Regio- and Enantioselective Asymmetric Transfer Hydrogenation of One Carbonyl Group in a Diketone through Steric Hindrance.

On the basis of steric hindrance, one carbonyl group in a diketone can be reduced in a regioselective manner, with high enantioselectivity. The methodology can be extended to ketones with varied length of hydrocarbon chain spacing, and the products can be converted by oxidation to hydroxy esters or lactones without loss of enantiopurity.

Increasing the versatility of the biphenyl-fused-dioxacyclodecyne class of strained alkynes.

Biphenyl-fused-dioxacyclodecynes are a promising class of strained alkyne for use in Cu-free 'click' reactions. In this paper, a series of functionalised derivatives of this class of reagent, containing fluorescent groups, are described. Studies aimed at understanding and increasing the reactivity of the alkynes are also presented, together with an investigation of the bioconjugation of the reagents with an azide-labelled protein.

Examining the substituent effect on mycosporine-inspired ultraviolet filters.

Current organic ultraviolet (UV) filters found in sunscreen formulations suffer a number of drawbacks. In this work, we have synthesised four biomimetic molecules built on the mycosporine molecular scaffold (a natural UV filter) with varying substituents at one of the carbons on the ring and investigated their photoprotective properties. From our findings, we infer design guidelines which may have a direct result on the production of next generation UV filters.

Asymmetric transfer hydrogenation of boronic acid pinacol ester (Bpin)-containing acetophenones.

A series of Bpin-containing acetophenone derivatives were reduced by asymmetric transfer hydrogenation (ATH), using Noyori-Ikariya catalysts, with formic acid/triethylamine, to alcohols in high ee when the Bpin is in the para- or meta-position. Substrates containing ortho-Bpin groups were reduced in lower ee, with formation of a cyclic boron-containing group. The products were converted to substituted derivatives using Pd-catalysed coupling reactions. The results represent the first examples of ATH of Bpin-containing ketones.

Asymmetric Transfer Hydrogenation: Dynamic Kinetic Resolution of α-Amino Ketones.

A series of α-amino ketones were reduced using asymmetric transfer hydrogenation (ATH) through a dynamic kinetic resolution (DKR). The protecting group was matched to the reducing agent, and following optimization, a series of substrates were investigated, giving products in high diastereoselectivity, over 99% ee in several cases and full conversion. The methodology was applied to the enantioselective synthesis of an MDM2-p53 inhibitor precursor.

Sulfone Group as a Versatile and Removable Directing Group for Asymmetric Transfer Hydrogenation of Ketones.

The sulfone functional group has a strong capacity to direct the asymmetric transfer hydrogenation (ATH) of ketones in the presence of [(arene)Ru(TsDPEN)H] complexes by adopting a position distal to the η6 -arene ring. This preference provides a means for the prediction of the sense of asymmetric reduction. The sulfone group also facilitates the formation of a range of reduction substrates, and its ready removal provides a route to enantiomerically enriched alcohols that would otherwise be extremely difficult to prepare by direct ATH of the corresponding ketones.

Applications of N'-monofunctionalised TsDPEN derivatives in asymmetric catalysis.

This review contains an account of recent developments in the applications of N'-monoalkylated or N'-mono(thio)acylated(N-sulfonyl)-1,2-diphenylethylene-1,2-diamine (TsDPEN) derivatives to asymmetric catalysis. The coverage features examples of applications of derivatives as ligands in organometallic complexes for use in asymmetric reduction and oxidation reactions. The use of TsDPEN derivatives as catalysts in a diverse range of C-C and C-S bond formation reactions is also described in detail.

Ruthenium-Catalyzed Asymmetric Reduction of Isoxazolium Salts: Access to Optically Active Δ4-Isoxazolines.

A tethered MsDPEN-ruthenium catalyst reduces a series of isoxazolium salts, affording optically active Δ4-isoxazolines in moderate to good yields and enantioenrichment. The redundancy of heating or high pressures allowed for chemoselective reduction with no subsequent heterocyclic ring opening. Our results reinforce our understanding of the workings of these Noyori-class catalysts.

Synthesis and cycloaddition reactions of strained alkynes derived from 2,2'-dihydroxy-1,1'-biaryls.

A series of strained alkynes, based on the 2,2'-dihydroxy-1,1'-biaryl structure, were prepared in a short sequence from readily-available starting materials. These compounds can be readily converted into further derivatives including examples containing fluorescent groups with potential for use as labelling reagents. The alkynes are able to react in cycloadditions with a range of azides without the requirement for a copper catalyst, in clean reactions with no observable side reactions.

