Diastereoisomers of 2-benzyl-2, 3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol: Potential anti-inflammatory agents

The synthesis and biological activity of the novel diastereoisomers of 2-benzyl-2,3-dihydro-2-(1H-inden-2-yl)-1H-inden-1-ol is reported. The 2,2-coupled indane dimers were synthesised by coupling of the silyl enol ether of 1-indanone with the dimethyl ketal of 2-indanone. The coupled product was directly alkylated to give the racemic ketone which was reduced to the diastereoisomeric alcohols. The alcohols were separated and their relative stereochemistry was established by X-ray crystallography. These molecules demonstrate significant anti-inflammatory activity in vivo and in vitro and may represent a new class of anti-inflammatory agent.     

The "heterolytic hydroperoxide lyase" is an isomerase producing a short-lived fatty acid hemiacetal

To elucidate the reaction mechanism of hydroperoxide lyase (HPL), the enzyme from guava (Psidium guajava) fruits, was incubated for 10-60 s at 0 degrees C with 13-HPOT. The products were rapidly extracted and derivatized by trimethylsilylation. Two trapping products, namely the trimethylsilyl ether/ester derivatives of the hemiacetal 12-(1'-hydroxy-3'-hexenyloxy)-9,11-dodecadienoic acid and the enol (9Z,11E)-12-hydroxy-9,11-dodecadienoic acid, were detected by gas chromatography-mass spectrometry (GC-MS) analyses. The structural assignments were supported by mass spectra recorded for (a) hydrogenated products; (b) products biosynthesized from [9,10,12,13,15,16] 13-HPOT or [(18)O(2)]13-HPOT; (c) chemically prepared reference compounds. Kinetic experiments showed that the hemiacetal and enol were both unstable and transiently appearing compounds (half-lives, ca. 20 s and 2 min, respectively). Hemiacetal and enol biosynthesized from [(18)O(2)]13-HPOT retained two and one (18)O atoms, respectively, whereas no (18)O was incorporated from [(18)O]water. The data demonstrated that: (1) the true enzymatic product formed from 13-HPOT in the presence of HPL is a short-lived hemiacetal; (2) the hemiacetal spontaneously dissociates into (3Z)-hexenal and the unstable enol form of (9Z)-12-oxo-9-dodecenoic acid; (3) the enzymatic isomerization of 13-HPOT into the hemiacetal occurs homolytically.     

Palladium-Mediated Coupling Reactions of an Aminosubstituted Heterocycle. Direct Synthesis of C-Nucleosides Related to Adenosine

Abstract

C-Nucleosides of the pyrazolo[1, 5-a]-1, 3, 5-triazine aglycon system have been prepared by palladium-mediated coupling of 8-iodopyrazolo[1, 5-a]-1, 3, 5-triazines. 4-(N, N-Diisobutyloxycarbonyl)amino-8-iodopyrazolo[1, 5-a]-1, 3, 5-triazine and the furanoid glycal 1, 4-anhydro-2-deoxy-3-O[(1, 1 dimethylethyl)diphenylsilyl]-D-erythro-pent-1-enitol coupled in the presence of catalytic palladium(0) to yield, after desilylation of the intermediate silyl enol ether, a C-glycoside analog of adenosine.     

A convenient method for library construction: parallel synthesis of beta-amino ester and quinoline derivatives in liquid phase using Ln(OTf)3-catalyzed three-component reactions

A convenient method for library construction in liquid phase, which is based on lanthanide triflate (Ln(OTf)3)-catalyzed three-component reactions, has been developed. Equimolar amounts of each component, an aldehyde, an amine, and a silyl enol ether or an alkene, react smoothly in the presence of Ln(OTf)3, and the work-up and purification processes are performed by simply passing through a short column. The key is to use Ln(OTf)3 as a Lewis acid catalyst, which is not decomposed during the work-up and purification steps, and is easily separated from products by the simple procedure. According to this method, various high-quality beta-amino ester and quinoline derivatives have been prepared in parallel in large quantities. Copyright 1998 John Wiley & Sons, Inc.     

