A novel synthesis of aryl-substituted, enantioenriched fulvenes from an oxidative Heck cascade and rearrangement of a carboxy-substituted spiro[4.4]nonatriene is disclosed. Mechanistic investigations with density functional theory (DFT) calculations and empirical results support the net transformation occurring through a novel Pd(ii)-mediated 1,5-vinyl shift from a vinyl-palladium intermediate that terminates with protodepalladation. This spiro-to-fused bicycle conversion tolerates a range of electron-rich and deficient arylboronic acids to give a range of mono- and diaryl substituted annulated fulvenes in moderate to good yields and enantiomeric ratios. Overall, this work connects two classes of molecules with a rich history in physical organic chemistry.

Prized for their ability to generate chemical complexity rapidly, catalytic carbon-hydrogen (C-H) activation and functionalization reactions have enabled a paradigm shift in the standard logic of synthetic chemistry. Directing group strategies have been used extensively in C-H activation reactions to control regio- and enantioselectivity with transition metal catalysts. However, current methods rely heavily on coordination with nitrogen and/or oxygen atoms in molecules and have therefore been found to exhibit limited generality in asymmetric syntheses. Here, we report enantioselective C-H activation with unsaturated hydrocarbons directed by phosphorus centres to rapidly construct libraries of axially chiral phosphines through dynamic kinetic resolution. High reactivity and enantioselectivity are derived from modular assembly of an iridium catalyst with an endogenous phosphorus atom and an exogenous chiral phosphorus ligand, as confirmed by detailed experimental and computational studies. This reaction mode significantly expands the pool of enantiomerically enriched functional phosphines, some of which have shown excellent efficiency for asymmetric catalysis.

Computations and experiments leading to new chiral phosphoric acids (CPAs) for epoxide thionations are reported. Density functional theory calculations reveal the mechanism and origin of the enantioselectivity of such CPA-catalyzed epoxide thionations. The calculated mechanistic information was used to design new efficient CPAs that were tested experimentally and found to be highly effective. Bulky ortho-substituents on the 3,3'-aryl groups of the CPA are important to restrict the position of the epoxide in the key transition states for the enantioselectivity-determining step. Larger para-substituents significantly improve the enantioselectivity of the reaction.

Direct molecular editing of heteroarene carbon-hydrogen (C-H) bonds through consecutive selective C-H functionalization has the potential to grant rapid access into diverse chemical spaces, which is a valuable but often challenging venture to achieve in medicinal chemistry1. In contrast to electronically biased heterocyclic C-H bonds2-9, remote benzocyclic C-H bonds on bicyclic aza-arenes are especially difficult to differentiate because of the lack of intrinsic steric/electronic biases10-12. Here we report two conceptually distinct directing templates that enable the modular differentiation and functionalization of adjacent remote (C6 versus C7) and positionally similar (C3 versus C7) positions on bicyclic aza-arenes through careful modulation of distance, geometry and previously unconsidered chirality in template design. This strategy enables direct C-H olefination, alkynylation and allylation at adjacent C6 and C7 positions of quinolines in the presence of a competing C3 position that is spatially similar to C7. Notably, such site-selective, iterative and late-stage C-H editing of quinoline-containing pharmacophores can be performed in a modular fashion in different orders to suit bespoke synthetic applications. This Article, in combination with previously reported complementary methods, now fully establishes a unified late-stage molecular editing strategy to directly modify bicyclic aza-arenes at any given site in different orders.

A simple and efficient nitrile-directed meta-C-H olefination, acetoxylation, and iodination of biaryl compounds is reported. Compared to the previous approach of installing a complex U-shaped template to achieve a molecular U-turn and assemble the large-sized cyclophane transition state for the remote C-H activation, a synthetically useful phenyl nitrile functional group could also direct remote meta-C-H activation. This reaction provides a useful method for the modification of biaryl compounds because the nitrile group can be readily converted to amines, acids, amides, or other heterocycles. Notably, the remote meta-selectivity of biphenylnitriles could not be expected from previous results with a macrocyclophane nitrile template. DFT computational studies show that a ligand-containing Pd-Ag heterodimeric transition state (TS) favors the desired remote meta-selectivity. Control experiments demonstrate the directing effect of the nitrile group and exclude the possibility of non-directed meta-C-H activation. Substituted 2-pyridone ligands were found to be key in assisting the cleavage of the meta-C-H bond in the concerted metalation-deprotonation (CMD) process.

