Quite a few interesting publications landed in my in box last week, here a selection.
From the Baran Group two papers appeared in JACS, the first dealing with the total synthesis of (-)-Taxuyunnanine D:
This was accomplished by a study of the potential sites of taxadiene that could be reactive towards controlled oxidation. They did a few MM2 calculations, and were able to pinpoint sites for selective allylic oxidation and screened a selection of 5 oxidising agents for their potential. I won’t go into detail here but refer you to the groups blog and of course the publication for further information. One interesting reagent emerged from the study, a Cr(V) oxidant:
The second contribution was a novel methylating agent which mimics S-adenosylmethionine (Nature’s methylating agent). Now methylation is important as uracil methylation assists in DNA biosynthesis and methylation of cysteine disrupts ubiquitin chain binding. Also it is well known in medicinal chemistry that the addition of a methyl group, strategically placed can sometimes improve the IC50 of a lead compound. So they designed a method for C-H methylation to assist in the addition of CH3 to various reactive substrates such as tryptophan, cysteine amongst others. This involved the addition of a “methyl radical surrogate” which installs a functional group that can later in the synthesis be easily unmasked to generate the methyl group. The current reagents that can achieve this are unreliable in their success so Baran etal came up with zinc bis(phenylsulphonylmethane sulphinate):
This compound inserts a phenylsulphonyl methyl group into a heteroarene C-H bond. The phenylsulphonyl group can easily be unmasked to reveal the methyl group by treatment with either Mg/MeOH, Raney Ni/EtOH or SmI2/water/THF in good yields. I also noticed that some of this work was presented at the recent ACS spring meeting in Dallas.
Kirschning, Geist and Schmidt published a review of sp3-sp3coupling reactions in natural product synthesis. This article covers the literature from 1995 to 2013 and is full of wonderful examples of this metal catalysed coupling reaction in total synthesis. Cossy etal discuss the isolation, structure determination of amphidinol 3 and synthetic attempts to this molecule that have appeared in the literature from 1991 – 2013. This is a suitably complicated molecule whose structure can be found here. The compound has not yet been synthesised but considerable effort has been made in the synthesis of fragments of the whole, not made easier by inaccurate structural information. The correct choice of protecting is important and they have to be picked carefully so that they can be selectively cleaved. With the different approaches reported in the literature, picking the right disconnections and the correct protecting groups should provide successful access to amphidinol 3, resulting in the confirmation of the structure.
The Kishi group published the synthesis of Halichondrin A. This compound was the missing link in this series of natural products, it has not yet been isolated from a natural source, but it has now been synthesised! All other things being equal it differs from halichondrin B by the presence of a diol as shown below:
The synthesis uses the asymmetric Ni/Cr coupling reaction as well as an asymmetric Cr coupling reaction to stitch the various units together. Naturally some of the building blocks used in the approach to halichondrin B were used in this synthesis. An interesting equilibration of the spiro [5,5] ketal was observed during the synthesis:
This equilibration is best achieved by the use of TMSOTf at -78°C in dichloromethane and gives a 10:1 ratio of A to epi-A and diethyl ether favours epi-A over A in a 1:5 ratio.
So all-in-all an interesting week with lots of new chemistry to be studied, learnt and applied. Good reading.
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