Search

A new synthesis of 3-oxo-28-hydroxylup-20(29)-ene from the available natural triterpenoid betulin was developed. α,ω-Diketodiesters were prepared for the first time by different methods from 3-oxo-28-hydroxylup-20(29)-ene and a series of natural dicarboxylic acids. Steglich reaction conditions gave the highest yields. One of the synthesized α,ω-diketodiesters was moderately active in vitro against A-549 lung carcinoma.

The review describes the most common macrolactonization reactions, including the activation of one and/or another terminal functional group in a seco acid in the synthesis of natural and biologically active compounds, and also analyzes the advantages and disadvantages of the described macrolactonization methods.

Single-pot ozonolytic synthesis of acylhydrazones based on ozonolytic cleavage of 1-methyl-2,2-dichloro-1-ethenylcyclopropane in methanol and the treatment of intermediate peroxides with a twofold excess of hydrazides of a series of carboxylic acids (decanoic, cyclohexanecarboxylic, isonicotinic, benzoic, p- and o-hydroxybenzoic ones) has been suggested.

The behavior of aliphatic (cyclohexanecarboxylic) and aromatic (salicylic and isonicotinic) carboxylic acid hydrazides toward peroxide products of ozonolysis of a terminal alkene, non-1-ene, in protic (methanol) and aprotic solvents (THF, methylene chloride) has been studied. These hydrazides are capable of acting as reducing agents or decomposing intermediate peroxides. For the synthesis of N′-octylidene isoniazid derivative, it is advisable to carry out the reaction in methanol, whereas the use of THF as solvent favors formation of N′-octylidenecyclohexane-1-carbonydrazide. Salicylic acid hydrazide showed a low efficiency; in this case, mixtures of the corresponding hydrazone with octanoic acid or its methyl ester were formed in a low yield.

Efficient methods have been developed for the synthesis of three potentially useful macroheterocycles containing pyridine-2,6-dicarboxylic and adipic acid ester and hydrazide fragments starting from tetrahydropyran (commercial petrochemical product) through intermediate 8-hydroxyoctan-2-one. The key stages were [2+1]-condensation of the latter with pyridine-2,6-dicarboxylic and adipic acid chlorides and [1+1]-condensation of the resulting α,ω-diketo diesters with dihydrazides derived from the same diacids. The structure of the synthesized compounds was confirmed by IR, NMR, and mass spectra.

Optically active cyclobutanediyl- and cyclopropanediylbisalkylidene dihydrazides of isonicotinic and salicylic acids were synthesized when the peroxide products of ozonolysis of (–)-α-pinene and (+)-Δ3-carene were reduced with isonicotinic and salicylic acid hydrazides in methanol, methylene chloride or tetrahydrofuran. Using QSAR models, high antituberculosis activity in combination with low values ​​of acute toxicity and minimal inhibitory concentration was predicted for the obtained compounds.

Treatment of peroxide ozonolysis products of the bicyclic monoterpenes (–)-α-pinene and (+)-3-carene with 4-hydroxybenzohydrazide in methylene chloride or tetrahydrofuran gave the corresponding keto acids, whereas keto esters were formed in methanol.

We earlier discovered a new reaction in the chemistry of organoaluminum compounds (OACs), specifically, the formation of O-isobutyl acetals on low-temperature (–70°C) treatment of seven-membered lactones with a double (or more) molar amount of diisobutylaluminum hydride (DIBAH) in methylene chloride. To assess the boundaries for the formation of isobutyl acetals depending on the ring size, we involved in the low-temperature hydride reduction six-, eight-, and thirteen-membered lactones. To determine how the scope of the new reaction depends on the nature of the organoaluminum reagent, we tested triisobutylaluminum (TIBA). To determine how the formation of isobutyl acetals on low-temperature (–70°C) reduction with excess DIBAH in CH2Cl2 depends on whether the starting ester is cyclic or acyclic and, if the former is the case, on the ring size in the ester, we used the acyclic methyl octadecanoate as the starting compound. It was found that the new reaction in the chemistry of AOC with DIBAH as the reducer is characteristic only of seven-membered lactones and atypical of acyclic methyl octadecanoate and ricinoleate (i.e. acids with the carbon chain length more than 6).

