Formyloxyacetoxyphenylmethane is a stable, water-tolerant, N-formylating reagent for primary and secondary amines that can be used under solvent-free conditions at room temperature to prepare a range of N-formamides, N-formylanilines, N-formyl-α-amino acids, N-formylpeptides, and an isocyanide.

Two boronate fluorescent probes have been developed for the detection of peroxynitrite (TCFB1 and TCFB2). TCFB1 was shown to have a low sensitvity towards peroxynitrite and have a poor solubility in aqueous solution whereas TCFB2 demonstrated high sensitivity towards peroxynitrite and mitochondria localisation with the ability to detect exogenous and endogenous peroxynitrite in live cells (Hep-G2, RAW 264.7, HeLa and A459).

With this research, we have developed a bodipy based system as the first “turn-on” fluorescence system for the detection hydroxylamine.

Aryl-aldehydes containing ortho-substituted propiolate fragments react with hydroxylamine to afford carbinolamine intermediates that undergo intramolecular aza-conjugate addition reactions to afford N-hydroxy-2.3-dihydro-isoindolin-1-ones that can be reduced to their corresponding isoindolin-1-ones and isoindoles.

A practically simple derivatization protocol for determining the enantiopurity of chiral diols by 1H NMR spectroscopic analysis is described. Diols were treated with 0.5 equiv of 1,3-phenyldiboronic acid to afford mixtures of diastereomeric boronate esters whose homochiral/heterochiral ratios are an accurate reflection of the diol’s enantiopurity.

Using the self-assembly of aromatic boronic acids with Alizarin Red S (ARS), we developed a new chemosensor for the selective detection of peroxynitrite. Phenylboronic acid (PBA), benzoboroxole (BBA) and 2-(N,N-dimethylaminomethyl)phenylboronic acid (NBA) were employed to bind with ARS to form the complex probes. In particular, the ARS–NBA system with a high binding affinity can preferably react with peroxynitrite over hydrogen peroxide and other ROS/RNS due to the protection of the boron via the solvent-insertion B–N interaction. Our simple system produces a visible colorimetric change and on–off fluorescence response towards peroxynitrite. By coupling a chemical reaction that leads to an indicator displacement, we have developed a new sensing strategy, referred to herein as RIA (Reaction-based Indicator displacement Assay).

Aryl-aldehydes containing ortho-substituted α,β-unsaturated carboxylic acid derivatives react with hydroxylamine to afford reactive N-hydroxy-carbinolamine intermediates that undergo intramolecular aza-conjugate addition reactions to afford isoindole nitrones and 3,4-dihydroisoquinoline nitrones in good yield. Conditions have been developed to reduce these isoindole nitrones to their corresponding hydroxylamine, enamine, and amine derivatives. Isoindole nitrones react with dimethyl acetylenedicarboxylate (DMAD) via a [4 + 2]-cycloaddition/deamination pathway to afford substituted naphthalene derivatives, while 3,4-dihydroisoquinoline nitrones react with DMAD via a [1,3]-dipolar cycloaddition pathway to afford tricyclic heteroarenes.

Aza-conjugate addition of the lithium anion of N-trimethylsilyl-p-methoxybenzylamine to tert-butyl enoate acceptors, in the presence of a stoichiometric amount of enantiopure 1,2-dimethoxy-1,2-diphenylethane and excess trimethylsilyl chloride, affords tert-butyl-N-p-methoxybenzyl-β-amino esters with excellent levels of enantiocontrol. These N-p-methoxybenzyl-β-amino-esters may be deprotected under oxidative conditions via treatment with ceric ammonium nitrate, followed by acid hydrolysis of the resultant imine intermediates, to afford enantiopure β-amino-esters containing hydrogenolytically sensitive functionality.

A water-soluble boronate-based fluorescent probe was evaluated for the detection of peroxynitrite (ONOO−) in the presence of a monosaccharide. The enhanced fluorescence of the probe when bound with D-fructose was switched off in the presence of peroxynitrite. In contrast, other reactive oxygen/nitrogen species (ROS/RNS) led to only slight fluorescence decreases due to protection by an internal N–B interaction. The interaction of the probe with D-fructose not only strengthens the fluorescence signal, but also protects the boronic acid from oxidation by other ROS/RNS. Therefore, under conditions generating various ROS/RNS, the boronate-based saccharide complex preferentially reacts with peroxynitrite. The probe was used in cell imaging experiments for the detection of endogenous and exogenous peroxynitrite. The sensor displays good “on–off” responses towards peroxynitrite, both in RAW 264.7 cells and HeLa cells.

