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The crystal structures of four representatives of sulfinamides of the thiazine series are comparatively analyzed for the occurrence of different supramolecular associates, inter- and intramolecular interactions. With a similar molecular geometry, different packing motifs occur in the crystals yielding different-type supramolecular associates due to classical N–H⋯O hydrogen bonds. The features of transferring the sulfinamide open-chain supramolecular synthon from racemic to homochiral environment consisting in the appearance of “secondary cross-linking” are studied.

The crystal structures of four sulfonamides of the benzothiazine series, fused to an epoxidized norbornane moiety and containing various substituents in the para position of the aromatic ring, were determined. Despite the different volume and acceptor/donor properties of substituents (hydrogen, a methyl group, a cyano group, fluorine), these compounds form isostructural crystals. The main supramolecular motif of these crystals consists of heterochiral chains, which run along a glide plane and are formed via hydrogen bonds between the axial oxygen atom of the sulfonyl group and the amino-group nitrogen atom. The chains are cross-linked to form a crystal structure through C—H…O interactions between the hydrogen atom at the epoxide ring and the equatorial sulfonyl oxygen atom.

In recent years, meroterpenoids have found wide biomedical application due to their synthetic availability, low toxicity, and biocompatibility. However, these compounds are not used in targeted drug delivery systems due to their high affinity for cell membranes, both healthy and in cancer cells. Using the approach of creating supramolecular amphiphiles, we have developed self-assembling systems based on water-soluble pillar[5]arene and synthetic meroterpenoids containing geraniol, myrtenol, farnesol, and phytol fragments. The resulting systems can be used as universal drug delivery systems. It was shown by turbidimetry that the obtained pillar[5]arene/synthetic meroterpenoid systems do not interact with the model cell membrane at pH = 7.4, but the associates are destroyed at pH = 4.1. In this case, the synthetic meroterpenoid is incorporated into the lipid bilayer of the model membrane. The characteristics of supramolecular self-assembly, association constants and stoichiometry of the most stable pillar[5]arene/synthetic meroterpenoid complexes were established by UV-vis spectroscopy and dynamic light scattering (DLS). It was shown that supramolecular amphiphiles based on pillar[5]arene/synthetic meroterpenoid systems form monodisperse associates in a wide range of concentrations. The inclusion of the antitumor drug 5-fluoro-2′-deoxyuridine (floxuridine) into the structure of the supramolecular associate was demonstrated by DLS, 19F, 2D DOSY NMR spectroscopy.

Acylation of benzothiazinesulfonamides obtained by the oxidation of N-sulfinylaniline and norbornadiene adducts with acid chlorides and carboxylic anhydrides led to the formation of N-acylated sulfonamide hybrid pharmacophores. Molecular and crystal structure of the acylated products was established by X-ray diffraction method.

The effects of temperature, solvent nature, and high hydrostatic pressure on the rate of the ene reaction of 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione with β-pinene have been studied. The reaction gives only one product and is accompanied by a large heat effect. Comparison of the activation and reaction volumes indicates cyclic structure of the transition state. The reaction rate changes by a factor of 200 in the series of nine examined solvents, but this variation is not determined by solvent polarity.

N-Sulfinylanilines derived from 4-bromoaniline, 3-nitroaniline, and 4,4′-di(ethane-1,2-diyl)dianiline were synthesized. X-ray diffraction analysis of 4-bromo-N-sulfinylaniline, 3-nitro-N-sulfinylaniline, and 4,4′-(ethane-1,2-diyl)di-N-sulfinylaniline was performed. The sulfinyl function in the planar conformation of the Ar-NSO fragment was found to have Z configuration. The nature of intra- and intermolecular structure-forming interactions was established.

A number of new membrane anchors based on water-soluble aminoglycerides with geraniol fragments have been synthesized. A biomimetic approach was used based on the design of meroterpenes structurally similar to archaeal lipids. Turbidimetry and laser Doppler microelectrophoresis showed that the synthesized compounds were incorporated into unilamellar dipalmitoylphosphatidylcholine (DPPC) vesicles.

