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Aminobenzosuberone-based PfA-M1 inhibitors were explored as novel antimalarial agents against two different Plasmodium falciparum strains. The 4-phenyl derivative 7c exhibited the most encouraging growth inhibitory activity with IC 50 values of 6.5-11.2 µM. X-ray crystal structures and early assessment of DMPK/ADME-Tox parameters allowed us to initiate structure-based drug design approach and understand the liabilities (such as potential metabolic and aqueous solubility issues) as well as identify the opportunities for improvement of this aminobenzosuberone series. It also suggested that compound 7c should be regarded as an attractive chemical tool to investigate the different biological roles of this multifunctional PfA-M1 protein., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The Sc(OTf)3-catalyzed [3 + 2]-annulation reaction between cyclopropenones and donor–acceptor cyclopropanes is described. The process leads directly to the formation of 4-oxaspiro[2.4]hept-1-ene derivatives in good to excellent reaction yields. Density functional theory calculations suggest that the [3 + 2]-annulation pathway is strongly preferred over the possible [3 + 3]-process.

The modular synthesis of photoprecursors and their photoinduced cyclization into substituted 1-benzazocanes of two distinct topologies is described. The key step producing an extended polyheterocyclic system involves the photogeneration of azaxylylenes and their subsequent intramolecular cycloaddition with furan-containing pendants tethered either via the aniline nitrogen or through the carbonyl group containing arm. The primary photoproducts-secondary or tertiary anilines which are not acylated at the nitrogen atom-undergo facile acid-catalyzed or spontaneous ring-opening-ring-closing rearrangement to yield fused polyheterocyclic structures possessing a 2,6-epoxyazocane (or oxamorphan) core.

A synthesis of iodo-substituted dibenzocyclohepten-5-ones by the iodine monochloride (or iodine)-induced intramolecular 7-endo-dig cyclization of 1-([1,1'-biphenyl]-2-yl)alkynones is reported. Detailed investigations on the substituent effects during the electrophilic iodocyclization of the alkynones show that they play a crucial role in determining the reaction pathways of the cyclization. By modifying the substitution pattern on the alkynone substrates, the cyclization takes place regioselectively, leading to either dibenzocyclohepten-5-ones, via a 7-endo-dig cyclization, or spiroconjugated compounds, via a 6-endo-dig cyclization.

A simple and effective method for the synthesis of 7-oxabicyclo[2.2.1]heptanes and 8-oxabicyclo[3.2.1]octanes from acetonyl C-glycoside substrates is described, which involves an intramolecular cyclization reaction through a nucleophilic substitution at C-5 or C-6 of C-glycosides by a 2'-enamine intermediate formed in the presence of pyrrolidine. Because anomeric epimerization occurs under these conditions, C-glycoside substrates with either anomeric configuration were converted to the same product(s) in same stereoselectivity and similar chemical yield.

We have developed an efficient and stereoselective route to trans-fused octahydrocyclohepta[b]pyrrol-4(1H)-ones. The key features of our synthesis include the regioselective epoxide ring-opening of alkynyl oxiranes and a stereoselective aza-Cope-Mannich reaction. The target compounds were prepared in 3-6 steps from commercially available starting materials (61-75% overall yield) with minimal chromatographic purification. We have devised an stereoselective route to target compounds using Shi epoxidation or (R)-1-phenylethylamine as a source of chirality.

A short access to homocalystegine analogues silylated at C7 is described. The synthesis involves the desymmetrization of a (phenyldimethylsilyl)methylcycloheptatriene using osmium-mediated dihydroxylation, followed by the diol protection and a cycloaddition involving the remaining diene moiety and an acylnitroso reagent. Additions of the osmium and acylnitroso reagents were shown, through X-ray diffraction studies of the resulting major isomers, to occur anti and syn, respectively, relative to the SiCH(2) substituent. N-O bond cleavage on the resulting cycloadduct then produces the aminopolyol having a silylmethyl substituent. Oxidation of the C-Si bond also afforded an access to unusual amino-heptitols having five contiguous stereogenic centers. In the course of this work, we finally observed a unusual rearrangement taking place on cycloheptanone 18 substituted by two acetyl groups and a neighboring Boc-protected amine. A profound reorganization of the substituents on the seven-membered ring effectively took place under acidic conditions (TFA) leading to the thermodynamically more stable homocalystegine-type compound. DFT calculations of the conformational energy of isomeric silyl homocalystegines indicated that the product observed upon the acid-mediated rearrangement was the most stable of a series of analogues with various distributions of substituents along the seven-membered ring backbone. A tentative mechanism is proposed to rationalize the acetate migrations and inversions of the stereochemistry at various stereocenters.

