Rokas Jankauskas

An efficient and stereoselective method for the synthesis of chiral biheterocyclic N-Boc-protected pyrrolidine derivatives bearing indole, pyrazole, and indazole moieties is presented. In this approach, nucleophilic substitution of heterocyclic carboxylates with enantiomerically pure N-Boc-3-methanesulfonyloxypyrrolidines is used to afford N-(pyrrolidin-3-yl) derivatives in high yields with an inverted configuration. The methodology accommodates a range of substrates, enabling structural diversity. Reactions with pyrazole- and indazolecarboxylates generate regioisomeric products. Representative peptide-coupling reactions further demonstrated the synthetic utility of the synthesized chiral biheterocyclic pyrrolidine derivatives containing protected amino and carboxyl functionalities as building blocks for peptide synthesis. Halogenated indole and pyrazole derivatives underwent further functionalization via palladium-catalyzed cross-coupling to introduce aryl, heteroaryl, and alkynyl substituents. All of the N-Boc-substituted biheterocycle–pyrrolidine carboxylates displayed NMR spectra with two sets of signals, notable signal broadening, or both. These effects are due to the dynamic equilibrium between two conformers in a deuterated solvent and were studied in depth. The structures and stereochemistry of the synthesized compounds were confirmed by means of chiral HPLC, single-crystal X-ray diffraction, and advanced NMR analyses. This synthetic strategy provides access to chiral heterocyclic amino acid-like building blocks for peptide synthesis and medicinal chemistry.

In this study, we prepared a series of new N -(aminocycloalkylene)amino acid derivatives for use in chiral building blocks.

In this paper, a simple and efficient synthetic route for the preparation of new heterocyclic amino acid derivatives containing azetidine and oxetane rings was described. The starting (N-Boc-azetidin-3-ylidene)acetate was obtained from (N-Boc)azetidin-3-one by the DBU-catalysed Horner–Wadsworth–Emmons reaction, followed by aza-Michael addition with NH-heterocycles to yield the target functionalised 3-substituted 3-(acetoxymethyl)azetidines. Methyl 2-(oxetan-3-ylidene)acetate was obtained in a similar manner, which was further treated with various (N-Boc-cycloaminyl)amines to yield the target 3-substituted 3-(acetoxymethyl)oxetane compounds. The synthesis and diversification of novel heterocyclic amino acid derivatives were achieved through the Suzuki–Miyaura cross-coupling from the corresponding brominated pyrazole–azetidine hybrid with boronic acids. The structures of the novel heterocyclic compounds were confirmed via ¹H-, ¹³C-, ¹⁵N-, and ¹⁹F-NMR spectroscopy, as well as HRMS investigations.