A Straightforward Synthesis of Enantiomerically Pure trans‐2, 5‐Bis(alkyloxymethyl) pyrrolidines by 1, 3‐Dipolar Cycloaddition Reactions of Azomethine Ylides

A new efficient method for the stereoselective preparation of trans‐2,5‐bis(alkyloxymethyl)pyrrolidines ( 7 ) using easily available starting materials is described. The main step of this synthesis is the stereoselective formation of the pyrrolidine ring by the 1,3‐dipolar cycloaddition reaction of an in situ generated azomethine ylide. Both enantiomers of the C₂‐symmetric auxiliaries are prepared separately in a short reaction sequence.     

Biomimetic Formation of 2‐Tropolones by Dioxygenase‐Catalysed Ring Expansion of Substituted 2,4‐Cyclohexadienones

Substituted 2‐tropolone natural products are found in plants and fungi. Their biosynthesis is thought to occur by ring expansion from a cyclohexadienone precursor, but this reaction has not previously been demonstrated experimentally. Treatment of 6‐hydroxy‐6‐hydroxymethylcyclohexa‐2,4‐dienone with the non‐haem iron(II)‐dependent extradiol catechol dioxygenase MhpB from Escherichia coli results in the formation of the 2‐tropolone ring‐expansion product through a pinacol‐type rearrangement. Three further substituted cyclohexa‐2,4‐dienone analogues were prepared, and treatment of each analogue was found to give the substituted 2‐tropolone ring‐expansion product. This ring expansion could also be effected nonenzymatically by treatment with 1,4,7‐triazacyclononane and FeCl₂. This is a novel transformation for non‐haem iron‐dependent enzymes, and this is the first experimental demonstration of the proposed ring‐expansion reaction in tropolone biosynthesis.     

Benzothiazole‐accelerated sulfur vulcanization. I. 2‐Mercaptobenzothiazole as accelerator for 2,3‐dimethyl‐2‐butene

2,3‐Dimethyl‐2‐butene (TME) was used as a model compound for polyisoprene in a study of 2‐mercaptobenzothiazole (MBT)‐accelerated sulfur vulcanization. Mixes that contained curatives only were heated in a DSC to various temperatures, while those that also contained TME were heated isothermally at 150°C in evacuated, sealed glass ampules. Heated mixtures were analyzed for residual curatives, intermediates, and reaction products by HPLC. It is proposed that MBT forms polysulfidic species (BtS_xH) in the presence of sulfur and that these react with TME via a concerted, substitutive reaction pathway to form polysulfidic hydrogen‐terminated pendent groups of varying sulfur rank (TME–S_xH). MBT is released as a by‐product of this reaction. Crosslinking occurs slowly as a result of the interaction of polythiol pendent groups, the rate being dependent on the pendent group concentration. H₂S is released on crosslinking. 2,3‐Dimethyl‐2‐butene–1‐thiol was synthesized and reacted in the presence of sulfur to confirm the formation of crosslinked products (TME–S_x–TME). Benzothiazole‐terminated pendent groups (TME–S_xBt) were not observed. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 76: 1377–1385, 2000     

Zeolite NaY‐Promoted Monocyclization of Epoxy Polyene Terpenes: A Unique Route for the Direct Synthesis of Incompletely Cyclized Naturally Occurring Terpenols

A variety of epoxy polyene terpenes cyclize readily by confinement within zeolite NaY to form primarily products of monocyclization. The monocyclization pathway is highly predominant, irrespectively of the side chain of the epoxy terpene, while the monocyclic products possess regioselectively an exomethylenic double bond. The selective monocyclization in the case of epoxyfarnesyl acetate, epoxyfarnesylacetone or 2,3‐epoxysqualene, provides a direct route to the synthesis of a variety of natural products, such as elengasidiol, farnesiferols B–D, achilleol A, camelliol C and to four farnesylacetone‐derived metabolites isolated from the brown algae Cystophora monoliformis. The optical rotation of achilleol A derived from the cyclization of (S)‐2,3‐epoxysqualene matches with that of the natural product, thus the absolute configuration of achilleol A was established as 1S,3R. From the mechanistic point of view, the NaY‐promoted cyclization of 9,10‐epoxygeranylacetone, selectively deuterium labelled at the C‐10 methyl group, is >97% stereoselective with respect to the topicity of the gem‐dimethyl group. This result is in agreement with a concerted mechanism. Finally, we have proved through labelling experiments, for the first time, that the biomimetic transformation of epoxy polyene terpenes to 2,3,4‐trimethylcyclohexanones upon acid catalysis is a highly stereoselective process. Thus, the less hindered gem‐methyl group on the epoxide functionality becomes α‐ to the carbonyl in the final isomerized product.     

