Late-Stage Functionalisation of Polycyclic (N-Hetero-) Aromatic Hydrocarbons by Detoxifying CYP5035S7 Monooxygenase of the White-Rot Fungus Polyporus arcularius

Functionalisation of polycyclic aromatic hydrocarbons (PAHs) and their N-heteroarene analogues (NPAHs) is a tedious synthetic endeavour that requires diverse bottom-up approaches. Cytochrome P450 enzymes of white-rot fungi were shown to participate in the fungal detoxification of xenobiotics and environmental hazards via hydroxylation of PAH compounds. In this paper, the recently discovered activity of the monooxygenase CYP5035S7 towards (N)PAHs was investigated in detail, and products formed from the substrates azulene, acenaphthene, fluorene, anthracene, and phenanthrene by whole-cell biocatalysis were isolated and characterised. The observed regioselectivity of CYP5035S7 could be explained by a combination of the substrate’s electron density and steric factors influencing the substrate orientation giving insight into the active-site geometry of the enzyme.

Pyrrolidine in Drug Discovery: A Versatile Scaffold for Novel Biologically Active Compounds

The five-membered pyrrolidine ring is one of the nitrogen heterocycles used widely by medicinal chemists to obtain compounds for the treatment of human diseases. The great interest in this saturated scaffold is enhanced by (1) the possibility to efficiently explore the pharmacophore space due to sp3-hybridization, (2) the contribution to the stereochemistry of the molecule, (3) and the increased three-dimensional (3D) coverage due to the non-planarity of the ring—a phenomenon called “pseudorotation”. In this review, we report bioactive molecules with target selectivity characterized by the pyrrolidine ring and its derivatives, including pyrrolizines, pyrrolidine-2-one, pyrrolidine-2,5-diones and prolinol described in the literature from 2015 to date. After a comparison of the physicochemical parameters of pyrrolidine with the parent aromatic pyrrole and cyclopentane, we investigate the influence of steric factors on biological activity, also describing the structure–activity relationship (SAR) of the studied compounds. To aid the reader’s approach to reading the manuscript, we have planned the review on the basis of the synthetic strategies used: (1) ring construction from different cyclic or acyclic precursors, reporting the synthesis and the reaction conditions, or (2) functionalization of preformed pyrrolidine rings, e.g., proline derivatives. Since one of the most significant features of the pyrrolidine ring is the stereogenicity of carbons, we highlight how the different stereoisomers and the spatial orientation of substituents can lead to a different biological profile of drug candidates, due to the different binding mode to enantioselective proteins. We believe that this work can guide medicinal chemists to the best approach in the design of new pyrrolidine compounds with different biological profiles.

VARIATIONS IN THE KARA SEA LEVEL, THEIR STERIC FACTORS, AND SOLAR RADIATION DURING 1993-2018

The GLORYS12v.1 and ERA5 reanalyses for different months are used to study a relationship between long-term variations in the monthly mean values of sea level in different areas of the Kara Sea and their steric factors during 1993-2018. The areas of the sea were identified where the relationships between these changes and variations in the mean temperature and salinity of the upper quasihomogeneous water layer, as well as the variations in the monthly mean intensity of their insolation, are statistically significant.

Progress and Achievements in Glycosylation of Flavonoids

In recent years, the chemistry of flavonoid glycosylation has undergone significant developments. This mini-review is devoted to summarizing existing strategies and methods for glycosylation of natural and synthetic flavonoids. Herein we overviewed the reaction conditions of flavonoid glycosylation depending on the position of hydroxyl groups in a parent molecule, the degree of it conjugation with the π-system, the presence of steric factors, the formation of intramolecular hydrogen bonds, etc. Especial attention was given to the choice of the glycosyl donor moiety, which has a significant effect on the yield of the final glycosidated products. Finally, a general strategy for regioselective glycosylation of flavonoids containing several hydroxyl groups is outlined.

Studies of Catalyst-Controlled Regioselective Acetalization and Its Application to Single-Pot Synthesis of Differentially Protected Saccharides.

This article describes the studies of regioselective acetal protection of monosaccharide-based diols using chiral phosphoric acids (CPAs) as the catalysts. These catalyst-controlled regioselective acetalizations were found to proceed with high regioselectivities (up to >25:1 rr) on various <i>D</i>-glucose, <i>D</i>-galactose, <i>D</i>-mannose and <i>L</i>-fucose derived 1,2-diols and could be carried with immobilized and recyclable catalyst. The utility of CPA-catalyzed acetalizations was further demonstrated for the regioselective single-pot preparation of various differentially protected mono- and disaccharide building blocks. The computational and mechanistic studies indicate complex temperature-dependent interplay of two reaction mechanisms, one involving an anomeric phosphate intermediate and another via concerted asynchronous formation of acetal. The computational models explain the steric factors responsible for the observed C2-selectivities and are consistent with the experimentally observed selectivity trends.

Studies of Catalyst-Controlled Regioselective Acetalization and Its Application to Single-Pot Synthesis of Differentially Protected Saccharides.

