Pergamon Tetrahedron Letters 41 (2000) 2745–2748 TETRAHEDRON LETTERS A straightforward synthesis of didehydro analogues of N-acetylardeemin Juan Domingo Sánchez, M. Teresa Ramos and Carmen Avendaño * Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain Received 21 December 1999; accepted 9 February 2000 Abstract The didehydro analogue of N-acetylardeemin 1b was synthesised in a seven step process that started with tryptamine. A regioselective oxidation of the 2-substituted precursor 3b, followed by a diastereoselective anti- cyclization reaction involving an acyliminium intermediate formed from the unisolated tosylate 2b, is the key-step of this strategy. Application of this procedure to 3a afforded, instead of the cyclization product, the cis-1-hydroxy derivative 2c which, after acid treatment, gave a 6/4 mixture of trans- and cis-isomers of the hexacyclic compound 1a. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: asymmetric induction; arylation; hypervalent iodine; iminium salts. The reactivity of 2,4-substituted 2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones as glycine templates is currently being investigated 1 in our group because this system contains three rings of the hexacyclic fungal metabolite N-acetylardeemin, which is one of the most potent known inhibitors of multidrug resistance (MDR) to antitumour agents. 2 According to its peptidomimetic structure, the first total synthesis of N-acetylardeemin was performed by Danishefsky using L-tryptophan, D-alanine and o-azidobenzoyl chloride (a synthetic equivalent of anthranilic acid), as starting materials. A tandem- nucleophilic–electrophilic addition to the C(2)_C(3) indole bond of tryptophan was used to form ring C in a first step. 3 A similar cyclization on cyclo-L-Trp-L-Ala was used in the preparation of simpler analogues, 4 while in the synthesis of C-homo-didehydro analogues, a Pictet–Spengler cyclization on L- TrpOMe was used to form ring C in a first step. 5 Here we report a concise procedure to form ring C of the new didehydro analogues 1 in the last step, by using compounds 2 as precursors of acyliminium intermediates (Fig. 1). The foregoing precursors can be generated by a new regioselective oxidation of compounds 3. Synthesis of 3a from 4a has been previously reported. 6 Compound 3b (Scheme 1), was obtained by a similar route from 4b, which was readily available by alkylation of tryptamine with ethyl bromoacetate. All steps gave good yields except the condensations of the lactim ethers derived from 5 with anthranilic * Corresponding author. E-mail: avendano@eucmax.sim.ucm.es (C. Avendaño) 0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(00)00253-7 tetl 16533