P450 BM3‐Catalyzed Regio‐ and Stereoselective Hydroxylation Aiming at the Synthesis of Phthalides and Isocoumarins

Cytochrome P450 BM3 monooxygenases are able to catalyze the regio‐ and stereoselective oxygenation of a broad range of substrates, with promising potential for synthetic applications. To study the suitability of P450 BM3 variants for stereoselective benzylic hydroxylation of 2‐alkylated benzoic acid esters, the biotransformation of methyl 2‐ethylbenzoate, resulting in both enantiomeric forms of 3‐methylphthalide, was investigated. In the case of methyl 2‐propylbenzoate as a substrate the regioselectivity of the reaction was shifted towards β‐hydroxylation, resulting in the synthesis of enantioenriched R‐ and S‐configured 3‐methylisochroman‐1‐one. The potential of P450 BM3 variants for regio‐ and stereoselective synthesis of phthalides and isocoumarins offers a new route to a class of compounds that are valuable synthons for a variety of natural compounds.     

Substitution of Two Active‐Site Residues Alters C9‐Hydroxylation in a Class II Diterpene Synthase

Diterpenes form a vast and diverse class of natural products of both ecological and economic importance. Class II diterpene synthase (diTPS) enzymes control the committed biosynthetic reactions underlying diterpene chemical diversity. Homology modelling with site‐directed mutagenesis identified two active‐site residues in the horehound (Marrubium vulgare) class II diTPS peregrinol diphosphate synthase (MvCPS1); residue substitutions abolished the unique MvCPS1‐catalysed water‐capture reaction at C9 and redirected enzyme activity toward formation of an alternative product, halima‐5(10),13‐dienyl diphosphate. These findings contributed new insight into the steric interactions that govern diTPS‐catalysed regiospecific oxygenation reactions and highlight the feasibility of diTPS engineering to provide a broader spectrum of bioactive diterpene natural products.     

N,N′‐Pentamethylenethiuram disulfide‐ and N,N′‐pentamethylenethiuram hexasulfide‐accelerated sulfur vulcanization. I. Interaction of curatives in the absence of rubber

N,N′‐pentamethylenethiuram disulfide (CPTD), CPTD/sulfur, and N,N′‐pentamethylenethiuram hexasulfide (CPTP6) were heated in a DSC at a programmed heating rate and isothermally at 140°C. Residual reactants and reaction products were analyzed by HPLC at various temperatures or reaction times. CPTD rapidly formed N,N′‐pentamethylenethiuram monosulfide (CPTM) and N,N′‐pentamethylenethiuram polysulfides (CPTP) of different sulfur rank, CPTP of higher sulfur rank forming sequentially, as reported earlier for tetramethylthiuram disulfide (TMTD). As with TMTD, the high concentration of the accelerator monosulfide that develops is attributed to an exchange between CPTD and sulfenyl radicals, produced on homolysis of CPTD. However, a different mechanism for CPTP formation to that suggested for TMTD is proposed. It is suggested that disulfenyl radicals, resulting from CPTM formation, exchange with CPTD and/or CPTP already formed, to give CPTP of higher sulfur rank. CPTD/sulfur and CPTP6 very rapidly form a similar product spectrum with CPTP of sulfur rank 1–14 being detectable. Unlike with TMTD/sulfur, polysulfides of high sulfur rank did not form sequentially when sulfur was present, CPTP of all sulfur rank being detected after 30 s. It is proposed that sulfur adds directly to thiuram sulfenyl radicals. Recombination with sulfenyl radicals, which would be the most plentiful in the system, would result in highly sulfurated unstable CPTP. CPTP of higher sulfur rank are less stable than are disulfides as persulfenyl radicals are stabilized by cyclization, and the rapid random dissociation of the highly sulfurated CPTP, followed by the rapid random recombination of the radicals, would result in the observed product spectrum. CPTP is thermally less stable than is TMTD and at 140°C decomposed rapidly to N,N′‐pentamethylenethiourea (CPTU), sulfur, and CS₂. At 120°C, little degradation was observed. The zinc complex, zinc bis(pentamethylenedithiocarbamate), did not form at vulcanization temperatures, although limited formation was observed above 170°C. ZnO inhibits degradation of CPTD to CPTU. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 77: 2718–2731, 2000     

Turn‐on chemosensors for silver ions based on oligomers with diaza‐16‐crown 6‐ether receptors and aromatic fluorophore end groups

