Enantiodivergent Synthesis of (+)- and (−)-Pyrrolidine 197B: Synthesis of trans-2,5-Disubstituted Pyrrolidines by Intramolecular Hydroamination

• Published in: Chemistry : a European journal Vol. 22; no. 43; pp. 15529 - 15535
• Main Authors: Pérez, Sixto J., Purino, Martín A., Cruz, Daniel A., López-Soria, Juan M., Carballo, Rubén M., Ramírez, Miguel A., Fernández, Israel, Martín, Víctor S., Padrón, Juan I.
• Format: Journal Article
• Language: English
• Published: WEINHEIM Blackwell Publishing Ltd 17.10.2016; Wiley
• Subjects: alkaloids; Amination; Catalysis; Chemistry; Chemistry, Multidisciplinary; cyclization; Ferric Compounds - chemistry; Glutamic Acid - chemistry; hydroamination; iron; nitrogen heterocycles; Physical Sciences; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Science & Technology; Stereoisomerism; PRINS-CYCLIZATION; ASYMMETRIC-SYNTHESIS; alkaloids; ALPHA-AMINO-ACIDS; cyclization; SOLENOPSIS; hydroamination; MAGNESIUM; ALKENES; INTERMOLECULAR HYDROAMINATION; nitrogen heterocycles; iron; STEREOSELECTIVE-SYNTHESIS; DERIVATIVES
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201602708

A highly efficient, diastereoselective, iron(III)‐catalyzed intramolecular hydroamination/cyclization reaction involving α‐substituted amino alkenes is described. Thus, enantiopure trans‐2,5‐disubstituted pyrrolidines and trans‐5‐substituted proline derivatives were synthesized by means of a combination of enantiopure starting materials, easily available from l‐α‐amino acids, with sustainable metal catalysts such as iron(III) salts. The scope of this methodology is highlighted in an enantiodivergent approach to the synthesis of both (+)‐ and (−)‐pyrrolidine 197B alkaloids from l‐glutamic acid. In addition, a computational study was carried out to gain insight into the complete diastereoselectivity of the transformation. Green route to 5‐membered azacycles: An innovative method to obtain enantiopure trans‐2,5‐disubstituted pyrrolidines and trans‐5‐proline derivatives was established. An enantiodivergent approach to the synthesis of both (+)‐ and (−)‐pyrrolidine 197B from l‐glutamic acid is presented (see scheme). The selectivity was explained by DFT calculations.