J. Caleb Hethcox

Enantioselective iodolactonization of disubstituted olefinic acids using a bifunctional catalyst.

The enantioselective iodolactonizations of a series of diversely substituted olefinic carboxylic acids are promoted by a BINOL-derived, bifunctional catalyst. Reactions involving 5-alkyl- and 5-aryl-4(Z)-pentenoic acids and 6-alkyl- and 6-aryl-5(Z)-hexenoic acids provide the corresponding γ- and δ-lactones having stereogenic C-I bonds in excellent yields and >97:3 er. Significantly, this represents the first organocatalyst that promotes both bromo- and iodolactonization with high enantioselectivities. The potential of this catalyst to induce kinetic resolutions of racemic unsaturated acids is also demonstrated.

Iridium-Catalyzed Diastereo-, Enantio-, and Regioselective Allylic Alkylation with Prochiral Enolates

Transition-metal-catalyzed asymmetric allylic alkylation of enolates is a powerful method for the formation of carbon− carbon bonds. Within this field, palladium-catalyzed allylic alkylation reactions have undoubtedly been the most studied. Aside from limited cases, palladium catalysts preferentially form the linear substitution product through alkylation at the less-substituted terminus of the allylic electrophile (Scheme 1). However, in contrast to palladium, most other transition metals (e.g., Mo, W, Fe, Ru, Co, Rh, Ni, Pt, and Ir) have been shown to favor the construction of the branched product, with iridium catalysts being some of the most efficient and selective. The potential application of these chiral, branched products to the synthesis of natural products and biologically active compounds has motivated the development of practical and reliable transition-metal-catalyzed methods for their construction.

Enantioselective Synthesis of Acyclic α-Quaternary Carboxylic Acid Derivatives through Iridium-Catalyzed Allylic Alkylation

The first highly enantioselective iridium-catalyzed allylic alkylation that provides access to products bearing an allylic all-carbon quaternary stereogenic center has been developed. The reaction utilizes a masked acyl cyanide (MAC) reagent, which enables the one-pot preparation of α-quaternary carboxylic acids, esters, and amides with a high degree of enantioselectivity. The utility of these products is further explored through a series of diverse product transformations.

Iridium‐Catalyzed Stereoselective Allylic Alkylation Reactions with Crotyl Chloride

The development of the first enantio-, diastereo-, and regioselective iridium-catalyzed allylic alkylation reaction of prochiral enolates to form an all-carbon quaternary stereogenic center with an aliphatic-substituted allylic electrophile is disclosed. The reaction proceeds with good to excellent selectivity with a range of substituted tetralone-derived nucleophiles furnishing products bearing a newly formed vicinal tertiary and all-carbon quaternary stereodyad. The utility of this protocol is further demonstrated via a number of synthetically diverse product transformations.

Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents

The first enantioselective iridium-catalyzed allylic alkylation reaction of a masked acyl cyanide (MAC) reagent has been developed. The transformation allows for the use of an umpoled synthon, which serves as a carbon monoxide equivalent. The reaction proceeds with good yield and excellent selectivity up to gram scale for a wide range of substituted allylic electrophiles, delivering products amenable to the synthesis of highly desirable, enantioenriched vinylated α-aryl carbonyl derivatives.

Atmospheric autoxidation is increasingly important in urban and suburban North America

Significance Unimolecular hydrogen shift reactions to peroxy radicals have been shown to be important in the atmospheric photooxidation of isoprene and α-pinene. These studies also report the efficient generation of highly oxidized organic molecules known to contribute to particle formation and growth. Here, we quantify the rate of this oxidation pathway for peroxy radicals produced in the oxidation of n-hexane under conditions relevant to the atmosphere. The results suggest that autoxidation pathways are competitive against bimolecular reactions for a broad range of substrates, including many that result from urban emissions. The formation of organic hydroperoxides from atmospheric autoxidation has unknown implications for air quality. Gas-phase autoxidation—regenerative peroxy radical formation following intramolecular hydrogen shifts—is known to be important in the combustion of organic materials. The relevance of this chemistry in the oxidation of organics in the atmosphere has received less attention due, in part, to the lack of kinetic data at relevant temperatures. Here, we combine computational and experimental approaches to investigate the rate of autoxidation for organic peroxy radicals (RO2) produced in the oxidation of a prototypical atmospheric pollutant, n-hexane. We find that the reaction rate depends critically on the molecular configuration of the RO2 radical undergoing hydrogen transfer (H-shift). RO2 H-shift rate coefficients via transition states involving six- and seven-membered rings (1,5 and 1,6 H-shifts, respectively) of α-OH hydrogens (HOC-H) formed in this system are of order 0.1 s−1 at 296 K, while the 1,4 H-shift is calculated to be orders of magnitude slower. Consistent with H-shift reactions over a substantial energetic barrier, we find that the rate coefficients of these reactions increase rapidly with temperature and exhibit a large, primary, kinetic isotope effect. The observed H-shift rate coefficients are sufficiently fast that, as a result of ongoing NOx emission reductions, autoxidation is now competing with bimolecular chemistry even in the most polluted North American cities, particularly during summer afternoons when NO levels are low and temperatures are elevated.