Current developments in the pharmaceutical industry indicate an increase in attention towards natural products and their analogues. This is primarily due to the availability and variety of natural organic structures that exhibit a wide range of biological activity. Unique among them is the several individual classes of natural products of mixed biogenic origin with isoprenyl fragments. These conjugated biosynthetic compounds are formed from isoprenyl fragments and fragments of other classes of natural metabolites (flavonoids, alkaloids, lipids, peptides, etc.) synthesized by other pathways. They are combined into one common group called meroterpenoids. Interest in meroterpenoids is due to their unique hybrid structure, where the terpene is either the main unit or is part of the compound as a functional group. Thus, they have diverse practical applications. For example, the biological properties of isoprenyl flavonoids are primarily associated with the properties of phenolic compounds, which are characterized by their antioxidant activity. Introduction of isoprenyl substituents, therefore, plays a modifying role, resulting in an increase in their lipophilicity and variation in their oxidation-reduction potential. Substances with antitumor activity, HIV-1 transcriptase inhibitors, immunomodulators, and antifeedants have been identified among meroterpenoids containing the quinone fragment. The presence of alkaloid and saponin meroterpenoids explains the medicinal properties of a number of plants used in medicinal chemistry around the world. The review considers progress in the synthesis and functionalization of isoprenoids in conjugate biosynthesis. A detailed classification of meroterpenoids is made in accordance with the role of the isoprenoid fragment and the class of compounds to which this fragment belongs. The schemes and mechanisms of conjugated biosynthesis are discussed. Particular attention is paid to the phenol-flavonoid derivatives, isoprenoid lipids, terpenic alkaloids and isoprenyl glycosides. Also, structure-property patterns are considered. In addition, issues related to the biological activity of various classes of meroterpenoids, which have found application in the therapy of cardiovascular diseases, diabetes, inflammatory processes, tumors, tropical diseases, etc., are discussed in detail.

1,2,3,4,4a,10b-Hexahydro-1,4-methano-6H-dibenzo[c,e]-5,6-thiazine-5,5-dioxide has been converted into the corresponding N-acyl derivatives via the reaction with acid chlorides and anhydrides. X-Ray diffraction data have revealed the presence of an intramolecular С–H···O=S hydrogen bond in the molecules of the obtained compounds.

In the last decade, the chemistry of meroterpenoids—conjugated molecules formed from isoprenyl fragments through biosynthetic pathways—has developed rapidly. The class includes some natural metabolites and fully synthetic fragments formed through nonbiological synthesis. In the field of synthetic receptors, a range of structures can be achieved by combining fragments of different classes of organic compounds into one hybrid macrocyclic platform which retains the properties of these fragments. This review discusses the successes in the synthesis and practical application of both natural and synthetic macrocycles. Among the natural macrocyclic meroterpenoids, special attention is paid to isoprenylated flavonoids and phenols, isoprenoid lipids, prenylated amino acids and alkaloids, and isoprenylpolyketides. Among the synthetic macrocyclic meroterpenoids obtained by combining the “classical” macrocyclic platforms, those based on cyclodextrins, together with meta- and paracyclophanes incorporating terpenoid fragments, and meroterpenoids obtained by macrocyclization of several terpene derivatives are considered. In addition, issues related to biomedical activity, processes of self-association and aggregation, and the formation of host–guest complexes of various classes of macrocyclic merotenoids are discussed in detail.

Reaction of 4-fluoro-N-sulfinylaniline with norbornene and norbornadiene has afforded the Diels–Alder adducts of benzothiazine structure that have been oxidized into the corresponding benzothiazine sulfonamides. Structure of the obtained compounds and stereochemistry of the diene addition and epoxidation of norbornene olefin bonds have established by means of X-ray diffraction method.