Heteroarenes containing carbon-silicon (C-Si) bonds are important building blocks that play an important role in the construction of natural products, pharmaceuticals, and organic materials. In this context, the C-H silylation of heteroarenes is a topic of intense interest. Indole C-H silylation can preferentially occur at the nucleophilic C3 and C2 position (pyrrole core), while accessing the C4-C7 positions (benzene core) of the indole remains highly challenging. Here, we show a general strategy for the regioselective C7-H silylation of indole derivatives. Mainly, the regioselectivity is determined by strong coordination of the palladium catalyst with phosphorus (III) directing group. Using this expedient synthetic strategy, the diverse C7-silylated indoles are synthesized effectively which exhibits the broad functional group compatibility. Moreover, this protocol also been extended to other heteroarenes such as carbazoles. The obtained silylated indoles have been employed in various transformations to enable the corresponding differently functionalized indole derivatives. Significantly, a cyclopalladated intermediate is successfully synthesized to test the hypothesis about the P(III)-directed C-H metalation event. A series of mechanistic experiments and density functional theory (M06-2X) calculations has shown the preferred pathway of this directed C-H silylation process.

Site-selective functionalization of C-H bonds will ultimately afford chemists transformative tools for editing and constructing complex molecular architectures. Towards this goal, it is essential to develop strategies to activate C-H bonds that are distal from a functional group. In this context, distinguishing remote C-H bonds on adjacent carbon atoms is an extraordinary challenge due to the lack of electronic or steric bias between the two positions. Herein, we report the design of a catalytic system leveraging a remote directing template and a transient norbornene mediator to selectively activate a previously inaccessible remote C-H bond that is one bond further away. The generality of this approach has been demonstrated with a range of heterocycles, including a complex anti-leukaemia agent and hydrocinnamic acid substrates.

A cornerstone of modern synthetic chemistry rests on the ability to manipulate the reactivity of a carbon center by rendering it either electrophilic or nucleophilic. However, accessing a similar reactivity spectrum with boron-based reagents has been significantly more challenging. While classical nucleophilic carbon-based reagents normally do not require steric protection, readily accessible, unprotected boron-based nucleophiles have not yet been realized. Herein, we demonstrate that the bench stable closo-hexaborate cluster anion can engage in a nucleophilic substitution reaction with a wide array of organic and main group electrophiles. The resulting molecules containing B‒C bonds can be further converted to tricoordinate boron species widely used in organic synthesis.

Lignin valorization is being intensely pursued via tandem catalytic depolymerization and biological funneling to produce single products. In many lignin depolymerization processes, aromatic dimers and oligomers linked by carbon-carbon bonds remain intact, necessitating the development of enzymes capable of cleaving these compounds to monomers. Recently, the catabolism of erythro-1,2-diguaiacylpropane-1,3-diol (erythro-DGPD), a ring-opened lignin-derived β-1 dimer, was reported in Novosphingobium aromaticivorans. The first enzyme in this pathway, LdpA (formerly LsdE), is a member of the nuclear transport factor 2 (NTF-2)-like structural superfamily that converts erythro-DGPD to lignostilbene through a heretofore unknown mechanism. In this study, we performed biochemical, structural, and mechanistic characterization of the N. aromaticivorans LdpA and another homolog identified in Sphingobium sp. SYK-6, for which activity was confirmed in vivo. For both enzymes, we first demonstrated that formaldehyde is the C1 reaction product, and we further demonstrated that both enantiomers of erythro-DGPD were transformed simultaneously, suggesting that LdpA, while diastereomerically specific, lacks enantioselectivity. We also show that LdpA is subject to a severe competitive product inhibition by lignostilbene. Three-dimensional structures of LdpA were determined using X-ray crystallography, including substrate-bound complexes, revealing several residues that were shown to be catalytically essential. We used density functional theory to validate a proposed mechanism that proceeds via dehydroxylation and formation of a quinone methide intermediate that serves as an electron sink for the ensuing deformylation. Overall, this study expands the range of chemistry catalyzed by the NTF-2-like protein family to a prevalent lignin dimer through a cofactorless deformylation reaction.