Diol Diesters Research Articles

Synthetic Approaches, Properties, and Applications of Acylals in Preparative and Medicinal Chemistry.

Diesters of geminal diols (R-CH(O-CO-R')2, RR'C(OCOR″)2, etc. with R = H, aryl or alkyl) are termed acylals according to IUPAC recommendations (Rule P-65.6.3.6 Acylals) if the acids involved are carboxylic acids. Similar condensation products can be obtained from various other acidic structures as well, but these related "non-classical acylals", as one might call them, differ in various aspects from classical acylals and will not be discussed in this article. Carboxylic acid diesters of geminal diols play a prominent role in organic chemistry, not only in their application as protective groups for aldehydes and ketones but also as precursors in the total synthesis of natural compounds and in a variety of organic reactions. What is more, acylals are useful as a key structural motif in clinically validated prodrug approaches. In this review, we summarise the syntheses and chemical properties of such classical acylals and show what potentially under-explored possibilities exist in the field of drug design, especially prodrugs, and classify this functional group in medicinal chemistry.

Design of a sustainable process for enzymatic production of ethylene glycol diesters via hydroesterification of used soybean cooking oil

The aim of this study was to produce diol diesters, an important class of synthetic esters with lubricant properties, via enzymatic hydroesterification of used soybean cooking oil (USCO). Initially, free fatty acids (FFAs) were produced through hydrolysis of USCO catalyzed using powder lipase extract from Candida rugosa. Afterwards, different diols and FFAs were esterified using Eversa® Transform 2.0, a low-cost liquid lipase derived from Thermomyces lanuginosus, immobilized via interfacial activation on polystyrene-divinylbenzene (PSty-DVB) beads as biocatalyst. The immobilization improved its catalytic activity and the best performance was observed using ethylene glycol (EG). Thus, it was selected for further ester production optimization. The effect of relevant factors on EG diesters production was assessed through a central composite rotatable design (CCRD). As a result, full OH conversion was achieved at 65 °C using EG:FFA molar ratio of 1:3% and 18% of mass of heterogeneous biocatalyst per mass of starting materials after 40 min of reaction. Maximum OH conversion was only 32.5% using soluble lipase under such conditions. The prepared biocatalyst retained ≈ 37% of its original activity after seven successive esterification batches. Viscosity index (166.2 ± 18.2), pour point (–9 ± 2 °C) and density at 20 °C (0.8794) values of the produced EG diesters were similar to other EG esters produced from soybean oil in literature and commercial synthetic neopolyol esters.

Asymmetric Synthesis of Biaryl Diols via Dynamic Kinetic Resolution

We have developed a protocol incuding dynamic kinetic resolution as the key step for the asymmetric synthesis of biaryl diol stereoisomers. The two aryl alkanols as the starting materials were cross‐coupled by palladium catalysis to give dl‐ and meso‐diol, which were then subject to chemoenzymatic dynamic kinetic resolution (DKR) for the transformation into single stereoisomeric diol diester. Diol diester was finally deacylated to give the corresponding biaryl diol stereoisomer. The chemoenzymatic DKR was performed with a ruthenium‐based racemization catalyst and a (R)‐selective lipoprotein lipase. Total 17 (R,R)‐diols including 7 C2‐symmetric diols were synthesized with excellent enantiopurities (>99% ee).

Lipids of the Tail Gland, Body and Muzzle Fur of the Red Fox, Vulpes vulpes.

