Joseph P. Adams

Development of GSK's reagent guides – embedding sustainability into reagent selection

Reagent guides ranking commonly used reagents for 15 transformations have been developed to reduce the environmental impact of drug discovery and development. Reagents have been scored by a combination of health, safety and environmental risk phrases, life cycle analysis (where possible) and an assessment of the chemistry including considerations of atom efficiency, stoichiometry, work-up and other issues. Guides covering alkene reduction, amide formation, C–H bromination, C–H chlorination, deoxychlorination, epoxidation, ester formation, ether formation, fluorination, iodination, ketone reduction, nitro reduction, oxidation of alcohols to aldehydes and ketones, reductive amination and sulfur oxidation are shared, with an explanation of the methodology behind their generation.

Imines, enamines and oximes

Covering: January 1997 to December 1998Continuing the coverage in Contemp. Org. Synth., 1997, 4, 517 np

Characterization of carboxylic acid reductases as enzymes in the toolbox for synthetic chemistry

Carboxylic acid reductase enzymes (CARs) meet the demand in synthetic chemistry for a green and regiospecific route to aldehydes from their respective carboxylic acids. However, relatively few of these enzymes have been characterized. A sequence alignment with members of the ANL (Acyl‐CoA synthetase/ NRPS adenylation domain/Luciferase) superfamily of enzymes shed light on CAR functional dynamics. Four unstudied enzymes were selected by using a phylogenetic analysis of known and hypothetical CARs, and for the first time, a thorough biochemical characterization was performed. Kinetic analysis of these enzymes with various substrates shows that they have a broad but similar substrate specificity. Electron‐rich acids are favored, which suggests that the first step in the proposed reaction mechanism, attack by the carboxylate on the α‐phosphate of adenosine triphosphate (ATP), is the step that determines the substrate specificity and reaction kinetics. The effects of pH and temperature provide a clear operational window for the use of these CARs, whereas an investigation of product inhibition by NADP+, adenosine monophosphate, and pyrophosphate indicates that the binding of substrates at the adenylation domain is ordered with ATP binding first. This study consolidates CARs as important and exciting enzymes in the toolbox for sustainable chemistry and provides specifications for their use as a biocatalyst.

Intramolecular nitrone dipolar cycloadditions: control of regioselectivity and synthesis of naturally-occurring spirocyclic alkaloids

The intramolecular nitrone dipolar cycloaddition of in situ-generated nitrones such as compound 26 has been used for the synthesis of cyclic isoxazolidines 27 and 29. The regioselectivity of the intramolecular cycloaddition depends on the nature of the terminal substituent on the dipolarophile. The influence of the substituent on the regioselectivity of the cycloaddition has been examined using several model systems and two methods of nitrone formation. These studies demonstrated that the cyano-substituent plays a special role in favouring the formation of the 6,6,5-ring fused adduct 27 under thermodynamically controlled conditions. The utility of the cyclo-adduct 57 (see Scheme 12) as a precursor for the naturally occurring histrionicotoxins is illustrated by the synthesis of three unsymmetrical (i.e. with each side chain bearing different functional groups) members of the histrionicotoxin family HTX-259A, HTX-285C and HTX-285E (2, 3 and 4 respectively).

Sustainable synthesis of enantiopure fluorolactam derivatives by a selective direct fluorination – amidase strategy

Pharmaceutically important chiral fluorolactam derivatives bearing a fluorine atom at a stereogenic centre were synthesized by a route involving copper catalyzed selective direct fluorination using fluorine gas for the construction of the key C–F bond and a biochemical amidase process for the crucial asymmetric cyclisation stage. A comparison of process green metrics with reported palladium catalyzed enantioselective fluorination methodology shows the fluorination-amidase route to be very efficient and more suitable for scale-up.

Nitro and related groups

Covering: the literature published between January 2000 and January 2002. Previous review: J. Chem. Soc., Perkin Trans. 1, 2000, 3695.

