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A new DBU-catalyzed formal [4 ​+ ​2] cycloaddition between ortho-hydroxyphenyl-substituted para-quinone methides and electron-deficient dienophiles including 3-methyleneoxindoles and 2-aryldeneindene-1,3-diones was established. A wide range of functionalized spiro[chromane-3,3′-indolines] and spiro[chromane-3,2′-indenes] were successfully synthesized in good yields and with high diastereoselectivity. The features of the reaction included readily available substrates, mild reaction conditions, convenient methodology and good functional group tolerance.

Monopropargyloxy-tripropoxy-calix[4]arene 1 was subjected to a propargyl Claisen rearrangement to give unusual calix[3]arene[1]chromene and homocalix[3]arene[1]benzofuran macrocycles. Quantum mechanical density functional theory calculations indicated that an initial [3,3] sigmatropic reaction affords a highly reactive allene intermediate, stabilized by two main diradical pathways leading to six- and five-membered oxygenated rings. In the presence of a n-butylammonium guest, calix[3]-arene[1]chromane 6 forms two stereoisomeric complexes stabilized by +N−H···O and cation···π interactions.

The 3-substituted chromane core is found in several bioactive natural products. Herein, we describe a route to 3-fluorinated chromanes from allylic phenol ethers. Our external oxidant-free approach takes advantage of an electro-chemical generation of a hypervalent iodine species, difluoro-λ3-tolyl iodane, which mediates the alkene fluoroaryla-tion. High yields and selectivity for this transformation are achieved for electron poor substrates. The redox chemistry has been characterized for the electrochemical generation of the iodane in the presence of fluoride, and insights into the mechanism are given. The transformation has been demonstrated on larger gram scales, which represents the potential broader utility of the process.

The gram-scale synthesis of 5,6-, 6,7-, and 7,8-chromene/chromane-type aryne precursors and their applications in regioselective transformation to other functional derivatives is reported. Chromene/chromane-type arynes are generated under mild conditions, which can further undergo [2 + 2], [3 + 2], and [4 + 2] cycloaddition reactions, nucleophilic addition reactions, and σ-insertion reactions to produce structurally novel substituted chromenes and chromanes. The excellent regioselectivity of the reaction is facilitated by the oxygen-containing guiding groups at the ortho-position of the triple bond, which can be removed or switched to other functional groups including alkenyl, aryl, heteroaryl, and arylamino groups.

Direct oxidative coupling of different inert C-H bonds is the most straightforward and environmentally benign method to construct C-C bonds. In this article, we developed a Pd-catalyzed intramolecular oxidative coupling between unactivated aliphatic and aryl C-H bonds. This chemistry showed great potential to build up fused cyclic scaffolds from linear substrates through oxidative couplings. Privileged chromane and tetralin scaffolds were constructed from readily available linear starting materials in the absence of any organohalides and organometallic partners.

The development of practical C−H/C−H coupling reactions remains a challenging yet appealing synthetic venture because it circumvents the need to prefunctionalize both coupling partners for the generation of C−C bonds. Herein, we report a cyclative C(sp3)−H/C(sp2)−H coupling reaction of free aliphatic acids enabled by a cyclopentane-based mono-N-protected β-amino acid ligand. This reaction uses inexpensive sodium percarbonate (Na2CO3·1.5H2O2) as the sole oxidant, generating water as the only byproduct. A range of biologically important scaffolds, including tetralins, chromanes, and indanes, could be easily prepared by this protocol. Finally, the synthetic application of this methodology is demonstrated by the concise total synthesis of (±)-russujaponol F in a four-step sequence starting from readily available phenylacetic acid and pivalic acid through the sequential functionalizations of four C−H bonds.

A Cu(I)/(R,R)-Ph-BPE-catalyzed enantioselective hydroamination of 2H-chromenes and 2H-thiochromenes with anthranils is developed, which enables highly efficient and atom-economical asymmetric access to a series of 4-arylamino chromanes and thiochromanes bearing a benzylic alcohol functionality in high yields (up to 96%) with excellent enantioselectivities (up to 99% ee). These valuable chiral chromane and thiochromane products may act as key intermediates to access nitrogen-, oxygen- and sulfur-containing bioactive compounds with more molecular complexity.

The σ1 receptor is implicated in regulating a diverse range of physiology and is a target for developing therapies for cancer, pain management, neural degradation, and COVID-19. This report describes 36 phenethylamine-containing 3-amino-chromane ligands, which bind to σ1 with low nM affinities. The family consists of 18 distinct compounds and each enantiomer was independently assayed. Three compounds with the greatest affinity bind in the 2 nM Ki range (∼8.7 pKi). Furthermore, ligands with the (3R,4R) absolute stereochemistry on the 3-amino-chromane core have a higher affinity and greater σ1 versus TMEM97 selectivity. The most promising ligands were assayed in 661W cells, which did not show significant protective effects.

