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.
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.
The reactions of 2-pyridones with benzyne were investigated in order to gain some insight into the structure–reactivity–chemoselectivity relationship involved in the tautomeric systems. All reactions examined have resulted in the formation of Diels-Alder and Michael-type adducts. It has been shown that the Diels-Alder reactivities were well correlated with the HOMO energy levels of the 2-pyridone form and the yields of the Michael-type adduct were closely associated with the tautomeric equilibria. In summary, the chemoselectivities of 2-pyridones in the reaction with benzyne were largely affected by the tautomeric properties.
Two distinct synthetic approaches to the biologically active and structurally unique endothelin antagonist J-104132 (1) have been developed Each synthesis involves a highly selective intramolecular cyclization of a late stage intermediate (bottom to top vs top to bottom) produced from a common early intermediate. Both routes initially yielded multi-gram quantities of the desired product, with the former ultimately developed to pilot scale readiness.Several novel reactions have been developed throughout the course of our studies. These involve a mild bromination of a pyridone to form a bromopyridine, a mild and efficient TEMPO catalyzed oxidation of an alcohol to give a carboxylic acid, as well as a novel stereoselective samarium iodide mediated deoxygenation reaction. These reactions have proved to be quite general and have been applied to a wide variety of substrates.
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