Asymmetric Total Synthesis of Griseofamine B and Its Three Stereoisomers

Abstract

The first total synthesis of griseofamine B is described starting from L-4-bromo tryptophan methyl ester hydrochloride via five steps and in 18% overall yield. Its three stereoisomers were also synthesized following the same procedure with the yields of 5%, 19%, and 5%, respectively. In vitro antibacterial activities were also evaluated. All four compounds exhibited less potent activity than griseofamine A.G riseofamines A (1) and B (2), two novel indole-tetramic acid alkaloids, were isolated from the growth medium produced by the fungus Penicillium griseof ulvum in 2018. 1 Griseofamine A (1) features a 6/5/6/5 tetracyclic ring skeleton by fusing the indole motif to the 3-acyl tetramic acid motif via a piperidine ring. Griseofamine B (2) is characterized by a 6/5/7/5 tetracyclic ring skeleton by the fusion of these two parts via an azepane ring.

Iron porphyrin-catalysed C(sp3)–H amination with alkyl azides for the synthesis of complex nitrogen-containing compounds

“…As shown in Scheme 6, azide 13 underwent intramolecular C(sp 3 )-H amination to afford 14 in 45% yield. 74 Starting from 14, cis-clavicipitic acid and 16-epi-griseofamine B could be synthesized according to the reported procedure. 74 Dibenz[c,e]azepines belong to a class of bridged biaryl frameworks that possess unique conformational features.…”

“…74 Starting from 14, cis-clavicipitic acid and 16-epi-griseofamine B could be synthesized according to the reported procedure. 74 Dibenz[c,e]azepines belong to a class of bridged biaryl frameworks that possess unique conformational features. Dibenz[c,e]azepines are also present in other bioactive compounds, such as anti-obesity drugs and analogues of the alkaloid colchicine, 75 and are key structural backbones in chiral catalysts.…”

Indole-Containing Natural Products 2019–2022: Isolations, Reappraisals, Syntheses, and Biological Activities

“…d-Enantiomer 4-bromo tryptophan methyl ester hydrochloride was used to synthesize compounds 321 and 323 . All four compounds were obtained in five steps with yields of 18%, 5%, 19%, and 5%, respectively ( Figure 20 ) [ 87 ]. Next, compound 309 was reacted with Boc 2 O, Et 3 N, and DMAP under reflux conditions in DCM to afford 310 in 90% yield.…”

“…A tandem acylation/Lacey–Dieckmann cyclization of 313 and 316 with diketene was performed to afford 314 and 317 , respectively. Additionally, using the same synthetic scheme with compound 318 as the starting reagent afforded compounds 321 and 323 [ 87 ].…”

“…The antibacterial activities of compounds 314 , 317 , 321 , and 323 were evaluated but were considerably less potent than their congener, griseofamine A’s activity (MIC = 8–16 µg/mL). Since all compounds tested contained the 3-acyltetramic acid moiety, the putative notion that the motif was a major determinant of antibacterial activity was not supported [ 87 ]. Compounds 347–352 displayed moderate to strong cytotoxicities against various cell lines.…”