Other Fluorinated Alkaloids

Kita anployed a hypervalent iodine species for the oxidative cyclization of phenol 310 as shown in Equation 12.54-1, Scheme 12.54 [190]. When allowed to react with phenyliodinedll) bisftrifluoroacetate) (FIFA), 310 delivered the desired galantamine skeleton in 40% yield. The cyclization most likely proceeds via the initial reaction of the phenolic oxygen with the hypervalent iodine reagent and subsequent nucleophilic attack of the second electron-rich aromatic ring onto the intermediary formed cation radical intermediate. Kita and coworkers outlined the importance of the fluorinated solvent. When carried out in benzene or dichloromethane, the desired product was not formed. A similar oxidative coupling protocol has been successfully employed by the authors for other Amaryllidaceae alkaloids [191]. 

Newer approaches make use of derivatives of quinuclidinc alkaloids, such as quinine. The quinine derivative is first converted into the fluorination reagent by Selectfluor, in one-pot procedure, and in a second step reacted with the desired substrate (Scheme 2.93). The enantiomeric excesses achieved with this type of reagent are higher than for the N-fluoroimides but still below those of other enantioselec-tive reactions. 

Whereas closely related catalysts allowed the Friedel-Crafts-type additions to be expanded to other carbonyl acceptors, such as isatins, the same reactions depicted in Schemes 14.17 and 14.18 have also been achieved in an environmentally more benign solvent, namely Solkane 365 mfc, a liquid hydrofluorocarbon (CF3CH2CF2CH3) that is nontoxic with no impact on the ozone layer, and is used as an insulating and blowing agent for polyurethane foams. To achieve useful yields and enantioselectivities in this fluorinated reaction medium, perfluorinated CPN and CPD Cinchona alkaloid derivatives, able to dissolve in it, were designed and synthesised by Shibata and coworkers (Figure 14.4). 

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