We have developed a simple and robust fluorescence based boronic-acid molecular sensor for determining the concentration of fluoride in water at environmentally significant levels. The simplicity of the method and the ability to measure fluoride in water between 0.1 and 1.5 ppm is particularly noteworthy given the WHO requirements for detecting levels of fluoride in drinking water below 1.5 ppm.

A practically simple three-component chiral derivatization protocol for determining the enantiopurity of chiral hydroxylamines by 1H NMR spectroscopic analysis is described, involving their treatment with 2-formylphenylboronic acid and enantiopure BINOL to afford a mixture of diastereomeric nitrono-boronate esters whose ratio is an accurate reflection of the enantiopurity of the parent hydroxylamine.

Treatment of a range of trisubstituted β,γ-unsaturated esters with 2 equiv of (−)-monoisopinocampheylborane results in hydroboration of their alkene functionalities and reduction of their ester groups to afford chiral 1,3-diols containing two new vicinal β,γ-(anti)-stereocentres in 67–85% enantiomeric excess.

Upon mixing a chiral amine, enantiopure BINOL, and o-formyl phenyl boronic acid, the three components assemble efficiently and rapidly into chiral host–guest structures that produce distinct circular dichroism signals for each enantiomer of the amine. Employing BINOL and two derivatives to create an array of receptors, the CD signals resulting from several α-chiral primary amines were processed by principal component analysis and linear discriminant analysis to give satisfactory discrimination of the amines studied. Not only was the system able to differentiate the analytes chemoselectively and enantioselectively, but it also allowed for the rapid determination of chiral amineee values.

Air-stable and crystalline N-acyl DBN tetraphenylborate salts have been shown to be effective O-acylating agents, reacting with both primary and secondary alcohols to give the corresponding esters in good yields. In the case of diols, the N-acyl DBN·BPh4 salts have been shown to acylate regioselectively the primary alcohol functionality in the presence of a secondary alcohol. The DBN hydrotetraphenylborate side product can be readily removed by filtration, providing the ester products without the need for further purification.

A method of preparing enantiopure hydroxy-γ-butyrolactones containing multiple contiguous stereocenters in high yield with good diastereoselectivity has been developed. Osmium tetroxide mediated dihydroxylation of a range of β-alkenyl-β-hydroxy-N-acyloxazolidin-2-ones results in formation of triols that undergo spontaneous intramolecular 5-exo-trig cyclization reactions to provide hydroxy-γ-butyrolactones. The stereochemistry of these hydroxy-γ-butyrolactones has been established using NOE spectroscopy, which revealed that 1-substituted, 1,1-disubstituted, (E)-1,2-disubstituted, (Z)-1,2-disubstituted, and 1,1,2-trisubstituted alkenes undergo dihydroxylation with anti-diastereoselectivity, while 1,2,2-trisubstituted systems afford syn-diastereoisomers. The synthetic utility of this methodology has been demonstrated for the asymmetric synthesis of the natural product 2-deoxy-d-ribonolactone.

Air-stable and crystalline N-acyl DBN tetraphenylborate salts have been synthesized from 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and the corresponding acyl chloride in the presence of sodium tetraphenylborate. The salts have been shown to be effective N-acylating agents, reacting with primary amines, secondary amines, and sulfonamides to form the corresponding N-acylated products in good yields. The DBN hydrotetraphenylborate byproduct can be conveniently removed by filtration, providing pure N-acylated products without the need for further purification. The N-acyl DBN tetraphenylborate salts are attractive alternatives to acyl halides as they can be stored in air without decomposition, avoid the production of free acid during acylation reactions, and can be used under more forcing thermal conditions.

N-Alkylation of a novel pyridine sensor results in pyridinium salts whose conformations are stabilised by pyridinium cation–π interactions resulting in a fluorescent response that can be used to sense the presence of alkylating agents in solution at low concentration.

