Synthetic Access to the Chlorocyclopentane Cores of the Proposed Original and Revised Structures of Palau′amine

Abstract

The pyrrole-imidazole alkaloids constitute a family of more than 100 natural products,[1,2] among which palau'amine (1, Scheme 1) exists as one of the more structurally complex members. This polycyclic guanidine alkaloid, which was isolated from Stylotella aurantium, was found to possess potent cytotoxic, antibiotic, and immunosuppressive activities.[3] Despite the fact that its acute toxicity is relatively low (LD50 = 13 mg kg−1 in mice), palau'amine exhibited significant cytotoxicity in a variety of cancer cell lines, including P-388 (IC50 = 0.1 μg mL−1) and A-549 (IC50 = 0.2 μg mL−1). Moreover, 1 exhibits remarkable immunosuppressive responses in the mixed lymphocyte assay (IC50< 18 ngmL−1). Elegant strategies for the synthesis of advanced cyclopentane fragments related to 1 have been reported.[4] These include, inter alia, a tethered Pauson–Khand approach,[5] Diels–Alder chlorination/ring contraction,[6,7] Diels–Alder oxidative ring contraction,[8,9] spirocyclization of alkylidene glycolamidines and alkylidene hydantoins,[10,11] 1,3-dipolar cycloaddition of thiosemicarbazide derivatives and alkene/enamide metathesis,[12,13] Diels–Alder cyclopropane fragmentation,[14] oxidative tandem radical cyclization,[15] and most recently intramolecular guanidine-conjugate addition[16,17] in a total synthesis of the related axinellamine alkaloids. Additionally, synthetic efforts toward the phakellin heterocyclic core of 1 have also been reported.[18–25]