Cyclic Ketal Research Articles

Fully Bio-based Poly(ketal-ester)s by Ring-opening Polymerization of a Bicylcic Lactone from Glycerol and Levulinic Acid.

A fully renewable bio-based bicyclic lactone containing a five-membered cyclic ketal moiety, 7-methyl-3,8,10-trioxabicyclo[5.2.1]decan-4-one (TOD), was synthesized through a two-step acid-catalyzed process from glycerol and levulinic acid. The ring-opening polymerization (ROP) of TOD at 30°C with benzyl alcohol (BnOH) as the initiator and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as the catalyst can afford high molar mass PTOD with a cis-2.4-disubstitued 2-methyl 1,3-dioxolane moiety in its repeating unit. PTOD is an amorphous polymer with a glass transition temperature (Tg ) of 13°C. It can be hydrolyzed into structurally defined small molecules under acidic or basic conditions by the selective cleavage of either the cyclic ketal or the ester linkage respectively. The TBD-catalyzed copolymerization of L-lactide (L-LA) and TOD at -20°C was investigated. It was confirmed that L-LA polymerized quickly with racemization to form PLA, followed by a slow incorporation of TOD into the formed PLA chains via transesterification. By varying the feed ratios of L-LA to TOD, a series of random copolymers (PLA-co-PTOD) with different TOD incorporation ratios and tunable Tg s were obtained. Under acidic conditions, PLA-co-PTOD degrades much faster than PLA via the selective cleavage of the cyclic ketal linkages. This work provides insights for the development of more sustainable and acid-accelerated degradable alternatives to aliphatic polyesters.

Photoredox Catalyzed Single C-F Bond Activation of Trifluoromethyl Ketones: A Solvent Controlled Divergent Access of gem-Difluoromethylene Containing Scaffolds.

Selective defluorinative functionalization of trifluoromethyl ketones is a long-standing challenge owing to the exhaustive mode of the process. To meet the demands for the installation of the gem-difluoromethylene unit for the construction of the molecular architectures of well-known pharmaceuticals and agrochemicals, a distinct pathway is thereby highly desirable. Here, a protocol is introduced that allows the divergent synthesis of gem-difluoromethylene group containing tetrahydrofuran derivatives and linear ketones via single C-F bond activation of trifluoromethyl ketones using visible-light photoredox catalysis in the presence of suitable olefins as trapping partner. The choice of appropriate solvent and catalyst plays a significant role in controlling the divergent behavior of this protocol. Highly reducing photo-excited catalysts are found to be responsible for the generation of α,α-difluoromethyl ketone (DFMK) radicals as the key intermediate via a SET process. This protocol also results in a high diastereoselectivity towards the formation of partially fluorinated cyclic ketal derivatives with simultaneous construction of one C-C and two C-O bonds. State-of-the-art DFT calculations are performed to address the origin of diastereoselectivity as well as the divergence of this protocol.

Design, synthesis, and biological activity of a synthetically accessible analog of aplysiatoxin with an (R)-(−)-carvone-based conformation-controlling unit

Simplified analogs of aplysiatoxin (ATX) such as 10-Me-aplog-1 exhibit potent antiproliferative activity toward human cancer cell lines by activating protein kinase C (PKC). However, the synthesis of 10-Me-aplog-1 involved a 23-step longest linear sequence (LLS). Therefore, we have been working toward the development of a more synthetically accessible analog of ATX. In this study, we designed a new analog of ATX wherein a cyclic ketal moiety derived from (R)-(-)-carvone replaced the spiroketal moiety in 18-deoxy-aplog-1. The new analog's synthesis proceeded in an 8-step LLS. Although the configuration at position 3 of the cyclic ketal in the (R)-(-)-carvone-based analog was opposite to those of ATX and 18-deoxy-aplog-1, the antiproliferative activity toward human cancer cell lines of the carvone-based analog was comparable with that of 18-deoxy-aplog-1. The obtained results indicate the potential of the carvone-based analog as a basis for discovering PKC-targeting molecules requiring a decreased number of synthetic steps.

