The isocyanide SN2 reaction Patil, Pravin; Zheng, Qiang; Kurpiewska, Katarzyna ...
Nature communications,
09/2023, Volume:
14, Issue:
1
Journal Article
Peer reviewed
Open access
Abstract
The S
N
2 nucleophilic substitution reaction is a vital organic transformation used for drug and natural product synthesis. Nucleophiles like cyanide, oxygen, nitrogen, sulfur, or ...phosphorous replace halogens or sulfonyl esters, forming new bonds. Isocyanides exhibit unique C-centered lone pair σ and π* orbitals, enabling diverse radical and multicomponent reactions. Despite this, their nucleophilic potential in S
N
2 reactions remains unexplored. We have uncovered that isocyanides act as versatile nucleophiles in S
N
2 reactions with alkyl halides. This yields highly substituted secondary amides through in situ nitrilium ion hydrolysis introducing an alternative bond break compared to classical amide synthesis. This novel 3-component process accommodates various isocyanide and electrophile structures, functional groups, scalability, late-stage drug modifications, and complex compound synthesis. This reaction greatly expands chemical diversity, nearly doubling the classical amid coupling’s chemical space. Notably, the isocyanide nucleophile presents an unconventional Umpolung amide carbanion synthon (R-NHC(-) = O), an alternative to classical amide couplings.
The morpholine and piperazine with their remarkable physical and biochemical properties are popular heterocycles in organic and medicinal chemistry used in rational property design. However, in the ...majority of cases these rings are added to an existing molecule in a building block approach thus limiting their substitution pattern and diversity. Here we introduce a versatile de novo synthesis of the morpholine and piperazine rings using multicomponent reaction chemistry. The large scale amenable building blocks can be further substituted at up to four positions, making this a very versatile scaffold synthesis strategy. Our methods thus fulfill the increasing demand for novel building block design and nontraditional scaffolds which previously were not accessible
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A concise four step synthetic route for glutarimide alkaloids of high biological interest is presented. The scaffold is accessed via an Ugi four component reaction, hereby introducing two points of ...variation. This is followed by a hydrolysis, a cyclization under mild conditions, and an amine deprotection. The diastereomers of the cyclized intermediate can be easily separated, thus leading to optically pure alkaloids. By this route, four natural products and ten derivatives were synthesized. The scope and limitations of the synthetic methodology were investigated.
A mild four‐step synthetic methodology for glutarimide alkaloids was established, based on the Ugi 4‐component reaction. Four natural products were synthesized, followed by the synthesis of a small library of derivatives. The stereochemistry, scope, and limitations of the methodology were investigated.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A series of unprecedented tetrazole-linked imidazo1,5-apyridines are synthesized from simple and readily available building blocks. The reaction sequence involves an azido-Ugi-deprotection reaction ...followed by an acetic anhydride-mediated N-acylation–cyclization process to afford the target heterocycle. Furthermore, the scope of the methodology was extended to diverse R3-substitutions by employing commercial anhydrides, acid chlorides, and acids as an acyl component. The scope for the postmodification reactions are explored and the usefulness of the synthesis is exemplified by an improved three-step synthesis of a guanylate cyclase stimulator.
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The design and synthesis of head‐to‐tail linked artificial macrocycles using the Ugi‐reaction has been developed. This synthetic approach of just two steps is unprecedented, short, efficient and ...works over a wide range of medium (8–11) and macrocyclic (≥12) loop sizes. The substrate scope and functional group tolerance is exceptional. Using this approach, we have synthesized 39 novel macrocycles by two or even one single synthetic operation. The properties of our macrocycles are discussed with respect to their potential to bind to biological targets that are not druggable by conventional, drug‐like compounds. As an application of these artificial macrocycles we highlight potent p53–MDM2 antagonism.
Short path, large rings: An unprecedented short and diverse 2‐step synthesis is described towards artificial 8–19‐membered macrocycles. Artificial macrocycles are useful tools to address difficult biological targets. An example of a designed macrocycle to antagonize the protein–protein interaction p53–MDM2 is given.
