Chemo-enzymatic synthesis of unnatural amino acids

A general chemo-enzymatic process has been developed to prepare enantiomerically pure L- and D-amino acids in high yield by deracemisation of racemic starting materials. The method has been developed from initial academic studies to be a robust, scalable industrial process. Unnatural amino acids, in high optical purity, are a rapidly growing class of intermediates required for pharmaceuticals, agrochemicals and other fine chemical applications. However, no single method has proven sufficiently adaptable to prepare these compounds generally at large scale. Our approach uses an enantioselective oxidase biocatalyst and a non-selective chemical reducing agent to effect the stereoinversion of one enantiomer and can result in an enantiomeric excess of > 99 % from a starting racemate, and product yields over 90 %. The current approach compares very favourably to resolution methods which have a maximum single pass yield of 50 %. Efficient methods have been developed to adapt the biocatalyst used in this process towards new target compounds and to optimise key factors which improve the process efficiency and offer competitive economics at scale.

Crystal structures and hydrogen bonding in the anhydrous tryptaminium salts of the isomeric (2,4-dichlorophenoxy)acetic and (3,5-dichlorophenoxy)acetic acids

The anhydrous salts of 1H-indole-3-ethanamine (tryptamine) with isomeric (2,4-dichlorophenoxy)acetic acid (2,4-D) and (3,5-dichlorophenoxy)acetic (3,5-D), C10H13N2+ (C8H5Cl2O3)-, [(I) and (II), respectively] have been determined and their one-dimensional hydrogen-bonded polymeric structures are described. In the crystal of (I),the aminium H-atoms are involved in three separate inter-species N-H...O hydrogen-bonding interactions, two with carboxyl O-atom acceptors and the third in an asymmetric three-centre bidentate carboxyl O,O' chelate [graph set R2/1(4)]. The indole H-atom forms an N-H...O~carboxyl~ hydrogen bond, extending the chain structure along the b axial direction. In (II), two of the three aminium H-atoms are also involved in N-H...O(carboxyl) hydrogen bonds similar to (I) but with the third, a three-centre asymmetric interaction with carboxyl and phenoxy O-atoms is found [graph set R2/1(5)]. The chain polymeric extension is also along b. There are no pi--pi ring interactions in either of the structures. The aminium side chain conformations differ significantly between the two structures, reflecting the conformational ambivalence of the tryptaminium cation, as found also in the benzoate salts.

TMIO-pyrimid hybrids are profluorescent, site-directed spin labels for nucleic acids

We report the synthesis of a new class of molecules which are hybrids of long-lived tetramethylisoindolinoxyl (TMIO) radicals and the pyrido[1,2-a]benzimidazole (PyrImid) scaffold. These compounds represent a new lead for noncovalently binding nucleic acid probes, as they interact with nucleic acids with previously unreported C (DNA) and C/U (RNA) complementarity, which can be detected by electron paramagnetic resonance (EPR) techniques. They also have promising properties for fluorimetric analysis, as their fluorescent spin-quenched derivatives exhibit a significant Stokes shift

Two-dimensional coordination polymeric structures in caesium complexes with ring-substituted phenoxyacetic acids

The two-dimensional polymeric structures of the caesium complexes with the phenoxyacetic acid analogues (4-fluorophenoxy)acetic acid, (3-chloro-2-methylphenoxy)acetic acid and the herbicidally active (2,4-dichlorophen­oxy)acetic acid (2,4-D), namely poly[[5-(4-fluorophenoxy)acetato][4-(4-fluorophenoxy)acetato]dicaesium], [Cs2(C8H6FO3)2]n, (I), poly[aqua[5-(3-chloro-2-methylphenoxy)acetato]caesium], [Cs(C9H8ClO3)(H2O)]n, (II), and poly[[7-(2,4-di­chlorophenoxy)acetato][(2,4-dichlorphenoxy)acetic acid]caesium], [Cs(C8H5Cl2O3)(C8H6Cl2O3)]n, (III), are described. In (I), the Cs+ cations of the two individual irregular coordination polyhedra in the asymmetric unit (one CsO7 and the other CsO8) are linked by bridging carboxylate O-atom donors from the two ligand molecules, both of which are involved in bidentate chelate Ocarboxy,Ophenoxy interactions, while only one has a bidentate carboxylate O,O'-chelate inter­action. Polymeric extension is achieved through a number of carboxylate O-atom bridges, with a minimum CsCs separation of 4.3231 (9) Å, giving layers which lie parallel to (001). In hydrated complex (II), the irregular nine-coordination about the Cs+ cation comprises a single monodentate water molecule, a bidentate Ocarboxy,Ophenoxy chelate interaction and six bridging carboxylate O-atom bonding interactions, giving a CsCs separation of 4.2473 (3) Å. The water mol­ecule forms intralayer hydrogen bonds within the two-dimensional layers, which lie parallel to (100). In complex (III), the irregular centrosymmetric CsO6Cl2 coordination environment comprises two O-atom donors and two ring-substituted Cl-atom donors from two hydrogen bis[(2,4-dichlorophenoxy)acetate] ligand species in a bidentate chelate mode, and four O-atom donors from bridging carboxyl groups. The duplex ligand species lie across crystallographic inversion centres, linked through a short O-HO hydrogen bond involving the single acid H atom. Structure extension gives layers which lie parallel to (001). The present set of structures of Cs salts of phenoxyacetic acids show previously demonstrated trends among the alkali metal salts of simple benzoic acids with no stereochemically favourable interactive substituent groups for formation of two-dimensional coordination polymers.

The effect of ongoing blood loss on human serum concentrations of perfluorinated acids

Perfluorinated alkyl acids (PFAAs) have been detected in serum at low concentrations in background populations. Higher concentrations haven been observed in adult males compared to females, with a possible explanation that menstruation offers females an additional elimination route. In this study, we examined the significance of blood loss as an elimination route of PFAAs. Pooled serum samples were collected from individuals undergoing a medical procedure involving ongoing blood withdrawal called venesection. Concentrations from male venesection patients were approximately 40% lower than males in the general population for perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA). A simple pharmacokinetic model was used to test the hypothesis that blood loss could explain why adult males have higher concentrations of PFAAs than females, and why males undergoing venesections had lower concentrations compared to males in the general population. The model application generally supported these hypotheses showing that venesection might reduce blood serum concentrations by 37% (PFOA) and 53% (PFOS) compared to the observed difference of 44% and 37%. Menstruation was modeled to show a 22% reduction in PFOA serum concentrations compared to a 24% difference in concentrations between males and females in the background population. Uncertainties in the modeling and the data are identified and discussed.