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, b-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 C19ÀC22 bond (sclerotiamide numbering) and the C17ÀN13 bond of the cyclic amino acid residue (proline, b-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, Scheme 1. Structures of several members of the paraherquamide/ stephacidin/brevianamide family of prenylated indole alkaloids.

Copying nature: A biomimetic total synthesis of stephacidin A has been accomplished using an intramolecular Diels–Alder reaction. Stephacidin A was then converted into notoamide B in a single step by oxaziridine‐mediated oxidation to provide the first biomimetic total synthesis of notoamide B (see scheme).

Dedicated to Professor David A. Evans on the occasion of his 65th birthdayThe past several years have seen an explosion of new metabolites that are isolated from fungi and have interesting biological activities. Our research group has a rich history in the synthesis [1] and elucidation of the biosynthesis [2] of fungal metabolites derived from tryptophan, isoprene, proline, and proline derivatives.[3] Recently, two research groups have reported structurally related alkaloids that were isolated from two different strains of fungi, cultivated from marine environments. Tsukamoto and co-workers recently isolated four new prenylated indole alkaloids named the notoamides A-D (1-4, Scheme 1), along with the known alkaloids sclerotiamide and stephacidin A (9), from a marine strain of Aspergillus sp. cultivated from the common mussel, Mytilus edulis.[4] The structures of the notoamides A-D contain a pyranoindole ring system similar to those found in the stephacidins [5,6] and several paraherquamides. [7] In addition, notoamide A (1) and B (2) possess the bridged [2.2.2]diazaoctane ring system commonly found in the paraherquamide and stephacidin family. Interestingly, the nitrogen atom of the 2-oxindole moiety of notoamide A is oxidized to the N-hydroxy group. The notoamides C (3) and D (4) lack the bridged bicycle of 1 and 2, and 4 contains the pyrrroloindole ring system.[8] The notoamides A-C exhibit moderate cytotoxicity against a panel of cancer cell lines but notoamide D shows no such activity.In 2005, a related alkaloid family, the norgeamides (5-8, Scheme 1), was reported by researchers at the Hans-Knöll Institute.[9] These compounds were isolated from a strain of cold water Aspergillius fungi growing in the North Sea [9] and bear a striking resemblance to 3 and 4. However, the distinguishing feature of the norgeamides is that the a position of the proline ring (at C17) has a methoxy substituent for norgeamide A (5) and a hydroxy group for norgeamide B (6) and D (8). As for the biological activity of the norgeamides, all have been found to inhibit the growth of a variety of cancer cell lines with different efficacies. Norgeamide A (5) was reported to be the most potent inhibitor of cell growth with observed values of 77-98 % inhibition. Norgeamide B (6), which only differs from 5 in the substitution at the C17 position, was 20-30 % less effective at inhibiting cell growth. The norgeamides C (7) and D (8) were the poorest inhibitors of this family of alkaloids with only 34-41 % inhibition being observed. In comparison with the notoamides, it is reasonable to assume that the oxidation state of the proline ring system is vital for biological activity.From a biosynthetic standpoint, one could envision a single biosynthetic pathway encompassing the notoamides and the norgeamides. To this end, a key starting substrate for this family, as well as for the stephacidins and several paraherquamide derivatives, would be substance 11 (Scheme 2). A single oxidation of 11 would generate the pyrroloindole ring system of 4. It is pa...

A biomimetic total synthesis of the fungal metabolite marcfortine C utilizing an intramolecular Diels-Alder reaction is described. In addition, a key stereoselective oxaziridine-mediated oxidation/pinacol rearrangement of indole 24 was used to complete the total synthesis.