Silyl linker-based approach to the solid-phase synthesis of Fmoc glycopeptide thioesters

An efficient solid-phase synthesis of Fmoc (glyco)peptide thioesters is described. Fmoc x Ser x OAll and Fmoc x Thr x OAll bound to resin with a silyl ether linker were deallylated by Pd(0) catalysis and condensed with thiophenol, benzyl mercaptane, and ethyl 3-mercaptopropionate by activation with DCC/HOBt. The thioesters were released from the resin either by treatment with CsF-AcOH or by acidic hydrolysis. The effectiveness of this silyl linker strategy is further demonstrated by the synthesis of more complex (glyco)peptide thioesters 25, 26 and 27 involving N-->C and C-->N peptide elongation.     

Asymmetric total synthesis of (+)- and (-)-clusianone and (+)- and (-)-clusianone methyl enol ether via ACC alkylation and evaluation of their anti-HIV activity

The total asymmetric synthesis of (+)- and (−)-clusianone and (+)- and (−)-clusianone methyl enol ether is reported. Asymmetric induction is achieved through the use of ACC alkylation, providing the key intermediates with an er of 99:1. The four synthetic compounds were evaluated for their anti-HIV activity. Both (+)- and (−)-clusianone displayed significant anti-HIV activity.     

Detection of an enol intermediate in the hydroperoxide lyase chain cleavage reaction

Guava (Psidium guajava) hydroperoxide lyase (HPL) preparations were incubated with [1-(14)C](9Z,11E,13S,15Z)-13-hydroperoxy-9,11,15-octadecatrienoic acid for 1 min at 0 degrees C, followed by rapid extraction/trimethylsilylation. Analysis of the trimethylsilylated products by gas chromatography-mass spectrometry and radio-high-performance liquid chromatography revealed a single predominant (14)C-labelled compound, identified by its (1)H-nuclear magnetic resonance, ultraviolet and mass spectra as the trimethylsilyl ether/ester of (9Z,11E)-12-hydroxy-9,11-dodecadienoic acid. Longer time incubations afford smaller yield of this enol due to its partial tautomerization into (9Z)-12-oxo-9-dodecenoic acid. The data obtained demonstrate that formation of (9Z)-12-oxo-9-dodecenoic acid in the HPL reaction is preceded by unstable enol oxylipin, and further suggest that hemiacetals are the true products of HPL catalysis.     

Stereoselective synthesis of C-[2-S-(p-tolyl)-2-thio-beta-D-galactopyranosyl] compounds using the reaction of TolSCl adducts of D-galactal with C-nucleophiles

Pyranosyl chlorides prepared in situ from tri-O-benzyl-D-galactal and TolSCl react with silyl enol ethers, allyltrimethylsilane, and vinyl ethers to give a mixture of beta-C-galacto and alpha-C-talopyranosides in a ratio of 19:1.     

Synthesis of 4-Deoxy-4-C-hydroxymethyl-α-L-Lyxo-Pyranosyl Thymine

Abstract

The synthesis of 1-[4-deoxy-4-C-hydroxymethyl-α-L-lyxopyranosyl]thymine has been accomplished by two synthetic routes both starting from methyl 2, 3-O-isopropylidene-β-D-ribopyranoside. The first route makes use of a ring opening, ring closure reaction sequence to increase the proportion of the desired L-isomers. The second route utilizes the soft nucleophilic character of malonyl anions and ozonolytic cleavage of enol ether to introduce the branched chain. The newly obtained pyranosyl nucleoside obtains a ⁴C₁ conformation with an equatorially oriented thymine moiety.     

Synthesis, crystal structure, and reactivity of a D-xylose based oxepine

The synthesis and X-ray crystal structure of a D-xylose-based oxepine are reported. The oxepine was prepared from 2,3,4-tri-O-benzyl-D-xylose by the three-step sequence (Wittig olefination, vinyl ether formation, and ring closing metathesis) we recently reported. Epoxidation of this cyclic enol ether using dimethyldioxirane (DMDO) gave 1,2-anhydro-beta-D-idoseptanose, which was trapped by a number of nucleophiles to give alpha-idoseptanosides. The stereochemistry of epoxidation was assigned based on product analysis. Spectroscopic data of methyl 2,3,4,5-tetra-O-acetyl-alpha-D-idoseptanoside, derived from the methanolysis product 11, was compared to data of its enantiomer, the known methyl 2,3,4,5-tetra-O-acetyl-alpha-L-idoseptanoside.     

