Bond Disconnection Research Articles

Triazenolysis of alkenes as an aza version of ozonolysis.

Alkenes are broadly used in synthetic applications, thanks to their abundance and versatility. Ozonolysis is one of the most canonical transformations that converts alkenes into molecules bearing carbon-oxygen motifs via C=C bond cleavage. Despite its extensive use in both industrial and laboratory settings, the aza version-cleavage of alkenes to form carbon-nitrogen bonds-remains elusive. Here we report the conversion of alkenes into valuable amines via complete C=C bond disconnection. This process, which we have termed 'triazenolysis', is initiated by a (3 + 2) cycloaddition of triazadienium cation to an alkene. The triazolinium salt formed accepts hydride from borohydride anion and spontaneously decomposes to create new C-N motifs upon further reduction. The developed reaction is applicable to a broad range of cyclic alkenes to produce diamines, while various acyclic C=C bonds may be broken to generate two separate amine units. Computational analysis provides insights into the mechanism, including identification of the key step and elucidating the significance of Lewis acid catalysis.

Photoinduced Deconstructive Alkylation Approach Enabled by Oxy-Radicals from Alcohols.

Alcohols are the most commercially abundant, synthetically versatile and operationally convenient functional groups in organic chemistry. Therefore, a strategy that utilizes hydroxy-containing compounds to develop novel bond disconnection and formation process would achieve molecular diversity. Herein, a deconstructive strategy for the generation of quinoxalin-2(1H)-one derivatives has been developed from alcohol precursors via oxy-radical-induced β-fragmentation. Additionally, 1,5-HAT and deoxygenation by P(III) along with oxy-radical were demonstrated as alternative pathways for this transformation. Furthermore, with the deep-seated reorganization of a few terpenes carbon framework, a unique activity with inhibition against the growth of pathogenic fungi was observed.

Efficient search for acetic acid synthesis pathway based on the bond disconnection process on Rh surface and Rh/metal oxide interface

The interfacial structure between Rh and the metal oxide support (or promoter) is thought to play an essential role in the synthesis of C2-oxygenated compounds such as acetic acid (CH3COOH). However, due to the complexity of the interface structure, the CH3COOH synthesis pathway has yet to be explored theoretically at the metal/metal oxide interface. In this study, we examined the CH3COOH synthesis pathway at the Rh surface and Rh/metal oxide interface based on the systematic investigation of bond disconnection of the CH3COOH molecule. First, CH3COOH synthesis pathways that include small activation energy Ea(c) were explored on the Rh(111) and it was shown that the reaction pathways CH + CO(H) → CHCO(H) → CH2CO(H) → CH3COH → CH3COOH were found [the rate-limiting step (RLS) is the C=O bond connection with Ea(c) = 1.41 eV]. After that, the CH3COOH synthesis pathway at the Rh/ZrO2 interface was investigated, and it was found that the CH3COOH synthesis pathway via the acetyl (CH3CO) generated from Rh–CH3 and Rh–CO with an oxygen atom in Rh–CO interacted with Zr cation (the RLS was the C–C bond connection with Ea(c) = 0.73 eV). This study provides guidelines for the design of a rational active metal/metal oxide interface for C2 oxygenates synthesis.

Olefin Difunctionalization for the Synthesis of Tetrahydroisoquinoline, Morpholine, Piperazine, and Azepane.

This report outlines a versatile strategy for synthesizing a diverse array of N-heterocycles. By the utilization of common olefins, this simple protocol facilitates their coupling with various bifunctional reagents. Furthermore, it can be integrated with C-H amination techniques to directly produce N-heterocycles in a multicomponent cascade coupling process. The unique bond disconnection logic employed in this process underscores its efficiency in achieving rapid simplification through cascade couplings.

Enzymatic Assembly of Diverse Lactone Structures: An Intramolecular C-H Functionalization Strategy.

