A Facile Oxidative Opening of the C-Ring in Luotonin A and Derivatives

Abstract

An oxidative ring opening reaction of the central ring C in the alkaloid Luotonin A and two of its derivatives was found to occur upon heating with an excess amine and potassium carbonate in dimethylsulfoxide (DMSO) solution in the presence of air oxygen. The structure of the novel amide-type products was elucidated and a possible mechanism for this reaction is proposed. Four of the new compounds show moderate in vitro anticancer activity towards human colon adenocarcinoma cells.

Position-Selective Synthesis and Biological Evaluation of Four Isomeric A-Ring Amino Derivatives of the Alkaloid Luotonin A

“…We succeeded in this alkylation to obtain compound 3b by applying a protocol that we had recently used for similarly insoluble substrates [ 17 ] (DMSO as solvent, finely powdered potassium hydroxide, tetrabutylammonium bromide as phase-transfer catalyst, ultrasound irradiation at room temperature). Assembly of the pentacyclic skeleton ( 4b ) then was easily accomplished by intramolecular [4 + 2] cycloaddition, mediated by bis(triphenyl)oxodiphosphonium triflate (Hendrickson’s reagent) [ 24 ] in dry dichloromethane at room temperature, conditions that had been previously applied for analogous transformations [ 16 , 17 , 18 , 21 ].…”

“…A systematic overview of the main synthetic routes to Luotonin A is given in a review article by Liang et al [ 8 ]. Among the more recent approaches, two orthogonal pathways have been shown by our group to be suitable for the specific placement of substituents at all possible positions of ring A: the “southern route” gives access to either 2- or 4-substituted Luotonin A derivatives [ 16 , 17 , 18 ] whereas the “northern route” leads to either 1- or 3-susbtituted congeners [ 19 ]. In both reaction sequences, intramolecular [4 + 2] cycloadditions represent the key step.…”

The Forty-Sixth Euro Congress on Drug Synthesis and Analysis: Snapshot †

“…Several of the A-ring-modified Luotonin A derivatives that have been synthesised via these two routes exhibit in vitro growth inhibitory activity towards selected human tumour cell lines with EC 50 values in the low micromolar range but so far, no candidate with sub-micromolar activity could be obtained. In an attempt to further modify the lead structure, nucleophilic displacement of a 4-fluoro substituent with primary and secondary amines was investigated [ 46 ]. Here, an unexpected oxidative C-ring opening reaction was observed that leads to carboxamides of the general structure shown in Scheme 3 .…”

Design, Synthesis, and Antifungal Evaluation of Luotonin A Derivatives against Phytopathogenic Fungi

“…Alkaloids have attracted great interest in drug development due to several well-known quinoline alkaloids (e.g., camptothecin and quinine). , Luotonin A is a quinoline alkaloid extracted from a traditional Chinese medicine plant with topoisomerase I and II inhibitory activity. , Compared with camptothecin, the E-ring structure of luotonin A is relatively stable and more efficient for total synthesis and modification optimization, which has attracted the attention of many researchers. , Until now, studies on luotonin A have mainly focused on improving antitumor activity, with fewer reports in the field of agricultural fungicides. Our group first reported the anti-phytopathogenic fungal and insecticidal activities of luotonin A and its derivatives, and although there is some enhancement of the related activities of luotonin A derivatives, we believe that they still have considerable potential …”