Long-Range Self-Assembly of an Electron-Deficient Hexaazatrinaphthylene with Out-of-Plane Substituents.

The unprecedented time-dependent long-range supramol-ecular assembly of electron-deficient hexaazatrinaphthylene (HATN) core based on peripheral crowding with three out-of-plane cyclic ketals is reported. The single-crystal X-ray structure of the diethyl derivative provided detailed information as to how four molecules in a repeating unit were packed in order to avoid steric crowding of the out-of-plane cyclic ketal side chain, providing locking and fastening for stabilizing the self-assembled structure. The polarizing optical microscopy (POM) and differential scanning calorimetry (DSC) did not instantaneously show any phase transition upon the cooling process. To our surprise, POM images showed a nucleation of spherulite up to 100 μm after 24 hour later. X-ray diffraction data further confirmed that these soft crystal formed a hexagonal-like crystal. The long-range self-assembly of the new material showed a slight red shift in the UV-vis absorption spectra and further substantiated by computational method.

Design of Safe Nanotherapeutics for the Excretion of Excess Systemic Toxic Iron.

Chronic transfusion of red blood cells (RBCs) to patients with β-thalassemia, sickle cell disease, and other acquired anemic disorders generates significant amounts of bioactive iron deposits in the body. The inactivation and excretion of redox active iron(III) from the blood pool and organs are critical to prevent organ damage, and are the focus of iron chelation therapy (ICT) using low molecular weight Fe(III) specific chelators. However, the current ICT is suboptimal because of the short circulation time of chelators, toxicity, severe side effects, difficult regime of administration, and patient noncompliance. To address this issue, we have designed long circulating and biodegradable nanoconjugates with enhanced circulation time and well-defined biodegradability to improve iron excretion and avoid nonspecific organ accumulation. A series of iron chelating nanoconjugates were generated with deferoxamine (DFO) as the iron(III) specific chelator using polymer scaffolds containing structurally different acidic pH sensitive ketal groups. The type of degradation linkages used in the polymer scaffold significantly influenced the vascular residence time, biodistribution, and mode of excretion of chelators in mice. Remarkably, the conjugate, BGD-60 (140 kDa; Rh, 10.6 nm; cyclic ketal), exhibited the long circulation half-life (t1/2β, 64 h), a 768-fold increase compared to DFO, and showed minimal polymer accumulation in major organs. The nanoconjugates were found to be nontoxic and excreted iron significantly better than DFO in iron overloaded mice. BGD-60 showed greater iron mobilization from plasma (p = 0.0390), spleen (p < 0.0001), and pancreas (p < 0.0001) whereas BDD-200 (340 kDa; Rh, 13.7 nm; linear ketal) mobilized iron significantly better from the spleen, liver, and pancreas (p < 0.0001, p < 0.0001, and p < 0.0001, respectively) compared to DFO at equivalent doses. The nanoconjugate’s favorable long blood circulation time, biodegradability, and iron excretion profiles highlight their potential for future clinical translation.

Acid-activated clay as heterogeneous and reusable catalyst for the synthesis ofbioactive cyclic ketal derivatives

A new heterogeneous acid catalyst based on a natural resource, Tunisian clay (Clay-H0.5), has been prepared and characterized by FT-IR, FE-SEM, and powder X-ray diffraction (XRD), as well as chemical composition, cation exchange capacity, specific surface area, and pore volume. Acid treatment for 0.5 h enlarged the surface area from 78.24 to 186.10 m$^{2}$/g and pore volume (PV) from 0.186 to 0.281 cm$^{3}$/g. The catalytic activity of this material was investigated in ketalization reaction under mild solvent-free conditions. This achieved up to 92% isolated yield for only 10 wt.% of the catalyst. This environmentally friendly method has advantages such as simple work-up procedure, avoidance of organic solvents, and good performance in ketalization reactions. Importantly, the Clay-H0.5 catalyst showed good recyclability where insignificant activity loss was exhibited even after six runs. Synthesized cyclic ketals were tested for their possible antileishmanial and antibacterial activities as well as antifungal activity. Biological screening showed that compound 11 had important antileishmanial activity against both L. major and L. infantum, while compound 14 also had significant antibacterial activity against four gram-positive and two gram-negative bacteria, and antifungal activity against Candida albicans, with minimal inhibitory concentration values ranging from 15.62 μg/mL to 125 μg/mL.