Lactones are cyclic esters with extensive applications in materials science, medicinal chemistry, and the food and perfume industries. Nature's strategy for the synthesis of many lactones found in natural products always relies on a single type of retrosynthetic strategy, a C-O bond disconnection. Here, we describe a set of laboratory-engineered enzymes that use a new-to-nature C-C bond-forming strategy to assemble diverse lactone structures. These engineered "carbene transferases" catalyze intramolecular carbene insertions into benzylic or allylic C-H bonds, which allow for the synthesis of lactones with different ring sizes and ring scaffolds from simple starting materials. Starting from a serine-ligated cytochrome P450 variant previously engineered for other carbene-transfer activities, directed evolution generated a variant P411-LAS-5247, which exhibits a high activity for constructing a five-membered ε-lactone, lactam, and cyclic ketone products (up to 5600 total turnovers (TTN) and >99% enantiomeric excess (ee)). Further engineering led to variants P411-LAS-5249 and P411-LAS-5264, which deliver six-membered δ-lactones and seven-membered ε-lactones, respectively, overcoming the thermodynamically unfavorable ring strain associated with these products compared to the γ-lactones. This new carbene-transfer activity was further extended to the synthesis of complex lactone scaffolds based on fused, bridged, and spiro rings. The enzymatic platform developed here complements natural biosynthetic strategies for lactone assembly and expands the structural diversity of lactones accessible through C-H functionalization.

Branched-Selective Cross-Electrophile Coupling of 2-Alkyl Aziridines and (Hetero)aryl Iodides Using Ti/Ni Catalysis.

The arylation of 2-alkyl aziridines by nucleophilic ring-opening or transition-metal-catalyzed cross-coupling enables facile access to biologically relevant β-phenethylamine derivatives. However, both approaches largely favor C-C bond formation at the less-substituted carbon of the aziridine, thus enabling access to only linear products. Consequently, despite the attractive bond disconnection that it poses, the synthesis of branched arylated products from 2-alkyl aziridines has remained inaccessible. Herein, we address this long-standing challenge and report the first branched-selective cross-coupling of 2-alkyl aziridines with aryl iodides. This unique selectivity is enabled by a Ti/Ni dual-catalytic system. We demonstrate the robustness of the method by a twofold approach: an additive screening campaign to probe functional group tolerance and a feature-driven substrate scope to study the effect of the local steric and electronic profile of each coupling partner on reactivity. Furthermore, the diversity of this feature-driven substrate scope enabled the generation of predictive reactivity models that guided mechanistic understanding. Mechanistic studies demonstrated that the branched selectivity arises from a TiIII-induced radical ring-opening of the aziridine.

Access to Diverse Organoborons by α-Deprotonation and Functionalization of Benzylboronates.

Described here is a simple and efficient method to prepare organoboron compounds through α-deprotonation and functionalization of benzylboronates. In addition to alkyl halides, chlorosilane, deuterium oxide, and trifluoromethyl alkene could also serve as electrophiles in this approach. Notably, the boryl group enables high diastereoselectivities when unsymmetrical secondary α-bromoesters are used. This methodology exhibits a broad substrate scope and high atomic efficiency and offers an alternative C-C bond disconnection for the synthesis of benzylboronates.

Recognition of Symmetry as a Powerful Tool in Natural Product Synthesis

AbstractThe design of concise and efficient synthetic strategies to access naturally occurring, pharmaceutically active complex molecules is of utmost importance in current chemistry. It not only enables rapid access to these molecules and their analogues but also provides sufficient quantities for their biological evaluation. Identification of any symmetric or pseudosymmetric synthetic intermediates upon retrosynthetic bond disconnection of the target molecule holds the promise to significantly streamline the route towards the compound of interest. This review will highlight recent examples of successful natural product syntheses reported within the past five years that benefited from the recognition of symmetry elements during the retrosynthetic design.1 Introduction2 Examples2.1 Chondrosterin I and J2.2 (–)-Bilobalide A2.3 Delavatine A2.4 Oxycodone2.5 (–)-20-epi-vincamine and (–)-20-epi-eburnamonine2.6 Reserpine2.7 (–)-Berkeleyone A2.8 (–)-Maximiscin2.9 Aplysiasecosterol A2.10 (–)-Batrachotoxinin A2.11 (–)-Mitrephorone A3 Conclusions

Photoinduced β-fragmentation of aliphatic alcohol derivatives for forging C–C bonds

Alcohols are ubiquitous in chemistry and are native functionalities in many natural products and bioactive molecules. As such, a strategy that utilizes hydroxy-containing compounds to develop bond disconnection and bond formation process would achieve molecular diversity. Herein we utilize bench-stable N-alkoxyphthalimides prepared from alcohols to couple with glycine derivatives via radical process under visible light irradiation, providing a variety of unnatural amino acid (UAA) and peptide derivatives. The approach allows to rapidly deconstruct molecular complexity via β-fragmentation such as saclareolide, β-pinene and camphor and provides products with unique scaffolds, which show inhibition toward the pathogenic fungi growth.

Exploiting photoredox catalysis for carbohydrate modification through C-H and C-C bond activation.

