A Concise Synthesis of Berkelic Acid Inspired by Combining the Natural Products Spicifernin and Pulvilloric Acid

A Concise Synthesis of Berkelic Acid Inspired by Combining the Natural Products Spicifernin and Pulvilloric Acid

Christopher F. Bender, Francis K. Yoshimoto, Christopher L. Paradise, and Jef K. De Brabander
DOI: http://dx.doi.org/ja905387r

Hey fellas,

really good stuff was published the last months and it was difficult to make a decision

… so I chose a synthesis from the De Brabander group published in July.

Though total syntheses from the Snider and Fürstner groups were published in 2008 and 2009 respectively there is always room for improvements because it shows some interesting biological activity:

Berkelic acid possesses selective activity against human ovarian cancer cells so a support of synthetic material is needed for further studies. Interestingly the true structure of berkelic acid was unknown until the synthesis from the Snider group in 2009.

Synthesis:

To shorten my review I will focus on the key step but discussions about specific reactions are welcome (I’m still trying to improve my style).

Retro:

retro_051109

The group recognised the fact that berkelic acid might be formed by a DA reaction of the already known compounds spicifernin and pulvilloric acid whose total syntheses were published some years ago.

Synthesis of the red fragment:

scheme_1_051109

A tBu-Valine enamine directed alkylation was followed after hydrolysis by a TiCl4 promoted aldol reaction giving the required α-β-unsatured ketone. A copper catalysed, anti-selective Michael addition with TMS-butyne, TMS and PMB-ether cleavage then gave the red fragment in good overall yield.

Synthesis of the blue fragment:

scheme_2_051109

A regioselective triflate formation/Suzuki-Miyaura reaction yields the symmetrical bis-hydroxy acid which was protected as the MOM-ether, epoxidized and hydrogenated at the benzylic position to give the racemic alcohol shown. Stereoselective Lipase catalysed acetylation of the R-alcohol and Mitsunobu reaction of the other enantiomer gave the required fully protected dihydroxy benzoic acid. Deprotection and exposure to TEOF/TFA yields the blue fragment through an oxo-Pictet-Spengler reaction again in an overall excellent yield.

Key step:

scheme_3_051109

Combining the 2 fragement in the presence of AgSbF6 produced berkelic acid methyl ester and additional diastereomers which could be separated after deprotection with (Bu3Sn)2O.

Mechanism:

mechanism_051109

3,5eq of AgSbF6 were required for the last transformation which can easily be seen from a mechanistic analysis:

The first equivalent produces the exo-methylene tetrahydrofuran, the second equivalent acts as a Lewis acid and oxidises the aromatic ring by cleaving the ethyl acetal. After formation of the required quinone methide the third equivalent catalyses the [4+2] addition yielding berkelic acid as the main diastereoisomer.

Nice work and sorry for the late review; I printed it some months ago but hm… it got lost 🙂

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