N-Sulfinyl-3-(trifluoromethyl)aniline reacted with bicyclo[2.2.1]hept-2-ene and bicyclo[2.2.1]-hepta-2,5-diene to give the corresponding Diels‒Alder adducts which were oxidized to 8-trifluoromethyl-2,3,4,4a,6,10b-hexahydro-5λ6-1,4-methanodibenzo[c,e][1,2]thiazine-5,5(1H)-diones. The cycloaddition occurred predominantly with participation of the S=N–C1=C6 fragment of N-sulfinyl-3-(trifluoromethyl)aniline and exclusively at the endo side of bicyclo[2.2.1]heptenes.

An X-ray crystallographic study of a new compound is performed and the structure of five sulfin- and sulfonamides of the thiazine series is discussed. The conformation of the thiazine ring in all structures (a distorted boat) is stabilized by the intramolecular interaction of the C-H…N type. The nitrogen atom of the thiazine ring has a pyramidal configuration. The geometry of isolated molecules is calculated at density functional theory level (PBE1PBE, 6-31G(d,p)) and compared to that observed in the crystals. In the crystal structures different packing motifs are implemented with the formation of supramolecular associates of different types due to classical hydrogen bonds such as N-H…O.

New water-soluble decasubstituted pillar[5]arenes containing glycine and glycylglycine fragments were synthesized and characterized. The UV, DLS and TEM study showed that interaction of self-associates of the glycylglycine derivatives with Bismarck brown Y produced particles of about 59 nm in size.

From substituted N-sulfinylanilines acting as dienes in the Diels-Alder reaction with norbornadiene S-oxides of benzo-ortho-thiazines were obtained, which were oxidized into the corresponding S,S-dioxides belonging to the class of hybrid thiazinesulfonamide compounds.

Reactions of N-sulfinylanilines with norbornene and norbornadiene result in the Diels-Alder adducts of benzo-ortho-thiazine structure, which was confirmed by the NMR, IR spectroscopy and XRD analysis. In all cases the diene added to the norbornenes bicyclic system at the side of the endo-methylene bridge. The methyl group of meta-N-sulfinyl toluidine directs the norbornene entry into the para-position.

An X-ray structural examination is carried out for 2,3-dimethyl-5-(2′-methylprop-1′-enyl)-6-(morpholyl-4′-carbonyl)-cyclohex-3-en-1-carboxlic acid that is one of the products of the Diels-Alder reaction of an acyclic monoterpene alloocimene with maleic and citraconic anhydrides followed by the ring opening of adducts with morpholine to corresponding amides. The crystals are triclinic; a = 10.619(1) A, b = 12.784(2) A, c = 14.328(2) A; α = 65.752(1)°, β = 87.932(1)°, γ = 78.120(1)°; V = 1733.0(3) A3, P-1 space group, Z = 4 (two independent molecules). In both molecules, the anti-conformation of the carboxylic group is observed, the conformation being stabilized by an intramolecular hydrogen bond involving the carboxylic hydrogen atom and ketonic oxygen.

Reactions of alloocimene with maleic and citraconic anhydrides gave the corresponding Diels-Alder cycloaddition products which may be regarded as new synthetic sesquiterpenoids. The molecular structures of the adducts, determined by X-ray analysis, indicated endo addition of the dienophiles at the most sterically accessible diene system and syn-boat conformation of the bicyclic skeleton.

