Intramolecular Carbolithiation Reactions of Chiral α-Amino-organolithium Species

• Published in: Chemistry : a European journal Vol. 8; no. 1; pp. 195 - 207
• Main Authors: Ashweek, Neil J., Coldham, Iain, Snowden, David J., Vennall, Graham P.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag GmbH 04.01.2002; WILEY‐VCH Verlag GmbH; Wiley
• Subjects: alkaloids; Alkenes - chemistry; Amines - chemistry; Catalysis; Chemical Phenomena; Chemistry; Chemistry, Multidisciplinary; Chemistry, Physical; Cyclization; Kinetics; lithium; Lithium - chemistry; Molecular Conformation; Molecular Structure; Nuclear Magnetic Resonance, Biomolecular; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Physical Sciences; Pyrrolidines - chemical synthesis; Pyrrolidines - chemistry; Pyrrolizidine Alkaloids - chemical synthesis; Pyrrolizidine Alkaloids - chemistry; Science & Technology; Stereoisomerism; Temperature; Time Factors; tin; Tin - chemistry; ASYMMETRIC-SYNTHESIS; MEDIATED CYCLIZATION; ENANTIOSELECTIVE SYNTHESIS; alkaloids; STEREOCHEMICAL COURSE; ANIONIC CYCLIZATIONS; cyclization; CONFIGURATIONAL STABILITY; lithium; ORGANOMETALLIC REAGENTS; tin; kinetics; OPTICAL PURITY; LITHIATION; CONJUGATE ADDITION
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/1521-3765(20020104)8:1<195::AID-CHEM195>3.0.CO;2-H

Enantiomerically enriched α‐amino‐organolithium species, in which the lithium atom is attached to a stereogenic carbon centre, have been found to be chemically stable at room temperature in a solvent of very low polarity and undergo intramolecular carbolithiation onto an unactivated alkene. The configurational stability of the chiral organolithium species, bearing a variety of N‐alkenyl substituents, was probed by studying the enantiomeric purity of the cyclization products. With N‐but‐3‐enyl‐2‐lithiopyrrolidine, cyclization to the five‐membered ring is more rapid than racemization and a high yield of the pyrrolizidine alkaloid (+)‐pseudoheliotridane was obtained with no loss of optical purity. In contrast, with N‐pent‐4‐enyl‐2‐lithiopyrrolidine, cyclization to the six‐membered ring was found to occur with significant loss of optical purity. The cyclization to the six‐membered ring was determined to occur with a half‐life, t1/2 ≈90 min at 23 °C. The epimerization of this organolithium species in hexane/Et2O 4:1 was calculated to have a half‐life, t1/2 ≈30 min at 23 °C. Enhanced levels of enantioselectivity for the formation of the indolizidine ring system were obtained using an alkene bearing a terminal phenylthio substituent. With N‐[(3‐phenylthio)prop‐2‐enyl]‐2‐lithiopyrrolidine, cyclization to the four‐membered ring occurs with poor enantioselectivity at low temperature in THF but is highly enantioselective at room temperature in a solvent of very low polarity. The relative rate of cyclization versus epimerization of chiral N‐alkenyl‐2‐lithiopyrrolidines has been studied. The rates depend on the length and substitution pattern of the alkenyl chain and on the solvent used. Cyclization leads to chiral bicyclic amine products.