Site-Isolated Rhodium(II) Metalloradicals Catalyze Olefin Hydrofunctionalization.

Rh(II) porphyrin complexes display pronounced metal-centered radical character and the ability to activate small molecules under mild conditions, but catalysis with Rh(II) porphyrins is extremely rare. In addition to facile dimerization, Rh(II) porphyrins readily engage in kinetically and thermodynamically facile reactions involving two Rh(II) centers to generate stable Rh(III)-X intermediates that obstruct turnover in thermal catalysis. Here we report site isolation of Rh(II) metalloradicals in a MOF host, which not only protects Rh(II) metalloradicals against dimerization, but also allows them to participate in thermal catalysis. Access to PCN-224 or PCN-222 in which the porphyrin linkers are fully metalated by Rh(II) in the absence of any accompanying Rh(0) nanoparticles was achieved via the first direct MOF synthesis with a linker containing a transition-metal alkyl moiety, followed by Rh(III)-C bond photolysis.

Transformations of Less-Activated Phenols and Phenol Derivatives via C-O Cleavage.

Employing phenols and phenol derivatives as electrophiles for cross-coupling reactions has numerous advantages over commonly used aryl halides in terms of environmental-friendliness and sustainability. In the early stage of discovering such transformations, most efforts have been devoted to utilizing highly activated sulfonate types of phenol derivatives (e.g., OTf, OTs, etc.), which have similar reactivities to the corresponding aryl halides. However, a continuing scientific challenge is how to achieve the direct C-O functionalizations of relatively less-activated phenol derivatives more efficiently. In this review, we will focus on the recent updates on the C-O functionalizations of less-activated phenol derivatives, from aryl carboxylates (e.g., pivalates, acetates, etc.), aryl carbamates and carbonates, to aryl ethers (anisoles, diaryl ethers, aryl pyridyl ethers, aryl silyl ethers), to phenolate salts, and ultimately to simply unprotected phenols, sorted by the types of bond formations. Both transition-metal-catalyzed and transition-metal-free protocols will be covered and discussed in detail. Instead, the C-O functionalizations of aryl sulfonates will not be covered extensively unless they are closely related, due to their high reactivity. Since aryl ethers and phenols represent the main linkages or units in lignin biomass, the successes of such transformations will potentially make major contributions to the direct lignin biomass upgrading and depolymerization.

Coupling without Coupling Reactions: En Route to Developing Phenols as Sustainable Coupling Partners via Dearomatization-Rearomatization Processes.

Transition-metal-catalyzed cross-coupling reactions represent one of the most straightforward and efficient protocols to assemble two different molecular motifs for the construction of carbon-carbon or carbon-heteroatom bonds. Because of their importance and wide applications in pharmaceuticals, agrochemicals, materials, etc., cross-coupling reactions have been well recognized in the 2010 Nobel Prize in chemistry. However, in the classical transition-metal-catalyzed cross-coupling reactions (e.g., the Suzuki-Miyaura, the Buchwald-Hartwig, and the Ullmann cross-coupling reactions), organohalides, which mainly stem from the nonrenewable fossil resources, are often utilized as coupling partners with halide wastes being generated after the reactions. To make cross-coupling reactions more sustainable, we initiated a general research program by employing phenols and cyclohexa(e)nones (the reduced forms of phenols) as pivotal feedstocks (coupling partners), instead of the commonly used fossil-derived organohalides, for cross-coupling reactions to build C-O, C-N, and C-C bonds. Phenols (cyclohexa(e)nones) are widely available and can be obtained from lignin biomass, highlighting their renewable and sustainable features. Moreover, water is expected to be the only stoichiometric byproduct, thus avoiding halide wastes.Notably, the cross-coupling reactions utilizing phenols/cyclohexa(e)nones are not based on the traditional transition-metal-catalyzed "oxidative-addition and reductive-elimination" mechanism, but via a novel "phenol-cyclohexanone" redox couple. This new working mechanism opens up new horizons of designing cross-coupling reactions via simple nucleophilic addition of cyclohexanones along with aromatization processes, thereby simplifying the design and avoiding laborious optimization of transition-metal precursors (e.g., Pd, Ni, Cu, etc.), as well as ligands in classical transition-metal-catalyzed cross-coupling reactions. Specifically, in this Account, we will summarize and discuss our related research work in the following three categories: "formal oxidative couplings of cyclohexa(e)nones", "formal reductive couplings of phenols", and "formal redox-neutral couplings of phenols". The successes of these research projects clearly demonstrated our initial inspirations and rational designs to develop cross-coupling reactions without the "conventional cross-coupling conditions" by pushing the reaction frontiers from initial cyclohexanones, ultimately, to the sustainable phenol targets.

