Rational Design 2-Hydroxypropylphosphonium Salts as Cancer Cell Mitochondria-Targeted Vectors: Synthesis, Structure, and Biological Properties

Abstract

It has been shown for a wide range of epoxy compounds that their interaction with triphenylphosphonium triflate occurs with a high chemoselectivity and leads to the formation of (2-hydroxypropyl)triphenylphosphonium triflates 3 substituted in the 3-position with an alkoxy, alkylcarboxyl group, or halogen, which were isolated in a high yield. Using the methodology for the disclosure of epichlorohydrin with alcohols in the presence of boron trifluoride etherate, followed by the substitution of iodine for chlorine and treatment with triphenylphosphine, 2-hydroxypropyltriphenylphosphonium iodides 4 were also obtained. The molecular and supramolecular structure of the obtained phosphonium salts was established, and their high antitumor activity was revealed in relation to duodenal adenocarcinoma. The formation of liposomal systems based on phosphonium salt 3 and L-α-phosphatidylcholine (PC) was employed for improving the bioavailability and reducing the toxicity. They were produced by the thin film rehydration method and exhibited cytotoxic properties. This rational design of phosphonium salts 3 and 4 has promising potential of new vectors for targeted delivery into mitochondria of tumor cells.

1. Introduction

Phosphonium salts (QPSs) are organoelement compounds of importance in chemistry, pharmacology, biochemistry, etc. [1,2,3,4]. QPSs are used as organocatalysts in the reactions of C–C bond formation, annulation, etc., as a Lewis acid in organic synthesis [5].

Penetration of QPSs across biological membranes is one of the important properties of these compounds. Their high hydrophobicity and delocalized positive charge on the phosphorus atom lead to the tendency to accumulate in areas with a high membrane potential. Therefore, QPSs are actively used for the mitochondria targeted drug delivery [6,7,8,9,10,11]. Mitochondrial dysfunction is one of the key pathogenetic links in many diseases, such as metabolic syndrome, and cardiovascular and neurological disorders [12]. In this respect, in recent decades, the mitochondria-oriented approach has been intensively studied for the treatment of metabolic and degenerative diseases [13,14,15,16,17,18,19,20]. QPSs play a key role in implementation of this approach. Moreover, anti-cancer drug functionalized with triarylphosphonium groups provides an expanding spectrum of biological activity and shows effectiveness in the case of the resistant cells and pathogenic microorganisms [21]. This is clearly demonstrated by numerous examples: QPS-derivatives of chlorambucil [22], paclitaxel [23], doxorubicin [24], and metformin [25]. Incorporation of QPS into antibiotic molecules such as ciprofloxacin [26,27], azithromycin [28,29], doxycycline [28,29] significantly improves the antibacterial activity of doxycycline against Gram-positive bacteria. Azithromycin and doxycycline can also be considered as anti-tumor agents.

It is important to note that phosphonium groups should be considered not only as vector fragments in drug conjugations, but also as a pharmacophore [30,31]. This is especially shown in inhibition of respiratory chain complexes [32,33], Krebs cycle enzymes [34].

Creation of effective targeting drug delivery systems to organs and tissues is a topic of medicinal chemistry and pharmacology. [35]. QPS-modified delivery systems exhibit improved cellular uptake and selective targeting to mitochondria. This leads to inhibition of P-glycoprotein and suppression of drug resistance and cancer metastasis. [36]. Similar actions were obtained with QPS-modified glycol-chitosan polymer microspheres [37] and QPS-functionalized epigallocatechin gallate capped gold nanoparticles [38].

The functionalized QPS-target compound’s efficiency largely depends on the structure, in particular on the functional environment. Undoubtedly, identification of the new vector systems containing a linker part for the lipophilicity correction and conformational rigidity of molecule is urgent. The most widespread conjugate formation is the linker approach supposing a spatial differentiation of the lipophilic triarylphosphonium group and an active moiety of conjugate. To implement this approach, synthesis of the functionally substituted QPSs bearing carboxyl, hydroxyl, and amino groups as an additional function was developed (Scheme 1). Due to the presence of these groups, functionally substituted QPSs can be easily conjugated to the corresponding functional groups of target drugs (hydroxyl and carboxyl) since esterification reactions and amide bond formation are the most developed processes in organic chemistry. This approach is the most gentle and rational way. The second approach is the esterification of drugs containing a carboxyl group with terminal bromo (iodine) alkanols with follow reaction with triphenylphosphine (Scheme 2). This approach is less convenient, especially when the parent drug contains other functional groups that can react with triphenylphosphine.

Currently, the most commonly used functionally substituted QPSs contain compounds with a carboxyl (I), hydroxyl (II), or amino (III) groups in the alkyl substituent of phosphorus atom (Scheme 3).

The most common method for the QPSs (I) synthesis is alkylation of triarylphosphines with halogenated carboxylic acids (Scheme 4a). This reaction is carried out both without a solvent and in various mediums (THF, benzene, xylene, acetonitrile, etc.). QPSs were obtained using this method from triphenylphosphine for n = 1 [39,40], 2 [39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59], 3 [39,40,45,47,60,61,62,63,64,65,66,67,68,69,70], 4 [40,44,47,62,65,71,72,73,74,75,76,77,78,79,80,81,82,83,84], 5 [45,55,61,62,65,67,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102], 6 [44,47,50,58,62,87,103,104,105,106,107,108,109,110,111,112,113,114], 7 [47,62,86,115,116,117,118,119,120,121,122], 8 [44,55,62,89,120,123,124,125,126,127,128], 9 [62,65,72,86,126,129,130,131], 10 [45,55,62,68,109,125,129,132,133,134,135], 11 [45,47,86,89,119], 12 [45,133], 15 [136]. Salts for n = 2 were obtained from tri(4-methoxyphenyl)phosphine, tri(2,4,6-trimethoxyphenyl)phosphine, and bromopropionic acid [137,138]. The second approach is the addition of triphenylphosphine to unsaturated carboxylic acids (Scheme 4b) followed by treatment with gaseous or concentrated HCl or HBr [139,140]. It should be mentioned the reactions of lactones with triphenylphosphine in the presence of hydrohalic acid (Scheme 4a) [141,142,143].

QPSs containing a hydroxyl group (II) are mainly obtained by the reaction of terminal halogen alkanols with triphenylphosphine (Scheme 4c) (for an overview, see [144]). The corresponding bromine(iodine) alkanols are usually heated with triphenylphosphine in acetonitrile. This method was used to obtain phosphonium salts for n = 2 [47,145], 3 [40,47,100,146,147], 4 [47], 5 [47,148], 6 [47,149,150,151,152,153,154], 7 [148,155], 8 [148,156,157], 9 [156,158,159,160], 10 [156,157,161,162,163,164,165], 11 [156,157,162,165], 12 [151,157,159], 13 [166], 14 [167].

Phosphonium salts with amino group (III) were obtained by reactions of corresponding terminal bromoamines with triarylphosphines, for example, for n = 2 [40,47], 3 [54,142].

This work proposes an efficient and versatile approach for the preparation of 2-hydroxypropylphosphonium salts containing various additional functional substituents (halogens, alkoxy, acyloxy). The approach is based on reaction of oxiranes with triphenylphosphonium triflate. These compounds display anti-tumor activity. To improve the bioavailability and cellular uptake of obtained functionalized phosphonium salts, the nanotechnology-based approach was developed. For this purpose, phosphonium salt-modified liposomal delivery systems based on L-α-phosphatidylcholine were prepared. The incorporation of phosphorus-containing pharmacophore/vector amphiphils into liposomal membrane provides an ability to trap drugs effectively and prevent their leakage as well as rapid release from liposomes.

2. Results and Discussion

2.1. Chemistry

2.1.1. Reaction of Triphenylphosphonium Triflate with Halomethyloxiranes

As a rule, the interaction of oxiranes with triarylphosphines is carried out under hard conditions and often leads to the dimerization and partial polymerization of oxirane. Thus, the reaction of triphenylphosphine with epichlorohydrin, recently studied in [168], leads to the oxirane dimerization into a dioxane structure ((1,4-dioxane-2,5-diyl)-bis(methylene))-bis(triphenylphosphonium)chloride. The opening of oxirane ring with the formation of triaryl (2-hydroxyalkyl) phosphonium salts occurs in the presence of acids in neutral solvents (alcohols, dichloromethane) [169,170,171,172,173] or during the triarylphosphine reaction in phenol used as the solvent [174].

In our work, this approach was applied to a wide range of new oxiranes using the most convenient and stable triphenylphosphonium triflate (1). This compound was easily obtained by mixing triphenylphosphine with trifluoromethanesulfonic acid in dichloromethane [170,173,175]. The signal in the ³¹P NMR spectrum of this compound strongly depends on the ratio of reagents. The signal of phosphonium salt 1 appears as a broadened singlet with a slight excess of triphenylphosphine. This signal shifts towards strong fields with an increase in the triphenylphosphine proportion. This is due to the exchange between triphenylphosphine and salt 1. The salt signal appears as a doublet (δ_P 4.0 ppm, ¹J_HP 532 Hz) at the exact ratio of the starting compounds [175].

The reaction of halomethyloxiranes 2a–e with compound 1 occurs under mild conditions (−10 °C) with regioselective opening of three-membered ring at the O¹–C³ bond in accordance with Krasusky’s rule for opening epoxides under neutral conditions [176,177,178] and the formation of triphenylphosphonium triflates 3a–e. Despite protonation of oxygen, which often leads to initial opening of oxirane at the O¹–C² bond and carbocation formation (S_N1 mechanism). In our case, the mechanism of S_N2 nucleophilic substitution at the C³ atom was realized precisely in the protonated form of oxirane (structure A, Scheme 5). This is consistent with the data of work [174]: The inversion of the configuration of corresponding chiral carbon atom (C³) proceeds under the action of triphenylphosphine in neutral conditions [176,177,178].

The use of optically active chloromethyloxiranes 2e (R and S) in this reaction led to the formation of salts 3e with the retained configuration of the C² atom (R and S). Even in a strongly acidic environment, the nucleophilic attack of triphenylphosphine on the C² atom is more preferable than the preliminary electrophilic opening of oxirane. QPS structures were confirmed by NMR, IR, and mass spectrometry. The characteristic values of chemical shifts and spin–spin coupling constants for sp²-carbons of phenyl substituents at phosphorus are observed in the ¹³C NMR spectra of salts 3, completely consistent with QPS structures [179]. The structure of all compounds, including optically active derivatives 3e, R and 3e, S was proven by XRD. Chiral derivatives 3e, R and 3e, S form enantiomeric crystals in the polar space group P2₁ with two independent molecules (formula units). Since the conformation of independent cations and anions is the same, therefore, one independent pair of anion–cation is shown in Figure 1.

An unexpected result was obtained in the study of 3a crystals synthesized from racemic epichlorohydrin. As in crystals of optically active compounds, racemic product 3a was crystallized in the same polar space group P2₁ with two independent molecules A and B (formula units). In this case, crystal cell parameters of 3a are different from those of crystals 3e, R and 3e, S. The hydroxyl substituent at the C² atom in one of independent molecules was disordered over two positions (Figure 2) with almost equal occupancy (0.48 and 0.52, respectively). This means that enantiomeric molecules with both R- and S-configurations of the C² atom were localized in the position of an independent molecule B.

Crystals of 3a are non-racemic. They have a ratio of enantiomeric molecules equal to 3:1. Since the substance is racemic in the mass, it should contain an equal ratio of isostructural enantiomeric crystals [R/S = 3/1 и R/S = 1/3]. Crystals of this type are called anomalous conglomerates.

Racemic compounds 3b–d crystallize in isostructural centrosymmetric crystals in the space group P2₁/n with one independent formula unit. The molecular geometry of 3b–d are shown in Figures S1–S3.

In this case, the unit cell volume of the crystals of this group has a similar value. It should be noted that the hydrogen bonds of hydroxyl group in enantiopure crystals 3e are formed with two oxygen atoms of triflate anion. One of independent molecules forms H-bonds with two oxygen atoms and one fluorine atom in crystal 3a and the second molecule (with a disordered hydroxyl group) forms with only one oxygen atom (Figure 2). H-bonds are formed only with one oxygen atom and one fluorine atom in centrosymmetric crystals 3b–d. Hydrogen bonds are formed only between the anion and the cation (0D-motive of hydrogen bonds) in both centrosymmetric and noncentrosymmetric crystals. Perhaps a formation of hydrogen bonds of cation with various atoms of anion leads to some differences in the compound packing of this group in crystals. The result is the formation of centrosymmetric and non-centrosymmetric crystals.

The molecule geometric parameters of 3a–d are the same within experimental errors and correspond to the bond lengths and angles in similar organic compound fragments and triflate anion. Crystal packing of this group is given by dispersion interactions, while π–stacking interactions between benzene rings were not observed.

2.1.2. Reaction of Triphenylphosphonium Triflate with Alkyl- and Acyl Glycidyl Ether

The reaction of alkyl- and acylglycidyl ethers 2f–l with triphenylphosphonium triflate was carried out under mild conditions, with a high regioselectivity, and led to the formation of 3-alkoxy(acyloxy)-2-hydroxypropyltriphenylphosphonium triflates 3f–l (Scheme 6) with almost quantitative yields.

The structures of all compounds were confirmed by NMR, IR, and mass spectrometry. Compounds 3h, k, l are thick oils, and other phosphonium salts are crystalline substances. The structures of salts 3f, g, i, j were proven by XRD. The molecule geometries in the crystal are shown in Figures S4–S7. The phosphorus atom has a distorted tetrahedral configuration both in salt molecules 3a–e and in compounds 3f, g, i, j. Unlike the former, the crystals of racemic compounds 3f, g, i, j are not isostructural. Crystals 3g and 3h are non-centrosymmetric, and their space groups are nonpolar (Pn and Cc). Taking into account unit cells parameters of 3f and 3g it was assumed that they are isostructural. The methoxy derivative 3f crystallizes in the centrosymmetric space group P2₁/n. Compound 3g crystallizes in the Pn group with two independent molecules per unit cell.

For crystals of all these compounds, hydrogen bonds are formed only between the anion and the cation (0D-motive hydrogen bonds).

2.1.3. Synthesis of 3-Alkoxy(Iodo)-2-hydroxypropyl Triphenylphosphonium Iodides

To obtain 3-alkoxy-2-hydroxypropyltriphenylphosphonium iodides, a two-stage approach was applied starting from epichlorohydrin (Scheme 7). Epichlorohydrin was disclosed with the corresponding alcohol in the presence of boron trifluoride etherate, according to [180]. The obtained 3-alkoxy-2-hydroxy-1-chloropropanes 5 were purified by distillation in vacuo. Then the Finkelstein reaction was carried out with sodium iodide in acetonitrile in the presence of dibenzo-18-crown-6 as a catalyst. The process was monitored by TLC and ¹H NMR. Target phosphonium salts 4 were formed by heating the obtained 3-alkoxy-2-hydroxy-1-iodopropanes 6 with triphenylphosphine in acetonitrile in high yields.

The structure of compounds 4a–d was proven by NMR and IR, and the structure of phosphonium salt 4a also by XRD. Molecule geometry 4a in the crystal is shown in Figure S8. It is interesting to note that Finkelstein’s reaction with compound 3a led to the formation of two phosphonium salts—2-hydroxy-3-iodotriphenylphosphonium triflate 3d and iodide 7 (Scheme 8). The obtained salts were isolated and purified by colomn chromqatography. The structure of salt 7 was proven by NMR and XRD (Figure S9).

Some regularities in the spatial structure of investigated 12 compounds were formulated. The conformation and geometry of isopropanoltriphenylphosphonium cations in crystals is the same. The propanol fragment has a transoidal conformation (the P–C¹–C²–C³ torsion angles are close to 180°). Hydroxyl groups of cations form hydrogen bonds with triflate or iodide anions. Closed 0D-hydrogen bond motifs were formed. Crystals of studied compounds are formed due to conventional dispersion interactions, while π–stacking interactions between benzene rings were not observed. All interplanar distances were more than 3.2 Å. Distances between the benzene rings were more than 5 Å. Bi- and trifurcate hydrogen bonds with two oxygen atoms and one fluorine atom of anion were observed in crystals with triflate anions. The increase in the ellipsoid size of anisotropic displacements of oxygen atoms can be explained by the “switching” of hydrogen bond from one oxygen atom to another (disorder of hydrogen bond).

2.1.4. Liposomal Systems Based on Amphiphilic Triflates of Acyloxypropylphosphonium and L-α-Phosphatidylcholine

The creation of drug and gene delivery nanosystems is one of innovative approaches in cancer treatment. Liposomal systems have been applied in clinical studies [181,182]. Since the first liposomal product Doxil^®, anticancer drugs such as DaunoXome^®, Depocyt^®, Myocet^®, Mepact^®, Marqibo^®, and Onivyde™ have been successfully created [183,184,185]. The range of liposomal preparations is constantly expanding. Nanocarriers improve bioavailability and ensure targeted drug transport, selective targeting of cancer cells, and controlled drug release [186]. To improve the stability of the liposome systems and to protect against capture by the immune system cells, liposomes were modified by the ionic or non-ionic surfactants and/or polymers incorporation into phospholipid membrane [187].

Liposomes were modified with synthetic amphiphiles 3k and 3l. Characteristics of obtained liposomal formulations—hydrodynamic diameter (Zaverage, (nm)), zeta potential (Z, mV), polydispersity index (PdI), encapsulation efficiency (EE, %), and loading capacity (LC, %)—are presented in Table 1. The fluorescent dye Rhodamine B was selected as a model drug.

The liposome size was about 100 nm, and the zeta potential of particles was +22.6 ± 2 and +6.1 ± 0.1 mV for the PC/3k and PC/3l formulations, respectively. The surface charge of liposomes increased when liposomes were modified with phosphorus-containing amphiphiles 3k and 3l. This indicates incorporation of 3k and 3l into liposome membrane. Incorporation of ionic surfactants into liposomes was investigated [189]. All liposome formulations showed a low polydispersity index below 0.2. Varying the percentage of PC/amphiphiles, namely, increasing amphiphile 3k and 3l content from 2 to 10% (wt.), was carried out. The zeta potential of nanoparticles increased from +23 to +46 mV upon increasing the content of 3k from 2% to 10% (wt.) for the PC/3k system. In the case of liposomal formulation PC/3l, the zeta potential increased from +6 to +8 mV. The charge of liposomal formulations depended both on the phosphorus-containing amphiphile content and on alkyl chain length. Most likely, this difference was associated with the amphiphiles penetration depth into the liposomal membrane, the level of incorporation into the double phospholipid bilayer, and the solubility of both amphiphiles [190]. There was a slight increase in the polydispersity when the model drug rhodamine B was encapsulated, but the polydispersity index did not exceed 0.2. The zeta potential of the PC/3l liposomal systems increased both in the presence of rhodamine B and with an increase (3l) content in formulation from +20.5 ± 2 to +26 ± 1 mV. The encapsulation efficiency of rhodamine was high, about 87%. EE increased to 93% with the growing amphiphile amount in the liposomal membrane. This increase may be related to stabilization of the liposomal membrane. All samples were stored in fridge (at 4 °C) in hermetically closed glass containers (to prevent from humidity during storage) for colloid stability studies upon three months. During the storage of 3 months, the characteristics of liposomes did not change, except for formulation PC/3l (with ratio 90/10, %w/w). It may be stated that 3k and 3l have a stabilizing effect on liposomes. The optimum concentration of 3k and 3l was observed. 3k and 3l nanoparticles and mixed self-assembles with PC formation were possible at high concentrations of 3k and 3l amphiphiles afer long storage.

UV spectra (A) and rhodamine B release profile (B) within time in the absence of nanoparticles (1) and encapsulated in liposomes (2–5) are shown in Figure 3. Rhodamine B (50%) was released from liposomes much slower (4 h) than in the case of aqueous solution (within 20 min). It should be noted that the release slowdown occurred in the case of liposome modified with amphiphil 3l. This confirmed the improved stabilization of liposomal systems by amphiphil 3l.

2.2. Biology

2.2.1. Cytotoxicity

Cytotoxicity against cancer and normal cell lines was tested for synthesized phosphonium salts. The cytotoxic activity is represented by IC₅₀ values (the compound concentration that causes the death of 50% of cells in the experimental cell population) in Table 2.

The studied phosphonium salts showed high and moderate cytotoxicity against some cancer lines and moderate activity against normal lung embryo cells. The most significant results were obtained for the duodenal adenocarcinoma cell line (HuTu 80) and cell line PC3 (human prostate cancer). Compounds 3j and 4c showed anti-cancer activity against the HuTu 80 cell line comparable to doxorubicin activity. The 3j and 4c cytotoxic effect against the PC3 line was two times higher than doxorubicin. Phosphonium salts 3j and 4c awere the most active compounds against other human cancer lines, and the IC₅₀ concentration values were in the range 1.1–3.7 μM.

Selectivity index (SI) was calculated to assess the cytotoxic effect as the ratio between the IC₅₀ value for normal cells and the IC₅₀ value for cancer cells (Table 2). All compounds showed the highest selectivity against HuTu 80 line. SI is 4–12.3. It should be noted that 4c has the highest SI equal to 12.3. Doxorubicin is significantly inferior to the leading compounds in selectivity.

The cytotoxic effect of liposome formulations PC/3k and PC/3l (with ratio 98/2, %w/w) in cancer cells and normal human cells was lower than for individual compounds 3k and 3l.

2.2.2. Induction of Apoptotic Effects by Lead Compounds

Apoptosis is one of the most significant mechanisms used for screening new anti-cancer agents. The apoptosis-inducing effect was carried out on lead compounds 3a, b, k, j and 4c showing high selectivity against HuTu-80 cells. The studies were carried out by flow cytometry at concentrations IC₅₀/2 and IC₅₀ (Figure 4). HuTu-80 cells actively induce apoptosis after 48-h incubation in the presence of 3a, b, k, j and 4c at concentrations IC₅₀/2. The percentage of apoptotic cells in early and late phases was slightly changed with increase compound concentration up to IC₅₀.

Apoptosis induction by 3a, b, k, j and 4c through the mitochondrial pathway and HuTu-80 cell line was studied by flow cytometry using the fluorescent dye JC-10 from the Mitochondria Membrane Potential Kit. JC-10 accumulated in the mitochondrial matrix and formed aggregates (J-aggregate) with red fluorescence in normal cells with a high mitochondrial membrane potential. The membrane potential decreased in apoptotic cells. JC-10 started to diffuse out from the mitochondria and converts to the monomeric form (J-monomer) and emits green fluorescence. This is recorded with a flow cytometer. A decrease the mitochondrial membrane potential of HuTu-80 cells occurs after treatment with 3a, b, k, j and 4c. The process became more pronounced with an increase of 3a, b, 3k, j and 4c concentrations up to IC₅₀ (Figure 5 and Figure 6). The obtained results suggest that the mechanism of 3a, b, k, j and 4c cytotoxic action is due to apoptosis induction through the internal mitochondrial pathway.

Increasing the production of reactive oxygen species (ROS) by compounds characterizes the mitochondrial apoptotic pathway. Mitochondria are a potential source and target of ROS. ROS lead to disruption of mitochondrial functions and, as a consequence, to irreversible cell damage. In this regard, the effect of test compounds in HuTu-80 cells on ROS production, using flow cytometry analysis and CellROX^® Deep Red flow cytometry kit was investigated. Data presented in Figure 7 show a significant increase in CellROX^® Deep Red fluorescence intensity. This indicates an increase in ROS production in the presence of the tested compounds. It should be noted that 3k, j and 4c were the most active to generate ROS in HuTu-80 cells as compared to 3a and 3b and control (untreated cells).

3. Materials and Methods

3.1. General

The NMR spectra were recorded at 25 °C using a Bruker Avance-400 NMR spectrometer (400.0 MHz, ¹H; 100.6 MHz, ¹³C; 162 MHz, ³¹P), a Bruker Avance-500 NMR spectrometer (500.0 MHz, ¹H; 125.75 MHz, ¹³C; 201.7 MHz, ³¹P) and a Bruker Avance-600 NMR spectrometer (600.0 MHz, ¹H; 150.9 MHz, ¹³C; 242 MHz, ³¹P). Chemical shifts were referenced to the residual solvent peak and reported in ppm (δ scale) and all coupling constant (J) values were given in Hz. IR spectra were recorded using a Bruker Vector 22 spectrometer for samples in KBr pellets or in film. MALDI mass spectra were acquired on a Bruker MALDI-MS Ultraflex III spectrometer. 2,5-Dihydroxybenzoic acid (5 mg/mL in methanol) and 4-nitroanilin (5 mg/mL in methanol) were used as a matrix. Melting points were determined on a Melting Point Apparatus Stuart SMP10. Optical rotations were determined on a Perkin Elmer 341 polarimeter (concentration c is given as g/mL). Elemental analysis was accomplished with an automated EuroVector EA3000 CHNS-O elemental analyzer (Euro-Vector, Pavia, Italy).