Gold-catalyzed reactions of conjugated haloacetylenes are well known and usually result in the formation of addition or dimerization products. Herein, we report a gold-catalyzed reaction of non-conjugated­ haloacetylenes, which leads exclusively to the halogenated cyclization products. Remarkable is the gold-catalyzed reaction of tritylhaloacetylenes to haloindene derivatives, as mechanistic studies reveal that an 1,2-aryl shift occurs in the initially formed gold complex. The potential functionalization at the halogen atom and the wide scope of these cyclization reactions make them an attractive method for the construction of cyclic systems.

Herein reported are results of the chemical and biological investigation of red propolis collected at the Brazilian Northeast coastline. New propolones A-D (1-4), with a 3-{3-[(2-phenylbenzofuran-3-yl)methyl]phenyl}chromane skeleton; propolonones A-C (5-7), with a 3-[3-(3-benzylbenzofuran-2-yl)phenyl]chromane skeleton; and propolol A (8), with a 6-(3-benzylbenzofuran-2-yl)-3-phenylchromane skeleton, were isolated as constituents of Brazilian red propolis by cytotoxicity-guided assays and structurally identified by analysis of their spectroscopic data. Propolone B (2) and propolonone A (5) display significant cytotoxic activities against an ovarian cancer cell line expressing a multiple drug resistance phenotype when compared with doxorubicin.

The chromane nucleus is common to a plenum of bioactive small molecules where it is frequently oxidized at position 3. Motivated by the importance of this position in conferring efficacy, and the prominence of bioisosterism in drug discovery, an iodine(I)/iodine(III) catalysis strategy to access enantioenriched 3‐fluorochromanes is disclosed (up to 7:93 e.r.). In situ generation of ArIF2 enables the direct fluorocyclization of allyl phenyl ethers to generate novel scaffolds that manifest the stereoelectronic gauche effect. Mechanistic interrogation using deuterated probes confirms a stereospecific process consistent with a type IIinv pathway., An iodine(I)/iodine(III) catalysis strategy to access enantioenriched 3‐fluorochromanes is disclosed (up to 7:93 e.r.). In situ generation of ArIF2 enables the direct fluorocyclization of allyl phenyl ethers to generate novel scaffolds that manifest the stereoelectronic gauche effect. Mechanistic interrogation using deuterated probes confirms a stereospecific process consistent with a type IIinv pathway.

A new Cu(II)-catalyzed formal [4 + 2] cycloaddition between quinone methides (QMs) including para-quinone methides (p-QMs) and ortho-quinone methides (o-QMs) and electron-poor 3-vinylindoles was established. A wide range of richly decorated indole-containing chromane derivatives were synthesized in acceptable yields and diastereoselectivity. Based on several control experiments, a possible mechanism was also proposed to elucidate the catalytic cycle pathway.

Phytochemical investigation of the ethanol extract of underground parts of Iris tenuifolia Pall. afforded five new compounds, an unusual macrolide termed moniristenulide (1), 5-methoxy-6,7-methylenedioxy-4-O-2′-cycloflavan (2), 5,7,2′,3′-tetrahydroxyflavanone (3), 5-hydroxy-6,7-dimethoxyisoflavone-2′-O-β-d-glucopyranoside (9), 5,2′,3′-dihydroxy-6,7-dimethoxyisoflavone (10), along with seven known compounds (4–8, 11–12). The structures of all purified compounds were established by analysis of 1D and 2D NMR spectroscopy and HR-ESI-MS. The antimicrobial activity of the compounds 1–3, 5, 9, and 10 was investigated using the agar diffusion method against fungi, Gram-positive and Gram-negative bacteria. In consequence, new compound 3 was found to possess the highest antibacterial activity against Enterococcus faecalis VRE and Mycobacterium vaccae. Cell proliferation and cytotoxicity tests were also applied on all isolated compounds and plant crude extract in vitro with the result of potent inhibitory effect against leukemia cells. In particular, the newly discovered isoflavone 10 was active against both of the leukemia cells K-562 and THP-1 while 4–6 of the flavanone type compounds were active against only THP-1.

