Potassium ions, effect intramolecular

The intramolecular aza Diels-Alder cycloaddition is also a valuable tool for the synthesis of alkaloids as demonstrated by the stereocontrolled synthesis of ( )-lepadifor-mine 137 (Scheme 41.29). This tricyclic alkaloid has been isolated from several species of Clavenia and Polycitoridae sea squirts and is moderately cytotoxic toward various tumor cell lines and effective to block potassium ion channels. Initial attempts to perform the aza Diels-Alder reaction with the racemic imino-diene t-butyl ester 134 in toluene at temperatures up to 165°C did not lead to the observation of any cycloadducts but to double bonds isomerization products. The corresponding free carboxylic acid only suffered decarboxylation. The addition of trifluoroacetic acid to generate an imminium species was also unsuccessful. 

Intramolecular electrophilic substitution of a pyrrole by a nitrile under acidic conditions generates a dihydropyrrolizine after hydrolysis of the iminium ion intermediate. This type of cyclization has received considerable attention. Braunholtz et al. demonstrated that improved yields (70%) in the cyclization step were effected with a melt of the chlorides of aluminum, potassium, and sodium, but the conditions were extremely critical. Meinwald and Meinwald used this method for their preparation of the dihydropyrrolizinone (50). This confirmed the structure of the major component of the hairpencil secretion of the male tropical butterfly Lycorea ceres ceres. None of the isomeric 2-methyl compound was formed during this synthesis [Eq. (17)]. It is suggested that the 3-methyl group of pyrrole activates the adjacent 2-position sufficiently to promote regiospecific intramolecular electrophilic substitution. 

Changing the metal carbonate also affected intramolecular cyclization to form the 10-membered macrocycle with three nitrogen atoms in the ring. Isolated yields were 0%, 21%, 75%, 75%, and 0% using lithium, sodium, potassium, cesium, and silver ions, respectively (Chavez and Sherry, 1989). This indicates that potassium and cesium carbonates are excellent bases for the deprotonation of the tosylamides in DMF and that a template effect is not the most important factor in this reaction. 

The yV-alkyl-substituted azadiol was treated with an equimolar amount of tosyl chloride and excess alkali metal hydroxide in an aprotic solvent (powdered NaOH, dioxane, room temperature, 3 hr) to give a 60% yield of the monoaza-crown (Kuo et al., 1978). Template effects are important in this cyclization reaction, so sodium hydroxide was used for aza-15-crown-5 and potassium hydroxide for aza-18-crown-6. The intramolecular ring-closure process is the result of the initial formation of a tosylate by the reaction of one alkoxide anion with tosyl chloride followed by displacement of the tosylate leaving group by the second alkoxide anion. The pure monoaza-crowns were isolated from their metal ion complexes by thermolysis under reduced pressure (Kuo et al., 1980). 

Photoswitching of the bis(crown) configuration by the photochromic diarylethene has also been demonstrated with a series of bis(benzocrown)-substituted dithienylperfluo-rocyclopentenes reported by Takeshita and Irie. In the benzo-15-crown-5-containing diarylethene, the open form with two crown moieties effectively binds with the potassium and the rubidium ions in an intramolecular sandwich fashion (Figme 46). However, such a binding mode is restricted by the confined conformation in the closed form. 

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