Highly Efficient Acetalization and Ketalization Catalyzed by Cobaloxime under Solvent-Free Condition

An efficient catalytic system was developed for the acetalization and ketalization of carbonyl compounds with polyhydric alcohols under mild solvent-free conditions. In the presence of 0.1 mol% CoCl2 and 0.2 mol% dimethylglyoxime at 70 °C under 5 KPa pressure for 1 h, 95.3% conversion of cyclohexanone and 100% selectivity of the corresponding cyclic ketal could be obtained, where TOF reached as high as 953 h−1. It is proposed that the in situ generated planartetracoordinate cobaloxime played the key role in the catalytic cycle and was responsible for the excellent catalytic performance.

Attempted [2]Catenane Synthesis via a Quasi[1]catenane by a Templated Backfolding Strategy

A templated backfolding concept to construct a [2]catenane was attempted via a quasi[1]catenane showing an inverted spiro geometry. The template is covalently connected to the ketal‐connected semi‐perpendicular‐arranged linear precursors and spatially directs the sterically congested backfolding macrocyclizations that are required to give a quasi[1]catenane. So far, we are unable to hydrolyze the cyclic ketal to liberate the [2]catenane.

Palladium on Carbon-Catalyzed Benzylic Methoxylation for Synthesis of Mixed Acetals and Orthoesters.

The palladium on carbon (Pd/C)-catalyzed direct methoxylation of the benzylic positions of linear benzyl and cyclic ether substrates proceeded in the presence of i-Pr2 NEt under an oxygen atmosphere to give the corresponding mixed acetals. Cyclic acetal derivatives could also be converted into orthoesters. The present direct methoxylation via a carbon-hydrogen (C-H) functionalization can be accomplished using the easily-removed Pd/C and molecular oxygen as a green oxidant. The obtained mixed acetals were transformed into the corresponding ether products by chemoselective substitution of the methoxy group using a silyltriflate, 2,4,6-collidine, and a nucleophile. The orthoester derivative could also be transformed into the cyclic ketal under similar reaction conditions.

New Lubricant from Used Cooking Oil: Cyclic Ketal of Ethyl 9,10-Dihydroxyoctadecanoate

A new ketal cyclic from ethyl 9,10-dihydroxyoctadecanoate with acetone had been synthesized by reflux and sonochemical method. The synthesis was performed via several steps of reaction, i.e.: transesterification, hydrolysis, oxidation with 1% KMnO4 in basic condition, esterification, and ketalization. The structures of the products were confirmed by FTIR, GC-MS, 1H- and 13C-NMR spectrometers. Direct transesterification of used cooking oil produced a mixture of ethyl ester in 82.94% yield meanwhile hydrolysis of this mixture gave free fatty acids mixture in 88.46% yield. Hydroxylation reaction of free fatty acids mixture yielded a white powder of 9,10-dihydroxyoctadecanoic acid in 46.52% yield. Esterification of 9,10-dihydroxyoctadecanoic acid and ethanol catalyzed by sulfuric acid with reflux condition for 4 hours and sonochemical method, respectively yielded 90% and 93.8% of ethyl 9,10-dihydroxystearate. In the other side, the utilization of KSF montmorillonite as catalyst conducted with reflux gave 52% in yield of ester. Furthermore, the use of acetone in 45 minutes sonochemical method with montmorillonite KSF catalyst gave cyclic ketal (ethyl 8-(2,2-dimethyl-5-octyl-1,3-dioxolan-4-yl)octanoate) as a yellow viscous liquid in 53.30% yield. From physicochemical properties –density, kinematic viscosity, viscosity index, total acid number, total base number and iodine value- gave the conclusion that this novel compound is potential biolubricant candidates to be developed.