A versatile methodology for the asymmetric synthesis of chiral δ-lactones containing multiple contiguous stereocenters has been developed that relies on a series of Evans’ aldol, hydroxyl-directed cyclopropanation, methanolysis, and Hg(II) mediated cyclopropane ring-opening reactions for stereocontrol.

A practically simple three-component Strecker reaction for the asymmetric synthesis of enantiopure α-arylglycines has been developed. Addition of a range of aryl-aldehydes to a solution of sodium cyanide and (S)-1-(4-methoxyphenyl)ethylamine affords highly crystalline (S,S)-α-aminonitriles that are easily obtained in diastereomerically pure form. Heating the resultant (S,S)-α-aminonitriles in 6 M aqueous HCl at reflux resulted in cleavage of their chiral auxiliary fragments and concomitant hydrolysis of their nitrile groups to afford enantiopure (S)-α-arylglycines. The enantiopurities of these (S)-α-arylglycines were determined via derivatization of their corresponding methyl esters with 2-formylphenylboronic acid and (S)-BINOL, followed by 1H NMR spectroscopic analysis of the resultant mixtures of diastereomeric iminoboronate esters.

2-Keto-3-deoxygluconate aldolase from the hyperthermophile Sulfolobus solfataricus is a highly thermostable type I aldolase that can catalyze carbon−carbon bond formation using nonphosphorylated substrates. However, it exhibits poor diastereocontrol in many of its aldol reactions, including the reaction of its natural substrates, pyruvate and d-glyceraldehyde, which afford a 55:45 mixture of d-2-keto-3-deoxygluconate (D-KDGlu) and d-2-keto-3-deoxy-galactonate (D-KDGal). We have employed detailed X-ray crystallographic structural information of this aldolase bound to these diastereoisomeric aldol products to selectively target specific amino acids for mutation for the rapid creation of stereochemically complementary mutants that catalyze either (Re)- or (Si)-facial selective aldol reactions to afford either D-KDGlu or D-KDGal with good levels of diastereocontrol.

1,5-Diazabicyclo[4.3.0]non-5-ene (DBN) has been shown to be an effective catalyst for the regioselective Friedel−Crafts C-acylation of pyrroles and indoles in high yields. A detailed mechanistic study implies that DBN is acting as a nucleophilic organocatalyst, with the X-ray crystal structure of a key N-acyl-amidine intermediate having been determined for the first time.

Treatment of β-vinyl-β-hydroxy-N-acyloxazolidin-2-ones with VO(acac)2 and tert-butyl hydroperoxide results in formation of unstable epoxides that are ring-opened by intramolecular nucleophilic attack of their exocyclic carbonyl fragments to afford highly functionalized trisubstituted hydroxy-γ-butyrolactones in >95% de, with a polymer-supported oxazolidin-2-one having been used to transfer this methodology to the solid phase.

A novel way of combining chiral auxiliaries and substrate directable reactions is described that employs a three-step sequence of aldol/cyclopropanation/retro-aldol reactions for the asymmetric synthesis of enantiopure cyclopropane-carboxaldehydes. In the first step, reaction of the boron enolate of (S)-N-propionyl-5,5-dimethyl-oxazolidin-2-one with a series of α,β-unsaturated aldehydes affords their corresponding syn-aldol products in high de. In the second step, directed cyclopropanation of the alkene functionalities of these syn-aldols occurs under the stereodirecting effect of their ‘temporary’β-hydroxyl stereocentres to give a series of cyclopropyl-aldols in high de. Finally, retro-aldol cleavage of the lithium alkoxide of these cyclopropyl-aldols results in destruction of their temporary β-hydroxy stereocentres to afford the parent chiral auxiliary and chiral cyclopropane-carboxaldehydes in >95% ee. The potential of this methodology has been demonstrated for the asymmetric synthesis of the cyclopropane containing natural product cascarillic acid in good yield.

A chiral pseudo-C3-symmetric titanium triflate that employs the point chirality of a single stereogenic centre to control the propeller chirality of its aryl rings has been used to catalyse an asymmetric sulfoxidation reaction.