Enantioselective Halolactonization Reactions using BINOL-Derived Bifunctional Catalysts: Methodology, Diversification, and Applications

A general protocol is described for inducing enantioselective halolactonizations of unsaturated carboxylic acids using novel bifunctional organic catalysts derived from a chiral binaphthalene scaffold. Bromo- and iodolactonization reactions of diversely substituted, unsaturated carboxylic acids proceed with high degrees of enantioselectivity, regioselectivity, and diastereoselectivity. Notably, these BINOL-derived catalysts are the first to induce the bromo- and iodolactonizations of 5-alkyl-4( Z)-olefinic acids via 5- exo mode cyclizations to give lactones in which new carbon-halogen bonds are created at a stereogenic center with high diastereo- and enantioselectivities. Iodolactonizations of 6-substituted-5( Z)-olefinic acids also occur via 6- exo cyclizations to provide δ-lactones with excellent enantioselectivities. Several notable applications of this halolactonization methodology were developed for desymmetrization, kinetic resolution, and epoxidation of Z-alkenes. The utility of these reactions is demonstrated by their application to a synthesis of precursors of the F-ring subunit of kibdelone C and to the shortest catalytic, enantioselective synthesis of (+)-disparlure reported to date.

Enantioselective Synthesis of Vicinal All‐Carbon Quaternary Centers via Iridium‐Catalyzed Allylic Alkylation

The development of the first enantioselective transition-metal-catalyzed allylic alkylation providing access to acyclic products bearing vicinal all-carbon quaternary centers is disclosed. The iridium-catalyzed allylic alkylation reaction proceeds with excellent yields and selectivities for a range of malononitrile-derived nucleophiles and trisubstituted allylic electrophiles. The utility of these sterically congested products is explored through a series of diverse chemo- and diastereoselective product transformations to afford a number of highly valuable, densely functionalized building blocks, including those containing vicinal all-carbon quaternary stereocenters.

Asymmetric synthesis of all-carbon quaternary spirocycles via a catalytic enantioselective allylic alkylation strategy

Rapid access to enantioenriched spirocycles possessing a 1,4-dicarbonyl moiety spanning an all-carbon quaternary stereogenic spirocenter was achieved using a masked bromomethyl vinyl ketone reagent. The developed protocol entails an enantioselective palladium-catalyzed allylic alkylation reaction followed by a one-pot unmasking/RCM sequence that provides access to the spirocyclic compounds in good yields and selectivities.

Synergistic O3+ OH oxidation pathway to extremely low-volatility dimers revealed in β-pinene secondary organic aerosol

Significance Secondary organic aerosol (SOA) is ubiquitous in the atmosphere and plays a pivotal role in climate, air quality, and health. Monoterpenes, emitted in large quantities from forested regions, are a dominant source of SOA globally, with dimers having been identified as key contributors to particle formation and growth. Here, we establish the role of concerted oxidation by O3 and OH as a significant route to dimer formation in SOA generated from β-pinene, the second-most-abundant monoterpene emitted to the atmosphere. Production of this class of dimers is found to occur through both gas- and particle-phase processes. Dimer formation via synergistic O3 + OH oxidation could represent an appreciable source of “missing” SOA not included in current atmospheric models. Dimeric compounds contribute significantly to the formation and growth of atmospheric secondary organic aerosol (SOA) derived from monoterpene oxidation. However, the mechanisms of dimer production, in particular the relevance of gas- vs. particle-phase chemistry, remain unclear. Here, through a combination of mass spectrometric, chromatographic, and synthetic techniques, we identify a suite of dimeric compounds (C15–19H24–32O5–11) formed from concerted O3 and OH oxidation of β-pinene (i.e., accretion of O3- and OH-derived products/intermediates). These dimers account for an appreciable fraction (5.9–25.4%) of the β-pinene SOA mass and are designated as extremely low-volatility organic compounds. Certain dimers, characterized as covalent dimer esters, are conclusively shown to form through heterogeneous chemistry, while evidence of dimer production via gas-phase reactions is also presented. The formation of dimers through synergistic O3 + OH oxidation represents a potentially significant, heretofore-unidentified source of low-volatility monoterpene SOA. This reactivity also suggests that the current treatment of SOA formation as a sum of products originating from the isolated oxidation of individual precursors fails to accurately reflect the complexity of oxidation pathways at play in the real atmosphere. Accounting for the role of synergistic oxidation in ambient SOA formation could help to resolve the discrepancy between the measured atmospheric burden of SOA and that predicted by regional air quality and global climate models.