Deoxygenation of polyhydroxybenzenes: an alternative strategy for the benzene-free synthesis of aromatic chemicals

New synthetic connections have been established between glucose and aromatic chemicals such as pyrogallol, hydroquinone, and resorcinol. The centerpiece of this approach is the removal of one oxygen atom from 1,2,3,4-tetrahydroxybenzene, hydroxyhydroquinone, and phloroglucinol methyl ether to form pyrogallol, hydroquinone, and resorcinol, respectively. Deoxygenations are accomplished by Rh-catalyzed hydrogenation of the starting polyhydroxybenzenes followed by acid-catalyzed dehydration of putative dihydro intermediates. Pyrogallol synthesis consists of converting glucose into myo-inositol, oxidation to myo-2-inosose, dehydration to 1,2,3,4-tetrahydroxybenzene, and deoxygenation to form pyrogallol. Synthesis of pyrogallol via myo-2-inosose requires 4 enzyme-catalyzed and 2 chemical steps. For comparison, synthesis of pyrogallol from glucose via gallic acid intermediacy and the shikimate pathway requires at least 20 enzyme-catalyzed steps. A new benzene-free synthesis of hydroquinone employs conversion of glucose into 2-deoxy-scyllo-inosose, dehydration of this inosose to hydroxyhydroquinone, and subsequent deoxygenation to form hydroquinone. Synthesis of hydroquinone via 2-deoxy-scyllo-inosose requires 2 enzyme-catalyzed and 2 chemical steps. By contrast, synthesis of hydroquinone using the shikimate pathway and intermediacy of quinic acid requires 18 enzyme-catalyzed steps and 1 chemical step. Methylation of triacetic acid lactone, cyclization, and regioselective deoxygenation of phloroglucinol methyl ether affords resorcinol. Given the ability to synthesize triacetic acid lactone from glucose, this constitutes the first benzene-free route for the synthesis of resorcinol.     

Studies toward the biomimetic synthesis of tropolone natural products via a hetero Diels-Alder reaction

Analogues of the tropolone natural products pycnidione and epolone B were synthesized via a hetero Diels-Alder reaction of benzotropolone 10 with humulene. The quinone methide benzotropolone 13 was generated in situ by thermalisation of benzotropolone 10. Benzotropolone 10 was derived from phthalic acid via carbonyl ylide 8a followed by an intramolecular 1,3-dipolar cycloaddition and subsequent acid-catalyzed ring opening.     

A computational investigation of the hydrogenation of imines catalyzed by rhodium thiolate complexes

The mechanism of imine hydrogenation catalyzed by thiolate complexes of Rh(III) bearing a hydrotris(3,5‐dimethylpyrazolyl)borato ligand has been investigated via the density functional theory calculations. The overall catalytic cycle for heterolytic cleavage of H₂ and hydrogenation of N‐benzylidenemethylamine by the model catalyst [TpRh(bdt)MeCN)] is presented in detail. The results show that the reaction proceeds via an ionic mechanism through three steps: formation of dihydrogen complex, protonation of imine and the hydride transfer process. Protonation of imine occurs after the formation of Rh(H)‐S(H) moiety. For the whole catalytic cycle, the heterolytic splitting of dihydrogen is the step with the highest free energy barrier. © 2014 Wiley Periodicals, Inc.     

Mechanism of Ru(II)-catalyzed olefin insertion and C-H activation from quantum chemical studies

The mechanism of catalytic hydroarylation of olefins by the homogeneous Ru(Tp)(CO)(Ph)(NCCH3) catalyst recently reported by Gunnoe et al. is characterized using quantum mechanics (density functional theory). The catalytic cycle features two key steps, 1,2-olefin insertion and C-H activation via an unusual mechanism, oxidative hydrogen migration. We find that these two key steps are competitive and that improving the rate of one step is detrimental to the rate of the other. The Ru catalyst has better balance and consequently higher activity than the previously explored Ir-based system.     

Improved Synthesis of 5,5-Diamino BINAP and Application to Asymmetric Hydrogenation

5,5-Diamino BINAP has been synthesized via three steps using BINAPO as starting material with high reaction yield. Present method needed only a stoichiometric quantity of nitric acid in the step of nitration of BINAPO, giving almost quantitative reaction yield. Based on 5,5-diamino BINAP, other three new BINAP derivatives have been synthesized. These modified BINAP ligands showed better catalytic properties as compared to BINAP itself in the asymmetric hydrogenation of 2-(6‘-methoxyl-2‘-naphthyl)acrylic acid.     