The X-ray diffraction data for the crystals (3b, 3c, 3d, 3f–3j, 4a) were collected on a Bruker D8 QUEST CCD diffractometerat temperature 100(2) K, (3a) and (3e) were collected on a Bruker Kappa Apex II CCD diffractometerat room temperature (296(2) K), in the ω and φ-scan modes using graphite monochromated MoK_α (λ = 0.71073 Å) radiation.

Data for the crystals (3–4a) were corrected for the absorption effect using SADABS program [191]. Data collection: images were indexed and integrated using the APEX2 data reduction package [192]. The structures were solved by direct method using SHELXT [193] and refined by the full matrix least-squares using SHELXL programs [194].

The X-ray diffraction data for the crystals (3e, S) and (3e, R) were collected on a Enraf–Nonius CAD-4 diffractometer at room temperature (296(2) K), in the ω/2θ-scan modes using graphite monochromated MoK_α (λ = 0.71073 Å) radiation. The structure was solved by direct method using and refined by the full matrix least-squares using MolEN [195] programs. Then the structure wasrefined by the full matrix least-squares using SHELXL programs [194] in the WinGX program package [196].

The X-ray diffraction data for the crystal (7) were collected on a XtaLAB Synergy, Single source at home/near, HyPix diffractometerat temperature 100(2) Kusing graphite monochromated CuK_α (λ = 1.54184 Å) radiation). The structure was solved by the direct method using SHELXS and refined by the full matrix least-squares using SHELXL programs. Hydrogen atoms in all structures were inserted at calculated positions and refined as riding atoms.Hydrogen atoms in the hydroxyl-groups were solved from difference Fourier maps and refined with fixed bond length and angles with rotation around C–O bonds. Analysis of the intermolecular interactions was performed using the program PLATON [197]. Mercury program package [198] was used for figures preparation.

Crystallographic data for the investigated structuresare seen in the Supplementary Materials and have been deposited in the Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC 2110389-2110402, respectively. Copies of the data can be obtained free of charge upon application to the CCDC (12 Union Road, Cambridge CB2 1EZ UK. Fax: (internat.) +44-1223/336-033; E-mail: [email protected]).

The synthesis of compounds 3d, 7 and their purity were monitored by TLC on Sorbfil plates (IMID Ltd., Krasnodar, Russian). The TLC plates were visualized by UV. The targeted compounds 3d, 7 were isolated using column chromatography on silica gel (60A, 60–200 μm, Acros, Belgium). Solvents were purified and dried by standard protocols.

3.2. Chemistry

3.2.1. General Procedure for the Synthesis of 1-Chloro-3-alkoxypropan-2-ol (5a–d)

Compounds 5a–d were synthesized according to a modified procedure [199]. To the corresponding alcohol (0.4 mol) was added 5 wt % of boron trifluoride etherate and epichlorohydrin (0.1 mol) and the reaction mixture was refluxed for 15 h until the reaction was completed. The mixture was then cooled at room temperature and diluted with water. The solution was exhaustively extracted with dichloromethane. The combined extracts were washed with brine and dried with anhydrous sodium sulfate, andfinally, the dichloromethane was evaporated in vacuo. 1-Chloro-3-alkoxypropan-2-ol was purified by vacuum distillation.

1-Chloro-3-methoxypropan-2-ol (5a). Yield: 67%; bp 87–90 °C (30 mmHg); n_D²⁰ 1.4424; ¹H NMR spectrum (600 MHz, CDCl₃) δ ppm (J Hz) 3.97 (m, H², 1H, ³J_HH 5.2–5.7), 3.58 and 3.62 (two m, H³, 2H, AB-part of ABX-spectrum, ²J_H^3A_H^3B 11.1, ³J_H²_H³ 5.7), 3.50 (m, H¹, AB-part of ABX-spectrum, ²J_H^1A_H^1B 10.4), 3.40 (s, H^1′, 3H), 2.65 br. s (OH, 1H). Found: anal. C, 38.43; H, 7.11; Cl, 28.30%, calcd. for C₄H₉ClO₂, C, 38.57; H, 7.28; Cl, 28.46%.

1-Chloro-3-ethoxypropan-2-ol (5b). Yield: 85%; bp 93–97 °C (25 mmHg); n_D²⁰ 1.4372; ¹H NMR spectrum (600 MHz, CDCl₃) δ ppm (J Hz) 3.97 (m, H², 1H, ³J_HH 5.0–5.6), 3.60 and 3.64 (two m, H³, 2H, AB-part of ABX-spectrum, ²J_H^3A_H^3B 11.1, ³J_H²_H³ 5.6), 3.54–3.56 (m, H¹ and H^1′, 4H), 2.53 (br. s, OH, 1H), 1.22 (t, H^2′, 3H, ³J_HH 7.0). Found: anal. C, 43.12; H, 7.88; Cl, 25.57%, calcd. for C₅H₁₁ClO₂, C, 43.33; H, 8.00; Cl, 25.58%.

1-Chloro-3-(decyloxy)propan-2-ol (5d). Yield: 72%; bp 128–130 (0.1 mmHg); n_D²⁰ 1.4530; IRS (film, cm⁻¹): 3418, 2954, 2925, 2855, 1598, 1465, 1430, 1378, 1299, 1260, 1120, 1074, 945, 910, 843, 753, 722, 624, 572; ¹H NMR spectrum (600 MHz, CDCl₃) δ ppm (J Hz) 3.97 (m, H², 1H, ³J_HH 5.4, ³J_HH 5.4), 3.60 and 3.64 (two m, H³, 2H, AB-part of ABX-spectrum, ²J_H^A_H^B 11.0, ³J_H²_H^A = ³J_H²_H^B 5.4), 3.53 (m, H^1′, 2H, AB-part of ABX₂-spectrum), 3.48 (m, H¹, 2H, AB-part of ABX-spectrum), 2.52 (br. s, OH, 1H), 1.28–1.31 (m, H^3′-H^9′, 14H), 0.89 (t, H^10′, 3H, ³J_HH 7.1); ¹³C NMR spectrum (100.6 MHz, CDCl₃) δ_C ppm (J Hz) 71.75 (tm (s) (here and below, the form of the signal in NMR¹³C-{¹H} spectra is indicated in parentheses), C³, ¹J_HC 140.4), 71.37 (tm (s), C^1′, ¹J_HC 141.7, ²J_HCC 2.9, ³J_HCCC 2.8, ³J_HCCC 2.8), 760.26 (dtt (s), C², ¹J_HC 145.6, ²J_HCC 2.6–2.8, ²J_HCC 2.6–2.8), 45.97 (brtt (s), C¹, ¹J_HC 150.8, ³J_HC³_CC 3.6, ²J_HCC 0), 31.92 (tm (s), C^2′, ¹J_HC 125.7, ³J_HCCC 4.2–5.0, ²J_HCC 2.8–3.2), 29.63 (tm (s), C^3′, ¹J_HC 124.0–125.0), 29.60 (tm (s), C^4′, ¹J_HC 124.0–125.0), 29.55 (tm (s), C^5′, ¹J_HC 124.0–125.0), 29.48 (tm (s), C^6′, ¹J_HC 124.0–125.0), 29.35 (tm (s), C^7′, ¹J_HC 125.1), 26.06 (tm (s), C^8′, ¹J_HC 125.1), 22.70 (tm (s), C^9′, ¹J_HC 125.0, ³J_HCCC 3.8–4.0, ²J_HCC 2.6–2.8), 14.11 (qm (s), C^10′, ¹J_HC 124.5). Found: anal. C, 62.14; H, 10.82; Cl, 14.09%, calcd. for C₁₃H₂₇ClO₂, C, 62.26; H, 10.85; Cl, 14.13%.

3.2.2. General Procedure for the Synthesis of 2-(Alkoxymethyl)oxirane (2f–j)

Compounds 2f–j were synthesized according to a modified procedure [180]. Sodium hydroxide (0.75 mmol) was added portion to a stirred solution of corresponding 3-alkoxy-1-chloropropan-2-ol(0.5 mol) in ether (500 mL) at 0 °C. The reaction mixture was stirred for 8 h at room temperature a then poured onto iced water (250 mL) and the layers formed were separated. The aqueous layer was extracted with ether, the combined ether solutions were evaporated in vacuum; 2-(alkoxymethyl)oxirane was purified by vacuum distillation.

3-(Methoxymethyl)oxirane(2f). Yield: 88%; bp 58–60 °C (90 mmHg); n_D²⁰ 1.4062; IRS (film, cm⁻¹): 3502, 3057, 2993, 2930, 2885, 2823, 1454, 1385, 1345, 1256, 1200, 1163, 1136, 1108, 1058, 988, 963, 939, 904, 848, 803, 764; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 3.64 (dd, H^3M, 1H, M-part of AMX-spectrum, ²J_H^3A_H^3M 11.4, ³J_H²_H^3M 3.0), 3.28 (dd, H^3A, 1H, A-part of AMX-spectrum, ²J_H^3M_H^3A 11.1, ³J_H²_H^3A 5.9), 3.36 (s, H^1′, 3H), 3.09 (m, H², ³J_H^3A_H² 5.9, ³J_H^1M_H² 4.2, ³J_H^3M_H² 3.0, ³J_H^1A_H² 2.7), 2.74 (dd, H^1M, 1H, ²J_H^1A_H^1M 5.1, ³J_H²_H^1M 4.2), 2.56 (dd, H^1A, 1H, ²J_H^1M_H^1A 5.1, ³J_H²_H^1A 2.7). Found: anal. C, 54.48; H, 9.10%, calcd. for C₄H₈O₂, C, 54.53; H, 9.15%.

3-(Ethoxymethyl)oxirane (2g). Yield: 90%; bp 55–60 °C (60 mmHg), n_D²⁰ 1.4110; IRS (film, cm⁻¹): 3585, 3517, 3055, 2978, 2931, 2872, 1486, 1446, 1396, 1335, 1254, 1161, 1113, 1019, 992, 915, 880, 856, 800, 762; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 3.64 (dd, H^3M, 1H, M-part of AMX-spectrum, ²J_H^3A_H^3M 11.4, ³J_H²_H^3M 3.0), 3.32 (dd, H^3A, 1H, A-part of AMX-spectrum, ²J_H^3M_H^3A 11.4, ³J_H²_H^3A 5.8), 3.48 and 3.51 (two m, H¹ spectrum (400 MHz, CDCl₃) δ ppm, 2H, AB-part of ABX₃-spectrum, ²J_H^1′A_H^1′B 9.4, ³J_HH 7.0), 3.08 (m, H², 1H, ³J_H^3A_H² 5.8, ³J_H^1M_H² 4.2, ³J_H^3M_H² 3.0, ³J_H^1A_H² 2.8), 2.72 (dd, H^1M, 1H, ²J_H^1A_H^1M 5.1, ³J_H²_H^1M 4.2), 2.54 (dd, H^1A, 1H, ²J_H^1M_H^1A 5.1, ³J_H²_H^1A 2.7), 1.16 (t, H^2′, 3H, ³J_HH 7.0). Found: anal. C, 58.72; H, 9.83%, calcd. for C₅H₁₀O₂, C, 58.80; H, 9.87%.

3-((2′,2′,3′,3′-Tetrafluoropropanoxy)methyl)oxirane (2h) obtained according to the method [200,201]. Yield: 80%; bp 100–110 °C (50 mmHg), n_D²⁰ 1.3650; IRS (film, cm⁻¹): 3501, 3067, 3069, 2933, 1466, 1445, 1405, 1344, 1279, 1231, 1266, 1109, 998, 939, 903, 833, 764, 746, 690; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 5.92 (tt, H^3′, 1H, ²J_F^3′_H^3′ 53.2, ³J_F^2′_H^3′ 5.0), 3.86 and 3.92 (two br m, H^1′, 2H, AB-part of ABX₂-spectrum, ²J_H^1′A_H^1′B 11.5, ³J_F^2′_H^1′ 12.0), 3.90 (dd, H^3M, 1H, ²J_H^3A_H^3M 11.8, ³J_H²_H^3M 2.4), 3.45 (dd, H^3A, 1H, ²J_H^3M_H^3A 11.8, ³J_H²_H^3A 6.1), 3.13 (m, H², 1H), 2.79 (dd, H^1M, 1H, ²J_H^1A_H^1M 4.9, ³J_H²_H^1M 4.2), 2.58 (dd, H^1A, 1H, ²J_H1MH1A 4.9, ³J_H2H1A 2.6). Found: anal. C, 38.43; H, 4.27%, calcd. for C₆H₈F₄O₂, C, 38.31; H, 4.29%.

3-((Allyloxy)methyl)oxirane (2i). Yield: 82%; bp 68–69 °C (20 mmHg), n_D²⁰ 1.4369; IRS (film, cm⁻¹): 3058, 2999, 2924, 2858, 1647, 1457, 1421, 1338, 1253, 1098, 994, 924, 855, 802, 763; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 5.88 (ddt, H^2′, 1H, ³J_H^3′_(X)H 17.2, ³J_H^3′A_H 10.4, ³J_H^1′_H 5.6), 5.26 (ddt, H^3′X, 1H, ³J_H^2′_H 17.2, ²J_HH 1.7, ⁴J_H^1′_H 1.6), 5.16 (ddt, H^3′A, 1H, ³J_H^2′_H 10.4, ²J_HH 1.6, ⁴J_H^1′_H 1.2), 4.04 (dddd, H^1′A, 1H, ²J 12.8, ³J_H^2′_H 5.6, ⁴J_H^3′_H 1.4, ⁴J_H^3′_H 1.3), 3.99 (dddd, H^1′B, 1H, ²J 12.8, ³J_H^2′_H 5.6, ⁴J_H^3′_H 1.4, ⁴J_H^3′_H 1.3), 3.64 (dd, H^3M, 1H, M-part of AMX-spectrum, ²J_H^3A_H^3M 11.4, ³J_H²_H^3M 3.1), 3.38 (dd, H^3A, 1H, A-part of AMX-spectrum, ²J_H^3M_H^3A 11.4, ³J_H²_H^3A 5.8), 3.12 (m, H², 1H, ³J_H^3A_H² 5.8, ³J_H^1M_H² 4.1, ³J_H^3M_H² 3.0, ³J_H^1A_H² 2.7), 2.76 (dd, H^1M, 1H, ²J_H^1A_H^1M 5.0, ³J_H²_H^1M 4.2), 2.58 (dd, H^1A, 1H, ²J_H^1M_H^1A 5.0, ³J_H²_H^1A 2.7). Found: anal. C, 63.02; H, 8.35%, calcd. for C₆H₁₀O₂, C, 63.14; H, 8.83%.

3-((Decyloxy)methyl)oxirane (2j). Yield: 90%; bp 87–92 °C (0.1 mmHg), n_D²⁰ 1.4430; IRS (film, cm⁻¹): 3051, 2926, 2855, 1613, 1467, 1338, 1253, 1158, 1111, 913, 848, 762, 722; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 3.47 (ddd, H^3B, 1H, B-part of ABX-spectrum, ²J_H^3A_H^3B 11.5, ³J_H²_H^3B 3.0, ⁴J_H¹_H^3B 1.4), 3.13 (ddd, H^3A, 1H, A-part of ABX-spectrum, ²J_H^3B_H^3A 11.5, ³J_H²_H^3A 5.8, ⁴J_H¹_H^3A 1.4), 3.23–3.26 (m, H^1′, 2H, AB-part of ABX₂-spectrum, ²J_H^1′A_H^1′B 10.0–11.0, ³J_H^2′_H^1′ 6.7, ⁴J_HH^1′ 1.3), 2.90 (m, H², 1H), 2.55 (m, H^1B, 1H, ²J_H^1A_H^1B 5.2, ³J_H²_H^1B 4.1, ⁴J_H^3B_H^1B 1.4), 2.36 (m, H^1A, 1H, ²J_H^1B_H^1A 5.2, ³J_H²_H^1A 2.6), 1.35 (m, H^2′, 2H, ³J_HH 6.7), 1.04–1.10 (m, H^3′-H^9′, 14H), 0.65 (t, H^10′, 3H, ³J_HH 6.7); ¹³C-{¹H} NMR spectrum (100.6 MHz, CDCl₃) δ_C ppm (J Hz) 71.58 (s, C³), 71.40 (s, C^1′), 50.75 (s, C²), 44.06 (s, C¹), 31.86 (s, C^2′), 29.66 (s, C^3′), 29.56 (s, C^4′), 29.53 (s, C^5′), 29.44 (s, C^6′), 29.29 (s, C^7′), 26.05 (s, C^8′), 22.62 (s, C^9′), 14.01 (s, C^10′). Found: anal. C, 72.70; H, 12.26%, calcd. for C₁₃H₂₆O₂, C, 72.85; H, 12.23%.

3.2.3. General Procedure for the Synthesis of 3-Alkoxy-1-iodopropan-2-ols (6a–d)

Compounds 6a–d were synthesized according to a modified procedure [202]. To a solution of the corresponding previously obtained compound 5a–d (3 mmol) in CH₃CN (5 mL) was added NaI (12 mmol) and 10% 18-crown-6. The reaction mixture was stirredunder reflux for 20 h. After cooling the mixture to room temperature, the precipitate was filtered. The mixture poured onto water (40 mL) and was extracted three times with ether. The combined ether solutions were washed with H₂O and then organic layer dried over MgSO₄, filtered, and concentrated in vacuo; 3-alkoxy-1-iodopropan-2-olwas purified by vacuum distillation.

1-Iodo-3-methoxypropan-2-ol (6a). Yield: 87%; bp 115–117 °C (30 mmHg); n_D²⁰ 1.5227; IRS (film, cm⁻¹): 3417 very br. s. (OH), 2984, 2927, 2892, 2825, 1638, 1453, 1415, 1378, 1329, 1285, 1251, 1198, 1185, 1119, 1065, 1031, 1006, 964, 933, 890, 861, 807, 745, 626, 542, 515, 465. ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 3.75 (m, H², 1H, ³J_HH 5.6, ³J_HH 5.6), 3.46 and 3.48 (two m, H³, 2H, AB-part of ABX-spectrum, ²J_H3AH3B 10.6, ³J_H2H3 5.6), 3.38 (s, H^1′, 3H), 3.25 and 3.29 (two m, H¹, 2H, AB-part of ABX-spectrum, ²J_H1AH1B 10.2, ³J_H2H1 5.6), 2.94 (very br s, OH, 1H); anal. C, 22.04; H, 4.14; I 58.30%. Found: calcd. for C₄H₉IO₂, C, 22.24; H, 4.20; I 58.75%.

1-Ethoxy-3-iodopropan-2-ol (6b). Yield: 92%; bp 122–125 °C (22 mmHg); n_D²⁰ 1.5180; IRS (film, cm⁻¹): 3417 very br. s. (OH), 2974, 2928, 2871, 1630, 1484, 1444, 1413, 1382, 1354, 1328, 1276, 1237, 1186, 1117, 1075, 1034, 1007, 936, 906, 867, 807, 627, 596, 514, 448. ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 3.74 (tdd, H², 1H, ³J_H^3A_H² 5.7, ³J_H^3B_H² 4.6, ³J_H¹_H² 5.7), 3.52 and 3.53 (two m, H^1′, 2H, AB-part of ABX₃-spectrum, ²J_H^1′A_H^1′B 10.0, ³J_HH 7.0), 3.50 and 3.51 (two m, H³, 2H, AB-part of ABX-spectrum, ²J_H^3A_H^3B 9.7, ³J_H²_H^3A 5.7, ³J_H²_H^3B 4.6), 3.25 and 3.31 (two m, H¹, 2H, AB-part of ABX-spectrum, ²J_H^1A_H^1B 10.2, ³J_H²_H^1A 5.7, ³J_H²_H^1B 5.7), 1.19 (t, H^2′, 3H, ³J_HH 7.0). Found: anal. C, 25.97; H, 4.80; I 55.00%, calcd. for C₅H₁₁IO₂, C, 26.11; H, 4.82; I 55.16%.

1-(Allyloxy)-3-iodopropan-2-ol (6c). Yield: 86%; n_D²⁰ 1.5305; bp 75–76 °C (0.1 mmHg); IRS (film, cm⁻¹): 3418, 3079, 3013, 2903, 2860, 1646, 1470, 1450, 1420, 1350, 1329, 1264, 1187, 1108, 1007, 931, 879, 807; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 5.91 (ddt, H^2′, 1H, ³J_H^3′X_H 17.2, ³J_H^3′A_H 10.4, ³J_H^1′_H 5.7), 5.29 (ddt, H^3′X, 1H, ³J_H^2′_H 17.2, ²J_HH 1.7, ⁴J_H^1′_H 1.6), 5.22 (ddt, H^3′A, 1H, ³J_H^2′_H 10.4, ²J_HH 1.6, ⁴J_H^1′_H 1.4), 4.04 (ddd, H^1′, 2H, ³J_H^2′_H 5.7, ⁴J_H^3′_H 1.6, ⁴J_H^3′_H 1.4), 3.79 (tdd, H², 1H, ³J_H³_H 5.8, ³J_H³_H 5.6, ³J_H¹_H 5.6), 3.55 (m, H¹, 2H, AB-part of ABX-spectrum, ³J_HH 5.6), 3.28 and 3.34 (two m, H³, 2H, AB-part of ABX-spectrum, ²J_H3AH3B 10.2, ³J_H2H1A 5.8, ³J_H2H1B 5.6), 2.64 br. s (OH, 1H). Found: anal. C, 29.63; H, 4.12; I 52.37%, calcd. for C₆H₁₁IO₂, C, 29.77; H, 4.58; I 52.43%.

1-(Decyloxy)-3-iodopropan-2-ol (6d). Yield: 82%; n_D²⁰ 1.4930; bp 132–134 °C (0.18 mmHg); IRS (film, cm⁻¹): 3417 very br. s. (OH), 2953, 2923, 2854, 1725, 1640, 1464, 1415, 1377, 1328, 1259, 1239, 1185, 1118, 1034, 1007, 939, 877, 808, 721, 629, 554, 537, 453. ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 3.77 (tt,H², 1H, ³J_HH 5.6, ³J_HH 5.6), 350 and 3.53 (two m, H³, 2H, AB-part of ABX-spectrum, ²J_H^3A_H^3B 10.5, ³J_H²_H³ 5.6), 3.49 (td, H^2′, 2H, ³J_HH 6.6–6.7, ⁴J_HH 1.4), 3.28 and 3.34 (two m, H¹, 2H, AB-part of ABX-spectrum, ²J_H^1A_H^1B 10.1, ³J_H²_H¹ 5.6), 2.55 (br s, OH, 1H), 1.59 (m, H^3′, 2H, ³J_HH 6.7–7.1), 1.28–1.32 (m, H^3′-H^9′, 14H), 0.90 (t, H^10′, 3H, ³J_HH 7.1). Found: anal. C, 45.60; H, 7.83; I 37.02%, calcd. for C₁₃H₂₇IO₂, C, 45.62; H, 7.95; I 37.08%.

3.2.4. General Procedure for the Synthesis of Triphenylphosphonium Salts (3a–e, 3f–j)

To a solution of triphenylphosphine (1 mmol) in anhydrous CH₂Cl₂ (20 mL), under argon, CF₃SO₃H (1 mmol) was added at −10 ÷ 0 °C. After 10 min at −10 ÷ 0 °C, a solution of 2a–j (1 mmol) in anhydrous CH₂Cl₂ (20 mL) was added dropwise. The solution was stirred under argon atmosphere at room temperature for 15 min and then a solution concentrated in vacuo. Petroleum ether (5 mL) was added to the reaction mixture. The resulting precipitate was washed with diethyl ether (3 mL) and dried in vacuo to give the pure TPP salt.

