Medium-sized Rings Research Articles

Catalytic Asymmetric Synthesis of Inherently Chiral Eight-Membered O-Heterocycles through Cross-[4+4] Cycloaddition of Quinone Methides.

Inherently chiral eight-membered rings embedded in tetraphenylene derivatives and hetero-analogues exhibit unique properties and allow diverse applications. A conceptually viable and straightforward approach to these frameworks is [4+4] cycloaddition, which still remains elusive. In this study, we describe the stereoselective cross-[4+4] cycloaddition of quinone methides (QMs), leading to the formation of oxa-analogues of tetraphenylene with exceptional chemo-, diastereo-, and enantioselectivity. The structures of these novel rigid eight-membered O-heterocycles were explored via single-crystal X-ray diffraction and their stereochemical stability was elaborated through both density functional theory (DFT) calculations and thermal racemization experiments. The developed methodology exhibited broad substrate scope and the resulting cross-[4+4] cycloadducts could be readily transformed into valuable chiral building blocks. Our findings expanded the inherently chiral library of medium-sized rings and also contributed to the advancement of asymmetric cross-[4+4] cycloadditions of quinone methides.

Ring Expansion Reactions via C-N Bond Cleavage in the Synthesis of Medium-sized Cycles and Macrocycles

The literature review discusses and systematizes synthetic approaches to medium-sized cycles and macrocycles based on ring expansion reactions of bi- or polycyclic systems via C-N bond cleavage. Ring expansion reactions of bicyclic ammonium salts proceed via thermal decomposition or the action of strong bases. Bi- or polycyclic systems containing a common amine group can be reduced with strong reducing reagents, e.g. lithium aluminum hydride. Ammonium derivatives are much more prone to nucleophilic attack and quite often are used as starting materials for the synthesis of medium-sized cycles. Bicyclic systems containing a common aminal or amidine group are used for the synthesis of medium-sized rings and macrocycles via cleavage of the endocyclic C-N bond. Various methods of their activation and reduction are discussed in the review.

Cyclization by Intramolecular Suzuki-Miyaura Cross-Coupling-A Review.

Ring systems of all sizes are frequent core or substructures in natural products and they are important elements of many drug molecules, as they often confer high binding affinity to and selectivity for disease-relevant biological targets. A uniform key transformation in the synthesis of such structures is the cyclization step. Among the various approaches that have been developed for ring closure, the intramolecular Suzuki-Miyaura reaction has emerged as a powerful option for the construction of normal- and medium-sized rings as well as macrocycles, due to its stereospecificity, the mild reaction conditions, and the non-toxic nature of the boron by-products. In this review, we summarize the state-of-the-art of the application of intramolecular Suzuki-Miyaura cross-coupling reactions in the construction of (macro)cyclic frameworks of natural products and bioactive molecules of synthetic origin, covering (mostly) examples that have been reported since 2015. Target molecules prepared via intramolecular Suzuki-Miyaura cross-coupling as a key step range from natural products/natural product analogs to synthetic drug candidates, featuring ring sizes from 4 to ≫12. We highlight the utility, scope, and limitations of the reaction for different ring sizes and arrays of functional groups. Where possible, comparisons with other methods of cyclization are provided.

Recent Advance in the Reductive Heck Cyclization for the Formation of Five to Nine Member Rings

Abstract: Palladium-catalyzed reactions are widely used for creating carbon-carbon and carbon-heteroatom bonds, with the Heck reaction being particularly valuable for forming rings of various sizes, including mediumsized rings. Recent reports have shown the synthetic potential of intramolecular Heck reactions for assembling rings of seven or more members. While the regioselectivity of this cyclization is often unpredictable in the absence of directing groups, the reductive Heck cyclization strategy can help minimize this issue. Nickel catalysts are also valuable due to their abundance and environmentally friendly nature, playing a pivotal role in producing biologically significant carbocycles and heterocycles. The use of both Pd(0) and Ni(0) catalysts, with or without chiral ligands, has been successful in forming five to nine-member ring heterocycles and carbocycles in a simple, cost-effective manner. This review provides a comprehensive survey of the literature from the past decade on the use of reductive Heck cyclization methodology, including mechanistic details as needed.

