N N Hachijodine G (2) N N OH Hachijodine F (1) N Common intermediate 3 OH TETRAHEDRON LETTERS Tetrahedron Letters 43 (2002) 2745–2747 Pergamon Total synthesis of cytotoxic sponge alkaloids hachijodines F and G William R. F. Goundry, Victor Lee and Jack E. Baldwin* The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX13QY, UK Received 16 January 2002; revised 15 February 2002; accepted 21 February 2002 Abstract—The total synthesis of two cytotoxic sponge alkaloids hachijodines F (1) and G (2) via a common intermediate 3 is described. © 2002 Elsevier Science Ltd. All rights reserved. Hachijodines F (1) and G (2) are 3-alkylpyridine alka- loids recently isolated among other alkaloids from the marine sponge of the genera Amphimedon. 1 Both 1 and 2 were found to be cytotoxic towards P388 murine leukaemia cells with IC 50 at 1 g/mL. The structures of 1 and 2 were established via NMR spectroscopy and mass spectrometry. The relatively low abundance of 1 and 2 from the natural source (10.2×10 -4 % and 30.2× 10 -4 % yield, respectively) and their interesting biologi- cal property prompt us to investigate their synthesis. Herein we describe the successful total synthesis of 1 and 2. The synthesis of 1 and 2 makes use of compound 3 as a common intermediate. The preparation of 3 is shown in Scheme 1. 5-Bromo-1-pentene 4 was treated with an excess of lithiated 3-picoline 2–5 (prepared from 3-picol- ine and LDA) in THF and DMPU to give 5 6 in 70% yield. Compound 5 was then subjected to the Lemieux– Johnson oxidation 7 to deliver aldehyde 6 in 73% yield. Conversion of 6 to acetylene 3 was effected in 79% yield with dimethyl(1-diazo-2-oxopropyl)phosphonate in the presence of potassium carbonate and methanol 8 (Scheme 1). The synthesis of hachijodine F (1) commenced with the selective monobromination 9 of octane-1,8-diol 7 to give 8-bromooctan-1-ol 8 in 95% yield. Compound 8 was converted to its tert -butyldiphenylsilyl ether 9 in 89% yield with tert -butyldiphenylsilyl chloride and imida- zole. 10 Iodide 10 was obtained in 95% yield from 9 via a Finkelstein reaction. 11 Compound 10 was reacted with the acetylide anion generated from 3 (3+ n BuLi in THF/DMPU) to deliver 11 in 48% yield. 12 Deprotec- tion of 11 was effected with ammonium fluoride in methanol 13 to afford alcohol 12 in 90% yield. Reaction of 12 with p -toluenesulphonyl chloride and triethylamine 14,15 gave tosylate 13 in 67% yield. Com- pound 13 was subjected to nucleophilic displacement with N -methylhydroxylamine under the modified Mukaiyama conditions 16 to give hachijodine F (1) in 61% yield (Scheme 2). The synthesis of hachijodine G (2) began with the selective protection of nonane-1,9-diol 14 with tert - butyldiphenylsilyl chloride with Hunig’s base in N,N - * Corresponding author. E-mail: j.e.baldwin@chem.ox.ac.uk 0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved. PII:S0040-4039(02)00379-9