Structure, biological activity, and a biomimetic partial synthesis of the lirofolines, novel pentacylic indole alkaloids from Tabernaemontana Yun-Yee Low a , Kuan-Hon Lim a,  , Yeun-Mun Choo a , Huey-Shen Pang a,à , Tadahiro Etoh b , Masahiko Hayashi b , Kanki Komiyama c , Toh-Seok Kam a, * a Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia b Faculty of Pharmacy, Iwaki Meisei University, 5-5-1 Iino, Chuo-dai, Iwaki, Fukushima 970-8551, Japan c The Center for Basic Research, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-642, Japan article info Article history: Received 6 August 2009 Revised 21 October 2009 Accepted 28 October 2009 Available online 30 October 2009 Keywords: Alkaloids NMR Partial synthesis Biological activity Tabernaemontana abstract Two new pentacyclic indole alkaloids, lirofolines A and B, possessing a novel rearranged ibogan ring system, are obtained from two Malayan Tabernaemontana species ( Tabernaemontana corymbosa and Tabernaemontana divaricata) and the structures are established by analysis of the spectroscopic data. A biomimetic partial synthesis of lirofoline A from ibogaine via the Polonovski reaction is carried out. Lirof- olines A and B showed significant activity in reversing multidrug resistance in vincristine-resistant KB cells (IC 50 3.4 and 7.5 lg/ml, respectively). Ó 2009 Elsevier Ltd. All rights reserved. Plants of the genus Tabernaemontana are rich sources of struc- turally novel, as well as biologically active, indole and bisindole alkaloids. 1–4 We recently reported the structures of three minor alkaloids isolated from the stem-bark extract of Tabernaemontana corymbosa, viz., conolutinine, 5 conoliferine, and isoconoliferine. 6 Conolutinine is characterized by a novel ring system incorporating a diazaspiro center and fused oxadiazepine–tetrahydrofuran rings, while conoliferine and isoconoliferine represent the first examples of alkaloid–lignan conjugates derived from the union of an iboga alkaloid and a lignan moiety. Other recent examples of unusual alkaloids from the Malayan Tabernaemontana which are notable for possessing novel ring systems, and which were postulated to be derived from known monoterpenoid indole precursors through pathways involving deep-seated rearrangements include, inter alia, the hexacyclic alkaloid, tronoharine, 7 the pentacyclic indole, tronocarpine, 8 and the indole-derived quinolinic alkaloids, voastrictine 9 and voaharine. 10 The Malayan representatives of this genus are also notable for producing new indole and bisindole alkaloids, including a number which exhibited important biologi- cal activities. 11–26 We now report the isolation and structure elucidation of two new pentacyclic indole alkaloids, lirofolines A (1) and B (2), from the stem-bark extracts of T. corymbosa and T. divaricata, respectively. 27 N N H H H MeO 1 R = H 2 R = CH 2 OH 17 16 6 9 12 5 3 15 18 20 21 R O Lirofoline A (1) was obtained as a colorless oil (yield, ca. 0.4 mg kg À1 ) from the stem-bark extract of T. corymbosa with [a] D À41 (c 1.36, CHCl 3 ). The UV spectrum (EtOH, k max 216, 258, 280, and 309 nm) indicated the presence of a conjugated indole chro- mophore, while the IR spectrum showed a band at 1651 cm À1 due to a conjugated carbonyl function. The presence of the methine signals at d H 10.1 and d C 182.9 revealed that the conjugated car- bonyl observed in the IR spectrum is due to an aldehyde function. The EIMS of 1 showed a molecular ion at m/z 324 as the base peak with a significant fragment ion peak at m/z 295 due to MÀCHO or MÀCH 2 CH 3 . 28 The 1 H NMR spectrum (Table 1) showed, in addition 0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.10.122 * Corresponding author. Tel.: +60 3 79674266; fax: +60 3 79674193. E-mail addresses: tskam@um.edu.my, tohseokkam@yahoo.com (T.-S. Kam).   Present address: School of Pharmacy, The University of Nottingham Malaysia Campus, Jalan Broga, 43500 Semenyih, Selangor Darul Ehsan, Malaysia. à Present address: HELP University College, A-Levels Department, BZ-2 Pusat Bandar Damansara, 50490 Kuala Lumpur, Malaysia. Tetrahedron Letters 51 (2010) 269–272 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet