Journal Name Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx Dynamic Article Links ► ARTICLE TYPE This journal is © The Royal Society of Chemistry [year] [journal], [year], [vol], 00–00 | 1 Stereoselective synthesis of (–)-lepadins A–C Mercedes Amat,* Alexandre Pinto, Rosa Griera, and Joan Bosch Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x A concise synthesis of the marine alkaloids (–)-lepadins A–C 5 from a phenylglycinol-derived tricyclic lactam is reported. Key steps from the stereochemical standpoint involve stereoselective cyclocondensation, double bond hydrogenation, oxazolidine opening, hydroboration- oxidation, and Horner-Wadsworth-Emmons reactions. 10 The lepadin alkaloids are a small group of cis- decahydroquinoline alkaloids isolated during the period 1991- 2002 from different marine sources such as the tunicate Clavelina lepadiformis 1 and its predator the flatworm Prostheceraeus villatus, 1b as well as the Australian Great Barrier Reef tunicate 15 Didemnun sp. 2 and ascidian Aplidium tabascum. 3 Structurally, all of them incorporate a methyl substituent at the C-2 position of the decahydroquinoline nucleus, a functionalized eight-carbon chain at C-5, and a free or acylated hydroxy group at C-3. However, they display a diversified array of relative 20 stereochemical relationships (Fig 1). Lepadins A and B have been shown to exhibit significant in vitro cytotoxicity against several human cancer cell lines. 1b In addition, lepadin B is a potent blocker for neuronal nicotinic acetylcholine receptors. 4 Lepadins D–F have low cytotoxicity but significant and selective 25 antiplasmodial and antitrypanosomal activity. 2 Further pharmacological research on these alkaloids has been hampered by the low quantities of samples available from natural sources. This has stimulated considerable synthetic effort in this area, 5 although the development of facile enantioselective routes to 30 lepadins or synthetic analogs is still required. Fig. 1 Lepadin alkaloids. In the context of our studies 6 on the use of phenylglycinol- 35 derived chiral tricyclic lactams for the enantioselective synthesis of alkaloids, we present herein a straightforward synthesis of (–)- lepadins A–C. Our approach takes advantage of unsaturated tricyclic lactams B, functionalized platforms that are assembled in a 40 straightforward manner by a cyclocondensation reaction between (R)-phenylglycinol and an appropriate cyclohexenone-derived δ- keto ester A. As outlined in Scheme 1, the synthesis of lepadins A–C from lactams B would involve (i) the stereoselective hydrogenation of the C–C double bond to obtain the required 45 configuration at C-5, (ii) the stereoselective opening of oxazolidine ring to give the natural cis-decahydroquinoline stereochemistry, (iii) the stereoselective introduction of the C-2 methyl and C-3 hydroxy substituents, taking advantage of the lactam carbonyl, and (iv) the elongation of the C-5 side chain. 50 Scheme 1 Synthetic strategy. 55 As a model system for evaluating the viability of our strategy, we selected the known 6 lactam 1, which lacks the functionalized carbon chain at C-5 but bears a methyl substituent instead. Slightly disappointingly, reductive cleavage of the oxazolidine C–O bond using Et 3 SiH/TiCl 4 took place with only moderate 60 stereoselectivity, leading to decahydroquinolone 2a as a 5:1 mixture of cis/trans epimers. A great improvement was achieved by using LiAlH 4 /AlCl 3 as the reductant, cis-decahydroquinoline 2b being stereoselectively obtained under these conditions. Although alane additionally caused the reduction of the lactam 65 carbonyl, this functionality was satisfactorily reinstalled, after N- debenzylation with simultaneous N-Boc protection, by ruthenium-promoted oxidation 7 of N-Boc derivative 3 (Scheme 2). From the resulting N-protected lactam 4, the introduction of