Total Synthesis of Cyathin A3 and Cyathin B2

Total Synthesis of Cyathin A3 and Cyathin B2

Part II – Retro schemes from Snider and Trost

As requested (from krest17) here are the two retro schemes from the Snider and Trost groups.

If you are interested in getting further details you find the links to the syntheses in the header.

(I prefer the one from the Trost group, again very cool transition metal chemistry)

Snider’s synthesis : http://dx.doi.org/10.1021/ja9615379

retro_snider_08.07.09

Trost’s synthesis: http://dx.doi.org/10.1021/ja0435586

retro_trost_08.07.09

I skipped the details but if you want to we can discuss them here…

Total Synthesis of Cyathin A3 and Cyathin B2

Keunho Kim and Jin Kun Cha

DOI: http://dx.doi.org/10.1002/ange.200901669

29.06.09_1

This time two diterpene natural products which were first isolated in the 1970’s by Ayers and co-workers and subjected to a number of total syntheses. If you’re interested, some older syntheses can be found from the Snider and Trost group during which the starting material for this approach was synthesied.
Before you ask why they did another synthesis of these two molecules one should remember the significant biological properties which lay in the stimulation of nerve growth factors and can therefore be used as models for synthetic analogues.
And because it’s another cool approach…

So let’s begin with the retro (I do like paper were they put in their retro… less work for me):

29.06.09_2

They planned as the key step a Prins-pinacol like tandem reaction (a reaction sequence used extensively by the Overman group) followed by a RCM reaction. The starting cyclopropanol originates from a known ester, synthesised from the Snider group in their earlier approach through a Kulinkovich reaction. This named reaction was new to me but is obviously a very useful manipulation.
So here the first scheme:

Scheme 1

29.06.09_3

We start with the above mentioned Kulinkovich reaction (the mechanism can be found in detail under the link) followed by TMSCl addition to give the cyclopropanol-TMS ether. This was reacted with dimethoxy-2-bromoethane to give after reductive elimination the intermediate cyclobutanone product. The interesting sequence here is the Prins-pinacol tandem sequence which I will present to you right now:

29.06.09_4

I suppose that the stereochemistry is fully controlled by the remote methyl group.

Next on a LHMDS induced aldolreaction with two various aldehydes was done followed by a Ti(iPrO)4 catalysed reaction similar to a Turbo-Grignard with the allylbromide shown. The resulting triene was used for a RCM to give the tetracyclic intermediate, ready for the second key step.

Scheme 2

29.06.09_5

They commenced with a radical thionylation ensued by a PPh3 * Br2 induced Grob fragmentation of the cyclobutanol to give the seven-membered unsatured ketone.
A mechanism is not given so here’s my proposal:

29.06.09_6

The styrene like double-bond was selectively dihydroxylated, cleaved with lead(IV)acetate and after decarbonylation using Wilkinson’s catalyst, realeased the quarternary methyl group.
Interestingly the PMB group cleavage gave better results than the Ph residue.

The sulfur was then oxidised using Davis oxaziridine and exposed to Pummerer rearrangement conditions (TFAA). This gives a mixture of products which were reacted without separation with acetic anhydride and mercury(II)trifluoroacetate to give in an overall yield of about 65% Cyathin B2.

Scheme 3

29.06.09_7

This could be converted to Cyathin A3 in 7 steps using standard chemistry which need no further explanation. Here the scheme:

Scheme 4

29.06.09_8

All in all another cool approach although not very atom economic. My favourites are the two presented key steps and the introduction of the methyl group through the styrene cleavage.
I would be thankful for every comment or suggestion. I’m looking forward to move this page to real .com-domain because it’s difficult to find this page with Google…

And if you’re interested in helping me with publishing reviews please send an eMail to synthetic.chemistry@googlemail.com. Help is always appreciated…

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7 Responses

  1. cool, but Turbo-Grignard is http://www.chemetalllithium.com/index.php?id=72

  2. thx for the comment…
    ok if they restrict the term “turbo-grignard” to the halogen-metal exchange to arylhalides i agree… let’s say it’s some kind of turbo-grignard…
    but the principle should be the same…

  3. it is a trade-name for iPrMgCl*LiCl, like selectride or redal.

  4. i recently heard a lecture from vic snieckus were he mentioned this combination of reagents… and yes you’re right he used it too for this Knochel reagent combined with aryl halides… changed it and cited your link…
    thx

  5. would be nice to see Snider and Trost ways – may be you can post retro-schemes – just to compare – for me posted synthesis is too long and not efficient – although one can learn out of it some new transformations

  6. k, try to finish it over the weekend. i only skimmed through the syntheses but good suggestion…
    i’m currently working on another nice synthesis from the trost group, hopefully paul did not review it before i do 😉
    thx

  7. thanks, I think he will do Vannusual – so, don’t worry

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