Reaction of 2-formyl-aryl-boronic acids with 1,2-amino alcohols results in dynamic covalent self assembly to quantitatively afford tetracyclic macrocyclic Schiff base boracycles containing bridging boron–oxygen–boron functionality.

NOEsy and fluorescence spectroscopy reveal that conversion of conformationally flexible (phenylalkyl)pyridines into their corresponding N-methyl-pyridinium iodides results in intramolecular π-stacking.

A cleavable linker strategy has been used to optimise the enolate alkylation reactions of a recyclable L-tyrosine derived polymer-supported oxazolidin-2-one for the asymmetric synthesis of a series of chiral α-alkyl acids.

Practically simple three-component chiral derivatisation protocols for determining the enantiopurity of vicinal C2-symmetric diamines by 1H NMR spectroscopic analysis are described. This involves the treatment of 1,2-diphenylethane-1,2-diamine or N-Boc-cyclohexane-1,2-diamine with 2-formylphenylboronic acid and enantiopure BINOL, which afford mixtures of diastereoisomeric boronate esters whose ratio is an accurate reflection of the enantiopurity of the parent diamine.(4S,5S)-2-(2-((R)-Naphtho[2,1,9,14-def][1,3,2]dioxaborepin-4-yl)phenyl)-4,5-diphenylimidazolidineC41H31BN2O2[α]D20=-302 (c 1.2, CH2Cl2)Absolute configuration: (4S,5S,R)(4R,5R)-2-(2-((R)-Naphtho[2,1,9,14-def][1,3,2]dioxaborepin-4-yl)phenyl)-4,5-diphenylimidazolidineC41H31BN2O2[α]D20=+314 (c 1.7, CH2Cl2)Absolute configuration: (4R,5R,R)tert-Butyl (E,1R,2R)-2-((2-((S)-naphtho[15,10,1,2-def][1,3,2]dioxaborepin-4-yl)phenyl)methyleneamino)cyclohexylcarbamateC38H37BN2O4[α]D20=-429 (c 1.1, CH2Cl2)Absolute configuration: (1R,2R,S)tert-Butyl (E,1S,2S)-2-((2-((S)-naphtho[15,10,1,2-def][1,3,2]dioxaborepin-4-yl)phenyl)methyleneamino)cyclohexylcarbamateC38H37BN2O4[α]D20=+414 (c 2.0, CH2Cl2)Absolute configuration: (1S,2S,S)

Treatment of (S)-3-isopropyl-2,5-dimethoxy-3,6-dihydropyrazine with trifluoroacetic acid in MeOD results in regioselective deuteration at its C6-position affording its corresponding (S)-[6-2H2]-isotopomer in excellent yield with no loss of stereochemical integrity at its C3-stereocentre. The lithium aza-enolate of this deuterated chiral template has been alkylated with a range of substituted benzyl bromides to afford (3S,6R)-[6-2H]-3-isopropyl-6-benzyl-bis-lactim ethers that were hydrolysed to afford their corresponding (R)-[α-2H]-phenylalanine methyl esters as hydrochloride salts in good yield.(3S)-[6-2H2]-3-Isopropyl-2,5-dimethoxy-3,6-dihydropyrazineC9H14D2N2O2[α]D23=+72.0 (c 1.0, EtOH)Source of chirality: l-valine(3S,6R)-[6-2H]-3-Isopropyl-6-benzyl-2,5-dimethoxy-3,6-dihydropyrazineC16H21DN2O2[α]D25=-41.2 (c 1.3, CH2Cl2)Source of chirality: l-valine(3S,6R)-[6-2H]-3-Isopropyl,6-(2-bromobenzyl)-2,5-dimethoxy-3,6-dihydropyrazineC16H20DBrN2O2[α]D25=-7.5 (c 1.0, EtOAc)Source of chirality: l-valine(3S,6R)-[6-2H]-3-Isopropyl,6-(2-iodobenzyl)-2,5-dimethoxy-3,6-dihydropyrazineC16H20DIN2O2[α]D25=-15.5 (c 1.0, EtOAc)Source of chirality: l-valine(3S,6R)-[6-2H]-3-Isopropyl,6-(4-fluorobenzyl)-2,5-dimethoxy-3,6-dihydropyrazineC16H20DFN2O2[α]D27=-62.4 (c 1.0, EtOAc)Source of chirality: l-valine(3S,6R)-[6-2H]-3-Isopropyl,6-(4-bromobenzyl)-2,5-dimethoxy-3,6-dihydropyrazineC16H20DBrN2O2[α]D25=-5.2 (c 1.0, EtOAc)Source of chirality: l-valine(3S,6R)-[6-2H]-3-Isopropyl,6-(4-trifluoromethylbenzyl)-2,5-dimethoxy-3,6-dihydropyrazineC17H20DF3N2O2[α]D25=-20.7 (c 1.0, EtOAc)Source of chirality: l-valine(R)-α-[2H]-Phenylalanine methyl ester hydrochlorideC10H13DClNO2[α]D25=-28.3 (c 1.0, EtOH)Source of chirality: l-valine(R)-α-[2H]-2-Bromophenylalanine methyl ester hydrochlorideC10H12DBrClNO2[α]D25=-20.1 (c 1.0, EtOH)Source of chirality: l-valine(R)-α-[2H]-2-Iodophenylalanine methyl ester hydrochlorideC10H12DClINO2[α]D25=-13.3 (c 1.0, EtOH)Source of chirality: l-valine(R)-α-[2H]-4-Fluorophenylalanine methyl ester hydrochlorideC10H12DClFNO2[α]D25=-34.3 (c 1.0, EtOH)Source of chirality: l-valine(R)-α-[2H]-4-Bromophenylalanine methyl ester hydrochlorideC10H12DBrClNO2[α]D25=-18.5 (c 1.0, EtOH)Source of chirality: l-valine(R)-α-[2H]-4-Trifluoromethylphenylalanine methyl ester hydrochlorideC11H12DClF3NO2[α]D25=-24.8 (c 1.0, EtOH)Source of chirality: l-valine