Photoredox catalysis has recently emerged as a powerful synthetic platform for accessing complex chemical structures through non-traditional bond disconnection strategies that proceed through free-radical intermediates. Such synthetic strategies have been used for a range of organic transformations; however, in carbohydrate chemistry they have primarily been applied to the generation of oxocarbenium ion intermediates in the ubiquitous glycosylation reaction. In this Review, we present more intricate light-induced synthetic strategies to modify native carbohydrates through homolytic C-H and C-C bond cleavage. These strategies allow access to glycans and glycoconjugates with profoundly altered carbohydrate skeletons, which are challenging to obtain through conventional synthetic means. Carbohydrate derivatives with such structural motifs represent a broad class of natural products integral to numerous biochemical processes and can be found in active pharmaceutical substances. Here we present progress made in C-H and C-C bond activation of carbohydrates through photoredox catalysis, focusing on the operational mechanisms and the scope of the described methodologies.

The Catalytic Synthesis of N-Aryl Indoles Featuring an Alternative Disconnection. Hydroaminoalkylation for a Telescoped Reaction Sequence.

A tricatalytic telescoped synthesis toward C3-methyl-N-aryl indoline and indole products is reported. An in situ generated tantalum(V) ureate catalyst is used for the hydroaminoalkylation of o-chlorostyrene with N-methylaniline to first make a Csp3─Csp3 bond. Subsequent nickel-catalyzed C-N coupling forms N-aryl indolines, and if desired, subsequent oxidation to N-aryl indoles can be achieved using catalytic [Cu(MeCN)4]BF4 and tert-butylperoxy-2-ethylhexyl carbonate as the terminal oxidant. This strategy highlights an alternative C-C bond disconnection for the synthesis of indoles, which is enabled by the atom-economic hydroaminoalkylation reaction. The method was streamlined using a three-step, two-pot approach to afford up to 73% overall isolated yield of variously substituted C3-methyl-N-aryl indoles.

Accessing Diverse Cross-Benzoin and α-Siloxy Ketone Products via Acyl Substitution Chemistry.

An approach to diverse cross-benzoin and α-siloxy ketone products which leverages a simple yet underutilized C-C bond disconnection strategy is reported. Acyl substitution of readily accessible α-siloxy Weinreb amides with organolithium compounds enables access to a broad scope of aryl, heteroaryl, alkyl, alkenyl, and alkynyl derivatives. Enantiopure benzoins can be accessed via a chiral pool approach, and the utility of accessible cross-benzoins and α-siloxy ketones is highlighted in a suite of downstream synthetic applications.

Merging enzymes with chemocatalysis for amide bond synthesis

Amides are one of the most fundamental chemical bonds in nature. In addition to proteins and other metabolites, many valuable synthetic products comprise amide bonds. Despite this, there is a need for more sustainable amide synthesis. Herein, we report an integrated next generation multi-catalytic system, merging nitrile hydratase enzymes with a Cu-catalysed N-arylation reaction in a single reaction vessel, for the construction of ubiquitous amide bonds. This synergistic one-pot combination of chemo- and biocatalysis provides an amide bond disconnection to precursors, that are orthogonal to those in classical amide synthesis, obviating the need for protecting groups and delivering amides in a manner unachievable using existing catalytic regimes. Our integrated approach also affords broad scope, very high (molar) substrate loading, and has excellent functional group tolerance, telescoping routes to natural product derivatives, drug molecules, and challenging chiral amides under environmentally friendly conditions at scale.

The Role of Psychological Distress in Relational Health Instability among Romantic Couples: A Qualitative Inquiry

Background: Relationship instability, which creates an additional burden to the couples, has contributed to relationship disconnection. Factor like stress plays a vital role in the flux of relationship status and in understanding the stability of intimate relationships and quality in romantic relationships. Yet, there is a dearth on psychological distress noted on non-marital relationship disconnection, since the most documented research has centered on the context of marital bond disconnection. Thus, it prompted the researcher to conduct a qualitative inquiry on the role of psychological distress among women with experiences on mutual bond disconnection. Methods: Constructivist grounded theory and feminist theory designs were utilized to describe the role of psychological distress in relational health instability from the lens of women who participated on this study. This study employed theoretical and purposive sampling methods to enter research interest on relationship loss. Guided by a semi-structured questionnaire, the researcher explored women’s experiences on mutual bond disconnection. However, this paper focused on the thoughts, views, and feelings among women on relational health instability among couples Results: Thematic analysis generated the participants’ psychological stressors such as disrespect, disinclination, and monetary issues that caused their relational health instability and further led to mutual bond disconnection. Moreover, it provided an in-depth understanding of the factors causing romantic relational health instability such as: (i) humiliation, and (ii) financial matters. Conclusion: The findings provided an increased in-depth understanding of the psychological factors that leads to unhealthy relationships among romantic couples which further cause the mutual bond disconnection.

