Diazo transfer to β-keto sulfoxides to form stable isolable α-diazo-β-keto sulfoxides has been achieved for the first time. Both monocyclic and benzofused ketone derived β-keto sulfoxides were successfully explored as substrates for diazo transfer. Use of continuous flow leads to isolation of the desired compounds in enhanced yields relative to standard batch conditions, with short reaction times, increased safety profile, and potential to scale up.

Enantioselectivities in C–H insertion reactions, employing the copper-bis(oxazoline)-NaBARF catalyst system, leading to cyclopentanones are highest with sulfonyl substituents on the carbene carbon, and furthermore, the impact is enhanced by increased steric demand on the sulfonyl substituent (up to 91%ee). Enantioselective intramolecular C–H insertion reactions of α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones are reported for the first time.

The hazardous diazo transfer reagent mesyl azide has been safely generated and used in situ for continuous diazo transfer as part of an integrated synthetic process with an embedded safety quench. Diazo transfer to β-keto esters and a β-ketosulfone was successful. In-line phase separation, by means of a continuous liquid–liquid separator, enabled direct telescoping with a thermal Wolff rearrangement.

Hydrolase-catalysed dynamic kinetic resolutions of chroman-2-ol and 3-methyl chroman-2-ol can be effected with up to 88% conversion and 92% ee through the use of organic solvents. Extension to the resolution of the tolterodine precursor 1 proved more challenging. The presence of the remote phenyl substituent had a significant impact on the resolution and it was not possible to achieve high enantioselectivity together with efficient conversion from the focussed panel of enzymes screened.Download high-res image (36KB)Download full-size image

By tuning the steric properties of the acyl group to control the efficiency and selectivity of the resolution, 2-phenyl-1-propanol 1a was prepared by lipase-catalysed hydrolysis using a short-chain acyl group, with E-values of up to 66 (ee up to 95%). 2-Phenylbutan-1-ol 1b was similarly resolved (up to 86% ee) using the optimised conditions, while the ester of the more sterically demanding 3-methyl-2-phenylbutan-1-ol 1c proved resistant to enzymatic hydrolysis under these conditions.Download high-res image (93KB)Download full-size image

Enantio- and diastereoselective hydrogenation of β-keto-γ-lactams with a ruthenium–BINAP catalyst, involving dynamic kinetic resolution, has been employed to provide a general, asymmetric approach to β-hydroxy-γ-lactams, a structural motif common to several bioactive compounds. Full conversion to the desired β-hydroxy-γ-lactams was achieved with high diastereoselectivity (up to >98% de) by addition of catalytic HCl and LiCl, while β-branching of the ketone substituent demonstrated a pronounced effect on the modest to excellent enantioselectivity (up to 97% ee) obtained.

Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small quantities of tosyl azide were accessed in a ‘one pot’ batch procedure using shelf stable, readily available reagents. For large scale diazo transfer reactions tosyl azide was generated and used in a telescoped flow process, to mitigate the risks associated with handling potentially explosive reagents on scale. The in situ formed tosyl azide was used to rapidly perform diazo transfer to a range of acceptors, including β-ketoesters, β-ketoamides, malonate esters and β-ketosulfones. An effective in-line quench of sulfonyl azides was also developed, whereby a sacrificial acceptor molecule ensured complete consumption of any residual hazardous diazo transfer reagent. The telescoped diazo transfer process with in-line quenching was used to safely prepare over 21 g of an α-diazocarbonyl in >98% purity without any column chromatography.

As α-carboxy nucleoside phosphonates (α-CNPs) have demonstrated a novel mode of action of HIV-1 reverse transcriptase inhibition, structurally related derivatives were synthesized, namely the malonate 2, the unsaturated and saturated bisphosphonates 3 and 4, respectively and the amide 5. These compounds were evaluated for inhibition of HIV-1 reverse transcriptase in cell-free assays. The importance of the α-carboxy phosphonoacetic acid moiety for achieving reverse transcriptase inhibition, without the need for prior phosphorylation, was confirmed. The malonate derivative 2 was less active by two orders of magnitude than the original α-CNPs, while displaying the same pattern of kinetic behavior; interestingly the activity resides in the “L”-enantiomer of 2, as seen with the earlier series of α-CNPs. A crystal structure with an RT/DNA complex at 2.95 Å resolution revealed the binding of the “L”-enantiomer of 2, at the polymerase active site with a weaker metal ion chelation environment compared to 1a (T-α-CNP) which may explain the lower inhibitory activity of 2.

•Metal-carbene C–H insertion of diazoacetamides leads to the formation of lactams.•Substrate and catalyst effects determine reactivity and selectivity.•Excellent chemo-, regio- and stereocontrol can be achieved.Intramolecular C–H insertion reactions of α-diazocarbonyl compounds typically proceed with preferential five-membered ring formation. However, the presence of a heteroatom such as nitrogen can activate an adjacent C–H site towards insertion resulting in regiocontrol issues. In the case of α-diazoacetamide derivatives, both β- and γ-lactam products are possible owing to this activating effect. Both β- and γ-lactam products are powerful synthetic building blocks in the area of organic synthesis, as well as a common scaffold in a range of natural and pharmaceutical products and therefore C–H insertion reactions to form such compounds are attractive processes.Figure optionsDownload full-size imageDownload as PowerPoint slide

A systematic investigation of the influence of substitution at positions C-2 and C-3 on the azulenone skeleton, based on NMR characterisation, is discussed with particular focus on the impact of the steric and electronic characteristics of substituents on the position of the norcaradiene–cycloheptatriene (NCD–CHT) equilibrium. Variable temperature (VT) NMR studies, undertaken to enable the resolution of signals for the equilibrating valence tautomers revealed, in addition, interesting shifts in the equilibrium.

