Modified Julia Olefination Approach to Chiral α‐Fluorovinyl Amino Alcohols and Amino Acids, via Fluorovinyl Oxazolidine Precursors, Conformational and Crystallographic Analyses

Synthesis of chiral α-fluorovinyl β-aryl/heteroaryl/alkyl amino alcohols was achieved via intermediate 4-(α-fluorovinyl) 2,2-dimethyloxazolidines with stereochemically defined preexisting stereogenic centers, derived from (S)- or (R)-serine. Previously unknown 4-fluorovinyl 2,2-dimethyloxazolidines with a fluorine atom placed alpha to the oxazolidine were prepared via Julia olefination of tert-butyl (S)-4-{(S)-[benzo[d]thiazol-2-ylsulfonyl]fluoromethyl}-2,2-dimethyloxazolidine-3-carboxylate and its (R,R) enantiomer, with a series of aldehydes. By choice of conditions, olefinations could be tuned towards Z- or E-selectivity. E/Z olefin mixtures with electron-rich aryl and heteroaryl substituents were isomerized exclusively or predominantly to the Z-isomer. N-Boc protected β-aryl/alkyl substituted α-fluorovinyl amino alcohols were obtained by oxazolidine hydrolysis. To demonstrate utility for synthesis of amino acids, (R,Z)- and (S,Z)-p-methoxyphenyl- and the (S,E)-p-cyanophenyl-substituted alkenes were subjected to oxidation, which was very challenging. The use of cat. TEMPO/cat. NaOCl/NaClO₂ gave the N-Boc protected fluorovinyl amino acids that were converted to their methyl esters. Enantioselective HPLC of the (S)- and (R)-p-methoxyphenyl-substituted products formed at each step of the synthetic sequence indicated that high enantiomeric purity was retained through the entire synthesis. Crystal structures of two fluorovinyl oxazolidines and one amino alcohol provided insight into the solid-state conformations. NMR and computational analyses were used to obtain insight into plausible solution conformations.