Mechanistic Investigation, Wavelength-Dependent Reactivity, and Expanded Reactivity of N-Aryl Azacycle Photomediated Ring Contractions.

Under mild blue-light irradiation, α-acylated saturated heterocycles undergo a photomediated one-atom ring contraction that extrudes a heteroatom from the cyclic core. However, for nitrogenous heterocycles, this powerful skeletal edit has been limited to substrates bearing electron-withdrawing substituents on nitrogen. Moreover, the mechanism and wavelength-dependent efficiency of this transformation have remained unclear. In this work, we increased the electron richness of nitrogen in saturated azacycles to improve light absorption and strengthen critical intramolecular hydrogen bonding while enabling the direct installation of the photoreactive handle. As a result, a broadly expanded substrate scope, including underexplored electron-rich substrates and previously unsuccessful heterocycles, has now been achieved. The significantly improved yields and diastereoselectivities have facilitated reaction rate, kinetic isotope effect (KIE), and quenching studies, in addition to the determination of quantum yields. Guided by these studies, we propose a revised ET/PT mechanism for the ring contraction, which is additionally corroborated by computational characterization of the lowest-energy excited states of α-acylated substrates through time-dependent DFT. The efficiency of the ring contraction at wavelengths longer than those strongly absorbed by the substrates was investigated through wavelength-dependent rate measurements, which revealed a red shift of the photochemical action plot relative to substrate absorbance. The elucidated mechanistic and photophysical details effectively rationalize empirical observations, including additive effects, that were previously poorly understood. Our findings not only demonstrate enhanced synthetic utility of the photomediated ring contraction and shed light on mechanistic details but may also offer valuable guidance for understanding wavelength-dependent reactivity for related photochemical systems.

Palladium-Catalyzed [3 + 2] Cycloaddition via Twofold 1,3-C(sp3)-H Activation.

Cycloaddition reactions provide an expeditious route to construct ring systems in a highly convergent and stereoselective manner. For a typical cycloaddition reaction to occur, however, the installation of multiple reactive functional groups (π-bonds, leaving group, etc.) is required within the substrates, compromising the overall efficiency or scope of the cycloaddition reaction. Here, we report a palladium-catalyzed [3 + 2] reaction that utilizes twofold C(sp3)-H activation to generate the three-carbon unit for formal cycloaddition. The initial ß-C(sp3)-H activation of aliphatic amide, followed by maleimide insertion, triggers a relayed, second C(sp3)-H activation to complete a formal [3 + 2] cycloaddition. The key to success was the use of weakly coordinating amide as the directing group, as previous studies have shown that Heck or alkylation pathways are preferred when stronger-coordinating directing groups are used with maleimide coupling partners. To promote the amide-directed C(sp3)-H activation step, the use of pyridine-3-sulfonic acid ligands is crucial. This method is compatible with a wide range of amide substrates, including lactams, which lead to spiro-bicyclic products. The [3 + 2] product is also shown to undergo a reductive desymmetrization process to access chiral cyclopentane bearing multiple stereocenters with excellent enantioselectivity.

Utilizing Carbonyl Coordination of Native Amides for Palladium-Catalyzed C(sp3 )-H Olefination.

PdII -catalyzed C(sp3 )-H olefination of weakly coordinating native amides is reported. Three major drawbacks of previous C(sp3 )-H olefination protocols, 1) in situ cyclization of products, 2) incompatibility with α-H-containing substrates, and 3) installation of exogenous directing groups, are addressed by harnessing the carbonyl coordination ability of amides to direct C(sp3 )-H activation. The method enables direct C(sp3 )-H functionalization of a wide range of native amide substrates, including secondary, tertiary, and cyclic amides, for the first time. The utility of this process is demonstrated by diverse transformations of the olefination products.

Diverse ortho-C(sp2)-H Functionalization of Benzaldehydes Using Transient Directing Groups.

Pd-catalyzed C-H functionalizations promoted by transient directing groups remain largely limited to C-H arylation only. Herein, we report a diverse set of ortho-C(sp2)-H functionalizations of benzaldehyde substrates using the transient directing group strategy. Without installing any auxiliary directing group, Pd(II)-catalyzed C-H arylation, chlorination, bromination, and Ir(III)-catalyzed amidation, could be achieved on benzaldehyde substrates. The transient directing groups formed in situ via imine linkage can override other coordinating functional groups capable of directing C-H activation or catalyst poisoning, significantly expanding the scope for metal-catalyzed C-H functionalization of benzaldehydes. The utility of this approach is demonstrated through multiple applications, including late-stage diversification of a drug analogue.

Risk Prediction of Emergency Department Visits in Patients With Lung Cancer Using Machine Learning: Retrospective Observational Study.