ChemInform Abstract: New Approach to the Synthesis of 1,3‐Dioxolanes

Abstractusing transketalization reactions of ketal (III)

New approach to the synthesis of 1,3-dioxolanes

Application of ethanol to the synthesis of 1,3-dioxolanes by the condensation of carbonyl compounds with vicinal diols results in a high yield of the reaction product and considerably reduces the duration of the process. It is assumed that the effect of the ethanol is caused by the adduct formation with carbonyl compounds (hemiacetals) which behave as active intermediates of the condensation. A cyclic ketal of acetone with glycerol obtained with the help of ethanol was used as a basis component in the synthesis of a series of ketals substituting diol or carbonyl components by transketalyzation mechanism proceeding without water liberation.

Protein extraction by Winsor‐III microemulsion systems

Proteins (bovine serum albumin (BSA), α-chymotrypsin, cytochrome c, and lysozyme) were extracted from 0.5 to 2.0 g L(-1) aqueous solution by adding an equal volume of isooctane solution that contained a surfactant mixture (Aerosol-OT, or AOT, and a 1,3-dioxolane (or cyclic ketal) alkyl ethoxylate, CK-2,13-E5.6), producing a three-phase (Winsor-III) microemulsion with a middle, bicontinuous microemulsion, phase highly concentrated in protein (5-13 g L(-1)) and small in volume (12-20% of entire volume). Greater than 90% forward extraction was achieved within a few minutes. Robust W-III microemulsion systems were formulated at 40°C, or at 25°C by including a surfactant with shorter ethoxylate length, CK-2,13-E3 , or 1.5% NaCl (aq). Successful forward extraction correlated with high partitioning of AOT in the middle phase (>95%). The driving force for forward extraction was mainly electrostatic attractions imposed by the anionic surfactant AOT, with the exception of BSA at high ionic strength, which interacted via hydrophobic interactions. Through use of aqueous stripping solutions of high ionic strength (5.0 wt %) and/or pH 12.0 (to negate the electrostatic attractive driving force), cytochrome c and α-chymotrypsin were back extracted from the middle phase at >75% by mass, with the specific activity of recovered α-chymotrypsin being >90% of its original value.

Ketalization of glycerol to solketal in supercritical acetone

In the last few years, the increasing production of biodiesel has led to an overproduction of glycerol, the main byproduct of this industry. This paper reports on the ketalization of glycerol in supercritical acetone to give solketal (4-hydroxymethyl-2,2-dimethyl-1,3-dioxolane), an oxygenated compound useful as chemical and fuel additive for gasoline, diesel and biodiesel. The application of supercritical fluids (SCFs) in the chemical synthesis was explored to carry out reactions to obtain the above cyclic ketal. The experimental results reveal a drastic change in the reaction behavior when the critical condition of acetone is reached ( T = 508 K). Below 508 K the reaction rate of solketal production is very low, but above this temperature a rapid increase in the reaction rate is observed. Finally, the reaction rate is stabilized at 533 K and higher temperatures due to the conversion of glycerol to acrolein and polymeric products as side reactions.

Amphiphilic Block Co-polyesters Bearing Pendant Cyclic Ketal Groups as Nanocarriers for Controlled Release of Camptothecin