There is a growing trend in Ireland toward greater collaboration between academia and the pharmaceutical industry. This is an activity encouraged at a national policy level as a means of providing researchers from academic institutions the opportunity to gain important first-hand experience in a commercial research environment, while also providing industry access to expertise and resources to develop new and improved processes for timely medicines. The participating company benefits in terms of its growth, the evolution of its strategic research and development, and the creation of new knowledge that it can use to generate commercial advantage. The research institute benefits in terms of developing skill sets, intellectual property, and publications, in addition to access to identified current industry challenges. A case study is provided describing the collaborative partnership between a synthetic chemistry research team at University College Cork (UCC) and Eli Lilly and Company.

The synthesis of the first series of a new class of nucleoside phosphonate analogues is described. Addition of a carboxyl group at the α position of carbocyclic nucleoside phosphonate analogues leads to a novel class of potent HIV reverse transcriptase (RT) inhibitors, α-carboxy nucleoside phosphonates (α-CNPs). Key steps in the synthesis of the compounds are Rh-catalyzed O–H insertion and Pd-catalyzed allylation reactions. In cell-free assays, the final products are markedly inhibitory against HIV RT and do not require phosphorylation to exhibit anti-RT activity, which indicates that the α-carboxyphosphonate function is efficiently recognized by HIV RT as a triphosphate entity, an unprecedented property of nucleoside monophosph(on)ates.

The first examples of asymmetric copper-catalysed intramolecular C–H insertion reactions of 2-sulfonyl-2-diazoacetamides are described; trans γ-lactams with up to 82% ee are achieved with the CuCl2-bisoxazoline-NaBARF catalyst system. The reactions generally display high efficiency and high trans selectivity, and also a strong regiochemical preference for insertion to lead to the formation of 5-membered rings over 4-membered rings. In cases where there are competing C–H insertion pathways available, to form sulfolanes or thiopyrans, only the insertion into the amide chain to form γ-lactams is observed. With phenylsulfonyl derivatives, a minor competing C–H insertion pathway leading to β-lactams is seen; interestingly, changing the identity of the copper ligand changes the product ratio of β/γ-lactams. The copper catalysed reactions compare favorably in terms of efficiency and enantioselectivity to the corresponding reactions catalysed by commercially available chiral rhodium catalysts.

The novel preparation of 2-aminopyridoimidazoles and 2-aminobenzimidazoles via the cyclization of (2-aminopyridin-3-yl)urea and (2-aminophenyl)urea substrates in the presence of phosphorus oxychloride is described. This methodology is demonstrated for a range of urea substrates with aminoimidazole products obtained in good yields and with excellent levels of purity.

Diazo transfer adjacent to a sulfoxide moiety to provide stable, isolable α-diazo-β-oxo sulfoxides has been achieved. Use of monocyclic and bicyclic sulfoxide precursors is critical in enabling isolation of stable derivatives, through introduction of conformational constraint, while acyclic α-diazo-β-oxo sulfoxides are too labile to isolate and characterize.

Copper-catalysed intramolecular C–H insertion reactions of α-diazo-β-keto esters and α-diazo-β-keto phosphonates are described, with moderate-to-good levels of enantioselectivity achieved for reactions employing the borate additive sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBARF). Notably, the first example of asymmetric induction reported to date for intramolecular C–H insertion of an α-diazo-β-keto phosphonate is also described.

Hydrolase-catalysed kinetic resolutions to provide enantioenriched α-substituted 3-aryl alkanoic acids are described. (S)-2-Methyl-3-phenylpropanoic acid (S)-1a was prepared in 96% ee by Pseudomonas fluorescens catalysed ester hydrolysis, while, Candida antarctica lipase B (immob) resolved the α-ethyl substituted 3-arylalkanoic acid (R)-1b in 82% ee. The influence of the position of the substituent relative to the ester site on the efficiency and enantioselectivity of the biotransformation is also explored; the same lipases were found to resolve both the α- and β-substituted alkanoic acids. Furthermore, the steric effect of substituents at the C2 stereogenic centre relative to that for their C3 substituted counterparts on the efficiency and stereoselectivity is discussed.(S)-2-Methyl-3-phenylpropanoic acidC10H12O296% ee[α]D20=+28.0 (c 0.82, CHCl3)Source of chirality: Lipase mediated hydrolysisAbsolute configuration: (S)Ethyl (R)-2-methyl-3-phenylpropanoateC12H16O2>98% ee[α]D20=-36.4 (c 1.0, CHCl3)Source of chirality: Lipase mediated hydrolysisAbsolute configuration: (R)(R)-2-Benzylbutanoic acidC11H14O282% ee[α]D20=-43.8 (c 1.0, CH2Cl2)Source of chirality: Lipase mediated hydrolysisAbsolute configuration: (R)Ethyl (S)-2-benzylbutanoateC13H18O226% ee[α]D20=+6.8 (c 1.0, CH2Cl2)Source of chirality: Lipase mediated hydrolysisAbsolute configuration: (S)