Metal-Free Direct Deoxygenative Borylation of Aldehydes and Ketones.

Direct conversion of aldehydes and ketones into alkylboronic esters via deoxygenative borylation represents an unknown yet highly desirable transformation. Herein, we present a one-step and metal-free method for carbonyl deoxy-borylation under mild conditions. A wide range of aromatic aldehydes and ketones are tolerated and successfully converted into the corresponding benzylboronates. By the same deoxygenation manifold with aliphatic aldehydes and ketones, we also enable a concise synthesis of 1,1,2-tris(boronates), a family of compounds that currently lack efficient synthetic methods. Given its simplicity and versatility, we expect that this novel borylation approach could show great promise in organoboron synthesis and inspire more carbonyl deoxygenative transformations in both academic and industrial settings.

Switch in Selectivity for Formal Hydroalkylation of 1,3-Dienes and Enynes with Simple Hydrazones.

Controlling reaction selectivity is a permanent pursuit for chemists. Regioselective catalysis, which exploits and/or overcomes innate steric and electronic bias to deliver diverse regio-enriched products from the same starting materials, represents a powerful tool for divergent synthesis. Recently, the 1,2-Markovnikov hydroalkylation of 1,3-dienes with simple hydrazones was reported to generate branched allylic compounds when a nickel catalyst was used. As part of the effort, shown here is that a complete switch of Markovnikov to anti-Markovnikov addition is obtained by changing to a ruthenium catalyst, thus providing direct and efficient access to homoallylic products exclusively. Isotopic substitution experiments indicate that no reversible hydro-metallation across the metal-π-allyl system occurred under ruthenium catalysis. Moreover, this protocol is applicable to the regiospecific hydroalkylation of the distal C=C bond of 1,3-enynes.

Palladium-Catalyzed Formal Hydroalkylation of Aryl-Substituted Alkynes with Hydrazones.

We have developed an unprecedented Pd-catalyzed formal hydroalkylation of alkynes with hydrazones, which are generated in situ from naturally abundant aldehydes, as both alkylation reagents and hydrogen donors. The hydroalkylation proceeds with high regio- and stereoselectivity to form (Z)-alkenes, which are more difficult to generate compared to (E)-alkenes. The reaction is compatible with a wide range of functional groups, including hydroxy, ester, ketone, nitrile, boronic ester, amine, and halide groups. Furthermore, late-stage modifications of natural products and pharmaceutical derivatives exemplify its unique chemoselectivity, regioselectivity, and synthetic applicability. Mechanistic studies indicate the possible involvement of Pd-hydride intermediates.

Synergistic Relay Reactions To Achieve Redox-Neutral α-Alkylations of Olefinic Alcohols with Ruthenium(II) Catalysis.

Herein, we report a ruthenium-catalyzed redox-neutral α-alkylation of unsaturated alcohols based on a synergistic relay process involving olefin isomerization (chain walking) and umpolung hydrazone addition, which takes advantage of the interaction between the two rather inefficient individual reaction steps to enable an efficient overall process. This transformation shows the compatibility of hydrazone-type "carbanions" and active protons in a one-pot reaction, and at the same time achieves the first Grignard-type nucleophilic addition using olefinic alcohols as latent carbonyl groups, providing a higher yield of the corresponding secondary alcohol than the classical hydrazone addition to aldehydes does. A broad scope of unsaturated alcohols and hydrazones, including some complex structures, can be successfully employed in this reaction, which shows the versatility of this approach and its suitability as an alternative, efficient means for the generation of secondary and tertiary alcohols.

Nickel-Catalyzed Cross-Coupling of Umpolung Carbonyls and Alkyl Halides.

An effective nickel-catalyzed cross-coupling of Umpolung carbonyls and alkyl halides was developed. Complementary to classical alkylation techniques, this reaction utilizes Umpolung carbonyls as the environmentally benign alkyl nucleophiles, providing an efficient and selective catalytic alternative to the traditional use of highly reactive alkyl organometallic reagents.

Palladium-Catalyzed Formal Cross-Coupling of Diaryl Ethers with Amines: Slicing the 4-O-5 Linkage in Lignin Models.

Lignin is the second most abundant organic matter on Earth, and is an underutilized renewable source for valuable aromatic chemicals. For future sustainable production of aromatic compounds, it is highly desirable to convert lignin into value-added platform chemicals instead of using fossil-based resources. Lignins are aromatic polymers linked by three types of ether bonds (α-O-4, ß-O-4, and 4-O-5 linkages) and other C-C bonds. Among the ether bonds, the bond dissociation energy of the 4-O-5 linkage is the highest and the most challenging to cleave. To date, 4-O-5 ether linkage model compounds have been cleaved to obtain phenol, cyclohexane, cyclohexanone, and cyclohexanol. The first example of direct formal cross-coupling of diaryl ether 4-O-5 linkage models with amines is reported, in which dual C(Ar)-O bond cleavages form valuable nitrogen-containing derivatives.

