Chemoenzymatic synthesis of enantiopure 1,4-dihydropyridine derivatives

1,4-Dihydropyridines possess a broad range of biological activities, such as the ability to control the influx of calcium into cells, as well as neuroprotective, antineurodegenerative, cognition and memory enhancing, anti-inflammatory, antiviral and many other properties. Chirality plays an important role in the biological activity of 1,4-dihydropyridines. The chemoenzymatic synthesis of 1,4-dihydropyridine derivatives in enantiopure form as the key intermediates for the synthesis of enantiopure drugs and chiral analogues of symmetrical drugs has become an advantageous alternative to the other synthetic methods. Hydrolytic enzymes, as efficient chemo-, regio- and stereoselective biocatalysts have been successfully applied for the asymmetrisation or kinetic resolution of various 1,4-dihydropyridine derivatives. Several synthetic strategies to overcome the inactivity of hydrolytic enzymes towards 1,4-dihydropyridine carboxylic acids have been developed during the last decade, often based on the introduction of a spacer between an enzymatically labile group and the 1,4-DHP nucleus. Good to excellent enantioselectivities can be obtained by careful optimisation of the reaction temperature and the organic (co)solvent used in the enzymatic transformations.     

2-Pyridylmetallocenes: Part I. Electrophilic halogenation of 2-pyridylferrocene. Molecular structures of 2-pyridylferrocene and its α-brominated and -fluorinated derivatives. Synthesis of 2-pyridylruthenocene and 2-pyridylcymantrene

A new high-yield synthesis of 2-pyridylferrocene (1) without formation of the 1,1′-disubstituted product has been developed. Also the corresponding ruthenocene and cymantrene derivatives [C₅H₄(2-C₅H₄N)]ML_n (ML_n = Ru(C₅H₅) (2), Mn(CO)₃ (3)) were prepared and fully characterized. Ortho-lithiation of 1 followed by electrophilic halogenation yielded [C₅H₃X(2-C₅H₄N)]Fe(C₅H₅) [X = F (4), Cl (5), Br (6), I (7)], with 4 only being the second reported and first fully characterized fluoroferrocene. The molecular structures of 1, 4 and 6 have been determined by X-ray crystallography.     

A convenient synthesis of the side chain of loteprednol etabonate--an ocular soft corticosteroid from 20-oxopregnanes using metal-mediated halogenation as a key reaction

A facile synthesis of the side chain of loteprednol etabonate, namely, chloromethyl-17α-[(ethoxycarbonyl))oxy]-11β-hydro of loteprednol etabonate, viz., chloromethyl-17α-[(ethoxycarbonyl))oxy]-11xy-3-oxoandrosta-1,4-diene-17β-carboxylate - an ocular soft corticosteroid, has been described starting from a 20-oxopregnane, namely, 3β-acetoxy-pregn-5(6),16(17)-diene-20-one (16-dehydropregnenolone acetate, i.e., 16-DPA) using our recently developed metal-mediated halogenation as a key reaction.     

DIFFERENT CHEMICAL TYPES OF PLOCAMIUM VIOLACEUM (RHODOPHYTA) FROM THE MONTEREY BAY REGION,CALIFORNIA1

Differences in the halogenated natural products of Plocamium violaceum Farlow can be noted from different sites in the Monterey Bay region, California. Specimens from the northern region produce a set of alicyclic halogenated monoterpenes which are not synthesized by those from the southern region. Instead, the latter elaborates a set of acyclic halogenated monoterpenes not observed from the former. This situation is invariant regardless of life history forms or different seasons. Similarly, the composition of halogenated monoterpene structures from P. cartilagineum (L.) Dixon varies at different locations. From the data presented herein we conclude that at least two chemical types can be identified for P. violaceum based upon differences in their halogenated products. Thus we suggest that the north Monterey form can be designated as chemotype α and the southern one as chemotype β.     

