Divergent Synthesis Research Articles

Photochemical Radical Bicyclization of 1,5-Enynes: Divergent Synthesis of Fluorenes and Azepinones.

A dual nickel- and iridium-photocatalyzed radical cascade bicyclization reaction for the synthesis of highly complex molecular structures in an atom- and step-economic manner has been described. A series of radical precursors are utilized for the divergent synthesis of diversely substituted fluorenes and indenoazepinones bearing quaternary carbons by using cascade cyclization reactions of 1,5-enynes. This reaction is characterized by its mild conditions, broad substrate scope, excellent selectivity, and satisfactory yield including facile scale-up synthesis.

Systematic Strategy for the Development of Glycosyltransferase Inhibitors: Diversity-Oriented Synthesis of FUT8 Inhibitors

AbstractGlycans control various biological processes, depending on their structures. Particularly, core fucose, formed by α1,6-fucosyltransferase (FUT8), has a substantial influence on multiple biological processes. In this study, we investigated the development of FUT8 inhibitors with structural elements encompassing both the glycosyl donor (GDP-fucose) and acceptor (N-glycan) of FUT8. To efficiently optimize the structure of FUT8 inhibitors, we employed a strategy involving fragmentation of the target structure, followed by a structure optimization using a diversity-oriented synthesis approach. This study proposes an efficient strategy to accelerate the structural optimization of middle molecules.

Highly Diastereoselective [3 + 2] Cycloaddition of Aziridines with Difluorinated Silyl Enol Ethers: Divergent Synthesis of 4,4-Difluoropyrrolidines and 4-Fluoropyrroles.

A highly diastereoselective [3 + 2] cycloaddition of aziridines with difluorinated silyl enol ethers has been developed. This approach provides a facile methodology for highly functionalized gem-difluorinated pyrrolidines in good to excellent yields with good functional group tolerance. A one-pot, two-step approach for synthesis of structurally interesting fluorinated pyrroles has also been developed through a cycloaddition/aromatization/desulfonation sequence. Moreover, readily available substrates, mild reaction conditions, and easy scale-up synthesis show practical advantages.

Alkaline-Metal-Promoted Divergent Synthesis of 1-Aminoisoquinolines and Isoquinolines.

Alkaline-metal-promoted divergent syntheses of 1-aminoisoquinolines and isoquinolines have been reported involving 2-methylaryl aldehydes, nitriles, and LiN(SiMe3)2 as reactants. In addition, the three-component reaction of 2-methylaryl nitriles, aldehydes, and LiN(SiMe3)2 has been developed to furnish 1-aminoisoquinolines. This protocol features readily available starting materials, excellent chemoselectivity, broad substrate scope, and satisfactory yields.

Palladium-Catalyzed Difluorocarbene Transfer Enabled Divergent Synthesis of γ-Butenolides and Ynones from Iodobenzene and Terminal Alkynes.

Herein, we report a ligand-controlled palladium-catalyzed method that enables the synthesis of ynones and γ-butenolides with excellent regioselectivity from the same set of readily available aryl iodides, aryl acetylenes, and BrCF2CO2K. In this reaction, the [PdII]═CF2 does demonstrate electrophilicity and can generate CO readily when reacting with H2O. It is environmentally friendly and safe compared to traditional methods, and the current protocol enables us to afford ynones and γ-butenolides in high yields with excellent functionality tolerance. Moreover, esters can also be obtained with corresponding phenols and alcohols utilizing this strategy. The success of late-stage functionalization of bioactive compounds further illustrates the synthetic utility of this protocol in material development and drug discovery.

Brønsted Acid-Catalyzed Dehydrative Nazarov-type Cyclization of CF3-Substituted 3-Indolylallyl Alcohols: Divergent Synthesis of 1-Trifluoromethylated Cyclopenta[b]indoles.

An expedient and efficient synthetic method for the divergent synthesis of 1-trifluoromethylated cyclopenta[b]indoles that relies on Brønsted acid-catalyzed dehydrative Nazarov-type cyclization of CF3-substituted 3-indolylallyl alcohols is described. Two classes of 1-trifluoromethylated cyclopenta[b]indoles can be easily accessed simply by changing the NH-protecting group of indoles. With arylsulfonyl protected 3-indolylallyl alcohols as starting materials, the reaction provided the arylsulfonyl protected 1-trifluoromethylated cyclopenta[b]indoles in good to excellent yields, whereas pivaloyl (Piv) protected substrates led to the formation of NH-free 1-trifluoromethylated cyclolopenta[b]indoles with another alkenyl isomer. This protocol features tunable chemoselectivity, operational simplicity, excellent functional group compatibility, and mild metal-free conditions.

Dual-Catalyzed Stereodivergent Electrooxidative Homocoupling of Benzoxazolyl Acetate.