Synthesis of a Library of Terpenoid Alkaloid-Like Compounds Containing Medium-Sized Rings via Reconstruction of the Humulene Skeleton.

The construction of a chemical library based on natural products is a promising method for the synthesis of natural product-like compounds. In this study, we synthesized a terpenoid alkaloid-like compound library based on the humulene skeleton. Our strategy, which enables access to diverse ring systems such as 11-membered monocyclic, oxabicyclic, and medium-sized aza ring-containing scaffolds, involves the introduction of a nitrogen atom, an intermolecular C-O bond formation via Lewis acid-mediated epoxide-opening transannulation, and a ring-reconstruction strategy based on olefin metathesis. A cheminformatics analysis based on their structural and physicochemical properties revealed that the synthesized compounds have high three-dimensionality and high natural product likeness scores but with structural novelty. The usefulness of the terpenoid alkaloid-like compound library for drug discovery and the accessibility to structure-activity relationship studies were validated by performing an assay for osteoclast-specific tartrate-resistant acid phosphatase activity, resulting in the identification of a seed compound for bone-resorptive diseases such as osteoporosis.

Synthesis of Oxa-bridged Medium-Sized Carbocyclic Rings

Abstract: Natural products with oxa-bridged medium-sized carbocyclic ring structure units play an important role in nature. Therefore, developing novel and efficient methods is essential for synthesizing complex natural products containing oxygen-bridged rings. In this article, progress toward the synthesis of oxygen-bridged seven and eight-membered rings is reviewed in terms of the strategies employed.

Enantioselective Synthesis of Oxazocines via MQ-Phos Enabled Palladium-Catalyzed Asymmetric Formal [4+4]-Cycloadditions.

Oxazocines are key structural intermediates in the synthesis of natural products and pharmaceutical molecules. However, the synthesis of oxazocines especially in a highly enantioselective manner, is a long-standing formidable challenge due to unfavorable energetics involved in cyclization. Herein, a series of new PNP-Ligand P-chiral stereocenter is first designed and synthesized, called MQ-Phos, and successfully applied it in the Pd-catalyzed enantioselective higher-order formal [4+4]-cycloaddition of α, β-unsaturated imines with 2-(hydroxymethyl)-1-arylallyl carbonates. The reaction features mild conditions, excellent regio- and enantiocontrol and a broad substrate scope (54 examples). Various medium-sized rings can be afforded in moderate to excellent yields (up to 92%) and excellent enantioselectivity (up to 99% ee). The newly developed MQ-Phos is critical for synthesis of the medium-sized ring in excellent catalytic reactivity and enantioselectivity.

Skeletal Editing of Isatins for Heterocycle Molecular Diversity.

Isatins have been widely used in the preparation of a variety of heterocyclic compounds, where the skeletal editing of isatins has shown significant advantages for the construction of diverse heterocycles. This review highlights the progress made in the last decade (2013-2023) in the skeletal editing of the isatin scaffold. A series of ring expansion reactions for the construction of quinoline skeleton, quinolone skeleton, polycyclic quinazoline skeleton, medium-sized ring skeleton, as well as a series of ring opening reactions for the generation of 2-(azoly)aniline skeleton by the cleavage of C-C bond and C-N bond are highlighted. It is hoped that this review will provide some understanding of the chemical transformations of isatins and contribute to the further realization of its molecular diversity.

Atroposelective synthesis of biaxial bridged eight-membered terphenyls via a Co/SPDO-catalyzed aerobic oxidative coupling/desymmetrization of phenols

Bridged chiral biaryls are axially chiral compounds with a medium-sized ring connecting the two arenes. Compared with plentiful methods for the enantioselective synthesis of biaryl compounds, synthetic approaches for this subclass of bridged atropisomers are limited. Here we show an atroposelective synthesis of 1,3-diaxial bridged eight-membered terphenyl atropisomers through an Co/SPDO (spirocyclic pyrrolidine oxazoline)-catalyzed aerobic oxidative coupling/desymmetrization reaction of prochiral phenols. This catalytic desymmetric process is enabled by combination of an earth-abundant Co(OAc)2 and a unique SPDO ligand in the presence of DABCO (1,4-diaza[2.2.2]bicyclooctane). An array of diaxial bridged terphenyls embedded in an azocane can be accessed in high yields (up to 99%) with excellent enantio- (>99% ee) and diastereoselectivities (>20:1 dr).

