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.

Auxin is a key plant growth regulator for diverse developmental processes in plants. Indole-3-acetic acid (IAA) is a primary plant auxin that regulates the formation of various organs. Plants also produce phenylacetic acid (PAA), another natural auxin, which occurs more abundantly than IAA in various plant species. Although it has been demonstrated that the two auxins have distinct transport characteristics, the metabolic pathways and physiological roles of PAA in plants remain unsolved. In this study, we investigated the role of Arabidopsis UDP-glucosyltransferase UGT84B1 in IAA and PAA metabolism. We demonstrated that UGT84B1, which converts IAA to IAA-glucoside (IAA-Glc), can also catalyze the conversion of PAA to PAA-glucoside (PAA-Glc), with a higher catalytic activity in vitro. Furthermore, we showed a significant increase in both the IAA and PAA levels in the ugt84b1 null mutants. However, no obvious developmental phenotypes were observed in the ugt84b1 mutants under laboratory growth conditions. Moreover, the overexpression of UGT84B1 resulted in auxin-deficient root phenotypes and changes in the IAA and PAA levels. Our results indicate that UGT84B1 plays an important role in IAA and PAA homeostasis in Arabidopsis.

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.

The phytohormone auxin plays a central role in many aspects of plant growth and development. IAA is the most studied natural auxin that possesses the property of polar transport in plants. Phenylacetic acid (PAA) has also been recognized as a natural auxin for >40 years, but its role in plant growth and development remains unclear. In this study, we show that IAA and PAA have overlapping regulatory roles but distinct transport characteristics as auxins in plants. PAA is widely distributed in vascular and non-vascular plants. Although the biological activities of PAA are lower than those of IAA, the endogenous levels of PAA are much higher than those of IAA in various plant tissues in Arabidopsis. PAA and IAA can regulate the same set of auxin-responsive genes through the TIR1/AFB pathway in Arabidopsis. IAA actively forms concentration gradients in maize coleoptiles in response to gravitropic stimulation, whereas PAA does not, indicating that PAA is not actively transported in a polar manner. The induction of the YUCCA (YUC) genes increases PAA metabolite levels in Arabidopsis, indicating that YUC flavin-containing monooxygenases may play a role in PAA biosynthesis. Our results provide new insights into the regulation of plant growth and development by different types of auxins.