Total Synthesis Blog

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.