Asymmetric Synthesis of 3-Hydroxy-pyrrolidines via Tin−Lithium Exchange and Cyclization

Abstract

We report a method for the synthesis of chiral pyrrolidines using tin-lithium exchange and cyclization reactions. The precursors are formed readily from simple starting materials and undergo tin-lithium exchange by treatment with n-butyllithium. Subsequent intramolecular carbolithiation is stereoselective to give highly enantiomerically enriched pyrrolidines in excellent yields.

Advances in Carbolithiation

“…An example of tin-lithium exchange followed by intramolecular carbolithiation has been reported as an efficient entry to the asymmetric synthesis of 3-hydroxypyrrolidines. For instance, the five-membered heterocycle 74 was obtained by this strategy in a nearly quantitative yield, and in excellent diastereo-and enantioselectivity (Scheme 11.20) [37]. In a similar manner, a tandem aminolithiation/carbolithiation reaction allowed the efficient preparation of bicyclic octahydroindolizines and hexahydro-1H-pyrrolizines.…”

“…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.…”

Carbometallation Reactions

“…The diastereomeric ratio of the pyrrolidine 174 was determined to be higher than 98 : 2, thus leading to an enantiomeric excess higher than 96% [47]. As shown in the aforementioned examples, the intramolecular carbolithiation of alkenes appears to be an attractive method for the preparation of functionalized five-membered carbocyclic and heterocyclic systems with high regio-and stereoselectivity.…”

“…The absolute configuration of the stereogenic center of the major enantiomer was determined to be (R) by chemical correlations with previously reported compounds [46]. An example of tin-lithium exchange followed by intramolecular carbolithiation of a carbon-carbon double bond as an efficient entry to the asymmetric synthesis of 3-hydroxy-pyrrolidines was reported by Hoppe et al [47]. When the easily accessible enantioenriched stannane 173 was treated with n-butyllithium at low temperature, the five-membered heterocycle 174 was obtained in nearly quantitative yield and with excellent diastereo-and enantioselectivity (Scheme 10.57).…”

“…Scheme 10.57Asymmetric synthesis of substituted pyrrolidines by an intramolecular carbolithiation reaction[47].…”