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Guest Post: Could New Tricks Turn Iron into a MedChem Champion?

Is iron on the brink of med chem stardom? SeeArrOh guest posts about the chemistry that makes it possible. SeeArrOh is a Ph.D. chemist working in industry.

Medicinal chemists know the drill: more molecules, faster please, and cheaper, if possible. A large portion of this effort goes towards making carbon “building blocks” with the correct atomic handles to link carbon atoms together, so called cross-couplings, which build the skeletons of most drugs.

“Ready for my close-up!" (photo credit: nuttakit)

Chemists have long dreamed that these well-known C-C cross couplings catalyzed by expensive precious metals could be performed by base metals such as copper or nickel.  Enter our old friend iron, that pennies-on-the-dollar redox champion and enzymatic superstar. Unfortunately, its strengths are also its weak points – paramagnetic behavior that distorts NMR signals, a tendency to oxidize readily, and ability to do 1-electron chemistry as easily as two, as opposed to the well-established 2-electron pathways for metals such as Pd, Pt, and Rh.

So, iron still has a long way to go before it’s adopted by chemists as a workhorse metal, but two new examples show that it may yet be tamed.

For iron’s first act, we go to Oregon State University. The Arp and Karplus groups (Science 2011, 332, 929) had recently collaborated to solve a crystal structure of a “highly symmetric” protein, which they dubbed symerythrin (get it?). Upon closer scrutiny, the structure contained something odd: a C-C crosslink between two otherwise unfunctionalized amino acids . . . and one side of the new bond is a methyl group, a traditionally tough substrate for this kind of reaction. Once the protein begins to organize its 3D architecture, the group hypothesizes that its di-iron core works its magic: in the presence of O2, a high-valent Fe(IV)-Fe(IV) species capable of abstracting a lone hydrogen from a valine (Val) residue is formed. The new alkyl radical reaches across the peptide chain to add to a nearby phenylalanine (Phe), and a reductant completes the cycle. The authors point out that protein cross-linking is not uncommon between sulfur, nitrogen, and oxygen-containing amino acids, but this is the first example between carbon residues. Hopefully, some new ideas about iron-catalyzed C-H activation or new ways to assemble druglike cyclic peptoids might spring out of this research.

For the encore, we travel across the country to Princeton University. Paul Chirik has recently disclosed (J. Am. Chem. Soc. ASAP DOI: 10.1021/ja202992p) a [2+2] cycloaddition catalyzed by an iron complex. The interesting twist here is that, despite the natural tendencies for dienes and olefins to form [4+2] adducts – see the disclosed Diels-Alderase from early 2011 – this reaction shows no products resulting from that pathway.  To explain the difference, Chirik provides the pièce de résistance: the crystal structure of a stable alkyliron complex that catches the two reactants in a C-C bonding “snapshot.”  Chirik admits that the reaction is fairly limited right now, since it only turns over one substrate (butadiene), but his mechanistic studies might lead to optimized catalysts for performing on-demand cyclobutane formation on more complex alkenes. Given the liberal use of cyclobutanes in medicinal leads, it’s only a matter of time before iron claims the limelight.

*Update: The Science article from ‘Act 1’ is rounding the blogosphere, having just appeared at The Curious Wavefunction and C&E News. ‘Act 2’ has garnered some attention over at Naturalproductman’s Blog.

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