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Self-assembled molecular monolayers (SAMs) have long been recognized as crucial “bridges” between redox enzymes and solid electrode surfaces, on which the enzymes undergo direct electron transfer (DET)—for example, in enzymatic biofuel cells (EBFCs) and biosensors. SAMs possess a wide range of terminal groups that enable productive enzyme adsorption and fine-tuning in favorable orientations on the electrode. The tunneling distance and SAM chain length, and the contacting terminal SAM groups, are the most significant controlling factors in DET-type bioelectrocatalysis. In particular, SAM-modified nanostructured electrode materials have recently been extensively explored to improve the catalytic activity and stability of redox proteins immobilized on electrochemical surfaces. In this report, we present an overview of recent investigations of electrochemical enzyme DET processes on SAMs with a focus on single-crystal and nanoporous gold electrodes. Specifically, we consider the preparation and characterization methods of SAMs, as well as SAM applications in promoting interfacial electrochemical electron transfer of redox proteins and enzymes. The strategic selection of SAMs to accord with the properties of the core redox protein/enzymes is also highlighted.

In this study 26 new oligophenol cellulase inhibitors were discovered from wheat straw pretreatment liquors. By consideration of the reaction mechanisms for their formation it is proposed that these oligophenols are formed during hydrothermal biomass pretreatment by pentose self-condensation reactions involving aldol condensations, 1,4 additions to α,β unsaturated carbonyl compounds, 3-keto acid decarboxylations and oxidations. Furthermore, pentose reactions with phenolic lignin components are suggested. The identification of the central role of xylose in the reaction routes for oligophenolic inhibitor formation led to the solution to protect the reactive anomeric center in xylose. It is shown that protection of the anomeric center in in situ generated xylose with ethylene glycol monobutyl ether, during pretreatment of wheat straw, reduces the level of oligophenols by 73%. The results pave the way for implementation of new types of reactions that hinder inhibitor formation in lignocellulosic biomass processing.

The Heck reaction of aryl iodides and bromides with allyl ethers has been investigated. Using phosphine-free Pd(OAc)2 in DMF at 90 °C in the presence of Bu4NOAc, the reaction gave cinnamyl derivatives, usually in good to high yields, with a wide range of aryl halides. The reaction tolerates a variety of functional groups, including ether, amide, alcohol, aldehyde, ketone, ester, cyano, carboxylic acid, and nitro groups. Ortho-substituted arylating agents afforded moderate yields in some cases, though good to high yields were obtained with o-iodotoluene, iodovanillin, and 1-iodonaphthalene. Several pieces of experimental evidence suggest that the observed selectivity in formation of the vinylic substitution products is kinetic in origin under these conditions. A DFT investigation has been performed to clarify the source of product selectivity and, in particular, the preference for cinnamyl ether over enol ether products. Interestingly, it was found that the product selectivity does not arise from competing...

The oxidative addition of PhI to Pd0 has been studied by DFT with a continuum representation of the solvent. It is shown that the preferred number of ligands on palladium is lower than would be expected from “conventional wisdom” and the 18-electron rule. The most favored oxidative addition is obtained when Pd is coordinated by only the aryl iodide and one additional ligand in a linear arrangement. The calculations indicate that p-orbitals on the central metal are not involved in bonding in any of the complexes described herein, in good agreement with classic ligand field theory and also with a recent bonding analysis by Weinhold and Landis, but in apparent violation of the 18-electron rule.

This paper describes a study of reactivity and enantioselectivity for a series of methyl-substituted styrenes in the Jacobsen-Katsuki (Mn(salen)-catalyzed) epoxidation reaction. Competition experiments provided kinetic data for the reactivity of the seven possible methyl-substituted styrenes (mono-, di- and trisubstituted) relative to styrene itself, ee values were measured by chiral GC, and absolute configurations were secured by chemical correlation. Of particular interest was the switch in absolute configuration at the benzylic position of the epoxides derived from (Z)- and (E)-alpha,beta-dimethylstyrene, respectively. The results could be rationalized in terms of an approach vector with the phenyl substituent proximal to the salen. As opposed to alkyl groups, a proximal phenyl group has very little effect on the rate of the reaction. Consideration of distal vs proximal approach allows prediction of absolute stereochemistry as a function of alkene substitution pattern. Trisubstituted alkenes with one phenyl group cis to the alkene hydrogen can be identified as a favored substrate class in the title reaction, with both rate and selectivity close to the classic (Z)-beta-substituted styrene substrates.