A common strategy for the synthesis of a 7-membered-ring system with a Suzuki-Miyaura coupling followed by an acid/base-promoted intramolecular aldol condensation reaction has been developed. The reaction of 2'-bromoacetophenones with 2-formylphenylboronic acids in the presence of Pd(OAc)(2) and CataCXium PIntB L8 efficiently provided biaryl compounds, which were transformed to a wide array of dibenzo[a,c]cyclohepten-5-ones in excellent yields by a sequential treatment with p-TsOH, followed by 10% aq NaOH.

The reactivity of (2-alkenyl-3-pentene-1,5-diyl)iron complexes toward olefin metathesis, cycloaddition, and mild oxidations (MnO 2 or mCPBA) was examined. Cycloaddition reactions were observed to occur with modest diastereoselectivity (33-63% de). Decomplexation of the (3-pentenediyl) ligand may be accomplished by oxidation with either CAN or alkaline hydrogen peroxide to afford vinylcyclopropanecarboxylates or divinylcyclopropanecarboxylates. Reduction of the latter, followed by Cope rearrangement generates cycloheptadienylmethanols. These studies demonstrate that (2-alkenyl-3-pentene-1,5-diyl)iron complexes can serve as organometallic scaffolds for the preparation of a wide variety of structural motifs containing up to 5 contiguous stereocenters.

The [3 + 2 + 2] cocyclization of ethyl cyclopropylideneacetate (1a) and various alkynes proceeded smoothly in the presence of Ni(cod)2-PPh3. The cycloheptadiene derivatives were synthesized in highly selective manners. The unique reactivity of 1a was essential for the progress of the reaction. The observed regioselectivity of the product formation and the mechanism of the reaction are discussed.

Chiral cycloalkane-trans-1,2-diols (+/-)-3 and (+/-)-8 having a diester moiety have been prepared from dimethyl dialkenylmalonate using olefin metathesis by Grubbs catalyst, followed by epoxidation and acidic hydrolysis. Kinetic resolution of racemic cyclopentane-trans-1,2-diol (+/-)-3 by lipase-catalyzed transesterification afforded an optically active monoacetate (-)-5 of 95% ee in 46% yield and the recovered diol (-)-3 of 92% ee in 51% yield, and that of cycloheptane-trans-1,2-diol (+/-)-8 gave a monoacetate (+)-10 of 95% ee in 51% yield and the diol (-)-8 of >99% ee in 43% yield, respectively. The enantiomer selectivity of racemic cyclic trans-1,2-diols bearing a diester moiety by lipases (Amano PS and Amano AK) was opposite to that of the reported simple racemic cycloalkane-trans-1,2-diols. To explain the lipase-catalyzed enantiomer selectivity, computer modeling of lipase-substrate complexes was performed. Furthermore, the optically active diester (-)-8 could be efficiently converted into an optically active seven-membered-ring alpha,alpha-disubstituted amino acid (4R,5R)-(-)-15.

Rhodium(II)-catalyzed reactions of aryldiazoacetates can be conducted in the presence of iodide, triflate, organoboron, and organostannane functionality, resulting in the formation of a variety of cyclopropanes or C-H insertion products with high stereoselectivity. The combination of the rhodium(II)-catalyzed reaction with a subsequent palladium(II)-catalyzed Suzuki coupling offers a novel strategy for diversity synthesis.

[reaction: see text] endo- and exo-2,3,4,7-tetrahydro-1H-1,4-methanobenzocycloheptene-7-carboxylic acid ethyl esters have been synthesized, and their Diels-Alder cycloaddition reactions with maleic anhydride, dimethyl acetylenedicarboxylate and singlet oxygen have been investigated. The X-ray analysis of four adducts indicated the pyramidalization of the central double bond. Density functional theory calculations on the isolated products and model compounds showed excellent agreement between the experimental and theoretical determined butterfly angles. Furthermore, it has been shown that a cyclopropyl group fused to [2.2.2] system decreases significantly the degree of the pyramidalization which is attributed to the steric interactions between the cyclopropyl group and ethano bridge of the norbornene systems. Due to the instability of the bicyclic endoperoxides, their X-ray analysis could not be carried out. DFT calculations on model compounds showed increased bending in the case of the product obtained by the addition of singlet oxygen to endo-2,3,4,7-tetrahydro-1H-1,4-methanobenzocycloheptene-7-carboxylic acid ethyl ester.

A "ring expansion-annulation strategy" for the synthesis of substituted azulenes is described based on the reaction of beta'-bromo-alpha-diazo ketones with rhodium carboxylates. The key transformation involves an intramolecular Buchner reaction followed by beta-elimination of bromide, tautomerization, and in situ trapping of the resulting 1-hydroxyazulene as a carboxylate or triflate ester. Further synthetic elaboration of the azulenyl halide and sulfonate annulation products can be achieved by employing Heck, Negishi, Stille, and Suzuki coupling reactions. Reaction of the azulenyl triflate 84 with pinacolborane provides access to the azulenylboronate 91, which participates in Suzuki coupling reactions with alkenyl and aryl iodides. The application of these coupling reactions to the synthesis of biazulenes, terazulene 101, and related oligoazulenes is described, as well as the preparation of the azulenyl amino acid derivative 110.

