Polycyclic Scaffolds Research Articles

Recent Developments in Transannular Reactions

AbstractTransannular reactions have shown a remarkable performance for the construction of polycyclic scaffolds from medium- or large-sized cyclic molecules in an unconventional manner. Recent examples of transannular reactions reported from 2011 have been reviewed, emphasizing the excellent performance of this approach when accessing the target compounds. This review also highlights how this methodology provides an alternative approach to other commonly used strategies for the construction of cyclic entities such as cyclization or cycloaddition reactions.1 Introduction2 Transannular Cycloadditions and Electrocyclizations3 Transannular Conjugate Additions4 Transannular 1,2-Addition to Ketones, Imines, Esters, and Amides5 Transannular Reactions via Electrophilic Activation of Olefins6 Transannular Ring-Opening of Epoxides7 Transannular Alkylations of Enolates and Related Species8 Miscellaneous Transannular Reactions9 Concluding Remarks

Inducing Curvature to Pyracylene upon π-Expansion.

We disclose a successive π‐expansion of pyracylene towards boat‐shaped polycyclic scaffolds. The unique structural features of the resulting compounds were revealed by X‐ray crystallographic analysis. Depending on the extent of π‐expansion the compounds display intense bathochromically shifted absorption bands in their UV/Vis spectra and are prone to several redox events as documented by cyclic voltammetry. The experimental observations are in line with the computational studies based on density functional theory, suggesting progressive narrowing of the HOMO–LUMO gap and distinct evolution of the electronic structure and aromaticity.

Aza-Ortho-Quinone Methides as Reactive Intermediates: Generation and Utility in Contemporary Asymmetric Synthesis.

The aza-ortho-quinone methide (aza-o-QM) chemistry has overwhelmingly progressed in the past few decades. This review aims to integrate various transition metal-catalyzed and organocatalytic strategies in taming aza-o-QM intermediates, including the aza-ortho-vinylidene quinone methide (aza-o-VQM), aza-ortho-alkynyl quinone methide (aza-o-AQM), aza-para-quinone methide (aza-p-QM), and indole-based aza-o-QM analog. These transient species are often utilized for the direct and enantioselective synthesis of complex (hetero)polycyclic or fused-ring molecular scaffolds such as tetrahydroquinoline and indoline, among others, which are abundant in many natural products, bioactive compounds, and pharmaceuticals.

Exploring the Acid-Catalyzed Reactions of 10,11-Epoxy-Dibenzo[a,d]cycloheptan-5-ol as the Synthetic Modules toward Polycyclic Aromatic Scaffolds.

The structural diversity of polycyclic aromatic hydrocarbons (PAHs) offers exciting opportunities for their applications. Yet, selective synthesis of such conjugated networks poses a formidable challenge. Compared to the prominence of transition-metal-catalyzed cross-coupling and oxidative Scholl reactions, cationic rearrangement in the synthesis of polycyclic aromatic hydrocarbon is an underexplored subject. In this study, we reveal that cationic intermediate generated from epoxy dibenzocycloheptanol can be transformed into acenes, azulene-embedded PAHs, and dibenzocycloheptanone derivatives. Reactive patterns, including Meinwald rearrangement, Nazarov cyclization, transannular aryl migration, and transannular Friedel–Crafts cyclization were identified. Both substrate structures and reaction temperature affect the reaction pathways in predictable and manageable manners. A mechanistic scheme was postulated as the working model to guide the reactivity for further application. Substrates containing heterocyclic and ferrocenyl groups exhibit similar reactivity profiles. The inquiry culminates in the selective synthesis of 5, 7, 12, 14-tetrasubstituted C2h and C2v pentacene derivatives. Our results demonstrate that polycyclic aromatic hydrocarbons can be selectively prepared with this cation-initiated strategy by methodically tuning the reactivity.

Palladium-Catalyzed Access to Benzocyclobutenone-Derived Ketonitrones via C(sp2)-H Functionalization.

