Unusual Cyclization Research Articles

Beyond the Conventional Limitation of Photocycloaddition Reaction in the Roomy Nanospace of a Metal-Organic Framework.

Topochemical reactions provide selective products based on the molecular position; however, they generally require molecules to be placed in strictly limited orientations and distances, making them less versatile. In this study, we found that by confining trans-4-styrylpyridine (4-spy) as a reactive substrate in a flexible metal-organic framework (MOF) nanospace, [2+2] cycloadducts can be selectively obtained, even when the distance between two C═C bonds of 4-spy in the crystal is 5.9 Å, which is much larger than the conventionally observed upper limit (4.2 Å). Such an unusual cyclization reaction is suggested to occur due to the transient proximity of the 4-spy due to the "swing" motion in the nanospace. The MOF nanospace, with its high degree of molecular structural freedom, can be applied to different platforms that do not require the fine constraints of reactive distances for solid-phase reactions.

Unusually cyclized triterpenoids: occurrence, biosynthesis and chemical synthesis.

Covering: 2009 to 2021Biosynthetically, most of the syntheses of triterpenes follow the cascade cyclization and rearrangement of the acyclic precursors viz., squalene (S) and 2,3-oxidosqualene (OS), which lead to the very well known tetra- and pentacyclic triterpene skeletons. Aside from these, numerous other triterpenoid molecules are also reported from various natural sources and their structures are derived from "S" and "OS" via some unusual cyclization operations which are different from the usual tetra- and pentacyclic frameworks. Numerous compelling advances have been made and reported in the identification of these unusual cyclized mono-, di-, tri- and tetracyclic triterpenes between 2009 and 2021. Besides a dramatic increase in the newly isolated uncommon cyclized triterpenoids, substantial progress in the (bio)-synthesis of these triterpenes has been published along with significant progress in their biological effects. In this review, 180 new unusual cyclized triterpenoids together with their demonstrated biogenetic pathways, syntheses and biological effects will be categorized and discussed.

Intramolecular trapping of spiro radicals to produce unusual cyclization products from usual migration substrates.

A conceptually new methodology to give unusual cyclization products from usual migration substrates was disclosed. The highly complex and structurally important and valuable spirocyclic compounds were produced through radical addition, intramolecular cyclization and ring opening instead of usual migration to the di-functionalization products of olefins. Furthermore, a plausible mechanism was proposed based on a series of mechanistic studies including radical trapping, radical clock, verification experiments of intermediates, isotope labeling and KIE experiments.

Unusual cyclization of N-imidazolyl quinone imines with the formation of thiadiazole ring and its subsequent recyclization

2,6-Di-tert-butyl-4-{[2-(2-aryl-2-oxoethylthio)-1H-imidazol-1-yl]imino}cyclohexa-2,5-dien-1-ones under the action of bases give products of the 2,3-dihydroimidazo[2,1-b]thiazol- 3-ol series by subsequent recyclization reaction of the intermediate imidazo[2,1-b][1,3,4]thiadiazoles. The structure of imidazo[2,1-b]thiazol-3-ol is supported by the X-ray diffraction. The features of the cyclization processes of quinone imine derivatives were stimulated by DFT calculations using the wB97XD/6-311++G** method.

Bioactive imidamide-based compounds targeted against nitric oxide synthase

The selective inhibition of inducible nitric oxide synthase (iNOS) has become an interesting goal for the treatment of diseases where the immune and inflammatory response of the organism is involved. Septic shock is one prominent example of this type of affections. In this paper, the design and synthesis of twelve substituted pyridinyl- imidamide derivatives is described, together with their biological evaluation as NOS inhibitors. The most potent and selective compound was N-(3-hydroxy-3-(pyridin-3-yl)propyl)acetimidamide 9a (IC50 = 4.6 µM, against iNOS). Pharmacological assays in aortic rat tissue, have confirmed its inhibitory activity on iNOS and the absence of undesired cardicovascular effects. In silico analysis of the most promising compounds (9a, 9b, 9e and 9g) have predicted good drug-likeness properties. Furthermore, they have shown an adequate cell viability. Docking studies carried out on 9a suggest a particular binding mode that involves the essential residue Glu377, and might explain its iNOS selectivity. From a chemical point of view, the article describes an unusual cyclization to obtain pyridinyl-pyrimidine derivatives with high yield.