Synthetic study of leptosperol A

Leptosperol A, isolated from the leaves of L. scoparium in 2020 together with leptosperol B, possesses a unique 1-benzyl-2-(2-phenylethyl) cyclodecane framework. A synthetic study of leptosperol A was performed based on a retrosynthetic analysis that indicated that leptosperols A and B could be synthesized efficiently via a common intermediate. Our study showed that unexpected transannular reactions easily occurred to give bicyclo [4.4.0] ring systems instead of the desired cyclodecane ring with a diene moiety. The results communicated here offers useful information to organic chemists involved in medium-sized ring systems.

Synthesis of Seven- and Eight-Membered Rings by a Brønsted Acid Catalyzed Cationic Carbocyclization of Biphenyl Embedded Enynes.

A Brønsted acid catalyzed cyclization of o-alkenyl-o'-alkynylbiaryls for the synthesis of biologically relevant dibenzo-fused medium-sized rings has been developed. The outcome of the cyclization is determined by the nature of the substituent at the alkyne, with arenes favoring seven-membered rings and alkyl substituents producing eight-membered rings. These reactions proceed via a vinyl cation, which is captured by water and, notably, by C-nucleophiles, such as electron-rich (hetero)arenes.

Medium-Sized Ring Expansion Strategies: Enhancing Small-Molecule Library Development.

The construction of a small molecule library that includes compounds with medium-sized rings is increasingly essential in drug discovery. These compounds are essential for identifying novel therapeutic agents capable of targeting "undruggable" targets through high-throughput and high-content screening, given their structural complexity and diversity. However, synthesizing medium-sized rings presents notable challenges, particularly with direct cyclization methods, due to issues such as transannular strain and reduced degrees of freedom. This review presents an overview of current strategies in synthesizing medium-sized rings, emphasizing innovative approaches like ring-expansion reactions. It highlights the challenges of synthesis and the potential of these compounds to diversify the chemical space for drug discovery, underscoring the importance of medium-sized rings in developing new bioactive compounds.

Chemoenzymatic tandem cyclization for the facile synthesis of bicyclic peptides

Bicyclic peptides exhibit improved metabolic stabilities and target specificities when compared to their linear or mono-cyclic counterparts; however, efficient and straightforward synthesis remains challenging due to their intricate architectures. Here, we present a highly selective and operationally simple one-pot chemoenzymatic tandem cyclization approach to synthesize bicyclic peptides with small to medium ring sizes. Penicillin-binding protein-type thioesterases (PBP-type TEs) efficiently cyclized azide/alkyne-containing peptides in a head-to-tail manner. Successive copper (I)-catalyzed azide-alkyne cycloaddition generated bicyclic peptides in one-pot, thus omitting the purification of monocyclic intermediates. This chemoenzymatic strategy enabled the facile synthesis of bicyclic peptides bearing hexa-, octa-, and undecapeptidyl head-to-tail cyclic scaffolds.

Heterogeneous Photocatalytic Ring Expansion of Cyclic Ketones for the Construction of Medium-Sized Lactams.

Construction of medium-sized ring compounds remains challenging in synthetic chemistry. Herein, we describe the synthesis of medium-sized lactams via a photoinduced ring expansion of benzo-fused cyclic ketones using graphitic carbon nitride (g-C3N4) as a photocatalyst. The ring expansion protocol provided an efficient access to 8-10-membered lactams in good yields and displayed good tolerance to a range of functional groups. The mechanism studies revealed that the photochemical reaction proceeds via an intermediary of a nitrogen radical, which is generated through an oxidative hydrogen atom transfer (HAT) process.

A Modular Strategy for the Synthesis of Macrocycles and Medium-Sized Rings via Cyclization/Ring Expansion Cascade Reactions.

