Concise asymmetric total syntheses of the fungal metabolites (−)-stephacidin A, (+)-stephacidin B, and (+)-notoamide B are described. Key features of these total syntheses include (1) a facile synthesis of (R)-allyl proline methyl ester, (2) a revised route toward the pyranoindole ring system, (3) a novel cross-metathesis strategy for the introduction of important functional groups, and (4) an S N 2′ cyclization to form the [2.2.2] bridged bicyclic ring system. Furthermore, our synthesis has taken advantage of microwave heating to shorten reaction times as well as increase yields for the preparation of vital intermediates.

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...

The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. We employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compound design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compounds demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.

A halogen-selective tandem intramolecular Heck/carbonylation reaction has been developed for the construction of the C,E,F-ring system and the C20 quaternary center found in perophoramidine (1). This process can be effected in good yields in the presence of both the chlorine and bromine atoms found in the natural product. In addition, it is possible to introduce the quaternary center at C4 in a stereoselective manner by a lactone enolate alkylation, using NaH and allyl bromide. [reaction: see text]