Synthesis of C-glycopyranosyl compounds by a palladium-catalyzed coupling reaction of 1-tributylstannyl-D-glucals with organic halides.

1-Tributylstannyl-D-glucals, prepared from the corresponding 1-phenylsulfonyl-D-glucals, were coupled efficiently to various organic halides in the presence of a palladium(0) catalyst. This mild reaction is specially useful for the preparation of 1-C-aryl-D-glucals and compatible with unprotected hydroxy groups or hindered aromatic bromides. It has been shown that the resulting 1-C-aryl(alkyl)-D-glucals are suited for further synthetic manipulation of the enol ether group, including stereoselective hydrogenation, hydroboration-oxidation, or epoxidation. All compounds formed resulted from the attack of the alpha-face of the glucal derivatives by the reagent. The reaction, extended to 1,3-, 1,4-di-, and 1,3,5-tri-bromobenzenes, leads to the corresponding symmetrical di-(tri)-C-glucosylbenzenes. Finally, a sequential di-C-glucosylation of 1,3-dibromobenzene with two different 1-stannylated glucals was obtained.     

Dipolar solvent relaxation on a nanosecond time scale in ether phospholipid membranes as determined by multifrequency phase and modulation fluorometry

The present study reports on the observation of dipolar solvent relaxation in phospholipid membranes using multifrequency phase and modulation fluorometry. We measured the time-resolved emission spectra of 6-propionyl-2-(dimethylamino)naphthalene (PRODAN) in artificial bilayer membranes of chemically defined acyl-, alkyl-, and alkenyl-substituted phospholipids at 15 degrees C. 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, 3-O-hexadecyl-2-oleoyl-sn-glycero-1-phosphocholine, or 1-O-hexadec-1'-enyl-2-oleoyl-sn-glycero-3-phosphocholine (plasmalogen) were used as matrix lipids. The chemical structures of these lipids differ only with respect to the type of linkage (carboxyl ester, ether, or enol ether bond) between glycerol and the hydrophobic chain linked to the primary hydroxyl of glycerol. At 15 degrees C, all the lipids are in the liquid crystalline state. PRODAN probably localizes at the hydrophobic-hydrophilic interface of the phospholipid bilayer [Chong, P. L. (1988) Biochemistry 27, 399-404]. We found faster solvent relaxation of PRODAN in membranes composed of the ether lipid compared to that in the ester lipid membranes. On the other hand, the fluorescence anisotropies of the label were very similar, showing that the motion of the label itself is similar in ether and carboxyl ester lipids. We conclude that the spectral differences observed for PRODAN in ether and ester lipids could be due to different dipolar relaxation of the immediate surroundings of the label, i.e., reorientation of lipid dipoles in the glycerol region and of water molecules residing therein.     

Enols of aldehydes in the peroxidase/oxidase-promoted generation of excited triplet species

General (acid and base) or specific (fluoride ion) catalysis generates the enol of isobutanal and propanal from the corresponding trimethylsilyl enol ethers. The enols are directly rapidly oxidized by peroxidase (acting as an oxidase) to triplet acetone or triplet acetaldehyde, respectively, and formic acid. Due to the faster rate of reaction and the absence of quenching by excess aldehyde, the excited carbonyl emits more strongly than when the aldehyde itself is the substrate. With both enols the emission is pure phosphorescence. Both triplet acetone and triplet acetaldehyde are generated within the enzyme, as shown by the different quenching by D- and L-tryptophan, and are somewhat protected from oxygen quenching, as attested by the very fact that phosphorescence is observed. The use of enol precursors as substrates opens wide possibilities for photochemical investigations in the absence of light over a much broader range of experimental conditions.     

