C–H ACTIVATION
Breaking isopropyl’s symmetry Palladium-ligand combo locks up isopropyl moiety to generate chiral molecules from feedstock derivative When it comes to classic human beauty, the feedstock chemical isobutyric acid as a people seem to prefer symmetry in facial substrate. When combined with palladium features and figures. But chemists syntheand a chiral bidentate ligand, one methyl sizing drug candidates doggedly pursue group of the isobutyric acid’s isopropyl asymmetry in their molecules. That’s moiety selectively undergoes C–H activabecause asymmetric molecules, or chiral tion and then reacts with an aryl, vinyl, or compounds, have distinct H H O Pd catalyst, properties arising from their ligand H I NHR + TIPS stereochemistry. Being able H to make such stereogenic TIPS centers directly saves chemH H ists time and resources. R = 4-(CF3)C6F4, TIPS = triisopropylsilyl Chemists at Scripps Research Institute California and Bristol-MyA bidentate ligand combined with ers Squibb now report a way to break the Pd catalyst enables enantioselective symmetry of an isopropyl group using C–H alkynylation of isobutyric acid derivative. activation chemistry (Science 2017, DOI: 10.1126/science.aal5175). Previously, such a alkynyl iodide. This process forms an α-chifeat of desymmetrization has been accomral center in the amide derivative. plished only by enzymes, notes Scripps’s The trick, Yu says, was to design a ligand Jin-Quan Yu, who spearheaded the project. that could lock the substrate’s methyl Yu’s group uses an amide derivative of groups into just the right position to react
the way the chemists wanted them to. “You can’t let them rotate,” Yu says. “You can’t let them slip away from the desired conformation.” “Yu and his team have accomplished a major advance in the enantioselective construction of chiral, α-substituted
O
O NHR
N H
N
O Ligand carboxylic acid derivatives,” says Scott Denmark, an expert in stereocontrol at the University of Illinois, Urbana-Champaign. “By harnessing the C–H bond functionalization of sp3 carbons with aryl, alkenyl, and alkynyl residues, these investigators have opened a fundamentally new avenue to accessing these highly privileged motifs.”—BETHANY HALFORD
BIOCATALYSIS
New mechanism for a methylating enzyme Radical SAM enzyme uses unexpected molecule as a methyl donor A team of researchers in China has found a reaction mechanism unprecedented for the many enzymes that add methyl groups to biomolecules. Most of these so-called methyltransferases depend on S-adenosylmethionine (SAM) as a methyl donor, plucking off the molecule’s methyl SAM group and relocating it either through an SN2 mechanism or through a radical mechanism. dAdo–SCH3 Many scientists thought this dAdo–SCH2 type of SAM-dependent enzyme exclusively produced S-adenosylhomocysteine as a coproduct during the transfer. N A team led by Qi Zhang H of Fudan University reports that’s not always the case. NosN, a class C radical SAM dAdo = O methyltransferase involved in the biosynthesis of a thioOH peptide antibiotic, uses a
converted into a 5′-deoxyadenosine (dAdo) radical, which initiates the reaction. The other SAM molecule is converted into different methyl donor and produces thio5′-methylthioadenosine (MTA). It is this adenosine as a coproduct (Angew. Chem. MTA that acts as the methyl donor. ThioadInt. Ed. 2017, DOI: 10.1002/anie.201609948). enosine is released as a coproduct. Knowledge of this mechanism could help rePreviously, researchers thought the searchers reengineer the enzyme to produce dAdo radical abstracted a hydrogen atom other compounds, Zhang says. from SAM to produce a radical cation, but Although NosN uses two that’s an energetically unfavorable process. SAM molecules, neither of “Our study shows that nature has solved SAM them serves directly as the this problem by simply converting SAM to methyl donor. Instead, MTA as a direct donor,” Zhang says. dAdo one SAM molecule is The finding is “potentially exciting,” dAdo says Squire J. Booker, a chemistry dAdoH S professor at Penn State UniverCH H dAdo–SH 3 sity whose group elucidated the S S S mechanism for class A radical SAM methylases. “No one really O O O N N liked the idea of a 5′-deoxyadeH H NH2 nosyl radical abstracting a hyN N The radical SAM methyltransferase NosN drogen atom from another molconverts one S-adenosylmethionine ecule of bound SAM” because N N to a dAdo radical (blue) that of the large amount of energy initiates the reaction and another to needed to break the bond, he OH 5′-methylthioadenosine (red), which acts as says.—CELIA ARNAUD
the methyl donor. FEBRUARY 6, 2017 | CEN.ACS.ORG | C&EN
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