This weeks’s morsel comes from  Prof. Tomas Hudlicky and V. Varghese at the Brock University, St. Catharines in Canada. It tells us about their successful efforts to employ a Diels-Alder cycloaddition to construct the B ring of a morphinan and delivers a first total synthesis of ent-hydromorphone.

The approach is based upon several sets of model studies designed to investigate the [4+2] cycloaddition of a dienone 2 obtained by oxidative dearomatisation of a suitably substituted phenol 1:

Interestingly the chirality of phenol 1 was obtained by a toluene dioxygenase-mediated dihydroxylation of an appropriately substituted aromatic ring. Now, given the availability of many substituted benzene rings this is a reaction that is not often employed routinely in synthesis or at least you don’t often see it in reaction schemes. This is a shame as it can be a very useful process. The reference can be found here.

Anyway back to the topic. The crucial Diels-Alder cyclisation proceeded after oxidative dearomatisation with lead tetraacetate and gave after  re-aromatisation compound 3:

The yield of this reaction is around 50%. Analysis of the intermediate revealed that only the exocyclic diene had reacted. The endocyclic diene is reactive but very likely due to steric factors is not available to the dienophile.  Re-aromatisation was carried out by treatment of the initial adduct with TFA, which also removed the Boc group (R = Boc in scheme above).

The ethylamino bridge now had to be installed to complete the formation of the D ring.  The obvious aminomercuration route did not work in this case as did a couple of other methods. This was surmised to be due to the instability of compound 3. Thus this compound was tosylated and the D ring formed by dissolving metal reduction (radical cyclisation), Li, t-BuOH,NH_3(liq), THF, -78°C, 10 minutes, 90% yield to give compound 4.

All that remained was removal of the OTBS group and oxidation of the alcohol to give the desired compound. The oxidation conditions are interesting using a modification of the procedure described by Woodward and also by Rapoport: tBuOK, PhCOPh, PhCH₃/DME, 85°C, 8 hr, 44%.

The route described above is enantiodivergent and equally applicable to the other enantiomer. Depending upon how one counts the number of steps is a maximum of 12 from β-bromoethylbenzene. This is one of the shortest synthesis of this ring system known.  A great effort and culmination of several years of research congratulations to all.

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