The development of a reliable strategy for stereodivergent radical reactions that allows convenient access to all stereoisomers of homocoupling adducts with multiple stereogenic centers remains an unmet goal in organic synthesis. Herein, we describe a dual-catalyzed electrooxidative C(sp3)-H/C(sp3)-H homocoupling with complete absolute and relative stereocontrol for the synthesis of molecules with contiguous quaternary stereocenters in a general and predictable manner. The stereodivergent electrooxidative homocoupling reaction is achieved by synergistically utilizing two distinct chiral catalysts that convert identical racemic substrates into inherently distinctive reactive chiral intermediates, dictate enantioselective radical addition, and allow access to the full complement of stereoisomeric products via simple catalyst permutation. The successful execution of the dual-electrocatalytic strategy programmed via electrooxidative activation provides a significant conceptual advantage and will serve as a useful foundation for further research into cooperative stereocontrolled radical transformations and diversity-oriented synthesis.

Isothiocyanate intermediates facilitate divergent synthesis of N-heterocycles for DNA-encoded libraries.

The versatile reactivity of isothiocyanate intermediates enabled the diversity-oriented synthesis (DOS) of N-heterocycles in a DNA-compatible manner. We first reported a mild in situ conversion of DNA-conjugated amines to isothiocyanates. Subsequently, a set of diverse transformations was successfully developed to construct 2-thioxo-quinazolinones, 1,2,4-thiadiazoles, and 2-imino thiazolines. Finally, the feasibility of these approaches in constructing DELs was further demonstrated through enzymatic ligation and mock pool preparation. This study demonstrated the advantages of combining in situ conversion strategies with DOS, which effectively broadened the chemical and structural diversity of DELs.

Divergent total syntheses of pyrroloiminoquinone alkaloids enabled by the development of a Larock/Buchwald-Hartwig annulation/cyclization.

Pyrroloiminoquinone alkaloids are a large class of natural products that display a wide range of biological activities. Synthetic approaches to these natural products typically rely on a common late-stage C10-oxygenated pyrroloiminoquinone intermediate, but these strategies often lead to lengthy synthetic sequences that are not amenable to divergent syntheses. We devised an alternative approach aimed at the early introduction of the C10 nitrogen, which we hypothesized would enable late-stage diversification. This strategy hinged upon a Larock/Buchwald-Hartwig annulation/cyclization to quickly access the core of these alkaloids. We report the development of this cascade process, which was facilitated by a dual ligand system in addition to selective functionalization of the key intermediate, to provide efficient syntheses of makaluvamines A, C, and D and isobatzelline B, and the first total synthesis of makaluvamine N.

Recent advances in ligand-enabled palladium-catalyzed divergent synthesis.

Developing efficient and straightforward strategies to rapidly construct structurally distinct and diverse organic molecules is one of the most fundamental tasks in organic synthesis, drug discovery and materials science. In recent years, divergent synthesis of organic functional molecules from the same starting materials has attracted significant attention and has been recognized as an efficient and powerful strategy. To achieve this objective, the proper adjustment of reaction conditions, such as catalysts, solvents, ligands, etc., is required. In this review, we summarized the recent efforts in chemo-, regio- and stereodivergent reactions involving acyclic and cyclic systems catalyzed by palladium complexes. Meanwhile, the reaction types, including carbonylative reactions, coupling reactions and cycloaddition reactions, as well as the probable mechanism have also been highlighted in detail.

Transition metal-catalyzed redox-neutral 1,3-dienylation of propargylic esters and divergent synthesis

Stereoselective dienylation of propargylic esters with nucleophiles via transition metal catalysis is a powerful method for accessing conjugated dienes. In particular, divergent synthesis beyond 1,3-dienes can be realized.

Modular and divergent synthesis of 2,N3-disubstituted 4-quinazolinones facilitated by regioselective N-alkylation.

The synthesis of a biologically relevant 2-amino-N3-alkylamido 4-quinazolinone has been accomplished in four steps from commercially available materials using design principles from both modular and divergent synthesis. N3-Alkylation of 2-chloro-4(3H)-quinazolinone using methyl bromoacetate, followed by C2-amination produced a suitable scaffold for introducing molecular diversity. Optimization of alkylation conditions afforded full regioselectivity, enabling exclusive access to the N-alkylated isomer. Subsequent C2-amination using piperidine, pyrrolidine, or diethylamine, followed by amide bond formation using variously substituted phenethylamines, generated fifteen unique 4-quinazolinones bearing C2-amino and N3-alkylamido substituents. These efforts highlight the reciprocal influence of C2 and N3 substitution on functionalization at either position, establish an effective synthetic pathway toward 2,N3-disubstituted 4-quinazolinones, and enable preliminary bioactivity studies while providing an experiential learning opportunity for undergraduate student researchers.

