The Synthesis of Alisamycin, Nisamycin, LL-C10037α and Novel Epoxyquinol and Epoxyquinone Analogues of Manumycin A

Abstract

Versatile synthetic routes are described for the preparation of a range of epoxyquinol and epoxyquinone analogues of the antitumour antibiotic manumycin A lacking the lower side chain, and these procedures have also been applied to prepare the bioactive natural product LL-C10037a. The extension of this methodology to provide a general synthetic route to the manumycin family of antibiotics is discussed and exemplified by the first total synthesis of alisamycin and ent-alisamycin. This route includes the novel, stereoselective organometallic addition of the Corey-Wollenberg reagent (E-2-tributylstannylethenyllithium) to the manumycin nucleus and palladium catalysed Stille coupling technology for the introduction of the polyunsaturated 2-amino-3hydroxycyclopentenone derived amide. Similar methodology has also been employed to complete the first total synthesis of the antibiotic nisamycin.

Syntheses of Natural Products Having an Epoxyquinone Structure

“…Deoxypreussomerin A (81) was reduced by NaBH 4 to give 118 as a single diastereomer, the stereochemistry of which was assigned to be syn from their previous result. 87 It was described that the 1 H and 13 C NMR data of the product 118 were entirely consistent with those of palmarumycin C 11 reported by Krohn et al 30 and Sch 53823 reported by Connolly et al 33,88 and Chu et al, 89 respectively. Although this result suggested that bipendensin and Sch 53823 have an antihydroxy-epoxide structure, Chu et al reported that Sch 53825, a cometabolite of Sch 53823, has a synhydroxy-epoxide structure from a NOESY experiment.…”

Recent advances in 1,4-benzoquinone chemistry

“…antibiotic LL-C10037a. [311][312][313] March et al 314 reported that phenylthiomonoketal (222) works efficiently as a masked p-benzoquinone in Diels-Alder reactions. These cycloadditions may be performed with certain Lewis acid catalyst like ZnBr 2 and give rise exclusively to endo adducts with a good to excellent anti-facial selectivity (Scheme 59).…”

Synthesis and Antiapoptotic Activity of a Novel Analogue of the Neutral Sphingomyelinase Inhibitor Scyphostatin

“…[38] In the course of our study, we probed the importance of the presence of an epoxide moiety located at the carbon centre activated by the a,b-unsaturated enone in the natural compound. While this unique structure is rare-for example, the family of manumycin antibiotics comprises a comparable epoxyquinone moiety [39] -it remains to be determined whether its presence is required for biological activity. Potentially reactive intermediates such as epoxides [40,41] are subjected to fast biotransformation.…”