The effect of the modification of bis(oxazoline) ligands on the outcome of copper-catalysed C–H insertion and aromatic addition reactions is described. In general, these reactions display minimum sensitivity in terms of enantiocontrol to variation of the electronic properties of the aryl moiety of the ligand however, some influence is observed for C–H insertions employing naphthyl-substituted bis(oxazolines) and for aromatic addition reactions of biphenyl diazo ketone substrates. The synthesis of the modified bis(oxazolines), which include four novel structures, is also described.2,2-Bis{2-[4(R)-(4-chlorophenyl)-1,3-oxazolinyl]}propaneC21H20Cl2N2O2[α]D20=+133.0 (c 0.37, CH2Cl2)Source of chirality: (R)-2-amino-2-(4-chlorophenyl)ethanolAbsolute configuration: (R)2,2-Bis{2-[4(R)-(4-fluorophenyl)-1,3-oxazolinyl]}propaneC21H20F2N2O2Chiralcel OD-H; hexane/IPA; 98/2; 0.5 mL/min254 nm; tR(R) = 31 min; tR(S) = 34 min[α]D20=+125.7 (c 0.30, CHCl3)Source of chirality: (R)-2-amino-2-(4-fluorophenyl)ethanolAbsolute configuration: (R)2,2-Bis{2-[4(R)-(4-methoxyphenyl)-1,3-oxazolinyl]}propaneC23H26N2O4[α]D25=+183.2 (c 0.50, CHCl3)Source of chirality: (R)-4-hydroxyglycineAbsolute configuration: (R)2,2′-(Propane-2,2-diyl)bis[4-(4-chlorobenzyl)-4,5-dihydrooxazole]C23H24Cl2N2O2Chiralcel OD-H; hexane/IPA; 95/5; 1 mL/min;220 nm; tR(R) = 14 min; tR(S) = 32 min[α]D20=+53.5 (c 0.30, CHCl3)Source of chirality: (R)-2-amino-3-(4-chlorophenyl)propan-1-olAbsolute configuration: (R)2,2′-(Propane-2,2-diyl)bis[4-(4-methoxybenzyl)-4,5-dihydrooxazole]C25H30N2O4Chiralcel OD-H; hexane/IPA; 95/5; 1 mL/min231 nm; tR(R) = 26 min; tR(S) = 40 min[α]D20=+25.7 (c 0.30, CHCl3)Source of chirality: (R)-2-amino-3-(4-methoxyphenyl)propan-1-olAbsolute configuration: (R)2,2′-(Propane-2,2-diyl)bis[4-(4-naphthalene-2-ylmethyl)-4,5-dihydrooxazole]C31H30N2O2Chiralcel OD-H; hexane/IPA; 95/5; 1 mL/min218 nm; tR(R) = 27 min; tR(S) = 41 min[α]D20=+33.7 (c 0.30, CHCl3)Source of chirality: (R)-2-amino-3-(naphthalene-2-yl)propan-1-olAbsolute configuration: (R)

An efficient synthetic approach leading to introduction of the hydroxymethyl group to an aryl moiety via combination of the Bouveault formylation and hydride reduction has been optimized using a rational, mechanistic-based approach. This approach enabled telescoping of the two steps into a single efficient process, readily amenable to scaleup.

Design, synthesis and structural characterization of a series of diphenylacetylene derivatives bearing organosulfur, amide and amine moieties has been achieved in which the molecular conformation is controlled through variation of the hydrogen bond properties on alteration of the oxidation level of sulfur.

The palladium-catalysed decarboxylative cross-coupling of heterocyclic aromatic carboxylates and aryl halides is described. The cross-coupling proceeds under relatively mild conditions using catalytic Pd(0) and tetrabutylammonium bromide (TBAB). Utilizing a mixed solvent system consisting of N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone (NMP), the cross-coupling system operated at temperatures ranging from 80 to 140 °C.

The asymmetric synthesis of cis-7-methoxycalamenene 1 has been accomplished using the intramolecular Buchner reaction of α-diazoketone 7 as the key step in the synthetic route. Upon reduction of the equilibrating azulenone structure 8, the resulting azulenol 9 rearranges to dihydronaphthalene 10 containing the 6,6-membered bicyclic ring system characteristic of 1, by means of an acid-catalyzed aromatization process. Transformation of 10 to 1 is accomplished through a three-step reaction sequence.

Copper-catalyzed asymmetric sulfoxidation of aryl benzyl and aryl alkyl sulfides, using aqueous hydrogen peroxide as the oxidant, has been investigated. A relationship between the steric effects of the sulfide substituents and the enantioselectivity of the oxidation has been observed, with up to 93% ee for 2-naphthylmethyl phenyl sulfoxide, in modest yield in this instance (up to 30%). The influence of variation of solvent and ligand structure was examined, and the optimized conditions were then used to oxidize a number of aryl alkyl and aryl benzyl sulfides, producing sulfoxides in excellent yields in most cases (up to 92%), and good enantiopurities in certain cases (up to 84% ee).

Asymmetric copper-catalysed intramolecular C–H insertion reactions of a series of α-diazo-β-keto sulfones are reported. Enantioselectivities of up to 82% ee were achieved in moderate to good yield. These results represent the highest level of enantiocontrol achieved to date for a copper-catalysed cyclopentanone synthesis via C–H insertion.

Synthetically versatile conjugate addition of a range of carbon, nitrogen, oxygen, sulfur and selenium nucleophiles to the highly functionalised 2-thio-3-chloroacrylamides is described. The stereochemical and synthetic features of this transformation are discussed in detail. In most instances, the nucleophile replaces the chloro substituent with retention of stereochemistry. With the oxygen nucleophiles, a second addition can occur leading to acetals, while with the nitrogen nucleophiles, E-Z isomerism occurs in the resulting enamine derivatives. The ratio of the E/Z isomers can be rationalised on the basis of the substituent and the level of oxidation.

