Evaluation of the Efficiency of the Macrolactonization Using MNBA in the Synthesis of Erythromycin A Aglycon

Abstract

Various intermediates for the synthesis of erythronolide A, an aglycon of erythromycin A, are prepared from the corresponding seco-acids using 2-methyl-6-nitrobenzoic anhydride (MNBA) in the presence of 4-(dimethylamino)pyridine (DMAP) with or without triethylamine. The efficiency of the MNBA lactonization is assessed by studying this method and comparing the results with those of the other established macrocyclization protocols. It has been finally concluded that (i) the conformationally appropriate substrate for the monomeric cyclization gave the desired lactone in excellent yield under mild reaction conditions in the presence of MNBA and DMAP, (ii) the highly-strained substrate for the cyclization also afforded the monomeric lactone in relatively good yield at 100 degrees C in toluene, and (iii) the seco-acid having stable linear conformation, which preferred dimerizing more than forming the monomeric lactone, provided the corresponding diolide in high yield with the constant ratio of the monomer to dimeric lactone (approximately 1/5).

Function-Oriented Synthesis: Design, Synthesis, and Evaluation of Highly Simplified Bryostatin Analogues

“…To avoid subsequent trans-esterification upon standing, crude alcohol 17 was immediately subjected to monoesterification with glutaric anhydride, and to our pleasure seco-acid 20 was isolated in 65% yield. Subsequently, seco-acid 20 underwent macro-lactonization using 2-methyl-6-nitrobenzoic anhydride in toluene at 50 °C, a condition that was developed by Shiina and co-workers, to give bis-lactone 21 in 25% isolated yield, 41% yield based on recovered starting material 20 .…”

Total Synthesis of Thailandepsin B, a Potent HDAC Inhibitor Isolated from a Microorganism

“…The subsequent macrolactonization of 9 was achieved by employing the Shiina method [13][14][15][16][17] [2-methyl-6-nitrobenzoic anhydride (MNBA) (1.3 equiv), 4-dimethylaminopyridine (DMAP) (3.0 equiv), CH 2 Cl 2 (1.0 mM), rt, 12 h], which resulted in the desired cyclization product 17 in 85% yield. Finally, simultaneous S-Tr deprotection and internal disulfide bond formation in 17 (95%), followed by the deprotection of the TBS group in the resulting disulfide 18 (90%) furnished thailandepsin B (2) …”

“…i-Pr 2 NEt (0.33 mL, 1.9 mmol) was added dropwise to a stirred solution of D-norleucine methyl ester hydrochloride (12) (88.0 mg, 0.48 mmol) 18) and (S,E)-3-(4-methoxybenzyloxy)-7-(tritylthio) hept-4-enoic acid (13) 7,9-12) (174 mg, 0.32 mmol) in MeCN (6.5 mL) containing (benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP) (252 mg, 0.48 mmol) at 0°C under argon, and stirring was continued for 2 h at room temperature. The reaction mixture was diluted with EtOAc (30 mL), and the organic layer was washed successively with 10% aqueous HCl (2×10 mL), saturated aqueous NaHCO 3 (2×10 mL) and brine (2×10 mL), then dried over Na 2 SO 4 .…”

Thorpe‐Ingold Effect on the ATRP‐Induced Cyclopolymerization of Bismethacrylate Tethered by a Substituted Silylene Moiety

“…[ 19 ] Indeed, numerous natural [ 20 ] and unnatural [ 21 ] products containing fourteen-membered rings are well documented. Free radical macrocylization furnishes a convenient route towards cyclotetradecanone derivatives with endo selectivity in moderate yield.…”