Total Synthesis Blog

Today, some nice-looking target – isolated from germinating sunflowers (Helianthus annus L.) – (+)-Sundiversifolide:

Nice structure and nice name (however, I prefer snow ). (+)-Sundiversifolide exhibits some interesting biological properties. For example it can inhibit root growth of some plants. Also it can inhibit (in small concentrations – about 100 μM) germination of some fungi species and therefore it can be used as natural herbicide.

Below I’ve shown my retrosynthetic approach to (+)-Sundiversifolide:

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The key steps involve Diels-Alder cyclization, ring expansion (with use diazo compound) and TPAP-promoted cyclization (see also Total Synthesis of Bruguierol C for other application of that key reaction). I’m waiting for your opinions.

The real retrosynthesis of (+)-Sundiversifolide is shown below:

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As you can see, intramolecular acylation with use of organolithium compound was taken advantage here to construct seven-membered carbon-framework of (+)-Sundiversifolide (with correct configurations on three stereogenic centers).

Complete synthesis of target molecule is drawn below.

(Click on image to enlarge it).

Synthesis starts with homopropargylic alcohol 2 which, first, is TBDPS-protected and then combined with paraform. In such way monoprotected unsaturated diol 3 is formed. Then triple carbon-carbon bond is reduced by Red-Al in ether to form alkene 4 in E configuration. In next step -OH functional group is exchanged to iodine which allow to alkylate 6 diastereoselectively with iodo-derivative 5 in presence of stron base (LDA). 7 is then dihydroxylated with AD-mix-β to generate 8 in situ, which undergo intramolecular reaction to form lactone 9. Free -OH functional group is then protected with TBSCl which allow to selective deprotecion of primary OH functional group with TBAF. Released OH group is exchanged to iodine under standart conditions to form iodo-derivative 12 which is used in next step.

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Organolithium compound 13 is generated in situ from iodo-derivative 12 and then intramolecular acylation reaction happens. Hemiacetale 14 which is in equilibrium with ketone 15 is result of this reaction. To shift equlibrium to ketone 15 reaction with TBDPSCl is performed.

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Then Grignard reaction occured to form 17 and TBS-protected alcohol was deprotected to release OH functional group. Newly formed -OH group was then oxidised and hemiacetale 19 (in equilibrium with corresponding ketone) was created. Next, deprotection of 19 occured followed by reaction with phosphorus ylide. Result of this reaction was forming 23 which contain fused seven- and – fivemembered rings. Next, exo ethylene group of 23 was converted to corresponding epoxide. That step allowed to stereoselective saturation double carbon-carbon in ring by “nickel borides”. Then dehydratation under kinetic control could be undergone to form 26. The last step involved reaction with ZnI₂ and NaBH₃CN (regioselective reduction of epoxide ring) and (+)-Sundiversifolide was in that way synthesised.

For more see:

M.Shindo et al., Organic Lett., 2008, 10, 1247.