(3-Chloro-2-hydroxypropyl)triphenylphosphonium trifluoromethanesulfonate (3a). Yield: 92%; mp 146–147 °C; IRS (cm⁻¹): 3365–3370 very br s (ν_OH), 1585, 1482, 1480, 1340, 1315, 1285, 1260, 1255, 1225, 1199, 1180, 1176, 1113, 1085, 1030, 1002, 928, 841, 790, 755, 750, 725, 713, 680, 645, 575, 535, 520, 510, 498, 466; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 7.78 (m, H^p, 3H, ³J_HH 7.4, ⁵J_HH 2.0), 7.72 (m, H^o, 6H, ³J_PH 12.8, ³J_HH 7.6), 7.68 (m, H^m, 6H, ³J_HH 7.4–7.6, ⁴J_PH 3.7), 4.81 (very br. s, OH, 1H), 4.17 (m, H², 1H, ³J_H^1B_H² 10.7, ³J_H³_H² 5.4, ²J_H^1A_H² 2.5), 3.70–3.71 (m, H³, 2H), 3.67 (ddd, H^1B, ²J_H^1A_H^1B 15.6, ²J_PH^1B 11.7, ³J_H²_H^1B 10.7), 3.48 (ddd, H^1A, 1H, ²J_H^1B_H^1A 15.6, ²J_PH^1A 13.4, ²J_H²_H^1A 2.5); ¹³C NMR spectrum (100.6 MHz, acetone-d₆ + 10% CDCl₃) δ_C ppm (J Hz) 135.50 (dtd (d), C^p, ¹J_HC 164.3, ³J_HCCC 7.2, ⁴J_PCCCC 2.9), 134.70 (dddd (d), C^o, ¹J_HC 166.3, ²J_PCC 10.3, ³J_HCCC 7.6, ³J_HCCC 7.0), 130.67 (ddd (d), C^m, ¹J_HC 166.8, ³J_PCCC 12.8, ³J_HCCC 7.5), 121.86 (q (q), CF₃, ¹J_FC 321.2), 120.08 (dt (d), Cⁱ, ¹J_PC 87.6, ³J_HCCC 8.3), 66.92 (dm (d), C², ¹J_HC 147.3, ²J_PCC 5.4, ²J_HCC 2.8–3.0, ²J_HCC 2.8–3.0), 28.42 (tdm (d), C¹, ¹J_HC 131.3, ¹J_PC 55.6), 49.89 (tddt (d), C³, ¹J_HC 152.0, ³J_PCCC 17.7, ²J_HCC 3.5, ³J_HCCC 2.0–2.2); ¹⁹F NMR spectrum (376.5 MHz, CDCl₃) δ_F −78.26 ppm (s); ³¹P-{¹H} NMR spectrum (CH₂Cl₂) δ_P 22.5 ppm; MALDI-MS, m/z 355.5 [M − CF₃SO₃]⁺. Calcd. for C₂₁H₂₁ClO₂P⁺: 355.8. Found: anal. C 52.55; H 4.16; Cl 6.98%, calcd. for C₂₂H₂₁ClF₃O₄PS, C 52.34; H 4.19, Cl 7.02%.

R-(3-Chloro-2-hydroxypropyl)triphenylphosphonium trifluoromethanesulfonate (3e, R). Yield: 93%; mp 137-138 °C; [α]_D²⁰ +26.0 (c 1.0, CHCl₃); ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 7.79 m (H^p, 3H, ³J_HH 7.3, ⁵J_HH 1.9), 7.72 m (H^o, 6H, ³J_PH 12.7, ³J_HH 7.6), 7.69 m (H^m, 6H, ³J_HH 7.3–7.6, ⁴J_PH 3.7), 4.37 br. s (OH, 1H), 4.18 br. m (H², 1H), 3.67–3.70 m (H^1B, H³, 3H, ²J_H^1A_H^1B 15.5, ²J_PH^1B 11.3, ³J_H²_H^1B 10.3), 3.46 ddd (H^1A, 1H, ²J_H^1B_H^1A 15.6, ²J_PH^1B 13.2, ²J_H²_H^1B 2.2).³¹P-{¹H} NMR spectrum (162.0 MHz, CDCl₃): δ_P 24.2 ppm.

S-(3-Chloro-2-hydroxypropyl)triphenylphosphonium trifluoromethanesulfonate (3e, S). Yield: 91%; mp 138 °C; [α]_D²⁰ −22.2 (c 1.0, CHCl₃); ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 7.81 m (H^p, 3H, ³J_HH 7.3, ⁵J_HH 1.9), 7.72 m (H^o, 6H, ³J_PH 12.7, ³J_HH 7.6), 7.69 m (H^m, 6H, ³J_HH 7.3–7.6, ⁴J_PH 3.7), 4.19 br. m (H², 1H), 3.70–3.73 m (H^1B, H³, 3H, ²J_H^1A_H^1B 15.5, ²J_PH^1B 11.3, ³J_H²_H^1B 10.3), 3.63 br. s (OH, 1H), 3.48 ddd (H^1A, 1H, ²J_H^1B_H^1A 15.6, ²J_PH1A 13.2, ²J_H2H1A 2.2). ³¹P-{¹H} NMR spectrum (162.0 MHz, CDCl₃): δ_P 24.2 ppm.

(3-Bromo-2-hydroxypropyl)triphenylphosphonium trifluoromethanesulfonate (3b). Yield: 95%; mp 161–162 °C (from methanol); IRS (cm⁻¹): 3358 (OH), 2961, 2914, 1588, 1485, 1439, 1419, 1400, 1335, 1313, 1283, 1247, 1222, 1170, 1164, 1110, 1068, 1026, 997, 913, 836, 789, 758, 750, 724, 716, 692, 639, 574, 550, 515, 505, 492, 464, 428, 410. ¹H NMR spectrum (250 MHz, CDCl₃) δppm (J Hz) 7.67–7.77 (m, C₆H₅, 15H), 4.16 (m, H², 1H), 3.66–3.70 (two m, H³, H^1B, ³J_H²_H 5.4; H^1B, ²J_H^A_H^B 14.7, ³J_PH^B 11.9, ³J_H²_H^B 11.0), 3.44 (ddd, H^1A, ²J_H^B_H^A 14.7, ³J_PH^A 13.6, ³J_H²_H^A 2.4); ¹H NMR spectrum (400 MHz, CDCl₃ + 10% acetone-d₆) δ ppm (J Hz) 7.70 and 7.84 (two m, C₆H₅, 15H), 4.19 (m, H², 1H), 3.94 (ddd, H^1B, 1H, B-part of ABX-spectru+m, ³J_H²_H^1B 10.6, ²J_H^1A_H^1B 15.6, ³J_PH^1B 12.2), 3.73 (ddd, H^1A, 1H, A-part of ABX-spectrum, ²J_H^1A_H^1B 15.6, ³J_PH^1A 12.2, ³J_H²_H^1A 2.8), 3.70 (m, H³, 2H, AB-part of ABX-spectrum); ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 7.69–7.85 (m, C₆H₅, 15H), 4.20 (m, H², 1H), 3.76–3.86 (m, H¹, 1H), 3.70 (m, H³, 2H), 3.51–3.59 (m, H¹, 1H); ¹³C NMR spectrum (100.6 MHz, CDCl₃ + 10% acetone-d₆) δ_C ppm (J Hz) 134.98 (dtd (d), C^p, ¹J_HC 163.9, ³J_HCCC 7.0, ⁴J_PCCCC 3.1), 133.84 (dddd (d), C⁰, ¹J_HC 164.5, ²J_PCC 10.3, ³J_HCCC 7.6, ³J_HCCC 6.5), 130.25 (ddd (d), C^m, ¹J_HC 165.9, ³J_PCCC 12.8, ³J_HCCC 7.2), 120.51 (q (q), CF₃, ¹J_FC 319.8), 118.54 (dt (d), Cⁱ, ¹J_PC 87.5, ³J_HCCC 8.0), 65.88 (dm (d), C², ¹J_HC 150.5, ²J_PCC 5.0), 38.05 (tdm (d), C³, ¹J_HC 151.6, ³J_PCCC 16.6, ²J_HCC 2.6, ³J_HCCC 2.4–2.6), 29.41 (tdm (d), C¹, ¹J_HC 132.0, ¹J_PC 55.4, ²J_HCC 4.8, ³J_HCCC 2.5); ¹³C-{¹H} NMR spectrum (125.76 MHz, CD₃CN) δ_C ppm (J Hz) 135.97 (d, C^p, ⁴J_PCCCC 3.0), 134.99 (d, C⁰, ²J_PCC 10.3), 131.10 (d, C^m, ³J_PCCC 12.8), 122.01 (q, CF₃, ¹J_FC 319.8), 120.05 (d, Cⁱ, ¹J_PC 87.7), 66.58 (d, C², ²J_PCC 5.2), 39.66 (d, C³, ³J_PCCC 17.6), 29.85 (d, C¹, ¹J_PC 55.6); ³¹P-{¹H} NMR spectrum (CDCl₃ + 10% acetone-d₆): δ_P 24.5 ppm. MALDI-MS, m/z 399.5 [M − CF₃SO₃]⁺. Calcd. for C₂₁H₂₁O₂P⁺: 400.2. Found: anal. C 48.15; H 3.88; Br 14.53%, calcd. for C₂₂H₂₁BrF₃O₄PS, C 48.10; H 3.85, Br 14.55%.

(3-Fluoro-2-hydroxypropyl)triphenylphosphonium trifluoromethanesulfonate (3c). Yield: 94%; mp 137 °C; IRS (cm⁻¹): 3386, 3065, 2957, 2917, 1588, 1486, 1441, 1399, 1264, 1226, 1148, 1112, 1029, 996, 900, 831, 786, 745, 726, 691, 637, 574, 497; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 7.81 (m, H^p, 3H), 7.72 and 7.69 (two m, H^o, H^m, 12H), 4.50 (br d, H³, 2H, ²J_FH 48.5), 4.21 (m, H², 1H), 3.89 (br s, OH, 1H), 3.72 (br ddd, H^1B, 1H, ²J_H^1A_H^1B 15.8, ²J_PH^1B 12.9, ³J_H²_H^1B 8.7), 3.34 (br dd, H^1A, 1H, ²J_H^1B_H^1A 15.8, ²J_PH^1A 12.1); ¹³C NMR spectrum (100.6 MHz, CDCl₃) δ_C ppm (J Hz) 135.08 (br d (d), C^p, ¹J_HC 164.6, ⁴J_PCCCC 2.9), 133.86 (br dm (d), C^o, ¹J_HC 164.5, ²J_PCC 10.3), 130.37 (ddd (d), C^m, ¹J_HC 165.9, ³J_PCCC 12.7, ³J_HCCC 6.5), 120.51 (q (q), CF₃, ¹J_FC 320.1), 118.41 (dt (d), Cⁱ, ¹J_PC 87.6, ³J_HCCC 7.3), 85.60 (dtm (dd), C³, ¹J_FC 173.6, ¹J_HC 160.3, ³J_PCCC 15.5), 65.84 (ddm (dd), C², ¹J_HC 147.4, ²J_FCC 20.5, ²J_PCC 5.6), 27.25 (tdm (dd), C¹, ¹J_HC 132.7, ¹J_PC 56.7, ³J_FCCC 4.7); ¹⁹F NMR spectrum (376.5 MHz, CDCl₃) δ_F −78.38 (s); ³¹P-{¹H} NMR spectrum (242.94 MHz, CDCl₃) δ_P 24.3 (s); MALDI-MS, m/z 339.5 [M − CF₃SO₃]⁺. Calcd. for C₂₁H₂₁O₂P⁺: 339.4. Found: anal. C 53.87; H 4.20%, calcd. for C₂₂H₂₁F₄O₄PS, C 54.10; H 4.33%.

(2-Hydroxy-3-methoxypropyl)triphenylphosphonium trifluoromethanesulfonate (3f). Yield: 78%; mp 122–124 °C; IRS (KBr pellet, cm⁻¹): 3399 br s (OH), 3064, 2996, 2960, 2923, 2910, 1588, 1486, 1459, 1439, 1416, 1382, 1337, 1282, 1249, 1225, 1196, 1161, 1110, 1046, 1026, 997, 969, 949, 869, 849, 843, 792, 750, 725, 715, 691, 638, 573, 540, 510, 497, 474; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 7.72 (m, H^p, 3H, ³J_HH 7.2, ⁵J_PH 2.0, ⁴J_HH 1.5), 7.67 (m, H^o, 6H, ³J_PH 12.5, ³J_HH 7.2, ⁴J_HH 1.5), 7.67 (m, H^m, 6H, ³J_HH 7.2, ³J_HH 7.2, ⁴J_PH 3.8), 5.85 (br s OH, 1H), 4.06 (m, H², 1H), 3.26 (s, C^1′, 3H), 3.54 (ddd, H^1B, 1H, B-part of ABX-spectrum, ²J_H^1A_H^1B 15.5, ²J_PH^1B 13.0, ²J_H²_H^1B 10.4), 3.34 (ddd, H^1A, 1H, A-part of ABX-spectrum, J_H^1B_H^1A 15.5, ²J_PH^1A 13.0, ³J_H²_H^1A 2.8), 3.49–3.50 (m, H³, 2H, AB-part of ABX-spectrum), 3.26 (s, H^1′, 3H); ¹³C NMR spectrum (100.6 MHz, CDCl₃) δ_C ppm (J Hz) 134.79 (dtd (d), C^p, ¹J_HC 163.8, ³J_HCCC 7.2, ⁴J_PCCCC 3.0), 133.56 (dddd (d), C^o, ¹J_HC 164.4, ²J_PCC 10.2, ³J_HCCC 7.4, ³J_HCCC 6.0–6.5), 130.10 (ddd (d), C^m, ¹J_HC 165.9, ³J_PCCC 12.8, ³J_HCCC 7.3), 120.37 (q (q), CF₃, ¹J_FC 320.2), 118.47 (dt (d), Cⁱ, ¹J_PC 87.2, ³J_HCCC 8.0), 75.49 (tddt (d), C³, ¹J_HC 142.0, ³J_PCCC 14.4, ²J_HCC 4.0, ³J_HCCC 2.0–2.2), 65.01 (dm (d), C², ¹J_HC 144.3, ²J_PCC 5.7, ²J_HCC 3.0–4.0, ²J_HCC 3.0–4.0), 58.88 (qt (s), C^1′, ¹J_HC 141.7, ³J_HCOC 2.6), 27.83 (tdm (d), C¹, ¹J_HC 130.4, ¹J_PC 55.0, ²J_HCC 4.5, ³J_HCCC 1.7–2.0); ¹⁹F NMR spectrum (376.5 MHz, CDCl₃) δ_F −78.33 (s); ³¹P-{¹H} NMR spectrum (162.0 MHz, CDCl₃) δ_P 24.7 (s); MALDI-MS, m/z 351.1 [M − CF₃SO₃]⁺. Calcd. for C₂₂H₂₄O₂P⁺: 351.4. Found: anal. C 55.16; H 4.73%, calcd. for C₂₃H₂₄F₃O₅PS, C 55.20; H 4.83%.

(3-Ethoxy-2-hydroxypropyl)triphenylphosphonium trifluoromethanesulfonate (3g). Yield: 77%; mp 99–101 °C; IRS (KBr pellet, cm⁻¹): 3386 br s (OH), 3058, 2973, 2922, 2892, 2802, 1589, 1486, 1440, 1411, 1375, 1357, 1286, 1247, 1226, 1158, 1110, 1061, 1029, 997, 949, 916, 869, 838, 793, 751, 724, 716, 690, 639, 573, 540, 509, 496, 476, 421; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 7.76 (m, H^p, 3H, ³J_HH 7.2, ⁵J_PH 2.1, ⁴J_HH 1.5), 7.70 (m, H^o, 6H, ³J_PH 12.5, ³J_HH 7.2, ⁴J_HH 1.5), 7.65 (m, H^m, 6H, ³J_HH 7.2, ³J_HH 7.2, ⁴J_PH 3.6), 5.08 (br s, OH, 1H), 4.10 (m, H², 1H, ³J_PH² 8.7, ³J_HH² 5.9, ³J_H^1A_H² 2.8), 3.40 (ddd, H^1A, 1H, A-part of ABX-spectrum, ²J_H^1B_H^1A 15.8, ²J_PH^1A 13.2, ³J_H²_H^1A 2.8), 3.56–3.58 (m, H³, H^1B, 3H), 3.47 and 3.50 (two m, H^1′, 2H, AB-part of ABX₃-spectrum, ²J_H^1′B_H^1′A 11.0, ³J_H^2′_H^1′ 7.0), 1.13 (t, H^2′, 3H, ³J_H^1′_H^2′ 7.0); ¹³C NMR spectrum (100.6 MHz, CDCl₃) δ_C ppm (J Hz) 134.86 (dtd (d), C^p, ¹J_HC 163.5, ³J_HCCC 7.2, ⁴J_PCCCC 3.0), 133.64 (dddd (d), C^o, ¹J_HC 164.3, ²J_PCC 10.2, ³J_HCCC 7.3, ³J_HCCC 6.5), 130.16 (ddd (d), C^m, ¹J_HC 166.0, ³J_PCCC 12.5, ³J_HCCC 7.2), 120.47 (q (q), CF₃, ¹J_FC 320.2), 118.55 (dt (d), Cⁱ, ¹J_PC 87.2, ³J_HCCC 8.0), 73.52 (tdm (d), C³, ¹J_HC 143.5, ³J_PCCC 14.7), 66.73 (tm (s), C^1′, ¹J_HC 140.4), 65.19 (ddm (d), C², ¹J_HC 146.3, ²J_PCC 5.7, ²J_HCC 4.0–4.2, ²J_HCC 4.0–4.2), 28.03 (tdm (d), C¹, ¹J_HC 132.0, ¹J_PC 54.9, ²J_HCC 4.0–4.2, ³J_HCCC 2.8–3.0), 14.93 (qt (s), C^2′, ¹J_HC 126.1, ²J_HCC 2.8-3.0); ¹⁹F NMR spectrum (376.5 MHz, CDCl₃) δ_F −78.31 (s); ³¹P-{¹H} NMR spectrum (162.0 MHz, CDCl₃) δ_P 24.1 (s); MALDI-MS, m/z 365.6 [M − CF₃SO₃]⁺. Calcd. for C₂₃H₂₆O₂P⁺: 365.4. Found: anal. C 55.89; H 4.84%, calcd. for C₂₄H₂₆F₃O₅PS, C 56.03; H 5.09%.

(2-Hydroxy-3-(2,2,3,3-tetrafluoropropoxy)propyl)triphenylphosphonium trifluoromethanesulfonate (3h). Yield: 65%; Oil; IRS (film, cm⁻¹): 3397 br s (OH), 3066, 2919, 1589, 1487, 1440, 1400, 1339, 1287, 1257, 1226, 1203, 1163, 1111, 1030, 998, 939, 886, 832, 787, 748, 722, 691, 639, 574, 543, 515, 443; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 7.77 (m, H^p, 3H, ³J_HH 7.2, ⁵J_PH 1.8, ⁴J_HH 1.5–1.6), 7.68 (m, H^o, 6H, ³J_PH 12.6, ³J_HH 7.2, ⁴J_HH 1.6), 7.65 (m, H^m, 6H, ³J_HH 7.2, ³J_HH 7.2, ⁴J_PH 3.7), 5.94 (tt, H^3′, 1H, ²J_FH 53.0, ³J_FH 5.2), 4.40 (br s, OH, 1H), 4.13 (br m, H², 1H), 3.88 and 3.85 (two m, H^1′, 2H, AB-part of ABX₂-spectrum, ³J_FH^A,B 12.4, ²J_H^1′A_H^1′B 12.2), 3.75 (m, H³, 2H, AB-part of ABX-spectrum, ²J_H^3A_H^3B 10.7), 3.57 (ddd, H^1B, 1H, B-part of ABX-spectrum, ²J_H^1B_H^1A 15.7, ²J_PH^1B 11.2, ³J_H²_H^1A 10.5), 3.35 (ddd, H^1A, 1H, A-part of ABX-spectrum, ²J_H^1B_H^1A 15.7, ²J_PH^1A 11.2, ³J_H²_H^1A 2.5); ¹³C NMR spectrum (100.6 MHz, CDCl₃) δ_C ppm (J Hz) 134.92 (dtd (d), C^p, ¹J_HC 163.7, ³J_HCCC 7.0, ⁴J_PCCCC 3.0), 133.68 (dddd (d), C^o, ¹J_HC 164.6, ²J_PCC 10.2, ³J_HCCC 7.6, ³J_HCCC 6.3), 130.22 (ddd (d), C^m, ¹J_HC 166.1, ³J_PCCC 12.8, ³J_HCCC 7.2), 120.50 (q (q), CF₃, ¹J_FC 320.2), 118.50 (dt (d), Cⁱ, ¹J_PC 87.5, ³J_HCCC 8.0), 114.96 (ttdt (tt), C^2′, ¹J_FC 250.0, ²J_FCC 26.6, ²J_HC^3′_C 5.7, ²J_HC^3′_C 1.6), 109.25 (tdtm (tt), C^3′, ¹J_FC 249.1, ¹J_HC 193.2, ²J_FCC 34.2, ³J_HC^1′_CC 1.8), 75.50 (tdm (d), C³, ¹J_HC 142.7, ³J_PCCC 5.2), 68.34 (ttt (t), C^1′, ¹J_HC 147.0, ²J_FCC 8.1, ²J_FCCC 3.2), 65.15 (dm (d), C², ¹J_HC 146.5, ²J_PCC 5.6, ²J_HCC 2.2–2.5), 27.60 (tdm (d), C¹, ¹J_HC 131.8, ¹J_PC 55.8); ¹⁹F NMR spectrum (376.5 MHz, CDCl₃, δ_F ppm, J Hz): −78.44 ((s), CF₃ 3F), −127.97 (tdt, C^2′F₂, 2F, ³J_H^1′_F^2′ 12.8, ³J_H^3′_F^2′ 5.4, ³J_F^3′_F^2′ 5.5), −132.20 (m, F^3′B, 1F, ²J_F^3′A_F^3′B 450.0, ²J_H^3′_F^3′B 52.9), −139.60 (m, F^3′A, 1F, ²J_F^3′B_F^3′A 450.0, ²J_H^3′_F^3′B’ 53.0, ³J_F^2′_F^3′A 5.5, ⁴J_H^1′_F^3′A 1.5); ³¹P-{¹H} NMR spectrum (162.0 MHz, CDCl₃) δ_P 24.1 (s); ³¹P-{¹H} NMR spectrum (162.0 MHz, CH₃CN) δ_P 25.1 (s); MALDI-MS, m/z 451.7 [M − CF₃SO₃]⁺. Calcd. for C₂₄H₂₄F₄O₂P⁺: 451.4. Found: anal. C 49.75; H 3.84%, calcd. for C₂₅H₂₄F₇O₅PS, C 50.01; H 4.03%.

