Synthetic studies on FR 901483, synthesis of N-Acetylneuraminic acid and synthetic approaches to lasonolide A

Abstract

Total synthesis of immunosuppressant FR901483 was attempted from the known cyclohexenone 30 via two synthetic approaches. In the first synthetic pathway, construction of piperidine ring was intended using 109-110,144-146 and 149. Oxazolines 88 and 141, possessing the requisite chiral amino group were obtained from the corresponding allylic alcohols 87a and 140 by iodine-promoted amidation, respectively. But electrophile-induced cyclization of 109-113, 144 and 146 or intramolecular 1,4-addition of amino group to the conjugated ester group in 144-146 and 149 did not give the desired piperidine compounds. Intramolecular amidation of allylic alcohol 157b afforded the undesired pyrrolidine compound 159b. In the second synthetic approach, the tertiary amino group was introduced by intramolecular cyclization of 175 and trichloroacetimidate prepared from 164 to provide the incorrect stereochemistry. Although the desired stereochemistry could be obtained with amidine 189 and oxazolidinone 193, hydrolysis of the generated cyclic urea failed. Synthesis of N-acetylneuraminic acid was accomplished from non-carbohydrate source using stereoselective phenylselenoamidation and dihydroxylation as key steps. Phenylselenonium ion-induced amidation of trichloroacetimidate derived from allylic alcohol 300a produced oxazoline 302. To achieve high diastereoselective dihydroxylation, oxazoline 302 was converted into oxazolidinone 305d, of which 2,4,6-trimethylbenzyl protecting group was installed because of its stability to subsequent basic hydrolysis. After transformation of trimethylbenzyl ether 305d to (-keto ester 244, its acidic hydrolysis furnished N-acetylneuraminic acid. The synthesis of macrocyclic lasonolide A was examined. In the first approach, formation of the ester bond was accomplished under Yamaguchi conditions between alcohol 337 and acid 338. But intramolecular Stille coupling of the resulting ester 336 was unsuccessful due to decomposition of vinyltin group in 337. A...