Concise stereoselective and stereodivergent syntheses of (±)-melicolones A and B

The first total syntheses of the epimeric (±)-melicolones A and B, which are bioactive constituents isolated as racemates from the leaves of Melicope ptelefolia, were achieved in 12.3% combined overall yield. The divergent approach to these unusual natural products is remarkably concise and required a longest linear sequence of only nine steps (11 total steps) from commercially available starting materials. The significant synthetic challenge posed by the unique and densely functionalized polycyclic framework characteristic of the melicolones was addressed by a novel and highly regioselective (16:1) and diastereoselective (15:1) dipolar cycloaddition to deliver the oxabicycloheptane core. This pivotal reaction featured an innovative combination of an unsaturated vinylogous ester dipolarophile with a carbonyl ylide that was generated by an unusual cyclization of the carbonyl oxygen atom of an aliphatic aldehyde with a rhodium carbenoid. Stereoselective prenylation of the ketone enolate derived from this bicyclic core gave an intermediate that was processed via a one-pot O-demethylation cycloaldolization sequence to give the penultimate intermediate. The synthesis was completed by a bioinspired tandem epoxidation of the prenyl substituent followed by a regioselective, acid-catalyzed cyclization to deliver (±)-melicolones A and B. This approach may be applicable to the syntheses of other melicolones having a tetracyclic core.

Serendipitous Formation of a Zwitterionic Imidazolium Molecule from α‐Diimine with Glyoxal as Unusual Cyclization Agent

AbstractImidazolium compounds have determined a profound impact on chemistry, and several synthetic methods to access them are well established. Here, we report the serendipitous discovery of the unprecedented route to a zwitterionic imidazolium molecule with the two nitrogen atoms substituted with 4‐cyclohexanecarboxylic acid: to build the five‐membered ring, glyoxal plays the double role of source for C2 and, unusually, C1 units, the latter via thermal decomposition affording carbon monoxide as side‐product. Compound I1 was characterized by elemental analysis, multinuclear NMR, IR and ESI‐MS spectroscopy.

Transformation of 3-(Furan-2-yl)-1,3-di(het)arylpropan-1-ones to Prop-2-en-1-ones via Oxidative Furan Dearomatization/2-Ene-1,4,7-triones Cyclization.

The approach to 3-(furan-2-yl)-1,3-di(het)arylprop-2-en-1-ones based on the oxidative dearomatization of 3-(furan-2-yl)-1,3-di(het)arylpropan-1-ones followed by an unusual cyclization of the formed di(het)aryl-substituted 2-ene-1,4,7-triones has been developed. The cyclization step is related to the Paal–Knorr synthesis, but the furan ring formation is accompanied in this case by a formal shift of the double bond through the formation of a fully conjugated 4,7-hydroxy-2,4,6-trien-1-one system or its surrogate.

Structural diversity of mixed polypnictogen complexes: dicationic E2E′2 (E ≠ E′ = P, As, Sb, Bi) chains, cycles and cages stabilized by transition metals

The reactivity of the tetrahedral dipnictogen complexes [{CpMo(CO)2}2(μ,η2:η2-EE′)] (E, E′ = P, As, Sb, Bi; “Mo2EE′”) towards different one-electron oxidation agents is reported. Oxidation with [Thia][TEF] (Thia+ = C12H8S2+; TEF− = Al{OC(CF3)3}4−) leads to the selective formation of the radical monocations [Mo2EE′]˙+, which immediately dimerize to the unprecedented dicationic E2E′2 ligand complexes [{CpMo(CO)2}4(μ4,η2:η2:η2:η2-E′EEE′)]2+via E–E bond formation. Single crystal X-ray diffraction revealed that, in the case of Mo2PAs and Mo2PSb, P–P bond formation occurs yielding zigzag E2P2 (E = As (1), Sb (2)) chains, whereas Mo2SbBi forms a Sb2Bi2 (5) cage, Mo2AsSb an unprecedented As2Sb2 unit representing an intermediate stage between a chain- and a cage-type structure, and Mo2AsBi a novel planar As2Bi2 (4a) cycle. Therefore, 1–5 bear the first substituent-free, dicationic hetero-E4 ligands, stabilized by transition metal fragments. Furthermore, in the case of Mo2AsSb, the exchange of the counterion causes changes in the molecular structure yielding an unusual, cyclic As2Sb2 ligand. The experimental results are corroborated by DFT calculations.

Total Syntheses of (±)-Melicolones A and B.

