Cycloadditions of Nonstabilized 2-Azaallyllithiums (2-Azaallyl Anions) and Azomethine Ylides with Alkenes: [3+2] Approaches to Pyrrolidines and Application to Alkaloid Total Synthesis

Abstract The [3+2] cycloaddition of 2-azaallyl anions with al­kenes represents an attractive strategy for the synthesis of substituted pyrrolidines. Although cycloadditions of 2-azaallyl anions stabilized by aryl and ester groups have been known for more than three decades, only recently have versions bearing simply hydrogen or alkyl groups been discovered. These nonstabilized 2-azaallyl anions are generated by the low temperature transmetalation of (2-azaallyl)stannanes with alkyllithiums. The resulting nonstabilized 2-azaallyllithiums undergo cycloaddition with certain alkenes and alkynes in both intra- and intermolecular modes to yield pyrrolidine or pyrroline cycloadducts. The methodology has been extended to 2-azapentadienyllithiums, heteroatom-substituted 2-azaallyllithiums, and polymer-supported 2-azaallyllithiums. Asymmetric 2-azaallyl anion cycloadditions have also been investigated. Nonstabilized azomethine ylides may also be generated from (2-azaallyl)stannanes via an N-alkylation/destannylation or N-protonation/destannylation sequence. Together, the cycloaddition of nonstabilized 2-azaallyllithiums and azomethine ylides with alkenes allows access to a broader range of pyrrolidines, since these species have complimentary reactivity profiles. 1 Introduction 2 Background: 2-Azaallyl Anions 2.1 Semistabilized 2-Azaallyl Anions 2.2 Stabilized 2-Azaallyl Anions 2.3 Nonstabilized 2-Azaallyl Anions 3 Methodology Development 3.1 Initial Attempts at Generating Nonstabilized 2-Azaallyl Anions 3.2 Tin-Lithium Exchange on (2-Azaallyl)stannanes 4 Cycloaddition of Simple Nonstabilized 2-Azaallyllithiums 4.1 Preparation of (2-Azaallyl)stannanes 4.2 Anionophiles and Quenches 4.3 Mechanism and Stereoselectivity 5 Variations on a Theme: Related Cycloadditions 5.1 Cycloadditions on Solid Support 5.2 2-Azapentadienyllithiums 5.3 Heteroatom-Substituted 2-Azaallyllithiums 5.4 Enantioselective Cycloadditions 5.5 Higher-Order Cycloadditions 6 Other Uses of (2-Azaallyl)stannanes 6.1 Azomethine Ylide Generation and Cycloaddition 6.2 Nucleophilic Additions to (2-Azaallyl)stannanes 7 Synthesis of Alkaloids 7.1 Intramolecular Cycloadditions 7.1.1 Amabiline and Augustamine 7.1.2 Mesembranes 7.1.3 Coccinine 7.1.4 Crinine and 6-Epicrinine 7.1.5 Approach to 6a-Epipretazettine 7.2 Intermolecular Cycloadditions 7.2.1 Lepadiformine Isomers 7.2.2 Lapidilectine B 7.2.3 Indolizidine 239CD 8 Commentary