The regioselectivity in the cationic Heck reaction of 4-substituted styrenes was addressed by a Hammett study. In this branching reaction, plots based on the substrate reactivity did not give meaningful data, whereas the product distribution was variable due to differing preferences for further substitution under the reaction conditions and, thus, unsuitable for Hammett plots. Mechanistically meaningful graphs were obtained by combination of the measured initial branching ratio with the approximately constant substrate reactivity. For the α-substitution a clear Hammett relation is observed, whereas β-substitution does not depend on electronic effects. This implies that, for α-substitution, the slow step of the addition is an electrophilic attack by Pd(II) on the double bond, followed by a rapid migratory insertion.

Some new results on asymmetric synthesis via the addition of α-metalated methyl tolyl sulfoxides to imines are presented. Good diastereoselectivity (up to >98% d.e. for product 3g) can be obtained under conditions of kinetic control (short reaction time, low temperature). The transition state (a six-membered "flat chair") was probed by quantum mechanical calculations, which underpinned the idea of using external chiral ligands to enhance the diastereoselectivity of otherwise moderately selective reactions. In this way, the diastereomeric ratio of the product 3a could be raised from (84:16) to (>99:1) by use of a readily available C2-symmetric bis(sulfonamide) ligand.

The reaction of stabilized Peterson reagents (alpha-silyl ester enolates) with ketones has been studied theoretically and experimentally. Enolate geometry was studied by trapping experiments and NMR spectroscopy and was found to differ markedly with the nature of the base (LiHMDS vs LDA vs KHMDS). The chelating effect of the lithium counterion was found to be critical for the reaction. For the two ketones studied, the combined weight of experimental and computational data assigns geometrical selectivity to the initial addition transition state, though in general there appears to be a fine balance between three possible choices for the rate-determining step.

[reaction: see text] A racemic aldehyde can undergo parallel kinetic resolution (PKR) by simultaneous reaction with two different chiral phosphonates, differing either in the structure of the chiral auxiliary or in the structure of the phosphoryl group (i.e., one (E)- and one (Z)-selective reagent). This strategy allows conversion of a racemic aldehyde to two different, synthetically useful chiral products with essentially doubled material throughput and similar or improved selectivities as compared to conventional kinetic resolution.

The chiral aziridino alcohols 1 -3 have been prepared either from amino acids (1a from serine; 1b - 1i and 3 from threonine; 2a - 2e from allo-threonine) or via asymmetric synthesis (1j, 1k, 1l and ...

A systematic study has been made of the utility of readily available C 2 -symmetric aziridines as auxiliaries for asymmetric alkylation and aldol rea

Herein is described the synthesis of a novel class of peptidyl FVIIa inhibitors having a C-terminal benzyl ketone group. This class is designed to be potentially suitable as stabilization agents of liquid formulations of rFVIIa, which is a serine protease used for the treatment of hemophilia A and B inhibitor patients. A library of compounds was synthesized with different tripeptide sequences, N-terminals and d -amino acids in the P3 position. Cbz- d -Phe–Phe–Arg–bk (33) was found to be the best candidate with a potency of Ki = 8 μM and no substantial inhibition of related blood coagulation factors (thrombin and FXa). Computational studies revealed that 33 has a very stable binding conformation due to intramolecular hydrogen bonds, which cannot be formed with l -Phe in the P3 position. Nonpolar amino acids were found to be superior, probably due to a minimization of the cost of desolvation upon binding to FVIIa.

The mechanism of the recently developed palladium-catalyzed ene-yne coupling has been evaluated by DFT methods. The calculations validate the previously proposed reaction mechanism and explain the stereoselectivity of the reaction (exclusive formation of the E isomer of the disubstituted alkene). Concerning chemoselectivity, the calculations also clarify why the ene-yne coupling is able to dominate over plausible alternative reaction pathways such as alkene homocoupling and alkyne polymerization. The role of the phosphine ligand at various stages of the catalytic cycle has also been delineated.

