Divergent Synthesis Research Articles

Base/Solvent Controlled Divergent Synthesis of Norbornane-Fused Dihydrophenanthrenes and Triphenylenes via Palladium Catalyst.

A base/solvent controlled divergent synthesis for the construction of polycyclic hydrocarbons has been developed. In this process, norbornene through a reagent role leads to the synthesis of norbornane-fused dihydrophenanthrenes, which are essential due to their biological activities. Amazingly, by switching solvent and base, the role of norbornene becomes limited to a mediator/catalyst; therefore, it is removed from the final scaffold, and triphenylenes are regioselectively synthesized. Additionally, by removing norbornene from the reaction conditions, a different path leading to synthesis of unsymmetrically substituted triphenylenes with exceptional regioselectivity is established. This reaction includes a rare domino decarboxylation/C-H activation/annulation in a chemo- and regioselective manner.

Organocatalytic Asymmetric Synthesis of Carbo- and Oxacyclic Seven-Membered Bridged Biaryls via Nucleophile-Dependent Switchable Domino Processes.

We disclose herein a highly diastereo- and enantioselective divergent synthesis of seven-membered biaryl-bridged carbo- and oxacyclic frameworks by utilizing the catalytic ability of bifunctional hydrogen-bonding squaramide organocatalysts. Starting with the same biaryl substrate bearing two distinct acceptor sites and by choosing soft or hard nucleophiles, we readily accessed the dibenzocycloheptanes or 5,7-dihydrodibenzo[c,e]oxepines bearing multiple elements of chirality via a domino 1,4/1,2-addition or 1,2/oxa-Michael addition sequence, respectively.

Strategies for the Controlled Hydrostannylation of Alkynes

AbstractOrganostannanes have represented one of the most widely applied reagents in modern cross‐coupling chemistry and represent a key reagent in the synthesis of a range of pharmaceutically relevant scaffolds. This Concept article reviews recent advances in approaches to the synthesis of these building blocks in a stereocontrolled and regiocontrolled manner. Particular focus is paid to methods which allow for divergent synthesis of alkenylstannanes and developments in methods which present opportunities for sustainable synthesis.

Single-Molecule Dendritic MRI Nanoprobes Reveal the Size-Dependent Tumor Entrance.

The tumor entrance of drug delivery systems, including therapeutic proteins and nanomedicine, plays an essential role in affecting the treatment outcome. Nanoparticle size is a critical but contradictory factor in making a trade-off among blood circulation, tumor accumulation, and penetration. Here, this work designs a series of single-molecule gadolinium (Gd)-based magnetic resonance imaging (MRI) nanoprobes with well-defined sizes to precisely explore the size-dependent tumor entrance in vivo. The MRI nanoprobes obtained by divergent synthesis contain a core molecule of macrocyclic Gd(III)-chelate and different layers of dendritic lysine units, mimicking globular protein. This work finds that the r1 relaxivity and MR imaging signals increase with the nanoparticle size. The nanoprobe with a lower limit of critical size threshold ≈8.0nm achieves superior tumor accumulation and penetration. These single-molecule MRI nanoprobes can be served to precisely examine the size-related nanoparticle-biological interactions.

Substrate-Controlled Diversity-Oriented Synthesis of Novel Polycyclic Frameworks via [4 + 2] and [3 + 2] Annulations of Ninhydrin-Derived MBH Adducts with 3,4-Dihydroisoquinolines.

Substrate-controlled diversity-oriented synthesis of polycyclic frameworks via [4 + 2] and [3 + 2] annulations between ninhydrin-derived Morita-Baylis-Hillman (MBH) adducts and 3,4-dihydroisoquinolines under similar reaction conditions have been developed. The reaction provides diversity-oriented synthesis of a series of novel and structurally complex spiro multi heterocyclic skeletons in good yields (up to 87% and 90%, respectively) with excellent diastereoselectivities (up to >25:1 dr). In particular, the switchable [4 + 2] and [3 + 2] annulation reactions are controlled by tuning the hydroxyl protecting group on the ninhydrin-derived MBH adduct to deliver structural diverse spiro[indene-2,2'-[1,3]oxazino[2,3-a]isoquinoline] and spiro[indene-2,1'-pyrrolo[2,1-a]isoquinoline], respectively. Furthermore, the relative configuration and chemical structure of two kinds of cycloadducts were confirmed through X-ray diffraction analysis.