Centrifugal partition chromatography in a biorefinery context: Optimisation and scale-up of monosaccharide fractionation from hydrolysed sugar beet pulp

The isolation of component sugars from biomass represents an important step in the bioprocessing of sustainable feedstocks such as sugar beet pulp. Centrifugal partition chromatography (CPC) is used here, as an alternative to multiple resin chromatography steps, to fractionate component monosaccharides from crude hydrolysed sugar beet pulp pectin. CPC separation of samples, prepared in the stationary phase, was carried out using an ethanol: ammonium sulphate (300gL-1) phase system (0.8:1.8v:v) in ascending mode. This enabled removal of crude feedstream impurities and separation of monosaccharides into three fractions (l-rhamnose, l-arabinose and d-galactose, and d-galacturonic acid) in a single step. Throughput was improved three-fold by increasing sample injection volume, from 4 to 16% of column volume, with similar separation performance maintained in all cases. Extrusion of the final galacturonic acid fraction increased the eluted solute concentration, reduced the total separation time by 24% and removed the need for further column regeneration. Reproducibility of the separation after extrusion was validated by using multiple stacked injections. Scale-up was performed linearly from a semi-preparative 250mL column to a preparative 950mL column with a scale-up ratio of 3.8 applied to mobile phase flow rate and sample injection volume. Throughputs of 9.4gL-1h-1 of total dissolved solids were achieved at the preparative scale with a throughput of 1.9gL-1h-1 of component monosaccharides. These results demonstrate the potential of CPC for both impurity removal and target fractionation within biorefinery separations.

Coupled Immobilized Amine Dehydrogenase and Glucose Dehydrogenase for Asymmetric Synthesis of Amines by Reductive Amination with Cofactor Recycling

The amine dehydrogenase (AmDH) engineered from the phenylalanine dehydrogenase of Rhodococcus sp. M4 was directly immobilized on magnetic nanoparticles (MNP) from the cell‐free extract containing his‐tagged AmDH through affinity attachment to give AmDH‐MNPs with high yield, enzyme loading efficiency, and specific enzyme loading. AmDH‐MNPs showed higher activity and productivity than the free enzyme for the asymmetric reductive amination of 4‐phenyl‐2‐butanone 1u2009a and phenylacetone 1u2009b, producing the corresponding amines (R)‐2u2009a,b in 99u2009% ee and 99u2009% yield, and with recycling of NADH for up to 3956u2005times. AmDH‐MNPs were easily recycled, retaining 91u2009% of the original productivity in the third cycle of the reductive amination of 1u2009a. Coupling of immobilized AmDH and immobilized glucose dehydrogenase (GDH) for the asymmetric reductive amination of 1u2009a gave (R)‐2u2009a in 99u2009% ee and 74u2009% yield, with a total turnover number (TTN) of 2940 for NADH recycling. Both immobilized enzymes showed good recyclability, retaining 81u2009% productivity in the third reaction cycle. The developed method with coupled immobilized AmDH and immobilized GDH for the asymmetric reductive amination of ketones is useful for the synthesis of enantiopure amines, superior to the use of coupled isolated enzymes with enhanced catalytic performance and reduced enzyme cost through catalyst recycling.

Nitrone dipolar cycloaddition routes to piperidines and indolizidines. Part 9. Formal synthesis of (−)-pinidine and total synthesis of (−)-histrionicotoxin, (+)-histrionicotoxin and (−)-histrionicotoxin 235A

An intramolecular hydroxylamine-alkyne cyclisation is used for the enantioselective synthesis of the cyclic nitrones 36 and 44. We have demonstrated the use of a novel nitrone protection strategy by cycloaddition of styrene to the cyclic nitrone 44 in the synthesis of the spirocyclic core of the histrionicotoxin family of alkaloids. Deprotection by dipolar cycloreversion of the styrene adduct (the bicyclic isoxazolidine 39) and in situ intramolecular dipolar cycloaddition of a pendant (Z)-α,β-unsaturated nitrile to the intermediate nitrone 50 gave the isoxazolidine 51 in high yield with a surprising degree of regioselectivity compared with the corresponding (Z)-enyne 36. nThe method is amenable to the synthesis of both enantiomers 51 and 62 of the tricyclic core structure which can be converted by way of the common intermediates (e.g.53 and ent-53) respectively into the natural configuration of alkaloids (−)-histrionicotoxin 1 and (−)-histrionicotoxin 235A 65 as well as the unnatural (+)-histrionicotoxin 63.

Synthesis of a novel spirocyclic lactone in a potential route to squalestatin 1

The isomeric butenolides 1 and 2 have been converted into the spiro-lactone derivative 20via sequential ring contraction–rearrangement processes. X-Ray crystal data have been obtained on compound 12b.