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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.

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.

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.

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 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.

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.

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.

Efficient syntheses of two potentially useful optically active macroheterocycles with esters and dihydrazides of 2,6-pyridinedicarboxylic and adipic acids starting from available natural L-menthol and passing through intermediate 8-hydroxy-2,6R-dimethyloctan-3-one were developed. The key steps were [2 + 1]-reaction of the last with 2,6-pyridinedicarboxylic acid chloride and [1 + 1]-condensation of the resulting α,ω-diketodiester with 2,6-pyridinedicarboxylic- and adipic-acid dihydrazides. The structures were confirmed using IR and NMR spectroscopy and LC-MS.

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.

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 .

Research from the last 20 years on the use of ozonolysis of cyclic and acyclic mono- and dienes and aromatic compounds in various steps of the total synthesis of insect pheromones and juvenoids was reviewed.

An optically active macrocyclic diesterdihydrazide with 2,6-pyridinedicarboxylic and adipic acid moieties was synthesized efficiently from available (–)-α-pinene through an intermediate hydroxyketone [1R-(1′-hydroxyethyl)-3R-(2″-hydroxyethyl)-2,2-dimethylcyclobutane) using successive [2 + 1]-reaction of the last with 2,6-pyridinedicarboxylic acid dichloride and [1 + 1]-condensation of the resulting diketodiester with adipic acid dihydrazide.

The reactivities of hydrazines of HCl and H2SO4 for (–)-α-pinene peroxide ozonolysis products were studied. It was shown that these reagents were less effective and selective than semicarbazide hydrochloride for transformations into cis-pinonic acid and its esters.

The reactions of (R)-n-menth-4-en-3-one and its derivatives with N-containing reagents were studied. New menthane-type acetamides were synthesized.

Examples of thiylation of natural mono- and bicyclic and variously functionalized monoterpenoids (alkenes, ketones, epoxides, alcohols) and the latest transformation pathways of the newly formed sulfur-containing derivatives were reviewed.

Thiylation of (R)-4-menthen-3-one and its derivatives was studied. New sulfides and sulfoxides of the menthane series were synthesized.

Features of the Wittig olefination reaction of menthone lactol and its aluminate by several n-alkylidenetriphenylphosphoranes were studied. The product of the reaction with ethylidenetriphenylphosphorane was used in the synthesis of the sex pheromone of peach leaf miner Lyonetia clerckella.

A synthesis of optically pure methyl- and isopropyl-branched 21-, 22-, 28-, and 29-membered azinodiesters and diesterdihydrazides from l-menthol using [2 + 1]-condensation of (6R)-8-hydroxy-2,6-dimethyloctan3-one and glutaric and adipic acid chlorides and [1 + 1]-reaction of the intermediate diketodiesters with hydrazine hydrate and glutaric acid dihydrazide was developed.

Optically active symmetric macrocyclic diesterazines and diesterdihydrazides were synthesized efficiently from the available natural monoterpene (+)-α-pinene (de 50%) using a [2+1]-reaction of 1′-[(1S,3S)-3-(2hydroxyethyl)-2,2-dimethylcyclobutyl]ethanone and glutaric and adipic acid chlorides followed by [1+1]condensation of the intermediate diketodiesters with hydrazine hydrate or glutaric acid dihydrazide.

Potentially useful symmetric macrocyclic diesterdihydrazides were synthesized efficiently from available petrochemical products (tetrahydropyran and 4-methyltetrahydropyran) using successive [2+1]-condensation of 8-hydroxyoctan-2-one and its 6-methyl derivative with glutaric and adipic chlorides and [1+1]-condensation of the intermediate diketodiesters with glutaric dihydrazide.

Formation of new asymmetric centers with primarily the (S)-configuration was induced by the optically active center of (R)-octadec-9Z-en-7-ol upon Prilezhaev dihydroxylation. This was proved by cyclization of a 1,3-glycol system (de 26%) into the corresponding 1,3-dioxane stereoisomers.

Potentially useful 17-, and 22÷25-membered macrolides containing azine or hydrazide groups were synthesized from tetrahydropyran via [1+1]-condensation at room temperature of 7-oxooctyl-7-oxooctanoate, which was obtained via Tishchenko reaction from 7-oxooctanal, with hydrazine hydrate and hydrazides of several dicarboxylic acids.