Use of (Cyclopentadienone)iron Tricarbonyl Complexes for C-N Bond Formation Reactions between Amines and Alcohols.

The application of a series of (cyclopentadienone)iron tricarbonyl complexes to "borrowing hydrogen" reactions between amines and alcohols was completed in order to assess their catalytic activity. The electronic variation of the aromatic groups flanking the C═O of the cyclopentadienone influenced the efficiency of the reactions; however, in other cases, the Knölker catalyst 1, containing trimethylsilyl groups flanking the cyclopentadienone ketone, gave the best results. In some cases, the change of the ratio of amine to alcohol improves the conversion significantly. The application of iron catalysts to the synthesis of a range of amines, including unsaturated amines, was investigated.

Strained alkynes derived from 2,2'-dihydroxy-1,1'-biaryls; synthesis and copper-free cycloaddition with azides.

A series of strained alkynes were prepared from 2,2'-dihydroxy-biaryls. Several were characterised by X-ray crystallography, revealing strained C(sp)-C(sp)-C(sp3) bond angles in the range of 163-167°. Their cycloadditions with azides proceed without a catalyst. Functionalised versions of these reagents have potential applications to materials synthesis and bioconjugations.

The Development of Phosphine-Free "Tethered" Ruthenium(II) Catalysts for the Asymmetric Reduction of Ketones and Imines.

In this account, we describe the design, synthesis and applications of tethered versions of the Ru(II)/N-tosyl-1,2-diphenylethylene-1,2-diamine (TsDPEN) class of catalyst that are commonly used for asymmetric transfer hydrogenation and asymmetric hydrogenation of ketones and imines. The review covers key aspects of the reaction mechanisms and examples of applications, including industrial applications to pharmaceutically important target molecules. In addition, closely related catalysts based on Rh(III) and Ir(III) are also described.

Easy To Synthesize, Robust Organo-osmium Asymmetric Transfer Hydrogenation Catalysts.

Asymmetric transfer hydrogenation (ATH) is an important process in organic synthesis for which the Noyori-type Ru(II) catalysts [(arene)Ru(Tsdiamine)] are now well established and widely used. We now demonstrate for the first time the catalytic activity of the osmium analogues. X-ray crystal structures of the 16-electron Os(II) catalysts are almost identical to those of Ru(II). Intriguingly the precursor complex was isolated as a dichlorido complex with a monodentate amine ligand. The Os(II) catalysts are readily synthesised (within 1 h) and exhibit excellent enantioselectivity in ATH reactions of ketones.

Asymmetric Reduction of Electron-Rich Ketones with Tethered Ru(II)/TsDPEN Catalysts Using Formic Acid/Triethylamine or Aqueous Sodium Formate.

The asymmetric transfer hydrogenation (ATH) of ketones under aqueous conditions using tethered Ru(II)/η(6)-arene/diamine catalysts is described, as is the ATH of electron-rich substrates containing amine and methoxy groups on the aromatic rings. Although such substrates are traditionally challenging ones for ATH, the tethered catalysts work very efficiently. In the case of amino-substituted ketones, aqueous conditions give excellent results; however, for methoxy-substituted substrates, the more established formic acid/triethylamine system gives superior results.

Mirror-image organometallic osmium arene iminopyridine halido complexes exhibit similar potent anticancer activity.

Four chiral Os(II) arene anticancer complexes have been isolated by fractional crystallization. The two iodido complexes, (S(Os),S(C))-[Os(η(6)-p-cym)(ImpyMe)I]PF6 (complex 2, (S)-ImpyMe: N-(2-pyridylmethylene)-(S)-1-phenylethylamine) and (R(Os),R(C))-[Os(η(6)-p-cym)(ImpyMe)I]PF6 (complex 4, (R)-ImpyMe: N-(2-pyridylmethylene)-(R)-1-phenylethylamine), showed higher anticancer activity (lower IC50 values) towards A2780 human ovarian cancer cells than cisplatin and were more active than the two chlorido derivatives, (S(Os),S(C))-[Os(η(6)-p-cym)(ImpyMe)Cl]PF6, 1, and (R(Os),R(C))-[Os(η(6)-p-cym)(ImpyMe)Cl]PF6, 3. The two iodido complexes were evaluated in the National Cancer Institute 60-cell-line screen, by using the COMPARE algorithm. This showed that the two potent iodido complexes, 2 (NSC: D-758116/1) and 4 (NSC: D-758118/1), share surprisingly similar cancer cell selectivity patterns with the anti-microtubule drug, vinblastine sulfate. However, no direct effect on tubulin polymerization was found for 2 and 4, an observation that appears to indicate a novel mechanism of action. In addition, complexes 2 and 4 demonstrated potential as transfer-hydrogenation catalysts for imine reduction.

