Kendall N. Houk

The availability of structurally and stereochemically diverse chemical scaffolds is important to support continual development of drug discovery, functional materials and asymmetric synthesis. Axially chiral 1,3-dienes, particularly acyclic ones, are potentially valuable yet underutilized skeletons due to concerns about chiral stability and the absence of suitable synthetic conditions. Here we show an organocatalytic strategy for the direct functionalization of alkenyl C–H bonds, enabling the challenging atroposelective construction of a broad range of acyclic chiral 1,3-dienes in a modular manner. Intensive studies on the reaction mechanism show that the current strategy not only bypasses the traditional indirect process for olefinic C–H functionalization but also represents a departure from transition-metal-catalysed C(sp2)–H activation. These findings are expected to open avenues for research on olefin chemistry and to …

Medium-sized rings (8–11-membered cycles) are often more challenging to synthesize than smaller rings (5–7-membered cycles) due to ring strain. Herein, we report a catalytic method for forming 8- and 9-membered rings that proceeds via the intramolecular Friedel–Crafts reactions of vinyl carbocation intermediates. These reactive species are generated catalytically through the ionization of vinyl toluenesulfonates by a Lewis acidic lithium cation–weakly coordinating anion salt.

Catalysis with engineered enzymes has provided more efficient routes for the production of active pharmaceutical agents. However, the potential of biocatalysis to assist in early-stage drug discovery campaigns remains largely untapped. In this study, we have developed a biocatalytic strategy for the construction of sp3-rich polycyclic compounds via the intramolecular cyclopropanation of benzothiophenes and related heterocycles. Two carbene transferases with complementary regioisomer selectivity were evolved to catalyse the stereoselective cyclization of benzothiophene substrates bearing diazo ester groups at the C2 or C3 position of the heterocycle. The detailed mechanisms of these reactions were elucidated by a combination of crystallographic and computational analyses. Leveraging these insights, the substrate scope of one of the biocatalysts could be expanded to include previously unreactive substrates …

The reaction of peracetic acid (PAA) and Fe(II) has recently gained attention due to its utility in wastewater treatment and its role in cloud chemistry. Aerosol-cloud interactions, partly mediated by aqueous hydroxyl radical (OH) chemistry, represent one of the largest uncertainties in the climate system. Ambiguities remain regarding the sources of OH in the cloud droplets. Our research group recently proposed that the dark and light-driven reaction of Fe(II) with peracids may be a key contributor to OH formation, producing a large burst of OH when aerosol particles take up water as they grow to become cloud droplets, in which reactants are consumed within 2 min. In this work, we quantify the OH production from the reaction of Fe(II) and PAA across a range of physical and chemical conditions. We show a strong dependence of OH formation on ultraviolet (UV) wavelength, with maximum OH formation at λ = 304 ± 5 nm …

Dibenzoannulated cyclooctynes have emerged as valuable compounds for bioorthogonal reactions. They are commonly used in combination with azides in strain-promoted 1,3-dipolar cycloadditions. They are typically, however, unreactive towards 3,6-disubstituted tetrazines in inverse electron-demand Diels–Alder cycloadditions. Recently a dibenzoannulated bicyclo[6.1.0]nonyne derivative (DMBO) with a cyclopropane fused to the cyclooctyne core was described, which showed surprising reactivity towards tetrazines. To elucidate the unusual reactivity of DMBO, we performed density functional theory calculations and revealed that a tub-like structure in the transition state results in a much lower activation barrier than in the absence of cyclopropane fusion. The same transition state geometry is found for different cycloalkanes fused to the cyclooctyne core albeit higher activation barriers are observed for increased …

We highlight key contributions in the field of direct radical CAr–H (hetero)aromatic functionalization involving fluorinated radicals. A compilation of Functional Group Transfer Reagents and their diverse activation mechanisms leading to the release of radicals are discussed. The substrate scope for each radical is analyzed and classified into three categories according to the electronic properties of the substrates. Density functional theory computational analysis provides insights into the chemical reactivity of several fluorinated radicals through their electrophilicity and nucleophilicity parameters. Theoretical analysis of their reduction potentials also highlights the remarkable correlation between electrophilicity and oxidizing ability. It is also established that highly fluorinated radicals (e.g.•OCF3) are capable of engaging in single‐electron transfer (SET) processes rather than radical addition, which is in good agreement …

In pursuit of potent pharmaceutical candidates and to further improve their chemical traits, small ring systems can serve as a potential starting point. Small ring units have the additional merit of loaded strain at their core, making them suitable reactants as they can capitalize on this intrinsic driving force. With the introduction of cyclobutenone as a strained precursor to ketene, the photocycloaddition with another strained unit, bicyclo[1.1.0]butane (BCB), enables the reactivity of both π-units in the transient ketene. This double strain-release driven [2π+2σ]-photocycloaddition promotes the synthesis of diverse heterobicyclo[2.1.1]hexane units, a pharmaceutically relevant bioisostere. The effective reactivity under catalyst-free conditions with a high functional group tolerance defines its synthetic utility. Experimental mechanistic studies and density functional theory (DFT) calculations suggest that the [2π+2σ …

Despite the significant achievements in dearomatization and C–H functionalization of arenes, the arene ring-opening remains a largely unmet challenge and is underdeveloped due to the high bond dissociation energy and strong resonance stabilization energy inherent in aromatic compounds. Herein, we demonstrate a novel carbene assisted strategy for arene ring-opening. The understanding of the mechanism by our DFT calculations will stimulate wide application of bulk arene chemicals for the synthesis of value-added polyconjugated chain molecules. Various aryl azide derivatives now can be directly converted into valuable polyconjugated enynes, avoiding traditional synthesis including multistep unsaturated precursors, poor selectivity control, and subsequent transition-metal catalyzed cross-coupling reactions. The simple conditions required were demonstrated in the late-stage modification of complex …