g., quinuclidine-2-carboxylic acid (39),118 which requires twelve steps with overall yield of only 4%. In the five-step synthesis starting from y-picoline the yield is 30%.00... 

One can divide syntheses of quinuclidine derivatives from quinuclidinecarboxylic acids into three main groups (a) reactions without any changes in the carbon skeleton, (b) reactions including fission of quinuclidine carbon-carbon bonds, and (c) processes extending the carbon chain. 

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 is to be expected that further investigations will reveal more completely the relationship between the pharmacological effects and the chemical structure of quinuclidine derivatives and their conformation, the character of the lone-pair electrons at the nitrogen atom, and so on, and that this will lead to the discovery of new pharmacologically active compounds. 

Quinuclidine derivatives, synthetic chemistry, and pharmacology of 83MI4. 

WAL 2014) is a quinuclidine derivative, a (M,) muscarinic CHOLINOCEPTOR AGONIST. It has been investigated for possible use in cholinergic-replacement therapy for Alzheimer s. 

The (ester) hydrolysis of BZ over a range of conditions of pH and temperature has been investigated (Hull et ak, 1979). Bromocresol Green forms a colored complex with 3-quinuclidmyl esters of hydroxyacetic acids, which has been used in the spectrophotometric analysis of mixtures containing these esters and 3-quinucfidinol (Stan kopv et ak, 1997). Analysis of the mass spectra of a number of quinuclidine derivatives is available (Vincze et ak, 1980). BZ has been safely destroyed pyrolytically (Jensen, 1991). 

Some other claims made for these quinuclidine derivatives are anti-Parkinson activity, antiarrhythmic and local anaesthetic effects, antimalarial activity, and central stimulation, but none of these properties has led to a therapeutic preparation. 

Iso-quinuclidine derivatives have not been investigated in detail. In 1958, a number of iso-quinuclidines were screened without success and later investigations did not reveal any activities suitable for human therapy. 

The synthetic investigations related to the quinuclidine moiety had as their first objectives the synthesis of simple quinuclidine derivatives and degradation products from the alkaloids. 

Relationships Between the Chemical Structure and Pharmacological Activity in a Series of Synthetic Quinuclidine Derivatives... 

Pharmacological Properties of Quinuclidine Derivatives Relationships between... 

The influence of structural rigidity on the basicity of quinuclidine derivatives is shown [21] by comparison of the pKa of the benzo- (and dibenzo-) quinuclidines with those of the structurally similar diethylaniline (pKa 6.56) [19] and diphenylamine (pKa 0.79) [19]. 

Unsaturated quinuclidine derivatives-Zl -dehydroquinuclidines (VII) [37, 38] together with quinuclidines with a semi-cychc double bond at position-2 (VIII) [39] - also have some chemical peculiarities. These compounds, as can be expected from their structure, have some properties which differ from those of common tertiary a-vinylamines. For example dehydroquinuclidines do not have the characteristic enamine absorption at 230 nm and cannot be hydrolysed under mild conditions with dilute acids. 

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