Lewis acid mediated tandem reaction of propargylic alcohols to tetrazoles involving C-O- and C-C-bond cleavage reactions and a C-N-bond formation.

A novel and direct synthesis of 1-aryl-5-arylvinyl-tetrazoles from easily prepared propargylic alcohols and TMSN3 is developed in the presence of TMSCl under mild conditions (TMS = trimethylsilyl). The process involves an allenylazide intermediate, followed by a C-C-bond cleavage and C-N-bond formation to afford the desired products. Moreover, this method offers a good functional-group applicability and can be scaled-up to grams (yield up to 85 %).

TMSCl-mediated synthesis of α,ß-unsaturated amides via C-C bond cleavage and C-N bond formation of propargyl alcohols with trimethylsilyl azide.

A new method with high efficiency for the synthesis of α,ß-unsaturated amides from the easily prepared propargyl alcohols and TMSN3 using TMSCl as an acid promoter is developed. A wide variety of α,ß-unsaturated amides were produced in moderate to excellent yields. Mechanistic studies indicate that this transformation involves TMSCl-mediated allenylazide intermediate formation, C-C bond cleavage, and C-N bond formation. Significantly, this reaction shows good functional group compatibility and high regioselectivity, with a relatively short reaction time and inexpensive reagents.

Palladium-catalyzed/norbornene-mediated ortho-amination/N-tosylhydrazone insertion reaction: an approach to the synthesis of ortho-aminated vinylarenes.

ortho-Aminated vinylarene derivatives were obtained via a reaction of aryl iodides, N-benzoyloxyamines, and N-tosylhydrazones. This approach involves a palladium-catalyzed, norbornene-mediated ortho-amination/N-tosylhydrazone insertion reaction. In this transformation, one C-N bond and one C-C bond are formed and an amine group is introduced at the ortho position successfully.

Copper-catalyzed one-pot trifluoromethylation/aryl migration/carbonyl formation with homopropargylic alcohols.

A novel copper-catalyzed one-pot functionalization of homopropargylic alcohols that involves trifluoromethylation, aryl migration, and formation of a carbonyl moiety has been developed. This reaction constitutes the first direct conversion of homopropargylic alcohols into CF3-containing 3-butenal or 3-buten-1-one derivatives in a regioselective manner. Mechanistic studies indicate that the 1,4-aryl migration proceeds through a radical pathway.

Influence of Cage Effects in Directing the Outcome of C-X Bond Forming Reactions.

Radical reactions have recently experienced a resurgence in organic chemistry after many decades of being considered to be too unselective to offer a viable solution for complex synthetic problems. Radical intermediates often have a number of different reaction pathways available to them that are all associated with insubstantial reaction barriers so that reaction outcomes can be controlled by proximity and dynamics. Cage effects consist of the effect of the surrounding medium, such as the solvent or the enzyme pocket, on the movement of radical intermediates and the medium's resulting influence over reaction outcomes and selectivity. Cage effects substantially affect the outcome of all transformations in condensed phases, which feature the intermediacy of radical pairs, and a suitable choice of the cage should thus constitute a key optimization parameter for radical reactions. This Perspective provides an overview of key aspects of the cage effect that can be of importance in synthetic chemistry and highlights its role in a number of recently reported transformations that forge C-X bonds via the intermediacy of radicals.

A reference-point-method-based online proton treatment plan re-optimization strategy and a novel solution to planning constraint infeasibility problem.

Objective. Propose a highly automated treatment plan re-optimization strategy suitable for online adaptive proton therapy. The strategy includes a rapid re-optimization method that generates quality replans and a novel solution that efficiently addresses the planning constraint infeasibility issue that can significantly prolong the re-optimization process.Approach. We propose a systematic reference point method (RPM) model that minimizes the l-infinity norm from the initial treatment plan in the daily objective space for online re-optimization. This model minimizes the largest objective value deviation among the objectives of the daily replan from their reference values, leading to a daily replan similar to the initial plan. Whether a set of planning constraints is feasible with respect to the daily anatomy cannot be known before solving the corresponding optimization problem. The conventional trial-and-error-based relaxation process can cost a significant amount of time. To that end, we propose an optimization problem that first estimates the magnitude of daily violation of each planning constraint. Guided by the violation magnitude and clinical importance of the constraints, the constraints are then iteratively converted into objectives based on their priority until the infeasibility issue is solved.Main results.The proposed RPM-based strategy generated replans similar to the offline manual replans within the online time requirement for six head and neck and four breast patients. The average targetD95and relevant organ at risk sparing parameter differences between the RPM replans and clinical offline replans were -0.23, -1.62 Gy for head and neck cases and 0.29, -0.39 Gy for breast cases. The proposed constraint relaxation solution made the RPM problem feasible after one round of relaxation for all four patients who encountered the infeasibility issue.Significance. We proposed a novel RPM-based re-optimization strategy and demonstrated its effectiveness on complex cases, regardless of whether constraint infeasibility is encountered.

