Enantioselective Formal Total Synthesis of (+)-Aspergillide C

Enantioselective Formal Total Synthesis of (+)-Aspergillide C

Joseph D.Panarese and Stephen P.Waters (this review)
DOI: http://dx.doi.org/10.1021/ol902154p

Tomohiro Nagasawa and Shigefumi Kuwahara (last 3 steps)
DOI: http://dx.doi.org/10.1021/ol802803x

Today I will present to you a short formal synthesis of Aspergillide C which makes use of a nice hetero DA followed by a Ferrier-type addition. The last 3 steps were taken from a synthesis published 9 months earlier. You should have a look in it.

I know there’s no KCN-like “never-used-before-in-total-synthesis”-chemistry in it but I were taken with how they accomplished this synthesis in only 9 steps as the longest linear sequence. Efficient and short as expected from a OL paper.

Let’s have a look at the retro:

Scheme 1

AspergillideC_retro_17.10.09

(I really like these paper with the retro already in it :))

As you can see they started with commercially available starting materials employing a DA, Ferrier alkylation and Pd(II)-catalysed lactonization. After installation of the side chain via Julia-Kocienski and macrolactonization they furnished Aspergillide C as described in the earlier synthesis from Nagasawa and Kuwahara.

Ok, before I forget it: the biological activity is again really interesting as Aspergillide C displays cytotoxicity against mouse lymphocytic leukaemia cells with a LD50 of 2µg/ml (don’t know why they did not use the IC50 value because as far as I know this is more significant…).

Scheme 2
scheme_2_171009

Starting as mentioned above with a hetero DA catalysed by zinc chloride gave the desired γ-pyrone which was stereoselectively reduced under Luche conditions and acetylated. A lithium perchlorate mediated Ferrier-type alkylation followed by Pinnick oxidation furnished the carboxylic acid which was cyclised to the lactone by a Wacker-type oxidation (take a look at the double bond which moves around the ring; nice). Now we have our red fragment in hand.

The mechanism of the Ferrier-type alkylation might look like this:

Scheme 3

mechanism_171009

Lithium mediated vinylogue elimination of the acetate followed by anti selective addition of the TBS enol ether yields the product shown.

Next the preparation of the Julia fragment:

Scheme 4

scheme_3_171009

They started with the commercially available hexenol which was protected, hydroborated and oxidised to the satured alcohol shown. Thioether formation under Mitsunobu conditions followed by ammonium heptamolybdate oxidation gave the green fragment in high yield.

The 2 fragments were combined after deprotection and diol cleavage of the red fragment under modified Julia-Kocienski conditions (normally it makes use of KHMDS).

Scheme 5

scheme_4_171009

The rest of the synthesis was taken from the earlier published paper.

Hydrolysis, TBS protection and PMB ether cleavage yields the free acid which was cyclised under Yamaguchi conditions. A bit of TBAF then furnished the desired product in good overall yield.

Scheme 6

scheme_5_171009

As mentioned earlier a very short and efficient synthesis again (17% yield over the longest linear sequence starting from protected glyceraldehyde) but hey, it serves the purpose.

I hope you enjoy reading this review though it is a bit shortspoken.

Ok, and next time I will feature a paper with this KCN-like chemistry, promised 🙂

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One Response

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