Insights into the reaction mechanism of soluble epoxide hydrolase from theoretical active site mutants

Density functional theory calculations of active site mutants are used to gain insights into the reaction mechanism of the soluble epoxide hydrolases (sEHs). The quantum chemical model is based on the X-ray crystal structure of the human soluble epoxide hydrolase. The role of two conserved active site tyrosines is explored through in silico single and double mutations to phenylalanine. Full potential energy curves for hydrolysis of (1S,2S)-beta-methylstyrene oxide are presented. The results indicate that the two active site tyrosines act in concert to lower the activation barrier for the alkylation step. For the wild-type and three different tyrosine mutant models, the regioselectivity of epoxide opening is compared for the substrates (1S,2S)-beta-methylstyrene oxide and (S)-styrene oxide. An additional part of our study focuses on the importance of the catalytic histidine for the alkylation half-reaction. Different models are presented to explore the protonation state of the catalytic histidine in the alkylation step and to evaluate the possibility of an interaction between the nucleophilic aspartate and the catalytic histidine.     

Concise synthesis of telmisartan via decarboxylative cross-coupling

An efficient synthesis of the angiotensin II receptor antagonist telmisartan is presented involving a decarboxylative cross-coupling of isopropyl phthalate (1) with 2-(4-chlorophenyl)-1,3-dioxolane (2c) as the key step (85% yield). The benzimidazole moiety is constructed regioselectively via a reductive amination-condensation sequence, replacing the previously published route via alkylation of the preformed benzimidazole. The product is obtained in an overall yield of 35% in a convergent synthesis with the longest sequence consisting of eight steps.     

An efficient nonisocyanate route to polyurethanes via thiol‐ene self‐addition

A novel and efficient strategy for the synthesis of nonisocyanate polyurethanes has been developed via thiol–ene self‐photopolymerization. An aliphatic thiol–ene carbamate monomer (allyl(2‐mercaptoethyl)carbamate, AMC) was synthesized by a one‐step synthesis procedure, from cysteamine and allyl chloroformate. The urethane group was therefore incorporated directly into the monomer precursor, avoiding the problems associated to toxic isocyanates. AMC was successfully stabilized with the radical inhibitor pyrogallol (1% wt). In addition, the use of phenyl phosphonic acid as coadditive allowed its stabilization for lower concentrations of pyrogallol (0.1% wt). AMC was directly transformed into thermoplastic polyurethane (TPU) through thiol–ene photopolymerization by UV‐irradiation at 365 nm. The obtained TPU presented semi‐crystalline nature and very high thermal stability (T_5% ～325 °C). It was found that high concentrations of pyrogallol decreased the reaction rate and final conversion of photopolymerization. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 3017–3025     

Solvent-free, direct synthesis of supramolecular nano-capsules

The single step direct synthesis of pyrogallol[4]arene via a solvent free protocol yields the pure product as a self-assembled nano-capsule, comprised of six macrocyclic building blocks.     

Edge plane sites on highly ordered pyrolytic graphite as templates for making palladium nanowires via electrochemical decoration

An approach for the fabrication of metal nanowires is presented. Palladium wires with diameters less than 50 nm were produced by electrochemical decoration of step edge sites on the surface of highly ordered pyrolytic graphite via the following three steps. First an electrochemical activation step was used to oxidize the edge plane sites on highly ordered pyrolytic graphite surfaces in 0.5 M Na(2)SO(4). Second, a potential cycling step in a 1 mM PdCl(2) solution in 0.1 M H(2)SO(4) was used to form palladium oxide (s) and/or complexes of Pd on the step edges. Third, Pd nanowires were formed by electroreduction after transfer of the graphite to 0.1 M H(2)SO(4). The resulting wires showed a high degree of uniformity. A merit of this approach is that it allowed metal nanowires to be fabricated without the simultaneous formation of nanoparticles on the basal plane terraces, in contrast to other studies of this type. The mesoscopic palladium wires are shown to be useful for the electrochemical sensing of hydrazine.     

