Manganese(III)-based oxidative cyclizations: Formal synthesis of 15-acetoxypallescensin A. Synthesis of hindered guanidines. Completion of the total synthesis of martinellic acid

Using a new variant of the Mn(OAc)₃ chemistry previously developed in our laboratories, a formal synthesis of 15-acetoxypallescensin A (1) was achieved in 5 steps as compared with the previously published 11 steps. β-Ketoester 3 was prepared in 3 steps from 2. Mn(OAc)₃ oxidative tandem cyclization of β-Ketoester 3 was shown to cyclize onto the reactive 2-position of the furan leading to the tricyclic β-Ketoester 5 after acidic workup. Reduction with lithium aluminum hydride (LAH) provided diol 6, which was a late intermediate in the synthesis of 1 reported by Zoretic. We also investigated cyclization onto the less reactive 4-position of furan 8 by protecting the 2-position. The 2-protected furyl β-ketoester 8 was prepared in 11 steps from 7. Unfortunately this substrate yielded none of the desired tricyclic product 9 when reacted with Mn(OAc)₃.; We further investigated the scope of a tandem oxidative free-radical approach to prepare decalin systems. Reaction of the (E, E)-diene geraniol-derived β-ketoester 10 to produce 11 was known. Additionally, it was known that the (Z, phenyl) substrate 12 formed several products when treated with Mn(OAc)₃. It was not known what effect on a tandem cyclization a Z-olefin in the right hand position of would have. We found that reaction of 6 with 2.4 equivalents of Mn(OAc)₃ in AcOH yields 2.0, 8.5, 3.2, 3.1 and 3.2% for 36, 37, 37a, 38 and 39, respectively.; Martinellic acid and martinelline were isolated by Witherup, Varga and co-workers at Merck Research Laboratories from the roots of the tropical plant Martinella iquitosensis. We developed a new method for the formation of the challenging N,N,N ′-trisubstituted guanidine from the hindered pyrrolidine using a cyanamide intermediate. Reaction of tricyclic model amine 92 with cyanogen bromide and NaHCO₃ in MeOH formed model cyanamide 93. Reaction of 93 with prenylamine in hexafluoroisopropanol at 120°C for 14 h produced tricyclic guanidinoester 94 84% yield. The ester of 94 was hydrolyzed by refluxing in methanol with Dowex 550A strongly basic ion exchange resin to form 96 in 73% yield.; The total synthesis of martinellic acid was completed by elaborating triamine 5 to bis-guanidine 28 followed by hydrolysis of the ester to form martinellic acid. Treatment of 5 with CNBr and NaHCO₃ in MeOH formed bis-cyanamide 26 in 82% yield. Treatment of 26 with 2.2 equiv of prenylamine formed bis-guanidinoester 28 in XX yield. Hydrolysis of 28 with ion exchange resin was not successful, but hydrolysis with aqueous NaOH in MeOH was effective thus completing the total synthesis.