On the basis of the finding that various aminoalkyl-substituted chromene and chromane derivatives possess strong and highly selective in vitro bioactivity against Plasmodium falciparum, the pathogen responsible for tropical malaria, we performed a structure–activity relationship study for such compounds. With structures and activity data of 52 congeneric compounds from our recent studies, we performed a three-dimensional quantitative structure–activity relationship (3D-QSAR) study using the comparative molecular field analysis (CoMFA) approach as implemented in the Open3DQSAR software. The resulting model displayed excellent internal and good external predictive power as well as good robustness. Besides insights into the molecular interactions and structural features influencing the antiplasmodial activity, this model now provides the possibility to predict the activity of further untested compounds to guide our further synthetic efforts to develop even more potent antiplasmodial chromenes/chromanes.

The direct formation of aryl C–O bonds via the intramolecular dehydrogenative coupling of a C–H bond and a pendant alcohol represents a powerful synthetic transformation. Herein, we report a method for intramolecular arene C–H etherification via an umpoled alcohol cyclization mediated by an I(III) N-HVI reagent. This approach provides access to functionalized chromane scaffolds from primary, secondary and tertiary alcohols via a cascade cyclization-iodonium salt formation, the latter providing a versatile functional handle for downstream derivatization. Computational studies support initial formation of an umpoled O-intermediate via I(III) ligand exchange, followed by competitive direct and spirocyclization/1,2-shift pathways.

As a significant co-activator involved in cell cycle and cell growth, differentiation and development, p300/CBP has shown extraordinary potential target in cancer therapy. Herein we designed new compounds from the lead compound A-485 based on molecular dynamic simulations. A series of new spirocyclic chroman derivatives was prepared, characterized and proven to be a potential treatment of prostate cancer. The most potent compound B16 inhibited the proliferation of enzalutamide-resistant 22Rv1 cells with an IC50 value of 96 nM. Furthermore, compounds B16–P2 displayed favorable overall pharmacokinetic profiles, and better tumor growth inhibition than A-485 in an in vivo xenograft model.

Controlling site selectivity of C–H activation without using a directing group remains a significant challenge. While Pd(II) catalysts modulated by a mutually repulsive pyridine-type ligand have been shown to favor the relatively electron-rich carbon centers of arenes, reversing the selectivity to favor palladation at the relatively electron-deficient positions has not been possible. Herein we report the first catalytic system that effectively performs meta C–H arylation of a variety of alkoxy aromatics including 2,3-dihydrobenzofuran and chromane with exclusive meta site selectivity, thus reversing the conventional site selectivity governed by native electronic effects. The identification of an effective ligand and modified norbornene (NBE-CO(2)Me), as well as taking advantage of the statistics, are essential for achieving the exclusive meta selectivity.

A new series of biologically active 3-[(2R*)-2-[(2S*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]-2-hydroxyethyl]-urea/thiourea derivatives (1) have been designed and synthesized in four steps from 6-fluoro-3,4-dihydro-2-(oxiran-2-yl)-2H-chromene (2). The structures of newly synthesized compounds (1a–j) were confirmed by 1H, 13C NMR, and HRMS. The major advantages of the present article include the development of an efficient eluent system for good separation of diastereomers (2a and 2b) with high yields and synthesis of (R*)-2-(benzylamino)-1-((S*)-6-fluoro-3,4-dihydro-2H-chromen-2-yl)ethanol (3) in high yields (87%) from epoxide (2a) through new reaction conditions. The synthesized compounds (1a–j) exhibited moderate to excellent antimicrobial activities against both bacterial strains (gram + Ve and gram –Ve strains) and fungal strains. Among the tested compounds, promising lead compounds were identified (compounds 1a and 1d against bacterial strains and compound 1h and 1j against fungal strains) and their antimicrobial activities are comparable with the reference standard.

Regioselective ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes with stabilized sulfonium ylides provided 2,3-trans-disubstituted 2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-ones in high yields without the formation of any isomers. The obtained product was readily converted into highly substituted chromane.

Excessive blood vessel formation in the eye is implicated in wet age-related macular degeneration, proliferative diabetic retinopathy, neovascular glaucoma, and retinopathy of prematurity, which are major causes of blindness. Small molecule antiangiogenic drugs are strongly needed to supplement existing biologics. Homoisoflavonoids have been previously shown to have potent antiproliferative activities in endothelial cells over other cell types. Moreover, they demonstrated a strong antiangiogenic potential in vitro and in vivo in animal models of ocular neovascularization. Here, we tested the antiangiogenic activity of a group of naturally occurring homoisoflavonoids isolated from the family Hyacinthaceae and related synthetic compounds, chosen for synthesis based on structure–activity relationship observations. Several compounds showed interesting antiproliferative and antiangiogenic activities in vitro on retinal microvascular endothelial cells, a disease-relevant cell type, with the synthetic chromane, 46, showing the best activity (GI50 of 2.3 × 10–4 μM).

