Publication of the week, number 34, 18th July 2014: Addendum

Firstly, thanks to the authors for providing me with a full copy of their supplementary information. No doubt Angewandte will get round to posting it soon.

I must congratulate them on an extremely comprehensive SI. Full experimentals, of course, with HPLC data for the %ee and all the relevant NMR’s. And  conversion of new compounds to known material for structural verification. There is a tremendous amount of work here.

A couple of comments: Discodermolide crystallises beautifully from acetonitrile/water (85:15) at pH 4 as sandy crystals in 95% yield.  We isolated it as a mono-hydrate. We found that acetonitrile was the best solvent for running the NMR and I reproduce the spectra for the mono-hydrate here: 1H-NMR (300 MHz, CD3CN), δ 6.58 (dtd, J = 16.73, 10.5 & 0.89 Hz, 1H), 5.99 (pseudo t, J = 11.1 Hz, 1H), 5.46 (pseudo t, J = 10.5 Hz, 1H), 5.38 – 5.25 (m, 2H), 5.17 (dd, J = 17.1 & 2.0 Hz, 1H), 5.10 – 4.92 (Brm, 3H), 4.88 (d, J = 10.1 Hz, 1H), 4.63 (dd, J = 7.99 & 3.85 Hz, 1H), 4.48 – 4.30 (m, 2H), 3.54 (pseudo q, J = 5.18 Hz, 1H), 3.25 (d, J = 4.88 Hz, 1H), 3.10 – 2.94 (m, 3H), 2.74 (d, J = 5.33 Hz, 1H), 2.62 (d, J = 5.33 Hz, 1H), 3.57 (d, J = 6.8 Hz, 1H), 2.55 – 2.44 (m, 2H), 2.18 (m, 1H), 1.80 – 1.46 (m, 8H), 1.38 (ddd, J = 14.5, 10.7 & 2.2 Hz, 1H), 1.10 (d, J = 7.3 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.80 (d, J = 5.8 Hz, 3H), 0.71 (d, J = 7.0 Hz, 3H). 13C-NMR (100 MHz, CD3CN), δ 173.4, 157, 132.9, 132.5, 132.4, 131.9, 129.8, 127.2, 116.9, 78.5, 77.9, 76.1, 74.7, 71.9, 62.0, 42.7, 40.9, 37.2, 35.7, 35.3, 35.0, 33.3, 32.9, 22.0, 18.4, 16.9, 16.3, 14.5, 14.3, 11.8, 7.9. [α]d = +20.1°, c = 1% in MeOH.

disco nmr

I apologise for the manipulated baseline, could not work the ACD software on this Mac very well. But it is from the original FID!

We also isolated side products where C16 had the opposite configuration. This arose from a minor aldol product in our route being carried through the synthesis, although we never isolated any of that material.

There are lots of very oxygen sensitive materials used in this synthesis requiring glove box and Schlenk techniques. This may actually work better on scale-up provided one can obtain the required quantities of the respective catalysts and their precursors. Diethylzinc may pose a problem, and the authors used it as a solution in DCM, and in toluene, presumably for solubility reasons? Interestingly they added benzaldehyde to the reaction mixture leading to this diene:

disc05

Why benzaldehyde? Well the provide a convincing explanation: It turns out that the hydroboration of the acetylene is not regioselective and the minor regioisomer produces an allene on reaction with the aldehyde. This was not separable and actually inhibits the Ni catalysed hydroboration. On presenting the mixture with benzaldehyde only the undesired hydroborated isomer reacts, leaving the desired compound to do it’s stuff. Quite a neat solution to a thorny problem.

I would also say that the hydroformylation would have caused problems in our pilot plant due to the use of carbon monoxide under pressure, especially with hydrogen being present, a nice explosive mixture here I think, what do you do with the excess gas mixture? Let’s not mention the exposure limits, which are very low. So I think this step needs a work round.

Still, in spite of these problems, which can be overcome, I think this is a neat route to discodermolide and I would welcome a stab at scale-up. Congratulations to the team for their excellent chemistry and detailed experimentals.

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Prof. dangerdackel (199 Posts)


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