A selective Sc(OTf)3-catalyzed trialkylsilyl ether to acetyl ester exchange reaction with beta-l-idopyranoside and 3,4-O-isopropylidene-beta-D-galactopyranoside derivatives

The selective silylation of monosaccharide building blocks is useful for preparing complex oligosaccharides. We now report that the diol, methyl (dimethylthexylsilyl 3-O-pivaloyl-beta-L-idopyranosyl)uronate, can be selectively silylated at the O-2 position by trialkylsilyl triflates. After protection of O-4, the O-2 silyl group can be selectively replaced by acetate by taking advantage of a trialkylsilyl-acetate exchange reaction catalyzed by Sc(OTf)3 in the presence of acetic anhydride. The high O-2 selectivity is shown for triethylsilyl (TES), tert-butyldimethylsilyl (TBS), and triisopropylsilyl (TIPS). The selective cleavage reaction only worked well for TES and TBS derivatives. A selection of silyl triflates and silyl chlorides were used as silylating reagents with ethyl 3,4-O-isopropylidene-1-thio-beta-D-galactopyranoside. In most cases, silylation afforded 2,6-di-O-silylated products in high yields. Studies on the cleavage reaction showed that only the primary silylated protecting groups were replaced by acetyl groups. This reaction worked with a variety of silyl protecting groups but not the tert-butyldiphenylsilyl (TBDPS) protecting group. Unfortunately, the 1-thioethyl group was also sensitive to the Sc(OTf)3, leading in these conditions to alpha/beta mixtures of the 1-acetates, which compromised the synthetic utility of this reaction for these compounds. The sequence presented here is a useful synthetic route to differentially protected L-iduronic acid building blocks.     

Transient state kinetics of the reactions of isobutyraldehyde with compounds I and II of horseradish peroxidase

Elementary reactions have been studied quantitatively in the complex overall process catalyzed by horseradish peroxidase whereby isobutyraldehyde and molecular oxygen react to form triplet state acetone and formic acid. The rate constant for the reaction of the enol form of isobutyraldehyde with compound I of peroxidase is (8 +/- 1) X 10(6) M-1 s-1 and with compound II (1.3 +/- 0.3) X 10(6) M-1 s-1. Neither the enolate anion nor the keto form is reactive. The reactivity of enols with peroxidase parallels that of unionized phenols and a common mechanism is proposed. The overall catalyzed reaction of isobutyraldehyde and oxygen consists of an initial burst followed by a steady state phase. The burst is caused by the following sequence: 1) an initial high yield of compound I is formed from reaction of native enzyme with the autoxidation product of isobutyraldehyde, a peracid and 2) compound I rapidly depletes the equilibrium pool of enol which is present. After this burst a steady state phase is observed in which the rate-limiting step is the conversion of the keto to the enol form of the aldehyde catalyzed by phosphate buffer. The rate constant for the keto form reacting with phosphate is (8.7 +/- 0.6) X 10(-5) M-1 s-1. All constants were measured in dilute aqueous ethanol at 35 degrees C, pH 7.4, and ionic strength 0.67 M. Both the initial burst of light and the steady state emission from triplet acetone can be observed with the naked eye. Since the magnitude of the burst is a measure of the equilibrium amount of enol, the keto-enol equilibrium constant is readily calculated and hence also the rate constant for conversion of enol to keto. The keto-enol equilibrium constant is unaffected by phosphate which therefore acts as a true catalyst.     

Syntheses and evaluation of pyridazine and pyrimidine containing bioisosteres of (+/-)-pyrido[3.4-b]homotropane and pyrido-[3.4-b]tropane as novel nAChR ligands.

Bioisosteric replacement of the pyridine pharmacophoric element in (+/-)-pyrido[3.4-b]homotropane (PHT) and pyrido[3.4-b]tropane with the pyridazine and pyrimidine nucleus resulted in hitherto unknown nAChR ligands such as 5-8. Inverse type Diels-Alder reactions constitute the key steps in the new routes to the pyridazine- or pyrimidine-annulated bioisosteres. The enantiopure (+)-2-tropinone (11) from the 'chiral pool' is transformed to the ring-expanded silyl enol ether 12 and to the enamine 15. Both proved to be highly dienophilic species in the inverse type [4+2] cycloaddition reactions with the 1,2,4,5-tetrazines 13 and 16a,b or with the 1,3,5-triazine 19 to provide the enantiopure target compounds 5-7. In the same way the racemic pyrimidine-annulated species 8 was obtained from 3-tropanone 21. The new ligands were tested for their in vitro affinity for (alpha4)2(beta2)3 and alpha7* nAChR subtype. In comparison to PHT, well known to exhibit affinity for agonist binding sites in rat brain approximately equivalent to that of (+)-anatoxin-a (1), replacement of the pyridine by the bioisosteric pyridazine resulted in 30-fold lower affinity at the (alpha4)2(beta2)3 subtype. The annulated diazinotropanes 6-8, ligands with ferruginine-like structures more or less retained the affinity of (-)-norferruginine (3) except of compound 7. Remarkably, all of the novel ligands are devoid of affinity at the alpha7* subtype.     