Photocatalytic Carboxylate to Sulfinamide Switching Delivers a Divergent Synthesis of Sulfonamides and Sulfonimidamides.

sulfinamides, sulfonamides, and sulfonimidamides are in-demand motifs in medicinal chemistry, yet methods for the synthesis of alkyl variants that start from simple, readily available feedstocks are scarce. In addition, bespoke syntheses of each class of molecules are usually needed. In this report, we detail the synthesis of these three distinct sulfur functional groups, using readily available and structurally diverse alkyl carboxylic acids as the starting materials. The method harnesses alkyl radical generation from carboxylic acids using acridine photocatalysts and 400 nm light with subsequent radical addition to sulfinylamine reagents, delivering sulfinamide products. Using the N-alkoxy sulfinylamine reagent t-BuO-NSO as the radical trap provides common N-alkoxy sulfinamide intermediates, which can be converted in a divergent manner to either sulfonamides or sulfonimidamides, by treatment with sodium hydroxide, or an amine, respectively. The reactions are scalable, tolerate a broad range of functional groups, and can be used for the diversification of complex biologically active compounds.

Preparation of Optically Active 2,2'‐Dibromo‐6,6'‐diiodo‐1,1'‐biphenyl: A Powerful Precursor for Modular Synthesis of Functionalized Atropisomers†

Comprehensive SummaryThe widespread applications of atropisomeric compounds have led to an increasing demand for their synthesis. Rather than synthesizing different functionalized atropisomers individually, an attractive alternative is to identify a key intermediate or precursor that can be readily elaborated and functionalized to realize divergent synthesis of this class of compounds. Building on our previous research on asymmetric ring‐opening of cyclic diaryliodoniums, in this work we developed a copper‐catalyzed enantioselective ring‐opening reaction of ortho,ortho’‐dibromo substituted cyclic diaryliodonium with lithium iodide. The resulting optically active product 2,2'‐dibromo‐6,6'‐diiodo‐1,1'‐biphenyl, possessing two C—Br bonds and two C—I bonds, can be selectively advanced to form different functionalities. Remarkably, the utilities of the product were highlighted by successively demonstrating C—I and C—Br metalation, followed by carboxylation, boroylation, oxygenation, allylation, phosphinylation, etc., all of which provide a new and convenient approach to synthesizing a range of functionalized axially chiral biphenyls.

Simultaneous diversity-oriented synthesis of diverse benzo[d][1,3]thiazine libraries from identical substrates

Using o-isothiocyanato-(E)-cinnamaldehydes as powerful and versatile precursors, a facile domino reaction for the simultaneous formation of a compound library similar to natural products 3,4-dihydroquinazoline derivatives and 2,4-dihydro-1H-benzo[d][1,3]thiazine derivatives has been developed. The domino reaction of o-isothiocyanato-(E)-cinnamaldehydes with hydroxylamine resulted in the simultaneous formation of N/S-heterocycles and N/N-heterocycles, generating six classes of previously unknown 2,4-dihydro-1H-benzo[d][1,3]thiazine derivatives with various functional groups. This strategy is a typical example of diversity-oriented synthesis method.

Divergent Synthesis of Trifluoromethyl-Substituted 1,2-Dihydroquinoxalines and Diimines by Cascade Reactions of CF3-Imidoyl Sulfoxonium Ylides with Azo Compounds.

A base-mediated cascade reaction of CF3-imidoyl sulfoxonium ylides and azo compounds has been achieved, allowing for facile access to trifluoromethyl-substituted 1,2-dihydroquinoxalines and diimines in moderate to excellent yields. Noteworthy is that the unusual N-N bond cleavage and rearrangement of azo compounds are involved in the transformations.

Semisynthesis of Novel Dispiro-pyrrolizidino/thiopyrrolizidino-oxindolo/indanedione Natural Product Hybrids of Parthenin Followed by Their Cytotoxicity Evaluation.

Natural products possess unique and broader intricacies in the chemical space and have been essential for drug discovery. The crucial factor for drug discovery success is not the size of the library but rather its structural diversity. Although reports on the number of new structurally diverse natural products (NPs) have declined recently, researchers follow the next logical step: synthesizing natural product hybrids and their analogues using the most potent tool, diversity-oriented synthesis (DOS). Here, we use weed Parthenium hysterophorus as a source of parthenin for synthesis of novel dispiro-pyrrolizidino/thiopyrrolizidino-oxindolo/indanedione natural product hybrids of parthenin via chemo-, regio-, and stereoselective azomethine ylide cycloaddition. All synthesized compounds were characterized through a detailed analysis of one-dimensional (1D) and two-dimensional (2D) NMR and HRMS data, and the stereochemistries of the compounds were confirmed by X-ray diffraction analysis. All compounds were evaluated for their cytotoxicity against four cell lines (HCT-116, A549, Mia-Paca-2, and MCF-7), and compound 6 inhibited the HCT-116 cells with an IC50 of 5.0 ± 0.08 μM.

