Totally Synthetic by Paul H. Docherty, 4 March 2007
Total Synthesis of Lepadiformine
J. J. Caldwell, D. Craig, Angew. Chem. Int. Ed. 2007, 46, 2631-2634.
Another elegant synthesis from Don Craig’s lab at Imperial College, focusing on lepadiformine, previously synthesised by the Kibayashi group amongst others. The biological profile, whilst interesting, is of no real efficacy, so I guess it’s popularity revolves around its interesting structure.
Their synthesis begins by formation of a exocyclic aziridine, from opening of the analogous epoxide with SES-amine and performing a Mitsunobu reaction on the resulting amino alcohol. Opening of this aziridine with a lithiated sulfone then gave the starting material (SM) for the following scheme:
Double-deprotonation of the SM allowed generation of the dianion, to which was added 2-benzyloxyethanal and then benzoyl chloride to quench. This gave the product, a spirocyclic pyrrolidine as a single diastereoisomer in a quite reasonable yield. Deprotection of the amine with TBAF, and the benzyl and acetal groups with BBr3 prompted imediate cyclisation onto the free aldehyde, producing the aminal, which was ready to be alkylated (remember it’s effectively at the aldehyde oxidation state).
Interestingly, addition of the unsaturated sidechain as a grignard reagent resulted in a decent yield of undesired diastereoisomer, but the acetylenic analogue reversed this result dramatically, resulting in addition to the desired Re face. The authors attribute this turnaround in selctivity to the difference in steric bulk of the two reagents. Conversion of this material to the natural product was relatively straight-forward, but required careful selection of a hydrogenation catalyst to reduce the acetylene. This done, the sulphonyl group was removed, and the alcohol sidechain epimerized by oxidation, deprotonation/reprotonation and reduction.