Potatoes, tomatoes, and aubergines are all species of the Solanum genus and contain a vast array of secondary metabolites including calystegine alkaloids, phenolic compounds, lectins, and glycoalkaloids. Glycoalkaloids have been the subject of many literature papers, occur widely in the human diet, and are known to induce toxicity. Therefore, from a food safety perspective further information is required regarding their analysis, toxicity, and bioavailability. This is especially important in crop cultivars derived from wild species to prevent glycoalkaloid-induced toxicity. A comprehensive review of the bioactivity of glycoalkaloids and their aglycones of the Solanum species, particularly focused on comparison of their bioactivities including their anticancer, anticholesterol, antimicrobial, anti-inflammatory, antinociceptive, and antipyretic effects, toxicity, and synergism of action of the principal Solanum glycoalkaloids, correlated to differences of their individual molecular structures is presented.

Hydrolase catalysed kinetic resolutions leading to a series of 3-aryl alkanoic acids (⩾94% ee) are described. Hydrolysis of the ethyl esters with a series of hydrolases was undertaken to identify biocatalysts that yield the corresponding acids with excellent enantiopurity in each case. Steric and electronic effects on the efficiency and enantioselectivity of the biocatalytic transformation were also explored.(S)-3-Phenylbutanoic acidC10H12O2[α]D20=+27.9 (c 1.0, EtOH)98% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (S)(R)-Ethyl 3-phenylbutanoateC12H16O2[α]D20=-27.6 (c 1.1, CHCl3)99% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (R)(R)-3-Phenylpentanoic acidC11H14O2[α]D20=-33.7 (c 1.37, C6H6)90% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (R)(S)-Ethyl 3-phenylpentanoateC13H18O2[α]D20=+9.5 (c 0.55, CHCl3)65% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (S)(S)-4-Methyl-3-phenylpentanoic acidC12H16O2[α]D20=-24.4 (c 0.655, CHCl3)98% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (S)(R)-Ethyl 4-methyl-3-phenylpentanoateC14H20O2[α]D20=+7.1 (c 1.0, CHCl3)26% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (R)(S)-4,4-Dimethyl-3-phenylpentanoic acidC13H18O2[α]D20=-10.5 (c 0.114, CHCl3)99% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (S)(R)-Ethyl 4,4-dimethyl-3-phenylpentanoateC15H22O2[α]D20=+8.0 (c 1.0, CHCl3)12% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (R)(S)-3-(4-Methylphenyl)butanoic acidC11H14O2[α]D20=+31.8 (c 1.0, CHCl3)⩾99% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (S)(R)-Ethyl 3-(4-methylphenyl)butanoateC13H18O2[α]D20=-28.7 (c 3.5, CHCl3)97% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (R)(S)-3-(3-Methylphenyl)butanoic acidC11H14O2[α]D20=+32.3 (c 0.622, CHCl3)⩾99% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (S)(R)-Ethyl 3-(3-methylphenyl)butanoateC13H18O2[α]D20=-24.4 (c 1.0, CHCl3)94% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (R)(S)-3-(2-Methylphenyl)butanoic acidC11H14O2[α]D20=+24.2 (c 1.38, CHCl3)⩾99% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (S)(R)-Ethyl 3-(2-methylphenyl)butanoateC13H18O2[α]D20=-11.0 (c 1.0, CHCl3)98% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (R)(S)-2-(4-Methoxyphenyl)butanoic acidC11H14O3[α]D20=+26.3 (c 1.0, EtOH)97% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (S)(R)-Ethyl 3-(4-methoxyphenyl)butanoateC13H18O3[α]D20=-30.0 (c 1.034, CHCl3)99% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (R)(S)-3-(4-Fluorophenyl)butanoic acidC10H11FO2[α]D20=+30.5 (c 1.016, CHCl3)97% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (S)(R)-Ethyl 3-(4-fluorophenyl)butanoateC12H15FO2[α]D20=-24.3 (c 1.0, CHCl3)⩾99% EeSource of chirality: lipase mediated hydrolysisAbsolute configuration: (R)

The preparation of enantiopure cyanohydrin acetates via enzymatic hydrolysis has been investigated by screening a range of biocatalysts and reaction conditions. Enzymatic resolution has been optimised through variation of the hydrolase biocatalyst and reaction conditions leading to synthetically useful routes to enantiopure cyanohydrin acetates.(R)-(−)-Acetoxy-3,4,5-trimethoxyphenylacetonitrileC13H15NO5[α]D20=-9.7 (c 3.0, CHCl3)>99% eeSource of chirality: enzymatic hydrolysisAbsolute configuration: (R)(R)-(+)-Acetoxy-2-bromophenylacetonitrileC10H8BrNO2[α]D20=+11.6 (c 3.0, CHCl3)>99% eeSource of chirality: enzymatic hydrolysisAbsolute configuration: (R)(R)-(+)-Acetoxy-2,5-difluorophenylacetonitrileC10H7F2NO2[α]D20=+17.7 (c 2.8, CHCl3)>99% eeSource of chirality: enzymatic hydrolysisAbsolute configuration: (R)(S)-(+)-Acetoxy-2-t-butylphenylacetonitrileC14H17NO2[α]D20=+8.9 (Please check the optical rotation value of compound C14H17NO2.c 4.4, CHCl3)>98% eeSource of chirality: enzymatic hydrolysisAbsolute configuration: (S)(R)-(+)-Acetoxy-2,5-dimethoxyphenylacetonitrileC12H13NO4[α]D20=+17.9 (c 1.7, CHCl3)>99% eeSource of chirality: enzymatic hydrolysisAbsolute configuration: (R)(R)-(−)-Hydroxy-2-bromophenylacetonitrileC8H6BrNO[α]D20=-13.4 (c 1.1, CHCl3)>99% eeSource of chirality: enzymatic hydrolysisAbsolute configuration: (R)

This critical review, which is relevant to researchers in synthetic organic chemistry, focuses on asymmetric 1,3-dipolar cycloadditions with acrylamides. The use of chiral acrylamides as dipolarophiles leads to high levels of stereocontrol, due to conformational constraint in the acrylamides. Employment of chiral tertiary acrylamides containing nitrogen heterocycles is particularly effective in controlling the stereoselectivity. Following a general overview of 1,3-dipolar cycloadditions, the main body of the review focuses on asymmetric 1,3-dipolar cycloadditions of acrylamides with nitrile oxides, nitrones, diazoalkanes and azomethine ylides, with particular emphasis on the rationale for the observed stereocontrol (215 references).

