US EPA

7443098 

Journal Article 

Total synthesis of the antitumor marine sponge alkaloid agelastatin A 

Stien, D; Anderson, GT; Chase, CE; Koh, Y; Weinreb, SM 

1999 

Yes 

Journal of the American Chemical Society
ISSN: 0002-7863
EISSN: 1520-5126 

AMER CHEMICAL SOC 

WASHINGTON 

121 

41 

9574-9579 

English 

10.1021/ja992487l 

WOS:000083280100012 

https://pubs.acs.org/doi/10.1021/ja992487l
Exit
 

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 sulfodiimide12c. Palladium-promoted cyclization of 2-acyl pyrroles 20 and 21 via a pi-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-l bromine substituent of agelastatin A, and thus silylpyrrole 58 could be converted to bromopyrrole 59. Finally, the D-ring could be annulated onto an a-amino ketone derived from 59 using methyl isocycanate, providing racemic agelastatin A (1). 

agelastatin a; alkaloid; antineoplastic agent; carbamic acid; cyclopentadiene derivative; isocyanate; ketone; unclassified drug; antineoplastic activity; article; chemical reaction; drug synthesis; hydrolysis; nonhuman; reaction analysis; sponge (porifera)