The reaction of N‐(2,4‐dinitrophenyl)pyridinium chloride ( 1 ), diaza‐18‐crown 6‐ether (DA18C6) and 2,5‐bis(aminophenyl)‐1,3,4‐oxadiazole ( 2 ) caused the opening of the pyridinium ring and yielded an ionic oligomer (oligomer‐1) comprising a 5‐DA18C6‐penta‐2,4‐dienylideneammonium chloride main chain and 2‐(4‐aminophenyl)‐5‐phenyl‐1,3,4‐oxadiazole or 2‐(4‐N‐phenylpyridinium)‐5‐phenyl‐1,3,4‐oxadiazole end groups. Accordingly, the reaction of 1 , DA18C6 and 2,7‐diaminofluorene ( 3 ) yielded oligomer‐2. The structures of oligomer‐1 and oligomer‐2 were determined by comparing their ¹H NMR spectra with those of model compounds, which were synthesized by the 1:1 reaction of 1 with 2 or 3 . Oligomer‐1 and oligomer‐2 exhibited weak bluish‐green photoluminescence (PL) before the inclusion of Ag⁺ in the DA18C6 receptor, after which they exhibited strong bluish‐green PL. These observations can be explained by the occurrence of photoinduced electron transfer in the oligomers. Copyright © 2011 Society of Chemical Industry     

In vitro Characterization of Enzymes Involved in the Synthesis of Nonproteinogenic Residue (2S,3S)‐β‐Methylphenylalanine in Glycopeptide Antibiotic Mannopeptimycin

Mannopeptimycin, a potent drug lead, has superior activity against difficult‐to‐treat multidrug‐resistant Gram‐positive pathogens such as methicillin‐resistant Staphylococcus aureus (MRSA). (2S,3S)‐β‐Methylphenylalanine is a residue in the cyclic hexapeptide core of mannopeptimycin, but the synthesis of this residue is far from clear. We report here on the reaction order and the stereochemical course of reaction in the formation of (2S,3S)‐β‐methylphenylalanine. The reaction is executed by the enzymes MppJ and TyrB, an S‐adenosyl methionine (SAM)‐dependent methyltransferase and an (S)‐aromatic‐amino‐acid aminotransferase, respectively. Phenylpyruvic acid is methylated by MppJ at its benzylic position at the expense of one equivalent of SAM. The resulting β‐methyl phenylpyruvic acid is then converted to (2S,3S)‐β‐methylphenylalanine by TyrB. MppJ was further determined to be regioselective and stereoselective in its catalysis of the formation of (3S)‐β‐methylphenylpyruvic acid. The binding constant (K_D) of MppJ versus SAM is 26 μM . The kinetic constants with respect to k_{cat Ppy} and K_{M Ppy}, and k_{cat SAM} and K_{M SAM} are 0.8 s^?1 and 2.5 mM , and 8.15 s^?1 and 0.014 mM , respectively. These results suggest SAM has higher binding affinity for MppJ than Ppy, and the C? C bond formation in βmPpy might be the rate‐limiting step, as opposed to the C? S bond breakage in SAM.     

Palladium‐Catalyzed Three‐Component Synthesis of Functionalized Allylamines by Intermolecular Tandem Carbopalladation–Amination

Highly regio‐ and stereoselective formation of allylamines has been achieved through a three‐component reaction between iodobenzene, an allene, and an amine in acetonitrile, catalyzed by in situ formed and by isolated palladium‐diphosphine catalysts.     

Combined experimental and numerical kinetic characterization of NR vulcanized with sulfur,N‐terbutyl, 2‐benzothiazylsulfenamide,and N,N‐diphenylguanidine

A comprehensive experimental and numerical analysis aimed at investigating the rheometer behavior of Natural Rubber (NR) vulcanized with sulfur and two accelerators [N,N‐diphenylguanidine (DPG) and N‐terbutyl, 2‐benzothiazylsulfenamide (TBBS)] is presented. To fit experimental data, the general reaction scheme proposed by Han and co‐workers for vulcanized sulfur NR is re‐adapted and suitably modified, taking into account DPG and TBBS single contributions. An ad hoc interactive software based on GUI technology is utilized to fit experimental data, allowing estimating kinetic constants also by unexperienced users. Chain reactions initiated by the formation of macrocompounds responsible for the formation of the instable crosslinked polymer are accounted for. In the presence of two accelerators, reactions are assumed to proceed in parallel, making the hypothesis of negligible interactions, being their concentrations rather similar. From the kinetic scheme adopted, a closed form solution is found for the crosslinking density, with the only limitation that the induction period is excluded from computations. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43519.     