A new way of combining chiral auxiliaries and substrate-directable reactions for asymmetric synthesis is described that employs a three-step sequence of aldol–cyclopropanation–retro-aldol reactions for the stereoselective synthesis of enantiopure cyclopropane carboxaldehydes.

A novel thermostable aldolase has been developed for synthetic application, and substrate engineering has been used to induce stereocontrol into aldol reactions of this naturally-promiscuous enzyme.

Potassium alkoxides of N-acyloxazolidin-2-one derived syn-aldolates undergo a novel tandem intramolecular cyclisation elimination reaction to afford trisubstituted (E)-α,β-unsaturated amides in high d.e., which may be converted into their corresponding acids or oxazolines in good yield.

Recent advances in the use of non-enzymatic chiral catalysts for the kinetic resolution or dynamic kinetic resolution of racemic substrates are described. Successful protocols that afford recovered starting material or products in high enantiomeric excess are included, and mechanistic detail is discussed where appropriate. Relevant examples illustrate the wide range of different reaction scenarios where kinetic resolution has recently been employed as a strategy for the efficient synthesis of enantiopure compounds.Recent advances in the use of non-enzymatic chiral catalysts for the kinetic resolution or dynamic kinetic resolution of racemic substrates are described. Successful protocols that afford recovered starting material or products in high enantiomeric excess are included, and mechanistic detail is discussed where appropriate. Relevant examples illustrate the wide range of different reaction scenarios where kinetic resolution has recently been employed as a strategy for the efficient synthesis of enantiopure compounds.

Non-linear effects reveal that the use of chiral BINOL–boron reagents for aza-Diels–Alder reactions results in an enantioselective catalytic species containing at least 2 equiv. of BINOL. Dynamic ligand exchange and ligand accelerated catalysis occurs in these reactions, consistent with the formation of a cyclic borate ester of BINOL with enhanced Lewis acidity.Graphic

Treatment of a range of trisubstituted β,γ-unsaturated esters with 2 equiv of (−)-monoisopinocampheylborane results in hydroboration of their alkene functionalities and reduction of their ester groups to afford chiral 1,3-diols containing two new vicinal β,γ-(anti)-stereocentres in 67–85% enantiomeric excess.Download full-size image

We have developed a simple and robust fluorescence based boronic-acid molecular sensor for determining the concentration of fluoride in water at environmentally significant levels. The simplicity of the method and the ability to measure fluoride in water between 0.1 and 1.5 ppm is particularly noteworthy given the WHO requirements for detecting levels of fluoride in drinking water below 1.5 ppm.

