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The tigliane ring system, which encompasses iconic members such as phorbol and TPA, is widely renowned due to numerous observations of displaying potent biological activity, and subsequent use as mainstream biochemical tools. Traditionally, naturally occurring phorboids are regarded as tumor promotors through PKC activation, although in recent times more highly oxidized natural derivatives have been identified as anti-tumor agents. In the view that only limited synthetic investigations toward skeletal stereochemical modification have been undertaken, non-natural systems could be useful for a better understanding of the tigliane pharmacophore via interrogation of cellular sensitivity. In this context the concise construction of a number of highly functionalized non-natural D-ring inverted phorbol esters were synthesized, via a rhodium-catalyzed [4+3] cycloaddition, and biologically evaluated using a range of cancer cell lines. The biological results highlight the notion that subtle changes in structure have dramatic effects on potency. Furthermore, although the non-natural derivatives did not outcompete the natural systems in the PKC-activation sensitive MCF7 cancer cell line, they outperformed in other cancer cell lines (MM96L and CAL27). This observation strongly suggested an alternate mode of action not involving activation of PKC, but instead involves thiol addition as indicated by glutathione addition and NF-κB reporter activity., (© 2020 Wiley-VCH GmbH.)

The hypercalins are dearomatized acylphloroglucinols with a pendant complex cyclopentane ring that exhibit activity against several cancer cell lines. We report the first total synthesis of (+)-hypercalin C employing a convergent strategy that enabled the dissection of the essential structural features required for the observed anticancer activity. A strategic disconnection involving an unusual C sp 3 -C sp 2 Suzuki-Miyaura coupling with an α-bromo enolether also revealed an unexpected C-H activation. This strategy targeted designed analogues along the synthetic route to address particular biological questions. These results support the hypothesis that hypercalin C may act as a proton shuttle with the dearomatized acylphloroglucinol moiety being essential for this activity., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Medium-sized lactams are important structural motifs found in a variety of bioactive compounds and natural products but are challenging to prepare, especially in optically active form. A Michael addition/proton transfer/lactamization organocascade process is described that delivers medium-sized lactams, including azepanones, benzazepinones, azocanones, and benzazocinones, in high enantiopurity through the intermediacy of chiral α,β-unsaturated acylammonium salts. An unexpected indoline synthesis was also uncovered, and the benzazocinone skeleton was transformed into other complex heterocyclic derivatives, including spiroglutarimides, isoquinolinones, and δ-lactones., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Although acylammonium salts are well-studied, chiral α,β-unsaturated acylammonium salts have received much less attention. While these intermediates are convenient synthons, which are readily available from several commodity unsaturated acids and acid chlorides, and possess three reactive sites, their application in organic synthesis has been limited because of the lack of appropriate chiral Lewis bases for their generation. In recent years, the utility of chiral, unsaturated acylammonium salts has expanded considerably, thus demonstrating the unique reactivity of this intermediate leading to the development of a diverse array of catalytic, asymmetric transformations including organocascade processes. This Minireview highlights the recent and growing interest in these intermediates which might spark further research into their untapped potential for asymmetric organocascade catalysis. A cursory comparison is made to related unsaturated iminium and acylazolium intermediates., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Triptolide is a key component of the traditional Chinese medicinal plant Thunder God Vine and has potent anticancer and immunosuppressive activities. It is an irreversible inhibitor of eukaryotic transcription through covalent modification of XPB, a subunit of the general transcription factor TFIIH. Cys342 of XPB was identified as the residue that undergoes covalent modification by the 12,13-epoxide group of triptolide. Mutation of Cys342 of XPB to threonine conferred resistance to triptolide on the mutant protein. Replacement of the endogenous wild-type XPB with the Cys342Thr mutant in a HEK293T cell line rendered it completely resistant to triptolide, thus validating XPB as the physiologically relevant target of triptolide. Together, these results deepen our understanding of the interaction between triptolide and XPB and have implications for the future development of new analogues of triptolide as leads for anticancer and immunosuppressive drugs., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

An eleven-step synthesis of (±)-spongiolactone from 1,3-cyclohexanedione is reported that relies on a diastereoselective, nucleophile-catalyzed aldol lactonization (NCAL) process with an advanced ketoacid intermediate that installed the anticipated β-lactone pharmacophore of the natural product. In addition, a stereoselective cyclohexenyl zinc addition to a substituted cyclohexanone simultaneously installed two fully substituted vicinal stereocenters. The reported synthesis enabled preliminary structure-activity studies that revealed a regio- and stereoisomeric derivative of spongiolactone with greater antiproliferative activity towards a leukemia (K562) cell line. Furthermore, unusual antiproliferative selectivity of these spongiolactone derivatives toward the K562 cell line was observed with no inhibition of the breast, liver, and lung cancer cell lines tested., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Taming the beast, asymmetrically: Modulation of the reactivity of acid chlorides, using cinchona alkaloid catalysts, results in chiral α,β-unsaturated acylammoniums, which react with nucleophiles enantioselectively to give pyrrolidinones, piperid-2-ones, and dihydropyridinones. This nucleophile-catalyzed Michael/proton transfer/lactamization or lactonization organocascade leads to chiral intermediates previously employed for the synthesis of bioactive pharmaceuticals., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A one-two punch: two potentially biosynthetically relevant cyclizations of a keramadine analogue give agelastatin A. A diastereoselective C-ring formation, which proceeds through a 5-exo-trig cyclization or a Nazarov cyclization of a red-colored N-acyliminium intermediate, generates the three contiguous stereocenters of the cyclopentane core. A silica gel assisted cyclization of a nagelamide J analogue gives agelastatin A., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Game-SET-match: Pyrrole aminoimidazole alkaloids (PAIs) are metabiosynthesized from chlorinated analogues of oroidin by cell-free enzyme preparations from PAI-producing sponges. Evidence and implications for the biosynthesis of PAIs include putative single-electron transfers (SETs) that promote C-C bond-forming reactions of precursors., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)