A lipase‐catalyzed process for green synthesis of temsirolimus

Temsirolimus is an intravenous drug for the treatment of renal cell carcinoma that can be prepared using enol acyl donors, which is not favorable in process development. An improved enzymatic process to prepare temsirolimus has been developed employing lipase‐catalyzed regioselective acylation of rapamycin with environmentally friendly acyl donors. After screening of common commercial lipases and none‐enol acyl donors, it was found that p‐nitrophenyl 2,2,5‐trimethyl‐1,3‐dioxane‐5‐carboxylate reacted as efficient acyl donor when catalyzed by immobilized Thermomyces lanuginose lipase. By optimizing the process conditions (i.e., reaction temperature, solvents, and additives), the reaction time was significantly shortened while the reaction conversion reached 95.4% in methyl tert‐butyl ether after 48 h at 50°C using the new acyl donors. This work demonstrated a cost‐effective, efficient, and scalable process to synthesize temsirolimus.     

Dehydroquinate synthase: the use of substrate analogues to probe the late steps of the catalyzed reaction

The later steps of the proposed mechanistic pathway for the reaction catalyzed by dehydroquinate synthase have been probed by using three substrate analogues. Each of these analogues is structurally prohibited from undergoing the ring-opening reaction that necessarily precedes the carbon-carbon bond-forming step in the overall conversion of the substrate 3-deoxy-D-arabino-heptulosonate 7-phosphate (1) to dehydroquinate (2). Two of the analogues (the 2-deoxy cyclic compound 3 and the carbacyclic material 4) are locked into a cyclic form, mimicking the pyranose form of the substrate DAHP. The third analogue, 5, contains no carbonyl group at C-2 and may thus resemble the open-chain form of DAHP. Analogues 3 and 4 each bind to the enzyme and are competitive inhibitors having Ki values of 35 and 0.12 microM, respectively. More importantly, however, incubation of these analogues with the enzyme leads to the catalytic production of Pi along with the corresponding exomethylene compounds that are analogous to the enol ether IV postulated for the normal synthase reaction. In contrast to these results, the acyclic analogue 5 is neither a substrate nor an inhibitor of the enzyme. These data suggest that the enzyme recognizes and acts upon the alpha-pyranose form of the natural substrate. The ready release of the exomethylene products from the processing of analogues 3 and 4 is consistent with the suggestion of Bartlett and his group that the enzyme may release the enol ether intermediate IV into solution, where the ring opening and cyclization occur nonenzymically. The use of 3 stereospecifically labeled with deuterium at C-7 allows the sterochemical course of the beta-elimination of phosphate to be established. This step proceeds with syn stereochemistry, which fits the pattern of enzyme-catalyzed elimination from substrates where the proton is lost from a position alpha to a ketone, an aldehyde, or a thiolester. Since the overall stereochemical course of the transformation mediated by dehydroquinate synthase had been shown to be inversion, the present finding of a syn elimination suggests that the transition state for the subsequent intramolecular aldol reaction has a chairlike geometry.     

Identification of the enol tautomer of imidazolone propionate as the urocanase reaction product

A fluorescent product was transiently formed during catalysis by urocanase from Pseudomonas putida. The fluorophore showed an emission maximum at 430 nm when excited at 330 nm, essentially identical to that exhibited by the enol tautomer of imidazolone propionate. The keto isomer was not fluorescent under these conditions. In aqueous acid solutions where imidazolone propionate is relatively stable, an equilibrium mixture of tautomeric forms contained approximately 1% of the enol isomer. In ethanolic solutions, the equilibrium concentration of enol tautomer increased to approximately 25%. The differing content of imidazolone propionate tautomers as a function of solvent conditions permitted a comparison of the keto and enol forms as substrates for the reverse reaction. This revealed an almost complete preference for the enol tautomer. These results are taken as direct proof that enol imidazolone propionate is the true urocanase reaction product.