Tag Archives: dimethylzinc

Publication of the week, number 109, 25th December 2015

Baran has attacked a synthetic and a biological problem in this week’s ASAP. He describes another scalable synthesis this time of antroquinonol a compound in phase II trials for various cancers.

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A relatively simple molecule however the synthesis still has its problems. The group evaluated several approaches to construct the ring  including a Diels-Alder reaction, stepwise conjugate addition/annulation amongst them. All had their problems, low yield, too long, unstable intermediates etc. In the end the simplest route from a quinone proved to be the one of choice. This ended up being a “six-step, enantioselective, scalable synthesis of antroquinonol”.

A, if not the, key step is the enantioselective conjugate addition of a methyl group to a mono-ketalised quinone followed by alkylation with farnesyl bromide –

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This scalable step used copper triflate, dimethylzinc (2.5 equiv.) a chiral phosphoramidite at -30°C followed by isolation of the intermediate then  LiHMDS, HMPA (2.5 equiv.) and farnesyl bromide. It gave the product in 51% yield and 96% ee for the sequence. A quick look in the supplementary info presents a different picture. The first step is isolated in 55% after chromatography and the alkylation product in 45% after chromatography. So I don’t see how this is 51% for the sequence! And what is the rest of the material? The products are oils, which is ok but makes things a bit more difficult on larger scale. The natural product itself is reported as a viscous oil. Chromatography is used in every step.

 Turning to the biological activity the authors found that “The reported IC50 value in the lung tumor cell line (A549) for the natural product is 25 μM. In our hands, 1 is ∼3−70-fold less cytotoxic against these cell lines except for the A549 cell line, where it is ∼4-fold more potent than previously reported. The activity of 1 in the Hep 3B cell line was particularly striking, where it is significantly less potent when compared to the natural product.” and “The observed and reported high micro-molar activity of 1 against a NSCLC cell line (A549) is somewhat puzzling since the natural product is in phase II trials for the treatment of this tumor type.

In order to try and explain these observations metabolites of the natural product were identified and synthesised by the same route. However they were also found to be wanting in biological activity. So here is a puzzle, especially as this compound is in phase II and “the lack of efficacy in an in vivo preclinical model would be a cause for concern if the compound were to be advanced into the clinic for treating hepatocellular carcinoma.

So an interesting problem here and a good synthesis to help it along the way.

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