Macrocycles and medium-sized rings are important in many scientific fields and technologies but are hard to make using current methods, especially on a large scale. Outlined herein is a strategy by which functionalized macrocycles and medium-sized rings can be prepared using cyclization/ring expansion (CRE) cascade reactions, without resorting to high dilution conditions. CRE cascade reactions are designed to operate exclusively via kinetically favorable 5-7-membered ring cyclization steps; this means that the problems typically associated with classical end-to-end macrocyclization reactions are avoided. A modular synthetic approach has been developed to facilitate the simple assembly of the requisite linear precursors, which can then be converted into an extremely broad range of functionalized macrocycles and medium-sized rings using one of nine CRE protocols.

Accessing Medium-Sized Rings via Vinyl Carbocation Intermediates.

Medium-sized rings (8-11-membered cycles) are often more challenging to synthesize than smaller rings (5-7-membered cycles) due to ring strain. Herein, we report a catalytic method for forming 8- and 9-membered rings that proceeds via the intramolecular Friedel-Crafts reactions of vinyl carbocation intermediates. These reactive species are generated catalytically through the ionization of vinyl toluenesulfonates by a Lewis acidic lithium cation-weakly coordinating anion salt.

Cascade ring expansion reactions for the synthesis of medium-sized rings and macrocycles.

This Feature Article discusses recent advances in the development of cascade ring expansion reactions for the synthesis of medium-sized rings and macrocycles. Cascade ring expansion reactions have much potential for use in the synthesis of biologically important medium-sized rings and macrocycles, most notably as they don't require high dilution conditions, which are commonly used in established end-to-end macrocyclisation methods. Operation by cascade ring expansion method can allow large ring products to be accessed via rearrangements that proceed exclusively by normal-sized ring cyclisation steps. Ensuring that there is adequate thermodynamic driving force for ring expansion is a key challenge when designing such methods, especially for the expansion of normal-sized rings into medium-sized rings. This Article is predominantly focused on methods developed in our own laboratory, with selected works by other groups also discussed. Thermodynamic considerations, mechanism, reaction design, route planning and future perspective for this field are all covered.

Expanding the scope of the successive ring expansion strategy for macrocycle and medium-sized ring synthesis: unreactive and reactive lactams.

New methods are described that expand the scope of the Successive Ring Expansion (SuRE) with respect to synthetically challenging lactams. A protocol has been developed for use with 'unreactive' lactams, enabling SuRE reactions to be performed on subsrates that fail under previously established conditions. Ring expansion is also demonstarted on 'reactive' lactams derived from iminosugars for the first time. The new SuRE methods were used to prepare a diverse array of medium-sized and macrocyclic lactams and lactones, which were evaluted in an anti-bacterial assay against E. coli BW25113WT.

Palladium-catalysed fragmentary esterification-induced allylic alkylation of allyl carbonates and cyclic vinylogous anhydrides.

An unprecedented palladium-catalysed fragmentary esterification-induced allylic alkylation (FEAA) of cyclic vinylogous anhydrides (CVAs) and allyl carbonates has been disclosed. The protocol features broad sp3-rich scaffold tolerance, rendering highly functionalized 1,6 and 1,7-dicarbonyls in up to high yields and diastereoselectivities. Three-component FEAA is also well tolerant to generate 1,6-dicarbonyls through the addition of extra O/N-nucleophiles. Furthermore, cyclic allyl carbonate-involved FEAA provides an efficient approach for the synthesis of structurally complex medium-sized rings.

Divergent Cascade Ring-Expansion Reactions of Acryloyl Imides.

Macrocyclic and medium-sized ring ketones, lactones and lactams can all be made from common acryloyl imide starting materials through divergent, one-pot cascade ring-expansion reactions. Following either conjugate addition with an amine or nitromethane, or osmium(VIII)-catalysed dihydoxylation, rearrangement through a four-atom ring expansion takes place spontaneously to form the ring expanded products. A second ring expansion can also be performed following a second iteration of imide formation and alkene functionalisation/ring expansion. In the dihydroxylation series, three- or four-atom ring expansion can be performed selectively, depending on whether the reaction is under kinetic or thermodynamic control.