A racemic aldehyde can undergo parallel kinetic resolution (PKR) by simultaneous reaction with two different chiral phosphonates, differing either in the structure of the chiral auxiliary or in the structure of the phosphoryl group (i.e., one (E)- and one (Z)-selective reagent). This strategy allows conversion of a racemic aldehyde to two different, synthetically useful chiral products with essentially doubled material throughput and similar or improved selectivities as compared to conventional kinetic resolution.

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner−Wadsworth−Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different α-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major α,β-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles. In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry with respect to both the allylic stereocenter and the alkene geometry. Thus, a single γ-substituted ester was obtained as the overall product, in high isomeric pu...

This paper describes two enantioselective aziridine-based routes toward 1β-methylthienamycin, 2, and related carbapenems, the key steps being completely regioselective ring-opening reactions of the chiral aziridines 7 and 10 with AlMe3.

Nucleophilic ring-opening of trans and cis aziridino alcohols 1 ( 1′ ) and 2 ( 2′ ) by hydride- and by methyl-transfer reagents has been studied. In general, good to excellent C-2 selectivity was observed (the regioselectivity being better for the trans isomers) and the results can be interpreted in terms of directive effects exerted by the C-1 hydroxyl group. However, complete C-3 selectivity was observed in the reactions of 1 and 2 with AlMe 3 , indicating a complexation effect of the C-4 benzyloxy group in those cases.

The tricyclic compound 13, representing the framework of the cylindricine 4 and lepadiformine 5alkaloids, was prepared in a single operation via the first example of a transannular Mannich reaction involving a macrocyclic diketoamine 12.

Pyrrolidine-2,4-diones have been identified as a novel starting point for the synthesis of peptide analogues. This paper describes a method for the efficient and diastereoselective incorporation of this moiety into peptide chains to furnish di- and tripeptide analogs. The stability of these pyrrolidinone modified di- and tripeptides was found to be markedly improved when compared to that of a natural peptide. In addition, solid phase peptide synthesis employing a pyrrolidinone containing tripeptide is demonstrated.

The pyrrolidine-2,4-diones have been identified as a convenient starting point for the synthesis of peptide analogues. Herein we describe an optimized two-step reductive amination procedure, which provides a small library of pyrrolidinone-containing dipeptide analogues in high yield and excellent diastereoselectivity.

This paper describes the development of a straightforward experimental protocol for copper-mediated cross-coupling of amino acid derived beta-amido-alkylzinc iodides 1 and 3 with a range of acid chlorides. The present method uses CuCN.2LiCl as the copper source and for organozinc reagent 1 the methodology appears to be limited to reaction with more stable acid chlorides, providing the desired products in moderate yields. When applied to organozinc reagent 3, however, the protocol is more general and provides the products in good yields in all but one of the cases tested.

The selectivity-determining step in enantioselective copper-catalyzed cyclopropanation with diazo compounds has been studied by experimental and computational methods. The addition of the very reactive metallacarbene intermediate in an early transition state to the substrate alkene is concerted but strongly asynchronous, with substantial cationic character on one alkene carbon in the neighborhood of the transition state. Evidence from isotope effects and Hammett studies supports the nature of the transition state. Formation of a metallacyclobutane intermediate by a [2+2] addition is kinetically disfavored. Ligand-substrate interactions influencing the enantio- and diastereoselectivity have been identified, and the preferred orientation of the alkene substrate during the addition is suggested.

A new method for enantioconvergent synthesis has been developed. The strategy relies on the combination of an asymmetric Horner-Wadsworth-Emmons (HWE) reaction and a palladium-catalyzed allylic substitution. Different alpha-oxygen-substituted, racemic aldehydes were initially transformed by asymmetric HWE reactions into mixtures of two major alpha,beta-unsaturated esters, possessing opposite configurations at their allylic stereocenters as well as opposite alkene geometry. Subsequently, these isomeric mixtures of alkenes could be subjected to palladium-catalyzed allylic substitution reactions with carbon, nitrogen, and oxygen nucleophiles. In this latter step, the respective (E) and (Z) alkene substrate isomers were observed to react with opposite stereospecificity: the (E) alkene reacted with retention and the (Z) alkene with inversion of stereochemistry with respect to both the allylic stereocenter and the alkene geometry. Thus, a single gamma-substituted ester was obtained as the overall product, in high isomeric purity. The method was applied to a synthesis of a subunit of the iejimalides, a group of cytotoxic macrolides.