An efficient approach for the synthesis of pyrazolopyridines containing the aminochromane motif through a base-catalyzed cyclization reaction is reported. The synthesis was carried out through a three-component reaction of (arylhydrazono)methyl-4H-chromen-4-one, malononitrile, primary amines in the presence of Et3N at room temperature. However, carrying out the reaction under the same conditions without base led to a fused chromanyl-cyanopyridine. High selectivity, high atom economy, and good to high yields in addition to mild reaction conditions are the advantages of this approach.

The title compound, is a Schiff base derivative of a thio­semicarbazide with a flavanone. In the crystal, mol­ecules are linked by two pairs of N—H⋯S hydrogen bonds, forming inversion dimers enclosing (8) ring motifs, which are linked to form ribbons propagating along the b-axis direction., In the title compound, C16H14N3OSCl, a Schiff base derivative of a thio­semicarbazide with a flavanone, the 4-chlorophenyl ring is inclined to the benzene ring of the chromane ring system by 30.72 (12)°. The pyran ring has an envelope conformation with the methine C atom as the flap. The mean plane of the thio­urea unit is twisted with respect to the benzene ring of the chromanone ring system, subtending a dihedral angle of 19.78 (19)°. In the crystal, mol­ecules are linked by two pairs of N—H⋯S hydrogen bonds, forming inversion dimers enclosing R 2 2(8) ring motifs, which are linked to form ribbons propagating along the b-axis direction. The inter­molecular contacts in the crystal have been analysed using Hirshfeld surface analysis.

Herein, a novel copper-catalyzed highly diastereoselective cross-dehydrogenative coupling reaction is reported. A broad range of 1,3-dicarbonyl compounds and 8-hydroxyisochromanes are applicable to this methodology, affording tricyclic chromane products in moderate to high yields with continuous stereocenters identical to natural penicitrinols.

Cancer is a major cause of death worldwide and novel anticancer agents for its better management are much needed. Benzopyrone-based compounds, such as chromones, possess several distinctive chemical and biological properties, of which the cytotoxicity against cancer cells seems to be prominent. In this study, two series of compounds based on chromen-4-one (3-10) and chromane-2,4-dione (11-18) scaffolds were synthesized in moderate/high yields and evaluated for cytotoxicity against HL-60, MOLT-4, and MCF-7 cancer cells using MTT assay. In general, the compounds exhibited moderate cytotoxic effects against the cancer cell lines, among which, a superior potency could be observed against MOLT-4 cells. Chroman-2,4-dione (11-18) derivatives had overall higher potencies compared to their chromen-4-one (3-10) counterparts. Compound 13 displayed the lowest IC50 values against HL-60 (IC50, 42.0 ± 2.7 μM) and MOLT-4 cell lines (IC50, 24.4 ± 2.6 μM), while derivative 11 showed the highest activity against MCF-7 cells (IC50, 68.4 ± 3.9 μM). In conclusion, this study provides important information on the cytotoxic effects of chromone derivatives. Benzochroman-2,4-dione has been identified as a promising scaffold, which its potency can be modulated by tailored synthesis with the aim of finding novel and dissimilar anticancer compounds.

Beyond the tandem oxa-Michael strategy, an N-heterocyclic carbene-catalyzed kinetic resolution approach to access highly diastereo- and enantioenriched 2-aryl-3-nitro-chromane derivatives has been developed. An efficient strategy for the kinetic resolution of racemic 2-aryl-3-nitro-2H-chromenes was also successfully achieved. This catalytic kinetic resolution method allows the synthetically valuable chiral scaffolds, chromane and 2H-chromene, to be accessed in a single catalytic and asymmetric transformation, through the NHC-bound azolium homoenolate pathway.

Polyketide-polyketide hybrids are unique natural products with promising bioactivity, but the hybridization processes remain poorly understood. Herein, we present that the biosynthetic pathways of two immunosuppressants, dalmanol A and acetodalmanol A, result from an unspecific monooxygenase triggered hybridization of two distinct polyketide (naphthalene and chromane) biosynthetic gene clusters. The orchestration of the functional dimorphism of the polyketide synthase (ChrA) ketoreductase (KR) domain (shortened as ChrA KR) with that of the KR partner (ChrB) in the bioassembly line increases the polyketide diversity and allows the fungal generation of plant chromanes (e.g., noreugenin) and phloroglucinols (e.g., 2,4,6-trihydroxyacetophenone). The simultaneous fungal biosynthesis of 1,3,6,8- and 2-acetyl-1,3,6,8-tetrahydroxynaphthalenes was addressed as well. Collectively, the work may symbolize a movement in understanding the multiple-gene-cluster involved natural product biosynthesis, and highlights the possible fungal generations of some chromane- and phloroglucinol-based phytochemicals.

