Cyclization Sequence Research Articles

Rh(III)-Catalyzed C-H Activation and [4+1+1] Sequential Cyclization Cascade to Give Highly Fused Indano[1,2-b]azirines.

A Rh(III)-catalyzed C-H activation of α-keto oximes and a cyclization cascade with diazo compounds were developed to construct the highly fused indano[1,2-b]azirine frameworks in good yields with a broad range of substrates under mild reaction conditions. More intriguingly, a [4+1+1] sequential annulation cascade is demonstrated for the first time in this reaction and opened a new reaction mode for α-keto oximes. These fused indano[1,2-b]azirine derivatives could also be further transformed into intriguing privileged drug scaffolds.

Base-Promoted 5-exo-dig Cyclization of o-Alkynylamides or 2-En-4-ynamides with CO2 toward Fully Substituted Acrylates.

A base-promoted sequential cyclization and carboxylation of o-alkynylamides or 2-en-4-ynamides with CO2 has been achieved with high efficiency, stereoselectivity, and regioselectivity. This approach begins with 5-exo-dig cyclization followed by trapping the resulting vinyl anion with CO2 and MeI, which provides a convenient access to diverse cyclic and fully substituted acrylates with CO2 as the carboxylic source.

Intrinsically unidirectional chemically fuelled rotary molecular motors.

Biological systems mainly utilize chemical energy to fuel autonomous molecular motors, enabling the system to be driven out of equilibrium1. Taking inspiration from rotary motors such as the bacterial flagellar motor2 and adenosine triphosphate synthase3, and building on the success of light-powered unidirectional rotary molecular motors4-6, scientists have pursued the design of synthetic molecular motors solely driven by chemical energy7-13. However, designing artificial rotary molecular motors operating autonomously using a chemical fuel and simultaneously featuring the intrinsic structural design elements to allow full 360° unidirectional rotary motion like adenosine triphosphate synthase remains challenging. Here we show that a homochiral biaryl Motor-3, with three distinct stereochemical elements, is a rotary motor that undergoes repetitive and unidirectional 360° rotation of the two aryl groups around a single-bond axle driven by a chemical fuel. It undergoes sequential ester cyclization, helix inversion and ring opening, and up to 99% unidirectionality is realized over the autonomous rotary cycle. The molecular rotary motor can be operated in two modes: synchronized motion with pulses of a chemical fuel and acid-base oscillations; and autonomous motion in the presence of a chemical fuel under slightly basic aqueous conditions. This rotary motor design with intrinsic control over the direction of rotation, simple chemical fuelling for autonomous motion and near-perfect unidirectionality illustrates the potential for future generations of multicomponent machines to perform mechanical functions.

Synthesis of o-Carborane-Fused Pyrazoles through Sequential C-N Bond Formation.

Transition-metal-free synthetic method for o-carborane-fused pyrazoles as a new scaffold has been developed from the reaction of B(4)-acylmethyl or B(3,5)-diacylmethyl o-carborane with 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (ADMP) in the presence of DBU in acetonitrile through sequential diazotization and cyclization reaction in one pot, consequently allowing twofold C-N bond formation under extremely mild conditions and high functional group tolerance.

Rhodium(III)-Catalyzed Sequential Cyclization of N-Boc Hydrazones with Propargylic Monofluoroalkynes via C-H Activation/C-F Cleavage for the Synthesis of Spiro[cyclobutane-1,9'-indeno[1,2-a]indenes

An effective rhodium(III) catalysis for the construction of valuable tetracyclic compounds is described herein. This domino process involving the C-H activation/[3 + 2] annulation/intramolecular Friedel-Crafts reaction sequences of simple and readily available N-Boc hydrazones and propargylic monofluoroalkynes afforded fused tetracyclic spiro[cyclobutane-1,9'-indeno[1,2-a]indenes] in moderate to good yields, featuring three C-C bond formation. Moreover, control experiments indicated that the C-H activation might be involved in the rate-determining step.

Zinc Aluminate (ZnAl2O4) Supported and Catalyzed Highly Effective Sonogashira Cross-Coupling and Cyclization Reaction Under Microwave Irradiation Used in One-Pot Tandem Synthesis of Furo[3,2-H]Quinolines

The Sonogashira reaction (SR) which forms a C–C bond by cross-coupling a vinyl/aryl halide with a terminal alkyne, uses a palladium species as a catalyst, with a copper species as co-catalysts and a phosphine/amine as ligand/base in its actual form. This efficient reaction is beneficial in synthesizing heterocycles, nanomaterials, medicines and other complex molecules with biological functions. However, in this study, we were able to successfully execute the SR under microwave irradiation, using zinc aluminate (ZnAl2O4) as the catalyst, without using palladium, phosphines/amine as a ligand/base. This method, therefore, particularly useful for adhering to green chemistry principles and achieving atom-friendly reaction. In order to do this, we adopted a straightforward and concise method involving the development of a convergent protocol for sequential coupling and cyclization from Acetylenic 8-quinolinols generated in situ by the microwave-assistance SR to synthesize furo[3,2-h]quinolines, using ZnAl2O4 as a catalyst.