Excellent enantiocontrol (up to 98% ee) is achieved in copper catalyzed C−H insertions of α-diazosulfones to form thiopyrans, with up to 60% ee in C−H insertions leading to sulfolanes.

Hydrogen bonding between the sulfur oxygens and the acidic α-hydrogens in sulfoxides and sulfones is proposed as a supramolecular synthon in crystal engineering. A systematic analysis of supramolecular interactions in the solid state of a series of structurally related aryl benzyl sulfides, sulfoxides and sulfones was undertaken to establish the extent to which such hydrogen bonds persist as a structure determining feature in the solid state. The impact of the level of oxidation at sulfur, steric and electronic effects of substituents on the aryl rings and methyl substitution α to the sulfur functional group on the solid state structure of the compounds have been explored. The impact of stereochemical features, including relative and absolute stereochemistry, is also discussed.

2-Thio-3-chloroacrylamides undergo 1,3-dipolar cycloadditions with diazoalkanes leading to a series of novel pyrazolines and pyrazoles. The mechanistic and synthetic features of the cycloadditions to the 2-thio-3-chloroacrylamides at both the sulfide and sulfoxide levels of oxidation are rationalised on the basis of the nature of the substituents.

The Diels–Alder cycloadditions of cyclopentadiene and 2,3-dimethyl-1,3-butadiene to a range of 2-thio-3-chloroacrylamides under thermal, catalytic and microwave conditions is described. The influence of reaction conditions on the outcome of the cycloadditions, in particular the stereoselectivity and reaction efficiency, is discussed. While the cycloadditions have been attempted at the sulfide, sulfoxide and sulfone levels of oxidation, use of the sulfoxide derivatives is clearly beneficial for stereoselective construction of Diels–Alder cycloadducts.

The synthesis and structural characterization of a series of oxides of stigmasterol is described providing a valuable series of reference standards for these oxides, analogous to the cholesterol oxidation products (COPs) which have been shown to have detrimental biological effects. Biological evaluation of the oxides of phytosterols is significant in the context of increased dietary use of phytosterols in the drive to reduce cholesterol absorption.

The kinetic bioresolution of 2-nitrocyclohexanol 1 was investigated by screening a range of hydrolases both for enantioselective transesterification and for enantioselective hydrolysis of the corresponding acetate. By appropriate choice of biocatalyst and conditions, both enantiomers of cis and trans 2-nitrocyclohexanol 1 can be accessed in enantiopure form.(1S,2S)-trans-2-NitrocyclohexanolC6H11NO3Source of chirality: hydrolase mediated transesterification[α]D20=+48.6 (c 1.0, CH2Cl2)>98% ee Chiral HPLC Daicel OJ-H columnAbsolute configuration: (1S,2S)(1R,2R)-trans-2-Nitrocyclohexyl acetateC8H13NO4Source of chirality: hydrolase mediated transesterification[α]D20=-40.65 (c 1.0, CH2Cl2)>98% ee Chiral HPLC Daicel OJ-H columnAbsolute configuration: (1R,2R)

