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25th October 2013
Stereocontrolled Total Synthesis of Sphingofungin E, Ikeuchi, K.; Hayashi, M.; Yamamoto, T.; Inai, M.; Asakawa, T.; Hamashima, Y.; Kan, T., Eur. J. Org. Chem., 2013, 6789.
Kan and co-workers have reported an effective route to sphingofungin E, a potent immunosuppressant, which does not rely upon chiral building blocks, and is therefore well suited for accessing other stereoisomers. To highlight the utility of their procedure, epoxide intermediate 1, which featured in the group’s total synthesis of another sphingosine derivative, ent-myriocin, in 2008, appears in their latest synthesis. A Mn(III)-catalysed allylic oxidation under Shing’s conditions, followed by a chemo- and stereoselective reduction of the resultant enone furnished allylic alcohol 2. Inversion of this hydroxyl group by way of a Mitsunobu reaction with p-nitrophenol, and subsequent regioselective opening of the epoxide ring/intramolecular cyclisation afforded cyclic carbonate 3. A further 5 steps were required to transform this compound into the fully protected cyclohexene 4. Ozonolysis of 4 under standard conditions completed the synthesis of the dialdehyde intermediate 5. With the dialdehyde in hand a Takai reaction was used to couple diiodide 6 to the more reactive secondary aldehyde thereby installing the remainder of the carbon backbone 7. Several steps converted the remaining aldehyde to amide 8 required for the subsequent Hofmann rearrangement. Treatment of 8 with a hypervalent iodide source was enough to not only effect the rearrangement of the amide to the isocyanate intermediate but also oxazolidinone formation generating a mixture of compounds 9 and 10. Acid/base hydrolysis and finally neutralisation were the final steps required to complete the synthesis of sphingofungin E.