The first total syntheses of (±)-melicolones A and B, which have a unique and densely functionalized framework derived from a rearranged prenylated acetophenone, were accomplished in 12.3% combined overall yield. The concise and divergent synthesis of these two natural products, which were isolated in racemic form, was achieved in a longest linear sequence requiring only 9 steps (11 total steps) and 8 isolated intermediates using commercially available starting materials. This approach, which might enable access to all tetracyclic melicolones, features the highly regioselective (16:1) and diastereoselective (15:1) dipolar cycloaddition of a carbonyl ylide generated by the unusual cyclization of a rhodium carbene with the carbonyl oxygen atom of an aliphatic aldehyde. This cycloaddition proceeds with dominant steric control to give a highly functionalized oxabicycloheptane core. Stereoselective enolate alkylation led to a prenylated intermediate that underwent an intramolecular aldol reaction to give the penultimate tricyclic intermediate. Tandem epoxidation of the pendant prenyl group followed by a regioselective, acid-catalyzed cyclization delivered (±)-melicolones A and B.

Rhodium-catalysed synthesis of fused pyrimidine derivatives employing N-sulfonyl-1,2,3-triazoles as a 1-aza-[4C] synthon

A new synthetic application of N-sulfonyl-1,2,3-triazoles acting as a 1-aza-[4C] synthon via the 1,2-shift reaction of an α-imine rhodium carbene was developed for the synthesis of fused pyrimidine derivatives. The high reactivity of the strained three-membered 2H-azirine ring facilitated the unusual cyclization of electron-deficient dienes with electron-deficient dienophiles. The compatibility was good with common functionalities tolerated. Excellent chemoselectivity was observed, and no reactions occurred between the rhodium carbene and 2H-azirine. The products could be converted into seven-membered multi-functionalized 1H-1,4-diazepine derivatives, illustrating the potential application of the protocol in medium-sized N-heterocycle synthesis.

A new ionone derivative from the leaves of Picrasma quassioides

Nigakialcohol A (1), as unusual cyclization ionone derivative, together with eight known ones (2–9), were isolated from the leaves of Picrasma quassioides (D. Don) Benn (Simaroubaceae). Their structures were elucidated by extensive spectroscopic analyses and comparison with literature data. Compound 2 showed a weak inhibitory effect on NO production at non-cytotoxic concentration (100 μM) with inhibitory rate of 59%, and thus it should be regarded as potential anti-inflammatory agents.

Diverged Plant Terpene Synthases Reroute the Carbocation Cyclization Path towards the Formation of Unprecedented 6/11/5 and 6/6/7/5 Sesterterpene Scaffolds

AbstractSesterterpenoids are a relatively rare class of plant terpenes. Sesterterpene synthase (STS)‐mediated cyclization of the linear C25 isoprenoid precursor geranylfarnesyl diphosphate (GFPP) defines sesterterpene scaffolds. So far only a very limited number of STSs have been characterized. The discovery of three new plant STSs is reported that produce a suite of sesterterpenes with unprecedented 6/11/5 and 6/6/7/5 fused ring systems when transiently co‐expressed with a GFPP synthase in Nicotiana benthamiana. Structural elucidation, feeding experiments, and quantum chemical calculations suggest that these STSs catalyze an unusual cyclization path involving reprotonation, intramolecular 1,6 proton transfer, and concerted but asynchronous bicyclization events. The cyclization is diverted from those catalyzed by the characterized plant STSs by forming unified 15/5 bicyclic sesterterpene intermediates. Mutagenesis further revealed a conserved amino acid residue implicated in reprotonation.

Diverged Plant Terpene Synthases Reroute the Carbocation Cyclization Path towards the Formation of Unprecedented 6/11/5 and 6/6/7/5 Sesterterpene Scaffolds.

Sesterterpenoids are a relatively rare class of plant terpenes. Sesterterpene synthase (STS)‐mediated cyclization of the linear C25 isoprenoid precursor geranylfarnesyl diphosphate (GFPP) defines sesterterpene scaffolds. So far only a very limited number of STSs have been characterized. The discovery of three new plant STSs is reported that produce a suite of sesterterpenes with unprecedented 6/11/5 and 6/6/7/5 fused ring systems when transiently co‐expressed with a GFPP synthase in Nicotiana benthamiana. Structural elucidation, feeding experiments, and quantum chemical calculations suggest that these STSs catalyze an unusual cyclization path involving reprotonation, intramolecular 1,6 proton transfer, and concerted but asynchronous bicyclization events. The cyclization is diverted from those catalyzed by the characterized plant STSs by forming unified 15/5 bicyclic sesterterpene intermediates. Mutagenesis further revealed a conserved amino acid residue implicated in reprotonation.

