Totally Synthetic by Paul H. Docherty, 13 January 2009
Total Synthesis of Phorbasin C
Micalizio
T. K. Macklin, G. C. Micalizio, J. Am. Chem. Soc. 2009, 131, 1392-1393.
DOI: 10.1021/ja809491b
This family of diterpenes has a pretty novel architecture. The unsaturated sidechain is intriguing, as skipped conjugation is difficult to construct and maintain. Phorbasin C also inhibits bacteria growth, and offers some cytotoxicty, but the compound is more an interesting test case for new synthetic methodology. Micalizio deals with the chemistry and the C-11 stereocenter, which was unassigned when they started their work…
As they didn’t know the configuration of the methyl group, they designed a route where the sidechain could be appended late-stage, and thus easily varied. This left them with the cyclohexenone as the initial target, and they decided to start with the ring already in place.
The starting material is cyclohexadiene bearing an asymmetric glycol and vinyl bromide. However, the compound is very expensive. The other problem is instability - I quote from the Sigma Aldrich website:
To recover the pure product from the suspension:
(1)Thaw the frozen suspension and filter the solid. (2) Rinse bottle with a few
milliliters of base-washed (aqueous Na2CO3) ethyl acetate. (3) Use the rinsing
to wash the solid. (4) Collect solid. (5) To further collect more product from
the filtrate: extract filtrate with equal volumes of base-washed (aqueous Na2CO3) ethyl acetate (repeat three times). (6) Dry the ethyl acetate extract
over MgSO4. (7) Evaporate the solvent - DO NOT HEAT! (8) Combine solids
collected from the suspension and the filtrate. Pure crystals should be stored
at -78°C. A suspension of the product in phosphate buffer is stable at 0°C.
However, from a chemistry point of view, it leads straight into their synthetic centrepiece: a titanium mediated coupling of TMS-propyne. This allows direct coupling (or rather a metallo-[3,3] rearrangement) of an unfunctionalised alkene with the silyl acetylene with exquisite control over the stereochemistry. A very interesting coupling, with more details here.
From a very complex reaction to a simple: deprotection of an acetate. However, they had to be careful, as monodeprotection of one acetate was desired. The use of scandium triflate provided site-selective deprotection. Presumably the rationale is neighbouring group participation…
To complete their work, a pair of Suzuki couplings with the enantiomeric sidechains was required. Unfortunately, this reaction seems to be problematic, as they needed to use several equivalents of thalium carbonate. However, their approach was ultimately successful, as one of their products bore an exactly opposing optical rotation to the isolate: the enantiomer. So their total synthesis led to ent-phorbasin C, but they did all the hard work for the group that makes the natural enantiomer.
Selected Comments
I would agree with you milkshake, thallium pulls iodide right out of reaction making it the far superior choice for this type of mild Xcoupl.
Hudlicky gets the start material stuff from bacterias fed with bromobenzene. It would get much cheaper if there was a big-scale application for it. (Fully-protected Lipitor homochiral sidechain costs only few USD thousands per kilo, even though it is made by a 5+ step sequence).
I speculate thalium is there to eat I(-) that normally complexes to Pd(0) strongly. If I remember correctly from Heck chemistry Pd hydrides such as L(n)PdH are rather stable in presence of iodide and are slow to disproportionate to Pd(0), Pd-hydride species can cause C=C migration, leading to the thermodyn. most stable olefin. To prevent this they would add thallium or silver salt into their Heck system.