The tail gland of the red fox (Vulpes vulpes) secretes lipids containing volatile terpenes used in social communication. We have analysed lipids extracted from fur of the tail gland, body (flanks) and muzzle of foxes. GC-MS showed a novel group of iso-valerate and tiglate monoesters of alkane-1,2-diols (C18:0-22:0). There was also a larger group of Type II diesters in which a second, longer chain, fatty acid (FA) was attached to the free alcohol group. LC-MS showed the full range of diol diesters, mostly C36:0-50:0, with smaller amounts of the corresponding mono-unsaturated tiglate esters. An additional group of diesters with higher MW (C49:0-62:0) containing two long-chain FA was present in the lipids of body and muzzle fur. After saponification and GC-MS, 98 fatty acids were characterized as their methyl esters. Apart from the C5 FA, most were saturated n-, iso-, anteiso- or other methyl-branched FA (C12:0-28:0) whose structures were determined by a combination of their mass spectra and Kovats retention indices. Several FA have not previously been found in nature or in vertebrates. Thirty-four alkane-1,2-diols were found as their TMS derivatives, mostly n-, iso- or anteiso-isomers of C16:0-25:0. The tail gland had the greatest amount of wax esters, from a greater variety of FA and diols, but lacked the esters with two long-chain FA. These findings show that fox skin lipids comprise mono- and di-esters of alkane-1,2-diols, and exhibit enormous complexity due to the diversity of their constituent FA, diols and the many possible isomers of their esters.

Synthesis of Unsaturated Diesters of Primary, Secondary and Tertiary Diols Derived from Dimethyl (+)‐Tartrate and Galactaric­ Acid

AbstractThe preparation of symmetrical unsaturated diesters of dioe first was the reaction of mixed anhydrides, obtained from α,β‐unsaturated acids and benzoyl chloride, with diols 3 (primary), 5 (secondary), and 7 (primary), i.e., Yamaguchi–SantaLucía's method, however only the symmetrical diacrylates of diols 5 and 7 were obtained quantitatively. In the other ten cases studied the reactions led to mixtures of symmetrical and unsymmetrical diesters that were difficult to separate. The mixed anhydrides did not react with the tertiary diols 4 (TADDOL) and 8. The average yield obtained in desired symmetrical diesters in the 12 cases studied was 54 %. The acylation of the diols with the anhydrides of the unsaturated acids, was found to be an excellent method, leading to the symmetrical unsaturated diesters of diols 3, 5, 7 as the only products of reaction, in an average yield of 83 %. Unfortunately, the method could not be applied to diesters derived from the tertiary diols 4 (TADDOL) and 8. The third method studied was the reaction between the alkoxides prepared with solutions of nBuLi in ether with the unsaturated acid chlorides at –50 °C, i.e., the Kaiser–Woodruff protocol. This was found to be the best of the three methods tested. The method was applied with success to the synthesis of the desired unsaturated diesters derived from diols 3–5, 7, and 8. The average yield of the 19 cases studied was 78 %.

Synthesis of diesters by addition of saturated carboxylic acids to tricyclodecenyl formate

Reaction of addition of C1-C5-saturated monobasic acids to tricyclo[5.2.1.02.6]dec-3-en-8(9)-yl for-mate in the presence of a catalyst, boron trifluoride etherate (BF3·OEt2), was used to synthesize homo- and mixed tricyclo[5.2.1.02.6]decane-3(4),8(9)-diol diesters. The synthesized formic-acetic and formic-propionic acid diesters have a pleasant odor and can be used as components for preparation of perfume formulations.

Synthesis and selected properties of polyurethanes with monodisperse hard segments based on hexane diisocyanate and three types of chain extenders

AbstractPoly(tetramethylene oxide)‐based segmented polyurethanes were synthesized by the chain extension of a poly(tetramethylene oxide) with a length of 1270 g/mol that was end‐capped with 1,6‐hexane diisocyanate. Three types of uniform chain extenders were used: a diamine diamide, a diol diamide, and a diol diester. The concentration of the monodisperse hard segments was approximately 32 wt %, and the materials were clear and tough. The polyurethanes with monodisperse hard segments were subsequently characterized with differential scanning calorimetry, dynamic mechanical thermal analysis, and compression set measurements and were found to display low glass‐transition temperatures, an almost temperature‐independent rubbery plateau, and sharp melting temperatures. The rate of crystallization (melting temperature − crystallization temperature) was moderately fast (36–54°C). Moreover, the melting temperature of the polyurethanes increased with the number of hydrogen‐bonding groups in the hard segment, whereas the modulus at room temperature was more dependent on the structural regularity of the extender. The best elastic properties were found for the materials extended with the diamine diamide. Finally, an interesting combination of properties was revealed for the polyurethane with a diol diamide extender based on aminopropanol. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012

