Category Archives: Azides

Publication of the week, number 74, 24th April 2015

A  synthetically useful purpose for 1,2,3-triazoles has been published this week by Boyer from the University of  Glasgow in a synthesis of (+)-petromyroxol an aquatic pheromone emitted by the larvae of the sea lamprey.

petro01

So we have a relatively simple natural product  but how is this related to 1,2,3-triazoles. In previous work Boyer showed that if you have an appropriately substituted triazole and a transition metal you can initiate loss of nitrogen to produce a metal carbenoid and if the right functional groups (allyl ethers and a N-tosyl substituent) are present they can react with the carbene, lose nitrogen, undergo a [2,3] sigmatropic rearrangement to efficiently produce a new C-C bond all with excellent stereocontrol:

petro02

So an excellent method for the synthesis of substituted tetrahydrofurans, of which petromyroxol is one. So all we need is an appropriate retrosynthesis leading to a 1,2,3-triazole! Surprise this is easily conceived. Simple functional group manipulation leads to a keto-tetrahydrofuran with a pendant allyl group, which is nothing but a triazole as shown above:

petro03

The synthesis of the tosyl-triazole is relatively straightforward. Starting from trans-1-chloro-2-octene it is obtained in 5 steps with a 45% yield. Notable here is the chirality introduction in the first step using a Sharpless asymmetric dihydroxylation which produces >95% ee of the diol. This was epoxidised and the epoxide opened with an aluminium acetylide:

petro04

So what’s next? Reaction with tosyl azide under anionic conditions to give the 1,2,3-triazole in 80% yield. Then ” The conditions developed previously, namely 5 mol % rhodium(II) acetate in toluene at reflux, were used to promote denitrogenation and rearrangement to form the furanone  with the desired trans-2,5-configuration.In contrast to previous observations, during this reaction baseline impurities were observed. It is suggested that the unhindered benzyl ether presents a number of alternative reaction pathways including [1,2]-sigmatropic shift and C−H bond functionalisation. However, formation of the five-membered oxonium intermediate species and rearrangement to give the dihydrofuran-3-one was the major pathway giving the heterocyclic scaffold  in 67% isolated yield of the desired isomer”.

petro05

From here it is relatively straightforward to obtain the natural product (3 steps, 50%). Ketone reduction was reasonably selective, 10:1 in favour of the desired compound.

Some nice solid chemistry here and good extension of the previous work. I wonder if allyl amines could be encouraged to do something similar to produce pyrrolidines?

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