Trifunctional Building Blocks Research Articles

Heterocyclization vs Coupling Reactions: A DNA-Encoded Libraries Case

Aim. DNA-encoded libraries technologies (DELT) are gradually becoming an important part of standard drug discovery toolbox. DELT is looking to find its place between classic low-molecular-weight drug candidates on the one hand, and high-molecular-weight antibodies and peptides on the other hand. On its natural path to overcoming the “childhood diseases” typical for every novel technology, DELT has reached a point where the chemical diversity of DNA-encoded libraries (DELs) becomes an important factor to look out for. In this paper, we aim to take a closer look at the chemical diversity of DELs in their present state and find the ways to improve it.Results and discussion. We have identified the DEL-viable building blocks from the Enamine Ltd. stock collection, as well as from Chemspace Ltd. virtual collection, using the SMARTS set, which takes into account all the necessary structural restrictions. Using modern cheminformatics tools, such as Synt-On, we have analyzed the scaffold diversity of both stock and virtual core bi- and tri-functional building blocks (BBs) suitable for DNA-tolerant reactions. The identification of scaffolds from the most recently published on-DNA heterocyclization reactions and analysis of their inclusion into the existing BBs space have shown that novel DNA-tolerant heterocyclizations are extremely useful for expanding chemical diversity in DEL technologies.Conclusions. The analysis performed allowed us to recognize which functional groups should be prioritized as the most impactful when the new BBs are designed. It is also made clear that the development of new DNA-tolerant reactions, including heterocyclizations, have a significant potential to further expand DEL molecular diversity.

Fermentative Production of l-2-Hydroxyglutarate by Engineered Corynebacterium glutamicum via Pathway Extension of l-Lysine Biosynthesis

l-2-hydroxyglutarate (l-2HG) is a trifunctional building block and highly attractive for the chemical and pharmaceutical industries. The natural l-lysine biosynthesis pathway of the amino acid producer Corynebacterium glutamicum was extended for the fermentative production of l-2HG. Since l-2HG is not native to the metabolism of C. glutamicum metabolic engineering of a genome-streamlined l-lysine overproducing strain was required to enable the conversion of l-lysine to l-2HG in a six-step synthetic pathway. To this end, l-lysine decarboxylase was cascaded with two transamination reactions, two NAD(P)-dependent oxidation reactions and the terminal 2-oxoglutarate-dependent glutarate hydroxylase. Of three sources for glutarate hydroxylase the metalloenzyme CsiD from Pseudomonas putida supported l-2HG production to the highest titers. Genetic experiments suggested a role of succinate exporter SucE for export of l-2HG and improving expression of its gene by chromosomal exchange of its native promoter improved l-2HG production. The availability of Fe2+ as cofactor of CsiD was identified as a major bottleneck in the conversion of glutarate to l-2HG. As consequence of strain engineering and media adaptation product titers of 34 ± 0 mM were obtained in a microcultivation system. The glucose-based process was stable in 2 L bioreactor cultivations and a l-2HG titer of 3.5 g L−1 was obtained at the higher of two tested aeration levels. Production of l-2HG from a sidestream of the starch industry as renewable substrate was demonstrated. To the best of our knowledge, this study is the first description of fermentative production of l-2HG, a monomeric precursor used in electrochromic polyamides, to cross-link polyamides or to increase their biodegradability.

Photochemical [2 + 2] Cycloaddition of Alkenyl Boronic Derivatives: An Entry into 3-Azabicyclo[3.2.0]heptane Scaffold.

The synthesis of 3-azabicyclo[3.2.0]heptyl boropinacolates and trifluoroborates via the [2 + 2] photocycloaddition of the corresponding alkenyl boronic derivatives and maleimides or maleic anhydride is described. Optimization of the reaction conditions (i.e., wavelength, concentration of the reagents, photosensitizer) was carried out, and the scope and limitations of the method were studied. Alkenyl boronic acid pinacolates were found to be more suitable for the [2 + 2] cycloaddition, providing better reaction outcomes compared to the trifluoroborates. The utility of this approach was shown by the preparation of bi- and trifunctional building blocks (21 examples), which could be easily synthesized on up to 60 g scale. These cycloadducts provide a convenient entry into the 3-azabicyclo[3.2.0]heptane scaffold through the C-C coupling or oxidative deborylation reactions.

Hydrothermal assembly, structures, topologies, luminescence, and magnetism of a novel series of coordination polymers driven by a trifunctional nicotinic acid building block.

