Project description:The recent development of a sequential, high-yielding route to activated pyrimidine nucleotides, under conditions thought to be prebiotic, is an encouraging step toward the greater goal of a plausible prebiotic pathway to RNA and the potential for an RNA world. However, this synthesis has led to a disparity in the methodology available for stepwise construction of the canonical pyrimidine and purine nucleotides. To address this problem, and further explore prebiotically accessible chemical systems, we have developed a high-yielding, aqueous, one-pot, multicomponent reaction that tethers masked-sugar moieties to prebiotically plausible purine precursors. A pH-dependent three-component reaction system has been discovered that utilizes key nucleotide synthons 2-aminooxazole and 5-aminoimidazoles, which allows the first divergent purine/pyrimidine synthesis to be proposed. Due to regiospecific aminoimidazole tethering, the pathway allows N9 purination only, thus suggesting the first prebiotically plausible mechanism for regiospecific N9 purination.
Project description:We propose a novel pathway for the prebiotic synthesis of 2'-deoxynucleotides. Consideration of the constitutional chemical relationships between glycolaldehyde and β-mercapto-acetaldehyde, and the corresponding proteinogenic amino acids, serine and cysteine, led us to explore the consequences of the corresponding sulfur substitution for our previously proposed pathways leading to the canonical ribonucleotides. We demonstrate that just as 2-aminooxazole-an important prebiotic ribonucleotide precursor-is readily formed from glycolaldehyde and cyanamide, so is 2-aminothiazole formed from β-mercapto-acetaldehyde and cyanamide in water at neutral pH. Indeed, both the oxazole and the thiazole can be formed together in a one-pot reaction, and can be co-purified by crystallization or sublimation. We then show that 2-aminothiazole can take part in a 3-component carbon-carbon bond-forming reaction in water that leads to the diastereoselective synthesis of masked 2'-thiosugars regiospecifically tethered to purine precursors, which would lead to 2'-deoxynucleotides upon desulfurization. The possibility of an abiotic route to the 2'-deoxynucleotides provides a new perspective on the evolutionary origins of DNA. We also show that 2-aminothiazole is able to sequester, through reversible aminal formation, the important nucleotide precursors glycolaldehyde and glyceraldehyde in a stable, crystalline form.
Project description:An operationally simple, one-pot multicomponent reaction has been developed for the assembly of 9H-benzo[f]imidazo[1,2-d][1,2,3]triazolo[1,5-a][1,4]diazepines adorned with three diversification points via an atom-economical transformation incorporating α-diketones, o-azidobenzaldehydes, propargylic amines, and ammonium acetate. This process involves tandem InCl3-catalyzed cyclocondensation and intramolecular azide-alkyne 1,3-dipolar cycloaddition reactions; optimization data, substrate scope, and mechanistic insights are discussed.
Project description:A one-pot synthesis of ethers derived from inosine, guanosine, 2'-deoxyguanosine, and pyrimidinones is described. Exposure of the heterocycle to 1H-benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and Cs(2)CO(3) produces a reactive intermediate, which is converted to the desired ether by subsequent addition of an appropriate alcohol or phenol and Cs(2)CO(3). Although rapid formation of HMPA from BOP can occur in the presence of an alcohol and base, as demonstrated by the reaction with methanol, under appropriate conditions these heteroaryl ethers can be efficiently synthesized.
Project description:Tetrasubstituted propargylamines comprise a unique class of highly useful compounds, which can be accessed through the multicomponent coupling between ketones, amines, and alkynes (KA2 coupling), an underexplored transformation. Herein, the development of a novel, highly efficient, and user-friendly catalytic system for the KA2 coupling, based on the environmentally benign, inexpensive, and readily available zinc acetate, is described. This system is employed in the multicomponent assembly of unprecedented, tetrasubstituted propargylamines derived from structurally diverse, challenging, and even biorelevant substrates. Notable features of this protocol include the demonstration of the enhancing effect that neat conditions can have on catalytic activity, as well as the expedient functionalization of hindered, prochiral cyclohexanones, linear ketones, and interesting molecular scaffolds such as norcamphor and nornicotine.
Project description:Discovery of new types of reactions is essential to organic chemistry because it expands the scope of accessible molecular scaffolds and can enable more economical syntheses of existing structures. In this context, the so-called multicomponent reactions, MCRs, are of particular interest because they can build complex scaffolds from multiple starting materials in just one step, without purification of intermediates. However, for over a century of active research, MCRs have been discovered rather than designed, and their number remains limited to only several hundred. This work demonstrates that computers taught the essential knowledge of reaction mechanisms and rules of physical-organic chemistry can design - completely autonomously and in large numbers - mechanistically distinct MCRs. Moreover, when supplemented by models to approximate kinetic rates, the algorithm can predict reaction yields and identify reactions that have potential for organocatalysis. These predictions are validated by experiments spanning different modes of reactivity and diverse product scaffolds.
Project description:Among the various strategies being developed in the field of protein degraders, HyTags remain relatively underexplored, despite their advantages over PROTACs. Their synthesis typically involves multistep procedures, including the use of coupling reagents and protection/deprotection steps. To develop a more sustainable and streamlined approach, we designed a versatile multicomponent platform that generates HyTags with diverse linkers and hydrophobic moieties in high yields. Using (+)-JQ1 as the POI ligand, we synthesized a series of BRD4-targeting HyTags and discovered that compound 23 induces degradation of BRD4 via the autophagy-lysosome pathway through ER stress. This finding further supports the valuable application of this synthetic methodology in the search for effective degraders.
Project description:Based on consecutive one-pot conditions combining three palladium-catalyzed reactions (Sonogashira, Heck and Suzuki-Miyaura reactions), a more efficient domino multicomponent method has been successfully developed to access a wide variety of 3-(diarylmethylene)oxindoles. Microwave irradiation and use of a silver salt were the most important factors to achieve high yields and stereoselectivity.
Project description:The one-pot synthesis of a target molecule in the same reaction vessel is widely considered to be an efficient approach in synthetic organic chemistry. In this review, the characteristics and limitations of various one-pot syntheses of biologically active molecules are explained, primarily involving organocatalytic methods as key tactics. Besides catalysis, the pot-economy concepts presented herein are also applicable to organometallic and organic reaction methods in general.
Project description:Multicomponent reactions, conducted in a domino, sequential or consecutive fashion, have not only considerably enhanced synthetic efficiency as one-pot methodology, but they have also become an enabling tool for interdisciplinary research. The highly diversity-oriented nature of the synthetic concept allows accessing huge structural and functional space. Already some decades ago this has been recognized for life sciences, in particular, lead finding and exploration in pharma and agricultural chemistry. The quest for novel functional materials has also opened the field for diversity-oriented syntheses of functional π-systems, i.e. dyes for photonic and electronic applications based on their electronic properties. This review summarizes recent developments in MCR syntheses of functional chromophores highlighting syntheses following either the framework forming scaffold approach by establishing connectivity between chromophores or the chromogenic chromophore approach by de novo formation of chromophore of interest. Both approaches warrant rapid access to molecular functional π-systems, i.e. chromophores, fluorophores, and electrophores for various applications. Graphical Abstract