[3 + 3] Annulations of exo-cyclic vinylogous amides and urethanes with vinyl iminium salts are described here. We observed an intriguing dichotomy in their reaction pathways. For pyrrolidineand azepane-based vinylogous amides or urethanes, aza-[3 + 3] annulation would dominate to give tetrahydroindolizidines, whereas, unexpectedly, for piperidine-based vinylogous amides or urethanes, carbo-[3 + 3] annulation was the pathway, leading to hexahydroquinolines. The origin for such a contrast is likely associated with a switch in the initial reaction pathway between C-1,2-addition and C-1,4-addition.

The first success in constructing a member of quinolizidine family of alkaloids employing an intramolecular aza-[3 + 3] annulation strategy is described here. The key feature is the usage of vinylogous urethane tethered to a vinyl iminium intermediate with trifluoroacetate serving as the counter anion. The proof-of-concept is illustrated with the synthesis of 2-deoxy-lasubine II. KeywordsIntramolecular aza- [3 + 3] annulation; lasubine I and II; quinolizidines; piperidinium trifluoroacetate salt; Barton's decarboxylationIn the last ten years, we have been developing an aza-[3 + 3] annulation reaction 1,2 as a general strategy toward alkaloid synthesis. 3,4 The intramolecular variant of this annulation has been particularly useful in natural product synthesis. Specifically, reactions of vinylogous amides 1 [Scheme 1] tethered to a vinyl iminium motif through a tandem sequence of N-1,4-addition and C-1,2-addition 3 can lead to a diverse array of nitrogen heterocycles 2a-e, which have been applied to a number of total syntheses of alkaloids. [5][6][7][8] Despite such success, our annulation strategy has not been useful in approaching simple quinolizidine and indolizidine structural motifs 3 and 4, which could be accessed only in low yields. Consequently, this limitation precluded us from synthesizing any quinolizidine and indolizidine alkaloids, and limited us to the construction of nitrogen heterocycles 2a-e with quinolizidine and indolizidine motifs embedded therein.It was not until recently did we learn that the counter anion [X ⊖ ] in these iminium salts plays a significant role in the annulation. 9 In particular, for the synthesis of 2e ,8b while iminium salts with acetate as the count anion was completely ineffective, generating the more reactive trifluoroacetate iminium salt 9 proved to be the solution, rendering a vinylogous urethane deployable for the first time in the aza-[3 + 3] annulation. 8 We had long recognized a distinct advantage of employing vinylogous urethanes in our aza- [3 + 3] annulation being that the resulting methoxy carbonyl group in 2e represents an excellent functional handle for further transformations or removal. 8 Therefore, we investigated annulation reactions of vinylogous urethanes 5 tethered to a trifluoroacetate iminium salt with the intent to develop a general approach toward the quinolizidine family of alkaloids [Scheme 2]. We report here our preliminary success in the synthesis of (±)-2-deoxy-lasubine II. 10 With the vinylogous urethane 13 tethered to the enal in hand, 50 mol% of piperidinium trifluoroacetate salt was used to promote the formation of vinyl iminium intermediate 14, and an in situ hydrogenation allowed successful isolation of the annulation product 16 in good yield over two operations. Although the initial annulation product 15 could be isolated, it is not as stable as 16. It is note-worthy that this work represents the first time our aza-[3 + 3] annulation method has succeeded in constructing a simple quinolizidine structural motif such as 16 in a sy...

Ring closure reactions O 0130 Aza-and Carbo-[3 + 3] Annulations of exo-Cyclic Vinylogous Amides and Urethanes. Synthesis of Tetrahydroindolizidines and an Unexpected Formation ofHexahydroquinolines. -Piperidine-based vinylogous amides or urethanes (I) and (IV) undergo an unexpected carbo-[3+3]-annulation with vinyl iminium salts, generated in situ from enals and piperidinium acetate, to give hexahydroquinolines. Pyrrolidine-and azepane-based vinylogous amides or urethanes undergo under the same reaction conditions an aza-[3+3]-annulation to afford tetrahydroindolizidines and azepane analogues, correspondingly. -(GHOSH, S. K.; BUCHANAN, G. S.; LONG, Q. A.; WEI, Y.; AL-RASHID, Z. F.; SKLENICKA, H. M.; HSUNG*, R. P.; Tetrahedron 64 (2008) 5, 883-893; Dep. Chem., Univ. Wis., Madison, WI 53705, USA; Eng.) -Klein 24-035

Alkaloids U 0600 A General Approach to the Quinolizidine Alkaloids via an Intramolecular Aza-[3 + 3] Annulation: Synthesis of (±)-2-Deoxylasubine II (V). -(ZHANG, Y.; GERASYUTO, A. I.; LONG, Q. A.; HSUNG*, R. P.; Synlett 2009, 2, 237-240; Dep. Chem., Univ. Wis., Madison, WI 53705, USA; Eng.) -Mais 22-194