Enzymatic Macrocyclization of 1,2,3‐Triazole Peptide Mimetics

The macrocyclization of linear peptides is very often accompanied by significant improvements in their stability and biological activity. Many strategies are available for their chemical macrocyclization, however, enzyme‐mediated methods remain of great interest in terms of synthetic utility. To date, known macrocyclization enzymes have been shown to be active on both peptide and protein substrates. Here we show that the macrocyclization enzyme of the cyanobactin family, PatGmac, is capable of macrocyclizing substrates with one, two, or three 1,4‐substituted 1,2,3‐triazole moieties. The introduction of non‐peptidic scaffolds into macrocycles is highly desirable in tuning the activity and physical properties of peptidic macrocycles. We have isolated and fully characterized nine non‐natural triazole‐containing cyclic peptides, a further ten molecules are also synthesized. PatGmac has now been shown to be an effective and versatile tool for the ring closure by peptide bond formation.     

Macrocyclization strategies in polyketide and nonribosomal peptide biosynthesis

Nonribosomal peptides and polyketides have attracted considerable attention in basic and applied research and have given rise to a multitude of therapeutic agents. The biological activity of many of these complex natural products, including for example the peptide antibiotics daptomycin and bacitracin or the polyketide anticancer agents epothilone and geldanamycin, specifically relies on the macrocyclization of linear acyl chains that form the backbone of these highly valuable molecules. The construction of the linear acyl precursors is accomplished by modular protein templates that follow comparable assembly line logic. As an enzymatic key step, macrocyclization is introduced after the consecutive condensation of amino acid or acyl-CoA building blocks by dedicated catalysts, and the mature product is released from the biosynthetic machinery. The diverse chain termination strategies of nonribosomal peptide and polyketide assembly lines, the structures and mechanisms of the versatile macrocyclization catalysts, and chemoenzymatic approaches for the development of new therapeutics are the focus of this review. Further, it is illustrated that macrocyclization is not restricted to secondary metabolites, but represents a commonly found structural motif of other biologically active proteins and peptides.     

Prins-type macrocyclizations as an efficient ring-closing strategy in natural product synthesis

Prins-type macrocyclizations have recently emerged as a successful strategy in the synthesis of polyketide-derived natural products. This reaction provides a concise and selective means to form tetrahydropyran-containing macrocyclic rings of varying size. A high degree of functionality within the macrocycle is tolerated and the yields for these transformations are typically good to excellent. Since the initial report of a Prins macrocyclization reaction in 1979, examples of this approach did not re-emerge until 2008. However, the use of this method in natural product synthesis has rapidly gained momentum in the synthetic community, with multiple examples of this macrocyclization tactic reported in the recent literature.     

N-Benzylazacyclophane synthesis via aromatic Mannich reaction

A new method for synthesizing phenolic N-benzylazacyclophanes starting from tyramine is presented here. Computational calculations showed that macrocyclization is favored by the formation of hydrogen bond-based templates; these templates are not affected by including benzyl groups in the nitrogen atom of the tyramine moiety. The results showed that N-benzyl groups with electron-donating substituents have more nucleophilic nitrogen atoms, thereby favoring macrocyclization, while electron-withdrawing groups favor polymerization.     

Resorcylic acid lactones as new lead structures for kinase inhibition

The naturally occurring resorcylic acid lactones LL-Z1640-2 (1), hypothemycin (2), L-783277 (3), radicicol A (4) and, to a somewhat lesser extent, aigialomycin D (5) have recently emerged as new lead structures for kinase inhibition. Total syntheses have now been reported for all of these natural products, most of which are based on macrocyclization through ester bond formation. However, RCM-based approaches have also been described and a variety of strategies have been pursued to obtain the requisite seco acids or dienes, respectively, as precursors for macrocyclization.     

芳酰胺类大环一步高效合成及其成环机理研究进展

总结了最近发现的新型芳酰胺及芳酰肼大环一步合成反应,着重探讨了由分子内三中心氢键所引导的高效一步成环反应机理.这类反应是由未成环寡聚物前体的折叠构象所构筑,不仅高效,而且反应机理新颖,提供了传统成环反应难以得到的几类刚性大环的合成方法.这些大环化合物表现出对客体识别的高度专一性,并能形成具有高通量性的跨膜孔道.     