The palladium-catalyzed C(sp2)–H functionalization of bromoaryl aldonitrones leading to benzocyclobutenone-derived ketonitrones is described. This method allows for the preparation of a wide range of strained, four-membered ketonitrones with broad functional group tolerance. Downstream transformations of the formed products were readily demonstrated, illustrating the synthetic utility of the obtained benzocyclobutenone-derived nitrones for the construction of polycyclic nitrogen-containing scaffolds.

Dearomative Iodocyclization of N-(o-Alkynyl)aryl Isoindole.

We present a dearomative iodocyclization of N-(o-alkynyl)aryl isoindole here, which affords various biologically active benzoindoleazine skeletons containing alkenyl iodine. The products can further undergo cycloaddition or coupling reactions to afford a series of highly functionalized N-fused polycyclic scaffolds.

Highly Stereoselective Ugi/Pictet-Spengler Sequence.

Discovering novel synthetic routes for rigid nitrogen-containing polyheterocycles using sustainable, atom-economical, and efficient (= short) synthetic pathways is of high interest in organic chemistry. Here, we describe an operationally simple and short synthesis of the privileged scaffold dihydropyrrolo[1,2-a]pyrazine-dione from readily accessible starting materials. The alkaloid-type polycyclic scaffold with potential bioactivity was achieved by a multicomponent reaction (MCR)-based protocol via a Ugi four-component reaction and Pictet–Spengler sequence under different conditions, yielding a diverse library of products.

Rapid Access to Multisubstituted Acrylamides from Cyclic Ketones via Palladium/Norbornene Cooperative Catalysis

AbstractA strategy to access diverse multisubstituted acrylamides from cyclic ketones is realized via palladium/norbornene‐catalyzed α‐carbamoylation and ipso‐functionalization of the corresponding enol triflates. The development of bulky C2 secondary amide‐substituted norbornene cocatalysts is the key to achieve the desired reactivity and selectivity. Readily available carbamoyl chlorides serve as effective electrophiles; various moieties including alkenyl, hydrogen, alkynyl, aryl, and alkyl groups can be installed at the ipso position. In addition, tandem α‐carbamoylation/ipso‐annulations are demonstrated to furnish lactam‐containing polycyclic scaffolds. The utility of this method is exemplified in the streamlined preparation of a platelet‐activating factor (PAF)‐antagonist.

Rapid Access to Multisubstituted Acrylamides from Cyclic Ketones via Palladium/Norbornene Cooperative Catalysis.

A strategy to access diverse multisubstituted acrylamides from cyclic ketones is realized via palladium/norbornene-catalyzed α-carbamoylation and ipso-functionalization of the corresponding enol triflates. The development of bulky C2 secondary amide-substituted norbornene cocatalysts is the key to achieve the desired reactivity and selectivity. Readily available carbamoyl chlorides serve as effective electrophiles; various moieties including alkenyl, hydrogen, alkynyl, aryl, and alkyl groups can be installed at the ipso position. In addition, tandem α-carbamoylation/ipso-annulations are demonstrated to furnish lactam-containing polycyclic scaffolds. The utility of this method is exemplified in the streamlined preparation of a platelet-activating factor (PAF)-antagonist.

Structure simplification of the Securinine skeleton reveals the importance of BCD ring system for the cytotoxic activity on HCT116 and HL60 cell lines

Function-oriented molecular editing of the polycyclic scaffold of securinine led to the preparation of a library of simplified analogs that have been evaluated for their cytotoxicity potential against HCT116 and HL60 human cell lines. Chemical diversity at the C14 position (securinine numbering) was generated through the site-selective γ-iodination followed by Pd-catalyzed Sonogashira and Suzuki-Miyaura reactions. To explain the selectivity in the iodination step, a reaction mechanism has been proposed. Surprisingly, the piperidine ring (ring A) of the securinine skeleton has been found to be irrelevant for the cytotoxic activity. Based on this finding, the pharmacophoric core of securinine could be simplified to the key BCD motif. The nature of the substituent at the nitrogen can vary from a methyl or an isobutyl group to a benzyl or a carbamate moiety. Interestingly, the N-benzyl substituted simplified analog exhibited the same cytotoxic activity as the parent compound securinine. This functional group tolerance paves the way for the installation of reactive handles for the synthesis of molecular probes for target identification.