Two different organocatalytic cascade reaction pathways have been developed toward the diversified synthesis of chromane-containing polyheterocyclic compounds from the readily available starting materials. The application of Hantzsch ester is proposed to be the key to achieve the switch between these two different cascade reaction pathways, and then the electron-deficient 1-aza-1,3-butadienes could be used as the four-atom and two-carbon unit, respectively, to react with 2-hydroxy cinnamaldehydes in a highly regio- and stereocontrolled manner. On the basis of larger-scale synthesis, further transformations of the obtained products have also been realized, leading to cycloadducts with high structural and stereogenic complexity bearing five stereogenic centers, and one is a tetrasubstituted stereocenter.

Coculturing two or more fungi is a useful strategy to awaken the silent genes to produce structurally diverse and bioactive natural products. Through the coculture of Pestalotiopsis sp. and Penicillium bialowiezense, six new isoprenylated chromane derivatives, including two pairs of enantiomeric ones (1a/1b–2a/2b) and two optical pure ones (3–4), two new isoprenylated phenol glucoside derivatives (6–7), as well as eight known structural analogues (5 and 8–14), were obtained. The structures of these new compounds were characterized by NMR spectroscopy, single-crystal X-ray crystallography, and ECD calculation. The Δ10,11 double bond of pestaloficin D (5) was revised to E-configurated based on the extensive spectroscopic analyses. Compounds 1a/1b and 2a/2b were the first examples of enantiomeric isoprenylated chromane derivatives, which were successfully separated by chiral HPLC. Additionally, all the isolated compounds were evaluated for the in vitro β-glucuronidase (GUS) and butyrylcholinesterase (BChE) inhibitory activities. Compounds 1a and 1b showed significant β-glucuronidase inhibitory potency with IC50 values of 7.6 and 10.3 μM, respectively. Compound 14 exhibited moderate BChE inhibitory activity with an IC50 value of 21.3 μM. In addition, the structure-enzyme inhibitory activity relationship of compounds 1–14 is discussed.

Herein, we described the asymmetric total synthesis of (–)-brazilane, an optically active natural product. The key steps of this synthetic approach are a lipase-catalyzed desymmetrisation reaction of a prochiral diol using vinyl acetate to prepare a chiral primary alcohol and a trifluoroacetic acid-catalyzed one pot intramolecular tandem Prins/Friedel-Crafts reaction used to construct the cis-fused chromane and indane framework.

Chromanes with high bioactivity play an important role in nature, and cyclization reactions of cyclopropanes with sulfonium ylides to form chromane skeletons have attracted great attention of scientists. The mechanism as well as origins of regioselectivity and stereoselectivity for the ring-opening/cyclization reactions between cyclohexane-1,3-dione-2-spirocyclopropanes and stabilized sulfonium ylides in CH2Cl2 were investigated by using the density functional theory (DFT) M06-2X/6–311+G(d,p)//M06-2X/6-31G(d,p) method combined with the SMD model. The calculated results revealed that the reaction process involved two key steps: the ring-opening step and the cyclization step, with the former being the rate-determining and stereoselectivity-determining step. The regioselectivity of the ring-opening step of spirocyclopropane indicated that the tertiary carbon was more preferential than the secondary one when sulfonium ylide attacked spirocyclopropane. The theoretical results confirmed that the stereoselectivity of the reaction to form the trans-isomer product is more favorable than the cis-isomer, and the calculated trans/cis ratio is in accordance with the experiment. Moreover, the conceptual density functional theory reactivity indices suggest that the electronic effect controls the regioselectivity. What is more, the stereoselectivity analyzed by weak non-covalent interaction also shows the importance of electronic effect.

International audience; Breast cancer is a major medical threat which cannot be sufficiently addressed by current therapies because of spontaneous or acquired treatment resistance. Besides, triple-negative breast cancer (TNBC) tumors do not respond to targeted therapies, thus new therapeutic strategies are needed. In this context, we designed and prepared new desulfured troglitazone (TGZ)-derived molecules and evaluated them in vitro for their anti-proliferative activity, with a special focus on triple-negative breast cancer cell lines. Optimization of the synthetic strategies and deracemization of the lead compound were performed to give highly active compound 10 with low-micromolar potency. Further studies revealed that this compound triggers apoptosis rather than cell cycle arrest as observed with TGZ.