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Understanding the stereoelectronic effects that govern selectivity in C(sp3)–H bond functionalization reactions is essential to develop efficient catalytic systems. We have curated a dataset of bromopropargyl cyclohexane derivatives displaying distinct substitution patterns and diverging regio- and diastereoselectivities in gold(I)-catalyzed cycloisomerizations. Simple uni- and bivariate correlations with steric features of the substrate suggested that the preferential axial orientation of the bromopropargyl chain favors cis-selectivity, while increased chair flexibility leads to higher regioselectivity. These models were validated on a substrate structurally similar to the training set and also found to be transferable to a more complex target. This work demonstrates how predictive selectivity models for C(sp3)–H functionalizations may help expand reaction scopes to more complex substrates.

The introduction of the gem‐dimethyl unit in different positions resulted in sharp conformational effects in the gold‐catalyzed cycloisomerization of aliphatic 1‐bromoalkynes. Additionally, the cyclopropane unit has been used as an isostere of the gem‐dimethyl unit. Surprisingly, in this context, such replacement was unsuccessful. The experimental observations were rationalized with the aid of density functional theory (DFT) calculations.

Natural terpene-derived substrates have been used as stereochemical templates in the gold(I)-catalyzed cycloisomerization of aliphatic 1-bromoalkynes. The conformational restrictions imposed by these substrates have unlocked an unprecedented 5-exo cyclization mode in gold catalysis. This reactivity was extended to structurally simplified substrates.

The use of cyclohexane derivatives displaying all possible substitution patterns has allowed us to study the influence of the conformational effects in the recently reported gold(I)-catalyzed cycloisomerization reaction of aliphatic 1-bromoalkynes that entails an unusual functionalization of a nonactivated C(sp³)-H bond. Some clear trends in terms of reactivity, regio- and stereoselectivity may be drawn from the experimental results and, in most cases, rationalized using intuitive conformational analysis arguments (i.e., equatorial/axial preferences). Occasionally, some unexpected results were also obtained, but they have also found a rational explanation. DFT calculations have been used to help us understand the underlying effects that dictate the reactivity or selectivity differences.

The gold(I)-catalyzed cycloisomerization of aliphatic 1-bromoalkynes has been applied to the synthesis of heterospirocycles. The reactivity of the C(sp²)-Br bond in the products allowed for further derivatization of the obtained scaffolds. In this way, spiroheterocycles decorated with a plethora of functional groups (i.e., CO₂H, NH₂, OH, and Bpin) were readily obtained. These spirocyclic compounds are valuable building blocks for modern drug discovery projects.

Protein–protein interactions (PPI) frequently involve α-helices and are challenging targets for small-molecule drugs. Here we report the design, synthesis and evaluation of new PPI inhibitors based on a bilaterally substituted p-terphenyl scaffold. The side groups of this scaffold are projected in a broad spatial angle and reproduced the interactions of the myosin A (MyoA) α-helix wrapped by the Myosin Tail Interacting Protein (MTIP) in Plasmodium parasites causing malaria. Fluorescence, calorimetry, and NMR spectroscopy analyses revealed that the terphenyl molecules recognized the MyoA binding site within the MTIP and were capable of displacing the α-helix from its protein receptor and triggering comparable conformational changes in MTIP. The MTIP affinity of the best inhibitor was strikingly close to that exhibited by the MyoA helix. These data indicate that a small-molecule terphenyl compound can efficiently mimic a four-times heavier polypeptide. These molecules may serve as probes for PPIs involving deeply buried α-helices.

The merger of two of the most rapidly growing fields in catalysis, namely gold-catalysis and C–H activation/functionalization has resulted in major breakthroughs, affording unprecedented transformations. This review covers the most relevant contributions in this field during the last 10 years, restricted to the intramolecular functionalization of C(sp3)–H bonds.1 Introduction2 Carbene/Vinylidene Insertion3 [1,5]-H Shift4 Gold-Stabilized Vinyl Cation Mediated5 Summary and Outlook

Alkynes have been the preferred substrates since the early development of gold catalysis at the dawn of this century. Amongst them, 1‐haloalkynes have gained increased interest in recent years due to the versatility offered by these bifunctional entities as well as the identification of unique reaction modes in this already mature research field. Herein, the seminal contributions that resulted in the observed growth in recent years and the most recent developments will be discussed.