No abstract

An efficient, practical, asymmetric synthesis of the endothelin receptor antagonist 1 is reported.The key pyridine-fused cyclopentane ring bearing three consecutive chiral centers was constructed by first an auxiliary induced asymmetric conjugate addition of the bottom aryllithium from 19 to an unsaturated ester 21 in high diastereoselectivity. After a highly diastereoselective addition of the top aryl Grignard reagent to the aldehyde 22, the alcohol product then underwent a stereospecific intramolecular alkylation of the ester enolate by the phosphate of the alcohol, resulting in the desired trans-trans relative stereochemistry on the cyclopentane ring. The two key chiral centers that set the chirality of the molecule were both induced from cis-1-amino-2-indanol-derived chiral auxiliaries, one in the conjugate addition reaction, the other in setting the chiral center of the bottom side chain via chiral alkylation of an enolate. Oxidation of the primary alcohol to the carboxylic acid in the bottom side chain was carried out with the newly developed TEMPO/bleachcatalyzed oxidation by sodium chlorite (NaClO 2 ) or chromium oxide catalyzed oxidation by periodic acid. The overall process has been run successfully to make multikilograms of the drug in high purity.

4‐Methoxyphenethyl alcohol 4‐Methoxyphenylacetic acid 2,2,6,6,‐Tetramethyl‐1‐piperidinyloxy (TEMPO) Sodium hypochlorite

Diels–Alder reactions of several N-unsubstituted tautomeric 2(1H)-pyridone-2-hydroxypyridines with benzyne were examined and found to afford 5,6-benzo-2-azabarrelenones, which were converted to hitherto unknown 5,6-benzo-2-azabarrelenes.

A new antimicrobial quinolone (—)BO‐2367, (‐)‐7‐[(1R*,2R*,6R*)‐2‐amino‐8‐azabicyclo[4.3.0.]‐non‐3‐en‐8‐yl]‐l‐cyclopropyl‐6,8‐difluoro‐l,4‐dihydro‐4‐oxo‐3‐quinorinecarboxyric acid, strongly inhibited both mammalian and bacterial topoisomerase II. The IC50 values of (—)BO‐2367 against the DNA relaxation activity of L1210 topoisomerase II and the supercoiling activities of Escherichia coli gyrase and Micrococcus luteus gyrase were 3.8, 0.5, and 1 μM, respectively. This compound enhanced double‐stranded DNA cleavage mediated by topoisomerase II not only with purified enzyme, but also with intact L1210 cells. All these activities of (—)BO‐2367 were more than 2‐fold stronger than those of VP‐16. Intriguingly, (+)BO‐2367, which has an enantiomeric substitnent at the C7 position of (‐)BO‐2367, did not affect the activity of the mammalian topoisomerase II, while it inhibited E. coll gyrase. Intraperitoneal injection of (‐)BO‐2367 at 0.08 mg/kg increased the lifespan of CDF1female mice bearing ascitic L1210 leukemia by 2.4 times, and subcutaneous injection at 1.25 mg/kg completely inhibited the growth of colon 26 carcinoma implanted subcutaneously. These results suggest that (—)BO‐2367 is a potent antitumor agent which targets topoisomerase II. These enantiomers should be a useful tool for studying drug‐topoisomerase II interactions.