Multicomponent macrocyclization reactions (MCMRs) employing highly reactive acyl ketene and nitrile oxide intermediates

An efficient synthesis of spiro-fused macrolactams by a multicomponent macrocyclization reaction (MCMR) is reported. The use of highly reactive, transient intermediates in this MCMR permits short reaction times, even at high dilution. The methods employed for this MCMR were first developed as a four-component strategy for the synthesis of β-ketoamide isoxazolines and a new macrocyclization reaction is reported.     

One‐Pot Assembly of Amino Acid Bridged Hybrid Macromulticyclic Cages through Multiple Multicomponent Macrocyclizations

An important development in the field of macrocyclization strategies towards molecular cages is described. The approach comprises the utilization of a double Ugi four‐component macrocyclization for the assembly of macromulticycles with up to four different tethers, that is, hybrid cages. The innovation of this method rests on setting up the macromulticycle connectivities not through the tethers but through the bridgeheads, which in this case involve N‐substituted amino acids. Both dilution and metal‐template‐driven macrocyclization conditions were implemented with success, enabling the one‐pot formation of cryptands and cages including steroidal, polyether, heterocyclic, peptidic, and aryl tethers. This method demonstrates substantial complexity‐generating character and is suitable for applications in molecular recognition and catalysis.     

Application of hitherto unexplored macrocyclization strategies in the epothilone series: novel epothilone analogs by total synthesis

A total synthesis of Epothilone 490 and a synthesis of 11-hydroxy dEpoB utilizing a vinyl-boronate cross-metathesis followed by a Suzuki macrocyclization. A mild route to reach aldehydes from terminal olefins, anticipating Nozaki-Kishi macrocyclization is described.     

Regioselective synthesis of syn disubstituted dibenzo-30-crown-10 ethers

A practical and regioselective synthetic method for the synthesis of syn substituted dibenzo-30-crown-10 ethers is reported. This novel methodology is reported with the syntheses of dibenzo crown ethers bearing nitro, formyl and carbomethoxy groups. The synthesis of macrocyclization precursors was accomplished in three steps and featured an application of para-methoxybenzyl group (PMB) as protecting group of phenol moiety that is orthogonal to NO₂, CHO and COOMe groups. General non-high dilution macrocyclization conditions have been developed that allow for the effective preparation of substituted large crown ethers.     

Cover Picture: Expanding the Toolbox of Target Directed Bio-Orthogonal Synthesis: In Situ Direct Macrocyclization by DNA Templates (Angew. Chem. Int. Ed. 7/2023)

Herein, we demonstrate for the first time that noncanonical DNA can direct macrocyclization-like challenging reactions to synthesize gene modulators. The planar G-quartets present in DNA G-quadruplexes (G4s) provide a size complementary reaction platform for the bio-orthogonal macrocyclization of bifunctional azide and alkyne fragments over oligo- and polymerization. G4s immobilized on gold-coated magnetic nanoparticles have been used as target templates to enable easy identification of a selective peptidomimetic macrocycle. Structurally similar macrocycles have been synthesized to understand their functional role in the modulation of gene function. The innate fluorescence of the in situ formed macrocycle has been utilized to monitor its cellular localization using a G4 antibody and its in cell formation from the corresponding azide and alkyne fragments. The successful execution of in situ macrocyclization in vitro and in cells would open up a new dimension for target-directed therapeutic applications.     

Palladium‐Catalzyed Atroposelective 16‐Membered Macrocyclization: Total Synthesis of Isoplagiochin D†

Isoplagiochin D is a ring‐strained macrocyclic bisbibenzylis, which showed stable axial chirality in one biaryl structure, and semistable axial chirality in the other biaryl moiety. We reported here an unprecedented example for the catalytically asymmetric synthesis of ring‐strained atropisomers via Pd‐catalyzed macrocyclization between benzyl halides and carbenes. This newly developed Pd‐catalyzed asymmetric macrocyclization protocol enabled us a quick synthesis of isoplagiochin D in a highly enantioselective manner.     

Total synthesis of aigialomycin D: surprising chemoselectivity dependence on alkyne structure in nickel-catalyzed cyclizations

The total synthesis of aigialomycin D was carried out using a nickel-catalyzed ynal macrocyclization as a key step. This key step allowed macrocycle assembly and formation of a disubstituted alkene and a secondary hydroxyl stereocenter in a single step, although the stereocenter was formed unselectively. An interesting side reaction involving five-membered-ring synthesis by an aldehyde/styrene cyclization was observed when macrocyclization of an alkynyl silane was attempted. A mechanistic basis for this surprising process is provided.     