N-tosyl amides and lactams can be prepared easily and under mild conditions by the inter- or intramolecular condensation of carboxylic acids and secondary sulfonamides. The coupling reagent used is dicyclohexyl-carbodiimide (DCC) in the presence of 4-pyrrolidinopyridine (4-PPY) and the reactions proceed readily, usually in high yield, at room temperature.

On prepare les composes du titre par double ou triple reaction de Wittig suivie d'une copulation reductrice de dialdehydes

An enantioselective synthesis of the carbapenem antibiotic (+)-PS-5 is described. The starting point is the chiral Sharpless epoxy-alcohol 3 which is transformed stereospecifically to the aziridine 6 . Regioselective ring-opening of 6 by LiEt2Cu followed by RuO4 oxidation yields the β-sulfonamido carboxylic acid 8 which is cyclised under mild conditions and in excellent yield to the N-tosyl azetidinone 9 . Deprotection at nitrogen, unmasking of the side-chain hydroxyl and oxidation then furnishes 11 , a known advanced intermediate for (+)-PS-5.

Two simple, efficient and stereocontrolled routes to the cis -azaspiro-[5-5]-undecan-8-ol skeleton of the histrionicotoxin alkaloids are described.

The title ketone has been synthesised in 96% e.e. from the corresponding methyl ester and MeLi. The [α]D value for the product was considerably higher than values previously reported for the enantiomer.

Three cyclophanes, each displaying a different type of dynamic process, have been studied by NMR methods. The barriers to these processes are attributed mainly to the decrease in π-electron overlap between the benzene rings and adjacent double bonds which occurs in the transition state for each process. In [5 2 ] paracyclophanetetraene, two successive flippings of the benzene rings interconvert the two hydrogens in the methylene groups (Scheme 1). In tetramethyl [2 4 ] paracyclophanetetraene, the passage of one methyl group through the central cavity of the molecule interconverts two conformations of similar, but not equal, free energy (Scheme 2). In [2 6 ] orthoparacyclophanehexaene, the orthosubstituted rings change sides by passing through the centre of the cyclophane (Scheme 3).

An enantioselective total synthesis of the 14-membered macrolide antibiotic ingramycin, 1 , is described. In a convergent approach three chiral fragments A , B and C are assembled, the allylic bromide A deriving its chirality from L -serine while the asymmetric centres in sulfones B and C are introduced via the Sharpless enantioselective epoxidation technique. After coupling of these fragments and a highly efficient macrolactonisation (82% yield) a final deprotection step furnishes the target compound.

Two stereocontrolled routes to the alkaloid depentylperhydrohistrionicotoxin 3 , are described. The key steps are alkylation, with retention of configuration, of the iodide 8 and the mesylate 12 , respectively. A tricyclic aziridinium species is proposed as the reactive intermediate in the latter reaction. The synthesis of 3 represents a formal total synthesis of the title alkaloid.

The title ketone has been synthesised in 96% e.e. from the corresponding methyl ester and MeLi. The [α]D value for the product was considerably higher than values previously reported for the enantiomer.

An enantioselective synthesis of the carbapenem antibiotic (+)-PS-5 is described. The starting point is the chiral Sharpless epoxy-alcohol 3 which is transformed stereospecifically to the aziridine 6 . Regioselective ring-opening of 6 by LiEt2Cu followed by RuO4 oxidation yields the β-sulfonamido carboxylic acid 8 which is cyclised under mild conditions and in excellent yield to the N-tosyl azetidinone 9 . Deprotection at nitrogen, unmasking of the side-chain hydroxyl and oxidation then furnishes 11 , a known advanced intermediate for (+)-PS-5.

Two stereocontrolled routes to the alkaloid depentylperhydrohistrionicotoxin 3 , are described. The key steps are alkylation, with retention of configuration, of the iodide 8 and the mesylate 12 , respectively. A tricyclic aziridinium species is proposed as the reactive intermediate in the latter reaction. The synthesis of 3 represents a formal total synthesis of the title alkaloid.