Efficient syntheses of six potentially useful optically pure macroheterocycles with ester and dihydrazide fragments were developed from available natural Δ3-carene through intermediate (31R,33S)-32,32-dimethyl-3(1,3)cyclopropyla-5-oxohexanoic acid using in the key steps [2+1]-reactions of the last with di- or triethylene glycol and [1+1]-condensation of the resulting α,ω-diketodiesters with several dicarboxylic acid dihydrazides. The structures of the obtained compounds were confirmed by IR and NMR spectroscopy and LC-MS.

Reduction of the peroxide ozonolysis products of (–)-α-pinene and (+)-3-carene by capric and benzoic acid hydrazides in CH2Cl2 or THF produced diacylhydrazones either pure or mixed with the corresponding ketoacids. The capric acid diacylhydrazone formed primarily in CH2Cl2; benzoic acid diacylhydrazone, in THF. The only reaction products formed in MeOH were the corresponding ketoesters.

Examples of hydroboration–oxidation of natural mono-, sesqui-, di-, and triterpenoids are reviewed. Diborane, BH3·THF, BH3·Me2S, disiamylborane, thexylborane, dicyclohexylborane, 9-borabicyclo[3,3,1]nonane (9-BBN), and diisopinocampheylborane are used as the hydroboration reagents; H2O2 mixed with KOH, NaOH, and NaOAc, as the oxidants. Most of the examples address mono- and sesquiterpenoids with far fewer describing di- and triterpenoids.

The results of development of the control system over the population of cotton bollworm Helicoverpa armigera Hbn are presented to protect seed plantings of tobacco with the use of plant isolation. The studies were conducted in the Krasnodar Territory on a tobacco variety Yubileiny novy 142. The regulation of the cotton bollworm population on tobacco seed plantings was carried out by the method of mass capture of male pests with pheromone traps in order to change the gender balance. This was done together with the application of a biopreparation and sowing of a trap crop (corn) to attract and catch butterfl ies at an earlier stage. At a high degree of bollworm population (4–10 specimens / tobacco infl orescence) on non-isolated plants, insecticides based on baculovirus of nuclear polyhedrosis of cotton bollworm FermoVirin XC (in the doze 1.0– 4.0 g/ha) and Helicovex (0.05–0.2 l/ha) were used three times with an interval of 7 days in combination with “male vacuum”. Biological effi ciency was 38– 77 and 62–84% in reducing the number of bollworm larvae, 41–75 and 60–79% in decreasing the damage, respectively. The decrease in the number of bollworm larvae on isolated plants reached 36– 70 and 58–79%, the decrease in damage – 39–69 and 60–72%, respectively. Treatment of seed plots with virus insecticides allowed to save from 22 to 43 kg of the biological yield of tobacco seeds per 1 ha on non-isolated plants and from 21 to 51 kg on isolated plants. With a low number of hatching larvae (14 specimens / 100 plants), a single use of the preparations Bitoxibacillin (Bacillus thuringiensis var. Thuringiensis) and Lepidocide (Bacillus thuringiensis var. Kurstaki) reduced the amount of phytophage by 47–75 and 48–64%, respectively. The system is recommended for use on other crops damaged by cotton bollworm, including in organic farming technologies.

The reaction of hydrazides of alicyclic capric and aromatic benzoic and p-hydroxybenzoic acids with the peroxide product of non-1-ene ozonolysis was studied. Capric acid hydrazide exhibits the strongest reducing properties in aprotic solvents (methylene chloride, THF) and leads to chemoselective and high-yield (~ 80%) formation of the corresponding acylhydrazone. p-Hydroxybenzoic acid hydrazide forms a similar derivative with a yield of 67% only in THF.

A three-step synthesis of potentially biologically active 30- and 32-membered macroheterocycles with esters and acylhydrazines starting from methyl undecylenate was developed based on [1+1]-condensation of intermediate tetraesters, i.e., bis(10′ -methoxy-10′-oxodecyl)- or bis(11′-methoxy-11′ -oxoundecyl)hexanedioate, with hydrazine hydrate. The structures of the synthesized compounds were confirmed using IR and NMR spectroscopy and mass spectrometry.

Six optically active macroheterocycles bearing ester and dihydrazide moieties were synthesized from available natural (-)-α-pinene through the intermediate keto acid, (31R,33R)- 1-hydroxy-32,32-dimethyl-1,4-dioxopentaphane, using the [2+1] reaction of this keto acid with di- or triethylene glycols and the [1+1] condensation of the resulting α,ω-diketo diesters with dicarboxylic acid dihydrazides in the key steps.

