Chemical Communications Blog

Researchers from the University of Oxford have completed the first synthesis of (±)-hydroxyanthecotulide, an antiparasitic molecule that displays a number of other interesting biological activities.

David Hodgson’s group used their previously developed Cr(II)-catalysed allylation reaction to construct the molecule’s carbon skeleton. Alcohol 1 was constructed in a single step and then oxidised to aldehyde 2, which was used crude in an allylation reaction with 3 to give the anti-product (5) in good yields and high levels of diastereoselectivity.

The desired enone functionality was revealed by a Meyer-Schuster rearrangement of 5, which proceeded in excellent yield with in situ desilylation occurring under the reaction conditions.

¹H and ¹³C NMR spectra of 6a were then compared with spectra of an authentic sample of (±)-hydroxyanthecotulide. Discrepancies in this spectral data encouraged the researchers to synthesise syn–6b, by inversion of the C-4 secondary alcohol.

Gratifyingly, the spectra of syn-(±)-hydroxyanthecotulide (6b) was found to match data for the authentic sample and HPLC analysis provided further evidence to confirm that natural (±)-hydroxyanthecotulide, possesses syn-stereochemistry.

This research enabled the synthesis of both anti– and syn-(±)-hydroxyanthecotulide in 5 and 7 steps respectively, and may provide an attractive synthetic route for access to analogues of this biologically relevant family of molecules.

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Paul Knochel from the Ludwig Maximilians University in Munich has developed a method to directly metalate and then functionalise N-protected indazoles.

Indazole heterocycles are important molecules in medicinal chemistry and methods to functionalise them are widely sought after. Direct metalation of indazoles at their 3 position is often problematic as this can quite easily lead to ring opening and formation of an aminonitrile product. Knochel overcame this problem by using a zinc reagent to form a bis-indazoylzinc compound.

The bis-indazoylzinc compound reacts with a wide range of electrophiles and can also undergo arylation in a Negishi cross-coupling reaction.  In general, such reactions are not possible using normal metalation reagents. Future work will concentrate on the synthesis of biologically active molecules using this methodology.

If you want to find out more then download the ChemComm article, free for a limited period.

Researchers from the University of Birmingham have developed a radical cascade process for rapid access to intermediates, which are important for the synthesis of alkaloids related to the stephacidin family.

Stephacidin A (1), along with other structurally related compounds, has been shown to possess activity against a number of tumour cell lines.

The group of Nigel Simpkins have demonstrated an elegant approach to the synthesis of the indoline core 3, present in a number of naturally occurring alkaloids.

Commencing from 4 ­­(available in five steps from tryptophan), a one-pot prenylation and sulfenylation sequence afforded cyclisation precursor 5 in good yield. Treatment of sulfenyl diketopiperazine 5 with Bu­₃SnH and ACCN facilitated a double radical cyclisation to provide 6a and 6b. Pleasingly, isomers possessing the correct C6 stereochemistry represented the major products (4.6–3:1 depending on R group), and desired product 1 could be obtained following deprotection of 6a and 6b and subsequent purification.

This work represents an efficient entry into the stephacidin alkaloids and a potentially powerful method for the synthesis of other medicinally relevant analogues.

To read more on Simpkin’s indoline synthesis, download the ChemComm article.