Enaminone-Based Synthesis of Dipodazine Derivatives by Jernej Wagger, David Bevk, Anton Meden, Jurij Svete*, and Branko Stanovnik* Faculty of Chemistry and Chemical Technology, University of Ljubljana, P.O. Box 537, SI-1001 Ljubljana, Slovenia (phone: + 386-1-2419100; fax: + 386-1-2419 220; e-mail: jurij.svete@fkkt.uni-lj.si, branko.stanovnik@fkkt.uni-lj.si) A series of racemic dipodazine analogues 9 were prepared in 22 – 80% yield from (3Z,6RS)-3-[(dime- thylamino)methylidene]-6-methyl-1-(phenylmethyl)piperazine-2,5-dione (7)(Scheme 1), which was pre- pared in four steps from (RS)-alanine methyl ester hydrochloride. The preparation of nonracemic 7 from (S)-alanine methyl ester hydrochloride failed, since the introduction of the enamino functionality at posi- tion 3 of the precursor 6 was accompanied by almost complete racemization. Introduction. – Many marine natural products with potent pharmacological activi- ties contain an indole nucleus [1]. Such indole derivatives are, e.g., aplysinopsins (1; Fig. 1), which have attracted considerable interest due to their cytotoxicity towards cancer cells and their ability to affect neurotransmitters [2]. Recently, the nortopsentins and meridianins (2), another series of indole alkaloids with interesting antitumor proper- ties, have been isolated from the sponge Spongosorites ruetzleri, and from tunicate Aplidium meridianum [3]. Structurally, the meridianins comprise a brominated and/ or hydroxylated indole nucleus bearing a 2-aminopyrimidine substituent at the 3-posi- tion [4] , and they are potent inhibitors of several protein kinases [5] . Other interesting biologically active indole alkaloids are 1) tryptophan-dehydrobutyrine diketopipera- zine (TDD; 3) [6] , a fungal metabolite isolated from Streptomyces spectabilis and Strep- tomyces sp. M1513-bF5; 2) barettin (4) [7], isolated from the marine sponge Geodia barretti, a diketopiperazine condensation product of 6-bromodehydrotryptophan and arginine; as well as 3) dipodazine (5) [8], a diketopiperazine derivative composed of dehydrotryptophan and glycine, which has been isolated from Penicillium dipodomyis and meat-associated P. nalgiovese. The syntheses of compounds 3 – 5 and their ana- logues include condensation of 1H-indole-3-carbaldehyde with piperazine-2,5-dione derivatives as the key-step [6 – 8]. Alkyl 3-(dimethylamino)propenoates and related enaminones have been recently used as building blocks for the preparation of dehydro-alanine derivatives and many heterocyclic systems such as fused pyridines, pyrimidines, pyranones, and other com- pounds, including some natural products (e.g., indole alkaloids) and their synthetic ana- logues [9]. Various chiral analogues of 3-(dimethylamino)propenoates have also been prepared from commercially available, enantiomerically pure starting materials such as a-amino acids and (+)-camphor, and were employed as key intermediates and reagents in the synthesis of 1) functionalized heterocycles, e.g., 3-heteroarylalanine derivatives and related compounds, 2) heterocyclic analogues of dipeptides, and 3) terpene-func- © 2006 Verlag Helvetica Chimica Acta AG, Zürich Helvetica Chimica Acta – Vol. 89 (2006) 240