Total Synthesis of Amphidinolide F

Total Synthesis of Amphidinolide F

Gaelle Valot, Christopher S. Regens, Daniel P. O’Malley, Edouard Godineau, Hiroshi Takikawa, and Alois Fürstner

DOI: http://dx.doi.org/10.1002/anie.201301700

 

Finally I found the time finish this nice paper form the Fürstner group. I was super busy the last weeks finishing some reports but I really wanted to feature this cool piece of work. This is the second total synthesis of amphidinolide F published so far, the first one dating back to 2012.[1]

Due to a promising biological profile i.e. exhibition of high cyctotoxicity against lymphoma and epidermoid carcinoma cells quite some endeavors towards syntheses of the amphidinolides have been undertaken. It should be noted that only amphidinolide C proved to be highly bioactive.

The general synthetic plan is outlined in scheme 1. The key steps being first the disconnection of the uncommon 1,4-diketone into a homopropargyl alcohol to give 2 which could be assembled by a RCAM to give acyclic precursor 3: This was broken down into three fragments of similar complexity which were stitched together by a Stille coupling and an esterification.

Scheme 1

 scheme_1_17052013

The synthesis of red fragment 4 began with monosilylation of propanediol and TEMPO oxidation to give aldehyde 7. Palladium mediated Marshall reaction furnished alcohol 8 which was pushed forward to aldehyde 9 through a four-step sequence consisting of deprotection/bis-protection/mono-deprotection/oxidation. A second indium mediated Marshall reaction yielded bisalkyne 10 in good yield. After TBS protection of the free alcohol a nice sila-cupration with subsequent methylation gave enyne 11. Next the TMS group was removed, the resulting alkyne methylated and the vinyl silane transformed into the corresponding vinyl iodide producing red fragment 4 in good overall yield.

 Scheme 2

scheme_2_17052013

Blue fragment 5 was synthesized in a straightforward manner starting from readily available epoxide 12 which was alkynylated with propyne to give alcohol 13. The next step made use of a facile cobalt mediated Mukaiyama oxidative aerobic cyclization yielding tetrahydrofuran 14.[2] Parikh-Doering oxidation and subsequent N-methylephedrine mediated alkenylation furnished diene 5.

 Scheme 3

scheme_3_17052013

The synthesis of green fragment 6 began with elaboration of readily available lactone 16 which was protected and methylated to give 17. Monoreduction and Wittig olefination provided alcohol 18 and after TBAF mediated cyclization followed by trityl cleavage tetrahydrofuran 19. Swern oxidation and subsequent proline catalyzed aldol reaction delivered ketone 20 which was protected and transformed into silyl enol ether 21. Palladium mediated stannylation and saponification of the ethyl ester then generated green fragment 6.

 Scheme 4

 scheme_4_17052013

With all three fragments in hand the group could finally stitch everything together. Blue and green fragment 5 and 6, respectively were combined under Yamaguchi esterification conditions. After some optimization fragments 22 and 4 could be joined together in a facile Stille coupling to give RCAM precursor 23 in moderate yield.

Two strategies were probed for the next step which turned out to give very similar yields. In a first shot the RCAM was run first with catalyst A followed by PPTS mediated TES deprotection. In a second round the TES group was removed first and the RCAM run in the presence of catalyst B.

 Scheme 5

 scheme_5_17052013

The resulting homopropargyl alcohol was then cyclized with catalytic PtII to give an intermediate dihydrofuran which was opened up to provide ketone 23. Ley oxidation and final global desilylation of three TBS groups under earlier reported deprotection conditions yielded amphidinolide F in good overall yield.

 

Scheme 6

 scheme_6_17052013

[1] It just happened to be that I am currently working next to the guy who completed the first total synthesis of amphidinolide F… which is pretty cool J

[2] The cited Pagenkopf paper states that the advantage of this second generation catalyst is the separation of the product from the catalyst which was a main drawback of earlier published systems. DOI: http://dx.doi.org/10.1021/ol9023375

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