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An efficient three-step synthesis of a novel family of enantiomerically pure isocyanides derived from β3-isocyanopropionic acids was elaborated. Easily available N-formylated α-amino acids were used as starting materials towards this aim. The 3-step sequence (Arndt-Eistert reaction-Wolff rearrangement-dehydration) resulted in target isonitriles in good yields (up to 97%). As a result a new family of isocyanides bearing a fragment of β3-amino acids with different functional groups (amides, esters and short peptides) was obtained. It was demonstrated that these new isonitriles can be used in the Ugi and Passerini reactions to prepare short peptides and depsipeptides having a β-amino acid fragment incorporated.

The Ugi-click-strategy was employed for the synthesis of 12–28 membered 1,2,3-triazole derived macrocyclic peptidomimetics. The Ugi reaction with acid components bearing acetylenic fragments and azidoisocyanides provided the corresponding peptidomimetics in up to 97% isolated yield. The subsequent CuAAC click reaction with these bifunctional substrates containing both acetylene and azide groups was investigated to reveal the influence of the structure of Ugi products on the direction of the click-cyclization. It was demonstrated that this approach allows efficient synthesis of either monomeric (12- and 13-membered) or dimeric (24-, 26- and 28-membered) macrocycles prepared in up to 85% yield. The scope and limitations of this method are discussed.

Enantioselective synthesis of α-perfluoroalkylated cyclic amino acids and their derivatives was elaborated using the organocatalytic Strecker reaction with 5-7 membered cyclic ketimines. The prepared amino nitriles could be transformed into chiral Rf-prolines and their 6,7-membered homologues as well as their corresponding amides and diamines (yields up to 99%, up to >99% ee).

CF3-Substituted ketimines synthesized from trifluoroacetone, hexafluoroacetone, and trifluoroacetophenones were studied in aza-Henry reactions with nitroalkanes. We found that nitromethane and nitropropane react with CF3-substituted ketimines to form the target β-nitroamines in high yield. The aza-Henry reaction proceeded under mild conditions in the presence of an appropriate base. A new simple method for the synthesis of β-nitroamines bearing CF3 group was developed. α-CF3-β-nitroamines can easily be converted into trifluoromethylated 1,2-diamines, α-aminooximes, and imidazolidinones.

The reaction of 2-perfluoroalkyl-substituted cyclic imines with arylhydrazines was investigated. We found that 2-perfluoroalkylated cyclic imines are highly reactive electrophiles that form, through ring opening, the corresponding hydrazones bearing an amine group at the end of the alkyl chain. Subsequent acidic treatment resulted in a Fischer rearrangement. Thus, a new synthesis of 2-perfluoroalkylated tryptamines and their homologues through a Fischer reaction was developed. The possibility of modification of the indole core of the 2-CF3-substituted tryptamine products was demonstrated, and various 2-trifluoromethylated tryptamines substituted at the 5-position were prepared.

The application of perfluoroalkylated cyclic imines in azido-Ugi reactions was studied. It was shown that the reaction allows access to five-, six- and seven-membered perfluoroalkylated cyclic amines connected to a tetrazole ring. The scope and limitations of this approach are discussed. When benzyl isocyanide was used in the azido-Ugi reaction, it was shown that the tetrazole products could easily be debenzylated by catalytic hydrogenation to form 1H-tetrazoles in excellent yields.

A Friedel–Crafts-type alkylation reaction was studied between various pyrroles and α-polyfluoroalkylated cyclic imines that were activated by Lewis acids. The reaction proceeded under mild conditions and provided a high yielding synthesis of α-CF3-substituted pyrrolidines and piperidines as well as seven-membered analogues that contained a pyrrole ring. The unpredictably high β-selectivity for the aminoalkylation of both 1H-pyrrole and N-substituted pyrrole was observed as a result of a thermodynamically-controlled electrophilic substitution reaction. The computational data are in full agreement with the experimental results, which confirmed the observed regioselectivity as a result of the lower energy of the β-substituted pyrroles that contain α-trifluoromethyl-substituted pyrrolidine, piperidine, and azepane rings.

The reaction of cyclic ketimines with indoles was studied. A dramatic difference between the electrophilicity of perfluoroalkyl-substituted and non-fluorinated imines was demonstrated. In good agreement with our calculations, the Friedel–Crafts-type alkylation of indoles only takes place with α-polyfluoroalkylated cyclic imines that are activated by boron trifluoride–diethyl ether. The reaction proceeds under mild conditions and provides the opportunity to obtain promising alkaloid-like structures that contain a fluoroalkyl group. As a result, α-CF3- and α-C2F5-substituted pyrrolidines, piperidines, and azepanes that contain an indole moiety can be prepared efficiently.

An efficient (one- and two-step) synthesis of trifluoromethylated derivatives of the natural alkaloids nazlinine, trypargine, and homotrypargine was elaborated. Trifluoromethyl-substituted 5–7-membered cyclic imines were used as a masked carbonyl component in the Pictet–Spengler reaction with various tryptamines. As a result, this approach opens access to a family of alkaloid-like compounds bearing a CF3 group at position 1 of tetrahydro-β-carboline.