Total Synthesis Blog

This sunday, very simple target molecule – aplysamine 6 which shows inhibition aganist isopropenylcysteine carboxy methyl transferase (Icmt), which is important in oncogenesis. The structure of aplysamine 6 is drawn below:

Let me add that aplysamine 6 is a natural product (of course) isolated from sponge Pseudoceratina sp.

Well, that’s not very complex target and the retrosynthesis and also total synthesis should be quite easy. My idea to disconnect this stuff is something like that:

Everything should by clear. All starting materials could be prepared from phenole or from commercialy avaiable anisaldehyde.

People who did the synthesis used very simmilar approach, so I didn’t draw retrosynthesis again. One important difference is use of Perkin condensation instead of something I labeled ‘Wittig-like’ reaction Let’s see how they completed whole total synthesis.

As you can see they started with p-anisaldehyde and they brominated it in first step. Ok, reaction is slow (there’s no Lewis acid), but more interesting is that aldehyde functional group isn’t oxidizied under such conditions. Coversion 3->4 is of course mentioned Perkin condensation (well, authors wrote that is Doebner-Knovenagel condensation… ok, probably it is ). Last step in this scheme is conversion of carboxylic acid to corresponding acyl chloride.

Now, second building block is prepared. They use p-hydroxy benzyl alcohol (can be obtained from p-anisaldehyde by its reduction) as second precursor. Next substitution oh hydroxyl group is performed to give 7. It’s a question why they didn’t convert -OH to better leaving group such as tosylate and so forth. 7 is reduced on palladium catalyst to amine hydrochloride 8, which in turn is brominated to 9 (again without any Lewis acid).

In next step two building blocks 5 and 9 are coupled and amide 10 is formed. OH group from aromatic ring of 9 isn’t acylated.

10 is a core of aplysamine 6. In next two steps primary amine moiety is attached to this structural core. This is achived by use of Williamson reaction (ether formation) with 1,3-dibromopropane to form derivative 11. 11 is converted to aplysamine 6 by well-known Sn2 reaction.

For more pieces of information please see:

N. Ullah, K. M. Arafeh, Tetrahedron Lett., 2009, 158-160.