Natural meroterpenoids often exhibit high and diverse biological activity [1] which is obviously related to their amphiphilicity. Well known examples are tocopherols, tocotrienols [2, 3], cannabinoids [4], prenylflavonoids, etc. [5, 6]. Synthesis of such compounds extends their structural diversity and hence the spectrum of their biological activity. As a rule, synthetic meroterpenoids are more accessible than natural ones whose concentration in natural sources is generally very low. We have studied the Diels–Alder reaction of myrcene as lipophilic diene with 1,4-benzoquinone as hydrophilic dienophile under the conditions allowing both electrophilic double bonds of the dienophile to be involved. Apart from the synthesis of a new meroterpenoid, 2 : 1 adduct of myrcene with benzoquinone, we have determined the regioselectivity of the addition of the second myrcene molecule to initially formed 1 : 1 adduct I which was reported in [7]. By heating benzoquinone with excess myrcene in boiling toluene for 8 h we obtained a crystalline product in ~75% yield. According to the GC/MS data, the crude product was a mixture of four isomers at a ratio of 10 : 15 : 70 : 5 (M 380) with very close retention times ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 12, pp. 1842–1844. © Pleiades Publishing, Ltd., 2014. Original Russian Text © A.V. Chuiko, O.A. Lodochnikova, S.A. Appolonova, V.V. Plemenkov, 2014, published in Zhurnal Organicheskoi Khimii, 2014, Vol. 50, No. 12, pp. 1859–1860.

The reactions of 1-methylcycloprop-2-ene-1-carbonitrile with cyclohexa-1,4-diene and alloocimene gave the corresponding 2:1 addition products as a result of consecutive (conjugate) Alder-ene and Diels-Alder reactions. 1-Methylcycloprop-2-ene-1-carbonitrile acts initially as enophile, and in the second step, as dieno- phile. The structure of the adducts was determined by X-ray analysis.

At elevated temperatures 3-methyl-cyclopropene-3-carbonitrile 1 was found to tetramerize giving compound 2 (3-methyl-2,3-bis(2-t-methyl-2-c-cyanocyclopropyl)-1-(2-t-methyl-2-c,3-c-dicyanocyclopropyl)-cyclopropene) in good yields. This is the first example of Alder-ene type oligomerization of a 3,3-disubstituted cyclopropene. On the basis of the product geometry and stereoselective character of the reaction, a mechanism of formation of 2 involving CN-Alder-ene reaction was proposed. DFT modeling of the mechanism has shown that the CN-Alder-ene reaction is possible as a stepwise process involving a biradical intermediate.

The molecular and crystal structure of dimethyl-(1,4-dimethyl-7-ethylazulyl)-sulfonium perchlorate and dimethyl-(1,4-dimethyl-7-isopropylazulyl)-sulfonium perchlorate was determined by X-ray diffraction analysis. Their crystal structure is mainly determined by C-H...π intermolecular interactions.

A new type of S-containing terpene lactones was produced by the reactions of limonene-1,2-oxide and β-pinene-α-oxide with mercaptoacetic acid.

Monoterpene derivatives with a cyclopropane moiety in the molecule were prepared by reactions of 3-methyl-3-cyanocyclopropene with several monoterpenes and terpenoids (β-myrcene, neoalloocimene, alloocimene, β-pinene, carvone). They were formed using the Diels-Alder reaction, Alder-ene synthesis, conjugated Alder-ene addition, and Diels-Alder cyclization.

Polyfunctional thioterpenoids were formed in the presence of a Lewis-acid catalyst by reaction of (-)-carvone with thiols that involved the endocyclic double bond and the carbonyl.

Reactions of (-)-carvone with aliphatic, aromatic, heterocyclic, and functional thiols, catalyzed with potassium carbonate, gave the corresponding derivatives in high yields. Isopropyl mercaptan, 2-mercaptoethanol, furfuryl mercaptan, and N-acetylcysteine add across the endocyclic double bond of (-)-carvone with the predominant formation of the isomers with the S configuration of C3, whereas addition of hexadecyl mercaptan and 1,2-ethanedithiol mainly yields the R isomers.

From substituted N-sulfinylanilines acting as dienes in the Diels-Alder reaction with norbornadiene S-oxides of benzo-ortho-thiazines were obtained, which were oxidized into the corresponding S,S-dioxides belonging to the class of hybrid thiazinesulfonamide compounds.

7,7-Dimethyl-2,10-epoxybicyclo[3.1.1]heptane obtained by treatment of (-)-β-pinene with peroxybenzimidic acid has α configuration.