Pyridoxamine protects proteins from damage by hypohalous acids in vitro and in vivo

Diabetes is characterized, in part, by activation of toxic oxidative and glycoxidative pathways that are triggered by persistent hyperglycemia and contribute to diabetic complications. Inhibition of these pathways may benefit diabetic patients by delaying the onset of complications. One such inhibitor, pyridoxamine (PM), had shown promise in clinical trials. However, the mechanism of PM action in vivo is not well understood. We have previously reported that hypohalous acids can cause disruption of the structure and function of renal collagen IV in experimental diabetes (K.L. Brown et al., Diabetes64:2242–2253, 2015). In the present study, we demonstrate that PM can protect protein functionality from hypochlorous and hypobromous acid-derived damage via a rapid direct reaction with and detoxification of these hypohalous acids. We further demonstrate that PM treatment can ameliorate specific hypohalous acid-derived structural and functional damage to the renal collagen IV network in a diabetic animal model. These findings suggest a new mechanism of PM action in diabetes, namely sequestration of hypohalous acids, which may contribute to known therapeutic effects of PM in human diabetic nephropathy.     

Electrochemical bromochlorination of peracetylated glycals

Peracetylated glycals—3,4,5-tri-O-acetyl-d-glucal (1a), 3,4,5-tri-O-acetyl-d-galactal (1b) and 3,4-di-O-acetyl-6-deoxy-l-glucal (1c)—have been bromochlorinated by a suitable halogenating agent, generated electrochemically from a mixture of bromides and chlorides in dichloromethane. The reaction was performed in two ways: (i) by a constant current electrolysis (2 F mol⁻¹) of bromides and substrates in a milieu containing an excess of chlorides (Br^?/1/Cl^? = 1:1:6.8) and (ii) by anodic generation of free chlorine from chlorides (2 F mol⁻¹) and subsequent addition of bromides and substrates in a ratio Br^?/1 = 1:1. The corresponding 2-bromo-2-deoxy-glycopyranosyl chlorides were obtained in high yields.     

High Performance Thick‐Film Nonfullerene Organic Solar Cells with Efficiency over 10% and Active Layer Thickness of 600 nm

Developing efficient organic solar cells (OSCs) with relatively thick active layer compatible with the roll to roll large area printing process is an inevitable requirement for the commercialization of this field. However, typical laboratory OSCs generally exhibit active layers with optimized thickness around 100 nm and very low thickness tolerance, which cannot be suitable for roll to roll process. In this work, high performance of thick‐film organic solar cells employing a nonfullerene acceptor F–2Cl and a polymer donor PM6 is demonstrated. High power conversion efficiencies (PCEs) of 13.80% in the inverted structure device and 12.83% in the conventional structure device are achieved under optimized conditions. PCE of 9.03% is obtained for the inverted device with active layer thickness of 500 nm. It is worth noting that the conventional structure device still maintains the PCE of over 10% when the film thickness of the active layer is 600 nm, which is the highest value for the NF‐OSCs with such a large active layer thickness. It is found that the performance difference between the thick active layer films based conventional and inverted devices is attributed to their different vertical phase separation in the active layers.     

The carbon-quality temperature hypothesis: Fact or artefact?

Climate warming can reduce global soil carbon stocks by enhancing microbial decomposition. However, the magnitude of this loss remains uncertain because the temperature sensitivity of the decomposition of the major fraction of soil carbon, namely resistant carbon, is not fully known. It is now believed that the resistance of soil carbon mostly depends on microbial accessibility of soil carbon with physical protection being the primary control of the decomposition of protected carbon, which is insensitive to temperature changes. However, it is still unclear whether the temperature sensitivity of the decomposition of unprotected carbon, for example, carbon that is not protected by the soil mineral matrix, may depend on the chemical recalcitrance of carbon compounds. In particular, the carbon-quality temperature (CQT) hypothesis asserts that recalcitrant low-quality carbon is more temperature-sensitive to decomposition than labile high-quality carbon. If the hypothesis is correct, climate warming could amplify the loss of unprotected, but chemically recalcitrant, carbon and the resultant CO₂ release from soils to the atmosphere. Previous research has supported this hypothesis based on reported negative relationships between temperature sensitivity and carbon quality, defined as the decomposition rate at a reference temperature. Here we show that negative relationships can arise simply from the arbitrary choice of reference temperature, inherently invalidating those tests. To avoid this artefact, we defined the carbon quality of different compounds as their uncatalysed reaction rates in the absence of enzymes. Taking the uncatalysed rate as the carbon quality index, we found that the CQT hypothesis is not supported for enzyme-catalysed reactions, which showed no relationship between carbon quality and temperature sensitivity. The lack of correlation in enzyme-catalysed reactions implies similar temperature sensitivity for microbial decomposition of soil carbon, regardless of its quality, thereby allaying concerns of acceleration of warming-induced decomposition of recalcitrant carbon.