Anti-Markovnikov Hydroalkylation of Styrene Derivatives via Hydrazones Catalyzed by Ru-PNP Complex.

A well-defined Ru(II)-PNP complex demonstrated high activity in the anti-Markovnikov hydroalkylation of nonpolarized terminal alkenes via hydrazones. Hydrazone served as a carbanion equivalent to combine with the electrophilic alkene substrate upon activation by the ruthenium catalyst, forming a new C-C bond in a concerted pathway with N2 as the only theoretical byproduct. Experimental and computational studies suggested the existence of a push-pull interaction that activated the alkene for hydrazone addition and then deduced the mechanism.

Brønsted acid catalyzed and NIS-promoted cyclization of diynones: selective synthesis of 4-pyrone, 4-pyridone, and 3-pyrrolone derivatives.

Brønsted acid catalyzed tandem cyclization was found to be highly effective for the preparation of a series of polysubstituted 4-pyrones from diynones (yield up to 99%). 4-Pyridone and 3-pyrrolone derivatives were also selectively synthesized by employing NIS and/or Brønsted acid. NIS as an electrophilic reagent could promote these reactions efficiently and rapidly under very mild reaction conditions.

Online adaptive planning methods for intensity-modulated radiotherapy.

Online adaptive radiation therapy aims at adapting a patient's treatment plan to their current anatomy to account for inter-fraction variations before daily treatment delivery. As this process needs to be accomplished while the patient is immobilized on the treatment couch, it requires time-efficient adaptive planning methods to generate a quality daily treatment plan rapidly. The conventional planning methods do not meet the time requirement of online adaptive radiation therapy because they often involve excessive human intervention, significantly prolonging the planning phase. This article reviews the planning strategies employed by current commercial online adaptive radiation therapy systems, research on online adaptive planning, and artificial intelligence's potential application to online adaptive planning.

Umpolung carbonyls enable direct allylation and olefination of carbohydrates.

Mother Nature has its own arts to build a vast number of carbohydrates; however, there is still a lack of tools for selective functionalization of native carbohydrates through C─C bond formation. Such a long-standing challenge for the synthetic community lies into the intrinsic problems related to the innate properties of carbohydrates, e.g., the ease to oligomerization or polymerization, the difficulty of chemoselectivity control in the presence of multiple hydroxyl groups, the great challenge to retain the multiple chiral centers during the transformation, etc. Here, by applying an umpolung strategy of carbohydrate carbonyls, we report a direct deoxygenative allylation and olefination of carbohydrates to tackle the abovementioned issues. The reaction is compatible with a wide range of natural carbohydrates, providing a direct synthetic method to use carbohydrates as multiple C-centered chiral synthons to achieve C─C bond cross-coupling reactions. Furthermore, the synthetic applicability is demonstrated by late-stage modifications of natural products and pharmaceutical derivatives.

Markov Decision Process Modeling for Multi-stage Optimization of Intervention and Treatment Strategies in Breast Cancer.

The breast cancer is a prevalent problem that undermines quality of patients' lives and causes significant impacts on psychosocial wellness. Advanced sensing provides unprecedented opportunities to develop smart cancer care. The available sensing data captured from individuals enable the extraction of information pertinent to the breast cancer conditions to construct efficient and personalized intervention and treatment strategies. This research develops a novel sequential decision-making framework to determine optimal intervention and treatment planning for breast cancer patients. We design a Markov decision process (MDP) model for both objectives of intervention and treatment costs as well as quality adjusted life years (QALYs) with the data-driven and state-dependent intervention and treatment actions. The state space is defined as a vector of age, health status, prior intervention, and treatment plans. Also, the action space includes wait, prophylactic surgery, radiation therapy, chemotherapy, and their combinations. Experimental results demonstrate that prophylactic mastectomy and chemotherapy are more effective than other intervention and treatment plans in minimizing the expected cancer cost of 25 to 60 years-old patient with in-situ stage of cancer. However, wait policy leads to an optimal quality of life for a patient with the same state. The proposed MDP framework can also be generally applicable to a variety of medical domains that entail evidence-based decision making.