Synthesis and biological evaluation of N-alkyl sulfonamides derived from polycyclic hydrocarbon scaffolds using a nitrogen-centered radical approach.

Polycyclic hydrocarbons (PH) provide intriguing potential as lipophilic scaffolds within medicinal chemistry, but are currently limited by the availability of synthetic tools for predictable modification of the PH unit. Herein we report the development of new methods for installation of a sulfonamide unit to PH cores. In the first method, a xanthate ester serves as reagent for aminosulfonation using pre-formed imidoiodinane as N-source. An investigation of the reaction mechanism was performed to implicate a process involving a N-centered radical. An additional method for sulfonamide installation is described that involves the use of commercially available reagents and operationally convenient conditions. Using the new synthetic methods, 22 compounds were prepared and screened for biological activity against 6 mammalian cell lines along with Gram-positive and Gram-negative bacterial strains. Results of the viability assays have identified compounds that exhibit higher potency than other known anticancer agents such as indisulam and ABT-751. Additionally, the physicochemical and drug-likeness properties of the synthesized compounds have been determined experimentally and using in silico predictive tools. The initial exploration into sulfonamide insertion into PH cores has resulted in a number of compounds that warrant further development to produce molecules with therapeutic value.

Diastereoselective intramolecular cyclization/Povarov reaction cascade for the one-pot synthesis of polycyclic quinolines.

The method for the synthesis of complex alkaloid-like aza-heterocycles has been developed through the Povarov reaction of in situ generated 2-oxoimidazolium cations. The reaction lead to the formation of 2 C-N, 2 C-C bonds and three stereocentres, and features excellent regio- and diastereoselectivity. Based on the controlled experiments and quantum chemistry data, the mechanism of the reaction cyclization was proposed and diastereoselectivity origins were rationalized. Additionally, a straightforward synthesis of hardly accessible 4,4'-bi(imidazol-2-one) derivatives has been achieved using the same methodology.

Palladium-catalyzed direct construction of oxazoline-containing polycyclic scaffolds via tandem addition/cyclization of nitriles and arylboronic acids

An efficient construction of oxazoline-containing polycyclic scaffolds through a Pd-catalyzed addition/cyclization of (hetero)arene tethered O-acyl cyanohydrin units and arylboronic acids is described.

Synthesis of chiral polycyclic N-heterocycles via gold(i)-catalyzed 1,6-enyne cyclization/intramolecular nucleophilic addition

A gold(i)-catalyzed synthesis of highly functionalized nitrogen-containing polycyclic scaffolds was developed (up to 92% yield and 93% ee).

Theoretical studies on cycloaddition reactions of N-allyl substituted polycyclic Isoindole-1,3-dione with nitrones and nitrile oxides

Bridged polycyclic molecular skeletons and related systems are key structural motifs in medicinal chemistry. The most efficient and widely accepted method for the syntheses of the bridged molecular polycyclic scaffolds is the 1,3-dipolar cycloaddition reactions. Herein, a systematic study on (3 + 2) cycloaddition reaction (32CA) of norbornene imide A with three-atom components (TACs), nitrile oxides and nitrones are presented at the M06-2X/6–311++G(d,p)-PCM(toluene), M06-2X-D3/6–311++G(d,p)-PCM(toluene) and MPWB1K/6–311++G(d,p)-PCM(toluene) levels of theory. The different reactivities of the strained endocyclic CC bond in the carbocyclic fragment and the less hindered N-allyl imide double bond in the alkene are evaluated. In the reaction of A and the nitrile oxides, four reaction pathways are characterized whereas eight distinctive reactive channels are located for nitrones. Trends in the calculated activation energies show that the 32CA reaction between A and nitrile oxides competitively occur at the endocyclic CC bond in the carbocyclic fragment and the N-allyl imide double bond. The cycloaddition of the nitrones favorably add across the less hindered N-allyl imide double bond. The trends in reactivity are in perfect agreement with local reactivity descriptors. Evaluation of TS geometries and bond distances validate that these 32CA reactions follow a one-step asynchronous molecular mechanism as proposed by Domingo. The activation energies suggest favored exo approach along all the reaction pathways, for that leads to better stabilization. Frontier molecular orbital analysis and global reactivity descriptors demonstrate that all the 32CA reactions proceed via an inverse electron demand character. Results from the local electrophilic (PK+) and nucleophilic (PK-) Parr functions show that the 32CA takes place at the atomic centers with the largest radical atomic spin densities in complete agreement with experimental outcomes.

