Isolation, Structure Elucidation, and Biomimetic Total Synthesis of Versicolamide B, and the Isolation of Antipodal (-)-Stephacidin A and (+)-Notoamide B from Aspergillus versicolor NRRL 35600

摘要

Prenylated indole alkaloids containing the bicyclo[2.2.2]diazaoctane ring system as a core structure, now number more than 38 family members. These natural substances, produced by various genera of fungi, in particular Aspergillus and Penicillium spp. (among others), exhibit a range of interesting structural and stereochemical features. Significantly, a myriad of biological activities, including insecticidal, antitumor, anthelmintic, calmodulin inhibitory, and antibacterial properties, are displayed by members of this family. Structurally, these substances arise from the oxidative condensation of one or two isoprene units, tryptophan, and another cyclic amino acid residue such as proline, -methylproline, or pipecolic acid. With respect to the relative stereochemistry within the core bicyclo[2.2.2]diazaoctane ring system, all of the known members of the paraherquamide family, for example, paraherquamides (1 and 2), stephacidins (3 and 4), and notoamides (5 and 6) possess a syn configuration, while only the brevianamides (9 and 10) possess the anti relative configuration (Scheme 1). The syn/anti relationship refers to the relative configuration between the C19C22 bond (sclerotiamide numbering) and the C17N13 bond of the cyclic amino acid residue (proline, -methylproline, or pipecolic acid; Scheme 2). This relationship reveals that to construct the core ring system biosynthetically in the oxidative cyclization process(es) both faces of the isoprene-derived dienophile participate in the ring-forming process. However, until now this stereochemical divergence was cleanly separated between the brevianamides and all other members of this growing family of natural products. Herein, we describe the isolation, structure elucidation, and confirmatory biomimetic total synthesis of the first member of the paraherquamide/stephacidin family to possess the rare anti relative configuration within the bicyclo[2.2.2]diazaoctane ring system. We propose the new name of versicolamide B for this natural product (8), which is a minor metabolite of Aspergillus versicolor NRRL 35600. We have assigned the absolute configuration to this compound on the basis of the circular dichroism (CD) spectra, and have concluded that it possesses the ent configuration with respect to the bicyclo[2.2.2]diazaoctane core. Surprisingly, and just as striking, we have also isolated (-)-stephacidin A and (+)-notoamide B from Aspergillus versicolor NRRL 35600 and conclude that these natural products are produced as the corresponding enantiomers to the structures that have been previously described. The provocative biogenetic implications of these stereochemical findings are discussed herein.