(3-(Allyloxy)-2-hydroxypropyl)triphenylphosphonium trifluoromethanesulfonate (3i). Yield: 87%; mp 124–125 °C (from the CH₂Cl₂-benzene mixture); IRS (cm⁻¹): 3370–3390 br s (ν_OH), 1615, 1590, 1488, 1440, 1355, 1340, 1305, 1290, 1250, 1230, 1175, 1160, 1115, 1054, 1033, 1001, 940, 890, 855, 845, 796, 755, 726, 717, 695, 643, 575, 541, 515, 500, 480; ¹H NMR spectrum (250 MHz, CD₃OD) δ ppm (J Hz) 7.90–8.02 (m, C₆H₅); 6.11 (ddt, =CH, ³J_H^X_H 17.3, ³J_H^A_H 10.4, ³J_HH 5.6), 5.47 (ddt, =CH, ³J_HH^X 17.3, ²J_H^gem_H 1.6, ⁴J_HH 1.5), 5.36 (ddt, =CH, ³J_H^A_H 10.4, ²J_H^gem_H 1.6, ⁴J_HH 1.3), 4.18 (m, CH–O, ³J_HH 5.5), 3.95 (ddd, PCH^B, ²J_H^A_H^B 15.5, ²J_PH^B 11.5, ³J_HH^B10.6), 3.74 (m, =CCH₂, ³J_HH 5.6, ⁴J_H^A_H 1.5, ⁴J_H^X_H 1.3), 3.69 (ddd, PCH^A, ²J_H^B_H^A 15.5, ²J_PH^A 13.8, ³J_HH^A 2.7); ¹H NMR spectrum (600 MHz, CDCl₃) δ ppm (J Hz) 7.74 (m, H^p, 3H, ³J_HH 7.4, ⁵J_HH 1.2), 7.67 (m, H^o, 6H, ³J_PH 12.8, ³J_HH 7.4), 7.63 (m, H^m, 6H, ³J_HH 7.4, ⁴J_PH 3.6), 5.81 (ddt, H^2′, 1H, ³J_HH 17.2, ³J_HH 10.4, ³J_HH 5.6), 5.18 (dd, H^3′X, 1H, ³J_HH 17.2, ²J_HH 1.2), 5.10 (dd, H^3′A, 1H, ³J_HH 10.4, ²J_HH 1.2), 4.10 (br m, H², OH, 2H), 3.93 (m, H^1′, 2H, AB-part of ABX-spectrum, ²J_H1′AH1′B 12.7, ³J_H2H1′ 5.6), 3.56 (m, H^1B, 1H, ²J_PH1B 12.0, ²J_H1AH1B 15.7, ³J_H2H1B 10.4), 3.37 (ddd, H^1A, 1H, ³J_H1BH1A 15.7, ²J_PH1A 12.0, ³J_H2H1A 2.4); ¹³C NMR spectrum (150.9 MHz, CDCl₃) δ_C ppm (J Hz) 134.91 (dtd (d), C^p, ¹J_HC 164.2, ³J_HCCC 7.3, ⁴J_PCCCC 3.1), 134.23 (ddt (s), C^2′, ¹J_HC 155.5, ²J_HCC 3.8, ²J_HCC 3.8), 133.71 (dddd (d), C^o, ¹J_HC 164.6, ²J_PCC 10.2, ³J_HCCC 7.8, ³J_HCCC 6.7), 130.23 (ddd (d), C^m, ¹J_HC 166.4, ³J_PCC 12.5, ³J_HCCC 7.4), 120.64 (q (q), CF₃, ¹J_FC 320.6), 118.67 (dt (d), Cⁱ, ¹J_PC 187.1, ³J_HCCC 8.4), 117.39 (ddt (s), C^3′, ¹J_HC 158.8, ¹J_HC 155.2, ³J_HCCC 5.6), 73.37 (tdm (d), C³, ¹J_HC 144.5, ³J_PCCC 14.5), 72.28 (tm (s), C^1′, ¹J_HC 141.8, ³J_HCCC 12.9, ³J_HCCC 6.9, ²J_HCC 4.4, ³J_HCOC 2.9), 65.28 (dm (d), C², ¹J_HC 147.1, ²J_PCC 5.8, ²J_HCC 2.8), 28.24 (br td (d), C¹, ¹J_HC 132.2, ¹J_PC 54.1); ¹⁹F NMR spectrum (376.5 MHz, CDCl₃) δ_F −78.29 (s); ³¹P-{¹H} NMR spectrum (162.0 MHz, CH₂Cl₂) δ_P 23.5; ³¹P-{¹H} NMR spectrum (242.94 MHz, CDCl₃) δ_P 24.2; MALDI-MS, m/z 377.4 [M − CF₃SO₃]⁺. Calcd. for C₂₄H₂₆O₂P⁺: 377.4. Found: anal. C 56.95; H 4.93%, calcd. for C₂₅H₂₆F₃O₅PS, C 57.03; H 4.98%.

(3-(Decyloxy)-2-hydroxypropyl)triphenylphosphonium trifluoromethanesulfonate (3j). Yield: 75%; mp 78–79 °C; IRS (cm⁻¹): 3381 br s (OH), 3066, 2927, 2856, 2795, 1486, 1467, 1459, 1440, 1406, 1363, 1287, 1246, 1227, 1162, 1111, 1031, 997, 950, 879, 838, 791, 748, 724, 715, 689, 640, 573, 530, 510, 497, 465; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 7.75 (m, H^p, 3H, ³J_HH 7.2, ⁵J_PH 2.0, ⁴J_HH 1.5), 7.68 (m, H^o, 6H, ³J_PH 12.5, ³J_HH 7.2, ⁴J_HH 1.5), 7.64 (m, H^m, 6H, ³J_HH 7.2, ⁴J_PH 3.6), 4.08 (m, H², 1H), 3.98 (br s, OH, 1H), 3.54–3.55 (m, H^1B, H³, 3H), 3.37–3.40 (m, H^1A, H^1′, 3H), 1.49 (m, H^2′, 2H, ³J_HH 6.8–6.9), 1.22 (m, H^3′-H^9′, 14H), 0.84 (t, H^10′, 3H, ³J_HH 7.0); ¹³C NMR spectrum (100.6 MHz, CDCl₃) δ_C ppm (J Hz) 134.91 (dtd (d), C^p, ¹J_HC 163.7, ³J_HCCC 7.1, ⁴J_PCCCC 3.0), 133.71 (dddd (d), C^o, ¹J_HC 165.1, ²J_PCC 10.3, ³J_HCCC 7.4, ³J_HCCC 6.4), 130.22 (ddd (d), C^m, ¹J_HC 166.0, ³J_PCCC 12.7, ³J_HCCC 7.2), 120.58 (q (q), CF₃, ¹J_FC 320.4), 118.63 (dt (d), Cⁱ, ¹J_PC 87.1, ³J_HCCC 8.0), 73.79 (tdm (d), C³, ¹J_HC 142.3, ³J_PCCC 14.6), 71.61 (tm (s), C^1′, ¹J_HC 141.6), 65.26 (dm (d), C², ¹J_HC 146.2, ²J_PCC 5.7, ²J_HCC 2.5–3.3), 32.84 (tm (s), C^2′, ¹J_HC 125.7), 29.58 (tm (s), C^3′, ¹J_HC 123.0–124.0), 29.51 (tm (s), C^4′, C^5′, ¹J_HC 124.0–125.0), 29.41 (tm (s), C^6′, ¹J_HC 124.0–125.0), 29.27 (tm (s), C^7′, ¹J_HC 123.0–124.0), 28.15 (tdm (d), C¹, ¹J_HC 134.0, ¹J_PC 54.6), 26.05 (tm (s), C^8′, ¹J_HC 124.0–125.0), 22.63 (tm (s), C^9′, ¹J_HC 124.3), 14.10 (qm (s), C^10′, ¹J_HC 125.0, ³J_HCCC 2.5–2.7, ²J_HCC 2.5); ¹⁹F NMR spectrum (376.5 MHz, CDCl₃) δ_F −78.28 (s); ³¹P-{¹H} NMR spectrum (162.0 MHz, CDCl₃) δ_P 24.2 (s); MALDI-MS, m/z 477.4 [M − CF₃SO₃]⁺. Calcd. for C₃₁H₄₂O₂P⁺: 477.7. Found: anal. C 61.16; H 6.54%, calcd. for C₃₂H₄₂F₃O₅PS, C 61.33; H 6.76%.

(2-Hydroxy-3-palmitoyloxy-propyl)triphenylphosphonium trifluoromethanesulfonate (3k). To a solution of glycidyl palmitate (for the synthesis and spectral data see [203]) (0.512 g, 1.64 mmol) in dry CHCl₃ (50 mL) was added a solution of triphenylphosphonium triflate in CHCl₃ (1.9 mL, 1.27 mmol, C = 0.2748 g/mL) in an argon atmosphere. The reaction mixture was stirred at room temperature for 3 h. The solvent was completely removed from the reaction medium in vacuo. The product was purified by filtration through a layer of silica gel, which was initially washed with a mixture of petroleum ether/ethyl acetate 3:1 (v/v), and then with ethanol. Yield: (95%); colorless amorphous powder; mp 40–41 °C; IRS (KBr, cm⁻¹): 3380, 3063, 2018, 1938, 1909, 1830, 1737, 1197, 1166, 1031; ¹H NMR spectrum (400 MHz, CDCl₃) δ 7.77, 7.69, 7.65 (three m, 15H, H^p, H^o, H^m, ³J_HH 7.6, ³J_PH 12.8, ⁴J_PH 3.3), 4.68 (brs, 1H, H²), 4.20 (br. s, 2H, H³), 3.64 (br. m, 1H, H^1B, ²J_HH 15.0, ²J_PH 14.0), 3.32 (br. d. d, 1H, H^1A, ²J_HH 15.0, ²J_PH 14.0), 2.26 (m, 2H, CH₂C(O), ³J_HH7.2), 1.54 (m, 2H, ³J_HH 7.2–7.4), 1.24 (br. s, 24H), 0.86 (t, 3H, ³J_HH 7.0); ¹³C–{¹H} NMR spectrum (100.6 MHz, CDCl₃) δ_C 173.83 (s, C(O)O), 135.04 (d, C^p, ⁴J_PC 3.0), 133.85 (s, C^o, ³J_PC 10.3), 130.34 (d, C^m, ³J_PC 12.8), 118.57 (q, CF₃, ¹J_FC 320.0), 118.57 (d, Cⁱ, ¹J_PC 87.4), 67.61 (d, C³, ³J_PC 15.9), 64.65 (d, C², ²J_PC 5.4), 34.02 (s, C^1′), 31.97 (s, C^2′), 29.75 (brs, C^3′, C^4′, C^5′), 29.72 (s, C^6′), 29.70 (s, C^7′), 29.69 (s, C^8′), 2954 (s, C^9′), 29.41 (s, C^10′) 29.38 (s, C^11′), 29.16 (s, C^12′), 28.32 (d, C¹, ¹J_PC 55.6), 24.85 (s, C^13′), 22.74 (s, C^14′), 14.19 (s, C^15′); ³¹P–{¹H} NMR spectrum (242.9 MHz, CDCl₃) δ_P 24.2 (s); MALDI-MS, m/z 575.3 [M − CF₃SO₃]⁺. Calcd. for C₃₇H₅₂O₃P⁺: 575.4. Found: anal. C 62.59; H 7.28%, calcd. for C₃₈H₅₂F₃O₆PS, C 62.97; H 7.23%.

(2-Hydroxy-3-stearoyloxy-propyl)triphenylphosphoniumtrifluoromethanesulfonate (3l). To a solution of glycidyl stearate (for the synthesis and spectral data see [203]) (0.5 g, 1.47 mmol) in dry CHCl₃ (50 mL) was added a solution of triphenylphosphonium triflate in CHCl₃ (1.85 mL, 1.23 mmol, C = 0.2748 g/mL) in an argon atmosphere. The reaction mixture was stirred at room temperature for 3 h. The solvent was completely removed from the reaction medium in vacuo. The product was purified by filtration through a layer of silica gel, which was initially washed with a mixture of petroleum ether/ethyl acetate 3:1 (v/v), and then with ethanol. Yield: 37%; colorless amorphous powder; mp = 60–61 °C; IRS (KBr, cm⁻¹) 3436, 3063, 2018, 1938, 1909, 1830, 1737, 1160, 1113, 1031; ¹H NMRspectrum (400 MHz, CDCl₃) δ 7.77, 7.71, 7.68 (three m, 15H, H^p, H^o, H^m), 4.52 (brs, 1H, OH), 4.22 (br. s., 1H, H²), 4.10–4.16 (m, 2H, H³), 3.63 (br. m, 1H, H^1B, ²J_HH 12.9, ²J_PH 11.1), 3.32 (br. d. d, 1H, H^1A, ²J_HH 12.9, ²J_PH 11.1), 2.30 (t, 2H, CH₂C(O), ³J_HH 7.5), 1.55 (m, 2H, ³J_HH 7.2–7.4), 1.24 (br. s, 28H), 0.86 (t, 3H, ³J_HH 7.0); ¹³C–{¹H} NMRspectrum (100.6 MHz, CDCl₃) δ_C 173.95 (s, C(O)O), 134.82 (d, C^p, ⁴J_PC 2.9), 133.78 (s, C^o, ³J_PC 10.2), 130.20 (d, C^m, ³J_PC 12.7), 120.43 (q, CF₃, ¹J_FC 320.0), 118.51 (d, Cⁱ, ¹J_PC 87.4), 67.65 (d, C³, ³J_PC 16.6), 64.69 (d, C², ²J_PC 5.7), 34.11 (s, C^1′), 31.93 (s, C^2′), 29.71 (brs, C^3′, C^4′, C^5′, C^6′), 29.67 (s, C^7′, C^8′, C^9′), 29.62 (s, C^10′), 29.47 (s, C^11′), 29.37 (s, C^12′), 29.67 (s, C^13′), 29.13 (s, C^14′), 29.42 (d, C¹, ¹J_PC 54.5), 24.89 (s, C^15′), 22.70 (s, C^16′), 14.13 (s, C^17′);³¹P–{¹H} NMRspectrum (242.9 MHz, CDCl₃) δ_P 24.3 (s); MALDI-MS, m/z 603.4 [M − CF₃SO₃]⁺. Calcd. for C₃₉H₅₆O₃P⁺: 603.9. Found: anal. C 63.74; H 7.57%, calcd. for C₄₀H₅₆F₃O₆PS, C 63.81; H 7.50%.

3.2.5. General Procedure for the Synthesis of (3-Alkoxy-2-hydroxypropyl)triphenylphosphonium Iodide (4a–d)

Triphenylphosphine (4–6 mmol) was added to the solution of iodide 6a–d (1 mmol) in dry acetonitrile under argon, and the mixture was stirred under reflux for 10 h. Acetonitrile was removed under reduced pressure, and the precipitate was washed with ether (3 × 5 mL). The resulting precipitate was dried in vacuo to give the pure TPP conjugate °C; IRS (KBr pellet, cm⁻¹): 3245 very br. s. (OH), 3051, 2982, 2931, 2876, 2828, 1585, 1482, 1461, 1437, 1413, 1390, 1301, 1239, 1196, 1153, 1121, 1110, 1044, 1029, 997, 868, 833, 791, 751, 719, 694, 588, 532, 500, 470, 448. ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 7.75 (m, H^p, 3H, ³J_HH 7.2, ⁵J_PH 2.0, ⁴J_HH 1.5), 7.72 (m, H^o, 6H, ³J_PH 12.2, ³J_HH 7.2, ⁴J_HH 1.5), 7.63 (m, H^m, 6H, ³J_HH 7.2, ⁴J_PH 3.5), 3.72 (very br s, OH, 1H), 4.22 (m, H², 1H, 10.0, ³J_H^3A_H² 7.1, ³J_H^3B_H² 6.1, ³J_H^1A_H² 2.8), 3.74 (ddd, H^1B, 1H, B-part of ABX-spectrum, ²J_H^1A_H^1B 15.6, ²J_PH^1B 12.0, ³J_H²_H^1B 10.0), 3.59 (ddd, H^1A, 1H, A-part of ABX-spectrum, ²J_H^1B_H^1A 15.6, ²J_PH^1A 12.0, ³J_H²_H^1A 2.8), 3.62–3.68 (m, H³, 2H, AB-part of ABXY-spectrum, ²J_H^3A_H^3B 9.6, ³J_H²_H^3A 7.1, ³J_H²_H^3B 6.1, ⁴J_PH^1A 2.2, ⁴J_PH^1B 1.1), 3.26 (s, H^1′, 3H), ¹³C NMR spectrum (100.6 MHz, CDCl₃) δ_C ppm (J Hz) 134.63 (dtd (d), C^p, ¹J_HC 163.8, ³J_HCCC 7.1, ⁴J_PCCCC 3.0), 133.55 (dddd (d), C^o, ¹J_HC 164.5, ²J_PCC 10.3, ³J_HCCC 7.3, ³J_HCCC 6.7), 129.99 (ddd (d), C^m, ¹J_HC 165.8, ³J_PCCC 12.7, ³J_HCCC 7.3), 118.19 (dt (d), Cⁱ, ¹J_PC 87.2, ³J_HCCC 8.4), 75.31 (tdm (d), C³, ¹J_HC 143.0, ³J_PCCC 14.0, ²J_HCC 4.8–5.0, ³J_HCCC 1.8–2.0), 64.56 (dt (d), C², ¹J_HC 146.6, ²J_PCC 5.6, ²J_HCC 2.8–3.1, ²J_HCC 2.8–3.1), 58.78 (qt (s), C^1′, ¹J_HC 141.6, ³J_HCOC 2.7), 27.87 (tdm, C¹, ¹J_HC 131.3, ¹J_PC 54.4, ²J_HCC 3.5–4.0, ³J_HCCC 2.6); ³¹P-{¹H} NMR spectrum (162.0 MHz, CDCl₃) δ_P 24.7 (s); MALDI-MS, m/z 351.4 [M − I]⁺. Calcd. for C₂₂H₂₄O₂P⁺351.2. Found: anal. C 55.19; H 4.96; I 26.50%, calcd. for C₂₂H₂₄IO₂P, C 55.24; H 5.06; I 26.53%.

(3-Ethoxy-2-hydroxypropyl)triphenylphosphonium iodide (4b). Yield: 95%; Oil; IRS (film, cm⁻¹): 3306 very br s (OH), 3055, 2974, 2870, 1615, 1588, 1485, 1438, 1384, 1337, 1316, 1271, 1238, 1181, 1114, 1086, 1027, 1014, 997, 935, 907, 868, 825, 783, 748, 722, 692, 618, 601, 542, 507, 444. ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz): 7.82 (m, H^p, 3H, ³J_HH7.2, ⁵J_PH 2.0, ⁴J_HH 1.5), 7.79 (m, H^o, 6H, ³J_PH 15.3, ³J_HH 7.2, ⁴J_HH 1.5), 7.68 (m, H^m, 6H, ³J_HH 7.2, ³J_HH 7.2, ⁴J_PH 3.3), 4.26 (m, H², 1H, ³J_H^1B_H² 10.3, ³J_H^1A_H² 2.8, ³J_H^3A_H² 2.5), 3.69 (ddd, H^1A, 1H, A-part of ABX-spectrum, ²J_H^1B_H^1A 15.3, ²J_PH^1A 12.0, ³J_H²_H^1A 2.8), 3.74 and 3.80 (two m, H³, 2H, AB-part of ABX-spectrum, ²J_H^3B_H^3A 9.5, ³J_H²_H^3B 6.6, ³J_H²_H^3A 2.5), 3.88 (ddd, H^1B, 1H, B-part of ABX-spectrum, ²J_H^1B_H^1A 15.3, ²J_PH^1B 12.0, ³J_H²_H^1B 10.3), 3.52–3.56 (m, H^1′, 2H, AB-part of ABX₃-spectrum, ²J_H^1′B_H^1′A 10.5, ³J_H^2′_H^1A’ 7.1, ³J_H^2′_H^1B’ 7.1), 1.16 (t, H^2′, 3H, ³J_H^1′_H^2′ 7.0–7.1); ¹³C NMR spectrum (100.6 MHz, CDCl₃) δ_C ppm (J Hz): 134.87 (dtd (d), C^p, ¹J_HC 163.7, ³J_HCCC 7.2, ⁴J_PCCCC 3.0), 133.89 (dddd (d) C^o, ¹J_HC 164.7, ²J_PCC 10.2, ³J_HCCC 7.6, ³J_HCCC 6.8), 130.23 (ddd (d), C^m, ¹J_HC 165.7, ³J_PCCC 12.8, ³J_HCCC 7.2), 118.65 (dt (d), Cⁱ, ¹J_PC 87.1, ³J_HCCC 8.4), 73.68 (tdm (d), C³, ¹J_HC 145.0, ³J_PCCC 14.5, ²J_HCC 3.4–3.5, ³J_HCCC 2.0–2.6), 66.76 (tm (s), C^1′, ¹J_HC 141.6, ²J_HCC 4.6, ³J_HCCC 2.1–2.2), 65.08 (ddm, C², ¹J_HC 147.5, ²J_PCC 5.7), 28.36 (tdm, C¹, ¹J_HC 130.0, ¹J_PC 54.2), 15.14 (qt (s), C^2′, ¹J_HC 126.0, ²J_HCC 2.5); ³¹P-{¹H} NMR spectrum (162.0 MHz, CDCl₃): δ_P 25.3 (s); MALDI-MS, m/z 365.5 [M − I]⁺. Calcd. for C₂₃H₂₆O₂P⁺: 365.4. Found: anal. C 56.05; H 5.27; I 25.70%, calcd. for C₂₃H₂₆IO₂P, C 56.11; H 5.32; I 25.78%.

(3-(Allyloxy)-2-hydroxypropyl)triphenylphosphonium iodide (4c). Yield is 90%; IRS (film, cm⁻¹): 3305, 3055, 2865, 1485, 1438, 1339, 1111, 997, 931, 826, 748, 721, 690; ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 7.76–7.77 (m, H^p, H^o, 6H), 7.66 (m, H^m, 6H, ³J_HH 7.7, ⁴J_PH 3.6), 5.84 (ddt, H^2′, 1H, ³J_HH 17.2, ³J_HH 10.4, ³J_HH 5.6), 5.21 (ddt, H^3′_trans, 1H, ³J_HH 17.2, ²J_HH 1.2, ⁴J_HH 1.2), 5.14 (br d, H^3′_cis, 1H, ³J_HH 10.4, ²J_HH 1.2, ⁴J_HH 0.9), 4.28 (br m, H², 1H), 3.98–4.0 (m, H³, 2H, AB-part of ABX-spectrum, ²J_H^3A_H^3B 12.8, ³J_H²_H³ 5.6), 3.74–3.83 (m, H^1B, H^1′, 3H, ²J_PH^1B 10.8, ²J_H^1A_H^1B 15.4, ³J_H²_H^1B 10.4), 3.67 (ddd, H^1A, 1H, ³J_H^1B_H^1A 15.4, ²J_PH^1A 13.2, ³J_H²_H^1A 2.4); ¹³C NMR spectrum (100.6 MHz, CDCl₃) δ_C ppm (J Hz) 134.98 (dtd (d), C^p, ¹J_HC 164.1, ³J_HCCC 7.1, ⁴J_PCCCC 3.1), 134.37 (dtdd (s), C^2′, ¹J_HC 155.3, ²J_HCC 4.5, ²J_HCC 4.5, ²J_HCC 2.8), 134.01 (dddd (d), C^o, ¹J_HC 164.6, ²J_PCC 10.3, ³J_HCCC 7.8, ³J_HCCC 6.5), 130.35 (ddd (d), C^m, ¹J_HC 165.8, ³J_PCC 12.9, ³J_HCCC 7.3), 118.76 (dt (d), Cⁱ, ¹J_PC 87.1, ³J_HCCC 8.5), 117.49 (ddt, C^3′, ¹J_HC 158.8, ¹J_HC 155.2, ³J_HCCC 5.5), 73.58 (tdm (d), C³, ¹J_HC 144.2, ³J_PCCC 14.3), 72.37 ((s), C^1′, ¹J_HC 142.3, ³J_HCCC 11.8, ³J_HCCC 6.9, ²J_HCC 10.3, ³J_HCOC 3.6), 65.24 (dm (d), C², ¹J_HC 147.1, ²J_PCC 5.7, ²J_HCC 2.8), 28.54 (tdm (d), C¹, ¹J_HC 131.8, ¹J_PC 54.1); ³¹P-{¹H} NMR spectrum (242.94 MHz, CDCl₃) δ_P 24.2. Found: anal.%: C 57.07; H 5.31; P 6.11, calcd. for C₂₄H₂₆IO₂P, %: C 57.16; H 5.20; P 6.14.

