Publication of the week, number 59, 9th January 2015

This week sees a reaction that is quite rarely used in organic synthesis, at least I have not been aware of recent applications of the nitroso ene reaction. It was used by Shenvi to synthesise the N-hydroxypurine diazepine unit which is the primary pharmacophore (red in structures below) of the asmarine alkaloids, a group of very potent cytotoxic compounds isolated from a Red Sea sponge.

asmar01

Synthesising the red bit of this molecule is a serious challenge. Apparently there is only one route in previous literature which uses quite forcing conditions (HBr/acetic at 100°C) and has no stereocontrol. Forming the 7-membered ring in a biomimetic sense from agelasine appeared to be a viable route provided that stereochemical control could be achieved by utilising the stereocenter of the decalin system to relay the chiral information during the formation of the C-N bond:-

asmar02

Firstly they examined the nitroso ene reaction in two model systems, one shown here:

asmar03

The best oxidant turned out to be lead tetraacetate in DMSO. The only product formed is the one shown and the reaction could be done on a gram scale. So, a great result.

Trying this out on the agelasine system shown above gave the product as a 1:1 mixture of diastereoisomers. Note: here they changed the oxidant to manganese dioxide with no explanation as to why! There was a marked solvent effect, a combination of ethanol/water 1:3 gave a ratio of 8:1 of the (S) isomer at the new stereocenter (X is an oxime). This compound turned out to be active in the biological assays. The other isomer was also active but only a factor of around 2 weaker. So the stereochemistry of this center does not seem to play a great role in the biological activity!

The ease of synthesis provoked the synthesis of a small library of structures:

asmar04

With R ranging from small carbon rings to aromatic systems to adamantyl groups. Where R = 1-adamantyl or 4-biphenyl the compounds were more potent than asmarine A and indeed the 1-adamantyl approached the excellent activity of asmarine B in HL60 cells.

So the stereochemical question turned out not to be significant for the biological activity and indeed this method lead to a number of potent simpler analogues of the natural products. Nice easy chemistry presented here with great potential. I look forward to more.

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Prof. dangerdackel (199 Posts)


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