Desymmetrization of meso-1,2-Diols via the Dynamic Kinetic Resolution of Its Monodichloroacetates

Enantioselective acylation catalyzed by the thioamide modified 1-methylhistidine methyl ester 1 in combination with DABCO-mediated racemization of the substrate led to the efficient dynamic kinetic resolution of meso-1,2-diol monodichloroacetates. In this way, cyclic and acyclic meso-1,2-diol monodichloroacetates can be transformed to the enantiomerically enriched (1S,2R)-heterosubstituted diol diesters which are stable in enantiomerically pure form and can be readily used for further organic transformations.

Lithium perchlorate promoted highly regioselective ring opening of epoxides under solvent-free conditions

A simple and efficient synthesis of diol diesters, protected chlorohydrins, chlorohydrins and β-hydroxy azides with acetyl or benzoyl, TMSN3 and TMSCl groups has been achieved by ring opening of epoxides with acetic anhydride, acetyl chloride or benzoyl chloride and TMSN3 using catalytic amount of lithium perchlorate under solvent-free conditions. All reactions proceeded in short times and afforded the corresponding products in good to excellent yields under mild reaction conditions. LiClO4 shows enhanced reactivity for the ring opening of epoxides under solvent-free conditions, therefore, reducing the reaction times dramatically and improved the yields and amount of catalyst.

F-actin-dependent endocytosis of cell wall pectins in meristematic root cells. Insights from brefeldin A-induced compartments.

Brefeldin A (BFA) inhibits exocytosis but allows endocytosis, making it a valuable agent to identify molecules that recycle at cell peripheries. In plants, formation of large intracellular compartments in response to BFA treatment is a unique feature of some, but not all, cells. Here, we have analyzed assembly and distribution of BFA compartments in development- and tissue-specific contexts of growing maize (Zea mays) root apices. Surprisingly, these unique compartments formed only in meristematic cells of the root body. On the other hand, BFA compartments were absent from secretory cells of root cap periphery, metaxylem cells, and most elongating cells, all of which are active in exocytosis. We report that cell wall pectin epitopes counting rhamnogalacturonan II dimers cross-linked by borate diol diester, partially esterified (up to 40%) homogalacturonan pectins, and (1-->4)-beta-D-galactan side chains of rhamnogalacturonan I were internalized into BFA compartments. In contrast, Golgi-derived secretory (esterified up to 80%) homogalacturonan pectins localized to the cytoplasm in control cells and did not accumulate within characteristic BFA compartments. Latrunculin B-mediated depolymerization of F-actin inhibited internalization and accumulation of cell wall pectins within intracellular BFA compartments. Importantly, cold treatment and protoplasting prevented internalization of wall pectins into root cells upon BFA treatment. These observations suggest that cell wall pectins of meristematic maize root cells undergo rapid endocytosis in an F-actin-dependent manner.

Short-term boron deprivation inhibits endocytosis of cell wall pectins in meristematic cells of maize and wheat root apices.