BACKGROUND: Patients with lung cancer are among the most frequent visitors to emergency departments due to cancer-related problems, and the prognosis for those who seek emergency care is dismal. Given that patients with lung cancer frequently visit health care facilities for treatment or follow-up, the ability to predict emergency department visits based on clinical information gleaned from their routine visits would enhance hospital resource utilization and patient outcomes. OBJECTIVE: This study proposed a machine learning-based prediction model to identify risk factors for emergency department visits by patients with lung cancer. METHODS: This was a retrospective observational study of patients with lung cancer diagnosed at Seoul National University Bundang Hospital, a tertiary general hospital in South Korea, between January 2010 and December 2017. The primary outcome was an emergency department visit within 30 days of an outpatient visit. This study developed a machine learning-based prediction model using a common data model. In addition, the importance of features that influenced the decision-making of the model output was analyzed to identify significant clinical factors. RESULTS: The model with the best performance demonstrated an area under the receiver operating characteristic curve of 0.73 in its ability to predict the attendance of patients with lung cancer in emergency departments. The frequency of recent visits to the emergency department and several laboratory test results that are typically collected during cancer treatment follow-up visits were revealed as influencing factors for the model output. CONCLUSIONS: This study developed a machine learning-based risk prediction model using a common data model and identified influencing factors for emergency department visits by patients with lung cancer. The predictive model contributes to the efficiency of resource utilization and health care service quality by facilitating the identification and early intervention of high-risk patients. This study demonstrated the possibility of collaborative research among different institutions using the common data model for precision medicine in lung cancer.

A C-H Functionalization Strategy Enables an Enantioselective Formal Synthesis of (-)-Aflatoxin B2.

An enantioselective formal synthesis of (-)-aflatoxin B2 from 4-methoxyphenylacetic acid has been achieved by an approach that produces a key carbon-carbon bond, a benzylic stereocenter, and two arene carbon-oxygen bonds in the course of three site-selective C-H functionalizations. The carbonyl-directed acetoxylation of two arene C-H bonds described herein is unprecedented in natural product synthesis and occurs under mild conditions that preserve the configuration of a sensitive benzylic stereocenter.

Controlling Pd(IV) reductive elimination pathways enables Pd(II)-catalysed enantioselective C(sp3)-H fluorination.

The development of a Pd(II)-catalysed enantioselective fluorination of C(sp3)-H bonds would offer a new approach to making chiral organofluorines. However, such a strategy is particularly challenging because of the difficulty in differentiating prochiral C(sp3)-H bonds through Pd(II)-insertion, as well as the sluggish reductive elimination involving Pd-F bonds. Here, we report the development of a Pd(II)-catalysed enantioselective C(sp3)-H fluorination using a chiral transient directing group strategy. In this work, a bulky, amino amide transient directing group was developed to control the stereochemistry of the C-H insertion step and selectively promote the C(sp3)-F reductive elimination pathway from the Pd(IV)-F intermediate. Stereochemical analysis revealed that while the desired C(sp3)-F formation proceeds via an inner-sphere pathway with retention of configuration, the undesired C(sp3)-O formation occurs through an SN2-type mechanism. Elucidation of the dual mechanism allows us to rationalize the profound ligand effect on controlling reductive elimination selectivity from high-valent Pd species.

Ligand-Enabled, Palladium-Catalyzed ß-C(sp3)-H Arylation of Weinreb Amides.

We report the development of Pd(II)-catalyzed C(sp3)-H arylation of Weinreb amides. This work demonstrates the first example of using Weinreb amide as a directing group for transition metal-catalyzed C(sp3)-H activation. Both the inductive effect and the potential bidentate coordination mode of the Weinreb amides pose a unique challenge for this reaction development. A pyridinesulfonic acid ligand is designed to accommodate the weak, neutral coordinating property of Weinreb amides via preserving the cationic character of Pd center through zwitterionic assembly of Pd/ligand complexes. DFT studies of the C-H cleavage step indicate that the superior reactivity of 3-pyridinesulfonic acid ligand compared to pyridine, Ac-Gly-OH, and ligandless conditions originates from the stabilization of overall substrate-bound Pd species.

Methylene C(sp3)-H Arylation of Aliphatic Ketones Using a Transient Directing Group.

Palladium-catalyzed methylene ß-C(sp3)-H arylation of aliphatic ketones using a transient directing group is developed. The use of α-benzyl ß-alanine directing group that forms a six-membered chelation with palladium is crucial for promoting the methylene C(sp3)-H bond activation.

Organic chemistry. Functionalization of C(sp3)-H bonds using a transient directing group.

Proximity-driven metalation has been extensively exploited to achieve reactivity and selectivity in carbon-hydrogen (C-H) bond activation. Despite the substantial improvement in developing more efficient and practical directing groups, their stoichiometric installation and removal limit efficiency and, often, applicability as well. Here we report the development of an amino acid reagent that reversibly reacts with aldehydes and ketones in situ via imine formation to serve as a transient directing group for activation of inert C-H bonds. Arylation of a wide range of aldehydes and ketones at the ß or γ positions proceeds in the presence of a palladium catalyst and a catalytic amount of amino acid. The feasibility of achieving enantioselective C-H activation reactions using a chiral amino acid as the transient directing group is also demonstrated.