Divergent Synthesis and Biological Evaluation of 2,6-Disubstituted Tetrahydropyran-Containing Natural Products: Parvistone E, Goniothalesdiol A, 6-epi-Goniothalesdiol A, and 8-epi-9-Deoxygoniopypyrone

AbstractThe concise and efficient synthesis of (+)-goniothalesdiol A and (–)-parvistone E (leiocarpin A), as well as the first total syntheses of (–)-6-epi-goniothalesdiol A and (–)-8-epi-9-deoxygoniopypyrone acetate, have been achieved in four or five longest linear steps based on the chiron approach. The potential biological activities of four 2,6-disubstituted tetrahydropyran-containing natural products were explored based on a panel of human cancer cell lines, BV-2 microglia and 3T3-L1 preadipocytes. Our results indicate that these four natural products display significant adipogenic activity in 3T3-L1 preadipocytes, but do not have clear effects on cancer cell proliferation or LPS stimulated microglia activation.

Ru(OAc)3-Catalyzed Regioselective Difunctionalization of Alkynes: Access to (E)-2-Bromo-1-alkenyl Sulfonates.

A new approach is proposed for the divergent and regioselective synthesis of (E)-2-bromo-1-phenylvinyl trifluoromethanesulfonates through alkyne difunctionalization by employing a compatible system of abundantly available alkynes, N-bromosuccinimide (NBS), and trimethylsilyl trifluoromethanesulfonate (TMSOTf) catalyzed by ruthenium(III) acetate [Ru(OAc)3]. It is a novel method for the preparation of vinyl triflate and it offers a fundamental basis for the development of advanced functional compounds, including drugs and organic functional materials. Unlike previously reported methods, the proposed protocol can tolerate a broad range of functional groups. Alkynes derived from bioactive molecules, such as l(-)-borneol, demonstrate the potential value of this new reaction in organic synthesis.

Chemoselective and Divergent Synthesis of Chlorohydrins and Oxaheterocycles via Ir-Catalyzed Asymmetric Hydrogenation.

Chlorohydrins and oxaheterocycles are synthetically valuable building blocks for diverse natural products and therapeutic substances. A highly efficient Ir/f-phamidol-catalyzed asymmetric hydrogenation of ω-chloroketones was successfully developed, and various chlorohydrins and oxaheterocycles were obtained divergently with excellent yields and enantioselectivities (up to >99% yield and >99% ee). Synthetic utilities of this divergent transformation were demonstrated by gram-scale synthesis of key intermediates of several enantiomerically enriched drugs via this catalytic methodology.

Total Synthesis of Metaphanine and Oxoepistephamiersine

AbstractHerein, we report a concise and divergent synthesis of the complex hasubanan alkaloids metaphanine and oxoepistephamiersine from commercially available and inexpensive cyclohexanedione monoethylene acetal. Our synthesis features a palladium‐catalyzed cascade cyclization reaction to set the tricyclic carbon framework of the desired molecules, a regioselective Baeyer–Villiger oxidation followed by a MeNH2 triggered skeletal reorganization cascade to construct the benzannulated aza[4.4.3]propellane, and a strategically late‐stage regio‐/diastereoselective oxidative annulation of sp3 C−H bond to form the challenging THF ring system and hemiketal moiety in a single step. In addition, a highly enantioselective alkylation of cyclohexanedione monoethylene acetal paved the way for the asymmetric synthesis of target molecular.

Copper-Promoted Intramolecular Oxidative Dehydrogenation for Synthesizing Dihydroisocoumarins and Isocoumarins.

Isocoumarins and dihydroisocoumarins are important skeletons with a wide range of biological activities, such as anti-bacterial, anti-allergy, anti-fungal, anti-tumor, and anti-HIV properties. Herein, we demonstrated divergent syntheses of isocoumarins and 3,4-dihydroisocoumarins by intramolecular dehydrogenative cyclization of 2-(3-oxobutyl) benzoic acids. This transformation undergoes Csp3-H bonds and O-H bonds coupling in air using copper salt. The reactions may undergo free radical process.

