I N MeO MeO CO 2 Et H N MeO MeO CO 2 Et R N O MeO OH Me N MeO OH Me N MeO MeO O Me N O MeO MeO Me 1 2a, R= H 2b, R= Me 3 4 5 6 i, ii iii iv v vi TETRAHEDRON LETTERS Tetrahedron Letters 42 (2001) 2307–2308 Pergamon First total synthesis of the 1,2,3,4-tetrahydronaphtho[2,1-f ]isoquinoline annoretine M. Carme Pampı ´n, Juan C. Este ´vez, Luis Castedo and Ramo ´n J. Este ´vez* Departamento de Quı ´mica Orga ´nica and Unidad Asociada al Instituto de Investigaciones Quı ´micas (CSIC), University of Santiago, 15706 Santiago de Compostela, Spain Received 25 January 2001; accepted 29 January 2001 Abstract—Here we describe the first total synthesis of the 1,2,3,4-tetrahydronaphtho[2,1-f ]isoquinoline (6) annoretine from N-carbethoxy-o -styrylphenylethylamines 2. The key steps were the Bischler–Napieralski reaction to form the isoquinoline unit and photocyclization of the resulting 5-styrylisoquinoline 3 to naphtoisoquinoline 4. © 2001 Elsevier Science Ltd. All rights reserved. The only natural products containing the 1,2,3,4-tetra- hydronaphtho[2,1-f ] isoquinoline skeleton are the rela- tively recently discovered alkaloids annoretine (6) 1 and litebamine. 2 This explains why the 1,2,3,4-tetra- hydronaphtho[2,1-f ] isoquinoline skeleton has received little chemical attention apart from a preliminary study of synthetic approaches 3 and a biomimetic synthesis from its probably biogenetic precursor boldine. 4,5 How- ever, pharmacological studies have established the antiplatelet effects and the anti-acetylcholinesterase activity of litebamine and the cytotoxic properties of annoretine. 6 Additionally, tetrahydronaphtho[2,1-f ]- isoquinolines are potential antibacterials and antitu- morals because they have a tetracyclic ring system that Scheme 1. Pd(OAc) 2 (10% molar), Ph 3 P, Et 3 N, MeCN, argon, 80°C, 24 h; (ii) (a) NaH, THF, rt, 30 min; (b) MeI, rt, 3 h; (iii) 5:3 Tf 2 O/DMAP, CH 2 Cl 2 , argon, 0°C, 1 h; (iv) UV light, I 2 ,O 2 , 95:5 Et 2 O/CH 2 Cl 2 , 2 h; (v) BCl 3 , CH 2 Cl 2 , argon, rt, 15 min; (vi) LiAlH 4 , THF, rt, 5 h. * Corresponding author. Tel.: +34 981 563100 ext. 14242; fax: +34 981 591014; e-mail: qorjec@usc.es 0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII:S0040-4039(01)00168-X