Copper catalyzed regioselective and stereospecific coupling between aziridines and in situ generated pyridine Grignard reagents is reported. This method provides β-pyridylethylamines with diverse structures and functionalities from aziridines and iodopyridines. β-Pyridylethylamines are potential scaffolds for the synthesis of biologically active compounds often found in pharmaceuticals. The synthesis of challenging chiral dihydroazaindoles was also achieved through mild one-pot reaction conditions via aziridine opening followed by nucleophilic cyclization.

Molecules that contain one or more fluorine atoms are crucial to drug discovery. There are protocols available for the selective synthesis of different organofluorine compounds, including those with a fluoro-substituted or a trifluoromethyl-substituted stereogenic carbon centre. However, approaches for synthesizing compounds with a trifluoromethyl-and fluoro-substituent stereogenic carbon centre are far less common. This potentially impactful set of molecules thus remains severely underdeveloped. Here we introduce a catalytic regio-, diastereoand enantioselective strategy for the preparation of homoallylic alcohols bearing a stereogenic carbon centre bound to a trifluoromethyl group and a fluorine atom. The process, which involves a polyfluoroallyl boronate and is catalysed by an in situ-formed organozinc complex, can be used for diastereodivergent preparation of tetrafluoro-monosaccharides, including ribose core analogues of the antiviral drug sofosbuvir (Sovaldi). Unexpected reactivity/selectivity profiles, probably originating from the trifluoromethyl-and fluoro-substituted carbon site, are discovered, foreshadowing other unique chemistries that remain unknown.The ease, economy, efficiency and selectivity with which organofluorine compounds are accessed is in the exclusive purview of chemical synthesis 1,2 . Efficient transformations that deliver valuable fluoro-organic products with high diastereo-and/or enantioselectivity open fresh vistas in drug discovery [3][4][5] , and facilitate the development of improved agrochemicals 6 and/or superior polymeric materials 7 . Among the areas to be impacted are oligonucleotide therapeutics and glycomimetic drug design [8][9][10][11] , where 2-fluoro-substituted monosaccharides are key (Fig. 1a). An example is sofosbuvir, sold under the name Sovaldi, which is used for the treatment of chronic hepatitis C virus infection [12][13][14][15] . A more potent derivative of Sovaldi has a fluoro,bromo-substituted stereogenic C2 (ref. 16 ). Bioactive pyranosides with a fluoro-substituted C2 are similarly sought-after, a prominent member being sialyltransferase inhibitor 3F ax -Neu 5 Ac 17,18 . These latter compounds are components of cancer vaccine candidates 19,20 that can be used discretely, or in combination with other drugs, to counter viral infections 21 , including ).In light of evidence vis-à-vis the beneficial impact of a trifluoromethyl group on bioavailability and/or metabolic stability of a therapeutic candidate 2,3 , the development of efficient and stereoselective pathways for the synthesis of unexplored furanosides and pyranosides with a trifluoromethyl-and fluoro-substituted C2 (refs. 2,25 ) is particularly desirable (Fig. 1a). Oxonium ion generation and the ensuing saccharide ring cleavage, a preamble to depurination 26,27 , might then be thwarted by the strong electronic pull caused by the trifluoromethyl-and fluoro-substituted stereogenic carbon (compared

The oxazepane pyridine intermediate, an important fragment of active pharmaceutical ingredients, is of great interest in the pharmaceutical industry. In this manuscript, a scalable and economical process for the synthesis of a fused 2′,3′-dihydro-5'Hspiro [cyclopropane-1,4′-pyrido[3,2-b][1,4]oxazepine]-8′-carboxylic acid 1 on multikilogram scales is described. The synthesis features a streamlined isolation process from the Mitsunobu reaction by using one solvent system for a two-step process. Furthermore, a robust palladium-catalyzed intramolecular amination for the seven-membered heterocycle was developed. The reproducible reaction rate was established by adding the catalyst and ligand as solids without preparing the palladium complex under nitrogen. The residual palladium was effectively reduced by recrystallization of the carboxylic ester intermediate 2. The synthesis of key intermediate 5 was realized via the Kulinkovich reaction from readily available simple building blocks. The regulatory starting material compound 1 was isolated in a high-purity profile after saponification of the ester 2 with an overall yield of 70% over five steps.