Fusarisetin A: scalable total synthesis and related studies

Abstract

Fusarisetin A (1) is a recently isolated natural product that displays an unprecedented chemical motif and remarkable bioactivities as a potent cancer migration inhibitor. We describe here our studies leading to an efficient and scalable total synthesis of 1. Essential to the strategy was the development of a new route for the formation of a trans-decalin moiety of this compound and the application of an oxidative radical cyclization (ORC) reaction that produces fusarisetin A (1) from equisetin (2) via a bio-inspired process. TEMPO-induced and metal/O2-promoted ORC reactions were evaluated. Biological screening in vitro confirms the reported potency of (+)-1. Importantly, ex vivo studies show that this compound is able to inhibit different types of cell migration. Moreover, the C5 epimer of (+)-1 was also identified as a potent cancer migration inhibitor, while (−)-1 and 2 were found to be significantly less potent. The optimized synthesis is applicable on gram scale and provides a solid platform for analogue synthesis and methodical biological study.

Fusarisetins: structure–function studies on a novel class of cell migration inhibitors

“…On the other hand, significant racemization at the C3 center was observed when a serine analog was cyclized under the same conditions en route to the synthesis of 1 . 15 This difference is attributed to the methyl hydroxy group of serine that inductively increases the acidity of the C3 proton. 21 Exposure to cerium ammonium nitrate (CAN) in acetic acid under oxygen atmosphere followed by reduction of the resulting endoperoxides, 22 produced fusarisetin analogs 8a–8d (18–25% overall yield).…”

“…Initial cell-based evaluation of all fusarisetins (synthetic material, 15 1–100μM) was performed using a well-described scratch wound assay. 24 MDA-MB-231 cells were grown as a confluent monolayer, scratched and treated with analogs over a 24 hour period.…”

Synthetic strategies toward the decalin motif of maklamicin and related spirotetronates

“…12c, 16 Under these conditions, the IMDA reaction was slow (3 days for completion) and produced exclusively the endo -equatorial adduct 4 . 15 The results indicate that the catalysis was not effective in our substrate, presumably due to the presence of the C4 methyl group adjacent to the carbonyl group. This methyl group likely prevents the transiently formed iminium intermediate from assuming the geometry needed for the desired facial selectivity of IMDA, thus diminishing the ability of the catalyst to direct the stereochemical outcome of this reaction.…”

“…Previously, we demonstrated that triene 3 , synthetically available from (−)-citronellal ( 10 ) in 3 steps, undergoes an IMDA in the presence of Et 2 AlCl at −78 °C to produce the endo -equatorial product 4 . 15 We hypothesized that an organocatalytic process could overcome the inherent substrate selectivity of this system and favor construction of cycloadduct 5 , the one encountered in the structure of maklamicin. These studies are summarized in Scheme 1.…”

“…18 The modified strategy departed from ( S )-(−)-citronellal ( 10 ) that, following established protocols, was converted to enal 11 . 15, 19 The difference in the chemoselectivity between the two carbonyl groups of 11 , allowed selective protection of aliphatic aldehyde with ethylene glycol and tosylic acid. The resulting acetal underwent Pinnick oxidation to afford the corresponding carboxylic acid 12 (80% yield over two steps).…”