In this work, a trifunctional N,O-building block, 5-(4-carboxyphenoxy)nicotinic acid (H2cpna), that combines three distinct types of functional groups (COOH, N-pyridyl, and O-ether) was used for the hydrothermal assembly of thirteen new coordination compounds: [Co(μ3-Hcpna)2]n (1), [Mn(μ4-cpna)(H2O)]n (2), [Mn(μ4-cpna)(H2O)2]n (3), [Mn(μ-cpna)(2,2'-bipy)(H2O)2]n (4), {[Ni(μ3-cpna)(2,2'-bipy)(H2O)]2·H2O}n (5), {[Cd(μ3-cpna)(2,2'-bipy)]·2H2O}n (6), [Zn2(μ-cpna)2(2,2'-bipy)2] (7), [Cu(μ-cpna)(2,2'-bipy)(H2O)]n (8), {[Mn(μ-cpna)(phen)2]·6H2O}n (9), {[Ni(μ3-cpna)(phen)(H2O)]·H2O}n (10), [Zn2(μ-cpna)2(phen)2] (11), {[Pb(μ3-cpna)(phen)]·H2O}n (12), and [Ni(μ3-cpna)(4,4'-bipy)0.5(H2O)]n (13). These products were synthesized from the corresponding metal(ii) chlorides, H2cpna, NaOH, and optional N-donor supporting ligands or templates {bis(4-pyridyl)amine (bpa), 2,2'-bipyridine (2,2'-bipy), 4,4'-bipyridine (4,4'-bipy), or 1,10-phenanthroline (phen)}. Products 1-13 were characterized in the solid state by standard methods, including elemental and thermogravimetric analysis (TGA), IR spectroscopy, and powder (PXRD) and single-crystal X-ray diffraction. The structures of 1-13 feature distinct structural types, namely the 3D metal-organic frameworks (MOFs 1-3), the 2D coordination polymers (5, 6, 10, 12, and 13), the 1D coordination polymers (4, 8, and 9), and the 0D discrete cyclic dimers (7 and 11). Such a wide structural diversity of 1-13 is driven by various factors, including the type of the metal(ii) node, the deprotonation degree of H2cpna, and/or the type of supporting ligand or template. Notably, an addition of bpa can tune the structure of MOF 3 by the template effect. Topological classification of underlying metal-organic networks was performed, leading to several distinct topological nets: rtl (in 1), hxg-d-4-C2/m (in 2), sra (in 3), 2C1 (in 4, 8 and 9), fes (in 5, 10, and 12), hcb (in 6), and 3,4L83 (in 13). The magnetic behavior of 1-5, 8-10, and 13 was studied and theoretically modeled, disclosing antiferromagnetic interactions. The luminescence behavior of 6, 7, 11, and 12 was also investigated.

Facile synthesis of 1H-imidazo[1,2-b]pyrazoles via a sequential one-pot synthetic approach.

5-Aminopyrazole-4-carbonitrile and ethyl 5-aminopyrazole-4-carboxylate, as potential trifunctional building blocks are introduced in a facile, chemo- and regioselective multicomponent assembly of imidazo[1,2-b]pyrazoles via the Groebke–Blackburn–Bienaymé reaction (GBB reaction). Besides the synthetic elaboration of a green-compatible isocyanide-based access in three-component mode, we describe an operationally simple, one-pot two-step GBB protocol for the rapid construction of a 46 membered imidazo[1,2-b]pyrazole library with yields up to 83%.

Coupling of an advanced tri-functional building block by reductive amination leads to a protected backbone of a new archetype of foldamer

In order to advance our project to explore a new archetype of foldamer that preferentially folds in water, we designed two types of tri-functional building blocks with increasingly favorable ketone deprotection properties. Both were selected for their ease of synthetic access and the availability of bulk starting material. While the first building block proved unsuitable for efficient coupling by reductive amination, the second gave rise to almost quantitative yields according to mass spectral monitoring. It was thus effectively turned into a protected dimer and a tetramer. Although their subsequent purification prior to exhaustive ketone deprotection was preparatively impractical in view of their high polarity/water solubility, the stage is now set for transfer of the oligomer synthesis onto the solid phase on resin in view of the efficient five-step synthetic access from affordable bulk material, the favorable deprotection properties, the perspective for introduction of a variety of backbone substituents, and the possibility to protect the amine terminus by Boc or Fmoc protection.

Supramolecular Compounds from Multiple Ugi Multicomponent Macrocyclizations: Peptoid-based Cryptands, Cages, and Cryptophanes

The first 3-fold multicomponent macrocyclizations of trifunctional building blocks were developed to produce, in one pot, cryptands, cages, and cryptophanes with peptoid tethers carrying additional recognition motifs. The straightforward, efficient, and diversity-oriented fashion by which these complex macromulticycles are obtained is suitable for building combinatorial libraries of synthetic receptors with potential applicability in catalysis and supramolecular and coordination chemistry. The strategy also easily allows creation of asymmetric macromulticyclic cavities, with up to 20 new bonds formed in one pot.

Novel Trifunctional Building Blocks for Fluorescent Polymers.

Herein, we describe the synthesis of fluorescent 2-(arylsulfonyl)methacrylates and its polymers. These novel trifunctional monomers, possessing a fluorescent arylsulfonyl (ArSO2) group, an alkyl group (R), and a polymerizable olefin, serve as useful building blocks for functionalized fluorescent polymers.

Novel trifunctional building blocks for fluorescent polymers.

[reaction: see text] Herein, we describe the synthesis of fluorescent 2-(arylsulfonyl)methacrylates and its polymers. These novel trifunctional monomers, possessing a fluorescent arylsulfonyl (ArSO(2)) group, an alkyl group (R), and a polymerizable olefin, serve as useful building blocks for functionalized fluorescent polymers.

Use of glucose as a trifunctional building block for chiral liquid crystals

Glucose is used as a trifunctional chiral central core in laterally substituted liquid crystals. The synthesis of 1′-(4-O-(4″-octyloxybenzoyl)-2,3,6-trideoxy-β-D-erythrohexopyranosyl)-4′-hexyloxybenzene and its related 6-halogeno derivatives is described as an example for rod-like molecules with small lateral substituents. All the compounds obtained exhibit a cholesteric mesophase. It is shown that there is a correlation between the size of the substituent at the 6-position and the transition temperature from the cholesteric to the isotropic phase. Also, the synthesis of Y-mesogenic compounds containing spaced and/or unspaced substituents in the 4- and 6-positions is described, followed by a qualitative discussion of the results obtained.