By using immunofluorescence microscopy, we observed rapidly altered distribution patterns of cell wall pectins in meristematic cells of maize (Zea mays) and wheat (Triticum aestivum) root apices. This response was shown for homogalacturonan pectins characterized by a low level (up to 40%) of methylesterification and for rhamnogalacturonan II pectins cross-linked by a borate diol diester. Under boron deprivation, abundance of these pectins rapidly increased in cell walls, whereas their internalization was inhibited, as evidenced by a reduced and even blocked accumulation of these cell wall pectins within brefeldin A-induced compartments. In contrast, root cells of species sensitive to the boron deprivation, like zucchini (Cucurbita pepo) and alfalfa (Medicago sativa), do not internalize cell wall pectins into brefeldin A compartments and do not show accumulation of pectins in their cell walls under boron deprivation. For maize and wheat root apices, we favor an apoplastic target for the primary action of boron deprivation, which signals deeper into the cell via endocytosis-mediated pectin signaling along putative cell wall-plasma membrane-cytoskeleton continuum.

Synthesis and characterization of some long‐chain diesters with branched or bulky moieties

AbstractSeveral novel fatty diesters with bulky moieties were synthesized by esterification of mono‐ or bifunctional fatty acids or with mono‐ or bifunctional alcohols using p‐toluenesulfonic acid as catalyst. They were characterized by 1H and 13C nuclear magnetic resonance as well as positive chemical ionization (PCl) mass spectrometry. The PCl mass spectra of the resulting diol diesters and diacid diesters are discussed and compared. The compounds were investigated as potential additives for improving the cold flow properties of vegetable oil esters used as biodiesel.

NMR spectroscopic analysis of the borate diol esters of methyl apiofuranosides

The borate diol esters formed by reacting methyl β- d- and methyl β- l-apiofuranosides with boric acid were studied by 11B, 1H and 13C NMR spectroscopy, and by FABMS. Methyl β- d-apiofuranoside was shown to form more stable borate diol diesters and a monoester than those of methyl β- l-apiofuranoside. The borate diol diesters of methyl β- d-apiofuranoside are present as two diastereomers in approximately equal molar ratios.

Improved delivery through biological membranes. 39. Brain-specific chemical delivery systems for .beta.-lactam antibiotics. In vitro and in vivo studies of some dihydropyridine and dihydroisoquinoline derivatives of benzylpenicillin in rats

Four chemical delivery systems (CDS's) based on a dihydropyridine----quaternary pyridinium salt redox system were used for the brain delivery of benzylpenicillin (BP). CDS's 5 and 9 are diesters of C1 and C2 diols in which one hydroxyl group is esterified by the benzylpenicillin-3-carboxylic group and the other by dihydrotrigonelline. CDS's 13a and 17 are benzylpenicillin esters of amino alcohols in which the amine group is acylated by dihydro-trigonelline (13a) or by 1,2-dihydro-2-methyl-4-isoquinolinecarboxylic acid (17). In vitro relative stability studies showed that both CDS's and quaternary pyridinium salts were quite unstable in rat and rabbit blood or brain but much more stable in dog or human blood. Kinetic studies performed in rat brain homogenate demonstrated the facile enzymatic oxidation of the CDS's to the corresponding quaternary salts. Hydrolysis of the CDS's and the quaternary salts resulted in the release of benzylpenicillin. In biological media CDS 13a also yielded a water addition product, the 6-hydroxy-1,4,5,6-tetrahydropyridine derivative. In vivo distribution studies were carried out in rats. After iv administration of equimolar doses of BP and CDS's, brain benzylpenicillin levels were found to be substantially higher and more prolonged in case of 5 and 9 than of BP itself. However, administration of 13a and 17 resulted in lower brain benzylpenicillin levels due to the water addition reaction and a nonspecific brain delivery, respectively. The remarkable increase of BP levels as well as the prolonged effect after the administration of 5 and 9 is a result of an improved penetration through the blood-brain barrier of the lipophilic CDS's and a "lock-in" effect of the corresponding quaternary salts generated in situ.