Molecular engineering of 3-arylated tetrazo[1,2-b]indazoles: divergent synthesis and structure-property relationships.

The synthetic scope of 3-arylated tetrazo[1,2-b]indazoles is reported based on a Pd-catalyzed Liebeskind-Srogl cross-coupling reaction followed by an N-cyclisation process. The reactivity of the nitrogen atoms was used to further diversify these N-rich polyaromatic tetrazo[1,2-b]indazoles in a panel of reactions (protonation, selective oxidation, metallations). Selective ortho-C-H activation/functionalization on the heterocycle was also demonstrated with three transition metals (TM = Pd, Ir and Rh). The effects of all these molecular engineering strategies, particularly the N-modifications, on the optical and redox properties of the 3-arylated tetrazoindazoles were studied experimentally and theoretically. This study highlights the diversity of molecular structures and electronic properties offered by the tetrazo[1,2-b]indazole platform.

Synthesis of the first 4-oxobutane-1,1,2,2-tetracarbonitriles containing a phenol fragment and their transformation into cyano-substituted pyrrol-2-ones showing three-position molecular switching.

The first example of the synthesis of 4-oxobutane-1,1,2,2-tetracarbonitriles (OTCs) containing a phenolic moiety has been described. The synthesis is based on the reaction between tetracyanoethylene and 4-hydroxyphenyl-substituted ketones under mild conditions. Due to the presence of a phenolic hydroxyl group, these compounds are more functionalized derivatives of the well-known OTC substrates used for diversity-oriented synthesis (DOS). The preserved synthetic potential of the OTCs for the preparation of phenol-containing derivatives with enhanced capabilities for tuning optical properties has been shown using the targeted synthesis of 2-(2-oxo-1,2-dihydro-3H-pyrrol-3-ylidene)malononitriles. Based on the obtained pyrroles and a model amine (pyrrolidine) a previously unknown type of thermosensitive three-position molecular switch is described. Reversible color changes of the dye are shown in both solution and on filter paper. The results reveal a new research branch of the OTC-based DOS strategy to access functionalized phenol-containing derivatives.

A one-pot telescopic synthesis of benzo[b]carbazoles and exploration of their liquid crystalline properties.

We describe a diversity-oriented one-pot telescopic synthesis of various benzo[b]carbazoles with the naphthannulation of indoles as the key step, enabled by an intramolecular furan-olefin Diels-Alder reaction. This strategy is general and efficient across a wide range of substrates. We applied this method to synthesize and characterize the first benzo[b]carbazole-based liquid crystalline materials, where the unique molecular design led to the formation of a rare nematic phase at room temperature.

Diversity-oriented multi-compound synthesis optimization

Development of an optimization algorithm to identify comprehensive sets of compounds that effectively cover the chemical space of interest with minimal synthesis effort.

Sequential Dieckmann cyclization enables the total synthesis of 7-epi-clusianone and 18-hydroxy-7-epi-clusianone.

A unified approach for the construction of the bicyclo[3.3.1]nonane-2,4,9-trione core of polycyclic polyprenylated acylphloroglucinols (PPAPs) was reported. This approach involves a sequential process of two distinct Dieckmann condensation reactions from the linear precursor. Using this method, the divergent total synthesis of the natural products 7-epi-clusianone and 18-hydroxy-7-epi-clusianone and the formal synthesis of sampsonione P were achieved. Additionally, other key steps to realize this strategy include RuCl3-catalyzed oxidative olefin cleavage and Pd-catalyzed Tsuji-Trost decarboxylative allylation. The synthesis indicated that bicyclo[3.3.1]nonane-2,4,9-triones could also be constructed via 6-membered intermediates.

Divergent process for the catalytic decarboxylative thiocyanation and isothiocyanation of carboxylic acids promoted by visible light.

A divergent photoinduced selective synthesis of thiocyanate and isothiocyanate derivatives from readily available carboxylic acids was developed using N-thiocyanatosaccharin and a catalytic amount of base or acid. This molecular editing strategy allowed the functionalization of bioactive compounds. A mechanism for the transformation was proposed based on control experiments.

Simultaneous diversity-oriented synthesis of benzothiazoles and related diverse analogues by iodine-catalyzed intramolecular cyclization from identical substrates

Simultaneous diversity-oriented synthesis of benzothiazoles and related diverse analogues by iodine-catalyzed intramolecular cyclization from identical substrates

Diversity-oriented synthesis enables the rapid development of quinoxaline-based bis-boron fluorophores: photophysical properties and sensing applications

Organoboron fluorophores have emerged as promising functional dyes with versatile photophysical properties. The innovative strategy of incorporating multiple boron coordination units has significantly broadened their application potential. Herein, a new...