Pyrrolidine synthesis by the (3+2) cycloaddition of 2-azaallyl anions with olefins: An application toward the total synthesis of (plus/minus)-pretazettine.

Abstract

Conceptually, one of the simplest and most direct methods for the construction of the pyrrolidine ring is the anionic (3 + 2) cycloaddition of a 2-azaallyl anion with an olefin. Studies previously disclosed by the W. H. Pearson group have described the synthesis and transmetalation of N-(trialkylstannyl)methanimines which were shown to undergo stereoselective cycloadditions with activated alkenes and alkynes. Despite the many advantages, synthesis of alkyl substituted (2-azaallyl)stannanes was limited to N-(trialkylstannyl)methanimines as attempts to prepare higher analogs failed. A new, more versatile method for the assembly of N-(trialkylstannyl)alkanimines has thus been developed by which condensation of linear or branched $\alpha$-tributylstannylamines with aldehydes and ketones provided access to the formerly elusive 1,3-dialkyl-(2-azaallyl)stannanes. Non-stabilized 1,3-dialkyl-2-azaallyl anions have been generated for the first time upon treatment of the branched (2-azaallyl)stannanes with n-butyllithium. Studies have revealed that these non-stabilized, 1,3-disubstituted 2-azaallyl anions also undergo highly stereoselective cycloadditions with activated alkenes such as stilbenes, phenyl vinyl sulfide, vinyltrimethylsilane and diphenyl acetylene and that they react, without exception, to provide cis-2,5-dialkylpyrrolidines. This observation provides the first direct evidence that these anions react in a "W" conformation. In an effort to demonstrate the utility and generality of the 2-azaallyl anion cycloaddition reaction, a synthesis of the moderately complex biologically active alkaloid pretazettine has been attempted. Our synthetic plan revolved around an unprecedented intramolecular cycloaddition of a non-stabilized 2-azaallyl anion onto a 1,3-diene. Although a total synthesis of this alkaloid was not achieved, the chemistry involving the intramolecular 2-azaallyl anion cycloaddition was flawless. In a single synthetic step, from an acyclic precursor, the functionalized tetrahydroindole skeleton of pretazettine was assembled, four new stereocenters were generated, yet only a single diastereomer was produced, in 54% yield over three chemical steps.