RESUMO
[reaction: see text] A new total synthesis of (-)-agelastatin A (1) has been achieved from the chiral oxazolidinone (-)-3. Although enone transposition was problematic when the Michael ring closure of 2 was attempted with strong base, the desired cyclization could be effected with Hunig's base after the pyrrole nucleus was brominated. Subsequent reduction and monobromination afforded synthetic (-)-agelastatin A (1).
Assuntos
Alcaloides/síntese química , Antineoplásicos/síntese química , Oxazolidinonas/síntese química , Poríferos/química , Alcaloides/farmacologia , Animais , Antineoplásicos/farmacologia , Catálise , Indicadores e Reagentes , Estrutura Molecular , Oxazolidinonas/farmacologia , EstereoisomerismoRESUMO
[reaction: see text] An enantiospecific total synthesis of Weinreb's advanced intermediate 2 for (-)-agelastatin A has been achieved from the Hough-Richardson aziridine 8. Noteworthy reactions in our sequence include the highly regioselective trans-diaxial ring-opening of 8 with azide ion to set up the vicinal diamido functionality present within (-)-2 and the Grubbs-Hoveyda ring-closing metathesis (RCM) reaction that was used to construct its cyclopentene core.
Assuntos
Alcaloides/síntese química , Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Oxazolidinonas/síntese química , Alcaloides/química , Alcaloides/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicogênio Sintase Quinase 3 beta , Oxazolidinonas/química , Oxazolidinonas/farmacologia , EstereoisomerismoRESUMO
Highly selective reaction of methyl tetra-O-pivaloyl-beta-D-glucopyranuronate 2 with iodotrimethylsilane or (Me3Si)2 and I2 affords, in excellent yield, the 'disarmed' glycosyl iodide 1 which has good stability at 20 degrees C and excellent stability at 0 degrees C; the X-ray crystal structure of 1 is described, along with a comparison of its utility as a glycosyl donor to that of the corresponding bromide.
Assuntos
Glucose/química , Iodetos/química , Modelos Moleculares , Estrutura Molecular , Difração de Raios XRESUMO
A number of analogues of morphine-6-glucuronide 1 have been prepared and evaluated as potential analgesic agents by competitive mu-receptor binding assay and in vivo antinociceptive activity. The analogues show variation in the nature of the carbohydrate residue, the N-substituent, the O(3)-substituent and saturation of the 7,8-double bond compared to 1. In general, only the 6beta-glucoside or beta-glucuronide carbohydrate residues showed potent agonism; other modified carbohydrates were less active or exhibited potential antagonism. Variations in N-substituent led to either reduced agonism (N-H) or potential antagonism [N-allyl, N-(cyclopropyl)methyl]; a polar N-substituent, carboxymethyl, failed to bind. Saturation of the 7,8-double bond led to increased agonism compared to the parent compound in all three examples studied.