Diastereoselective sulfur oxidation in 2-thio-3-chloroacrylamides is described. A range of chiral amine auxiliaries was incorporated in the β-chloroacrylamide, and the efficiency with which the stereochemistry was relayed to the sulfur centre during sulfoxidation was investigated. Diastereomeric ratios of up to 3.3:1 were achieved.2-(Benzylthio)-N-[(R)-1-phenylethyl]propanamideC18H21NOS[α]D20=+43.2 (c 0.1, CHCl3)Source of chirality: (R)-(+)-α-methylbenzylamine2-(Benzylthio)-N-[(1R)-2-hydroxy-1-phenylethyl]propanamideC18H21NO2S[α]D20=-49.5 (c 0.3, EtOH)Source of chirality: (R)-(+)-2-phenylglycinol2-(Benzylthio)-N-[(S)-1-hydroxy-3-phenylpropan-2-yl]propanamideC19H23NO2S[α]D20=-17.9 (c 0.4, EtOH)Source of chirality: d-(+)-phenylalaninol2-(Benzylthio)-N-[(S)-1-hydroxy-3,3-dimethylbutan-2-yl]propanamideC16H25NO2S[α]D20=+6.0 (c 0.5, CHCl3)Source of chirality: (S)-(+)-tert-leucinolN-[(R)-1-Phenylethyl]-2-(phenylthio)propanamideC17H19NOS[α]D20=+58.1 (c 0.2, CHCl3)Source of chirality: (R)-(+)-α-methylbenzylamineN-[(1R)-2-Hydroxy-1-phenylethyl]-2-(phenylthio)propanamideC17H19NO2S[α]D20=-49.9 (c 0.1, EtOH)Source of chirality: (R)-(+)-2-phenylglycinolN-[(1R,2S)-2,3-Dihydro-2-hydroxy-1H-inden-1-yl]-2-(phenylthio)propanamideC18H19NO2S[α]D20=+19.1 (c 0.2, CHCl3)Source of chirality: (1R,2S)-(+)-cis-1-amino-2-indanolN-[(S)-1-Hydroxy-3-phenylpropan-2-yl]-2-(phenylthio)propanamideC18H21NO2S[α]D20=+27.0 (c 0.1, EtOH)Source of chirality: d-(+)-phenylalaninolN-[(S)-1-Hydroxy-3,3-dimethylbutan-2-yl]-2-(phenylthio)propanamideC15H23NO2S[α]D20=+1.8 (c 0.5, CHCl3)Source of chirality: (S)-(+)-tert-leucinolN-[(R)-3,3-Dimethylbutan-2-yl]-2-(phenylthio)propanamideC15H23NOS[α]D20=+20.4 (c 0.14, CHCl3)Source of chirality: (S)-(+)-3,3-dimethyl-2-butylamine(Z)-2-(Benzylthio)-3-chloro-N-[(R)-1-phenylethyl)acrylamideC18H18ClNOS[α]D20=+66.5 (c 0.5, CHCl3)Source of chirality: (R)-(+)-α-methylbenzylamine(Z)-2-(Benzylthio)-3-chloro-N-[(R)-2-hydroxy-1-phenylethyl]acrylamideC18H18ClNO2S[α]D20=-54.2 (c 0.1, CHCl3)Source of chirality: (R)-(+)-2-phenylglycinol(Z)-2-(Benzylthio)-3-chloro-N-[(S)-1-hydroxy-3-phenylpropan-2-yl]acrylamideC19H20ClNO2S[α]D20=-30.0 (c 0.1, CHCl3)Source of chirality: d-(+)-phenylalaninol(Z)-2-(Benzylthio)-3-chloro-N-[(S)-1-hydroxy-3,3-dimethylbutan-2-yl]acrylamideC16H22ClNO2S[α]D20=+106.0 (c 0.1, CHCl3)Source of chirality: (S)-(+)-tert-leucinol(Z)-2-(Phenylthio)-3-chloro-N-[(R)-1-phenylethyl)acrylamideC17H16ClNOS[α]D20=+6.4 (c 0.5, EtOH)Source of chirality: (R)-(+)-α-methylbenzylamine(Z)-3-Chloro-N-[(R)-2-hydroxy-1-phenylethyl]-2-(phenylthio)acrylamideC17H16ClNO2S[α]D20=+64.5 (c 0.5, CHCl3)Source of chirality: (R)-(+)-2-phenylglycinol(Z)-3-Chloro-N-[(1R,2S)-2,3-dihydro-2-hydroxy-1H-inden-1-yl]-2-(phenylthio)acrylamideC18H16ClNO2S[α]D20=+60.1 (c 0.5, CHCl3)Source of chirality: (1R,2S)-(+)-cis-1-amino-2-indanol(Z)-3-Chloro-N-[(S)-1-hydroxy-3-phenylpropan-2-yl]-2-(phenylthio)acrylamideC18H18ClNO2S[α]D20=+84.3 (c 0.1, EtOH)Source of chirality: d-(+)-phenylalaninol(Z)-3-Chloro-N-[(S)-1-hydroxy-3,3-dimethylbutan-2-yl]-2-(phenylthio)acrylamideC15H20ClNO2S[α]D20=-67.7 (c 0.5, CHCl3)Source of chirality: (S)-(+)-tert-leucinol(Z)-3-Chloro-N-[(R)-3,3-dimethylbutan-2-yl]-2-(phenylthio)acrylamideC15H20ClNOS[α]D20=+92.9 (c 0.1, CHCl3)Source of chirality: (S)-(+)-3,3-dimethyl-2-butylamine(Z)-2-(Ss)-(Benzylsulfinyl)-3-chloro-N-[(R)-1-phenylethyl]acrylamideC18H18ClNO2S[α]D20=-179.0 (c 0.4, CHCl3)Source of chirality: diastereoselective oxidationAbsolute configuration: (Ss)-(1′S)(Z)-2-(Ss/Rs)-(Benzylsulfinyl)-3-chloro-N-[(R)-2-hydroxy-1-phenylethyl]acrylamideC18H18NO3SCl[α]D20=-67.5 (c 0.1, CHCl3) and [α]D20=+122.6 (c 0.08, CHCl3)Source of chirality: diastereoselective oxidation(Z)-3-Chloro-N-[(R)-2-hydroxy-1-phenylethyl]-2-(Ss/Rs)-(benzenesulfinyl)acrylamideC17H16NO3SCl[α]D20=-139.5 (c 0.1, CHCl3) and [α]D20=-65.0 (c 0.1, CHCl3)Source of chirality: diastereoselective oxidation(Z)-3-Chloro-N-[(1R,2S)-2,3-dihydro-2-hydroxy-1H-inden-1-yl]-2-(Ss/Rs)-(benzenesulfinyl)acrylamideC18H17NO3S35Cl[α]D20=+99.3 (c 0.1, CHCl3)Source of chirality: diastereoselective oxidation(Z)-2-(Ss/Rs)-(Benzylsulfinyl)-3-chloro-N-[(S)-1-hydroxy-3-phenylpropan-2-yl]acrylamideC19H20NO3SClSource of chirality: diastereoselective oxidation(Z)-3-Chloro-N-[(S)-1-hydroxy-3-phenylpropan-2-yl]-2-(Ss/Rs)-(benzenesulfinyl)acrylamideC18H18NO3SClSource of chirality: diastereoselective oxidation(Z)-2-(Ss/Rs)-(Benzylsulfinyl)-3-chloro-N-[(S)-1-hydroxy-3,3-dimethylbutan-2-yl]acrylamideC16H22NO3SCl[α]D20=+193.7 (c 0.2, CHCl3) and [α]D20=-123.50 (c 0.12, CHCl3)Source of chirality: diastereoselective oxidation(Z)-3-Chloro-N-[(S)-1-hydroxy-3,3-dimethylbutan-2-yl]-2-(Ss/Rs)-(benzenesulfinyl)acrylamideC15H20NO3SCl[α]D20=+127.20 (c 0.1, CHCl3) and [α]D20=-109.30 (c 0.2, CHCl3)Source of chirality: diastereoselective oxidation

The investigation of the stereoselective reaction of α-thiopropanoyloxazolidin-2-ones with NCS to yield α-thio-β-chloropropenyloxazolidin-2-ones is described. Diastereoselective sulfur oxidation of the resulting α-thio-β-chloropropenyloxazolidin-2-ones shows modest diastereocontrol. However, via a combination of diastereoselective oxidation and subsequent kinetic resolution in the sulfoxide oxidation, diastereoselectivities of up to 94% de have been achieved.

