Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines

Abstract

Enantiopure 4-formyl-β-lactams were deployed as synthons for the diastereoselective formation of chiral 2-(2,2,2-trifluoro-1-hydroxyethyl)azetidines via trifluoromethylation through aldehyde modification followed by reductive removal of the β-lactam carbonyl moiety. Subsequent treatment of the (in situ) activated 2-trifluoroethylated azetidines with a variety of nitrogen, oxygen, sulfur, and fluorine nucleophiles afforded chiral 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines in good to excellent yields (45-99%) and high diastereoselectivities (dr >99/1, H NMR) via interception of bicyclic aziridinium intermediates. Furthermore, representative pyrrolidines were N,O-debenzylated in a selective way and used for further synthetic elaboration to produce, for example, a CF-substituted 2-oxa-4,7-diazabicyclo[3.3.0]octan-3-one system.

Azetidiniums: Ring‐Expansion to Pyrrolidines, Piperidines, Azepanes, and Azocanes

“…Recently, the synthesis of 2‐trifluoromethyl pyrrolidines 72 from C2'‐trifluoromethyl‐substituted azetidines was reported by D'hooghe et al [ 17 ] By treatment of 69 with triflic anhydride (proton sponge, CH 2 Cl 2, 0 °C), [ 18 ] triflates 70 were generated and after heating in refluxing CH 2 Cl 2 in the presence of an amine, these triflates were converted to 2‐trifluoromethyl 3‐amino pyrrolidines 72 with good diastereoselectivities (de > 96 %) and yields (65–89 %), via bicyclic azetidiniums 71 (Scheme 23).…”

“…DFT calculations corroborated this observation and allowed to confirm that a high energy is necessary to access the bicyclic azetidinium intermediate from ( 2R,3S,1'R )‐azetidines (Scheme 25). [ 17 ]…”

Diethylaminosulfur Trifluoride (DAST) Mediated Transformations Leading to Valuable Building Blocks and Bioactive Compounds

“…This time a fluorine atom was introduced into the azetidine 29 using DAST. [30] The substrate for this reaction was obtained by selective removal of the carbonyl group from the corresponding β-lactam. The fluorination/ring expansion reaction was also very efficient, while the proposed mechanism proceeded through the formation of the bicyclic aziridinium intermediate 30.…”

“…Synthesis of 2-(trifluoromethyl)pyrrolidine. [30] Scheme 8. Synthesis of 3-fluoro-2-(trifluoromethyl)piperidine derivatives.…”

Regio- and Diastereoselective Synthesis of 2-Arylazetidines: Quantum Chemical Explanation of Baldwin’s Rules for the Ring-Formation Reactions of Oxiranes

“…In general, azetidines are considered the most difficult of all to form . Azetidines have excellent physicochemical properties, bioavailability and metabolic stability. − A wide variety of antibiotics, − numerous anticancer agents , containing azetidines, and other drug molecules have been developed over the last decade. ,− They have a significant role as synthetic building blocks of foldamers, , N -heterocycles, − and polymers . It has also been demonstrated, that the introduction of these strained rings improves enormously the fluorescent properties of rhodamines − and coumarins and the efficacy of homogenous catalysts as ligands, , which makes them an attractive and challenging synthetic topic for chemists nowadays.…”