ChemInform Abstract: THE ASYMMETRIC ULLMANN COUPLING REACTION OF CHIRAL DIOL DIESTERS OF 1‐BROMO‐2‐NAPHTHOIC ACID AND 2‐HALO‐3‐NITROBENZOIC ACIDS: HIGHLY DIASTEREOSELECTIVE SYNTHESIS OF ATROPISOMERIC 6,6′‐DINITRODIPHENIC ACIDS

AbstractDie Cu‐katalysierte Ullmann‐Reaktion der aus den Komponenten (I) und (II) gebildeten chiralen Diol′‐ 25 ester (III)führt nach reduktiver Spaltung der Esterbindungen unter Bildung von l′,l′‐Binaphthylbindungen zu den chiralen Produkten (IVa)‐(IVc); im Falle des analog erhältlichen (IIId) wird kaum asymm. Induktion erreicht.

The Asymmetric Ullmann Coupling Reaction of Chiral Diol Diesters of 1-Bromo-2-naphthoic Acid and 2-Halo-3-nitrobenzoic Acids: Highly Diastereoselective Synthesis of Atropisomeric 6,6′-Dinitrodiphenic Acids

Abstract The copper-promoted Ullmann reaction of chiral diol diesters of 1-bromo-2-naphthoic acid induced axial dissymmetry into the newly formed 1,1′-binaphthyl bond: chiral diol, apparent net optical yield for the joining of two naphthyl units, and axial chirality induced are as follows: (S)-1,1′-binaphthyl-2,2′-diol, 71%, S; (1S,2S)-1,2-diphenyl-1,2-ethanediol, 32%, S; (1R,2R)-1,2-bis(ethoxycarbonyl)-1,2-ethanediol, 33%, S; (4S,5S)-bis(hydroxymethyl)-2,2-dimethyl-1,3-dioxolane, 3.7%, R. The reaction of (R)-1,1′-binaphthyl-2,2′-diol esters of 2-halo-3-nitrobenzoic acids gave up to 85% net optical yield for the coupling; the intramolecular cyclization proceeded with virtually complete diastereoselectivity to give cyclic diester of R,R-configuration in a 42% isolated yield. This remarkable stereocontrol is ascribed to the steric requirement of the 12-membered cyclic diester structure containing rigid 1,1′-binaphthyl and 1,1′-biphenyl moiety.

ChemInform Abstract: AN ESR STUDY OF ELECTRON REACTIONS WITH ESTERS AND TRIGLYCERIDES

Reactions which occurred after electron attachment at 77K to a number of small carboxylic acid esters and triglycerides in an aqueous glass are reported. Most ester anions are found to decay on warming to form alkyl radicals by ..beta.. scission: RC(O/sup -/)OR' ..-->.. RCO/sub 2//sup -/ + R'.. The alkyl radical (R'.) produced by annealing is found to abstract hydrogen from the parent ester at an ..cap alpha..-carbon site, R'.+ R''CH/sub 2/CO/sub 2/R' ..-->.. R''CHCO/sub 2/R', or in the case of ethyl formate from the formate hydrogen, CH/sub 3/CH/sub 2/.+ HCO/sub 2/C/sub 2/H/sub 5/ ..-->.. C/sub 2/H/sub 6/ +.CO/sub 2/C/sub 2/H/sub 5/. Results found for the methyl formate anion suggest hydrogen abstraction by the anion itself may compete with alkyl radical formation. The anion of the triglyceride triacetin is found to undergo an analogous mechanism to the ester anions producing the propane diol diester radical, .CH/sub 2/CH(Ac)CH/sub 2/(Ac), Ac = acetate. This species subsequently abstracts hydrogen from the parent compound to produce the ..cap alpha..-carbon radical, .CH/sub 2/CO/sub 2/R. Results found after annealing the tripropionin radical anion give evidence for abstraction from the ..cap alpha.. carbon in the propionate side groups producing CH/sub 3/CHCO/sub 2/R. Studies of a ..gamma..-irradiated estermore » (ethyl myristate) and two triglycerides (tripalmitin and tristearin) yield results which suggest that the mechanism of ester anion decay found in aqueous glasses applies to ..gamma..-irradiated neat long-chain esters and triglycerides. Results found in this work are compared to the results of product analysis.« less

