Total Synthesis of the Antitumor Marine Sponge Alkaloid Agelastatin A

Abstract

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).

Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe

“…1 Since its isolation in 1993 by Pietra and co-workers from the sponge AglAs dendromorpha , 2 this family has grown to include six agelastatin congeners (A through F, Figure 1a). 3 Weinreb 4 described the first total synthesis of AglA and since then several additional racemic 5 and enantioselective 6 syntheses of AglA have been reported. 7 Recently, Movassaghi developed an elegant and efficient bioinspired approach to AglA and all congeners that involved a late stage C4-C8 bond formation.…”

Syntheses of cyclic guanidine-containing natural products

“…Oxidation, cyclization, and oligomerization of 5 provide a diverse set of new molecules. 47-53 Among the monomeric family members, hymenialdisines ( 6 ), 54-61 cyclooroidin ( 7 ), 52,62-64 agelastatins ( 8 ), 53,65-82 and dibromophakellin/dibromophakellstatin ( 9 ) 48,83-90 have been the most popular synthetic targets (Fig. 2).…”

Recent advances in the total synthesis of agelastatins

“…Weinreb's group accomplished the first total synthesis of racemic agelastatin A in 1999 [15]. Their strategy for the ABC-ring synthesis is illustrated in Scheme 2.…”