The total synthesis of (6)-arisugacin A Richard P. Hsung, * ,† Kevin P. Cole, Luke R. Zehnder, Jiashi Wang, Lin-Li Wei, Xiao-Fang Yang and Heather A. Coverdale Department of Chemistry, University of Minnesota, 207 Pleasant Street S.E., Minneapolis, MN 55455-0431, USA Received 4 October 2002; accepted 21 November 2002 This paper is dedicated to Professor Gilbert Stork on the occasion of his 80th birthday Abstract—A 20-step total synthesis of (^)-arisugacin A with an overall yield of 2.1% is described here in detail. This synthesis features a formal [3þ3] cycloaddition reaction of a,b-unsaturated iminium salts with 6-aryl-4-hydroxy-2-pyrones through a highly stereoselective 6p-electron electrocyclic ring-closure of 1-oxatriene. A strategic dihydroxylation – deoxygenation protocol leading to the desired angular C12a – OH was developed to serve as a critical step in leading to the final total syntheses of arisugacin A. This synthetic endeavor also led to an interesting and unexpected retro-aldol – aldol sequence in the AB-ring. q 2003 Elsevier Science Ltd. All rights reserved. 1. Introduction Arisugacin A (1), isolated from Penicillium Sp. Fo-4259 by O ˜ mura, is a potent and selective inhibitor of acetylcholin- esterase with an IC 50 of 1 nM, 1 thereby possessing significance in treatment of dementia diseases such as Alzheimer’s disease. 2 Given its biological relevance and unique meroterpenoidal structure (a hybrid of polyketide and terpenoid) that resembles other important natural products such as the territrems (3) 3 and pyripyropenes, 4 we have investigated a number of different synthetic routes seeking an efficient synthesis of arisugacin A. 5–8 In particular, we have been developing a formal [3þ3] cyclo-addition method 9–11 that involves condensing a,b-unsaturated iminium salts 7 with 6-aryl-4-hydroxy-2-pyrones such as 8 through a stereoselective 6p-electron electrocyclic ring- closure 12 of the 1-oxatriene intermediate 10 (Fig. 1). In this tandem Knoevenagel condensation–pericyclic ring- closure sequence, 13 two s-bonds and a new stereocenter adjacent to the oxygen atom are formed, leading to a convergent synthesis of the advanced pentacyclic inter- mediate 6 7,8 in a highly stereoselective manner (C6a in 6). We have applied this stepwise cycloaddition to total syntheses of pyranoquinoline alkaloids 14 and expanded it to synthesis of dihydropyridines using vinylogous amides. 15 Recently, O ˜ mura’s group and ours independently communi- cated total syntheses of (^)-arisugacin A featuring this 0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. PII: S0040-4020(02)01524-7 Tetrahedron 59 (2003) 311–324 Figure 1. † A recipient of 2001 Camille Dreyfus Teacher-Scholar and 2001–2003 McKnight New Faculty Awards. * Corresponding author. Tel.: þ1-612-625-3045; fax: þ1-612-626-7541; e-mail: hsung@chem.umn.edu Keywords: arisugacin A; formal [3þ3] cycloaddition; iminium salts; stereoselective pericyclic ring-closure; retro-aldol – aldol sequence.