This paper presents a short synthesis of oncinotin-1 I-one (ll), a minor alkaloid of Oncinotis tenuiioba (Apocynaceae). Based on a disconnection approach, the spermidine portion of the key intermediate 6 was constructed consecutively by simple N-alkylations starting from ethyl piperidine-2-carboxylate (1). Treatment of 6 with in situ lithiated 2-[(10-bromodecyl)oxy]tetrahydropyran resulted in the formation of the keto moiety under simultanous deprotection of the lactarn N-atom to give the amino ketone 7 in 71% yield. Cleavage of the tetrahydro-2H-pyran-2-yl (Thp) portion and Jones oxidation of the resulting alcohol 8 gave the amino acid 9 which was cyclized. Final N-debenzylation of 10 provided the natural alkaloid 11. Only two protective groups were needed in this synthesis. The reaction of N-alkyl-lactams with organometallic reagents is discussed.
1. Introduction.
-Oncinotin-11-one') (11) was isolated as a minor constituent from the leaves of Oncinotis tenuiloba STAPF accompanied by other bicyclic macrolactam alkaloids of the same structural type, representing the so-called oncinotines [l]. Since the structure of 11 (Scheme 1) was deduced by spectroscopic means, synthetic material was necessary to establish the structure by comparison of the spectroscopic data and chromatographic properties.
The original isolation of the parent 1 1-deoxo congener oncinotine has been reported in 1968 [2], and its first synthesis was completed in 1974 [3]. A more general synthetic access to oncinotine-type alkaloids was elaborated two years later, based on the typical protective-group approach commonly encountered with the preparation of polyamine alkaloids [4]. In a more recent synthesis of the structurally related inandenin-12-one, a Rh/Pd-mediated macrocyclization was chosen as the key step. Initial formation of the N( 5)-C(6) bond led to an unsaturated intermediate which in situ underwent a second ring closure (N(5)-C( 10)) affording oncinotin-12-one, but only scant experimental details were reported IS]. A different route leading to oncinotine derivatives involves the preparation of inandenin-10-one via ring enlargement (Zip reactions). Following intramolecular reductive amination, formation of the N(5)-C(10) bond finally leads to oncinotine [6]. Recently, (-)-oncinotine was synthesized in optically pure form starting from N-protected (S)-piperidine-2-acetaldehyde. Oncinotine was obtained via formation of the C(4)-N(5) bond by an intramolecular iminium ion cyclization [7] [8]. I) ' )