Potentially useful 15- and 20-membered macrolides containing azine or hydrazide groups were synthesized from L-menthol via [1+1]-condensation at room temperature of 3R,7-dimethyl-6-oxooctyl-3R,7-dimethyl-6-oxooctanoate, which was obtained from 3R,7-dimethyl-6-oxooctanal via a Tishchenko reaction, with hydrazine hydrate or malonic acid dihydrazide.

Transformations of peroxide ozonolysis products of cyclic and acyclic natural olefins with different degrees of saturation by hydroxylamine and semicarbazide hydrochlorides were investigated.

Using RHF/3-21G, RHF/6-31G(d, p), MP2/6-31G(d, p), B3LYP/6-31G(fd, p) approximations the structure and 13C NMR spectra of 2-alkylsubstituted cyclohexene-2-ones and 2-alkylacroleins are studied and calculated. In the series of 2-alkylcyclohexene-2-ones the effect of the substituent on a deviation from coplanarity of the C=C-C=O fragment is more expressed in comparison with 2-alkylacroleins. This deviation (5°) is not enough to explain the observed properties of 2-alkylcyclohexene-2-ones due to disturbed conjugation. The particular behavior of (R)-4-mentenone in reactions of 1,4-addition and ozonolysis is explained by a more expressed +I-effect of the alkyl substituent in α-position.

Ozonolysis and reduction of olefinic derivatives of ricinolic acid and L-menthol were studied using hydroxylamine hydrochloride and sodium trisacetoxyborohydride to reduce the peroxide products.

Three new approaches to the synthesis of 1-bromo-3S-methylundecane, a key synthon in the synthesis of (S,S,S)-diprionylacetate, a sex pheromone of pine sawflies of the genera Diprion and Neodiprion, were proposed based on chemo-and stereoselective transformations of L-(-)-menthol derivatives.

The possibility of functionalizing the alkyl part of ricinolic acid using the Barton reaction was investigated.

The literature on oxidative transformations of natural monoterpenoids to synthesize insect pheromones was reviewed.

Synthetic approaches to (±)- and (3S)-analogs of the AI component of the Aonidiella aurantii sex pheromone (3S)-methyl-6R-isopropenyldec-9-en-1-ylacetate based on stepwise alkylation of acetoacetic ester by 3-butenylbromide and 1,5-bifunctional 3-methylpentanes were investigated.

A synthesis of the promising optically pure synthon isopropyl-4R-methyl-6-iodohexanoate based on ozonolytic transformation of the product of regiospecific dehydratation of L-(-)-menthol, (R)-p-menth-3-ene, into 2,6R-dimethyl-8-hydroxyoctan-3-one was proposed.

The synthesis of two potentially useful optically active 23- and 30-membered macrolides containing a 1,2-diol system and dihydrazide fragments was developed starting from tetrahydropyran. It was based on [1+1]-condensation of 7-oxooctyl-7-oxooctanoate and bis(7-oxooctyl)hexanedioate with L-(+)-tartaric acid hydrazide.

A novel synthesis of the promising optically pure chiral (4R)-4-methylpentanolide that is based on several regiospecific oxidative transformations of (4R)-2,4-dimethyl-1-(1-methylethyl)-1-cyclohexene, the product of addition of (−)-menthone and methylmagnesium iodide followed by acid dehydration, was proposed.

It was shown that the most effective and stereospecific hydride reductant for (R)-4-menthen-3-one to (1R,3R)-menthen-3-ol was i-Bu2AlH whereas the complex BH3·THF, which exhibited the same properties relative to the substrate carbonyl, was a regiospecific but relatively non-stereospecific hydroborating reagent of its double bond.

A synthesis of two potentially useful bicyclic 26- and 33-membered macrolides containing 1,3-dioxolane and hydrazide fragments was developed starting from tetrahydropyran via a [1+1]-condensation of 7′-oxooctyl-7-oxooctanoate and bis(7-oxooctyl)hexanedioate with hydrazide of L-(+)-tartaric acid acetonide derivative.

(R)-4-Menthenone anti-oxime was synthesized for the first time. Its transformations under Beckman rearrangement conditions were studied.

A new procedure was developed for the synthesis of racemic analogs of 1,5-dimethyl-branched insect pheromones based on monoalkylation of ethyl acetoacetate with 1-acetoxy-5-bromo-3-methylpentane produced upon decyclization of 4-methyltetrahydropyran.