A facile synthesis of ascamycin and related analogues

Synthesis and Aminoacyl-tRNA Synthetase Inhibitory Activity of Prolyl Adenylate Analogs

“…A common synthetic intermediate for the growing family of aminoacyl sulfamoyl adenylates is 2Ј,3Ј-O-isopropylidene-5Ј-O-sulfamoyladenosine (1). This compound may be prepared directly from sulfamoyl chloride and a 2Ј,3Ј-acetal derivative of adenosine using NaH in DME as originally described by Shuman et al (47,48), or via an in situ formed 5Ј-Otributyltin ether (25,26). We found that high yields of 1 were obtained most conveniently using NaH/DME conditions and freshly prepared and recrystallized sulfamoyl chloride.…”

“…1) (46) and structurally related synthetic 5Ј-O-[N-(aminoacyl)-sulfamoyl]adenosine derivatives (21,25). These compounds mimic the natural aminoacyl-tRNA synthetase substrates, but replacement of the phosphate ester with the nearly isosteric, yet stable sulfamoyl linkage (21) provides nonhydrolyzable substrate analogs.…”

“…Direct aminoacylation of the 5Ј-sulfamoyl group of 1 was accomplished as described by Castro-Pichel et al (25) without protection of the N6 amino group. Thus, …”

“…temperature (25). Workup and purification provided L-PSA (4) as an amorphous white solid in 74% yield.…”

Design, synthesis, and biological evaluation of α-hydroxyacyl-AMS inhibitors of amino acid adenylation enzymes

“…Thus, alanyl-AMS ( 4a , Figure 1b), lactyl-AMS ( 4b ), and cysteyl-AMS ( 4c ) were synthesized as previously described. 47,82 The corresponding α-hydroxy-cysteyl-AMS analogue 4d was synthesized from (2 S )-methyl glycidate ( 6 ) by epoxide opening with tritylthiol 83 and alcohol protection to form protected hydroxycysteine 7 , followed by conversion to the corresponding N -hydroxysuccinimidyl (NHS) ester 8 (Scheme 1). Coupling to 2´,3´-acetonide-protected 5´- O -sulfamoyladenosine ( 9 ), 82 prepared as previously described, 84 and global deprotection with acid afforded α-hydroxy-cysteyl-AMS ( 4d ).…”