Asymmetric Total Synthesis of (-)-Phaeocaulisin A.

The therapeutic properties of Curcuma (ginger and turmeric’s family) have long been known in traditional medicine. However, only recently have guaiane-type sesquiterpenes extracted from Curcuma phaeocaulis been submitted to biological testing, and their enhanced bioactivity was highlighted. Among these compounds, phaeocaulisin A has shown remarkable anti-inflammatory and anticancer activity, which appears to be tied to the unique bridged acetal moiety embedded in its tetracyclic framework. Prompted by the promising biological profile of phaeocaulisin A and by the absence of a synthetic route for its provision, we have implemented the first enantioselective total synthesis of phaeocaulisin A in 17 steps with 2% overall yield. Our route design builds on the identification of an enantioenriched lactone intermediate, tailored with both a ketone moiety and a conjugated alkene system. Taking advantage of the umpolung carbonyl-olefin coupling reactivity enabled by the archetypal single-electron transfer (SET) reductant samarium diiodide (SmI2), the lactone intermediate was submitted to two sequential SmI2-mediated cyclizations to stereoselectively construct the polycyclic core of the natural product. Crucially, by exploiting the innate inner-sphere nature of carbonyl reduction using SmI2, we have used a steric blocking strategy to render sites SET-unreceptive and thus achieve chemoselective reduction in a complex substrate. Our asymmetric route enabled elucidation of the naturally occurring isomer of phaeocaulisin A and provides a synthetic platform to access other guaiane-type sesquiterpenes from C. phaeocaulis—as well as their synthetic derivatives—for medicinal chemistry and drug design.

Synthesis of Trifluoromethylated 4H‐1‐Benzopyran Derivatives via Photocatalytic Trifluoromethylation/Oxidation/Conjugate Addition, and Cyclization Sequences of Vinyl Phenols

AbstractThe objective of this study was to describe a cyclization reaction of photoredox generated ortho‐quinone methides using 1,3‐diketones for the synthesis of trifluoromethylated 4H‐1‐benzopyrans with moderate to high yields. This process resulted in in situ formation of trifluoromethylated ortho‐quinone methides from 2‐vinyl phenols with Umemoto's reagent, followed by conjugate addition and cyclization reaction of 1,3‐diketones.

One-Pot Synthesis of Cyclopentenols from Vinylethylene Carbonates via Palladium-Catalyzed Decarboxylative Allylation and Cascade Oxidation-Cyclization

Abstract An efficient, one-pot protocol for the synthesis of highly functionalized cyclopentenols has been accomplished starting from vinylethylene carbonates and bissulfonylmethanes. This protocol proceeds via sequential palladium-catalyzed decarboxylative allylation and oxidative cyclization in an operationally simple manner. A wide range of substrates is well-accommodated to afford diverse cyclopentenols in moderate to good yields with excellent selectivity. Further control experiments demonstrated that the selective formation of the isolatable (Z)-allyl alcohols (up to Z/E = >19:1) underlies the success of the subsequent cascade oxidation-cyclization.

Electrochemical bromolactonization of alkenoic acids with carbon tetrabromide: Synthesis of bromomethylated γ-lactones

Electrochemical radical bromination and cyclization sequences of alkenoic acids developed in this study. This approach is environmental-friendly by using carbon tetrabromide as a bromine radical precursor. The electrochemical protocol offers a facile way to prepare bromomethylated γ-lactones derivatives in moderate to high yields.

Investigating flaviviral genomic cyclization

Japanese Encephalitis Virus (JEV) belongs to the viral family Flaviviridae, transmitted through competent mosquito vectors. JEV is responsible for ∼68,000 clinical cases each year; 25% result in death, while 20-30% of survivors have resultant neurological sequelae. This family includes many other deadly viruses such as Zika, Dengue, and West Nile. Studies have shown, and others theorized that flavivirusesundergo long-range 5' - 3' terminal region (TR) interactions mediated by a complementary cyclization sequence.

Exploring the chemistry of E/Z configuration in gold-catalyzed domino cyclization: Insights on the stereoselectivity

The mechanism and origins of Z/E configuration selectivity of gold-catalyzed domino cyclization were computationally investigated. The influence of the nature of the different substitutions present in the gold catalyst on the Z/E selectivity is investigated. The Z/E configuration selectivity involved in two processes: initial spirocyclization and hydroamination. The spirocyclization step represents the rate-determining step. Computational results indicated a strong energetic preference for Z configuration based on transition states analysis, which provided hints for further developments of new templates. This quantitatively analyzed model would be helpful in understanding and tuning the conformation preference in sequential cyclization to construct chiral center.

Synthesis of 2‐Benzyl‐3,4‐dihydronaphthalenes via Oxidative Radical Opening/Cyclization of Methylenecyclopropanes with Potassium Benzyltrifluoroborates

AbstractA Copper‐catalyzed benzylation of methylenecyclopropanes with potassium benzyltrifluoroborate salts has been developed to produce 2‐benzyl‐3,4‐dihydronaphthalenes in moderate to good yields. This oxidative cyclization reaction proceeds well via a sequence of radical addition, ring‐opening, and cyclization. This protocol represents a new example of methylenecyclopropane oxidative cyclization and tolerates a diverse range of substrate.

