Total Synthesis of the Alkaloid ()-Aspidophytine Based on Carbonyl Ylide Cycloaddition Chemistry by Jose ´ M. Mejía-Oneto and Albert Padwa* Department of Chemistry, Emory University, Atlanta, Georgia 30322, USA (phone: þ 1-4047270283; fax: þ 1-4047276629; e-mail: chemap@emory.edu) The Rh II -catalyzed cycloaddition cascade of an indolyl-substituted a-diazo imide was used for the total synthesis of the complex pentacyclic alkaloid ()-aspidophytine. Treatment of the resulting dipolar cycloadduct with BF 3 ·OEt 2 induces a domino fragmentation cascade. The reaction proceeds by an initial cleavage of the oxabicyclic ring and formation of a transient N-acyl iminium ion which reacts further with the adjacent tert-butyl ester and sets the required lactone ring present in aspidophytine. A three-step sequence was then used to remove both the ester and OH groups. Subsequent functional group manipulations allowed for the high-yielding conversion to ()-aspidophytine. Introduction. – Construction of azapolyheterocycles through dipolar cycloaddition chemistry has been a particularly fruitful area of investigation, and the synthesis of various types of alkaloids by this approach has been carried out by numerous investigators [1]. Several years ago, we began a synthetic program to provide general access to a variety of Aspidosperma alkaloids by making use of a rhodium(II)-catalyzed reaction of a-diazo imides [2]. The Aspidosperma alkaloids occupy a central place in natural-product chemistry because of their wide range of complex structural variations and diverse biological activity [3]. This family of indole alkaloids contains over 250 members that share in their molecular structure a common pentacyclic ABCDE framework, with the C-ring being of critical importance, because all of the stereogenic centers and most of the functional groups are located in this ring [4]. Individual members differ mainly in functionality and configuration. Our earlier approach toward deacetoxy-4-oxo-6,7-dihydrovindorosine (4) involved the initial generation of carbonyl ylide 2 from the Rh II -catalyzed cyclization reaction of a-diazo imide 1 [5]. This was followed by an intramolecular 1,3-dipolar cycloaddition across the tethered indolyl p- bond [6]. The resulting pentacyclic adduct 3 was then converted into 4 in several additional steps ( Scheme 1) [7]. Prompted by our initial work, we decided to initiate a synthetic project using this general approach for the construction of ()-aspidophytine, a structurally more demanding aspidosperma target. In 1973, Cava and Yates reported on the structural determination of haplophytine ( 5), a (bisindole) alkaloid isolated from the leaves of Haplophyton cimicidum [8][9]. The structure of 5 was firmly established by an X-ray crystallographic analysis [10]. Acid cleavage of haplophytine ( 5) led to aspidophytine (6) [11] ( Scheme 2), a lactonic Aspidospermine type of alkaloid which has been suggested to be not only a biosynthetic precursor of 5 but also a possible intermediate to be used in its synthesis [12][13]. Because of its intriguing structure, aspidophytine has attracted the attention of several Helvetica Chimica Acta – Vol. 91 (2008) 285 # 2008 Verlag Helvetica Chimica Acta AG, Zürich