Facultat de Farmàcia
Laboratori de Química Orgànica
Avda. de Joan XXIII, s/n.
08028 Barcelona
Tel. +34 93 402 45 37
Fax +34 93 402 45 39
Màster de Biotecnologia Molecular
Oferta per a la realització del treball fi de màster
Enantioselective synthesis of marine alkaloids of the lepadin group
Responsable del treball: Mercedes Amat Tusón (amat@ub.edu)
Departament de Farmacologia i Química Terapèutica
Facultat de Farmàcia
Universitat de Barcelona
The lepadin alkaloids, comprising eight cis-decahydroquinoline members, were identified from 1991 to 2002 from different
marine sources such as the tunicate Clavelina lepadinformis, flatworm Prostheceraeus villatus, tropical marine tunicate
Didemnun sp., and Australian Great Barrier Reef ascidian Aplidium tabascum.1 Lepadins A and B have been shown to
exhibit significant in vitro cytotoxicity against several human cancer cell lines.1a,b In addition, lepadin B is a potent blocker for
neuronal nicotinic acetylcholine receptors (nAChR's).2 As these receptors are involved in several neurological disorders,
including nicotinic addiction, epilepsy, Parkinson's and Alzheimer's diseases, lepadin B could represent a new lead for the
development of nicotinic-based therapies. Lepadins D-F have low cytotoxicity but significant and selective antiplasmodial and
antitrypanosomal activity.3 These findings suggest that these compounds might serve as new lead structures for the
development of novel antimalarian drugs. However, further pharmacological research on these alkaloids is hampered by the
low quantities of available samples. Consequently, a facile route to these alkaloids or synthetic analogues is required. 4
All the members of the lepadin family contain as common structural features a cis-decahydroquinoline nucleus bearing a
methyl substituent at the C-2 position, an eight-carbon chain at C-5 that can incorporate double bonds and/or an oxygenated
functionality (alcohol or ketone), and a free or acylated hydroxy group at C-3. However, they display a diversified array of
relative stereochemical relationships at the five stereogenic centers on the decahydroquinoline nucleus (C-2, C-3, C-4a, C-5,
and C-8a). The C-2/C-3 relative configuration is cis in lepadins A-C, F, and G and trans in lepadins D, E, and H. The relative
configuration of the C-3 and C-4a stereocenters is cis in lepadins A-C and trans in lepadins D-H. The C-4a/C-5 relative
configuration is trans in lepadins A-C and cis in D-H. Finally, the relative configuration of the C-2 and C-8a stereocenters
next to the nitrogen atom is cis in lepadins A-E and H and trans in lepadins F and G. Consequently, the lepadin family can be
divided into three major subfamilies based on the relative stereochemical relationship of the stereogenic centers in the
azabicyclic nucleus.
The lepadin alkaloids
1. Enantioselective synthesis of lepadins A-C from chiral tricyclic lactams.
In previous work our research group has developed a new methodology for the enantioselective synthesis of
decahydroquinoline derivatives based on the use of chiral aminoalcohol-derived tricyclic lactams as enantiomeric scaffolds.5
Our next goal is to demonstrate the utility and versatility of this methodology for the synthesis of natural products and
biologically interesting compounds.
The synthesis of lepadins A-C from cis-decahydroquinolone 1, easily available from an appropriately C-8 substituted chiral
tricyclic lactam (Figure 1), involves the stereoselective installation of the methyl and hydroxy substituents at C-2 and C-3 of
the decahydroquinoline system and the elongation of the C-5 substituent with an appropriate seven-carbon chain. The total
synthesis of lepadins A and C would require the additional acylation of the hydroxy substituent.
Synthetic strategy for the synthesis of lepadins A-C
Figure 1
The required methyl and hydroxy substituents at the C-2 and C-3 positions, respectively, would be introduced taking
advantage of the lactam carbonyl of cis-decahydroquinoline 1 (Figure 2). The corresponding vinyl triflate 2 will be subjected
to organometallic coupling reactions in order to introduce the methyl substituent at C-2. A regio- and stereoselective
hydroboration-oxidation of the resulting enamide 3 should give the desired 3-hydroxy derivative 4. An approach of the borane
reagent from the less hindered convex face of the cis-octahydroquinoline system would lead to the C-2/C-3 trans and C-2/C8a cis relative configurations, as depicted for compound 4. Consequently, the synthesis of lepadins A-C would require the
inversion of the configuration at C-3 by using conventional Mitsunobu procedures or by oxidation and stereoselective
reduction of the corresponding ketone to give the required C-2/C-3 cis relative configuration. Finally, elaboration of the eightcarbon chain (C-1'/C-8') by Horner-Wadsworth-Emmons type reactions from the aldehyde resulting from the oxidation of the
hydroxymethyl substituent of 5 will be tested. When required, acylation of the hydroxy substituent at C-3 following reported
procedures will be carried out in order to complete the synthesis of lepadins A-C.
