A Concise Total Synthesis of the Notoamides C and D

Abstract

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...

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

“…[1a, 4] The synthesized compounds include brevianamide B (10), stephacidin A (3), marcfortine C, and the recently discovered fungal metabolite notoamide B (6; Scheme 1). [4,5] We demonstrate herein that this general strategy was easily amendable to the total synthesis of versicolamide B and provided unambiguous structural and relative stereochemical corroboration for this stereochemically unique natural product.…”

“…[4] However, this protocol proved problematic for the completion of the synthesis of (AE )-versicolamide B (8) from the corresponding anti-cycloadduct 15. The intermediate indole derived from cleavage of the lactim ether of 15 was found to be unstable when exposed to the atmosphere and underwent a facile ring-opening/hydrolysis of the diketopiperazine to produce the corresponding amino acid.…”

“…[5] The structure and relative configuration of versicolamide B were corroborated through a biomimetic, racemic total synthesis. Our synthesis of 8 commenced with a Mitsonobutype elimination (PBu 3 , DEAD) of the recently prepared alcohol 11 [4] to afford an intermediate enamide, which was then treated with Me 3 OBF 4 and Cs 2 CO 3 to cleanly provide the desired lactim ether 12 in good yield (Scheme 3). With lactim ether 12 in hand, we were ready to try the key biomimetic cycloaddition reaction.…”

MgI2‐Mediated Chemoselective Cleavage of Protecting Groups: An Alternative to Conventional Deprotection Methodologies

“…[4][5][6][7] Besides tediously efficient or racemizing procedures using CaCl 2 , or AlCl 3 /DMA, [8] organotins seem to be the most reliable reagents. [4] So, trimethyltin hydroxide (TMTOH), initially explored by O. Mascaretti et al, [9] and further applieda taspecific point in at otal synthesis reaction, [10] was describedt oc leave ethyl/ methyl estersw ithout affecting the Fmoc PG in good yields with occasional slight epimerization.I nF moc-free syntheses, ethyl,i sopropyl, or allyl estersw ere partially susceptible to deprotection in the presence of TMTOH,w hereas Boc and Alloc remained stable. In am ore general way,awide range of mild methodsu sing Lewisa cids to remove PGs were advanced to overcome basic racemizing conditions, side reactions inherent to strong acidolytic deprotections, catalytic hydrogenolysis, or even palladium-catalyzed PG cleavages.…”

Effective Use of Heterologous Hosts for Characterization of Biosynthetic Enzymes Allows Production of Natural Products and Promotes New Natural Product Discovery

“…In the case of notoamide biosynthesis, installation of an α-face epoxide will lead to a β-face migration of the prenyl group to yield an S-configured carbon at C-3 of 41. 87) On the other hand, installation of a β-face epoxide can result in an α-face migration of the prenyl group to form a C-3 R-configured 3-epi-notoamide C 84) (Chart 9B). Thus, it can be hypothesized that the marine-derived Aspergillus carries an FMO that performs a β-face epoxidation, while the terrestrial Aspergillus has an α-face-specific FMO for a parallel biosynthesis of enantiometrically opposite natural products.…”