Enantioselective Total Syntheses of (+)-Arborescidine A, (-)-Arborescidine B, and (-)-Arborescidine C Leonardo S. Santos, † Ronaldo A. Pilli,* ,† and Viresh H. Rawal* ,‡ Instituto de Quimica, Universidade Estadual de Campinas (Unicamp), CP 6154, 13084-971 Campinas, SP, Brazil, and Department of Chemistry, The University of Chicago, Chicago, Illinois 60637 pilli@iqm.unicamp.br; vrawal@uchicago.edu Received August 7, 2003 Described are the first enantioselective total syntheses of (+)-arborescidine A ((+)-1), (-)- arborescidine B ((-)-2), and (-)-arborescidine C ((-)-3), via routes that proceeded in five steps and 50% overall yield, eight steps and 61% overall yield, and nine steps and 51% overall yield, respectively, from 6-bromotryptamine (7). The syntheses feature the use of the Noyori catalytic asymmetric hydrogen-transfer reaction to introduce chirality in dihydro--carbolines 6 and 8. On the basis of an ample precedent from Noyori’s work, the reduction produces dihydro--carbolines, and ultimately the natural products, possessing the R absolute configuration. The synthetic arborescidines displayed optical rotations that were opposite in sign those of the natural products, thereby supporting the S configuration for natural arborescidines A (1) and B (2) and the (3S,17S) configuration for natural arborescidine C (3). Our results are in agreement with the initial stereochemical assignment by Paı ¨s and co-workers, and are counter to their recently revised assignment. Introduction A wide variety of biologically active 6-bromoindole derivatives have been isolated from marine invertebrates, such as sponges, coelenterates, and tunicates. These secondary metabolites are believed to function as chemi- cal defense agents against parasites. 1 In 1993, Paı ¨s and co-workers isolated four new brominated alkaloids of the tetrahydro--carboline family from the marine tunicate Pseudodistoma arborescens and characterized them as arborescidine A (1), arborescidine B (2), arborescidine C (3), and arborescidine Dsa diastereoisomer of 3 that possesses the opposite configuration at C-17 (Figure 1). 2 The absolute stereochemistry of 1 was initially suggested to be S on the basis of circular dichroism studies by Paı ¨s and co-workers. Assuming a common biosynthesis for all four compounds, the same C-3 configuration was also tentatively assigned to arborescidines B-D. However, recent X-ray crystallography studies using the anomalous dispersion of the bromine atom have resulted in the assignment of arborescidine C to be changed to 3R,17R. 3 Inspired in part by this controversy, we undertook the stereoselective synthesis of 1-3. In 1998, Koomen and co-workers reported a racemic approach to these alka- loids. 4 We envisaged efficient, enantiocontrolled synthe- ses of these alkaloids by taking advantage of the Noyori asymmetric hydrogen-transfer reaction of appropriately functionalized -carboline derivatives. 5 Results Structurally, the arborescidines comprise a tetracyclic framework featuring a common octahydropyrido[2,1-a]- -carboline core. The retrosynthetic analysis for the basic framework of arborescidines A-C is depicted in Figure 1 and features the Noyori asymmetric hydrogen-transfer reaction (6 to 5 and 8 to 9) as a key step. Although demonstrated as a useful synthetic method, this asym- metric reduction remains to be fully explored in the arena of total synthesis of alkaloid natural products. 6 The ubiquitous nature of the indole framework has stimulated the development of numerous methods for the † Unicamp. ‡ The University of Chicago. (1) Baker, J. T.; Murphy, V. Handbook of Marine Science: Com- pounds from Marine Organisms; CRC: Cleveland, OH, 1976; Vol. 1. (2) Chbani, M.; Paı ¨s, M. J. Nat. Prod. 1993, 56, 99. (3) Schubot, F. D.; Hossain, M. B.; van der Helm, D.; Paı ¨s, M.; Debitus, C. J. Chem. Crystallogr. 1998, 28, 23. (4) Burm, B. E. A.; Meijler, M. M.; Korver, J.; Warnner, M. J.; Koomen, G.-J. Tetrahedron 1998, 54, 6135. (5) (a) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 4916. (b) Yamakawa, M.; Ito, H.; Noyori, R. J. Am. Chem. Soc. 2000, 122, 1466. (c) Mao, J.; Baker, D. C. Org. Lett. 1999. 1, 841. (d) James, B. R. Catal. Today 1997, 37, 209. (e) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069. (6) The Noyori enantioselective hydrogenation was utilized to introduce the initial chirality in the asymmetric total synthesis of (+)- geissoschizine: Reddy, T. J.; Birman, V. B. Unpublished results. See: (a) Birman, V. B. Ph.D. Dissertation, The University of Chicago, 2000. (b) Reddy, T. 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