Controlled ozonolysis of (S)-(–)-limonene in the presence of Py gave 4-methyl-3-(3-oxobutyl)pent-4-enal or 4-methyl-3-(3-oxobutyl)pent-4-enoic acid depending on the solvent (CH2Cl2 or MeOH). Exhaustive ozonolysis produced 3-acetyl-6-oxoheptanoic acid. Ozonolysis of abietic acid in CH2Cl2 in the presence of Py formed stable epoxytrioxolaneabietic acid; in MeOH–Py, the epoxyketoaldehyde corresponding to cleavage of the C13–C14 bond.

Four potentially biologically active 31-, 32-, and 33-membered macroheterocycles with ester and hydrazide fragments have been synthesized by [1 + 1]-condensation of ethane-1,2-diyl bis(10-oxoundecanoate) with malonic, glutaric, L-(+)-tartaric, and pyridine-2,6-dicarboxylic acid dihydrazides. The product structure has been confirmed by IR, NMR, and mass spectra.

An improved procedure for preparing 4Z-nonen-1-ol, a key intermediate in the synthesis of sex pheromones of cabbage moth and cotton bollworm, from the cyclic butadiene-isoprene dimer (1-methyl-1Z,5Z-cyclooctadiene) was developed. In this procedure, the peroxide product of regioselective partial ozonolysis (0.9 equiv of O3) of the codimer across the trisubstituted double bond is converted in one step to 9-hydroxy-5Z-nonen-2-one with NaBH(OAc)3, the reagent that does not affect the keto groups present in the structure or formed in the process.

Effective syntheses of three optically active macroheterocycles with ester, azine, and dihydrazide fragments were developed from available natural L-menthol through intermediate 3R,7-dimethyl-6-oxooctanoic acid using [2 + 1]-reaction of the last with diethylene glycol and [1 + 1]-condensation of the resulting α,ω-diketodiester with hydrazine hydrate and dihydrazides of several dicarboxylic acids in the key steps. The structures of the synthesized compounds were confirmed using IR and NMR spectroscopy and GC-MS.

A new version has been proposed for the synthesis of analogs of the known herbicides mecoprop (MCPP) and dichlorprop (2,4-DP) by ozonolysis of chloro derivatives of (pent-3-en-2-yloxy)benzene.

Reactions were studied of peroxide ozonolysis products obtained from linear and cyclic alkenes with hydroxylamine prepared in situ from NH2OH·HCl by hydrogen chloride neutralization with sodium acetate. A one-pot reactions sequence was performed: alkene oxidation with ozone → reduction to a carbonyl compound with hydroxylamine → condensation of the carbonyl compound with hydroxylamine providing a possibility of direct transformation of alkenes in keto- and aldoximes excluding the stage of preparation and isolation of the carbonyl compound.

A mixture of cyclic lactones [7- (mentholactone), 14-, 21-, 28-, and 35-membered polylactones] instead of the expected [2 + 1]-condensation products was obtained from the reaction of 3R,7-dimethyl-6Shydroxyoctanoic acid, which is accessible from l-menthol, and glutaric, adipic, and bicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid dichlorides in Py in the presence of N,N-dimethylaminopyridine. The structures were confirmed using PMR, 13C NMR, and mass spectra.

Low-temperature ozonolysis of 2-alkenyl-1,1-dichlorocyclopropanes under different conditions (O3/MeOH–CH2Cl2–NaOH, O3/MeOH or O3/CH2Cl2–AcOH with subsequent treatment with semicarbazide hydrochloride) afforded the corresponding carbonyl and carboxy derivatives at different ratios, depending on the substrate structure and workup procedure. Peroxide products of ozonolysis of 1,1-dichloro-2-ethenylcyclopropane [3-(2,2-dichlorocyclopropyl)-1,2,4-trioxolane and (2,2-dichlorocyclopropyl)(methoxy)methyl hydroperoxide] turned out to be more stable than those derived from 1,1-dichloro-2-ethenyl-2-methylcyclopropane and were isolated in the pure state.

