Polycyclic aromatic hydrocarbons are important structural motifs in organic chemistry, pharmaceutical chemistry, and materials science. The development of a new synthetic strategy toward these compounds is described based on the design principle of iron(III)-catalyzed carbonyl–olefin metathesis reactions. This approach is characterized by its operational simplicity, high functional group compatibility, and regioselectivity while relying on FeCl3 as an environmentally benign, earth-abundant metal catalyst. Experimental evidence for oxetanes as reactive intermediates in the catalytic carbonyl–olefin ring-closing metathesis has been obtained.

Iron(III)-catalyzed carbonyl-olefin ring-closing metathesis represents a new approach toward the assembly of molecules traditionally generated by olefin–olefin metathesis or olefination. Herein, we report detailed synthetic, spectroscopic, kinetic, and computational studies to determine the mechanistic features imparted by iron(III), substrate, and temperature to the catalytic cycle. These data are consistent with an iron(III)-mediated asynchronous, concerted [2+2]-cycloaddition to form an intermediate oxetane as the turnover-limiting step. Fragmentation of the oxetane via Lewis acid-activation results in the formation of five- and six-membered unsaturated carbocycles.

The development of acid chlorides as formal dianion linchpin reagents that enable access to cyclic 2-alkyl- and 2-acyl-1,3-alkanediones from dicarboxylic acids is described herein. Mechanistic experiments relying on 13C-labeling studies confirm the role of acid chlorides as carbon dianion linchpin reagents and have led to a revised reaction mechanism for the aluminum(III)-mediated Dieckmann cyclization of dicarboxylic acids with acid chlorides.

A mild, catalytic method for the synthesis of 3-carboxy-2,5-disubstituted furans is reported proceeding via a 5-exo-dig cycloisomerization reaction. The iron(III) chloride-catalyzed transformation of aryl- and alkyl β-ketoesters enables synthetic access to functionalized furan core structures found in many natural products and complex molecules of biological importance. The method described herein, represents a mild and efficient alternative to currently available reaction protocols.Download high-res image (80KB)Download full-size image

Jacob R. Ludwig received his BSc in chemistry in 2014 from Michigan State University, where he performed research in the laboratory of Jetze Tepe. After graduation, he joined the Schindler lab at the University of Michigan to pursue his PhD degree.Corinna S. Schindler received her diploma in chemistry from the Technical University of Munich. After a research stay with K.C. Nicolaou at the Scripps Research Institute, she joined the group of Erick Carreira at ETH Zürich for her graduate studies. She then returned to the US to conduct postdoctoral studies with Eric Jacobsen at Harvard before starting her independent career at the University of Michigan in 2013.

A mild, catalytic method for the synthesis of 3,4-dihydro-2H-pyrans is described. The FeCl3-catalyzed transformation of aryl- and alkyl β-diketones enables synthetic access to functionalized pyran core structures incorporated in many natural products and biologically active target structures. The method represents a mild alternative to currently available reaction protocols relying on stoichiometric reagents and harsh reaction conditions. This FeCl3-catalyzed transformation has enabled the selective synthesis of α-lapachone in two synthetic transformations and subsequently β-lapachone in three synthetic transformations, which is currently undergoing clinical trials as a potent anticancer agent.

A 7-step synthesis of pharbinilic acid, a member of the gibberellin family of natural products and the first naturally occurring allogibberic acid, is reported. An efficient decarboxylative aromatization reaction enables the synthesis of pharbinilic acid and related analogs for evaluation as modulators of NF-κB activity. Remarkably, one analog displays a 2 μM IC50 in an NF-κB activity assay and inhibits an endogenous NF-κB-regulated pathway.

A 7-step synthesis of pharbinilic acid, a member of the gibberellin family of natural products and the first naturally occurring allogibberic acid, is reported. An efficient decarboxylative aromatization reaction enables the synthesis of pharbinilic acid and related analogs for evaluation as modulators of NF-κB activity. Remarkably, one analog displays a 2 μM IC50 in an NF-κB activity assay and inhibits an endogenous NF-κB-regulated pathway.