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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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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 .

Low-temperature treatment of acyclic (–)-mentholactone derivatives with excess diisobutylaluminum hydride in methylene chloride afforded O-isobutyl derivatives of seven-membered lactols. Methyl 6-hydroxy-3,7-dimethyloctanoate behaved similarly to (–)-mentholactone, and its 6-oxo analog, similarly to (–)-mentholactone and isomentholactone.

Transformations of peroxy products formed by ozonolysis of undecylenic acid derivatives (methyl ester and hydride reduction product, 10-undecen-1-ol) in various protic and aprotic solvents (MeOH, PriOH, tetrahydrofuran, 1: 5 AcOH–CH2Cl2 mixture), occurring under the action of such reductants as hydroxylamine and semicarbazide hydrochlorides, were studied. These reductants exhibit high performance and in some cases high chemoselectivity, which allowed the development of a number of one-pot procedures for the synthesis of acyclic α,ω-bifunctional compounds, the majority of which are widely used in medicine, perfumery, cosmetics, engineering, and chemical industry, e.g., as block synthons in targeted organic synthesis.

The condensation of 7-oxooctyl 7-oxooctanoate and bis(7-oxooctyl) hexanedioate with bicyclo-[2.2.1]heptane-2-endo,3-endo-dicarbohydrazide and its 5-endo,6-endo- and 5-endo,6-exo-dihydroxy derivatives obtained from dimethyl norbornene-2-endo,3-endo-dicarboxylate gave the corresponding macrocyclic lactones containing a ketone azine fragment instead of the expected hydrazide moiety.

Peroxide products of oleic acid ozonolysis treated with semicarbazide and hydroxylamine hydrochlorides in methanol are predominantly converted into methyl nonanoate and dimethyl nonanedioate, in 2-propanol, into isopropyl nonanoate and monoisopropyl ester of nonanedioic acid, and also into nonanenitrile, in tetrahydrofuran and in a mixture of acetic acid with dichloromethane, into nonanoic and nonanedioc acids, and also in nonanal oxime and 9-(hydroxyimino)nonanoic acid.

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.

Here we report on new versions of this reaction by the examples of adamantanolactone (XII), β-campholide (XIII), caranolactone (XIV), and also allobetulonolactone (XV) and norallobetulonolactone (XVI) obtained from betulin [3]. At the reduction of adamantanolactone (XII) isobutylacetal (VII) formed in 60% yield. β-Campholide (XIII) afforded a diastereomeric mixture (58 : 42 according to Н NMR data) of acetal VIII. In the stereochemical assignment of the NMR spectra of compound VIII the chemical shift values of the bridgehead carbon atoms (С, С) and those in the bottom of the boat (С, С), and also the chemical shifts and coupling constants of the anomeric proton Н are informative. Relatively downfield signals of the mentioned atoms С (~δ 1–2.5 ppm), and also more upfield shift of the anomeric proton Н at 5.06 ppm and a large value of J3,4 5.3 Hz indicate the equatorial orientation of the i-BuО group in the prevailing stereoisomer. According to Н NMR data compound IX formed as a mixture (3 : 1) of epimers with respect to asymmetric acetal center. The value J2,3 8.9 Hz of the anomeric proton in the predominant stereoisomer indicates its axial orientation and consequently the equatorial position of the isobutoxy group.

Hydrochlorides of hydroxylamine and semicarbazide efficiently reduce peroxide products of olefin ozonolysis in a system CH2Cl2-AcOH leading to the formation of carboxylic acids and their derivatives. The application of water as the solvent component favors the increase in the fraction of nitrogen-containing organic compounds (semicarbazones, keto- and aldoximes, nitriles) and reduction in the yield of carboxylic acids.

Treatment with hydroxylamine and semicarbazide hydrochlorides of peroxide products obtained by ozonolysis of olefins in tetrahydrofuran gives mainly carboxylic acids and their derivatives.

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.

In this work, we report the results of lowtempera� ture ozonolysis of benzyl and phenyl allyl ethers for the preparation of methyl benzyland phenoxyace� tates. The esters of arylacetic acids were prepared by two methods: in the methanol-methylene chloride system in the presence of alkali at -65°C or in methanol at -78°C followed by the treatment of intermediate per� oxide products with semicarbazide hydrochloride. The ozonolysis of benzyl and phenyl allyl ethers Ia and Ib in the presence of NaOH was found to lead in high yield and selectivity to esters IIa and IIb, respectively. Byproducts formed in small amounts are the corre� sponding alkoxyacetic aldehydes IIIa and IIIb. At the same time, the treatment of primary ozonation prod� ucts (peroxides) with semicarbazide hydrochloride gives a mixture of esters IIa and IIb and acetals IVa and IVb (Table 1).

Ozonolysis of (1R,3R)-p-menth-4-en-3-ol in methylene chloride or methanol in the presence of pyridine afforded a mixture of equimolar amounts of epimeric 1-[(2R,4S,6S)- and 1-[(2S,4S,6S)-6-hydroxy-4-methyltetrahydro-2H-pyran-2-yl]-2-methylpropan-1-ones. A probable reaction mechanism is discussed.

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

Hydroxylamine and semicarbazide hydrochlorides were shown to be efficient as reducing agents toward peroxide products of ozonolysis of various olefins with different degrees of substitution. The rate of the transformations aldehyde → aldehyde oxime → nitrile → ester upon treatment of peroxides with hydroxylamine hydrochloride in isopropyl alcohol was lower than in methanol.