Ni-catalyzed C(sp 3)-O bond activation provides a useful approach to synthesize enantioenriched products from readily available enantioenriched benzylic alcohol derivatives. The control of stereospecificity is key to the success of these transformations. To elucidate the reversed stereospecificity and chemoselectivity of Ni-catalyzed Kumada and cross-electrophile coupling reactions with benzylic ethers, a combined computational and experimental study is performed to reach a unified mechanistic understanding. Kumada coupling proceeds via a classic cross-coupling mechanism. Initial rate-determining oxidative addition occurs with stereoinversion of the benzylic stereogenic center. Subsequent transmetallation with the Grignard reagent and syn reductive elimination produces the Kumada coupling product with overall stereoinversion at the benzylic position. The cross-electrophile coupling reaction initiates with the same benzylic CO bond cleavage and transmetallation to form a common benzylnickel intermediate. However, the presence of the tethered alkyl chloride allows a facile intramolecular S N 2 attack by the benzylnickel moiety. This step circumvents the competing Kumada coupling, leading to the excellent chemoselectivity of cross-electrophile coupling. These mechanisms account for the observed stereospecificity of the Kumada and cross-electrophile couplings, providing a rationale for double inversion of the benzylic stereogenic center in cross-electrophile coupling. The improved mechanistic understanding will enable design of stereoselective transformations involving Ni-catalyzed C(sp 3)-O bond activation.

The stereospecific reductive cross-electrophile coupling reaction of 2-aryl-4-chlorotetrahydropyrans to afford disubstituted cyclopropanes is reported. This ring contraction presents surprises with respect to the stereochemical outcome of reaction of the alkyl halide moiety. While cross-coupling and reductive cross-electrophile coupling reactions of alkyl halides are typically stereoablative, using a chiral catalyst to set the stereocenter, this transformation proceeds with high stereochemical fidelity at the alkyl halide and ether bearing stereogenic centers. This approach provides straightforward access to highly substituted cyclopropanes in two steps from commercially available aldehydes.

The stereospecific reductive cross-electrophile coupling reaction of 2-vinyl-4-halotetrahydropyrans for vinylcyclopropane synthesis is reported. The nickel-catalyzed reaction occurs with both alkyl fluorides and alkyl chlorides. To the best of our knowledge, this is the first reported cross-electrophile coupling reaction of an alkyl fluoride. Ring contraction proceeds with high stereospecificity, providing selective synthesis of either diastereomer of di- and trisubstituted cyclopropanes. The utility of this methodology is demonstrated by several synthetic applications including the synthesis of the natural product dictyopterene A. 2-Vinyl-4-fluorotetrahydrofurans also undergo stereospecific ring contractions, providing access to synthetically useful hydroxymethyl cyclopropanes.

We introduce a versatile strategy for the bioreversible modification of proteins. Our strategy is based on a tricomponent molecule, synthesized in three steps, that incorporates a diazo moiety for chemoselective esterification of carboxyl groups, a pyridyl disulfide group for late-stage functionalization with thiolated ligands, and a self-immolative carbonate group for esterase-mediated cleavage. Using cytochrome c (Cyt c) and the green fluorescent protein (GFP) as models, we generated protein conjugates modified with diverse domains for cellular delivery that include a small molecule, targeting and cell-penetrating peptides (CPPs), and a large polysaccharide. As a proof of concept, we used our strategy to effect the delivery of proteins into the cytosol of live mammalian cells in the presence of serum. The cellular delivery of functional Cyt c, which induces apoptosis, highlighted the advantage of bioreversible conjugation on a carboxyl group versus irreversible conjugation on an amino group. The ease and utility of this traceless modification provide new opportunities for chemical biologists.

Stereospecific synthesis of di‐ and trisubstituted cyclopropanes is achieved via a Ni‐catalyzed reductive cross‐electrophile coupling of chlorotetrahydropyrans.