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.

Today, total synthesis of hyptolide which was published in Tetrahedron Letters. Structure of target molecule is drawn below (click on images to enlarge them ):

Authors wrote about some “important biological activities” and “interesting pharmacological properties” and they wrote nothing more So, what do we have here? Well, four stereocentres, two double bonds and α,β-unsaturated δ-lactone ring makes hyptolide really nice target molecule.

Hyptolide is present in plants from family called Lamiaceae, especially in genera Hyptis and Syncolostemon. There are several compounds related to hyptolide: spicigerolide, anamarine and synrotolide. Their are shown below.

I’ve tried to plan the synthesis of hyptolide and my proposition of retrosynthesis is presented at next images.

I hope that everything is clear (P means some protecting groups)

The real retrosynthesis of hyptolide:

As you can see I’ve labeled the picture with three reactions but key transformations are connected to epoxide chemistry.

Synthesis starts with racemic allylic alcohol 5 which undergo kinetic resolution under Sharpless conditions (Sharpless epoxidation). In next few steps, involving protection/deprotection reactions, oxirane 6 is formed which in turn is converted (Swern oxidation) to α,β-unsaturated aldehyde 7:

It seems to me that mechanism of conversion 6 to 7 involve standard oxidation of primary -OH and then attack of base on α-hydrogen. Developing carboanion leads to opening of epoxide ring. That’s my theory

Let’s return to synthesis. In few next steps second epoxide 9 is generated stereoselectively. And this epoxide is reduced by titanocene-like complex. Unfortuanelly, author didn’t write anything about stereo- and regioselectivity. But 10 was obtained in 85% yield, so stereoselectivities probably were high.

Resulting 1,3-diol 10 is next protected by conversion to its acetonide 12 (in the presence of CSA – camphorsulfonic acid). Deprotection of 12 with TBAF (tetrabutylammonium fluoride) gives 13. Only primary TBDPS-protected hydroxy group was removed.

Next steps ivolve construction of Z double bond. To achive this goal Still olefination (another modification of Wittig-Horner-and so forth;)) was chosen as key reaction. Z : E selectivity of formed product was good.

Conversion of 16 to 18 is also interesting. Direct reduction of ester 16 with DIBAL-H gives allylic alcohol 17, not desired aldehyde. So, there is necessity of introduction additional step – Dess-Martin oxidation.

With 18 in hand final steps could be undergone. Allylboration of 18 gives alcohol 19 which, in turn, is converted to its acrylate. Now, everything is ready to do ring-closing metathesis (RCM) reaction and obtain framework of hyptolide 22. 22 is deprotected then and transformed to its triacetylated form – hyptolide.

As always – for more see:

T. K. Chakraborty, S. Purkait, Tetrahedron Lett., 2008, 49, 5502.

As you can see – it really doesn’t look terrible: two stereocentres and only one ring. It’s hard to believe that only several approaches to such system was developed (authors of paper claim: only four approaches). Let’s say something about biological properties of (2S,3R)-3-hydroxypipecolic acid… Well, structural feature of 3-hydroxypipecolic acid is preasent in many natural and non-natural compounds, for example tetrazomine which was isolated from Saccharothrix mutabilis and exhibiting antitumor activity (3-hydroxypipecolic acid subunit is marked):

The retrosynthesis of (2S,3R)-3-hydroxypipecolic acid is shown below:

(Click on image to enlarge it)

Retrosynthesis is very interesting because of usage of oxazoline moiety to construct stereoselectively piperidine skeleton. Nice way to do such systems, in my opinion. Also synthesis of oxazoline from acyclic precursor looks nice, especially stereochemistry of that reaction. Let’s look at synthesis of 3-hydroxypipecolic acid:

(Click on image to enlarge it)

Compound 3 is converted to oxazoline 4 by treatment palladium(0) complex with triphenylphosphine and K₂CO₃. In my opinion mechanism involves forming π allyl-palladium complex with parallel removal of OAc group. It means that in this step one stereocentre in destroyed (in my opinion of course), but second stereocentre govern stereochemistry of oxazoline ring-closure. Probably K₂CO₃ act as base which can detach hydrogen atom from NH group. Next cyclization occurs. But I can be wrong – Have you got any other suggestions?

4 is then converted to corresponding aldehyde, 5, by ozonolysis. Next, Wittig-Horner reaction is undergone and in that way α,β-unsaturated ester, 6, is formed. 6 can be then saturated by L-Selectride in t-BuOH/THF to form 7. Next hydrogenolysis occurs which produces piperidine skeleton. Other interesting step is selective TBS-deprotection: only primary alcohol group is deprotected, secondary OH group doesn’t react in such (AcOH + H₂O + THF) conditions.

My retrosynthetic approach is shown below… Well… in comparsion with mentioned retrosynthesis, my analysis looks like a little bit… childish

I’ve tride to apply in this case malonic ester-type synthesis… But this is only my try

For more see:

V.-T. Pham et al., Tetrahedron: Asymmetry, 2008, 19, 318.

That 2,6-disubstituted piperidine-derived alkaloid was isolated from plant Andrachne aspera (picture taken from http://www.teline.fr/:

Yes… target seems to be easy to synthesise, but its synthesis is quite complicated. Retrosynthesis of (-)-andrachcinidine is shown below:

As you can see intramolecular Sn2 cyclization and olefin-cross metathesis are key reactions for this synthesis.

Let’s see synthesis of compound 3:

First step leading form 5 to 7 is epoxide ring opening by hydride anion form Red-Al. Alkoxide anion is generated in such way which in turn reacts with benzaldehyde acetal – giving another acetal. That one is reduced to corresponding ether 7 by LiAlH4-AlCl3. Next, 7 is oxidised under Swern condition and formed aldehyde is stereoselectively allylated.

Also synthesis of 4 is drawn below:

Here, we have Wittig olefination of Garner’s aldehyde 6 and followed hydroboration which gives 8. Next, 8 is TBDPS-protected and then ring opening occurs in presence of copper chloride hydrate. Then, Swern oxidation and Wittig olefination of 9 are undergone to form 4.

Having synthesised 3 and 4 olefin cross-metathesis could be done.

There were a few transformations after metathesis to get final product…

For more information see:

P. R. Krishna, G. Dayaker, Tetrahedron Lett., 2007, 48, 7279.