Toward a catalytic cycle for the Mn-salen mediated alkene epoxidation: a computational approach

BP86 density functional calculations for the title reaction are presented, where a model catalyst with hypochlorite as oxygen-containing counter ligand, (ClO)(O)Mn(acacen') (acacen' = -O(CH)3N-C2H4-N(CH)3O-), is employed. The epoxidation reaction on potential energy surfaces corresponding to an overall spin-density of two and four unpaired electrons is investigated. The presence of the hypochlorite ligand is found to cause the reaction to proceed under conservation of spin. Further, the oxygen-containing counter ligand causes reoxidation of the Mn-center, thus closing the catalytic cycle. A catalytic scheme is therefore proposed, which includes a step of regeneration of the catalytically active species. Energetic estimates including corrections for solvent effects are presented for the relevant steps constituting the proposed catalytic scheme.     

A stereoselective approach to optically active butenolides by Horner–Wadsworth–Emmons olefination reaction of α-hydroxy ketones

Di- and trisubstituted butenolides and tricyclic unsaturated lactones, of high enantiomeric excess were prepared via the efficient sequential esterification Horner–Wadsworth–Emmons reaction of enantiomerically enriched 2-hydroxy-substituted phenones and aromatic cyclic α-hydroxy ketones in good yield.     

Theoretical modeling study for the phosphonylation mechanisms of the catalytic triad of acetylcholinesterase by sarin

Potential energy surfaces for the process of phosphonylation of the catalytic triad of acetylcholinesterase by sarin have been explored at the B3LYP/6-311G(d,p) level of theory through a computational study. It is concluded that the phosphonylation process involves a critical addition-elimination mechanism. The first nucleophilic addition process is the rate-determining step. The following elimination process of the fluoride ion comprises a composite reaction that includes several steps, and it occurs rapidly by comparison with the rate-determining step. The mobility characteristics of histidine play an important role in the reaction. A double proton-transfer mechanism is proposed for the catalytic triad during the phosphonylation process of sarin on AChE. The effect of aqueous solvation has been considered via the polarizable continuum model (PCM). One concludes that the energy barriers are generally lowered in solvent, compared to the gas-phase reactions.     

Studien zur Benzotropolonbildung aus 3-Hydroxy-o-benzochinon

Zusammenfassung Die Benzotropolonbildung aus Brenzcatechin- und Pyrogallolderivaten hängt von Art, Größe und Stellung der Substituenten in den Reaktionspartnern ab. Nur in die 5-Stellung des Pyrogallols können elektrophile Substituenten eingebaut werden, ohne daß die Fähigkeit zur Benzotropolonbildung verlorengeht. Dieses Verhalten wird durch die Symmetrie der elektronischen Struktur des als 1,3-Dipol wirkenden Anions erklärt.In 4- und 6-Stellung durch Methyl-, Äthyl- und Phenylgruppen substituierte Pyrogallole liefern mit 3-Methoxy-o-benzochinon Benzotropolone; Isopropyl- undtert. Butylgruppen in den gleichen Positionen verhindern aus sterischen Gründen die Benzotropolonbildung.Es wird versucht, aus der Produktanalyse von Benzotropolongemischen, die durch oxydative Verknüpfung von Brenzcatechinderivaten mit Pyrogallolderivaten hervorgegangen sind, Einblick in die den Mechanismus bestimmenden Faktoren zu erhalten. Verbindliche Aussagen hierüber werden durch die mangelhaften Stoffbildungen unmöglich gemacht.

---

The formation of benzotropolone compounds from catechol and pyrogallol derivatives depends upon the type, size, and position of the substituents in the reactants. Electrophilic substituents can be installed only in the 5-position of pyrogallol without loosing the capability of forming benzotropolones. This behavior is explained by the symmetrical electronic structure of the anion acting as 1.3-dipole.Pyrogallols, substituted in the 4- and 6-position by either methyl-, ethyl- or phenyl-groups, yield benzotropolones with 3-methoxy-o-benzoquinone. Isopropyl- andtert. butyl-groups in the same positions hinder benzotropolone formation because of steric hindrance. It was attempted to clarify the effect of the factors on the reaction mechanism by analysis of mixtures of benzotropolones, formed by oxidative coupling of catechol derivatives with pyrogallol-derivatives. On account of deficient yields this could not be done.

---

---

Fritz Wessely in herzlicher Verbundenheit zum 70. Geburtstag gewidmet.

