Pergamon Tetrahedron: Asymmetry 9 (1998) 4275–4284 TETRAHEDRON: ASYMMETRY Asymmetrically induced alkylation of 2-benzyl-4-isopropyl-2,4- dihydro-1H -pyrazino[2,1-b]quinazoline-3,6-dione Félix L. Buenadicha, Carmen Avendaño ∗ and Mónica Söllhuber Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain Received 6 November 1998; accepted 11 November 1998 Abstract The substitution of the 4-methyl group by a 4-isopropyl group in the 2-benzyl-2,4-dihydro-1H-pyrazino[2,1- b]quinazoline-3,6-dione system allows a notable improvement in the stereoselective alkylation at C-1. The configuration of the newly introduced stereogenic centre has been assigned on the basis of 1 H NMR data and NOE measurements. © 1998 Elsevier Science Ltd. All rights reserved. 1. Introduction By far the most popular and extensively studied glycine template among Schöllkopf’s bis-lactim ethers used as anion precursors in the synthesis of optically active α-amino acids, is that derived from valine and glycine. 1 Its homologue derived from cyclo-Val-Ala has also been used for similar purposes. 2 Anions derived from N,N ′ -disubstituted chiral piperazine-2,5-diones have been exploited to a much lesser extent than the bis-lactim ethers. Intramolecular C–C bond-forming cyclizations, 3 asymmetric induction studies 4 and enhancement of diastereocontrol by chiral relay auxiliary 5 have been reported in this context. We have shown that, because of its locked pseudoaxial disposition, the 4-methyl substituent in anions derived from 2-substituted (4S)-4-methyl-2,4-dihydro-1H-pyrazino[2,1-b]quinazoline-3,6-diones (1a and 1b) induces the asymmetric alkylation at C-1, with the preferential formation of the 1,4-anti isomers in kinetically controlled reactions. Under thermodynamic conditions, these isomers equilibrate to the more stable syn-isomers through the corresponding anions. 6,7 This tricyclic system can be considered a β-turn template and attracted our attention because it contains three of the six rings of the fungal metabolite N-acetylardeemin. This natural compound has been described as a potent reversal agent of multiple drug resistance (MDR) in tumour cell lines 8 by inhibiting the membrane glycoprotein Pgp-170, which is thought to function by lowering the intracellular levels of many antineoplastic drugs. 9 In our ∗ Corresponding author. E-mail: msollhub@eucmax.sim.ucm.es 0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved. PII: S0957-4166(98)00464-9