An investigation of the chemoselective and enantioselective oxidation of α-thio-β-chloroacrylamides is described. The α-thio-β-chloroacrylamides can be selectively oxidised to either the racemic sulfoxide or the sulfone very efficiently. The asymmetric sulfur oxidation of α-thio-β-chloroacrylamides is also discussed, with sulfoxide enantioselectivities of up to 52% ee achieved using the Kagan oxidation, and up to 71% ee when the Bolm oxidation is employed. While the enantioselectivities achieved are modest, these are among the most highly functionalised sulfides investigated in catalytic asymmetric oxidation, and the resulting enantioenriched sulfoxides have significant synthetic potential.(S)-N-4′-Methylphenyl-Z-3-chloro-2-(n-butylsulfinyl)propenamideEe = 51%[α]D24=-84 (c 1.8, DCM)Source of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-N-4′-Fluorophenyl-Z-3-chloro-2-(n-butylsulfinyl)propenamideEe = 51%[α]D24=-98 (c 1.3, DCM)Source of chirality: asymmetric synthesisAbsolute configuration: (S)(S)-N-4′-Fluorophenyl-Z-3-chloro-2-(methylsulfinyl)propenamideEe = 71% (>98% after recrystallisation)[α]D24=-117 (c 2, acetone)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

Treatment of a series of α-thioamides with N-chlorosuccinimide results in efficient transformation to the analogous α-thio-β-chloroacrylamides. The mechanistic pathway has been established through isolation and characterisation of intermediate compounds. The scope of the transformation has been explored—aryl and alkylthio substituents, primary, secondary and tertiary amides can be employed. In most instances, the chloroacrylamides are formed exclusively as the Z-stereoisomer; however, with tertiary propanamides or with amides derived from butanoic or pentanoic acid a mixture of E- and Z-stereoisomers is formed.

The substrate scope of three mutants of phenylalanine dehydrogenase as biocatalysts for the transformation of a series of 2-oxo acids, structurally related to phenylpyruvic acid, to the analogous α-amino acids, non-natural analogues of phenylalanine, has been investigated. The mutant enzymes are more tolerant than the wild type enzyme of the non-natural substrates, especially those with substituents at the 4-position on the phenyl ring. Excellent enantiocontrol resulted in all cases.

•Method developed for extraction and analysis of an antimicrobial coated orthopedic device.•Evaluated the effect of light, humidity, oxygen and heat on the storage stability of drug coatings.•Also evaluated the influence of γ-ray sterilization on the chemical composition of drug coatings.A systematic approach was developed to investigate the stability of gentamicin sulfate (GS) and GS/poly (lactic-co-glycolic acid) (PLGA) coatings on hydroxyapatite surfaces. The influence of environmental factors (light, humidity, oxidation and heat) upon degradation of the drug in the coatings was investigated using liquid chromatography with evaporative light scattering detection and mass spectrometry. GS coated rods were found to be stable across the range of environments assessed, with only an oxidizing atmosphere resulting in significant changes to the gentamicin composition. In contrast, rods coated with GS/PLGA were more sensitive to storage conditions with compositional changes being detected after storage at 60 °C, 75% relative humidity or exposure to light. The effect of γ-irradiation on the coated rods was also investigated and found to have no significant effect. Finally, liquid chromatography–mass spectrometry analysis revealed that known gentamines C1, C1a and C2 were the major degradants formed. Forced degradation of gentamicin coatings did not produce any unexpected degradants or impurities.Download high-res image (184KB)Download full-size image

This critical review, which is relevant to researchers in synthetic organic chemistry, focuses on asymmetric 1,3-dipolar cycloadditions with acrylamides. The use of chiral acrylamides as dipolarophiles leads to high levels of stereocontrol, due to conformational constraint in the acrylamides. Employment of chiral tertiary acrylamides containing nitrogen heterocycles is particularly effective in controlling the stereoselectivity. Following a general overview of 1,3-dipolar cycloadditions, the main body of the review focuses on asymmetric 1,3-dipolar cycloadditions of acrylamides with nitrile oxides, nitrones, diazoalkanes and azomethine ylides, with particular emphasis on the rationale for the observed stereocontrol (215 references).

Enantioselectivities in C–H insertion reactions, employing the copper-bis(oxazoline)-NaBARF catalyst system, leading to cyclopentanones are highest with sulfonyl substituents on the carbene carbon, and furthermore, the impact is enhanced by increased steric demand on the sulfonyl substituent (up to 91%ee). Enantioselective intramolecular C–H insertion reactions of α-diazo-β-keto phosphine oxides and 2-diazo-1,3-diketones are reported for the first time.

A systematic investigation of the influence of substitution at positions C-2 and C-3 on the azulenone skeleton, based on NMR characterisation, is discussed with particular focus on the impact of the steric and electronic characteristics of substituents on the position of the norcaradiene–cycloheptatriene (NCD–CHT) equilibrium. Variable temperature (VT) NMR studies, undertaken to enable the resolution of signals for the equilibrating valence tautomers revealed, in addition, interesting shifts in the equilibrium.