An ESR study of electron reactions with esters and triglycerides

Reactions which occurred after electron attachment at 77K to a number of small carboxylic acid esters and triglycerides in an aqueous glass are reported. Most ester anions are found to decay on warming to form alkyl radicals by ..beta.. scission: RC(O/sup -/)OR' ..-->.. RCO/sub 2//sup -/ + R'.. The alkyl radical (R'.) produced by annealing is found to abstract hydrogen from the parent ester at an ..cap alpha..-carbon site, R'.+ R''CH/sub 2/CO/sub 2/R' ..-->.. R''CHCO/sub 2/R', or in the case of ethyl formate from the formate hydrogen, CH/sub 3/CH/sub 2/.+ HCO/sub 2/C/sub 2/H/sub 5/ ..-->.. C/sub 2/H/sub 6/ +.CO/sub 2/C/sub 2/H/sub 5/. Results found for the methyl formate anion suggest hydrogen abstraction by the anion itself may compete with alkyl radical formation. The anion of the triglyceride triacetin is found to undergo an analogous mechanism to the ester anions producing the propane diol diester radical, .CH/sub 2/CH(Ac)CH/sub 2/(Ac), Ac = acetate. This species subsequently abstracts hydrogen from the parent compound to produce the ..cap alpha..-carbon radical, .CH/sub 2/CO/sub 2/R. Results found after annealing the tripropionin radical anion give evidence for abstraction from the ..cap alpha.. carbon in the propionate side groups producing CH/sub 3/CHCO/sub 2/R. Studies of a ..gamma..-irradiated estermore » (ethyl myristate) and two triglycerides (tripalmitin and tristearin) yield results which suggest that the mechanism of ester anion decay found in aqueous glasses applies to ..gamma..-irradiated neat long-chain esters and triglycerides. Results found in this work are compared to the results of product analysis.« less

Metabolism of hydroxy sterols by rat liver

5 α-[16- 3 H] lanost-8- ene-3 β,15 α- diol and 5 α-[16- 3 H] lanost-8- ene-3 β,15 β- diol were both extensively metabolised by rat liver enzymes in vitro. Quantitatively, the most important product in both cases was a more polar compound, tentatively identified as a 5 α- lanost-8- enetriol. In addition, 5 α-[16- 3 H] lanost-8- ene-3 β,15 β- diol gave rise to the corresponding 3 β,15 β- diol diester, whilst with 5 α-[16- 3 H] lanost-8- ene-3 β,15 α- diol only the 3 β- hydroxyl group was esterified. The enzymes involved may normally be responsible for metabolising spontaneously produced non-enzymic oxidation products of dietary or cellular cholesterol. High concentrations of 5 α-[16- 3 H] lanost-8- ene-3 β,15 β- diol stimulated ester formation. With both substrates, carbon monoxide inhibited formation of the polar sterol metabolite but stimulated ester formation. Under all conditions, cholesterol was a relatively minor metabolic product of either of the 5 α- lanost-8- ene-3 β,15- diols.

The Effect of Temperature on the Uropygial Gland Alkane Diol Diesters in the Kn Mutation of the Domestic Chicken

Lipids from the uropygial glands of Kn/Kn males raised at 34.4 C, and Kn/Kn and k+/k+ males raised at 22.2 C were quantitatively analyzed to determine if lowering the metabolic rate of this semi-naked mutant would alter the composition of its uropygial gland lipids. No significant differences were found between the two Kn/Kn groups in fatty acid or diol composition. Body weights also did not significantly differ nor did total gland weight as a percent of body weight or lipid weight as a percent of total gland weight. The only significant difference was in comb weight as a percent of body weight. The Kn/Kn males raised at 34.4 C had much larger combs as compared to the Kn/Kn males raised at 22.2 C.