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Catalytic asymmetric [3+2] cycloaddition of azomethine ylides is one of the best methods for constructing enantioenriched heterocyclic pyrrolidines, [1] and extensive studies have been conducted on the use of various electron-deficient alkenes as the 2p synthons over the past decade. [2] However, although there are elegant and creative azomethine-ylideinvolved cycloaddition reactions toward the construction of five-membered pyrrolidine architectures, [1,2] the direct catalytic asymmetric approach to enantioenriched six-membered heterocyclic piperidines, which are prevalent scaffolds that serve as the core structures of natural alkaloids and bioactive molecules, [3] has met with little success, [4] and we believe this represents a considerable challenge.In 2003, Hong et al. [5] reported a [6+3] cycloaddition of azomethine ylides with fulvenes [6] , in which fulvenes served as 6p components, thus leading to the synthesis of racemic sixmembered piperidine derivatives. However, there is a lack of catalytic asymmetric [6+3] cycloadditions which tolerate variations in both the azomethine ylides and fulvenes. Stimulated by the biological significance of piperidine derivatives and the challenging synthetic difficulties associated with enantio-and diastereoselectivity control, we questioned whether fulvenes containing no electron-withdrawing groups could be employed as efficient 6p dipolarophiles and provide a straightforward and asymmetric approach to enantioenriched piperidines. Very recently, one example on the asymmetric cycloaddition of unsymmetrical fulvenes and azomethine ylides has been published concurrently with the preparation of the present manuscript. [7] Herein, we report the Cu I /TF-BiphamPhos-catalyzed asymmetric synthesis of highly substituted piperidines by the [6+3] cycloaddition of azomethine ylides with various fulvenes (Scheme 1, right), and subsequent transformations which allow facile access to enantioenriched fused polycyclic piperidine derivatives without loss in diastereoselectivity and enantioselectivity.For our initial studies, the readily available fulvene 2 a [8] was chosen as the model 6p component. Initially we began our investigations by examining the ability of Cu I /TF-BiphamPhos and Ag I /TF-BiphamPhos [9] complexes to probe the possibility of an asymmetric variant of this challenging [6+3] cycloaddition reaction employing the N-(4-chlorobenzylidene)glycine methyl ester 3 a as the dipole precursor (Table 1). To our delight, the reaction was completed in less than 24 hours with AgOAc/(S)-TF-BiphamPhos (1 a) as the catalyst and Et 3 N as the base in dichloromethane at room temperature, thus yielding the expected six-membered heterocyclic piperidine 4 a with excellent diastereoselectivity and 36 % ee (Table 1, entry 1). Neither [3+2] nor regioisomeric [6+3] cycloadducts were observed although the by-product [10] formed by self-cycloaddition of 3 a was isolated in 10 % yield. The cycloadduct 4 a is formed exclusively and no [1,5] Hshift [11] occurred, probably because most of the subst...

An unprecedented Ag(i)-catalyzed tandem [6+3] cycloaddition/isomerization of isocyanoacetates with fulvenes has been developed, affording the fused dihydropyridine derivatives in good yields with exclusive regioselectivities.