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The direct nonpeptidic macrocycle synthesis of α-isocyano-ω-amines via the classical Ugi four-component reaction (U-4CR) is introduced. Herein an efficient and flexible two-step procedure to complex ...macrocycles is reported. In the first step, the reaction between unprotected diamines and isocyanocarboxylic acids gives high diversity of unprecedented building blocks in high yield. In the next step, the α-isocyano-ω-amines undergo a U-4CR with high diversity of aldehydes and carboxylic acids in a one-pot procedure. This synthetic approach is short and efficient and leads to a wide range of macrocycles with different ring sizes.
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This study presents a comprehensive structural analysis of the adducts formed upon the reaction of two Ru(III) complexes HIsq
-Ru
Cl
(dmso)(Isq) (
) and H
Ind
-Ru
Cl
(dmso)(HInd) (
) (where ...HInd-indazole, Isq-isoquinoline, analogs of NAMI-A) and two Ru(II) complexes,
-RuCl
(dmso)
(
) and
-RuCl
(dmso)
(
), with hen-egg white lysozyme (HEWL). Additionally, the crystal structure of an adduct of human lysozyme (HL) with ruthenium complex, H
Ind
-RuCl
(dmso)(HInd) was solved. X-ray crystallographic data analysis revealed that all studied Ru complexes, regardless of coordination surroundings and metal center charge, coordinate to the same amino acids (His15, Arg14, and Asp101) of HEWL, losing most of their original ligands. In the case of the
-HL adduct, two distinct metalation sites: (i) Arg107, Arg113 and (ii) Gln127, Gln129, were identified. Crystallographic data were supported by studies of the interaction of
and
with HEWL in an aqueous solution. Hydrolytic stability studies revealed that both complexes
and
liberate the N-heterocyclic ligand under crystallization-like conditions (pH 4.5) as well as under physiological pH conditions, and this process is not significantly affected by the presence of HEWL. A comparative examination of nine crystal structures of Ru complexes with lysozyme, obtained through soaking and co-crystallization experiments, together with in-solution studies of the interaction between
and
with HEWL, indicates that the hydrolytic release of the N-heterocyclic ligand is one of the critical factors in the interaction between Ru complexes and lysozyme. This understanding is crucial in shedding light on the tendency of Ru complexes to target diverse metalation sites during the formation and in the final forms of the adducts with proteins.
Lactoferrin is considered as a part of the innate immune system that plays a crucial role in preventing bacterial growth, mostly via an iron sequestration mechanism. Recent data show that bovine ...lactoferrin prevents late-onset sepsis in preterm very low birth weight neonates by serving as an iron chelator for some bacterial strains; thus, it is very important to control the iron saturation level during diet supplementation. An accurate estimation of lactoferrin iron saturation is essential not only because of its clinical applications but also for a wide range of biochemical experiments. A comprehensive method for the quantification of iron saturation in lactoferrin preparations was developed to obtain a calibration curve enabling the determination of iron saturation levels relying exclusively on the defined ratio of absorbances at 280 and 466 nm (
A
280/466
). To achieve this goal, selected techniques such as spectrophotometry, ELISA, and ICP-MS were combined. The ability to obtain samples of lactoferrin with determination of its iron content in a simple and fast way has been proven to be very useful. Furthermore, a similar approach could easily be implemented to facilitate the determination of iron saturation level for other metalloproteins in which metal binding results in the appearance of a distinct band in the visible part of the spectrum.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
An Ugi multicomponent reaction based two-step strategy was applied to generate medium-sized rings. In the first linear expansion phase, a series of diamines reacted with cyclic anhydrides to produce ...different lengths of terminal synthetic amino acids as the starting material for the second phase. The Ugi-4-center 3-component reaction was utilized to construct complex medium-sized rings (8–11) by the addition of isocyanides and oxo components. This method features mild conditions and a broad substrate scope.
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