61st Annual Report on Research 2016

Following our preliminary results described in this proposal, we have developed an iron(III)-catalyzed carbonyl-olefin ring-closing metathesis reaction for aryl ketone substrates. A first report on this method was published in Nature (Ludwig, J.R.; Zimmerman, P.M.; Gianino, J.B.; Schindler, C.S. Nature 2016, 533, 374) and includes 48 examples proceeding in up to 99% yield (Figure 1). Our current mechanistic hypothesis for this transformation relies on initial Lewis acid-activation of the carbonyl moiety to undergo a concerted, yet asynchronous (2+2)-cycloaddition to form an intermediate oxetane. A subsequent (2+2)-retro-cycloaddition reaction results in the fragmentation of this oxetane and yields the corresponding metathesis product. Initial DFT calculations to support this mechanistic hypothesis were performed in collaboration with Prof. Paul Zimmerman (University of Michigan, Department of Chemistry).

The design principle for iron(III)-catalyzed carbonyl-olefin metathesis was further developed to enable the synthesis of polycyclic aromatic compounds (PACs). A first communication of this work was published in JACS earlier this year (McAtee, C.M.; Riehl, P.S.; Schindler, C.S. J. Am. Chem. Soc. 2017, 139, 2960) and includes 52 examples which undergo carbonyl-olefin metathesis in up to 99% yield. PACs represent important structural motifs in materials science, natural product synthesis, and asymmetric catalysis. This new approach towards PACs is characterized by its operational simplicity, high functional group compatibility, and regioselectivity while relying on FeCl3 as an environmentally benign, earth-abundant metal catalyst (Figure 2). Several polycyclic aromatic hydrocarbon motifs are readily accessible based on this method, including phenanthrenes, chrysenes, tetraphenes, pyrenes, and picenes. Importantly, we were able to isolate and characterize an oxetane intermediate in the course of this work which supports the notion that iron(III)-catalyzed carbonyl-olefin metathesis reactions do indeed proceed via oxetanes as reactive intermediates.

Pyrrole and chiral pyrrolidine compounds are important structural motifs in pharmaceutical chemistry, naturally occurring compounds and asymmetric catalysis. We have developed a new approach for the synthesis of chiral 3-pyrrolines based on iron(III)-catalyzed carbonyl-olefin metathesis that relies on commercially available natural and unnatural amino acids as chiral pool reagents. The carbonyl-olefin metathesis substrates are accessible in a 3-step sequence which enables distinct variations of the ?-amino as well as aryl ketone subunit (Figure 3). Commercially available amino acids are first converted to the corresponding Weinreb amides which upon arylation using either aryl lithium or aryl Grignard reagents result in the corresponding aryl ketones. Final alkylation with prenyl bromide gives rise to the carbonyl-olefin metathesis starting materials in up to 78% yield (over 3 steps, 2.5 g scale). Substrates containing nitrogen heteroatoms have proven problematic in our earlier studies of iron(III)-catalyzed carbonyl-olefin metathesis reactions due to competitive binding of the distinct Lewis basic sites to the active catalyst, thus preventing catalytic turnover. In this work we were able to show that attenuating the electronic properties of a sulfonamide functionality by adding electron-withdrawing groups to the aromatic ring disfavors binding of FeCl3 by competitive Lewis basic sites (e.g. F-Ts instead of a Ts nitrogen-protecting group) and prevent stalling of the carbonyl-olefin metathesis reaction (Figure 4). Importantly, no erosion in enantioselectivity was observed in the carbonyl-olefin metathesis reaction, resulting in the formation of the desired 3-pyrroline substrates in up to 98% ee. A first report on this work which includes 34 examples and proceeds in up to 99% yield was submitted for publication and is currently under review (Groso, E.J.; Golonka, A.N.; Harding, R.A.; Sodano, T.M.; Schindler, C.S. Manuscript submitted).

During our efforts towards the development of an iron(III)-catalyzed carbonyl-olefin ring-closing metathesis reaction, we investigated the a variety of ?-ketoester derivatives bearing differential substitution patterns in the ?-position. When ?-ketoesters bearing an alkyne instead of a prenyl fragment under otherwise identical reaction conditions relying on 10 mol% FeCl3 as catalyst, the corresponding 3-carboxy-2,5-disubstituted furans were isolated in good to excellent yields as the sole products of this reaction (Figure 5). In subsequent studies, we developed this initial result into a mild and efficient method for the synthesis of trisubstituted furans proceeding via Lewis acid-catalyzed 5-exo-dig cycloisomerization of ?-ketoesters. A manuscript including 16 examples of this transformation proceeding in up to 95% yield was published as an invited contribution to the Tetrahedron Symposium in print on pericyclic reactions (Golonka, A.N.; Schindler, C.S. Tetrahedron doi:10.1016/j.tet.2017.04.030).