Mn(iii)-Catalyzed cascade cyclization reaction ofo-acyl aromatic isocyanides with boronic acids

A Mn(iii)-catalyzed cascade cyclization of o-acyl aromatic isocyanides with boronic acids was examined to give a series of 3-hydroxyindolenines in single-step. This cascade process involved a transmetalation/nucleophilic addition/intramolecular cyclization sequence.

Difluorodiazoethane as a masked acetylene equivalent in formal [3 + 2] cycloadditions with ketones to access 2,3-functionalized furans

A transition-metal-free [3+2] cycloaddition of CF2HCHN2 with β-ketones is reported, which enables the synthesis of 2,3-functionalized furans. Sequential defluorination, nucleophilic addition, and cyclization are key elemental steps of the reaction.

Efficient Synthesis of Isoquinoline Derivatives through Sequential Cyclization–Deoxygenation Reaction of 2-Alkynylbenzaldoximes

AbstractWe describe a novel, simple, robust, and efficient cyclization/deoxygenation approach for the synthesis of functionalized isoquinoline derivatives. Over the course of continued studies on o-alkynylbenzaldoxime cyclization reactions, the formation of cyclic nitrones through 6-endo-dig cyclization was achieved using silver triflate or bromine as an electrophile, and subsequently, the deoxygenation process was carried out in the presence of CS2 in good to high yields.

Transformation of Crowded Oligoarylene into Perylene-Cored Chiral Nanographene by Sequential Oxidative Cyclization and 1,2-Phenyl Migration.

Synthetic innovation for constructing sophisticated nanographenes is of fundamental significance for a variety of advanced applications. Herein, we report a distinctive method to prepare π-extended chiral nanographenes with 29 benzenoid rings and two helical breaches from a highly crowded perylene-cored oligoarylene precursor. Under Scholl's conditions, the reaction predominantly involves the regioselective and sequential cyclization in the peri- and bay regions of the perylene core, and the complanation of the 1-phenyl[5]helicene intermediate module via 1,2-phenyl migration. The resulting chiral nanographenes are configurationally stable at 180 °C due to the high diastereomerization barriers of ca. 45 kcal mol-1 . These molecules also possess globally delocalized π-systems with low HOMO/LUMO gaps, leading to nearly panchromatic absorption, intensive electronic circular dichroism signals and deep-red circularly polarized luminescence.

Transformation of Crowded Oligoarylene into Perylene‐Cored Chiral Nanographene by Sequential Oxidative Cyclization and 1,2‐Phenyl Migration

AbstractSynthetic innovation for constructing sophisticated nanographenes is of fundamental significance for a variety of advanced applications. Herein, we report a distinctive method to prepare π‐extended chiral nanographenes with 29 benzenoid rings and two helical breaches from a highly crowded perylene‐cored oligoarylene precursor. Under Scholl's conditions, the reaction predominantly involves the regioselective and sequential cyclization in the peri‐ and bay regions of the perylene core, and the complanation of the 1‐phenyl[5]helicene intermediate module via 1,2‐phenyl migration. The resulting chiral nanographenes are configurationally stable at 180 °C due to the high diastereomerization barriers of ca. 45 kcal mol−1. These molecules also possess globally delocalized π‐systems with low HOMO/LUMO gaps, leading to nearly panchromatic absorption, intensive electronic circular dichroism signals and deep‐red circularly polarized luminescence.

Rapid Construction of Hexacyclic Indolines via the Ru(II)-Catalyzed C-H Activation Initiated Cascade Cyclization of Phenidones with Enynones.

A highly efficient cascade cyclization of phenidones and enynones has been developed via a Ru(II)-catalyzed C-H activation initiated indole formation/Diels-Alder reaction/iminium ion cyclization sequence, which afforded hexacyclic indolines as single diastereomer in good to excellent yields with a broad substrate scope under mild conditions. The reaction features the simultaneous generation of five new chemical bonds and four new rings in one pot, providing a rapid and concise approach toward polycyclic indoline alkaloids and their analogues.

An efficient synthesis of 6‐arylpyrazolo[4′,3′:4,5]pyrimido[2,1‐a] isoquinolin‐8(9H)‐one derivatives catalyzed by AgOTf

AbstractA new AgOTf‐catalyzed domino reaction of 2‐alkynylbenzaldehyde and 4‐amino‐1‐methyl‐3‐propyl‐1H‐pyrazole‐5‐carboxamide has been reported via a sequential condensation, cyclization, and acetylenic hydroamination process. The developed protocol provides an efficient and modular access to a range of new fused tetracyclic heterocycle 6‐aryl‐9‐methyl‐11‐propyl pyrazolo[4′,3′:4,5]pyrimido[2,1‐a]isoquinolin‐8(9H)‐ones with two new rings in good yields.