(3-(Decyloxy)-2-hydroxypropyl)triphenylphosphonium iodide (4d). Yield: 81%; mp 75–77 °C; IRS (KBr, cm⁻¹): 3297 very br s (OH), 3054, 3023, 2991, 2922, 2853, 1587, 1484, 1459, 1436, 1403, 1369, 1335, 1299, 1234, 1189, 1111, 1026, 996, 943, 877, 834, 793, 746, 716, 689, 533, 508, 494. ¹H NMR spectrum (400 MHz, CDCl₃) δ ppm (J Hz) 7.39–7.41 (m, H^p, H^o, 9H), 7.28 (m, H^m, 6H, ³J_HH 7.0–7.2, ⁴J_PH 3.4), 4.28 (very br s OH, 1H), 3.86 (m, H², 1H), 3.41 (ddd, H^1B, 1H, ²J_H^1A_H^1B 15.3, ²J_PH^1B 11.1, ³J_H²_H^1B 10.3), 3.28–3.30 (m, H^1A, A-part of ABXY-spectrum; H³, AB-part of ABX-spectrum, 3H), 3.02–3.06 (m, H^1′, 2H, AB-part of ABX₂-spectrum), 1.12 (m, H^3′, 2H, ³J_HH 6.8–7.0), 0.85–0.88 (m, H^4′-H^9′, 14H), 0.46 (t, H^10′, 3H, ³J_HH 7.1); ¹³C NMR spectrum (100.6 MHz, CDCl₃) δ_C ppm (J Hz) 134.30 (dtd (d), C^p, ¹J_HC 163.7, ³J_HCCC 7.0, ⁴J_PCCCC 2.8), 133.37 (dddd (d), C^o, ¹J_HC 164.7, ²J_PCC 10.3, ³J_HCCC 7.4, ³J_HCCC 6.7), 129.69 (ddd (d), C^m, ¹J_HC 165.8, ³J_PCCC 12.8, ³J_HCCC 7.4), 118.15 (dt (d), Cⁱ, ¹J_PC 87.2, ³J_HCCC 8.3), 73.44 (tdm (d), C³, ¹J_HC 142.8, ³J_PCCC 14.6), 70.99 (br tm (s), C^1′, ¹J_HC 141.0), 64.52 (br dm (d), C², ¹J_HC 145.6, ²J_PCC 5.7), 31.26 (tm (s), C^2′, ¹J_HC 125.7), 20.02 (tm (s), C^3′, C^4′, ¹J_HC 124.4–124.6), 28.95 (tm, (s) C^5′, ¹J_HC 124.0–125.0), 28.87 (tm, (s) C^6′, ¹J_HC 124.0–125.0), 28.70 (tm (s), C^7′, ¹J_HC 124.0–125.0), 27.65 (tdm (d), C¹, ¹J_HC 133.1, ¹J_PC 54.2), 25.62 (tm (s), C^8′, ¹J_HC 124.4), 22.03 (tm (s), C^9′, ¹J_HC 125.8), 13.48 (qm (s), C^10′, ¹J_HC 124.2); ³¹P-{¹H} NMR spectrum (162.0 MHz, CDCl₃) δ_P 25.1 (s);¹H NMR spectrum (400 MHz, CD₃CN) δ ppm (J Hz) 7.85 (m, H^p, 3H, ³J_HH 7.0–7.2, ⁵J_PH 2.0, ⁴J_HH 1.2), 7.82 (m, H^o, 6H, ³J_PH 13.6, ³J_HH 7.0–7.2, ⁴J_HH 1.3), 7.70 (m, H^m, 6H, ³J_HH 7.0–7.2, ⁴J_PH 3.5), 4.09 (m, H², 1H), 3.78 (ddd, H^1B, 1H, ²J_H^1A_H^1B 15.7, ²J_PH^1B 11.5, ³J_H²_H^1B 10.2), 3.89 (br s, OH, 1H), 3.56–3.62 (m, H^1A, H³, 3H), 3.42 and 3.45 (two m, H^1′, 2H, AB-part of ABX₂-spectrum, ²J_H^1′A_H^1′B 9.5, ³J_HH 6.6–6.8), 1.53 (m, H^2′, 2H, ³J_HH 7.0–7.1, ³J_HH 7.0–7.1), 1.27–1.34 (m, H^4′-H^9′, 14H), 0.88 (t, H^10′, 3H, ³J_HH 6.8); ¹³C NMR spectrum (100.6 MHz, CD₃CN) δ_C ppm (J Hz) 135.46 (dtm (d), C^p, ¹J_HC 164.9, ³J_HCCC 7.3, ⁴J_PCCCC 3.0, ²J_HCC 1.4, ²J_HCC 0), 134.71 (ddm (d), C^o, ¹J_HC 165.2, ²J_PCC 10.3, ³J_HCCC 7.8, ³J_HCCC 7.0), 130.83 (ddd (d), C^m, ¹J_HC 166.2, ³J_PCCC 12.8, ³J_HCCC7.3), 119.97 (dt (d), Cⁱ, ¹J_PC 87.4, ³J_HCCC 7.4), 74.87 (tdm (d), C³, ¹J_HC 142.0, ³J_PCCC 14.8), 71.96 (tm (s), C^1′, ¹J_HC 140.1), 65.64 (dm (d), C², ¹J_HC 145.6, ²J_PCC 5.8, ²J_HCC 2.8, ²J_HCC 2.8), 32.34 (tm (s), C^2′, ¹J_HC 125.3), 30.13 (tm (s), C^3′, ¹J_HC 124.0–125.0), 30.10 (tm (s), C^4′, ¹J_HC 124.0–125.0), 30.03 (tm (s), C^5′, ¹J_HC 124.0–125.0), 29.93 (tm (s), C^6′, ¹J_HC 124.0–125.0), 29.77 (tm (s), C^7′, ¹J_HC 124.0–125.0), 28.09 (tdm (d), C¹, ¹J_HC 134.0, ¹J_PC 54.6), 26.61 (tm (s), C^8′, ¹J_HC 124.4), 23.11 (tm (s), C^9′, ¹J_HC 124.5), 14.22 (qm (s), C^10′, ¹J_HC 124.4, ³J_HCCC 3.5–4.0, ²J_HCC 3.3–3.4); ³¹P-{¹H} NMR spectrum (162.0 MHz, CD₃CN) δ_P 24.6 (s); MALDI-MS, m/z 477.6 [M − I]⁺. Calcd. for C₃₁H₄₂O₂P⁺: 477.7. Found: anal. C 62.03; H 6.87; I 20.94%, calcd. for C₃₁H₄₂IO₂P, C 61.59; H 7.00; I 20.99%.

3.2.6. Synthesis of 3d and 7

To a solution of the corresponding previously obtained compound 3a (1.5 g, 3 mmol) in CH₃CN (5 mL) was added NaI (1.8 g, 12 mmol) and 10% 18-crown-6 (0.08 g). The reaction mixture was stirredunder reflux for 36 (h). After cooling the mixture to room temperature, the precipitate was remover and the solvent was evaporatedin vacuo. The residue was purified by chromatography on silica gel using a EtOAc as eluent to afford the desired product 3d and 7.

(2-Hydroxy-3-iodopropyl)triphenylphosphonium trifluoromethanesulfonate (3d). Yield: 31%; R_f = 0.88 (silica gel, CH₃CN); mp 178–180 °C; IRS (KBr, cm⁻¹): 3219 (OH), 2869, 1438, 1407, 1251, 1180, 1109, 1040, 769, 752, 721, 692, 653, 580, 539, 521, 499, 475; ¹H NMR spectrum (400 MHz, CD₃CN) δ ppm (J Hz) 7.88 (m, H^p, 3H, ³J_HH 7.2, ⁵J_PH 1.8, ⁴J_HH 1.7), 7.78 (m, H^o, 6H, ³J_PH 12.8, ³J_HH 7.2, ⁴J_HH 1.7), 7.73 (m, H^m, 6H, ³J_HH 7.2, ³J_HH 7.2, ⁴J_PH 3.7), 4.24 (br d, OH, 1H, ³J_HH 4.0), 3.84 (m, H², 1H), 3.70 (ddd, H^1B, 1H, B-part of ABX-spectrum, ²J_H^1A_H^1B 15.2, ²J_PH^1B 11.5, ³J_H2H1B 10.5), 3.50–3.56 (m, H^1A, H³, 3H); ¹³C NMR spectrum (150.9 MHz, CD₃CN, δ_C ppm, J Hz): 135.92 (dtm (d), C^p, ¹J_HC 161.7, ³J_HCCC 7.3, ⁴J_PCCCC 3.0, ²J_HCC 1.8), 135.02 (dddd (d), C^o, ¹J_HC 165.1, ²J_PCC 10.4, ³J_HCCC 7.6, ³J_HCCC 6.5), 131.08 (dddd (d), C^m, ¹J_HC 164.7–165.5, ³J_PCCC 12.8, ³J_HCCC 7.3–7.5, ²J_HCC 1.8–2.4), 121.95 (q (q), CF₃, ¹J_FC 320.2), 120.10 (ddd (d), Cⁱ, ¹J_PC 87.6, ³J_HCCC 8.0, ³J_HCCC 7.1), 66.41 (dm (d), C², ¹J_HC 142.2, ³J_PCCC 3.4), 31.35 (tdm (d), C¹, ¹J_HC 132.1, ¹J_PC 54.5, ²J_HCC 4.2, ³J_HCCC 2.0–2.2), 15.06 (tdm (d), C³, ¹J_HC 152.8, ³J_PCCC 17.4, ²J_HCC 3.6, ³J_HCCC 2.3); ¹⁹F NMR spectrum (376.5 MHz, CDCl₃) δ_F −78.27 (s); ³¹P-{¹H} NMR spectrum (242.94 MHz, CD₃CN) δ_P 23.3 (s); MALDI-MS, m/z 447.1 [M − CF₃SO₃]⁺. Calcd. for C₂₁H₂₁IOP⁺: 447.3. Found: anal. C 44.26; H 3.33; I 21.25%, calcd. for C₂₂H₂₁F₃IO₄PS, C 44.31; H 3.55, I 21.28%.

(2-Hydroxy-3-iodopropyl)triphenylphosphonium iodide (7). Yield: 56%; R_f = 0.69 (silica gel, CH₃CN); mp 197–198 °C; IRS (KBr, cm⁻¹): 3399 br s, 3064, 2996, 2960, 2923, 2910, 1588, 1486, 1459, 1439, 1416, 1382, 1337, 1282, 1249, 1225, 1196, 1161, 1110, 1046, 1026, 997, 969, 949, 869, 849, 843, 792, 750, 725, 715, 691, 638, 573, 540, 510, 497, 474. ¹H NMR spectrum (400 MHz, CD₃CN) δ ppm (J Hz) 7.76–7.79 (br m, H^p, H^o, 9H, ³J_HH 7.1–7.2, ³J_PH 12.5), 7.68 (m, H^m, 6H, ³J_HH 7.1–7.2, ³J_HH 7.1–7.2, ⁴J_PH 3.3), 4.62 (br s, OH, 1H), 4.00 (m, H², 1H), 3.79–4.85 (m, H¹, 2H), 3.61 (m, H³, 2H); ¹³C NMR spectrum (100.6 MHz, CDCl₃ + 20% DMCO-d₆) δ ppm (J Hz) 133.55 (dtd (d), C^p, ¹J_HC 164.2, ³J_HCCC 7.2, ⁴J_PCCCC 2.6), 132.66 (dddd (d), C^o, ¹J_HC 165.1, ²J_PCC 10.4, ³J_HCCC 7.2, ³J_HCCC 6.7), 128.78 (ddd (d), C^m, ¹J_HC 165.9, ³J_PCCC 12.8, ³J_HCCC 7.4), 117.72 (ddd (d), Cⁱ, ¹J_PC 87.5, ³J_HCCC 9.0), 63.76 (dm (d), C², ¹J_HC 149.5, ²J_PCC 5.0), 29.58 (tdm (d), C¹, ¹J_HC 131.0, ¹J_PC 53.7), 14.56 (tdm (d), C³, ¹J_HC 151.5, ³J_PCCC 17.8, ²J_HCC 4.3).¹³C NMR spectrum (150.9 MHz, CDCl₃ + 10% MeCN) δ_C ppm (J Hz) 135.13 (d. t. d (d), C^p, ¹J_HC 165.1, ³J_HCCC 7.2, ⁴J_PCCCC 2.9), 134.16 (dddd (d), C^o, ¹J_HC 165.0, ²J_PCC 10.4, ³J_HCCC 7.6, ³J_HCCC 6.7), 130.46 (ddd (d), C^m, ¹J_HC 166.9, ³J_PCCC 12.7, ³J_HCCC 7.2), 118.59 (ddd (d), Cⁱ, ¹J_PC 87.2, ³J_HCCC 8.4), 65.72 (dm (d), C², ¹J_HC 148.5, ²J_PCC 4.4), 31.10 (tdm (d), C¹, ¹J_HC 130.1, ¹J_PC 54.6), 14.56 (tdm (d), C³, ¹J_HC 152.1, ³J_PCCC 16.9, ²J_HCC 3.4).³¹P-{¹H} NMR spectrum (242.94 MHz, CD₃CN) δ_P 23.9 (s); MALDI-MS, m/z 447.4[M − I]⁺. Calcd. for C₂₁H₂₁IOP⁺: 447.3. Found: anal. C 43.72; H 3.62; I 44.10%, calcd. for C₂₁H₂₁I₂OP, C 43.93; H 3.69; I 44.20%.

3.2.7. Preparation and Characterization Phosphorus-Containing Amphiphile Liposomes

Chemicals

L-α-phosphatidylcholine (PC) (Soy, 95%, Avanti polar lipids), rhodamine B (99%, ACROS Organics, NJ, USA), Ultra-purified water (18.2 MΩcm resistivity at 25 °C) was produced from Direct-Q 5 UV equipment (Millipore S.A.S. 67120 Molsheim, France). All reagents were used without further treatment.

Preparation and Characterization

L-α-phosphatidylcholine (PC) and 3k,l (5% w/w) were dissolved in 1 mL of ethanol. The homogeneous solution was kept in a water bath at 60 °C until alcohol evaporation to obtain a thin lipid film. Ultra-purified waterwas pre-heated to 60 °C and added to rehydrate the lipids at 60 °C in the absence or presence of Rhodamine B (0.1% w/w). The solution was stirred under magnetic stirring (750 rpm) (Heidolph, Germany) for 30 min at the same temperature. Then the solution was kept for 1.5 h in a water bath at 37 °C. The multilamellar liposomes were extruded 15 times by passage through a polycarbonate membrane of 100 nm pore size (Mini-Extruder Extrusion Technique, Avanti Polar Lipids, Inc., Birmingham, AL, USA).

The mean particle size, zeta potential, and polydispersity index were determined by dynamic light scattering (DLS), using a Malvern Instrument Zetasizer Nano (Malvern, Worcestershire, UK) and Litesizer 500 Anton Paar (Anto Paar Graz, Graz, Austria). The size (hydrodynamic diameter, nm) was calculated according to the Einstein–Stokes relationship D = kBT/3πηx, in which D is the diffusion coefficient, k_B is the Boltzmann’s constant, T is the absolute temperature, η is the viscosity, and x is the hydrodynamic diameter of the nanoparticles. The diffusion coefficient was determined at least in triplicate for each sample. The average error of the measurements was approximately 10%. All samples were diluted (20 times)with ultra-purified water to a suitable concentration (2.5 mg/mL) and analyzed in triplicate.

In Vitro Rhodamine B Release Profile

The monitoring of rhodamine B release from liposomes was performed using the dialysis bag diffusion method. Dialysis bags retain liposomes and allow the released rhodamine B to diffuse into the medium. The bags were soaked in Milli-Q water for 12 h before use. Then, 0.4 mL of liposomes were poured into the dialysis bag. The two bag ends were sealed with clamps. The bags were then placed in a vessel containing 100 mL of 0.025 M sodium phosphate buffer pH 7.4, the receiving phase. The vessel was placed in a thermostatic shaker (New Brunswick, NJ, USA) at 37 °C, under a stirring rate of 150 rpm. At predetermined time intervals, 0.5 mL of samples were withdrawn, and their absorbance at 554 nm was measured using Perkin Elmer λ35 (Perkin Elmer Instruments, Norwalk, CT, USA). All samples were analyzed in triplicate. The extinction coefficient of rhodamine B is 106,089 M⁻¹ cm⁻¹ at pH = 7.4.

Encapsulation Efficiency and Loading Capacity

Encapsulation efficiency (EE, %) and loading capacity (LC, %) were assessed for samples containing rhodamine B. These parameters were determined indirectly by filtration/centrifugation technique, measuring free rhodamine B (non-encapsulated) by spectrophotometry. A volume of 50 µL of each rhodamine B-loaded liposomes was placed in centrifugal filter devices Nanosep centrifugal device 3K Omega (Pall Corporation) to separate lipid and aqueous phases and centrifuged at 10,000 rpm for 30 min using centrifuge MiniSpin plus (Eppendorf AG, Hamburg, Germany). Free rhodamine B was quantified by UV absorbance using PerkinElmer λ35 (Perkin Elmer Instruments, Waltham, MA, USA) at 554 nm (ε = 106,089 M⁻¹ cm⁻¹ in 0.0025 M phosphate buffer at pH = 7.4). The encapsulation parameters were calculated against appropriate calibration curve, using the following equation:

(1)$\mathrm{EE}(\%)=\frac{\mathrm{Total} \mathrm{amount} \mathrm{of} \mathrm{RhodB}-\mathrm{Free} \mathrm{RhodB}}{\mathrm{Total} \mathrm{amount} \mathrm{of} \mathrm{RhodB}}\times 100\%$

(2)$\mathrm{LC}(\%)=\frac{\mathrm{Total} \mathrm{amount} \mathrm{of} \mathrm{RhodB}-\mathrm{Free} \mathrm{RhodB}}{\mathrm{Total} \mathrm{amount} \mathrm{of} \mathrm{phospholipid}}\times 100\%$

3.3. Biology

3.3.1. Cell Toxicity Assay (MTT-Test)

The toxic effect on cells was determined using the colorimetric method of cell proliferation MTT (Thiazolyl Blue Tetrazolium Bromide, Sigma). For this, 10 μL of MTT reagent in Hank’s balanced salt solution (HBSS) (final concentration 0.5 mg/mL) was added to each well. The plates were incubated at 37 °C for 2–3 h in an atmosphere humidified with 5% CO₂. Absorbance was recorded at 540 nm using an Invitrologic microplate reader (Russia). Experiments for all compounds were repeated three times. The M-HeLa clone 11 human, epithelioid cervical carcinoma, strain of HeLa, clone of M– HeLa; human alveolar adenocarcinoma cells (A549); human duodenal cancer cell line (HuTu 80); human breast adenocarcinoma cells (MCF-7); glioblastoma cell line (T98G); Wi-38 VA-13 cell culture, subline 2RA (human embryonic lung) from the Type Culture Collection of the Institute of Cytology (Russian Academy of Sciences) and PC-3 human Caucasian prostate adenocarcinoma from Type Culture Collection (ATCC, Manassas, VA, USA) were used in the experiments. The cells were cultured on a standard nutrient medium “Igla” produced by the Moscow Institute of Poliomyelitis and Viral Encephalitis. M.P.Chumakov by PanEco with the addition of 10% fetal calf serum and 1% nonessential amino acids (NEAA).

The cells were sown on a 96-well panel from Eppendorf at a concentration of 5 × 103 cells per well in a volume of 100 μL of medium and cultured in a CO₂ incubator at 37 °C. In 48 h after planting the cells, the culture medium was taken into the wells, and 100 μL of solutions of the studied drug in the specified dilutions were added to the wells. Dilutions of the compounds were prepared directly in growth medium supplemented with 5% DMSO to improve solubility. The cytotoxic effect of the test compounds was determined at concentrations of 0.1–100 μM. The calculation of the IC₅₀, the concentration of the drug causing inhibition of cell growth by 50%, was performed using the program: MLA−“Quest Graph ™ IC₅₀ Calculator.” AAT Bioquest, Inc., https://www.aatbio.com/tools/ic50-calculator, accessed on 25 June 2021.

3.3.2. Induction of Apoptotic Effects by Test Compounds (Flow Cytometry Assay)

Cell Culture

HuTu 80 cells at 1 × 10⁶ cells/well in a final volume of 2 mL were seeded into six-well plates. After 48 h of incubation, various concentrations of compounds 3a,b and 3k were added to wells.

Cell Apoptosis Analysis

The cells were harvested at 2000 rpm for 5 min and, then, washed twice with ice-cold PBS, followed by resuspension in binding buffer. Next, the samples were incubated with 5 μL of annexin V-Alexa Fluor 647 (Sigma–Aldrich, St. Louis, MO, USA) and 5 μL of propidium iodide for 15 min at room temperature in the dark. Finally, the cells were analyzed by flow cytometry (Guava easy Cyte, MERCK, Rahway, NJ, USA) within 1 h. The experiments were repeated three times.

Mitochondrial Membrane Potential

Cells were harvested at 2000 rpm for 5 min and then washed twice with ice-cold PBS, followed by resuspension in JC-10 (10 µg/mL) and incubation at 37 °C for 10 min. After the cells were rinsed three times and suspended in PBS, the JC-10 fluorescence was observed by flow cytometry (Guava easy Cyte, MERCK, NJ, USA).

Detection of Intracellular ROS

HuTu 80 cells were incubated with compounds 3a,b and 3k at concentrations of IC₅₀/2 and IC₅₀ for 48 h. ROS generation was investigated using flow cytometry assay and CellROX^® Deep Red flow cytometry kit. For this HuTu 80 cells were harvested at 2000 rpm for 5 min and then washed twice with ice-cold PBS, followed by resuspension in 0.1 mL of medium without FBS, to which was added 0.2 μL of Cell ROX^® Deep Red and incubated at 37 °C for 30 min After three times washing the cells and suspending them in PBS, the production of ROS in the cells was immediately monitored using flow cytometer Guava easy Cyte, MERCK, NJ, USA).

Statistical Analysis

The IC₅₀ values were calculated using the online calculator MLA−Quest Graph™ IC₅₀ Calculator AAT Bioquest, Inc., 25 June 2021. Statistical analysis was performed using the Mann–Whitney test (p < 0.05). Tabular and graphical data contains averages and standard error.

4. Conclusions

A mild and effective approach to the synthesis of the functionally substituted (2-hydroxypropyl) triphenylphosphonium triflates is chemoselective reaction of triphenylphosphonium triflate with halomethyloxiranes and glycidyl ethers, proceeding by the S_N2 mechanism. Another convenient method for the 3-alkoxy-(2-hydroxypropyl) triphenylphosphonium iodides synthesis is based on the reaction of 3-alkoxy-2-hydroxyiodopropane with triphenylphosphine. All molecular and crystal structures were corroborated by NMR and XRD.

All obtained phosphonium salts exhibit from moderate to high cytotoxicity against human cancer cell lines M-HeLa, MCF-7, A549, HuTu-80, PC3, T98G. The cytotoxic activity of the most active compounds 3a, b, k, j and 4c is caused by the induction of apoptosis via the mitochondrial ROS pathway. Improving the bioavailability, cytotoxicity, stability, and reducing the toxicity of phosphonium salts was achieved by using a nanotechnological approach based on liposomal systems.

The development of functionalized 2-hydroxypropylphosphonium salts is promising for creation of the new effective mitochondria-targeted anticancer agents. The presence a hydroxyl group will allow further introduction of the additional pharmacophore fragments.

Author Contributions

Supervision, V.F.M.; NMR investigation, A.V.N.; synthesis, O.V.T., M.N.D. and E.A.T.; biological investigations, A.D.V., A.P.L. and S.K.A.; X-ray diffraction, I.A.L., A.T.G. and D.R.I.; liposomal systems, T.N.P.; writing—original draft, A.V.N.; writing—review and editing, V.F.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Science and Higher Education of the Russian Federation, Agreement number 075-15-2020-777.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are available on request from the corresponding author.

Acknowledgments

The financial support by the Ministry of Science and Higher Education of the Russian Federation (Agreement No. 075-15-2020-777) is gratefully acknowledged.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compoundsare not available from the authors.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures, Schemes and Tables

Scheme 1. The methods of conjugating drugs with phosphonium salts.

Scheme 2. The method of obtaining phosphonium salts by alkylation of triphenylphosphine with halogen-alkyl derivatives of drugs.

Scheme 3. Types of the most commonly used functionally substituted QPSs.

Scheme 4. Some methods for the synthesis of functionally substituted phosphonium salts.

Scheme 5. Synthesis of 3-halo-2-hydroxypropyltriphenylphosphonium triflates 3a–e.

Figure 1. Molecular geometry 3e, S in crystal. Hereinafter, hydrogen atoms are shown as spheres of arbitrary radius. Thermal ellipsoids are presented with a probability of 50%. The cell contains two independent molecules. To simplify, only one molecule is shown.

Figure 2. Geometry of independent part of crystal 3a. The hydroxyl group disorder is shown in molecule B. Anisotropic displacement ellipsoids are shown with a 50% probability. Hydrogen bonds are shown as dashed lines.

Scheme 6. Synthesis of 3-alkoxy(acyloxy)-2-hydroxypropyltriphenylphosphoniumtriflates 3f–l.

Scheme 7. Synthesis of 3-alkoxy-2 hydroxypropyltriphenylphosphonium iodides 4a–d.

Scheme 8. Synthesis of 3-iodo-2-hydroxypropyltriphenylphosphonium iodides 3d, 7.

Figure 3. Spectra (A) and release profile (B) of Rhodamine B in free solutions (without nanoparticles) (1), from PC-liposomes (2) and PC/3l-lipososmes (3–5) with ratio 98/2 (3), 95/5 (4), and 90/10 (5), (n = 3, 3 times were replicated), phosphatebuffer (0.025 M), pH = 7.4, 37 °C.

Figure 4. Induction of apoptosis in HuTu-80 cells incubated with compounds 3a, b, k, j and 4c at a concentration of IC50/2 and IC50 in μM for 48 h. L—living cells; D—dead cells; Ea—early apoptotic cells; La—late apoptotic cells.

Figure 5. Flow cytometry analysis of HuTu-80 cells treated with compounds 3a, b, k, j and 4c at the concentrations of IC50/2 and IC50 in μM for 48 h.

Figure 6. Quantitative determination of % cells with red aggregates.

Figure 7. Induction of ROS production by 3a, b, k, j and 4c at the concentration of IC50/2 and IC50 in μM for 48 h; (∗) p < 0.05 ompared to control.

Table 1

Characteristics of Liposomal Systems (25 °C).