Total synthesis of cytotoxic macrolide amphidinolide B1 and the proposed structure of amphidinolide B2

The first enantioselective total syntheses of cytotoxic macrolide amphidinolide B1 and the proposed structure for amphidinolide B2 have been accomplished. Key features of the syntheses include a diastereoselective aldol condensation, a spontaneous Wadsworth-Emmons macrocyclization and a directed epoxidation/elimination sequence.     

Total synthesis of (+)-phomactin a using a B-alkyl Suzuki macrocyclization

A total synthesis of (+)-phomactin A is described using a B-alkyl Suzuki macrocyclization to incorporate the isolated trisubstituted olefin. This macrocyclization was accomplished with the sensitive hydrated furan ring in place. (R)-(+)-pulegone was used to establish the highly substituted cyclohexene core of the molecule.     

Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles

Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput chemistry (e.g., microwave-assisted and/or solid-phase synthesis) to access various macrocycle entities have attracted great interest in this chemical space. This article serves as an update on our previous review related to macrocyclic drugs and new synthetic strategies toward macrocycles (Molecules, 2013, 18, 6230). In this work, I first reviewed recent FDA-approved macrocyclic drugs since 2014, followed by new advances in macrocycle synthesis using high throughput chemistry, including microwave-assisted and/or solid-supported macrocyclization strategies. Examples and highlights of macrocyclization include macrolactonization and macrolactamization, transition-metal catalyzed olefin ring-closure metathesis, intramolecular C–C and C–heteroatom cross-coupling, copper- or ruthenium-catalyzed azide–alkyne cycloaddition, intramolecular S_NAr or S_N2 nucleophilic substitution, condensation reaction, and multi-component reaction-mediated macrocyclization, and covering the literature since 2010.     

Synthesis of New Multibenzo Oxygen–Sulfur Donor Macrocycles Containing Lactams at Room Temperature

Some new oxygen–sulfur, multibenzo macrocyclic ligands containing amide groups have been prepared using the macrocyclization process with the reaction of 2,2′-thiobis-[4-methyl(2-aminophenoxy)phenyl ether] as a symmetrical diamine with appropriate dicarboxylicacid dichlorides in moderate yields. This macrocyclization led to the formation of di- and tetramide macrocycles. These reactions were routinely carried out at ambient temperature in CH₂Cl₂ as solvent in high dilution without template effect conditions. It is found that sulfur the atom affects the rigidity of the macrocycles and diastereotopicity of nuclei in the ring of these series of macrocyclic compounds.     

One-pot synthesis of hybrid macrocyclic pentamers with variable functionalizations around the periphery

Rather than four- or six-residue macrocylces, one-pot macrocyclization allows for the highly selective formation of five-residue macrocycles rigidified by intramolecular hydrogen bonds. Variable functionalizations around the pentameric periphery were achieved by reacting monomers with higher oligomers bearing different exterior side chains. The formation of these hybrid pentamers suggests a chain-growth mechanism for the one-pot macrocyclization where the successive addition of monomers onto higher oligomers is faster than those between two monomers or two higher oligomers.     

Synthesis of IB-01211, a cyclic peptide containing 2,4-concatenated thia- and oxazoles, via Hantzsch macrocyclization

[structure: see text] An efficient and versatile convergent synthesis of IB-01211 based on a combination of peptide and heterocyclic chemistry is described. The key step in the synthesis is macrocyclization through intramolecular Hantzsch formation of the thiazole ring. Dehydration of a free primary alcohol to furnish the exocyclic methylidene present in the natural product was applied during the macrocyclization.     

Chiral macrocyclic aliphatic oligoimines derived from trans-1,2-diaminocyclohexane

Aliphatic dialdehydes of rigid structures having a cyclohexane, a bicyclo[2.2.2]octane or a [7]triangulane skeleton, have been condensed with enantiomerically pure trans-1,2-diaminocyclohexane to give [3+3] or [2+2] macrocyclization products. Unlike acyclic aliphatic imines, these macrocyclic oligoimines show enhanced stabilities and their structures in the crystals could be determined by X-ray diffraction analyses. The enantiomerically pure [7]triangulane dialdehyde showed remarkable diastereoselectivity in the condensation with the two enantiomers of trans-1,2-diaminocyclohexane: only one of the enantiomers gave a [2+2] macrocyclization product. Circular dichroism measurements combined with computational analysis show that the lowest energy electronic transition in these cyclic oligoimines is of n-pi* type.