---

28. Mitt.:L. Horner undK. H. Weber, Chem. Ber., z. Zt. im Druck.     

Total synthesis of +/--hyphodermins A and D

An efficient formal synthesis of (+/-)-hyphodermins A and D, metabolites of Hyphoderma radula, has been completed in 12 and 11 steps, respectively. The tricyclic carbon skeleton of enone 6 was rapidly assembled from diester 11 via an alpha brominationn-elimination sequence followed by anhydride formation. Regioselective reduction of the lactone group of enone 6 with LiAlH(t-BuO) 3 gave lactol 15. Lactol 15 was converted in two steps to (+/-)-hyphodermin D, without the need for complex protection-deprotection strategies. Lactol 15 was converted in three steps to (+/-)-hyphodermin A, via the key step of epoxidation of an enone in the presence of a THP lactol. A combination of NMR and ab initio studies suggests that the structures of hyphodermin C and D should be interchanged.     

Preparation of N-alkylbis(3-aminopropyl)amines by the catalytic hydrogenation of N-alkylbis(cyanoethyl)amines

An improved process for the preparation of N-alkylbis(3-aminopropyl)amines is described. These triamines are of interest as monomers for the condensation polymerization with esterified carbohydrate diacids (aldaric acids) to generate the corresponding poly(4-alkyl-4-azaheptamethylene aldaramides). The triamine synthesis is comprised of two efficient steps and requires no chromatographic purification. Bisconjugate addition of alkylamines to acrylonitrile followed by catalytic hydrogenation of the N-alkylbis(cyanoethyl)amines over Raney nickel yields the target N-alkylbis(3-aminopropyl)amines. Much less solvent was used in the bisconjugate addition step then previously reported, and in the second step, a relatively low-pressure catalytic hydrogenation (50 psi of hydrogen) was employed using Raney nickel as the catalyst in a 7 N methanolic ammonia solvent system to afford the N-alkylbis(3-aminopropyl)amines of high purity in nearly quantitative yield.     

Formal enantioselective synthesis of (+)-estrone

A formal total synthesis of (+)-estrone (4% overall yield; ca. 12 steps) could be achieved via the Torgov diene. An asymmetric allylic substitution is the key step for the construction of the chiral quaternary carbon center of a synthetic intermediate which was converted in four steps to the Torgov diene. [reaction: see text]     

Enantioselective synthesis of (-)-cis-clavicipitic acid

An enantioselective synthetic method for (-)-cis-clavicipitic acid (1) was reported. 1 was obtained in 10 steps (99% ee and 20% overall yield) from 1H-indole-3-carboxylic acid methyl ester (9) via asymmetric phase-transfer catalytic alkylation and diastereoselective Pd(II)-catalyzed intramolecular aminocyclization as key steps.     

Ruthenium-catalyzed propargylic substitution reactions of propargylic alcohols with oxygen-, nitrogen-, and phosphorus-centered nucleophiles

The scope and limitations of the ruthenium-catalyzed propargylic substitution reaction of propargylic alcohols with heteroatom-centered nucleophiles are presented. Oxygen-, nitrogen-, and phosphorus-centered nucleophiles such as alcohols, amines, amides, and phosphine oxide are available for this catalytic reaction. Only the thiolate-bridged diruthenium complexes can work as catalysts for this reaction. Results of some stoichiometric and catalytic reactions indicate that the catalytic propargylic substitution reaction proceeds via an allenylidene complex formed in situ, whereby the attack of nucleophiles to the allenylidene C(gamma) atom is a key step. Investigation of the relative rate constants for the reaction of propargylic alcohols with several para-substituted anilines reveals that the attack of anilines on the allenylidene C(gamma) atom is not involved in the rate-determining step and rather the acidity of conjugated anilines of an alkynyl complex, which is formed after the attack of aniline on the C(gamma) atom, is considered to be the most important factor to determine the rate of this catalytic reaction. The key point to promote this catalytic reaction by using the thiolate-bridged diruthenium complexes is considered to be the ease of the ligand exchange step between a vinylidene ligand on the diruthenium complexes and another propargylic alcohol in the catalytic cycle. The reason why only the thiolate-bridged diruthenium complexes promote the ligand exchange step more easily with respect to other monoruthenium complexes in this catalytic reaction should be that one Ru moiety, which is not involved in the allenylidene formation, works as an electron pool or a mobile ligand to another Ru site. The catalytic procedure presented here provides a versatile, direct, and one-step method for propargylic substitution of propargylic alcohols in contrast to the so far well-known stoichiometric and stepwise Nicholas reaction.     

A concise synthesis of (+)-pancratistatin using pinitol as a chiral building block

A concise approach toward (+)-Pancratistatin has been achieved via 12 steps from pinitol. An ultrasound assisted arylcerium induced ring opening of cyclic sulfate was employed as a key step.