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Totally Synthetic by See-Arr-Oh, 16 June 2011

Total Synthesis of Loline


M. Cakmak, P. Mayer, D. Trauner, Nat. Chem. 2011, 3, 543-545.

DOI: 10.1038/nchem.1072

Simple tricyclic morpholine derivative with four stereocenters. Can’t take that much effort, can it? Well, yes it can - and it's amazing how tricky this synthesis is! Trauner explains in the informative introduction that only one successful synthesis has been completed - taking twenty steps to get to the racemic target. Clearly that leaves the team in Germany with a lot of room for improvement.

The team made the first intermediate in the scheme above by using metathesis to form that eight-member ring. The diol stereochemistry was unsurprisingly installed using Sharpless' chemistry - in this case a desymmeterising asymmetric epoxidation, followed by opening of the allylic epoxide to install the amine. Treatment of the diol with a thionyl chloride then results in a slightly unusual reaction (I’d perhaps expect allylic displacement and installation of a chloride), forming a cyclic sulfite. This is still a rather neat leaving group, as treatment with lithium azide results in formation of the azide - apparently completely selective for the allylic azide.

At this point it helps to consider the third-dimension: the structure of the medium ring is heavily puckered, means that the secondary amine is actually quite close to the olefin. Thus, addition of bromine in methanol allows formation of the bromonium ion, which is trapped by the amine to ultimately give the bicyclic tertiary amine after neutralisation of the salt. Interestingly, the neutralisation was conducted with lithium chloride present, which does an Appel reaction, displacing the bromide for a chloride with inversion of stereochemistry. Whether this reaction really is an SN2 is a matter of some consideration - but not right now…

What to me is amazing is that the azide group seems remarkably unconcerned with the reaction conditions used so far. Even more surprising is that heating it up in a microwave is also tolerate, meaning the group can complete the morpholine ring by intra-molecular displacement of the chloride by the proximal hydroxide (again, try to consider the ring pucker allowing the hydroxide to easily attack the secondary chloride.

Examination of the target shows that the group was almost there - reduction of the azide by hydrogen / metal led to Temuline (or norloline), whilst the same reaction in the presence of Boc anhydride results in the protected derivative, which was reduced to Loline via hydride reduction.