Intramolecular Carbolithiation Reactions of Chiralα-Amino-organolithium Species

Abstract

Enantiomerically enriched alpha-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, t(1/2) approximately 90 min at 23 degrees C. The epimerization of this organolithium species in hexane/Et2O 4:1 was calculated to have a half-life, t(1/2) approximately 30 min at 23 degrees 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.

Advances in Carbolithiation

“…Several strategies were reported for the generation of alkyl or alkenyllithium species in the presence of an ω-alkene such as reductive lithiation using aryl radical anions [32,33], and halogen-lithium [34,35], tin-lithium [36][37][38], or selenium-lithium exchange [39][40][41]. Intramolecular carbolithiation reactions are usually highly stereoselective [42] as entropy factors favor the monoaddition of the starting organolithium compound even if it has higher reactivity than the carbometallated product.…”

Enantioselective Synthesis of Substituted Pyrrolidines by Dynamic Resolution

“…[10] We have found, however, that the formation of a-amino organolithium species and their racemization is possible at room temperature. [11] We therefore set out to substitute racemic a-amino organolithium species asymmetrically in the presence of a chiral ligand.Extending our work on intramolecular carbolithiation, [11,12] we studied the dynamic resolution of chiral 2-lithiopyrrol-ZUSCHRIFTEN 4043 detected by ESMS analysis of this mixture. Deprotonation of 1 with nbutyllithium/TMEDA at À78 8C followed by trapping with Ph 2 PCl at À30 8C provided the product of ortho lithiation±trapping in low yield.…”

“…[10] We have found, however, that the formation of a-amino organolithium species and their racemization is possible at room temperature. [11] We therefore set out to substitute racemic a-amino organolithium species asymmetrically in the presence of a chiral ligand.…”

“…Extending our work on intramolecular carbolithiation, [11,12] we studied the dynamic resolution of chiral 2-lithiopyrrol-ZUSCHRIFTEN 4043 detected by ESMS analysis of this mixture. Deprotonation of 1 with nbutyllithium/TMEDA at À78 8C followed by trapping with Ph 2 PCl at À30 8C provided the product of ortho lithiation±trapping in low yield.…”

“…Extending our work on intramolecular carbolithiation, [11,12] Chem. , 61, 1629 Although the lithium aggregate is depicted in A to be on the face of the tBu substituent, it alternatively could be oriented towards the chromium tripod.…”