FLUPYR · Synthesis of Fluorinated Pyrrolidines

Synthesis of fluorinated pyrrolidines

Fluorinated nitrogen-containing heterocycles are key targets for the pharma- and agrochemical industry. Considering the poor accessibility of these compounds, we propose to explore new synthetic methodologies to access fluoropyrrolidines. In the light of the abundant literature on electrophile-induced cyclisations, a very attractive route to access fluoro nitrogen-containing heterocycles is the electrophilic fluorocyclisation of alkenes bearing a pending nucleophilic amino group. However, this route is currently not possible because unactivated alkenes do not react with existing (easy to handle) electrophilic fluorinating N-F reagents. In this project, we propose several solutions to this problem based on the use of a silyl group to temporarily activate the alkene toward electrophilic fluorination or the enhanced reactivity of some heterocyles bearing and heteroatom that will play the role of an activator of the double bond. The first approach features a key electrophilic fluorocyclisation of various allylsilanes bearing a pending nucleophilic tosylated amino group. This reaction generates silylated fluoropyrrolidines which upon oxidative cleavage release the desired fluorinated pyrrolidines. This route presents the advantage to allow for modulation of the stereochemistry of the targets as a function of the E/Z geometry of the allylsilanes. On the other hand, the second approach will provide us with very useful fluorinated tricyclic structures that can be applied to the preparation of future more elaborated targets either natural products or drugs. Some silyated alkenes were prepared in order to perform the electrophilic fluorocyclisation to obtain the fluorintated pyrrolidines In general, reactions worked affording the desired cyclised products with moderate yields. In some cases, some by-products were isolated as a result of a fluorodesilylation reaction which was supposed to be minimised by the use of bulkier substituents for the silicon group like isopropyl or diisopropyl tolyl but with no success. Pleasingly, the diastereomeric ratio of the product mirrored the starting E/Z ratio of the starting protected amines. After these preliminary results, we explored the possibility to carry out this particular fluorocyclisation reaction asymmetrically. It has been previously described in our group, 1 the asymmetric fluorodesilylation of trialkylsilanes using a combination of cinchona alkaloids and selectfluor with very good results. Moreover, Shibata and co workers 2 reported the same transformation but using this alkaloids catalytically. With this information in hand, we tried to perform the fluorocyclisation reaction using this clever transfer of fluorine from an achiral source, selectfluor, to the chiral one, cinchona alkaloid, and finally to our substrate. Unfortunately, all attempts carried out were not successful due to a lack of reactivity of the starting materials. Only when the alkene activity was enhanced by the use of a silicon atom and a phenyl ring the asymmetric version of the reaction was achieved with a 43 % ee and a 70 % yield and to the best of our knowledge it is the first example in the literature (Angew. Chem. Int. Ed. 2009, 48, 7083-7086). However, as we have encountered a general lack of reactivity in the previous substrates, we decided to dramatically change the point of view taking into account the reaction mechanism. We envisage the new substrates to deal with from now on taking advantage of the double activation of the alkene by the phenyl ring and the heteroatom included in the heterocyclic ring of the indole nucleus.

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