HNS-32, an azulene-1-carboxamidine derivative, is an originally synthesized antiarrhythmic compound. Its cardiovascular effects after oral administration (1-10 mg/kg) were assessed using the pentobarbital-anesthetized in vivo rat model in comparison with those of verapamil (3 mg/kg, p.o.). Verapamil decreased the heart rate and mean blood pressure and prolonged the PR interval without changing the QRS width (n = 6). Similar results were observed for HNS-32 except that the QRS width was prolonged by the highest dose and the effects occurred slowly and lasted longer. These results suggest that HNS-32 is an orally active slowly-acting calcium plus sodium channel blocker.

The relationship between free radicals and acute or chronic inflammation has been well established. We have previously reported the significant antioxidant activity of the natural azulene derivatives chamazulene and guaiazulene. Furthermore, some synthetic azulene analogues have been found to possess anti-inflammatory activity. In this investigation we report the synthesis of five 3-alkyl or 3-(hydroxy)alkylazulene-1-carboxylic acids and esters, from tropolone, via the corresponding furanone. The synthesised compounds were tested for their effect on the peroxidation of rat hepatic microsomal membrane lipids, applying the 2-thiobarbituric acid test. Their anti-inflammatory activity was evaluated in vitro by the offered inhibition of soybean lipoxygenase. All the tested molecules were found to inhibit lipid peroxidation by 100% at 1 mM. They were also found to considerably inhibit lipoxygenase activity. The above results are discussed in relation to the structure and physicochemical properties of the examined azulene derivatives.

The title compound, C(20)H(21)NO(3), is a derivative of Aib (alpha-aminoisobutyric acid) and is cyclized at the C(alpha) position by biphenyl rings. The seven-membered ring possesses C2 symmetry. The C(alpha) cyclization causes the backbone to assume a helical conformation in the crystal structure. The packing of the molecules is stabilized by intermolecular C-H.O, C-H.pi and N-H.O hydrogen bonds.

Photochemical rearrangement of hydroxy ester 2, easily obtained from santonin (1), afforded butenolide 4, a good starting material for the synthesis of 7,11-guaien-8,12-olides. Compound 4 has been transformed into compound 10, which has been used for the synthesis of podoandin (5) and (+)-zedolactone A (ent-6). Regioselective elimination of the acetyl group on C10 afforded directly podoandin (5). For the synthesis of ent-6, a hydroxyl group has been regio- and stereoselectively introduced at the 4alpha-position through the 3alpha,4alpha-epoxide 15. The basic hydrolysis of the 10-acetyl group in compound 18 took place with concomitant intramolecular conjugated addition of the alkoxide to the butenolide moiety to give ether 19. Cleavage of the 7,10-oxido bridge via the lactone enolate afforded (+)-zedolactone A (ent-6). This synthesis has allowed for the establishment of the absolute stereochemistry of natural zedolactone A as the enantiomer of our synthetic product.

3-Methyl-1,8-dihydrocycloheptapyrazol-8-ones (2a-c), prepared from 3-acetyltropolones (1a-c), were treated with diazomethane, methyl iodide, dimethyl sulfate, and diethyl sulfate to give 1- and 2-alkylated compounds. The 1,8-dihydrocycloheptapyrazol-8-one (2a) also reacted with 2-(dimethylamino)ethyl, 2-(diethylamino)ethyl, 3-(dimethylamino)propyl, and 2,3-dihydroxypropyl chloride to afford the corresponding 1-substituted products. A preliminary study was made of the biological activities of some of the obtained compounds.

A series of alkylazulene-1-sodium sulfonate derivatives which has an isopropyl group at 6-position were synthesized, and their anti-ulcer activities were examined in Shay pylorus-ligated rats. The values of lipophilicity (log P) as a parameter of these new azulene derivatives were also examined in reference to the structure-activity relationship. The optimum value of log P, which showed maximal anti-ulcer activity, was about -0.46. Among the derivatives of azulene examined, 3-ethyl-6-isopropylazulene-1-sodium sulfonate (compound IXb:XT1-785) exhibited the most potent inhibitory action against Shay ulcer, and its anti-peptic activity was similar to that of 3-ethyl-7-isopropylazulene-1-sodium sulfonate (KT1-32). It also had more activity than guaiazulene sodium sulfonate (GAS). Furthermore, KT1-785 was extremely stable under heating as compared to GAS.

A series of novel, representatively substituted amides of thujic acid were prepared and screened for insect repellent and attractant potential. In repel-lency tests the N,N-diethylamide was the most potent compound, surpassing the activity of the standard repellents dimethyl phthalate and fencholic acid. In contrast, the N-monoethylamide displayed attractant activity.