9īoth the challenging molecular architecture and the broad variety of biological activities of these natural products have kindled an interest in their total synthesis.
9 The cytotoxicity of 4 was found to be correlated with its complexation of Ca 2+. 7 Cylindramide ( 4) originally isolated in 1993 from the marine sponge Halichondria cylindrata exhibits pronounced cytotoxicity against B16 melanoma cells 8 and other mammalian cell lines, as was published in 2007. 6 They postulated a biosynthetic pathway and common biosynthetic origins for polycyclic tetramate macrolactams. In 2010 Clardy and coworkers isolated clifednamide A ( 3a) and B ( 3b) from a strain Streptomyces sp. 5 It is an antifungal compound which is active against various human-pathogenic and phytopathogenic fungi. 4 Maltophilin ( 2), bearing a cyclopentaindene core, was obtained from strains of Stenotrophomonas maltophilia R3089. 2 The structure and absolute stereochemistry of 1 was assigned by chemical degradation and spectroscopic methods, 3 and recently, its biosynthesis has been reconstituted in Escherichia coli. Ikarugamycin ( 1) which was isolated in 1972 from a culture broth of Streptomyces phaeochromogenes 2 shows strong specific antiprotozoal activity, antiamoebic activity and activity against some Gram-positive bacteria. 1 Representative polycyclic tetramate macrolactams 1–4. Representative examples are ikarugamycin ( 1), maltophilin ( 2), clifednamide A ( 3a) and B ( 3b) as well as cylindramide ( 4) ( Fig. This class of structurally complex molecules is characterized by a macrocyclic lactam ring with incorporated tetramic acid moiety, fused to carbocycles based on either bicyclooctane or a dodecahydro- as-indacene or a related system.
Introduction Macrocyclic tetramic acid lactams are a subfamily among the 2,4-pyrrolidinedione (tetramic acid) natural products 1 with a wide range of biological activities. Quantum-chemical investigations of this intramolecular Diels–Alder reaction support the proposed configuration of the final product. A subsequent Diels–Alder reaction yielded the target ethyl hexahydro-1 H-indene-carboxylate with high diastereoselectivity. This rearrangement proceeded diastereoselectively only in the presence of an allyl silyl ether instead of the parent enone in the side chain, as suggested by deuteration experiments. Starting from di- O-isopropylidene- D-mannitol the allyl carboxylate precursor for the sigmatropic rearrangement was prepared. In order to construct the functionalized AB ring system of clifednamide, member of the class of macrocyclic tetramic acid lactams, a synthesis was developed which utilized an Ireland–Claisen rearrangement and an intramolecular Diels–Alder reaction.