Amphiphilic block co-polymers consisting of hydrophilic poly(ethylene glycol) and hydrophobic polyester bearing pendent cyclic ketals were synthesized by ring-opening co-polymerization of ε-caprolactone (CL) and 1,4,8-trioxaspiro-[4,6]-9-undecanone (TSU) using α-hydroxyl, ω-methoxy, poly(ethylene glycol) as the initiator and stannous octoate as the catalyst. Compositional analyses indicate that TSU was randomly distributed in the hydrophobic blocks. When the TSU content in the co-polymers increased, the polymer crystallinity decreased progressively and the glass transition temperature increased accordingly. The hydrophobic, anticancer drug, camptothecin (CPT), was successfully encapsulated in the block copolymer nanoparticles. The CPT encapsulation efficiency and release kinetics were strongly dependent on the co-polymer composition and crystallinity. CPT release from nanoparticles constructed from co-polymers containing 0, 39 and 100 mol% TSU in the hydrophobic block followed the same trend, with an initial burst of approx. 40% within one day followed by a moderate and slow release lasting up to 7 days. At a TSU content of 14 mol%, CPT was released in a continuous and controlled fashion with a reduced initial burst and a 73% cumulative release by day 7. The in vitro cytoxicity assay showed that the blank nanoparticles were not toxic to the cultured bone metastatic prostate cancer cells (C4-2B). Compared to the free drug, the encapsulated CPT was more effective in inducing apoptotic responses in C4-2B cells. Modulating the physical characteristics of the amphiphilic co-polymers via co-polymerization offers a facile method for controlling the bioavailability of anticancer drugs, ultimately increasing effectiveness and minimizing toxicity.

Synthesis of exo enol ether-cyclic ketal isomers of substituted furanmethanol structures related to marine furanocembranoids

Oxidations of the 2-alkenylfurans 8a and 8b, using peroxy reagents, lead to the dienedione 9 and the furan epoxide 10, respectively. Treatment of the epoxide 10 with p-TSA in MeOH produces the enol ether cyclic ketal 12, which is rapidly isomerised to the furanmethanol ether 15, isolated in 80% yield. By contrast, when the propanol-substituted furan epoxide 23 was kept in CDCl3 containing traces of HCl for 2 h, a 3:2 mixture of Z- and E-isomers of the enol ether spiro ketals 25a and 25b was produced in >92% yield; after 24 h this mixture of isomers underwent dehydration leading to the corresponding enol ether triene 26 (70%). When a solution of the dienedione 9 in H2O–THF containing p-TSA was stirred at 25 °C for 20 h, the tertiary alcohol 27 was produced which, after a further 20 h was converted into the furan vicinal diol 29. Likewise, when the ‘cembranoid’ dienedione 31 was treated with p-TSA–H2O, the hydroxymethyl-substituted furanobutenolide 33 was produced in 40% yield. It is probable that the enol ether cyclic hemiketals 28 and 32/34, which are related to 12 and 25, and also to the naturally occurring cembranoids 1 and 2 found in corals, are transient intermediates in the conversions leading to 29 and 33 from 9 and 31, respectively.

Synthesis of the northern sector (C8–C19) of rapamycin via Chan rearrangement and oxidation of an α-acyloxyacetate

Two routes to the masked tricarbonyl segment of the immunosuppressant rapamycin comprising C8–C19 were explored beginning from d-xylose. The first approach employed a protected form of 2,4,5-trihydroxypentanol to obtain dithiane 43, which failed to react with dimethyl oxalate to give a 1,2,3-tricarbonyl unit corresponding to the northern sector of rapamycin. A second approach employing carboxylic acid 61 derived from 43 utilized base-mediated (Chan) rearrangement of α-acyloxyacetate 62 with trapping of the resultant enediolate as bis silyl ether 63. Epoxidation of this diene afforded masked tri-keto ester 65 which underwent acid-catalyzed methanolysis to produce cyclic ketal 67.

Isolation of Sulfated Galactan from Codium fragile and Its Antiviral Effect

A sulfated galactan (FG) was isolated from the green alga, Codium fragile. Chemical analysis revealed that FG mainly consisted of D-galactose with pyruvic acid (12.3%) and sulfate (11.0%). Methylation and NMR analyses showed that FG was composed of -->3)-beta-D-Galp-(1-->, beta-D-Galp-(1--> and -->3,6)-beta-D-Galp-(1--> residue. In addition, pyruvic acid was suggested to be present as (1'-carboxy)-ethylidene cyclic ketal at O-3 and O-4 of non-reducing terminal galactose residues, whereas sulfate was substituted at O-4 of other galactose residues. When the antiviral potency of FG was evaluated, it inhibited the replication of herpes simplex virus type 2 (HSV-2), and the mechanism of action was suggested to be interference in the early steps such as virus adsorption to and penetration into host cells. Furthermore, it was shown that FG directly reduced virus infection rates. In a genital infection model using HSV-2-infected mice, FG improved mortality and lesion scores and reduced virus yields by intravaginal administration. These results suggest that FG might be a potent candidate as a prophylactic agent for HSV-2 infection.

