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Totally Synthetic by Paul H. Docherty, 11 October 2006

Total Synthesis of Antheliolide A


C. S. Mushti, J.-H. Kim, E. J. Corey, J. Am. Chem. Soc. 2006, 128, 14050-14052.

DOI: 10.1021/ja066336b

Another top total synthesis of an interesting polycyclic target, this one features a complex nine-four-six ring system at its core. The structure was determined almost twenty years ago, but the synthesis has apparently slipped through, along with the absolute stereochemistry. No details on the activity of the compound were given in the paper, but I haven't read the isolation reference yet, so perhaps it shows some activity… However, the synthesis is what we’re interested in!

After eight steps, the workers achieved a complex cyclisation precursor, full of synthetic handles. After saponification of the ester however, salt formation and treatment with tosyl chloride in base, a ketene intermediate is formed. This then performed an intramolecular [2+2] cycloaddition, generating the cyclobutane and the useful remaining carbonyl group. This transformation has been somewhat of a Corey favourite, and several references in the paper point to other work containing this style of reaction.

With the carbonyl handle, functionalisation of the cyclobutane was easy, allowing ethylation, and at this point they did a resolution via chiral HPLC. Further functionalisation led them to a β-keto sulfone, with which they did an interesting Pd catalysed [2,3]-sigmatropic rearrangement:

Again, this interesting cyclisation left them with a useful synthetic handle, as well as the desired ring (in this case a difficult to form trans-nonene); however, the sulfone was removed using Al-Hg amalgam. Completion of the synthesis was then in sight, via eventual clevage of the five-member ring (using a periodate on silica reagent), and formation of some six-member rings by stirring in silica:

Selected Comments

11 October, 2006 at 22:33, movies says:
I’ve been waiting for this synthesis to show up here
My favorite part is that the right-hand portion (the 4,9 fused system) is essentially caryophyllene, another natural product that Corey made over 40 years ago!!
Check it out: JACS 1964, 86, 485-492.
11 October, 2006 at 23:04 Ashutosh says:
Why does LiOH deprotect only the TMS and not the TBDPS group? You also must have checked Baran’s Chartelline synthesis from the same ASAP which is also pretty interesting.
12 October, 2006 at 0:46, Tot. Syn. says:
Well, the simple answer is that TBDPS is the daddy of Si protecting groups, and takes a fair beating to remove. In an uncrowded hydroxyl, TBAF will remove TBDPS, but you often have to use HF/py.
TMS is the easiest Si group to remove, and will fall-off in mild base. I’m using KOH in MeOH to do that tomorrow, in the presence of a TBDPS group. Also, the mechanisms can be different - the TMS group is protecting an acetylene, so has a different character to the TBDPS group on an hydroxyl.
12 October, 2006 at 0:49, Tot. Syn. says:
There’s some useful information about protecting groups here:
but the best place IMHO is Phil Kocienski’s book.