As α-carboxy nucleoside phosphonates (α-CNPs) have demonstrated a novel mode of action of HIV-1 reverse transcriptase inhibition, structurally related derivatives were synthesized, namely the malonate 2, the unsaturated and saturated bisphosphonates 3 and 4, respectively and the amide 5. These compounds were evaluated for inhibition of HIV-1 reverse transcriptase in cell-free assays. The importance of the α-carboxy phosphonoacetic acid moiety for achieving reverse transcriptase inhibition, without the need for prior phosphorylation, was confirmed. The malonate derivative 2 was less active by two orders of magnitude than the original α-CNPs, while displaying the same pattern of kinetic behavior; interestingly the activity resides in the “L”-enantiomer of 2, as seen with the earlier series of α-CNPs. A crystal structure with an RT/DNA complex at 2.95 Å resolution revealed the binding of the “L”-enantiomer of 2, at the polymerase active site with a weaker metal ion chelation environment compared to 1a (T-α-CNP) which may explain the lower inhibitory activity of 2.

Heat and shock sensitive tosyl azide was generated and used on demand in a telescoped diazo transfer process. Small quantities of tosyl azide were accessed in a ‘one pot’ batch procedure using shelf stable, readily available reagents. For large scale diazo transfer reactions tosyl azide was generated and used in a telescoped flow process, to mitigate the risks associated with handling potentially explosive reagents on scale. The in situ formed tosyl azide was used to rapidly perform diazo transfer to a range of acceptors, including β-ketoesters, β-ketoamides, malonate esters and β-ketosulfones. An effective in-line quench of sulfonyl azides was also developed, whereby a sacrificial acceptor molecule ensured complete consumption of any residual hazardous diazo transfer reagent. The telescoped diazo transfer process with in-line quenching was used to safely prepare over 21 g of an α-diazocarbonyl in >98% purity without any column chromatography.

The first examples of asymmetric copper-catalysed intramolecular C–H insertion reactions of 2-sulfonyl-2-diazoacetamides are described; trans γ-lactams with up to 82% ee are achieved with the CuCl2-bisoxazoline-NaBARF catalyst system. The reactions generally display high efficiency and high trans selectivity, and also a strong regiochemical preference for insertion to lead to the formation of 5-membered rings over 4-membered rings. In cases where there are competing C–H insertion pathways available, to form sulfolanes or thiopyrans, only the insertion into the amide chain to form γ-lactams is observed. With phenylsulfonyl derivatives, a minor competing C–H insertion pathway leading to β-lactams is seen; interestingly, changing the identity of the copper ligand changes the product ratio of β/γ-lactams. The copper catalysed reactions compare favorably in terms of efficiency and enantioselectivity to the corresponding reactions catalysed by commercially available chiral rhodium catalysts.

Diazo transfer adjacent to a sulfoxide moiety to provide stable, isolable α-diazo-β-oxo sulfoxides has been achieved. Use of monocyclic and bicyclic sulfoxide precursors is critical in enabling isolation of stable derivatives, through introduction of conformational constraint, while acyclic α-diazo-β-oxo sulfoxides are too labile to isolate and characterize.

Asymmetric copper-catalysed intramolecular C–H insertion reactions of a series of α-diazo-β-keto sulfones are reported. Enantioselectivities of up to 82% ee were achieved in moderate to good yield. These results represent the highest level of enantiocontrol achieved to date for a copper-catalysed cyclopentanone synthesis via C–H insertion.

Synthetically versatile conjugate addition of a range of carbon, nitrogen, oxygen, sulfur and selenium nucleophiles to the highly functionalised 2-thio-3-chloroacrylamides is described. The stereochemical and synthetic features of this transformation are discussed in detail. In most instances, the nucleophile replaces the chloro substituent with retention of stereochemistry. With the oxygen nucleophiles, a second addition can occur leading to acetals, while with the nitrogen nucleophiles, E-Z isomerism occurs in the resulting enamine derivatives. The ratio of the E/Z isomers can be rationalised on the basis of the substituent and the level of oxidation.

Treatment of a series of α-thioamides with N-chlorosuccinimide results in efficient transformation to the analogous α-thio-β-chloroacrylamides. The mechanistic pathway has been established through isolation and characterisation of intermediate compounds. The scope of the transformation has been explored—aryl and alkylthio substituents, primary, secondary and tertiary amides can be employed. In most instances, the chloroacrylamides are formed exclusively as the Z-stereoisomer; however, with tertiary propanamides or with amides derived from butanoic or pentanoic acid a mixture of E- and Z-stereoisomers is formed.

2-Thio-3-chloroacrylamides undergo 1,3-dipolar cycloadditions with diazoalkanes leading to a series of novel pyrazolines and pyrazoles. The mechanistic and synthetic features of the cycloadditions to the 2-thio-3-chloroacrylamides at both the sulfide and sulfoxide levels of oxidation are rationalised on the basis of the nature of the substituents.

The Diels–Alder cycloadditions of cyclopentadiene and 2,3-dimethyl-1,3-butadiene to a range of 2-thio-3-chloroacrylamides under thermal, catalytic and microwave conditions is described. The influence of reaction conditions on the outcome of the cycloadditions, in particular the stereoselectivity and reaction efficiency, is discussed. While the cycloadditions have been attempted at the sulfide, sulfoxide and sulfone levels of oxidation, use of the sulfoxide derivatives is clearly beneficial for stereoselective construction of Diels–Alder cycloadducts.