Total synthesis of the antitumor marine sponge alkaloid agelastatin A

The first total synthesis of the cytotoxic marine metabolite agelastatin A (1) has been achieved in about 14 steps performed in 12 operations in appro ximately 7% overall yield starting from cyclopentadiene. Hetero Diels-Alder cycloaddition of cyclopentadiene with N-sulfinyl methyl carbamate (7) affo rded cycloadduct 8, which without purification was converted to allylic sul foxide 9 and then by a [2,3]-sigmatropic rearrangement into bicyclic oxazol idinone 11. The C-5a nitrogen was introduced into the oxazolidinone Boc der ivative 16 by a Sharpless/Kresze allylic amination with SES sulfodiimide12c . Palladium-promoted cyclization of 2-acyl pyrroles 20 and 21 via a pi-ally lpalladium intermediate 22 led to ABC-tricycles 23 and 24, respectively. A hydroxyl urea D-ring model system was constructed by hydroborating 24, lead ing eventually to keto amide 31 and then to tetracycle 33. A modified strat egy was developed for synthesis of the pivotal tricyclic ketone 58, involvi ng as key steps a chemoselective hydrolysis of N-Boc oxazolidinone 54 and a n internal conjugate addition of pyrrolo cyclopentenone 57. A TMS group was used as a convenient substitute for the C-l bromine substituent of agelast atin A, and thus silylpyrrole 58 could be converted to bromopyrrole 59. Fin ally, the D-ring could be annulated onto an a-amino ketone derived from 59 using methyl isocycanate, providing racemic agelastatin A (1).