The in situ formation of a Cu(II) mesoionic complex via unexpected ring closure and investigation of its magnetic properties

The reaction of diphenylthiocarbazone, picolinic acid (HL1) with Cu(OAc)2·H2O under base condition yields a mesoionic complex [Cu(II)(L1)2(L2)]·MeOH, where L2, mesoionic ligand 2,3-diphenyltetrazole-5-thione ligand, derived from an unusual cyclization of diphenylthiocarbazone. Crystallographic studies show that the mesoionic ligand L2 is weakly interacted with a planar Cu(II) complex via S…Cu electrostatic force while S donor atom sits on the top of a pyramidal geometry of five-coordinated Cu complex. π-contacts between two adjacent mesoionic ligands L2 in the crystal are also observed. The complex is characterized by IR, UV/vis, Powder XRD, and SQuID magnetometry studies on magnetic property of the powder sample are also discussed.

A furazan-fused pyrazole N-oxide via unusual cyclization

A highly energetic fused nitrogen-rich anion, 6-nitro-pyrazolo-[3,4-c]furazanate 5-oxide, was synthesized by an unusual cyclization reaction.

ChemInform Abstract: Unexpected “Reverse” Cyclization of 2‐Mercaptobenzimidazole with Chlorotrifluoroethylene and Hexafluoropropene.

Abstract The unusual cyclization mode of 2-mercaptobenzimidazole with chlorotrifluoroethylene and hexafluoropropene has been found. Such unexpected products as 2-chloro-2,3,3-trifluoro-2,3-dihydrobenzimidazo[4,5b]thiazole-1,3 and 2-trifluoromethyl-2,3,3-trifluoro-2,3-dihydrobenzimidazo[4,5b]thiazole-1,3 were isolated. The structures of obtained compounds were supported by single crystal X-ray diffraction analysis and the possible reaction route was proposed.

Phenalenone Polyketide Cyclization Catalyzed by Fungal Polyketide Synthase and Flavin-Dependent Monooxygenase.

Phenalenones are polyketide natural products that display diverse structures and biological activities. The core of phenalenones is a peri-fused tricyclic ring system cyclized from a linear polyketide precursor via an unresolved mechanism. Toward understanding the unusual cyclization steps, the phn biosynthetic gene cluster responsible for herqueinone biosynthesis was identified from the genome of Penicillium herquei. A nonreducing polyketide synthase (NR-PKS) PhnA was shown to synthesize the heptaketide backbone and cyclize it into the angular, hemiketal-containing naphtho-γ-pyrone prephenalenone. The product template (PT) domain of PhnA catalyzes only the C4-C9 aldol condensation, which is unprecedented among known PT domains. The transformation of prephenalenone to phenalenone requires an FAD-dependent monooxygenase (FMO) PhnB, which catalyzes the C2 aromatic hydroxylation of prephenalenone and ring opening of the γ-pyrone ring simultaneously. Density functional theory calculations provide insights into why the hydroxylated intermediate undergoes an aldol-like phenoxide-ketone cyclization to yield the phenalenone core. This study therefore unveiled new routes and biocatalysts for polyketide cyclization.

Unexpected “reverse” cyclization of 2-mercaptobenzimidazole with chlorotrifluoroethylene and hexafluoropropene

Abstract The unusual cyclization mode of 2-mercaptobenzimidazole with chlorotrifluoroethylene and hexafluoropropene has been found. Such unexpected products as 2-chloro-2,3,3-trifluoro-2,3-dihydrobenzimidazo[4,5b]thiazole-1,3 and 2-trifluoromethyl-2,3,3-trifluoro-2,3-dihydrobenzimidazo[4,5b]thiazole-1,3 were isolated. The structures of obtained compounds were supported by single crystal X-ray diffraction analysis and the possible reaction route was proposed.

Onocerin Biosynthesis Requires Two Highly Dedicated Triterpene Cyclases in a Fern Lycopodium clavatum.

Onocerin is known for its unusual structure among triterpenoids, with a symmetrical structure that is formed by cyclizations at the both termini of dioxidosqualene. The nature of the enzyme catalyzing these unusual cyclizations has remained elusive for decades. Here, we report the cloning of genes responsible for these reactions; they exhibited unprecedented substrate specificities among oxidosqualene cyclase family members. Two genes, LCC and LCD, were identified from the fern Lycopodium clavatum. Expression in yeast revealed that both were required to produce α-onocerin. LCC, the first dioxidosqualene cyclase, catalyzed the production of a novel intermediate pre-α-onocerin from only dioxidosqualene as a substrate; LCD catalyzed the second half of the cyclization, exclusively from pre-α-onocerin. These results demonstrated that these two most unusual oxidosqualene cyclases were involved in onocerin biosynthesis.