Asymmetric transfer hydrogenation of functionalized acetylenic ketones.

A systematic study of the asymmetric transfer hydrogenations of functionalized acetylenic ketones and diketones has been completed, together with a total synthesis of (S,S)-(-)-yashabushidiol B. In several cases, excellent enantioselectivities and yields were achieved.

Chemoselective derivatisation and ultrahigh resolution mass spectrometry for the determination of hydroxyl functional groups within complex bio-oils.

Bio-oils are a renewable alternative resource for the production of fine chemicals and fuels. Bio-oils are characterised by a high content of oxygenated compounds with a diverse array of different chemical functionalities. Here, we performed a chemical reaction to transform the hydroxyl group of the various components in a bio-oil prior to characterisation with ultrahigh resolution mass spectrometry (UHRMS). The derivatisations were first evaluated using twenty lignin-representative standards with different structural features. Our results indicate a highly chemoselective transformation of the hydroxyl group despite the presence of other functional groups. Mono- and di-acetate products were observed in acetone-acetic anhydride (acetone-Ac2O) mixtures for non-sterically hindered phenols, catechols and benzene diols. Dimethyl sulfoxide-Ac2O (DMSO-Ac2O) reactions favoured the oxidation of primary and secondary alcohols and the formation of methylthiomethyl (MTM) products of phenols. The derivatisations were then performed in a complex bio-oil sample to gain insights into the hydroxyl group profile of the bio-oil. Our results indicate that the bio-oil before derivatisation is composed of 4500 elemental compositions containing 1-12 oxygen atoms. After the derivatisation in DMSO-Ac2O mixtures, the total number of compositions increased approximately five-fold. The reaction was indicative of the variety of hydroxyl group profiles within the sample in particular the presence of phenols that were ortho and para substituted, non-hindered phenols (about 34%), aromatic alcohols (including benzylic and other non-phenolic alcohols) (25%), and aliphatic alcohols (6.3%) could be inferred. Phenolic compositions are known as coke precursors in catalytic pyrolysis and upgrading processes. Thus, the combination of chemoselective derivatisations in conjunction with UHRMS can be a valuable resource to outline the hydroxyl group profile in elemental chemical compositions in complex mixtures.

Synthesis and characterisation of novel composite sunscreens containing both avobenzone and octocrylene motifs.

Avobenzone and octocrylene are popular sunscreen active ingredients. Experiments that probe the stability of avobenzone in binary mixtures with octocrylene are presented, together with the synthesis of a class of novel composite sunscreens that were designed by covalently linking avobenzone and octocrylene groups. Spectroscopy, both steady-state and time-resolved, of the fused molecules was performed to investigate the stability of the new molecules and their potential function as ultraviolet filters. Computational results are detailed for truncated versions of a subset of the molecules to reveal the energy states underlying the absorption processes of this new class of sunscreen. The results indicate that the combination of elements of the two sunscreen molecules into one molecule creates a derivative with good stability to UV light in ethanol and in which the main degradation pathway of the avobenzone component in acetonitrile is reduced. Derivatives containing p-chloro substituents are particularly stable to UV light.

Developing asymmetric iron and ruthenium-based cyclone complexes; complex factors influence the asymmetric induction in the transfer hydrogenation of ketones.

The preparation of a range of asymmetric iron and ruthenium-cyclone complexes, and their application to the asymmetric reduction of a ketone, are described. The enantioselectivity of ketone reduction is influenced by a single chiral centre in the catalyst, as well as by the planar chirality in the catalyst. This represents the first example of asymmetric ketone reduction using an iron cyclone catalyst.

Heterocycle-containing Noyori-Ikariya catalysts for asymmetric transfer hydrogenation of ketones.

The synthesis of a range of N-(heterocyclesulfonyl)-functionalised Noyori-Ikariya catalysts is described. The complexes were prepared through a short sequence from C2-symmetric 1,2-diphenylethylene-1,2-diamine (DPEN) and were characterised by a range of methods including X-ray crystallography. The complexes were active catalysts for the asymmetric transfer hydrogenation (ATH) of a range of acetophenone derivatives, giving products of high ee in most cases, with notably good results for ortho-substituted acetophenones.