A one-pot procedure has been developed for the synthesis of phenylhydrazones by ozonolysis of olefins in methanol at 0°C and subsequent reduction of peroxide intermediate with excess 1: 2 mixture of phenylhydrazine hydrochloride and sodium acetate.

Tosylhydrazide was shown to be an effective reductant in protic solvents for the peroxide ozonolysis products of ∆3-carene, (–)-α-pinene, and (S)-limonene. Either α,ω-ditosylhydrazones or α,ω-ketotosylhydrazonoacids were formed depending on the nature of the trisubstituted cycloalkene.

An effective scheme for the synthesis of optically active sex pheromone of the yellow mealmoth has been developed and its preparative form has been created.

A stereoselective synthesis of natural (+)-caparratriene was developed starting from commercially available L-menthol and tiglic aldehyde. The key step was a Wittig reaction of the latter with the triphenylphosphorane generated from (R)-(–)-citronellyl bromide. (+)-Caparratriene as a mixture (4:1) of 2E,4E- and 2E,4Z-stereoisomers is a known anticancer agent.

Hydroboration-oxidation of methyl abietate by diborane in THF occurred preferentially at the sterically unhindered β-side of the molecule without involving the ester. The known hydroboration-oxidation product methyl 7β-hydroxy-13α-isopropylpodocarp-8(14)-en-15α-oate and previously unknown methyl 7β-hydroxy-13-isopropyl-8β-podocarp-13(14)-en-15α-oate, 14β-hydroxy-13α-isopropylpodocarp-7(8)-en-15α-oate, and 7β,14-dihydroxy-13α-isopropyl-8β-podocarpan-15α-oate, i.e., products from monohydroboration-oxidation at the ∆7,8- and ∆13,14-bonds without their respective shifts and from dihydroboration, were obtained.

Optically active isoniazid derivatives containing a cyclopropane or cyclobutane fragment have been synthesized by ozonolysis of (+)-Δ3-carene and (–)-α-pinene, followed by treatment of the ozonolysis products with isonicotinic acid hydrazide.

A one-step synthesis of potentially useful enantiomerically pure macroheterocycles with four esters was developed starting from natural castor oil [(R,Z)-(+)-12-hydroxy-9-octadecenoic acid triglyceride].

The reactivities of the keto analogs of methyl ricinolate and its triglyceride with hydrazine hydrate were studied. The ester was found to be inert, which made it possible to synthesize a macrocyclic azine with a side chain hydrazone moiety from a 12-oxo-derivative.

Until now, about 400 different natural seven-membered terpenoid lactones have been isolated from a broad spectrum of organisms. The majority (245) of the reported compounds occurred in plants. A significant number (101) of the sevenmembered lactones were isolated from marine organisms. The fewest (22) were secondary metabolites of microorganisms. Thus, oxepanones are confirmed to be widely distributed natural compounds that play various biological roles in diverse living organisms. Research on the biological activities of the principal isolated 2-oxepanones showed that most of them exhibit antimicrobial, antifeedant, insecticidal, antioxidant, anti-inflammatory, and anticancer properties. Several of them are used in agriculture as plant growth inhibitors. For example, limonoids isolated from Harrisonia abyssinica suppressed sprouting of seeds of the pathogenic plant Striga, which parasitizes the root system of crops and reduces the yields of grains and beans [1]. Derivatives of natural seven-membered lactones are also used in pharmacology. Thus, the limonoid prieurianin, which was isolated from Entandrophragma candolei (Meliaceae), could be used to prevent obesity even in diabetes patients [2]. Chiisanogenin obtained from the alcohol extract of Acanthopanax (Eleutherococcus) senticosus is a biologically active constituent that treats diseases associated with glycation [3]. Despite definite success, information on the biological properties of natural seven-membered terpene lactones is still limited. Further research could embellish the understanding of their mechanisms of biogenesis and their biological roles in nature and medicine. The goal of the present review was to organize information on seven-membered terpene lactones with respect to their structures, occurrence in nature, synthetic accessibility, and pharmacological activity. 1. Natural seven-membered terpene lactones: structures, occurrence in nature, and biological activity

The behavior of seven-membered lactones from the triterpenoid betulin and S-(+)-camphor in a novel reaction with organoaluminum compounds was studied using low-temperature reduction of monoterpene sevenmembered lactones by an excess of diisobutylaluminum hydride in CH 2 Cl 2 .