Composition	Ratio, w/w,%	Concentrationof Rhodamine B, (%, w/w)	Zaverage(nm)	PdI	Z(mV)	EE,(%)	LC,(%)
PC *	100	–	119 ± 2	0.12 ± 0.02	−7.0 ± 2
PC/3k	98/2	–	129 ± 1	0.14 ± 0.01	+23.0 ± 2	–	–
PC/3k	95/5	–	125 ± 1	0.16 ± 0.02	+39.0 ± 3	–	–
PC/3k	90/10	–	128 ± 1	0.16 ± 0.01	+46.0 ± 3	–	–
PC/3l	98/2	–	127 ± 0.5	0.11 ± 0.01	+6.1 ± 0.1	–	–
PC/3l	98/2	–	128 ± 0.5	0.12 ± 0.01	+6.1 ± 0.1	–	–
PC/3l	95/5	–	116 ± 0.2	0.07 ± 0.01	+4.4 ± 0.1	–	–
PC/3l **	95/5	–	117 ± 0.2	0.09 ± 0.01	+4.4 ± 0.1	–	–
PC/3l	90/10	–	111 ± 0.5	0.08 ± 0.01	+7.8 ± 0.2	–	–
PC/3l **	90/10	–	112 ± 0.5	0.09 ± 0.01	+7.2 ± 0.2	–	–
PC	100	0.1	121 ± 1	0.14 ± 0.01	+20.5 ± 2	87 ± 1	1.74
PC **	100	0.1	122 ± 1	0.14 ± 0.01	+12.0 ± 0.2	–	–
PC/3l	98/2	0.1	113 ± 1	0.13 ± 0.01	+21.0 ± 1	80 ± 1	1.6
PC/3l **	98/2	0.1	113 ± 1	0.08 ± 0.01	+21.0 ± 0.1	–	–
PC/3l	95/5	0.1	109 ± 1	0.16 ± 0.01	+22.0 ± 1	93 ± 1	1.86
PC/3l **	95/5	0.1	109 ± 1	0.13 ± 0.01	+22.0 ± 0.5	–	–
PC/3l	90/10	0.1	110 ± 1	0.17 ± 0.01	+26.0 ± 1	93 ± 1	1.86
PC/3l **	90/10	0.1	550 ± 50	0.4 ± 0.05	+4.0 ± 0.5	–	–

* [188]. ** after 3 months.

Table 2

In vitro cytotoxicity (μM) of 2-hydroxypropylphosphonium salts against human cancer and human normal cell lines and selectivity index values (SI) of lead compounds.

Test Compound	Cancer Cell Lines												Normal Cell Lines
	HuTu 80 a		PC3 b		M-HeLa c		MCF-7 d		A549 e		T98G f		WI38 gIC50
	IC50	SI	IC50	SI	IC50	SI	IC50	SI	IC50	SI	IC50	SI
3a	10.1 ± 0.8	4	45.0 ± 3.6	ns	66.7 ± 5.5	ns	56.1 ± 4.5	ns	64.4 ± 4.9	ns	64.3 ± 5.3	ns	37.5 ± 3.1
3b	3.0 ± 0.1	5	23.3 ± 1.9	ns	30.1 ± 2.4	ns	34.0 ± 2.6	ns	>100	ns	56.0 ± 4.5	ns	13.8 ± 1.1
3c	19.1 ± 1.6	2.5	53.5 ± 4.2	ns	90.6 ± 8.6	ns	56.5 ± 4.5	ns	>100	ns	52.1 ± 4.1	ns	47.3 ± 3.8
3d	9.4 ± 0.7	4	39.1 ± 3.1	ns	50.0 ± 4.3	ns	88.6 ± 7.1	ns	74.2 ± 5.6	ns	64.0 ± 4.8	ns	35.2 ± 2.3
3f	23.6 ± 1.8	1.5	55.2 ± 4.5	ns	56.2 ± 4.7	ns	60.7 ± 4.9	ns	39.0 ± 3.0	ns	60.4 ± 4.4	ns	35.6 ± 2.6
3g	18.4 ± 1.5	1.6	48.9 ± 3.9	ns	63.7 ± 5.2	ns	66.8 ± 5.3	ns	42.2 ± 3.2	ns	62.9 ± 4.6	ns	30.1 ± 2.3
3h	28.9 ± 2.1	ns	48.7 ± 3.7	ns	100 ± 8.6	ns	64.4 ± 5.0	ns	34.3 ± 2.6	ns	63.4 ± 4.8	ns	43.7 ± 3.5
3i	7.1 ± 0.06	5	71.8 ± 6.6	ns	60.8 ± 5.2	ns	70.5 ± 5.6	ns	41.0 ± 3.3	ns	50.4 ± 4.0	ns	34.2 ± 2.7
3j	0.5 ± 0.03	6.2	0.6 ± 0.05	5.2	1.1 ± 0.09	3	2.9 ± 0.2	1.1	3.7 ± 0.3	ns	1.7 ± 0.1	2	3.1 ± 0.2
3k	3.5 ± 0.3	5	25.0 ± 2.0	ns	40.3 ± 3.5	ns	30.5 ± 2.5	ns	54.7 ± 4.4	ns	55.8 ± 4.7	ns	16.2 ± 1.3
PC/3k	3.8 ± 0.4	7.5	27.0 ± 2.2	1.1	48.9 ± 38	ns	35.8 ± 2.8	ns	88.7 ± 7.3	ns	>100	ns	28.4 ± 2.4
3l	45.0 ± 3.5	ns	53.8 ± 4.4	ns	59.2 ± 5.1	ns	52.8 ± 4.2	ns	75.1 ± 5.7	ns	55.9 ± 5.0	ns	50.0 ± 3.9
PC/3l	38.6 ± 3.1	ns	56.2 ± 4.5	ns	21.3 ± 1.7	ns	78.1 ± 6.2	ns	>100	ns	64.7 ± 4.9	ns	26.8 ± 2.2
4a	26.7 ± 2.1	1.4	50.3 ± 4.0	ns	57.3 ± 4.7	ns	75.7 ± 5.9	ns	36.0 ± 2.8	ns	55.3 ± 4.4	ns	36.5 ± 2.8
4b	3.4 ± 0.3	7	42.4 ± 3.3	ns	68.4 ± 5.9	ns	60.3 ± 4.7	ns	39.1 ± 3.1	ns	49.7 ± 4.0	ns	22.9 ± 1.9
4c	0.3 ± 0.02	12.3	0.7 ± 0.06	5.3	1.1 ± 0.09	3.4	2.7 ± 0.2	1.4	2.6 ± 0.2	1.4	2.0 ± 0.1	1.8	3.7 ± 0.3
4i	5.0 ± 0.4	7	44.5 ± 3.5	ns	87.2 ± 7.9	ns	68.0 ± 5.5	ns	61.8 ± 5.0	ns	>100	ns	34.2
Dox	0.2 ± 0.01	4	1.4 ± 0.1	ns	2.1 ± 0.1	ns	0.4 ± 0.03	2	0.7 ± 0.5	1.1	2.0 ± 0.1	ns	0.8 ± 0.07

The experiments were performed in triplicate. Results are expressed as the mean ± standard deviation (SD); ns: no selectivity. ^a HuTu-80 is a human duodenal adenocarcinoma; ^b PC3 is a human prostate adenocarcinoma; ^c M-HeLa is a human cervix epitheloid carcinoma; ^d MCF-7 is a human breast adenocarcinoma (pleural fluid); ^e A549 is a human lung carcinoma; ^f T98G glioblastoma cell line; ^g Wi-38 is a diploid human embryo lung; the experiments were repeated 3 times.

Supplementary Materials

The following are available online. Online supplementary informationincludes crystal data and refinement details for compounds (3b–g, i, j) and (4a, 7) (Tables S1–S4), figures of molecular geometries (Figures S1–S9), NMR spectra of starting and final compounds (Figures S10–S178), cif and checkcif files of compounds (3b–g, i, j) and (4a, 7) (totally 23 files).

References

1. Moura, I.M.R.; Tranquilino, A.; Sátiro, B.G.; Silva, R.O.; de Oliveira-Silva, D.; Oliveirsa, R.A.; Menezes, P.H. Unusual application for phosphonium salts and phosphoranes: Synthesis of chalcogenides. J. Org. Chem.; 2021; 86, pp. 5954-5964. [DOI: https://dx.doi.org/10.1021/acs.joc.1c00114]

2. Fink, J. Hydraulic Fracturing Chemicals and Fluids Technology; 2nd ed. Elsevier: Amsterdam, The Netherlands, 2020.

3. Wakelyn, P.J. Environmentally friendly flame resistant textiles. Advances in Fire Retardant Materials; 1st ed. Horrocks, A.R.; Price, D. Woodhead Publishing Limited: Sawston, UK, CRC Press: Boca Raton, FL, USA, 2008; pp. 188-212.

4. Corbridge, D.E.C. Phosphorus: An Outline of Its Chemistry, Biochemistry, and Technology; 5th ed. Elsevier: Amsterdam, The Netherlands, 1995; 1220.

5. Li, H.; Liu, H.; Guo, H. Recent Advances in Phosphonium Salt Catalysis. Adv. Synth. Catal.; 2021; 363, pp. 2023-2036. [DOI: https://dx.doi.org/10.1002/adsc.202001604]

6. Jean, S.R.; Ahmed, M.; Lei, E.K.; Wisnovsky, S.P.; Kelley, S.O. Peptide-mediated delivery of chemical probes and therapeutics to mitochondria. Acc. Chem. Res.; 2016; 49, pp. 1893-1902. [DOI: https://dx.doi.org/10.1021/acs.accounts.6b00277] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27529125]

7. Smith, R.A.J.; Hartley, R.C.; Murphy, M.P. Mitochondria-targeted small molecule therapeutics and probes. Antioxid. Redox Signal.; 2011; 15, pp. 30231-33038. [DOI: https://dx.doi.org/10.1089/ars.2011.3969]

8. Murphy, M. Targeting lipophilic cations to mitochondria. Biochim. Biophys. Acta Bioenerg.; 2008; 1777, pp. 1028-1031. [DOI: https://dx.doi.org/10.1016/j.bbabio.2008.03.029] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18439417]

9. Murphy, M.P.; Smith, R.A. Targeting antioxidants to mitochondria by conjugation to lipophilic cations. Annu. Rev. Pharmacol. Toxicol.; 2007; 47, pp. 629-656. [DOI: https://dx.doi.org/10.1146/annurev.pharmtox.47.120505.105110]

10. Ross, M.F.; Prime, T.A.; Abakumova, I.; James, A.M.; Porteous, C.M.; Smith, R.A.; Murphy, M.P. Rapid and extensive uptake and activation of hydrophobic triphenylphosphonium cations within cells. Biochem. J.; 2008; 411, pp. 633-645. [DOI: https://dx.doi.org/10.1042/BJ20080063]

11. Zielonka, J.; Joseph, J.; Sikora, A.; Hardy, M.; Ouari, O.; Vasquez-Vivar, J.; Cheng, G.; Lopez, M.; Kalyanaraman, B. Mitochondria-targeted triphenylphosphonium-based compounds: Syntheses, mechanisms of action, and therapeutic and diagnostic applications. Chem. Rev.; 2017; 117, pp. 10043-10120. [DOI: https://dx.doi.org/10.1021/acs.chemrev.7b00042]

12. Pourahmad, J.; Salimi, A.; Seydi, E. Mitochondrial targeting for drug development. Toxicology Studies—Cells, Drugs and Environment; 1st ed. Andreazza, A.C.; Scola, G. InTech: Rijeka, Croatia, 2015; pp. 61-82.

13. Apostolova, N.; Victor, V.M. Molecular strategies for targeting antioxidants to mitochondria: Therapeutic implications. Antioxid. Redox Signal.; 2015; 22, pp. 686-729. [DOI: https://dx.doi.org/10.1089/ars.2014.5952]

14. Kelso, G.F.; Porteous, C.M.; Coulter, C.V.; Hughes, G.; Porteous, W.K.; Ledgerwood, E.C.; Smith, R.A.; Murphy, M.P. Selective targeting of a redox-active ubiquinone to mitochondria within cells: Antioxidant and antiapoptotic properties. J. Biol. Chem.; 2001; 276, pp. 4588-4596. [DOI: https://dx.doi.org/10.1074/jbc.M009093200]

15. Asin-Cayuela, J.; Manas, A.R.; James, A.M.; Smith, R.A.; Murphy, M.P. Fine-tuning the hydrophobicity of a mitochondria-targeted antioxidant. FEBS Lett.; 2004; 571, pp. 9-16. [DOI: https://dx.doi.org/10.1016/j.febslet.2004.06.045]

16. Smith, R.A.; Porteous, C.M.; Coulter, C.M.; Murphy, M.P. Selective targeting of an antioxidant to mitochondria. Eur. J. Biochem.; 1999; 263, pp. 709-716. [DOI: https://dx.doi.org/10.1046/j.1432-1327.1999.00543.x]

17. Filipovska, A.; Kelso, G.F.; Brown, S.E.; Beer, S.M.; Smith, R.A.; Murphy, M.P. Synthesis and characterization of a triphenylphosphonium-conjugated peroxidase mimetic: Insights into the interaction of ebselen with mitochondria. J. Biol. Chem.; 2005; 280, pp. 24113-24126. [DOI: https://dx.doi.org/10.1074/jbc.M501148200]

18. Finichiu, P.G.; Larsen, D.S.; Evans, C.; Larsen, L.; Bright, T.P.; Robb, E.L.; Trnka, J.; Prime, T.A.; James, A.M.; Smith, R.A. et al. A mitochondria-targeted derivative of ascorbate: MitoC. Free Radic. Biol. Med.; 2015; 89, pp. 668-678. [DOI: https://dx.doi.org/10.1016/j.freeradbiomed.2015.07.160]

19. Langley, M.; Ghosh, A.; Charli, A.; Sarkar, S.; Ay, M.; Luo, J.; Zielonka, J.; Brenza, T.; Bennett, B.; Jin, H. et al. Mito-apocynin prevents mitochondrial dysfunction, microglial activation, oxidative damage, and progressive neurodegeneration in mitopark transgenic mice. Antioxid. Redox Signal.; 2017; 27, pp. 1048-1066. [DOI: https://dx.doi.org/10.1089/ars.2016.6905] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28375739]

20. Trnka, J.; Blaikie, F.H.; Smith, R.A.; Murphy, M.P. A mitochondria-targeted nitroxide is reduced to its hydroxylamine by ubiquinol in mitochondria. Free Radic. Biol. Med.; 2008; 44, pp. 1406-1419. [DOI: https://dx.doi.org/10.1016/j.freeradbiomed.2007.12.036] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18206669]

21. Pavlova, J.A.; Khairullina, Z.Z.; Tereshchenkov, A.G.; Nazarov, P.A.; Lukianov, D.A.; Volynkina, I.A.; Skvortsov, D.A.; Makarov, G.I.; Abad, E.; Murayama, S.Y. et al. Triphenilphosphonium analogs of chloramphenicol as dual-acting antimicrobial and antiproliferating agents. Antibiotics; 2021; 10, 489. [DOI: https://dx.doi.org/10.3390/antibiotics10050489]

22. Millard, M.; Gallagher, J.D.; Olenyuk, B.Z.; Neamati, N. A selective mitochondrial-targeted chlorambucil with remarkable cytotoxicity in breast and pancreatic cancers. J. Med. Chem.; 2013; 56, pp. 9170-9179. [DOI: https://dx.doi.org/10.1021/jm4012438] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24147900]

23. Zhou, J.; Zhao, W.Y.; Ma, X.; Ju, R.J.; Li, X.Y.; Li, N.; Sun, M.G.; Shi, J.F.; Zhang, C.X.; Lu, W.L. The anticancer efficacy of paclitaxel liposomes modified with mitochondrial targeting conjugate in resistant lung cancer. Biomaterials; 2013; 34, pp. 3626-3638. [DOI: https://dx.doi.org/10.1016/j.biomaterials.2013.01.078]

24. Liu, H.N.; Guo, N.N.; Wang, T.T.; Guo, W.W.; Lin, M.T.; Huang-Fu, M.Y.; Vakili, M.R.; Xu, W.H.; Chen, J.J.; Wei, Q.C. et al. Mitochondrial Targeted Doxorubicin-Triphenylphosphonium Delivered by Hyaluronic Acid Modified and pH Responsive Nanocarriers to Breast Tumor: In Vitro and in Vivo Studies. Mol. Pharm.; 2018; 15, pp. 882-891. [DOI: https://dx.doi.org/10.1021/acs.molpharmaceut.7b00793] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29357260]

25. Cheng, G.; Zielonka, J.; Ouari, O.; Lopez, M.; McAllister, D.; Boyle, K.; Barrios, C.S.; Weber, J.J.; Johnson, B.D.; Hardy, M. et al. Mitochondria-targeted analogues of metformin exhibit enhanced antiproliferative and radiosensitizing effects in pancreatic cancer cells. Cancer Res.; 2016; 76, pp. 3904-3915. [DOI: https://dx.doi.org/10.1158/0008-5472.CAN-15-2534]

26. Kang, S.; Sunwoo, K.; Jung, Y.; Hur, J.K.; Park, K.H.; Kim, J.S.; Kim, D. Membrane-targeting triphenylphosphonium functionalized ciprofloxacin for methicillin-resistant Staphylococcus aureus (MRSA). Antibiotics; 2020; 9, 758. [DOI: https://dx.doi.org/10.3390/antibiotics9110758]

27. Sunwoo, K.; Won, M.; Ko, K.P.; Choi, M.; Arambula, J.F.; Chi, S.G.; Sessler, J.L.; Verwilst, P.; Kim, J.S. Mitochondrial relocation of a common synthetic antibiotic: A non-genotoxic approach to cancer therapy. Chemistry; 2020; 6, pp. 1408-1419. [DOI: https://dx.doi.org/10.1016/j.chempr.2020.03.004]

28. Cochrane, E.J.; Hulit, J.; Lagasse, F.P.; Lechertier, T.; Stevenson, B.; Tudor, C.; Trebicka, D.; Sparey, T.; Ratcliffe, A.J. Impact of Mitochondrial Targeting Antibiotics on Mitochondrial Function and Proliferation of Cancer Cells. ACS Med. Chem. Lett.; 2021; 12, pp. 579-584. [DOI: https://dx.doi.org/10.1021/acsmedchemlett.0c00632]

29. Ózsvári, B.; Magalhães, L.G.; Latimer, J.; Kangasmetsa, J.; Sotgia, F.; Lisanti, M.P. A myristoyl amide derivative of doxycycline potently targets cancer stem cells (CSCs) and prevents spontaneous metastasis, without retaining antibiotic activity. Front. Oncol.; 2020; 10, 1528. [DOI: https://dx.doi.org/10.3389/fonc.2020.01528] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33042796]

30. Kulkarni, C.A.; Fink, B.D.; Gibbs, B.E.; Chheda, P.R.; Wu, M.; Sivitz, W.I.; Kerns, R.J. A novel triphenylphosphonium carrier to target mitochondria without uncoupling oxidative phosphorylation. J. Med. Chem.; 2021; 64, pp. 662-676. [DOI: https://dx.doi.org/10.1021/acs.jmedchem.0c01671] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33395531]

31. Millard, M.; Pathania, D.; Shabaik, Y.; Taheri, L.; Deng, J.; Neamati, N. From broad-spectrum biocides to quorum sensing disruptors and mussel repellents: Antifouling profile of alkyl triphenylphosphonium salts. PLoS ONE; 2010; 5, e0123652.

32. Reily, C.; Mitchell, T.; Chacko, B.K.; Benavides, G.; Murphy, M.P.; Darley-Usmar, V. Mitochondrially targeted compounds and their impact on cellular bioenergetics. Redox Biol.; 2013; 1, pp. 86-93. [DOI: https://dx.doi.org/10.1016/j.redox.2012.11.009]

33. Trnka, J.; Elkalaf, M.; Anděl, M. Lipophilic triphenylphosphonium cations inhibit mitochondrial electron transport chain and induce mitochondrial proton leak. PLoS ONE; 2015; 10, e0121837. [DOI: https://dx.doi.org/10.1371/journal.pone.0121837]

34. Elkalaf, M.; Tuma, P.; Weiszenstein, M.; Polák, J.; Trnka, J. Mitochondrial probe methyltriphenylphosphonium (TPMP) inhibits the krebs cycle enzyme 2-Oxoglutarate dehydrogenase. PLoS ONE; 2016; 11, e0161413. [DOI: https://dx.doi.org/10.1371/journal.pone.0161413]

35. Filipczaka, N.; Pana, J.; Yalamartya, S.S.K.; Torchilin, V.P. Recent advancements in liposome technology. Adv. Drug Deliv. Rev.; 2020; 156, pp. 4-22. [DOI: https://dx.doi.org/10.1016/j.addr.2020.06.022] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32593642]

36. Wang, H.; Shi, W.; Zeng, D.; Huang, Q.; Xie, J.; Wen, H.; Li, J.; Yu, X.; Qin, L.; Zhou, Y. pH-activated, mitochondria-targeted, and redox-responsive delivery of paclitaxel nanomicelles to overcome drug resistance and suppress metastasis in lung cancer. J. Nanobiotech.; 2021; 19, 152. [DOI: https://dx.doi.org/10.1186/s12951-021-00895-4]

37. Lee, Y.H.; Park, H.I.; Chang, W.S.; Choi, J.S. Triphenylphosphonium-conjugated glycol chitosan microspheres for mitochondria-targeted drug delivery. Int. J. Biol. Macromol.; 2021; 167, pp. 35-45. [DOI: https://dx.doi.org/10.1016/j.ijbiomac.2020.11.129]

38. Oladimeji, O.; Akinyelu, J.; Daniels, A.; Singh, M. Modified gold nanoparticles for efficient delivery of betulinic acid to cancer cell mitochondria. Int. J. Mol. Sci.; 2021; 22, 5072. [DOI: https://dx.doi.org/10.3390/ijms22105072]

39. Denney, D.B.; Smith, L.C. Preparation and Reactions of Some Phosphobetaines. J. Org. Chem.; 1962; 27, pp. 3404-3408. [DOI: https://dx.doi.org/10.1021/jo01057a005]

40. Wei-Li, D.; Bi, J.; Sheng-Lian, L.; Xu-Biao, L.; Xin-Man, T.; Chak-Tong, A. Functionalized phosphonium-based ionic liquids as efficient catalysts for the synthesis of cyclic carbonate from epoxides and carbon dioxide. Appl. Catal. A Gen.; 2014; 470, pp. 183-188. [DOI: https://dx.doi.org/10.1016/j.apcata.2013.10.060]

41. Hudson, R.F.; Chopard, P.A. Structure et réactions du composé d’addition: Triphénylphosphine–anhydride maléique. Helv. Chim. Acta; 1963; 46, pp. 2178-2185. [DOI: https://dx.doi.org/10.1002/hlca.19630460638]

42. Findlay, J.A.; Kwan, D. Metabolites from a Scytalidium Species. Can. J. Chem.; 1973; 51, pp. 3299-3301. [DOI: https://dx.doi.org/10.1139/v73-492]

43. Hayashi, M.; Wakatsuka, H.; Kori, S. Trans-Δ2-Prostaglandins. U.S. Patent; 3931296, 6 January 1976.

44. Bundy, G.L. Phenyl-Substituted Prostaglandin-f Type Analogs. U.S. Patent; 3987087, 19 October 1976.

45. Narayanan, K.S.; Berlin, K.D. Novel synthesis of .omega.-(diphenylphosphinyl)alkylcarboxylic acids from triphenyl-.omega.-carboxyalkylphosphonium salts. J. Org. Chem.; 1980; 45, pp. 2240-2243. [DOI: https://dx.doi.org/10.1021/jo01299a040]

46. Hann, M.M.; Sammes, P.G.; Kennewell, P.D.; Taylor, J.B. On the double bond isostere of the peptide bond: Preparation of an enkephalin analogue. J. Chem. Soc. Perkin Trans. 1; 1982; 1, pp. 307-314. [DOI: https://dx.doi.org/10.1039/p19820000307]

47. Maryanoff, B.E.; Reitz, A.B.; Duhl-Emswiler, B.A. Stereochemistry of the Wittig reaction. Effect of nucleophilic groups in the phosphonium ylide. J. Am. Chem. Soc.; 1985; 107, pp. 217-226. [DOI: https://dx.doi.org/10.1021/ja00287a040]

48. Carr, G.; Whittaker, D. Lactone formation in superacidic media. J. Chem. Soc. Perkin Trans. II; 1987; 12, pp. 1877-1880. [DOI: https://dx.doi.org/10.1039/p29870001877]

49. Cheskis, B.A.; Shpiro, N.A.; Moiseenkov, A.M. Effective synthesis of femrrulactone II based on the use of 2-carhoxyethyltriphenylphosphonium bromide. Russ. Chem. Bull.; 1993; 42, pp. 760-763. [DOI: https://dx.doi.org/10.1007/BF00704022]

50. Wakita, H.; Yoshiwara, H.; Nishiyama, H.; Nagase, H. Total Synthesis of Optically Active m-Phenyline PGI2 Derivative: Beraprost. Heterocycles; 2000; 53, pp. 1085-1110.

