Synthesis of the Monomeric Unit of the Lomaiviticin Aglycon

Synthesis of the Monomeric Unit of the Lomaiviticin Aglycon

K. C. Nicolaou, Andrea L. Nold, and Hongming Li

DOI: http://dx.doi.org/10.1002/anie.200902509

Hello again,

it took some time to get this post done but I was again busy learning some mathematics and physical chemistry… Boring stuff…

But nevertheless here it is: the nice KCN approach to the relatively new class of Lomaiviticins A and B which structures reminds me somewhat of a class of compounds reviewed by Paul: http://totallysynthetic.com/blog/?p=1520

So what’s it all about with this class of compounds? As usual they exhibit an impressive activity against cancer cell lines through a novel type of action which is currently under investigation. They’re acting through cleavage of the DNA in cancer cells. Interesting stuff but let’s get started with the chemistry:

(As you can see I almost got my ChemDraw installed and it’s great… much better than this shitty ISIS Draw)

Lomaiviticin

In this publication we’re dealing as mentioned above with the monomeric units of these two condensed polycycles. The retro is short and straightforward:

retro

First the blue fragment:

They started with the readily available aldehyde which was debenzylated with AlCl3, oxidised to the p-quinone which was protected as the SEM-ether after reduction to give the blue fragment:

Scheme 1

scheme_1

The synthesis of the red fragment is also very short. Readily available ethyl-cyclohexenone was exposed to a Sharpless asymmetric dihydroxylation and protected as the acetonide. A Saegusa oxidation furnished a new double bond which is regioselectively iodinated:

Scheme 2

scheme_2

Now comes the interesting part: The union of the two fragments and the formation of the remaining five membered ring containing the unusual diazo-cyclopentadiene motif. Starting with an Ullmann coupling followed by a benzoin condensation using Rovis catalyst gives the almost finished product.

Scheme 3

scheme_3

They had some problems with the benzoin condensation in first instance by using this catalyst and a different naphthalene unit cause it lead to the formation of the Stetter product. This problem could be overcome by using the shown starting material under the same conditions.

Next a SmI2 induced hydroxyl transposition gives the almost functionalised intermediate. Again they had some problems with their own standard protocol http://pubs.acs.org/doi/abs/10.1021/ja074297d from an older synthesis, so they modified and studied this reaction extensively and got good results with the following reaction sequence:

Scheme 4

scheme_SmI2

Very cool stuff but I were wondering if they didn’t try to transpose the hydroxyl group through a chrome(VI) induced allylic oxidation followed by chemoselective reduction of the resulting ketone. Nevertheless a very effective reaction protocol.

At least they installed the diazo motif by forming the hydrazone with TsNHNH2 and oxidised it using Dess-Martin-periodinane which also cleaved the SEM-groups to give the expected quinone system. Reduction and subsequent acetylation, followed by SEM-ether cleavage with TMSOTf, oxidation using CAN and hydrolysis furnished the final product.

Scheme 5

scheme_4

This is a really short and effective approach to this exciting class of compounds, hopefully followed by the condensation of the monomers. Even though it is a typical KCN publication the extensive colouring is missing… Maybe he forgot it? Or they omitted it for clarity…

Suggestions are as usual welcome…