A water-soluble boronate-based fluorescent probe was evaluated for the detection of peroxynitrite (ONOO−) in the presence of a monosaccharide. The enhanced fluorescence of the probe when bound with D-fructose was switched off in the presence of peroxynitrite. In contrast, other reactive oxygen/nitrogen species (ROS/RNS) led to only slight fluorescence decreases due to protection by an internal N–B interaction. The interaction of the probe with D-fructose not only strengthens the fluorescence signal, but also protects the boronic acid from oxidation by other ROS/RNS. Therefore, under conditions generating various ROS/RNS, the boronate-based saccharide complex preferentially reacts with peroxynitrite. The probe was used in cell imaging experiments for the detection of endogenous and exogenous peroxynitrite. The sensor displays good “on–off” responses towards peroxynitrite, both in RAW 264.7 cells and HeLa cells.

A novel way of combining chiral auxiliaries and substrate directable reactions is described that employs a three-step sequence of aldol/cyclopropanation/retro-aldol reactions for the asymmetric synthesis of enantiopure cyclopropane-carboxaldehydes. In the first step, reaction of the boron enolate of (S)-N-propionyl-5,5-dimethyl-oxazolidin-2-one with a series of α,β-unsaturated aldehydes affords their corresponding syn-aldol products in high de. In the second step, directed cyclopropanation of the alkene functionalities of these syn-aldols occurs under the stereodirecting effect of their ‘temporary’β-hydroxyl stereocentres to give a series of cyclopropyl-aldols in high de. Finally, retro-aldol cleavage of the lithium alkoxide of these cyclopropyl-aldols results in destruction of their temporary β-hydroxy stereocentres to afford the parent chiral auxiliary and chiral cyclopropane-carboxaldehydes in >95% ee. The potential of this methodology has been demonstrated for the asymmetric synthesis of the cyclopropane containing natural product cascarillic acid in good yield.

A cleavable linker strategy has been used to optimise the enolate alkylation reactions of a recyclable L-tyrosine derived polymer-supported oxazolidin-2-one for the asymmetric synthesis of a series of chiral α-alkyl acids.

N-Alkylation of a novel pyridine sensor results in pyridinium salts whose conformations are stabilised by pyridinium cation–π interactions resulting in a fluorescent response that can be used to sense the presence of alkylating agents in solution at low concentration.

Upon mixing a chiral amine, enantiopure BINOL, and o-formyl phenyl boronic acid, the three components assemble efficiently and rapidly into chiral host–guest structures that produce distinct circular dichroism signals for each enantiomer of the amine. Employing BINOL and two derivatives to create an array of receptors, the CD signals resulting from several α-chiral primary amines were processed by principal component analysis and linear discriminant analysis to give satisfactory discrimination of the amines studied. Not only was the system able to differentiate the analytes chemoselectively and enantioselectively, but it also allowed for the rapid determination of chiral amineee values.

Using the self-assembly of aromatic boronic acids with Alizarin Red S (ARS), we developed a new chemosensor for the selective detection of peroxynitrite. Phenylboronic acid (PBA), benzoboroxole (BBA) and 2-(N,N-dimethylaminomethyl)phenylboronic acid (NBA) were employed to bind with ARS to form the complex probes. In particular, the ARS–NBA system with a high binding affinity can preferably react with peroxynitrite over hydrogen peroxide and other ROS/RNS due to the protection of the boron via the solvent-insertion B–N interaction. Our simple system produces a visible colorimetric change and on–off fluorescence response towards peroxynitrite. By coupling a chemical reaction that leads to an indicator displacement, we have developed a new sensing strategy, referred to herein as RIA (Reaction-based Indicator displacement Assay).

NOEsy and fluorescence spectroscopy reveal that conversion of conformationally flexible (phenylalkyl)pyridines into their corresponding N-methyl-pyridinium iodides results in intramolecular π-stacking.

A chiral pseudo-C3-symmetric titanium triflate that employs the point chirality of a single stereogenic centre to control the propeller chirality of its aryl rings has been used to catalyse an asymmetric sulfoxidation reaction.