51. Wiech, N.L.; Lan-Hargest, H.-Y. Histone Deacetylase Inhibitors. U.S. Patent; 2006160902, 20 July 2006.

52. Ahmed, R.; Altieri, A.; D’Souza, D.M.; Leigh, D.A.; Mullen, K.M.; Papmeyer, M.; Slawin, A.M.Z.; Wong, J.K.Y.; Woollins, J.D. Phosphorus-Based Functional Groups as Hydrogen Bonding Templates for Rotaxane Formation. J. Am. Chem. Soc.; 2011; 133, pp. 12304-12310. [DOI: https://dx.doi.org/10.1021/ja2049786]

53. Bakhtiyarova, Y.V.; Aksunova, A.F.; Galkina, I.V.; Galkin, V.I.; Lodochnikova, O.A.; Kataeva, O.N. Crystal structure of new carboxylate phosphabetaines and phosphonium salts conjugated with them. Russ. Chem. Bull.; 2016; 65, pp. 1313-1318. [DOI: https://dx.doi.org/10.1007/s11172-016-1454-4]

54. Xu, J.; Zeng, F.; Wu, H.; Wu, S. A Mitochondria-targeted and NO-based Anticancer Nanosystem with Enhanced Photo-controllability and Low Dark-toxicity. J. Mater. Chem. B; 2015; 3, pp. 4904-4912. [DOI: https://dx.doi.org/10.1039/C5TB00522A]

55. Sodano, F.; Rolando, B.; Spyrakis, F.; Failla, M.; Lazzarato, L.; Gazzano, E.; Riganti, C.; Fruttero, R.; Gasco, A.; Sortino, S. Tuning the Hydrophobicity of a Mitochondria-Targeted NO Photodonor. ChemMedChem; 2018; 13, pp. 1238-1245. [DOI: https://dx.doi.org/10.1002/cmdc.201800088]

56. Brooks, A.F.; Ichiishi, N.; Jackson, I.M.; Lee, S.J.; Sanford, M.S.; Scott, P.J.H.; Thompson, S. Synthesis of [¹⁸F]-γ-fluoro-α,β-unsaturated esters and ketones via vinylogous ¹⁸F-fluorination of α-diazoacetates with [¹⁸F]AgF. Synthesis; 2019; 51, pp. 4401-4407.

57. Drikermann, D.; Mößel, R.S.; Al-Jammal, W.K.; Vilotijevic, I. Synthesis of Allylboranes via Cu(I)-catalyzed B-H Insertion of Vinyldiazoacetates into Phosphine-Borane Adducts. Org. Lett.; 2020; 22, pp. 1091-1095. [DOI: https://dx.doi.org/10.1021/acs.orglett.9b04619]

58. Testai, L.; Sestito, S.; Martelli, A.; Gorica, E.; Flori, L.; Calderone, V.; Rapposelli, S. Synthesis and pharmacological characterization of mitochondrial KATP channel openers with enhanced mitochondriotropic effects. Bioorg. Chem.; 2021; 107, 104572. [DOI: https://dx.doi.org/10.1016/j.bioorg.2020.104572] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33418316]

59. Chen, Y.; Wang, Y.; Wang, S.; Ma, Y.-Y.; Zhao, D.-G.; Zhan, R.; Huang, H. Asymmetric Construction of Cyclobutanes via Direct Vinylogous Michael Addition/Cyclization of β,γ-Unsaturated Amides. Org. Lett.; 2020; 22, pp. 7135-7140. [DOI: https://dx.doi.org/10.1021/acs.orglett.0c02488]

60. Schweizer, E.E.; Wehmann, A.T. Reactions of phosphorus compounds. Part XXII. A reinvestigation of the reactions of activated alkynes with triphenylphosphine hydrobromide. An investigation of the reactions with bases of the vinylphosphonium salts prepared. J. Chem. Soc. C; 1970; pp. 1901-1905. [DOI: https://dx.doi.org/10.1039/j39700001901]

61. Bundy, G.L.; Nelson, N.A. Cis-4,5-didehydro-15 or 16-Alkylated 11-Deoxy-PGE1 Analogs. U.S. Patent; 3987072, 19 October 1976.

62. Kato, K.; Ohkawa, S.; Terao, S.; Terashita, Z.; Nishikawa, K. Thromboxane synthetase inhibitors (TXSI). Design, synthesis, and evaluation of a novel series of .omega.-pyridylalkenoic acids. J. Med. Chem.; 1985; 28, pp. 287-294. [DOI: https://dx.doi.org/10.1021/jm00381a005]

63. Caldwell, C.; Chapman, K.T.; Hale, J.; Kim, D.; Lynch, C.; Maccoss, M.; Mills, S.G.; Rosauer, K.; Willoughby, C.; Berk, S. Pyrrolidine Modulators of Chemokine Receptor Activity. U.S. Patent; 6265434, 24 July 2001.

64. Mukku, V.J.R.V.; Maskey, R.P.; Monecke, P.; Grün-Wollny, I.; Laatsch, H. 5-(2-Methylphenyl)-4-pentenoic Acid from a Terrestrial Streptomycete. Z. Naturforsch. B; 2002; 57, pp. 335-337. [DOI: https://dx.doi.org/10.1515/znb-2002-0312]

65. Wube, A.A.; Hüfner, A.; Thomaschitz, C.; Blunder, M.; Kollroser, M.; Bauer, R.; Bucar, F. Design, synthesis and antimycobacterial activities of 1-methyl-2-alkenyl-4(1H)-quinolones. Bioorg. Med. Chem.; 2011; 19, pp. 567-579. [DOI: https://dx.doi.org/10.1016/j.bmc.2010.10.060]

66. Luo, D.; Sharma, H.; Yedlapudi, D.; Antonio, T.; Reith, M.E.A.; Dutta, A.K. Novel multifunctional dopamine D2/D3 receptors agonists with potential neuroprotection and anti-alpha synuclein protein aggregation properties. Bioorg. Med. Chem.; 2016; 24, pp. 5088-5102. [DOI: https://dx.doi.org/10.1016/j.bmc.2016.08.021]

67. Chevalier, A.; Zhang, Y.; Khdour, O.M.; Hecht, S.M. Selective Functionalization of Antimycin A Through an N-Transacylation Reaction. Org. Lett.; 2016; 18, pp. 2395-2398. [DOI: https://dx.doi.org/10.1021/acs.orglett.6b00882]

68. Yalla, R.; Raghavan, S. Synthesis of solandelactone F, constanolactone A and an advanced intermediate towards solandelactone E from a common synthetic intermediate. Org. Biomol. Chem.; 2019; 17, pp. 4572-4592. [DOI: https://dx.doi.org/10.1039/C9OB00623K]

69. Wang, Y.; Wei, G.; Yang, G.; Zhang, X.; Zhao, J.; Zhou, S. Stepwise dual targeting and dual responsive polymer micelles for mitochondrion therapy. J. Control. Release; 2020; 322, pp. 157-169.

70. Deng, H.; Discordia, R.; Feng, X.; Jin, Z.; Leigh, C.; Moshos, K.; Sun, G. Cannabinoids and Uses Thereof. W.O. Patent; 2021113669, 10 June 2021.

71. Plattner, J.J.; Bhalerao, U.T.; Rapoport, H. Synthesis of dl-Sirenin. J. Am. Chem. Soc.; 1969; 91, pp. 4933-4934. [DOI: https://dx.doi.org/10.1021/ja01045a066]

72. Uijttewaal, A.P.; Jonkers, F.L.; Van der Gen, A. Reactions of esters with phosphorus ylides. 3. Direct conversion into branched olefins. J. Org. Chem.; 1979; 44, pp. 3157-3168. [DOI: https://dx.doi.org/10.1021/jo01332a014]

73. Bergman, N.A.; Jansson, M.; Chiang, Y.; Kresge, A.J.; Yin, Y. Synthesis and kinetic studies of a simple prostacyclin model. J. Org. Chem.; 1987; 52, pp. 4449-4453. [DOI: https://dx.doi.org/10.1021/jo00229a004]

74. Misra, R.N.; Hüfner Sher, P.M.; Stein, P.D.; Hall, S.E.; Floyd, D.; Barrish, J.C. 7-Oxabicycloheptyl Substituted Heterocyclic Amide or Ester Prostaglandin Analogs Useful in the Treatment of Thrombotic and Vasospastic Disease. U.S. Patent; 5100889, 31 March 1992.

75. Provent, C.; Chautemps, P.; Gellon, G.; Pierre, J.-L. Double Wittig reactions with 4-carboxybutylidene triphenylphosphorane as the key step in the synthesis of benzene derivatives metadisubstituted with ωω’-difunctionalized six-carbon chains. Tetrahedron Lett.; 1996; 37, pp. 1393-1396. [DOI: https://dx.doi.org/10.1016/0040-4039(96)00032-9]

76. Rey, M.D.L.A.; Martinez-Perez, J.A.; Fernandez-Gacio, A.; Halkes, K.; Fall, Y.; Granja, J.; Mourino, A. New Synthetic Strategies to Vitamin D Analogues Modified at the Side Chain and D Ring. Synthesis of 1alpha,25-Dihydroxy-16-ene-vitamin D(3) and C-20 Analogues(1). J. Org. Chem.; 1999; 64, pp. 3196-3206.

77. Henry-Riyad, H.; Tidwell, T.T. Cyclization of 5-hexenyl radicals from nitroxyl radical additions to 4-pentenylketenes and from the acyloin reaction. Canad. J. Chem.; 2003; 81, pp. 697-704. [DOI: https://dx.doi.org/10.1139/v03-076]

78. Aotsuka, T.; Kumazawa, K.; Wagatsuma, N.; Ishitani, K. Novel 1,8-Naphthyridin-2(1H)-one Derivatives. U.S. Patent; 2003036651, 4 December 2003.

79. Henschke, J.P.; Liu, Y.; Huang, X.; Chen, Y.; Meng, D.; Xia, L.; Wei, X.; Xie, A.; Li, D.; Huang, Q. et al. The Manufacture of a Homochiral 4-Silyloxycyclopentenone Intermediate for the Synthesis of Prostaglandin Analogues. Org. Proc. Res. Dev.; 2012; 16, pp. 1905-1916. [DOI: https://dx.doi.org/10.1021/op300188x]

80. Wang, K. Preparation Method of Optically Pure Dextro Cloprostenol Sodium. Patent CN; 104513186, 5 October 2016.

81. Ye, Y.; Zhang, T.; Yuan, H.; Li, D.; Lou, H.; Fan, P. Mitochondria-Targeted Lupane Triterpenoid Derivatives and Their Selective Apoptosis-Inducing Anticancer Mechanisms. J. Med. Chem.; 2017; 60, pp. 6353-6363.

82. Cui, D.; Yue, C.; Yang, Y. Mitochondrion-Targeting Nano-Drug Delivery System and Preparation Method and Application Thereof. Patent CN; 105833289, 9 April 2019.

83. Hamri, S.; Jouha, J.; Oumessaoud, A.; Pujol, M.D.; Khouili, M.; Guillaumet, G. Convenient approach for the synthesis of ONO-LB-457, a potent leukotriene B₄ receptor antagonist. Tetrahedron; 2021; 77, 131740. [DOI: https://dx.doi.org/10.1016/j.tet.2020.131740]

84. Bogdanov, A.A.; Chen, C.-W.; Khairullina, Z.Z.; Konevega, A.L.; Lukianov, D.A.; Makarov, G.I.; Osterman, I.A.; Paleskava, A.; Pavlova, J.A.; Polikanov, Y.S. et al. Binding and Action of Triphenylphosphonium Analog of Chloramphenicol upon the Bacterial Ribosome. Antibiotics; 2021; 10, 390.

85. Castellanos, L.; Gateau-Olesker, A.; Panne-Jacolot, F.; Cleophax, J.; Gero, S.D. Synthèse d’analogues de derives dioxaprostanoïques à partir du D et DU L-xylose. Tetrahedron; 1981; 37, pp. 1691-1696. [DOI: https://dx.doi.org/10.1016/S0040-4020(01)98932-X]

86. Dobner, B.; Nuhn, P.; Burkhardt, U. Synthese mittelständig methylverzweigter Fettsäuren. Z. Chem.; 1987; 27, pp. 63-64. [DOI: https://dx.doi.org/10.1002/zfch.19870270207]

87. Carballeira, N.M.; Cruz, H.; Hill, C.A.; De Voss, J.J.; Garson, M. Identification and Total Synthesis of Novel Fatty Acids from the Siphonarid Limpet Siphonaria denticulate. J. Nat. Prod.; 2001; 64, pp. 1426-1429. [DOI: https://dx.doi.org/10.1021/np010307r] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11720525]

88. Momán, E.; Nicoletti, D.; Mouriňo, A. Synthesis of novel analogues of 1α,25-dihydroxyvitamin D3 with side chains at C-18. J. Org. Chem.; 2004; 69, pp. 4615-4625. [DOI: https://dx.doi.org/10.1021/jo0498664] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15230583]

89. Ramon-Azcon, J.; Galve, R.; Sanchez-Baeza, F.; Marco, M.-P. Development of An Enzyme-Linked Immunosorbent Assay (ELISA) for the Determination of the Linear Alkylbenzene Sulfonates (LAS) and long chain Sulfophenhyl Carboxylates (SPCs) using Antibodies Generated by pseudo-Heterologous Immunization. Anal. Chem.; 2006; 78, pp. 71-81. [DOI: https://dx.doi.org/10.1021/ac051141s] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16383312]

90. Hardouin, C.; Kelso, M.J.; Romero, F.A.; Rayl, T.J.; Leung, D.; Hwang, I.; Cravatt, B.F.; Boger, D.L. Structure–Activity Relationships of α-Keto Oxazole Inhibitors of Fatty Acid Amide Hydrolase. J. Med. Chem.; 2007; 50, pp. 3359-3368. [DOI: https://dx.doi.org/10.1021/jm061414r] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17559203]

91. Boger, D.L. Tricyclic Inhibitors of Fatty Acid Amide Hydrolase. Patent WO; 2008150492, 11 December 2008.

92. Zhao, G.; Yang, C.; Li, B.; Xia, W. A new phenylethyl alkyl amide from the Ambrostoma quadriimpressum Motschulsky. Beilstein J. Org. Chem.; 2011; 7, pp. 1342-1346. [DOI: https://dx.doi.org/10.3762/bjoc.7.158] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22043245]

93. Kristiansen, K.; Mainkar, P.S. PPAR Modulators. U.S. Patent; 2011178112, 21 July 2011.

94. Wang, Y.; Wang, B.; Liao, H.; Song, X.; Wu, H.; Wang, H.; Shen, H.; Ma, X.; Tan, M. Liposomal nanohybrid cerasomes for mitochondria-targeted drug delivery. J. Mater. Chem. B; 2015; 3, pp. 7291-7299. [DOI: https://dx.doi.org/10.1039/C5TB01197C]

95. Guo, R.; Huang, J.; Huang, H.; Zhao, X. Organoselenium-Catalyzed Synthesis of Oxygen- and Nitrogen-Containing Heterocycles. Org. Lett.; 2016; 18, pp. 504-507. [DOI: https://dx.doi.org/10.1021/acs.orglett.5b03543]

96. Kalathil, A.A.; Kumar, A.; Banik, B.; Ruiter, T.A.; Pathak, R.K.; Dhar, S. New formulation of old aspirin for better delivery. Chem. Comm.; 2016; 52, pp. 140-143. [DOI: https://dx.doi.org/10.1039/C5CC07316B] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26503669]

97. Chang, Y.-T.; Alamudi, S.H.; Satapathy, R.; Su, D. Background-Free Fluorescent Probes for Live Cell Imaging. Patent WO; 201778623, 30 March 2011.

98. Cheng, J. Method for Preparing 6-Bromotriphenylphosphonio-n-Caproic Acid. Patent CN; 106632474, 7 September 2018.

99. Kalathil, A.A.; Banik, B.; Kumar, A.; Dhar, S. Modification of Drugs for Incorporation into Nanoparticles. U.S. Patent; 2017087167, 30 March 2017.

100. Dhar, S.; Pathak, R. Precise Delivery of Therapeutic Agents to Cell Mitochondria for Anti-Cancer Therapy. U.S. Patent; 10004809, 26 June 2018.

101. Pantelia, A.; Daskalaki, I.; Cuquerella, M.C.; Rotas, G.; Miranda, M.A.; Vougioukalakis, G.C. Synthesis and Chemiluminescent Properties of Amino-Acylated luminol Derivatives Bearing Phosphonium Cations. Molecules; 2019; 24, 3957. [DOI: https://dx.doi.org/10.3390/molecules24213957] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31683732]

102. Chen, Z.; Zhang, Z.; Chen, M.; Xie, S.; Wang, T.; Li, X. Synergistic antitumor efficacy of hybrid micelles with mitochondrial targeting and stimuli-responsive drug release. J. Mater. Chem. B; 2019; 7, pp. 1415-1426. [DOI: https://dx.doi.org/10.1039/C8TB02843E]

103. Bundy, G.L. 9-Deoxy-PGF₂ Analogs. U.S. Patent; 4033989, 5 July 1977.

104. Bundy, G.L.; Nelson, N.A. 2a,2b-Dihomo-11-deoxy-17(substituted phenyl)-18,19,20-trinor-PGE₂ Compounds and Their Corresponding Esters. U.S. Patent; 4029693, 14 July 1977.

105. Youngdale, G.A. 2a,2b-Dihomo-16,16-dimethyl-PGF₂ Analogs. U.S. Patent; 4067891, 10 January 1978.

106. Smith, H.W. 13,14-Didehydro-PGA₁ Compounds. U.S. Patent; 4086258, 25 April 1978.

107. Nelson, N.A. 15-Epi-15-methyl-16-phenoxy-PGE Compounds. U.S. Patent; 4154950, 15 May 1979.

108. Allais, A.; Clemence, F.; Meier, J.; Deraedt, R. Novel Carboxylic Acids, Benzoyl Phenyl Alkanoic Acids and Use Thereof. U.S. Patent; 4337353, 29 June 1982.

109. Johnson, A.T.; Jiao, G.-S. Hydroxamic Acid Derivatives of 3-Phenyl Propionic Acids Useful as Therapeutic Agents for Treating Anthrax Poisoning. U.S. Patent; 2008188566, 5 October 2010.

110. Kim, S.; Jiao, G.-S.; Moayeri, M.; Crown, D.; Cregar-Hernandez, L.; McKasson, L.; Margosiak, S.A.; Leppla, S.H.; Johnson, A.T. Antidotes to anthrax lethal factor intoxication. Part 2: Structural modifications leading to improved in vivo efficacy. Bioorg. Med. Chem. Lett.; 2011; 21, pp. 2030-2033. [DOI: https://dx.doi.org/10.1016/j.bmcl.2011.02.010] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21334206]

111. Migglautsch, A.K.; Willim, M.; Schweda, B.; Glieder, A.; Breinbauer, R.; Winkler, M. Aliphatic hydroxylation and epoxidation of capsaicin by cytochrome P450 CYP505X. Tetrahedron; 2018; 74, pp. 6199-6204. [DOI: https://dx.doi.org/10.1016/j.tet.2018.08.049]

112. Li, S.; Quan, X.; Xu, J.; Li, J.; Xie, J. Preparation and Application of Quaternary Phosphonium Salt Modified Dendriform Molecule. Patent CN; 104844650, 29 December 2017.

113. Suzuki, Y.; Takahashi, Y. Cationic Lipid. Patent EP; 3476832, 1 May 2019.

114. Chun, J.; Cincilla, G.; Del Valle, C.R.; Devesa, I.; Ferrer-Montiel, A.V.; González-Gil, I.; Hernández-Torres, G.; Khiar-Fernández, N.; Kihara, Y.; López-Rodríguez, M.L. et al. A novel agonist of the type 1 lysophosphatidic acid receptor (LPA1), UCM-05194, shows efficacy in neuropathic pain amelioration. J. Med. Chem.; 2019; 63, pp. 2372-2390.

115. Dawson, M.I.; Vasser, M. Synthesis of prostaglandin synthetase substrate analogs. 1. (Z)-14-Hydroxy-12,13-methano-8-nonadecenoic acid. J. Org. Chem.; 1977; 42, pp. 2783-2785. [DOI: https://dx.doi.org/10.1021/jo00436a030]

116. Guthrie, R.W.; Kierstead, R.W. Pyridine Compounds Which Are Useful in Treating a Disease State Characterized by an Excess of Platelet Activating Factors. U.S. Patent; 4927838, 22 May 1990.

117. Nanda, S.; Yadav, J.S. Asymmetric synthesis of unnatural (Z, Z, E)-octadecatrienoid and eicosatrienoid by lipoxygenase-catalyzed oxygenation. Tetrahedron Asymm.; 2003; 14, pp. 1799-1806. [DOI: https://dx.doi.org/10.1016/S0957-4166(03)00369-0]

118. Mor, M.; Lodola, A.; Rivara, S.; Vacondio, F.; Duranti, A.; Tontini, A.; Sanchini, S.; Piersanti, G.F.; Clapper, J.R.; King, A.R. et al. Synthesis and Quantitative Structure−Activity Relationship of Fatty Acid Amide Hydrolase Inhibitors: Modulation at the N-Portion of Biphenyl-3-yl Alkylcarbamates. J. Med. Chem.; 2008; 51, pp. 3487-3498. [DOI: https://dx.doi.org/10.1021/jm701631z]

119. Sparey, T.; Ratcliffe, A.; Cochrane, E.; Stevenson, B.; Hallett, D.; Lagasse, F.; Lassalle, G.; Froidbise, A. Azithromycin Derivatives Containing a Phosphonium Ion as Anticancer Agents. Patent WO; 2018193113, 25 October 2018.

120. Linnebank, P.R.; Ferreira, S.F.; Kluwer, A.M.; Reek, J.N.H. Regioselective Hydroformylation of Internal and Terminal Alkenes via Remote Supramolecular Control. Chem. Eur. J.; 2020; 26, pp. 8214-8219. [DOI: https://dx.doi.org/10.1002/chem.202000620]

121. Sparey, T.; Ratcliffe, A.; Cochrane, E.; Stevenson, B.; Hallett, D.; Lagasse, F.; Lassalle, G.; Froidbise, A. Phosphonium-Ion Tethered Tetracycline Drugs for Treatment of Cancer. U.S. Patent; 2020123182, 23 April 2020.

122. Lou, H.; Wang, X.; Liu, J. Triazole Compounds, Preparation Method and Application of Triazole Compounds in Antifungal Drugs. Patent CN; 111647019, 11 September 2020.

123. Rao, A.V.R.; Reddy, E.R.; Purandare, A.V.; Varaprasad, C.V.N.S. Stereoselective synthesis of unsaturated C-18 hydroxy fatty acids the self defensive substances. Tetrahedron; 1987; 43, pp. 4385-4394. [DOI: https://dx.doi.org/10.1016/S0040-4020(01)90314-X]

124. Buchanan, G.W.; Smits, R.; Munteanu, E. Synthesis and ¹⁹F NMR study of R_F-oleic acid-F₁₃. J. Fluor. Chem.; 2003; 123, pp. 255-259. [DOI: https://dx.doi.org/10.1016/S0022-1139(03)00162-3]

125. Duffy, P.E.; Quinn, S.M.; Roche, H.M.; Evans, P. Synthesis of trans-vaccenic acid and cis-9-trans-11-conjugated linoleic acid. Tetrahedron; 2006; 62, pp. 4838-4843. [DOI: https://dx.doi.org/10.1016/j.tet.2006.03.006]

126. Thurnhofer, S.; Saskia, W. Synthesis of (S)-(+)-enantiomers of food-relevant (n-5)-monoenoic and saturated anteiso-fatty acids by a Wittig reaction. Tetrahedron; 2007; 63, pp. 1140-1145. [DOI: https://dx.doi.org/10.1016/j.tet.2006.11.059]

127. Andjelkovic, M.; Ceccarelli, S.M.; Chomienne, O.; Kaplan, G.L.; Mattei, P.; Tilley, J.W. 4-Dimethylaminobutyric Acid Derivatives. U.S. Patent; 2009270505, 29 October 2009.