Iron‐Catalyzed Transfer Hydrogenation: Divergent Synthesis of Quinolines and Quinolones from ortho‐Nitrobenzyl Alcohols

AbstractHerein, we report the divergent synthesis of quinolines and quinolones via a transfer hydrogenative condensation of ortho‐nitrobenzyl alcohols in one step. The reaction proceeded using the cyclopentadienone iron complex without any additional redox reagents. After transfer hydrogenation between ortho‐nitrobenzyl alcohols and secondary alcohols, the subsequent Friedländer annulation affords polysubstituted quinoline products in 22–90% (39 examples). The developed method was also applied to synthesize quinolones by using primary alcohols instead of secondary alcohols (12 examples). The obtained quinoline products were converted into several drug candidates to demonstrate its synthetic potential.

Total Synthesis of Metaphanine and Oxoepistephamiersine.

Herein, we report a concise and divergent synthesis of the complex hasubanan alkaloids metaphanine and oxoepistephamiersine from commercially available and inexpensive cyclohexanedione monoethylene acetal. Our synthesis features a palladium-catalyzed cascade cyclization reaction to set the tricyclic carbon framework of the desired molecules, a regioselective Baeyer-Villiger oxidation followed by a MeNH2 triggered skeletal reorganization cascade to construct the benzannulated aza[4.4.3]propellane, and a strategically late-stage regio-/diastereoselective oxidative annulation of sp3 C-H bond to form the challenging THF ring system and hemiketal moiety in a single step. In addition, a highly enantioselective alkylation of cyclohexanedione monoethylene acetal paved the way for the asymmetric synthesis of target molecular.

Sustainable Syntheses of Paracetamol and Ibuprofen from Biorenewable β-pinene.

Scalable processes have been developed to convert β-pinene into 4-isopropenylcyclohexanone which is then used as a feedstock for the divergent synthesis of sustainable versions of the common painkillers, paracetamol and ibuprofen. Both synthetic routes use Pd(0) catalysed reactions to aromatise the cyclohexenyl rings of key intermediates to produce the benzenoid ring systems of both drugs. The potential of using bioderived 4-hydroxyacetophenone as a drop-in feedstock replacement to produce sustainable aromatic products is also discussed within a terpene biorefinery context.

Tunable Synthesis of Monofluoroalkenes and Gem-Difluoroalkenes via Solvent-Controlled Rhodium-Catalyzed Arylation of 1-Bromo-2,2-difluoroethylene.

Divergent synthesis of fluorine-containing scaffolds starting from a suite of raw materials is an intriguing topic. Herein, we report the solvent-controlled rhodium-catalyzed tunable arylation of 1-bromo-2,2-difluoroethylene. The selection of the reaction solvents provides switchable defluorinated or debrominated arylation from readily available feedstock resources (both arylboronic acids/esters and 1-bromo-2,2-difluoroethylene are commercially available). This switch is feasible because of the difference in coordination ability between the solvent (CH2 Cl2 or CH3 CN) and the rhodium center, resulting in different olefin insertion. This protocol allows the convenient synthesis of monofluoroalkenes and gem-difluoroalkenes, both of which are important scaffolds in the fields of medicine and materials. Moreover, this newly developed solvent-regulated reaction system can be applied to the site-selective dechlorinated arylation of trichloroethylene. Overall, this study provides a useful strategy for the divergent synthesis of fluorine-containing scaffolds and provides insight into the importance of solvent selection in catalytic reactions.

Tunable Synthesis of Monofluoroalkenes and Gem‐Difluoroalkenes via Solvent‐Controlled Rhodium‐Catalyzed Arylation of 1‐Bromo‐2,2‐difluoroethylene

AbstractDivergent synthesis of fluorine‐containing scaffolds starting from a suite of raw materials is an intriguing topic. Herein, we report the solvent‐controlled rhodium‐catalyzed tunable arylation of 1‐bromo‐2,2‐difluoroethylene. The selection of the reaction solvents provides switchable defluorinated or debrominated arylation from readily available feedstock resources (both arylboronic acids/esters and 1‐bromo‐2,2‐difluoroethylene are commercially available). This switch is feasible because of the difference in coordination ability between the solvent (CH2Cl2 or CH3CN) and the rhodium center, resulting in different olefin insertion. This protocol allows the convenient synthesis of monofluoroalkenes and gem‐difluoroalkenes, both of which are important scaffolds in the fields of medicine and materials. Moreover, this newly developed solvent‐regulated reaction system can be applied to the site‐selective dechlorinated arylation of trichloroethylene. Overall, this study provides a useful strategy for the divergent synthesis of fluorine‐containing scaffolds and provides insight into the importance of solvent selection in catalytic reactions.