Highly Regio‐ and Stereoselective Iodohydroxylation of Non‐ Heteroatom‐Substituted Allenes: An Efficient Synthesis of 4‐[3′‐Hydroxy‐2′‐iodoalk‐1′(Z)‐enyl]‐2(5H)‐furanone Derivatives

An efficient protocol for the highly regio‐ and stereoselective synthesis of 4‐(3′‐hydroxy‐2′‐iodoalk‐1′(Z)‐enyl)furan‐2(5H)‐one derivatives via selective iodohydroxylation of non‐heteroatom‐substituted allenes, i.e., 4‐allenyl‐2(5H)furanones, has been developed. The regio‐ and stereoselectivity of this reaction may be controlled by the electronic and steric effects of the furanone ring.     

Enantioselective Synthesis of α‐Hydroxy Ketones via Benzaldehyde Lyase‐Catalyzed C−C Bond Formation Reaction

(R)‐Benzoins and (R)‐2‐hydroxypropiophenone derivatives are formed on a preparative scale by benzaldehyde lyase (BAL)‐catalyzed C−C bond formation from aromatic aldehydes and acetaldehyde in aqueous buffer/DMSO solution with remarkable ease in high chemical yield and high optical purity. The substrate range of this thiamin diphosphate‐dependent enzyme was examined with respect to a broad applicability of this benzoin condensation‐type reaction in stereoselective synthesis.     

Nickel(II)‐Magnesium‐Catalyzed Cross‐Coupling of 1,1‐Dibromo‐1‐alkenes with Diphenylphosphine Oxide: One‐Pot Synthesis of (E)‐1‐Alkenylphosphine Oxides or Bisphosphine Oxides

A novel nickel(II)‐magnesium‐mediated cross‐coupling of diphenylphosphine oxide with a variety of 1,1‐dibromo‐1‐alkenes has been developed, which provides a powerful and general methodology for the stereoselective synthesis of various (E)‐1‐alkenylphosphine oxides or bisphosphine oxides, with operational simplicity of the procedure, good to high yields and broad substrate applicability. Mechanistic studies reveal that the reaction might involve a Hirao reduction, cross‐coupling and Michael addition.     

Photooxygenation Catalysis with a Polyol‐Decorated Disc‐Shaped Porphyrin Sensitizer: Shell‐Recognition Effects

Polar meso‐tetraarylporphyrins 2 – 4 were synthesized from tetrakis‐4‐hydroxyphenylporphyrin 1 as the central building block by consecutive base‐induced reactions with glycidol. The decorating units form a polar hydrogen‐bonded shell around the sensitizer core which is proposed as the binding site for polar substrates in photocatalyzed oxygenation reactions. As substrate, the polarity‐sensor mesitylol ( 5 ) was applied and the reaction constrained in a polystyrene matrix. Increasing shell dimensions lead to increased diastereoselectivities for the allylic hydroperoxides 6 and thus clearly demonstrate the concept of shell‐induced substrate stereoselectivity in singlet oxygen reactions.     

N,N′‐Pentamethylenethiuram disulfide and N,N′‐pentamethylenethiuram hexasulfide accelerated sulfur vulcanization. III. Vulcanization of polyisoprene and 2,3‐dimethyl‐2‐butene in the absence of ZnO

Polyisoprene and model compound, 2,3‐dimethyl‐2‐butene, were vulcanized with N,N′‐dipentamethylenethiuram disulfide (CPTD), CPTD/sulfur and N,N′‐dipentamethylenethiuram hexasulfide (CPTP6) in the absence of ZnO and residual extractable curatives and reaction intermediates analyzed by HPLC at various stages of the reaction. Accelerator polysulfides, required for the formation of accelerator‐terminated polysulfidic pendent groups, form rapidly, or are present from the outset in the case of CPTP6. Model compounds confirm the formation of thiuram‐terminated polysulfidic pendent groups as intermediates in the vulcanization process. Removal of pentamethylenedithiocarbamic acid (Hpmtc) from the system during heating delays the onset of vulcanization and leads to very low crosslink densities. Rubbers heated under vacuum can subsequently be crosslinked by the addition of zinc stearate, pointing to the presence in the compound of thiuram‐terminated pendent groups. However, such pendent groups do not readily crosslink on their own, and hydrogen‐terminated polysulfidic pendent groups, formed by the reaction of sulfurated Hpmtc with the polymer, are suggested to be involved in the crosslink formation. N,N′‐Pentamethylenethiurea forms in the vulcanizate, but is not as product of crosslinking reactions, rather of CPTD degradation. The data are discussed with respect to mechanisms proposed in the literature for crosslinking, and it is concluded that the data support recently formulated mechanisms in which crosslinking involves reaction between thiuram and thiol‐terminated pendent groups, with Hmptc playing and essential role in the overall process. © 2000 John Wiley & Sons, Inc. J Appl Polym Sci 78: 1100–1111, 2000     