This article describes the studies of regioselective acetal protection of monosaccharide-based diols using chiral phosphoric acids (CPAs) as the catalysts. These catalyst-controlled regioselective acetalizations were found to proceed with high regioselectivities (up to >25:1 rr) on various <i>D</i>-glucose, <i>D</i>-galactose, <i>D</i>-mannose and <i>L</i>-fucose derived 1,2-diols and could be carried with immobilized and recyclable catalyst. The utility of CPA-catalyzed acetalizations was further demonstrated for the regioselective single-pot preparation of various differentially protected mono- and disaccharide building blocks. The computational and mechanistic studies indicate complex temperature-dependent interplay of two reaction mechanisms, one involving an anomeric phosphate intermediate and another via concerted asynchronous formation of acetal. The computational models explain the steric factors responsible for the observed C2-selectivities and are consistent with the experimentally observed selectivity trends.

Unprecedented η3-Coordination and Functionalization of the 2-Phosphaethynthiolate Anion at Lanthanum(III)

We present the unprecedented <i>η</i>3-coordination of the 2-phosphaethynthiolate anion in the complex (PN)₂La(SCP) (<b>2</b>) [PN = N-(2-(diisopropylphosphanyl)-4-methylphenyl)-2,4,6-trimethylanilide)]. Structural comparison with dinuclear thiocyanate bridged (PN)₂La(<i>μ</i>-1,3-SCN)₂La(PN)₂ (<b>3</b>) and azide bridged (PN)₂La(<i>μ</i>-1,3-N3)₂La(PN)₂ (<b>4</b>) complexes indicates that the [SCP]^– coordination mode is mainly governed by electronic, rather than steric factors. Quantum mechanical investigations reveal large contributions of the antibonding π-orbital of the [SCP]^– ligand to the LUMO of complex <b>2</b>, rendering it the ideal precursor for the first functionalization of the [SCP]^– anion. Complex <b>2</b> was therefore reacted with CAACs which induced a selective rearrangement of the [SCP]^– ligand to form the first CAAC stabilized group 15 – group 16 fulminate-type complexes (PN)₂La{SPC(^RCAAC)} (<b>5a,b</b>) (R = Ad, Me). A detailed reaction mechanism for the SCP to SPC isomerization is proposed based on DFT calculations.

Unprecedented η3-Coordination and Functionalization of the 2-Phosphaethynthiolate Anion at Lanthanum(III)

We present the unprecedented <i>η</i>3-coordination of the 2-phosphaethynthiolate anion in the complex (PN)₂La(SCP) (<b>2</b>) [PN = N-(2-(diisopropylphosphanyl)-4-methylphenyl)-2,4,6-trimethylanilide)]. Structural comparison with dinuclear thiocyanate bridged (PN)₂La(<i>μ</i>-1,3-SCN)₂La(PN)₂ (<b>3</b>) and azide bridged (PN)₂La(<i>μ</i>-1,3-N3)₂La(PN)₂ (<b>4</b>) complexes indicates that the [SCP]^– coordination mode is mainly governed by electronic, rather than steric factors. Quantum mechanical investigations reveal large contributions of the antibonding π-orbital of the [SCP]^– ligand to the LUMO of complex <b>2</b>, rendering it the ideal precursor for the first functionalization of the [SCP]^– anion. Complex <b>2</b> was therefore reacted with CAACs which induced a selective rearrangement of the [SCP]^– ligand to form the first CAAC stabilized group 15 – group 16 fulminate-type complexes (PN)₂La{SPC(^RCAAC)} (<b>5a,b</b>) (R = Ad, Me). A detailed reaction mechanism for the SCP to SPC isomerization is proposed based on DFT calculations.

Oligosilanylated Silocanes

A number of mono- and dioligosilanylated silocanes were prepared. Compounds included silocanes with 1-methyl-1-tris(trimethylsilyl)silyl, 1,1-bis[tris(trimethylsilyl)silyl], and 1,1-bis[tris(trimethylsilyl)germyl] substitution pattern as well as two examples where the silocane silicon atom is part of a cyclosilane or oxacyclosilane ring. The mono-tris(trimethylsilyl)silylated compound could be converted to the respective silocanylbis(trimethylsilyl)silanides by reaction with KOtBu and in similar reactions the cyclosilanes were transformed to oligosilane-1,3-diides. However, the reaction of the 1,1-bis[tris(trimethylsilyl)silylated] silocane with two equivalents of KOtBu leads to the replacement of one tris(trimethylsilyl)silyl unit with a tert-butoxy substituent followed by silanide formation via KOtBu attack at one of the SiMe3 units of remaining tris(trimethylsilyl)silyl group. For none of the silylated silocanes, signs of hypercoordinative interaction between the nitrogen and silicon silocane atoms were detected either in the solid state. by single crystal XRD analysis, nor in solution by 29Si-NMR spectroscopy. This was further confirmed by cyclic voltammetry and a DFT study, which demonstrated that the N-Si distance in silocanes is not only dependent on the energy of a potential N-Si interaction, but also on steric factors and through-space interactions of the neighboring groups at Si and N, imposing the orientation of the pz(N) orbital relative to the N-Si-X axis.