The C-2 methyl and C-3 hydroxy substituents
Figure 2
2. Enantioselective synthesis of lepadins D, E, and H from cis-decahydroquinoline 4.
Decahydroquinoline 4 has the correct stereochemistry at the C-2, C-3, C-4a, and C-8a stereocenters, but not at the C-5
position, for the synthesis of lepadins D, E and H. For this reason, we also plan to explore a procedure for the stereoselective
generation of C-4a/C-5 cis derivatives, by inversion of the C-5 configuration starting from 4. Oxidation of the C-5
hydroxymethyl to aldehyde 6, generation of the corresponding vinyl triflate 7, and Pd-catalyzed methoxycarbonylation would
afford the unsaturated ester 8. A catalytic hydrogenation of the carbon-carbon double bond from the less hindered convex
face of 8 should stereoselectively give cis-decahydroquinoline-5-acetate 9 with the desired configuration at C-5. Compound 9
(Pr2 = H and Pr3 = TBS) has recently been transformed into lepadins D, E, and H.
Inversion of the configuration at the C-5 stereocenter of 4
Figure 3
References
1. For isolation of (-)-lepadin A, see: a) Steffan, B. Tetrahedron 1991, 47, 8729-8732; b) for isolation of (-)-B and (-)-C, see:
Kubanek, J.; Williams, D. E.; de Silva, E. D.; Allen, T.; Anderson, R. J. Tetrahedron Lett. 1995, 36, 6189-6192; c) for isolation
(+)-D, (-)-E, and (-)-F, see: Wright, A. D.; Goclik, E.; König, G. M.; Kaminsky, R. J. Med. Chem. 2002, 45, 3067-3072; d) for
isolation of (+)-F, (+)-G, and (+)-H, see: Davis, R. A.; Carroll, A. R.; Quinn, R. J. J. Nat. Prod. 2002, 65, 454-457.
2. Tsuneki, H.; You, Y.; Toyooka, N.; Sasaoka, T.; Nemoto, H.; Dani, J. A.; Kimura, I. Biol. Pharm. Bull. 2005, 28, 611-614.
3. Wright, A. D.; Goclick, E.; König, G. M.; Kaminsky, R. J. Med. Chem. 2002, 45, 3067-3072.
4. For previous syntheses, see: a) Ozawa, T.; Aoyagi, S.; Kibayashi, C. J. Org. Chem. 2001, 66, 3338-3347; b) Kalaï, C.; Tate,
E.; Zard, S. Z. Chem. Commun. 2002, 1430-1431; c) Pu, X.; Ma, D. J. Org. Chem. 2006, 71, 6562-6572; d) Barbe, G.;
Charette, A. B. J. Am. Chem. Soc. 2008, 130, 13873-13875; e) Niethe, A.; Fischer, D.; Blechert, S. J. Org. Chem. 2008, 73,
3088-3093; f) Li, G.; Hsung, R. P.; Slafer, B. W.; Sagamanova, I. K. Org. Lett. 2008, 10, 4991-4994; g) Li, G.; Hsung, R. P.
Org. Lett. 2009, 11, 4616-4619.
5. a) Amat, M.; Fabregat, R.; Griera, R.; Bosch, J. J. Org. Chem. 2009, 74, 1794-1797; b) Amat, M.; Navío, L.; Llor, N.; Molins,
E. Bosch, J. Org. Lett. 2012, 14, 210-213; c) Amat, M.; Fabregat, R.; Griera, R.; Florindo, P.; Molins, E.; Bosch, J. J. Org.
Chem. 2010, 75, 3797-3805; d) Amat, M.; Griera, R.; Fabregat, R.; Molins, E.; Bosch, J. Angew. Chem. Int. Ed. 2008, 47,
3348-3351.