Reversibly crosslinked self‐healing PCL‐based networks

Poly(ε‐caprolactone) (PCL)‐based thermoreversible networks with self‐healing properties were prepared through Diels–Alder (DA) and retro‐DA reactions. Bis‐ or Tris‐maleimide compounds and a series of copolymer(caprolactone‐diene) PCL_XF_Y (X: degree of polymerization and Y: furan‐average functionality) with Y between 2.4 and 4.9 were used. The successive sequences of formation and dissociation of polycaprolactone networks via DA and retro‐DA reactions were observed repeatedly by dynamic mechanical analyses (DMA) and their gel‐temperatures determined. The cross‐linking densities, thermal properties, and thermal reversibility of the PCL_XF_Y/multimaleimide polymers have been modulated by the structure and functionalities of the used diene and dienophile moieties. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013     

Polyether–maleimide‐based crosslinked self‐healing polyurethane with Diels–Alder bonds

The Diels–Alder (DA) reaction is particularly desirable for the preparation of heat‐stimuli self‐healing polymeric materials because of its thermal reversibility, high yield, and minimal side reactions. Some attempts were conducted to synthesize polyether–maleimide‐based crosslinked self‐healing polyurethane with DA bonds (C‐PEMIPU–DA) through the reactions of the prepolymer (polymeric MDI/PBA‐1000) functionalized by furfuryl amine and polyether–maleimide without benzene in this study. The structures of intermediates and C‐PEMIPU–DA were first confirmed by ¹H‐NMR, Fourier transform infrared spectroscopy, and differential scanning calorimetry. Next, the thermal reversibility and the self‐healing performance of C‐PEMIPU–DA were studied by ¹H‐NMR, polarizing optical microscopy, tensile testing, and a sol–gel process. The results show that C‐PEMIPU–DA exhibited interesting properties of thermal reversibility and self‐healing. The polymers could be applied to self‐healing materials or recyclable materials in the fields of the repair of composite structures and aging parts because of their thermosetting properties at room temperature and thermoplasticity at higher temperatures. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41944.     

Diels–Alder‐based crosslinked self‐healing polyurethane/urea from polymeric methylene diphenyl diisocyanate

Crosslinked self‐healing polyurethane/urea based on a Diels–Alder reaction (C‐PMPU–DA) was synthesized from a multiple‐furan monomer and a commercial bismaleimide. The multiple‐furan monomer (PMPU–furan) was obtained from a functionalized prepolymer (polymeric MDI: PBA‐2000 = 2:1) by furfuryl amine. The structures of both the PMPU–furan and C‐PMPU–DA were characterized by attenuated total reflectance (ATR)–Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and ¹H‐NMR. The Diels–Alder bonds enabled C‐PMPU–DA thermal reversibility, which was investigated by ATR–FTIR spectroscopy, ¹H‐NMR, gel–solution–gel experiments, and viscosity tests. Meanwhile, the self‐healing properties of C‐PMPU–DA were also investigated by the recovery of the mechanical properties. The results showed that C‐PMPU–DA exhibited good thermal reversibility and self‐healing properties. C‐PMPU–DA exhibited thermosetting properties at room temperature, although it exhibited thermoplastic properties at higher temperatures and may find applications in self‐healing materials, recyclable materials, or removable materials. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40234.     

But‐2‐ene‐1,4‐diamine and But‐2‐ene‐1,4‐diol as Donors for Thermodynamically Favored Transaminase‐ and Alcohol Dehydrogenase‐Catalyzed Processes

Both cis‐ and trans‐but‐2‐ene‐1,4‐diamines have been prepared and efficiently applied as sacrificial cosubstrates in enzymatic transamination reactions. The best results were obtained with the cis‐diamine. The thermodynamic equilibrium of the stereoselective transamination process is shifted to the amine formation due to tautomerization of 5H‐pyrrole into 1H‐pyrrole, achieving high conversions (78–99%) and enantiomeric excess (up to >99%) by using a small excess of the amine donor. Furthermore, when the reaction proceeded, a strong coloration was observed due to polymerization of 1H‐pyrrole. A structurally related compound, cis‐but‐2‐ene‐1,4‐diol, has been utilized as cosubstrate in different alcohol dehydrogenase (ADH)‐mediated bioreductions. In this case, high conversions (91–99%) were observed due to a lactonization process. Both strategies are convenient from both synthetic and atom economy points of view in the production of valuable optically active products.