Total syntheses of (+/-)-rhopaloic acid A, (+)-fumiquinazoline G, (-)-asperlicin and (-)-asperlicin C

A six-step synthesis of rhopaloic acid A (1.1E) was accomplished in 25% overall yield using the Pd(0)-mediated cyclization and methoxycarbonylation of allenyl alcohol 1.3 which afford 83% of a 6:1 mixture of tetrahydropyranylacrylates 1.2 and 1.8, as the key step. An attempted asymmetric synthesis of rhopaloic acid A failed since primary alkyl iodide 1.5 is not reactive enough to alkylate the enolate of optically pure acyl oxazolidinone 1.11.;An efficient twelve-step synthesis of (+)-fumiquinazoline G was accomplished in 11% overall yield. This scheme features the acylation of indole nitrogens with amino acids, indirect formation of quinazolin-4-one by intramolecular aza-Wittig reaction, and an extensive survey of protection groups for lactam. Although the direct formation of quinazolin-4-ones through imido chloride and an attempted synthesis of spiroquinazoline were unsuccessful, the chemistry discovered will be valuable for the syntheses of more complex fumiquinazolines and spiroquinazoline.;We reinvestigated Wang and Ganesan's syntheses of quinazolin-4-ones by the direct dehydration of tripeptides. We observed that no quinozolin-4-ones were generated. Instead, isoquinazolinones were produced in moderate yield. We also observed that isoquinazolinone 4.59b could isomerize to quinazolinone 4.58b on treatment of piperidine. This isomerization is still under investigation.;The concise syntheses of the quinazolinone alkaloids (-)-asperlicin and (-)-asperlicin C were also accomplished. The important aspect of this work is the stereocontrolled construction of the hydroxyimidazoindolone ring system embodied in asperlicin. This ring system is similarly found in tryptoquivaline G which was first synthesized by Buchi and subsequently by Ban, and Nakagawa and Hino. Our approach is distinct from previous work which proceeded along more biomimetic lines. The preparation of the imidazoindolone by Buchwald's Pd-catalyzed amidation chemistry, and its conversion to (-)-asperlicin using stereoselective epoxidation and reduction protocols represents a novel and attractive route which should be applicable for the synthesis of structurally related fumiquinazoline A. The overreduction of the quinazolinone does not significantly detract from the overall approach since it can be recovered readily by DDQ oxidation.