Three-component microemulsions formed using pH-degradable 1,3-dioxolane alkyl ethoxylate surfactants

A series of three nonionic surfactants which undergo acid-catalyzed hydrolysis, O-[(2,2-dialkyl-1,3-dioxolan-4-yl) methoxy] – O′-methoxy poly(ethylene glycol), or cyclic ketal (CK), were synthesized. The surfactants shared similar HLB values (9.2–9.8) but differed in the relative length of their two alkyl tails. Water/CK/isooctane microemulsion systems formed by each of the three surfactants also shared similar phase behavior, physical properties, and surfactant hydrolysis kinetics. The apparent critical microemulsion concentration for three CK surfactants, 0.060–0.075 g g −1 (in both water and isooctane), and the efficiency, the minimum amount of surfactant required to totally mix water and oil into single microemulsion phase, 0.35–0.40 g g −1, are significantly higher than values possessed by regular, linear, alkyl ethoxylate surfactants. The underlying causes for the high values were investigated. Due to the broad distribution of its ethoxylate head group size, CK surfactants were distributed among all phases within two- and three-phases systems, with CKs possessing shorter ethoxylate groups partitioning to the oil phase and CKs with larger ethoxylate groups to the aqueous phase. Small-angle neutron scattering experiments suggest that CK exists as monomers or very small pre-micellar aggregates in isooctane at 12% and as ellipsoidal aggregates in water at 2.5–25%. Surface pressure versus surface area measurements of CK surfactant monolayers at the water-air interface demonstrate two differences from linear alkyl ethoxylate monolayers: the occurrence of a collapse at moderately low surface pressure (30 mN m −1) and high surface area per molecule (0.59 nm 2) and the inability to undergo dissolution when subjected to a constant, moderately high surface pressure (25 mN m −1). The results suggest that CK molecules are not able to pack as efficiently as linear alkyl ethoxylates at interfaces, and are strongly anchored to monolayers in aqueous media.

The Self‐Ordering Properties of Novel Phthalocyanines with Out‐of‐Plane Alkyl Substituents

Two novel homologous series of phthalocyanines were prepared from 2,2-dialkylindane and 2,2-dialkyl-1,3-benzodioxole precursors. It was anticipated that attaching alkyl chains to five-membered rings, fused to the peripheral sites of the phthalocyanine ring, would result in the adoption of an out-of-plane configuration and thereby discourage cofacial aggregation, to provide an analogy with picket-fence porphyrins. This strategy proved partially successful. Some members of the series of phthalocyanines derived from 2,2-dialkyl-1,3-benzodioxoles, in which the alkyl chains are linked to the phthalocyanine via a cyclic ketal, form spin-coated thin films in which the phthalocyanine cores are perfectly isolated. This behaviour is associated with the formation of a disordered crystal that appears as a mesophase in the thermal profile of these materials. However, the phthalocyanines derived from 2,2-dialkylindanes display a columnar mesophase over a wide temperature range, with some liquid crystalline derivatives at ambient temperature. A single-crystal X-ray diffraction structure of the octahexyl derivative of this series shows how the columnar assembly accommodates the out-of-plane alkyl chains by tilting the macrocyclic plane of the phthalocyanine components with respect to the axis of the column. This study helps to emphasise the importance of both the steric and electronic effects of substituents on the packing behaviour of phthalocyanines in the condensed phase, and especially the role of electron-donating oxygen atoms directly attached to the ring.