Divergent and Modular Synthesis of Terpenoid Scaffolds via a AuI Catalyzed One-Pot Cascade.

A one-pot cascade sequence to generate synthetically challenging polycyclic scaffolds is reported utilizing a novel Lewis acid gold catalyst for the key cyclization step, enabling the divergent synthesis of both 6,6,5-tricyclic and 6,6,6,5-tetracyclic cores through both ligand and reaction condition control. We have combined the intrinsic complexity and stereoselectivity of cycloadditions with the electronic and steric properties of gold complexes to selectively generate complex polycyclic scaffolds in a single operation.

Divergent and Modular Synthesis of Terpenoid Scaffolds via a AuI Catalyzed One‐Pot Cascade

AbstractA one‐pot cascade sequence to generate synthetically challenging polycyclic scaffolds is reported utilizing a novel Lewis acid gold catalyst for the key cyclization step, enabling the divergent synthesis of both 6,6,5‐tricyclic and 6,6,6,5‐tetracyclic cores through both ligand and reaction condition control. We have combined the intrinsic complexity and stereoselectivity of cycloadditions with the electronic and steric properties of gold complexes to selectively generate complex polycyclic scaffolds in a single operation.

Rhodium-Catalyzed Enantioselective and Desymmetrizative Pauson-Khand Reaction: Access to Tricyclo[6.2.1.04,11]undecenes.

Rhodium-catalyzed asymmetric desymmetrization Pauson-Khand reaction of C4-alkynyl-tethered cyclohexadienones has been developed as a novel strategy for access to fused 6-5-5 tricycles bearing three consecutive stereogenic centers. An array of chiral tricyclo[6.2.1.04,11]undecenes have been synthesized in high yields and enantioselectivities in a single step under mild conditions. This strategy employs readily accessible internal-olefin-containing 1,6-enynes, providing a potentially powerful tool for constructing chiral polycyclic scaffolds of complex molecules containing cyclopentenones and cyclohexenones.

Three-Component Difunctionalization of Cyclohexenyl Triflates: Direct Access to Versatile Cyclohexenes via Cyclohexynes.

Difunctionalization of strained cyclic alkynes presents a powerful strategy to build richly functionalized cyclic alkenes in an expedient fashion. Herein we disclose an efficient and flexible approach to achieve carbohalogenation, dicarbofunctionalization, aminohalogenation and aminocarbonation of readily available cyclohexenyl triflates. We have demonstrated the novel use of zincate base/nucleophile system for effective formation of key cyclohexyne intermediates and selective addition of various carbon and nitrogen nucleophiles. Importantly, leveraging the resulting organozincates enables the incorporation of a broad range of electrophilic partners to deliver structurally diverse cyclohexene motifs. The importance and utility of this method is also exemplified by the modularity of this approach and the ease in which even highly complex polycyclic scaffolds can be accessed in one step.

Three‐Component Difunctionalization of Cyclohexenyl Triflates: Direct Access to Versatile Cyclohexenes via Cyclohexynes

AbstractDifunctionalization of strained cyclic alkynes presents a powerful strategy to build richly functionalized cyclic alkenes in an expedient fashion. Herein we disclose an efficient and flexible approach to achieve carbohalogenation, dicarbofunctionalization, aminohalogenation and aminocarbonation of readily available cyclohexenyl triflates. We have demonstrated the novel use of zincate base/nucleophile system for effective formation of key cyclohexyne intermediates and selective addition of various carbon and nitrogen nucleophiles. Importantly, leveraging the resulting organozincates enables the incorporation of a broad range of electrophilic partners to deliver structurally diverse cyclohexene motifs. The importance and utility of this method is also exemplified by the modularity of this approach and the ease in which even highly complex polycyclic scaffolds can be accessed in one step.