Single-electron oxidation in acetonitrile and reduction in DMF of sulfides of 3-RS-1,4-dimethyl-7- ethylazulenes (R = Me, Et, Ph, p-MeC6H4, p-MeOC6H4, N-1-phenyltetrazolyl) leads to stable radical cations and radical anions, respectively. The found reduction potentials of sulfides of the azulene series are close to those of natural and synthetic bioantioxidants. In the radical cations the unpaired electron is essentially delocalized over the cyclopentadienyl fragment of the molecule, and the sulfide group in large measure defines the distribution of spin density. In the radical anion spin density is delocalized in the tropylium cycle, and the influence of the sulfide group is insignificant. Electrochemical oxidation of unsubstituted 1,4-dimethyl-7-ethylazulene results in the formation of a dimeric radical cation.

The stereochemistry of elimination in chlorocyclopropane was investigated using ab initio (6-31(+)G∗//HF/6-31(+)G∗) calculations. The competitive SN2 route was also considered. Transition states were located for the E2(anti), E2(syn) and SN2 reactions. The three-membered ring has a pronounced effect on the syn/anti preference of E2 elimination; the barrier of syn elimination (22.2 kcal mol−1) is only 3.6 kcal mol−1 larger than that of anti elimination. The small syn/anti difference is related to the inherent periplanarity of the syn transition state and the torsional ring strain of the anti transition state. Comparing the reaction of F− with cyclopropyl, cyclopentyl and cyclohexyl chlorides, it was found that the tendency for anti elimination is especially reduced in the three-membered ring because of the non-periplanar conformation of the anti transition state. According to theory, the initial reactant complex can react further via the E2(anti) pathway or SN2 substitution. The barrier to substitution is 2.5 kcal mol−1 and the SN2 pathway dominates over elimination in this system. At the MP2/6-31(+)G∗//HF/6-31(+)G∗ level, the SN2 pathway has a lower activation barrier by 7.3 kcal mol−1 compared with the E2(anti) pathway.

The optimal method for isolating the sesquiterpene lactone britanin from the aerial part of Inula britannica L. (Asteraceae) was developed. Britanin was functionalized by reacting it with methyl mercaptoacetate.

Reactions of the methoxide ion with substituted halocyclopropanes, which result in E2 elimination, have been studied by the semiempirical quantum-chemical AM1 method. The transition states corresponding totrans andcis routes have been localized. The energetic predominance of thetrans route over thecis route is reduced by 2.6 kcal mol−1 on going from 1-chloropropane to chlorocyclopropane because of the features of cyclopropane geometry. It has been demonstrated that, in the gas phase,cis elimination may predominate overtrans elimination for a particular stereoisomer of 2-cyano-2-methyl-1-halocyclopropanes due to weakening of orbital interactions and Coulomb repulsion between the cyano group and the MeO− anion in thetrans E2 transition state.

A convenient method has been developed for obtaining 3-carene α- and β-sulfides from which isomeric 4-RS-carane-3-thiols have been obtained by the nucelophilic addition of thiols under the conditions of base catalysis. The S-alkylation of the latter has formed the corresponding 4-RS-3-R'S-caranes. A high degree of regio- and stereoselectivity of the reactions studied has been found.

Pure trans-diepoxy derivative of limonene was synthesized for the first time. Its reactions with sulfur-containing nucleophiles in basic medium resulted in formation of polyfunctional derivatives of the menthane series, 2,9-bis(R-thio)-trans-p-menthane-1,8-diols.

The reactions of 1-methylcycloprop-2-ene-1-carbonitrile with cyclohexa-1,4-diene and alloocimene gave the corresponding 2:1 addition products as a result of consecutive (conjugate) Alder-ene and Diels-Alder reactions. 1-Methylcycloprop-2-ene-1-carbonitrile acts initially as enophile, and in the second step, as dieno- phile. The structure of the adducts was determined by X-ray analysis.