Total Synthesis Blog

Deja vu? Maybe yes because (+)-Dodoneine is also – similary to hyptolide – α,β-unsaturated δ-lactone. Just look at the structure of (+)-Dodoneine:

It’s not so complicated (it has only two chiral carbon atoms, hyptolide – four) as hyptolide, but synthetic approach to this target is quite different than to previous one.

But now, let’s say something about its biological properties.

(+)-Dodoneine was isolated from methanolic extract from plant called ‘african mistletoe’ with very nice-sounded latin name Tapinathus dodoneifolius. This plants grow somwhere in West Africa. Authors of paper wrote that ‘african mistletoe’ is applied in treatment of wide spectrum of diseases, including cardiovascular and respiratory. It’s also used as remedy aganist cholera, diarrhoea, stomach ache and wounds. It’s possible that (+)-dodoneine could find interesting medical applications.

In my opinion, (+)-Dodoneine can be synthesized analogically like hyptolide. Proposition of retrosynthesis is shown below:

Authors have chosen other synthetic route:

As you can see – only two olefinations and only two stereoselective aldol condesations. Full retrosynthetic analysis is shown below:

Ok. As you can see, total synthesis starts with p-hydroxybenzaldehyde (2) which is undergone some kind of Wittig-type reaction to give α,β-unsaturated ethyl ester 3. Then phenolic -OH group is protected. In next step 4 is first reduced by LiAlH₄ and then oxidized to form aldehyde 5. It’s interesting that LiAlH₄ can reduce ester functional group and carbon-carbon double bond.

Now, stereoselective Crimmins aldol reaction can be carried out. I’ve never heard about this reaction before, but it looks promisingly. Reagent 6 can be divided into two parts: real reagent which is blue (or something like that;) ) and chiral auxiliary (which is, say, red;) ). Diastereselectivity of the reaction isn’t very high, but I think that is acceptable. Diasteroisomers 7a and 7b could be easily separated.

Hydroxy group of 7a was then TBS-protected (in the presence of base called 2,6-lutidine which is of course 2,6-dimethylpiridine) to give 8. Now, chiral auxiliary is removed by using reducing agent – DIBAL-H. Released aldehyde 9 combines with Crimmins reagent (6) again to give diasteroisomers 10a and 10b.

Following two steps are protection and removal of chiral auxiliary. Now, aldehyde 12 is undergone olefination reaction. Do you remember reagent 13, that nice modified phosphonate? Well, people who done total synthesis of hyptolide talked about Still olefination. Now – the same reaction is called Horner-Wadsworth-Emmons olefination. Well, I’ll be saying just “Wittig-like”

One-pot removal of all protecting groups from 14 gives desired target (+)-Dodoneine, 1:

Final product does not forms purely because there are significant amounts of (+)-Dodoneine ‘internal adduct’ (formed in internal Michael reaction):

Forming of 15 critically depends on hydrolytic conditions.

For more of course see:

P. Srihari, G. Rajendar, R. Srinivasa Rao, J. S. Yadar, Tetrahedron Lett., 2008, 49, 5590.