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 approximately 7% overall yield starting from cyclopentadiene. Hetero Diels−Alder cycloaddition of cyclopentadiene with N -sulfinyl methyl carbamate ( 7 ) afforded cycloadduct 8, which without purification was converted to allylic sulfoxide 9 and then by a [2,3]-sigmatropic rearrangement into bicyclic oxazolidinone 11 . The C-5a nitrogen was introduced into the oxazolidinone Boc derivative 16 by a Sharpless/Kresze allylic amination with SES sulfodiimide 12c . Palladium-promoted cyclization of 2-acyl pyrroles 20 and 21 via a π-allylpalladium intermediate 22 led to ABC-tricycles 23 and 24, respectively. A hydroxyl urea D-ring model system was constructed by hydroborating 24, leading eventually to keto amide 31 and then to tetracycle 33 . A modified strategy was developed for synthesis of the pivotal tricyclic ketone 58, involving as key steps a chemoselective hydrolysis of N -Boc oxazolidinone 54 and an internal conjugate addition of pyrrolo cyclopentenone 57 . A TMS group was used as a convenient substitute for the C-1 bromine substituent of agelastatin A, and thus silylpyrrole 58 could be converted to bromopyrrole 59 . Finally, the D-ring could be annulated onto an α-amino ketone derived from 59 using methyl isocycanate, providing racemic agelastatin A ( 1 ).