Decarboxylation‐Initiated Intermolecular Carbon‐Heteroatom Bond Formation

AbstractCarboxylic acids are among the most used feedstock chemicals due to their great structural diversity and easy handling. The use of carboxylic acids and their derivatives in decarboxylative couplings has proven to be a valuable tool for the construction of C−C and C‐heteroatom bonds. This synthetic strategy provides a complementary bond disconnection to traditional cross‐coupling methods. In this review, we provide a comprehensive overview of decarboxylation‐initiated intermolecular C‐heteroatom bond formation, outlining several main mechanistic concepts combined with early examples and highlighting the achievements made in the past decade until January 2021. In these reactions, carboxylic acids and their derivatives undergo initial decarboxylation and then react with other heteroatom electrophiles and nucleophiles, thus replacing the carboxylate group with a valuable and prevalent heteroatom functionality.magnified image

Deconstructive Functionalization of Ketones via an LMCT-Promoted C–C Cleavage

In this issue of Chem, Zuo and coworkers report an exciting new strategy for the deconstructive functionalization of ketones. Through merging Lewis-acid-catalyzed nucleophilic 1,2-addition and ligand-to-metal charge transfer (LMCT)-promoted C–C cleavage, common strained and unstrained ketones are transformed into synthetically valuable scaffolds with high efficiency under mild conditions.

Iron Hydride Radical Reductive Alkylation of Unactivated Alkenes.

Iron-catalyzed hydrogen atom transfer-mediated intermolecular C-C coupling reactions between alkenes and tosylhydrazones, followed by in situ cleavage of the tosylhydrazine intermediates using Et3N, are described. The process involves a new strategic bond disconnection resulting in the reductive alkylation of nonactivated alkenes. The reaction is operationally simple, proceeds under mild conditions, and has a wide substrate scope.

Metal-Catalyzed Ionic Decarboxylative Cross-Coupling Reactions of C(sp3) Acids: Reaction Development, Mechanisms, and Application

The direct transition-metal-catalyzed conversion of carboxylic acid groups into other C–C or C–X bonds provides a complementary bond disconnection to traditional cross-coupling manifolds. Decarboxy...

2‐Methyltetrahydrofuran (2‐MeTHF): A Green Solvent for Pd−NHC‐Catalyzed Amide and Ester Suzuki‐Miyaura Cross‐Coupling by N−C/O−C Cleavage

AbstractThe palladium‐NHC‐catalyzed (NHC=N‐heterocyclic carbene) Suzuki‐Miyaura cross‐coupling of amides and esters via highly chemoselective N−C(O) and O−C(O) cleavage with aryl boronic acids using green, sustainable and eco‐friendly 2‐methyltetrahydrofuran (2‐MeTHF) is reported. A variety of amides and aryl esters were coupled with aryl boronic acids in high to excellent yields. This method employs commercially‐available, air‐ and moisture‐stable Pd(II) −NHC precatalysts. Crucially, the use of 2‐MeTHF leads to the highest TON reported to date in amide N−C(O) bond cross‐coupling. This operationally‐simple protocol was utilized in the synthesis a bioactive ketone intermediate, emphasizing the potential of 2‐MeTHF as a green solvent in unconventional amide bond disconnection. Given the tremendous importance of amide bond cross‐coupling strategies and the drive to maintain full sustainability in cross‐coupling processes, we expect that the synthetic method will be of broad interest.magnified image

Palladium-Catalyzed Decarboxylative Alkynylation of α-Acyloxyketones by C(sp3 )-O Bond Cleavage.

Palladium-catalyzed decarboxylative alkynylation of α-acyloxyketones triggered by C(sp3 )-O bond cleavage is disclosed. The decarboxylation strategy featuring a neutral reaction condition enabled an unprecedent catalytic alkynylation of a ketone enolate. The reaction was applied to a variety of substrates, giving desired products in good yields. We successfully obtained X-ray crystallography of a new palladium-enolate intermediate that was synthesized by a reaction of [Pd(cod)(CH2 TMS)2 ] with XPhos and α-acyloxyketone at room temperature, indicating facile C(sp3 )-O bond disconnection.