Eleutherobin

The generosity of mother nature is limitless and it will not stop giving for humankind to thrive. Besides that, nature has been a close friend with chemists especially organic chemists. Complex structures of natural products have been a great interest as it provides to develop synthetic methods to synthesise natural products. One of the 'hunting grounds' of synthetic organic chemists is the sea, and one of the products is called eleutherobin, 1.

Eleutherobin can be isolated form a species of marine soft corals Eleutherobia collected in the Indian Ocean near Bennett's Shoal in Western Australia. Despite its rarity, eleutherobin is a potent compound against selected breast, renal, ovarian, and lung cancer cells. This highly potential compound drove Nicolaou's group to synthesise this compound.

The structure of eleutherobin is quite complex as it has tricyclic skeleton and two side chains containing methylurocanic acid residue and arabinopyranose unit. The strategy to synthesise 1 is based on the retrosynthetic analysis below indicating the strategic disconnection.

Disconnection strategy of eleutherobin

From this disconnection, a modified carvone compound was used as the starting material of this synthesis.

Construction of glycosylated ynal 17

A modified carvone 2 underwent aldol-type reaction to introduce ketone functional group which then reacted with Grignard reagent 5 forming 6. This alkyne functionality would be used to close the ring.
After forming 6, alcohol groups was protected with TES group followed by selective deprotection leaving primary alcohol unprotected which then oxidised to give 9. The formed aldehyde 9 then underwent Knoevenagel condensation to give 11 which then reduced by DIBAL to give 12. The formed alcohol functionality was used to connect with protected D-arabinopyranose, which synthesised separately from 13, to give 17. The formed 17 existed as both anomers, with β-glycosidic bond is the intended product. The main building block of main skeleton is completed, so the next step would be closing the main ring and attaching the urocanic acid group.

Total synthesis of eleutherobin 1

The cyclisation of the main skeleton of 1 was done by deprotonation of alkyne group by LiHMDS which then acted as nucleophile to attack the aldehyde giving 19. The formed alcohol then oxidised by Dess-Martin periodinane to give 20 to give conjugated keto-ene-yne moiety. Following the formation of 20, deprotection of PMB group using DDQ then followed by protection using acetyl group were done; TES groups were deproctected afterwards using TBAF. Then, alkyne group was reduced using H₂ and Lindlar's catalyst to give Z-alkene which makes one of the OH group could attack the ketone to give the 5-membered hemiacetal group and combination of PPTS and MeOH gave the intended acetal group and finishing the construction of main skeleton of 1, The attachment of 25, which was prepared separately from its ethyl ester, was done under basic condition and DMAP and the synthesis was completed.

The structure and synthesis of eleutherobin analogues 27 and 30

The synthesis of 1 gave a new pathway to synthesise the analogue compounds to investigate its potency. The anomer of 1 with α-glycosidic bond, which was synthesised as well using the same method, and another analogue by replacing urocanic acid with thiazole functionality showed a comparable potency with Taxol; The potency of of 1 showed a consistency with the one isolated from nature.

This study shows a new pathway to synthesise 1 and its analogues in practical scale. Besides that, this synthesis allowed to assign the absolute stereochemistry of 1. Furthermore, this synthesis can be applied for larger scale of 1 and the generation of combinatorial libraries of 1 for chemical biology studies are possible.

Reference
K. C. Nicolaou, F. van Delft, T. Ohshima, D. Vourloumis, J. Xu, S. Hosokawa, J. Pfefferkorn, S. Kim, and T. Li, Angew. Chem. Int. Ed., 1997, 36, 2520-2524.