128. Kumari, A.; Gholap, S.P.; Fernandes, R.A. Tandem IBX-Promoted Primary Alcohol Oxidation/Opening of Intermediate β, γ-Diolcarbonate Aldehydes to (E)-γ-Hydroxy-α, β-enals. Chem. Asian J.; 2019; 14, pp. 2278-2290. [DOI: https://dx.doi.org/10.1002/asia.201900421] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31062934]

129. Wood, M.; Whiteman, M.; Perry, A. Hydrogen Sulfide Releasing Compounds and Their Use. Patent WO; 201345951, 4 April 2013.

130. Le Trionnaire, S.; Perry, A.; Szczesny, B.; Szabo, C.; Winyard, P.G.; Whatmore, J.L.; Wood, M.E.; Whiteman, M. The synthesis and functional evaluation of a mitochondria-targeted hydrogen sulfide donor,(10-oxo-10-(4-(3-thioxo-3 H-1,2-dithiol-5-yl) phenoxy) decyl) triphenylphosphonium bromide (AP39). MedChemComm; 2014; 5, pp. 728-736. [DOI: https://dx.doi.org/10.1039/C3MD00323J]

131. Sparey, T.; Ratcliffe, A.; Hallett, D.; Cochrane, E.; Lassalle, G.; Froidbise, A.; Stevenson, B. Triphenylphosphonium-Tethered Tetracycyclines for Use in Treating Cancer. Patent WO; 2018193114, 25 October 2018.

132. Baran, J.S.; Lowrie, H.S. Metabolites of Pentanedioic Acid Derivatives. U.S. Patent; 5055613, 8 October 1991.

133. Müller, S.; Schmidt, R.R. Synthesis of Unique Ceramides and Cerebrosides Occurring in Human Epidermis. Helv. Chim. Acta; 1993; 76, pp. 616-630. [DOI: https://dx.doi.org/10.1002/hlca.19930760141]

134. Skulachev, M.V.; Skulachev, V.P.; Zamyatin, A.A.; Efremov, E.S.; Tashlitsky, V.N.; Yaguzhinsky, L.S.; Korshunova, G.A.; Sumbatyan, N.V.; Antonenko, Y.N.; Severina, I.I. et al. Pharmaceutical Substances on the Basis of Mitochondria-Addressed Antioxidants. U.S. Patent; 2012259110, 12 January 2016.

135. Martín-Rodríguez, A.J.; Babarro, J.M.F.; Lahoz, F.; Sansón, M.; Martín, V.S.; Norte, M.; Fernández, J.J. From broad-spectrum biocides to quorum sensing disruptors and mussel repellents: Antifouling profile of alkyl triphenylphosphonium salts. PLoS ONE; 2015; 10, e0123652. [DOI: https://dx.doi.org/10.1371/journal.pone.0123652] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25897858]

136. Opálka, L.; Kováčik, A.; Sochorová, M.; Roh, J.; Kuneš, J.; Lenčo, J.; Vávrová, K. Scalable Synthesis of Human Ultralong Chain Ceramides. Org. Lett.; 2015; 17, pp. 5456-5459. [DOI: https://dx.doi.org/10.1021/acs.orglett.5b02816]

137. Kluba, C.A.; Bauman, A.; Valverde, I.E.; Vomstein, S.; Mindt, T.L. Dual-targeting conjugates designed to improve the efficacy of radiolabeled peptides. Org. Biomol. Chem.; 2012; 10, pp. 7594-7602. [DOI: https://dx.doi.org/10.1039/c2ob26127h]

138. Leavens, W.J.; Lane, S.J.; Carr, R.M.; Lockie, A.M.; Waterhouse, I. Derivatization for liquid chromatography/electrospray mass spectrometry: Synthesis of tris(trimethoxyphenyl)phosphonium compounds and their derivatives of amine and carboxylic acids. Rapid Commun. Mass Spectr.; 2002; 16, pp. 433-441. [DOI: https://dx.doi.org/10.1002/rcm.559] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/11857728]

139. Hoffmann, H. Zur Reaktion von Triphenylphosphin mit Olefinen. Chem. Ber.; 1961; 94, pp. 1331-1336. [DOI: https://dx.doi.org/10.1002/cber.19610940525]

140. Romanov, S.; Aksunova, A.; Bakhtiyarova, Y.; Shulaeva, M.; Pozdeev, O.; Egorova, S.; Galkina, I.; Galkin, V. Tertiary phosphines in reactions with substituted cinnamic acids. J. Organomet. Chem.; 2020; 910, 121130. [DOI: https://dx.doi.org/10.1016/j.jorganchem.2020.121130]

141. Bestmann, H.J.; Mott, L.; Lienert, J. Reaktionen mit Triphenylphosphin sowie dessen Hydrobromid und Dibromid, III. Äther und Esterspaltungen mit Triphenylphosphinhydrobromid. Justus Liebigs Ann. Chem.; 1967; 709, pp. 105-112. [DOI: https://dx.doi.org/10.1002/jlac.19677090112]

142. Kiuchi, F.; Nakamura, N.; Saito, M.; Komagome, K.; Hiramatsu, H.; Takimoto, N.; Akao, N.; Kondo, K.; Tsuda, Y. Synthesis and Nematocidal Activity of Aralkyl- and Aralkenylamides Related to Piperamide on Second-Stage Larvae of Toxocara canis. Chem. Pharm. Bull.; 1997; 45, pp. 685-696. [DOI: https://dx.doi.org/10.1248/cpb.45.685]

143. Sancéau, J.-Y.; Maltais, R.; Poirier, D.; Marette, A. Total Synthesis of the Antidiabetic (Type 2) Lipid Mediator Protectin DX/PDX. J. Org. Chem.; 2019; 84, pp. 495-505. [DOI: https://dx.doi.org/10.1021/acs.joc.8b01973]

144. Virieux, D.; Volle, J.-N.; Pirat, J.-L. Product class 12: Alkylphosphonium salts. Sci. Synth.; 2009; 42, pp. 503-594.

145. Büttner, H.; Steinbauer, J.; Werner, T. Synthesis of Cyclic Carbonates from Epoxides and Carbon Dioxide by Using Bifunctional One-Component Phosphorus-Based Organocatalysts. ChemSusChem; 2015; 8, pp. 2655-2669. [DOI: https://dx.doi.org/10.1002/cssc.201500612]

146. Wang, Y.; Jiang, M.; Liu, J.-T. Copper-Catalyzed Diastereoselective Synthesis of Trifluoromethylated Tetrahydrofurans. Adv. Synth. Cat.; 2016; 358, pp. 1322-1327. [DOI: https://dx.doi.org/10.1002/adsc.201501166]

147. Atkinson, J.; Stuart, J.; Kagan, V.E.; Stoyanovsky, D.A.; Epperly, M.W.; Greenberger, J.S.; Bayir, H. Mitochondria-Targeted Inhibitors of Cytochrome C Peroxidase for Protection from Apoptosis. U.S. Patent; 9365597, 14 June 2016.

148. Lei, H.; Atkinson, J. Synthesis of phytyl-and chroman-derivatized photoaffinity labels based on α-tocopherol. J. Org. Chem.; 2000; 65, pp. 2560-2567. [DOI: https://dx.doi.org/10.1021/jo000029l] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/10789472]

149. Horiike, M.; Tanouchi, M.; Hirano, C. Synthesis of insect sex pheromones and their homologues;(Z)-6-Alkenyl acetates from the Wittig reaction. Agric. Biol. Chem.; 1978; 42, pp. 1963-1965.

150. Cripe, T.A.; Connor, D.S.; Vinson, P.K.; Burckett-St, L.J.C.; Willman, K.W. Polyoxyalkylene Surfactants. U.S. Patent; 6093856, 25 July 2000.

151. Culcasi, M.; Casano, G.; Lucchesi, C.; Mercier, A.; Clement, J.-L.; Pique, V.; Michelet, L.; Krieger-Liszkay, A.; Robin, M.; Pietri, S. Synthesis and biological characterization of new aminophosphonates for mitochondrial pH determination by ³¹P NMR spectroscopy. J. Med. Chem.; 2013; 56, pp. 2487-2499. [DOI: https://dx.doi.org/10.1021/jm301866e] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23437893]

152. Muratore, A.; Plessis, C.; Chanot, J.-J. Novel Cycloalkane Aldehydes, Method for Preparing Same, and Use Thereof in the Perfume Industry. U.S. Patent; 9051531, 9 June 2015.

153. He, J.; Baldwin, J.E.; Lee, V. Studies towards the Synthesis of the Antibiotic Tetrodecamycin. Synlett; 2018; 29, pp. 1117-1121.

154. Xue, J.; Zhao, X.; Huang, Y. Double-Targeted Phthalocyanine Anti-Cancer Photosensitizer and Preparation Method Thereof. Patent CN; 109081852, 25 December 2018.

155. Horiike, M.; Hirano, C. A Facile Synthesis of the Sex Pheromones (Z)-7-Dodecen-1-yl Acetate and Its Homologues. Agric. Biol. Chem.; 1980; 44, pp. 2229-2230. [DOI: https://dx.doi.org/10.1080/00021369.1980.10864303]

156. Horiike, M.; Tanouchi, M.; Hirano, C. A convenient method for synthesizing (Z)-alkenols and their acetates. Agric. Biol. Chem.; 1980; 44, pp. 257-261. [DOI: https://dx.doi.org/10.1080/00021369.1980.10863936]

157. Jara, J.A.; Castro-Castillo, V.; Saavedra-Olavarría, J.; Peredo, L.; Pavanni, M.; Jana, F.; Letelier, M.E.; Parra, E.; Becker, M.I.; Morello, A. et al. Antiproliferative and uncoupling effects of delocalized, lipophilic, cationic gallic acid derivatives on cancer cell lines. Validation in vivo in singenic mice. J. Med. Chem.; 2014; 57, pp. 2440-2454. [DOI: https://dx.doi.org/10.1021/jm500174v]

158. Bruns, H.; Thiel, V.; Voget, S.; Patzelt, D.; Daniel, R.; Wagner-Doebler, I.; Schulz, S. N-acylated alanine methyl esters (NAMEs) from Roseovarius tolerans, structural analogs of quorum-sensing autoinducers, N-acylhomoserine lactones. Chem. Biodiver.; 2013; 10, pp. 1559-1573. [DOI: https://dx.doi.org/10.1002/cbdv.201300210]

159. Bruns, H.; Herrmann, J.; Müller, R.; Wang, H.; Wagner-Döbler, I.; Schulz, S. Oxygenated N-acyl alanine methyl esters (NAMEs) from the marine bacterium Roseovarius tolerans EL-164//Journal of natural products. J. Nat. Prod.; 2018; 81, pp. 131-139. [DOI: https://dx.doi.org/10.1021/acs.jnatprod.7b00757] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29261310]

160. Zhong, J.; Sun, X.; Yuan, C.; Ma, S.; Zhou, Y.; Bian, Q.; Wang, M. Method for Synthesizing Grassland Spodoptera Litura Sex Pheromone Active Ingredients. Patent CN; 111269114, 12 June 2020.

161. Baker, S.R.; Ross, W.J. Sulfur Containing Alkenylenyl Substituted Benzoic Acids and Phenyl Tetrazoles and Their Use as Anti-allergic Agents. U.S. Patent; 4675335, 23 June 1987.

162. Lermer, L.; Neeland, E.G.; Ounsworth, J.P.; Sims, R.J.; Tischler, S.A.; Weiler, L. The synthesis of β-keto lactones via cyclization of β-keto ester dianions or the cyclization of Meldrum’s acid derivatives. Can. J. Chem.; 1992; 70, pp. 1427-1445. [DOI: https://dx.doi.org/10.1139/v92-180]

163. Okuda, K.; Hasui, K.; Abe, M.; Matsumoto, K.; Shindo, M. Molecular design, synthesis, and evaluation of novel potent apoptosis inhibitors inspired from bongkrekic acid. Chem. Res. Toxicol.; 2012; 25, pp. 2253-2260. [DOI: https://dx.doi.org/10.1021/tx300315h] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22998163]

164. Liang, B.; Shao, W.; Zhu, C.; Wen, G.; Yue, X.; Wang, R.; Quan, J.; Du, J.; Bu, X. Mitochondria-targeted approach: Remarkably enhanced cellular bioactivities of TPP2a as selective inhibitor and probe toward TrxR. ACS Chem. Biol.; 2016; 11, pp. 425-434. [DOI: https://dx.doi.org/10.1021/acschembio.5b00708] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26653078]

165. Catalán, M.; Castro-Castillo, V.; Gajardo-de la Fuente, J.; Aguilera, J.; Ferreira, J.; Ramires-Fernandez, R.; Olmedo, I.; Molina-Berríos, A.; Palominos, C.; Valencia, M. et al. Continuous flow synthesis of lipophilic cations derived from benzoic acid as new cytotoxic chemical entities in human head and neck carcinoma cell lines. RSC Med. Chem.; 2020; 11, pp. 1210-1225. [DOI: https://dx.doi.org/10.1039/D0MD00153H] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33479625]

166. Liu, F.; Zhang, Z.; Kong, X.; Zhang, S. Micromelalopha Troglodyta Sex Pheromone Attractant Composition, Lure and Preparation Method and Application Thereof. Patent CN; 110959613, 17 April 2020.

167. Alunda, J.M.; Cueto-Díaz, E.J.; Dardonville, C.; Gamarro, F.; Herraiz, T.; Manzano, J.I.; Olías-Molero, A.I.; Perea, A.; Torrado, J.J. Discovery and pharmacological studies of 4-hydroxyphenyl-derived phosphonium salts active in a mouse model of visceral leishmaniasis. J. Med. Chem.; 2019; 62, pp. 10664-10675.

168. Mannu, A.; Di Pietro, M.E.; Priola, E.; Baldino, S.; Sacchetti, A.; Mele, A. Unconventional reactivity of epichlorohydrin in the presence of triphenylphosphine: Isolation of ((1,4-dioxane-2,5-diyl)-bis-(methylene))-bis-(triphenylphosphonium) chloride. Res. Chem. Intermed.; 2021; 47, pp. 1663-1674. [DOI: https://dx.doi.org/10.1007/s11164-020-04364-9]

169. Wada, M.; Tsuboi, A. Reactions of tris(2,6-dimethoxyphenyl)phosphine with epoxides. J. Chem. Soc. Perkin Trans. 1; 1987; pp. 151-154. [DOI: https://dx.doi.org/10.1039/p19870000151]

170. Yamamoto, S.; Okuma, K.; Ohta, H. General synthesis of 2-, 3-, and 4-hydroxyalkylphosphonium salts by the reaction of triphenylphosphine with cyclic ethers in the presence of strong acids. Bull. Chem. Soc. Jpn.; 1988; 61, pp. 4476-4478. [DOI: https://dx.doi.org/10.1246/bcsj.61.4476]

171. Yamamoto, S.-I.; Takeuchi, H.; Tanaka, Y.; Okuma, K.; Ohta, H. Synthesis and reaction of optically active 2-and 3-hydroxyalkylphosphonium salts. Chem. Lett.; 1991; 20, pp. 113-116. [DOI: https://dx.doi.org/10.1246/cl.1991.113]

172. Plénat, F.; Grelet, D.; Ozon, V.; Cristau, H.-J. Synthesis of new functionalized hydroxyalkyl phosphonium salts. Synlett; 1994; 4, pp. 269-270. [DOI: https://dx.doi.org/10.1055/s-1994-22823]

173. Mironov, V.F.; Karaseva, A.N.; Nizamov, I.S.; Kedrov, I.S.; Konovalov, A.I. Triphenylphosphonium Trifluoromethanesulfonate in Reactions with Epoxy Derivatives. Russ. J. Org. Chem.; 2004; 40, pp. 910-911. [DOI: https://dx.doi.org/10.1023/B:RUJO.0000044560.16795.94]

174. Christol, H.; Grelet, D.; Darvich, M.R.; Fallouh, F.; Plenat, F.; Cristau, H.-J. Réaction des oxiranes avec la triphénylphosphine en milieu phénolique. Bull. Soc. Chim. Fr.; 1989; pp. 477-483.

175. Tolstikova, L.L.; Bel’skikh, A.V.; Shainyan, B.A. Protonation and alkylation of organophosphorus compounds with trifluoromethanesulfonic acid derivatives. Russ. J. Gen. Chem.; 2011; 81, pp. 474-480. [DOI: https://dx.doi.org/10.1134/S1070363211030054]

176. Parker, R.E.; Isaacs, N.S. Mechanisms of epoxide reactions. Chem. Rev.; 1959; 59, pp. 737-799. [DOI: https://dx.doi.org/10.1021/cr50028a006]

177. Rosowsky, A. Ethylene Oxides. Hеtеrocуclic Compounds with Three- and Four-Membered Rings; Weissberger, A. Interscie: New York, NY, USA, London, UK, Sуdneу, Australia, 1964; Part I, pp. 1-523.

178. Wohl, R.A. Mechanism of acid-catalyzed ring-opening of epoxides-reinterpretative review. Chimia; 1974; 28, pp. 1-5.

179. Gray, G.A. Carbon-13 nuclear magnetic resonance of organophosphorus compounds. VIII. Triphenylphosphoranes and triphenylphosphonium salts. J. Am. Chem. Soc.; 1973; 95, pp. 7736-7742. [DOI: https://dx.doi.org/10.1021/ja00804a032]

180. Flores-Gallardo, H.; Pollard, C.B. Epoxy ethers and ether amino alcohols. J. Org. Chem.; 1947; 12, pp. 831-833. [DOI: https://dx.doi.org/10.1021/jo01170a015]

181. Giodini, L.; Lo Re, F.; Campagnol, D.; Marangon, E.; Posocco, B.; Dreussi, E.; Toffoli, G. Nanocarriers in cancer clinical practice: A pharmacokinetic issue. Nanomed. Nanotechnol. Biol. Med.; 2017; 13, pp. 583-599. [DOI: https://dx.doi.org/10.1016/j.nano.2016.07.012] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27520727]

182. Allen, T.M.; Cullis, P.R. Liposomal drug delivery systems: From concept to clinical applications. Adv. Drug Deliv. Rev.; 2013; 65, pp. 36-48. [DOI: https://dx.doi.org/10.1016/j.addr.2012.09.037] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23036225]

183. Barenholz, Y. Doxil^®—The first FDA-approved nano-drug: Lessons learned. J. Control. Release; 2012; 160, pp. 117-134. [DOI: https://dx.doi.org/10.1016/j.jconrel.2012.03.020] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22484195]

184. Forssen, E.A. The design and development of DaunoXome^® for solid tumor targeting in vivo. Adv. Drug Deliv. Rev.; 1997; 24, pp. 133-150. [DOI: https://dx.doi.org/10.1016/S0169-409X(96)00453-X]

185. Leonard, R.C.F.; Williams, S.; Tulpule, A.; Levine, A.M.; Oliveros, S. The design and development of DaunoXome^® for solid tumor targeting in vivo. Breast; 2009; 18, pp. 218-224. [DOI: https://dx.doi.org/10.1016/j.breast.2009.05.004]

186. Bourquin, J.; Milosevic, A.; Hauser, D.; Lehner, R.; Blank, F.; Petri-Fink, A.; Rothen-Rutishauser, B. Biodistribution, clearance, and long-term fate of clinically relevant nanomaterials. Adv. Mater.; 2018; 30, 1704307. [DOI: https://dx.doi.org/10.1002/adma.201704307]

187. Tomsen-Melero, J.; Passemard, S.; Garcia-Aranda, N.; Diaz-Riascos, Z.V.; Gonzalez-Rioja, R.; Pedersen, J.N.; Lyngsø, J.; Merlo-Mas, J.; Cristobal-Lecina, E.; Corchero, J.L. et al. Impact of chemical composition on the nanostructure and biological activity of α-galactosidase-loaded nanovesicles for fabry disease treatment. ACS Appl. Mater. Interfaces; 2021; 13, pp. 7825-7838. [DOI: https://dx.doi.org/10.1021/acsami.0c16871]

188. Pashirova, T.N.; Sapunova, A.S.; Lukashenko, S.S.; Burilova, E.A.; Lubina, A.P.; Shaihutdinova, Z.M.; Gerasimova, T.P.; Kovalenko, V.I.; Voloshina, A.D.; Souto, E.B. et al. Synthesis, structure-activity relationship and biological evaluation of tetracationic gemini Dabco-surfactants for transdermal liposomal formulations. Int. J. Pharm.; 2020; 575, 118953. [DOI: https://dx.doi.org/10.1016/j.ijpharm.2019.118953]

189. Sęk, A.; Perczyk, P.; Wydro, P.; Gruszecki, W.I.; Szczes, A. Effect of trace amounts of ionic surfactants on the zeta potential of DPPC liposomes. Chem. Phys. Lipids; 2021; 235, 105059. [DOI: https://dx.doi.org/10.1016/j.chemphyslip.2021.105059]

190. Pashirova, T.N.; Burilova, E.A.; Tagasheva, R.G.; Zueva, I.V.; Gibadullina, E.M.; Nizameev, I.R.; Sudakov, I.A.; Vyshtakalyuk, A.B.; Voloshina, A.D.; Kadirov, M.K. et al. Delivery nanosystems based on sterically hindered phenol derivatives containing a quaternary ammonium moiety: Synthesis, cholinesterase inhibition and antioxidant activity. Chem. Biol. Interact.; 2019; 310, 108753. [DOI: https://dx.doi.org/10.1016/j.cbi.2019.108753] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31319075]

191. Sheldrick, G. SADABS. Program for Empirical X-ray Absorption Correction; Bruker-Nonius: Gottingen, Germany, 2004.

192. APEX2 (Version 2.1), SAINTPlus. Data Reduction and Correction Program (Version 7.31A); BrukerAXS Inc.: Madison, WI, USA, 2006.

193. Sheldrick, G.M. SHELXT—Integrated space-group and crystal-structure determination. Acta Crystallogr. Sect. A; 2015; 71, pp. 3-8. [DOI: https://dx.doi.org/10.1107/S2053273314026370] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25537383]

194. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. Sect. C; 2015; 71, pp. 3-8. [DOI: https://dx.doi.org/10.1107/S2053273314026370] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25537383]

195. Straver, L.H.; Schierbeek, A.J. MOLEN. Structure Determination System. Program Description; Nonius, B.V.: Delft, The Netherlands, 1994; Volume 1, 180.

196. Farrugia, L. WinGX and ORTEP for Windows: An update. J. Appl. Crystallogr.; 2012; 45, pp. 849-854. [DOI: https://dx.doi.org/10.1107/S0021889812029111]

197. Spek, A.L. Structure validation in chemical crystallography. Acta Crystallogr. Sect. D; 2009; 65, pp. 148-155. [DOI: https://dx.doi.org/10.1107/S090744490804362X] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19171970]

198. Macrae, C.F.; Edgington, P.R.; McCabe, P.; Pidcock, E.; Shields, G.P.; Taylor, R.; Towler, M.; van de Streek, J. Mercury: Visualization and analysis of crystal structures. J. Appl. Crystallogr.; 2006; 39, pp. 453-459. [DOI: https://dx.doi.org/10.1107/S002188980600731X]

199. Al-Lal, A.M.; Garcнa-González, J.E.; Llamas, A.; Monjas, A.; Canoira, L.L. A new route to synthesize tert-butyl ethers of bioglycerol. Fuel; 2012; 93, pp. 632-637. [DOI: https://dx.doi.org/10.1016/j.fuel.2011.09.055]

200. Solov’ev, D.V.; Kolomenskaya, L.V.; Rodin, A.A.; Zenkevich, I.G.; Lavrent’ev, A.N. Fluorine-containing 2, 3-epoxypropyl ethers. synthesis and spectral characteristics. J. Gen. Chem. USSR; 1991; 61, pp. 611-615.

201. Il’in, A.A.; Il’in, A.N.; Bakhmutov, Y.L.; Furin, G.G.; Pokrovskii, L.M. Promising prospects for using partially fluorinated alcohols as O-nucleophilic reagents in organofluoric synthesis. Russ. J. Appl. Chem.; 2007; 80, pp. 405-418. [DOI: https://dx.doi.org/10.1134/S1070427207030123]

202. Pfeiffer, P.; Bauer, K. Synthese des Bis-ß-chromanons. Chem. Ber.; 1947; 80, pp. 7-19. [DOI: https://dx.doi.org/10.1002/cber.19470800103]

203. Reyhanoglu, Y.; Sahmetlioglu, E.; Gokturk, E. Alternative approach for synthesizing polyglycolic acid copolymers from C1 feedstocks and fatty ester epoxides. ACS Sustain. Chem. Eng.; 2019; 7, pp. 5103-5110. [DOI: https://dx.doi.org/10.1021/acssuschemeng.8b05940]