Perla Islas-Jácome

Natural products remain privileged starting points in drug discovery because of their structural complexity, stereochemical richness, and bioactive scaffolds. Semisynthesis enables the transformation of natural products or naturally occurring precursors into structurally modified analogs, helping overcome limitations in supply, physicochemical properties, toxicity, or pharmacokinetic behavior. In this context, isocyanide-based multicomponent reactions (I-MCRs) provide rapid, modular, and operationally simple synthetic tools for the diversification of natural product-derived substrates. This review summarizes the application of I-MCRs in natural product semisynthesis, including Ugi four-component reactions (U-4CR), Passerini three-component reactions (P-3CRs), Groebke–Blackburn–Bienaymé three-component reactions (GBB-3CRs), Ugi–azide four-component reactions (UA-4CRs), and other related I-MCRs. The collected literature indicates that U-4CR is the most-explored MCR, whereas P-3CRs, GBB-3CRs, and, particularly, the UA-4CRs remain underexplored. A chemoinformatic characterization of 162 semisynthetic I-MCR products revealed that these compounds occupy a chemical space comparable to that of FDA-approved natural product-derived drugs, while retaining natural product-like complexity and three-dimensionality. In addition, molecular docking against CXCR3 was performed as a hypothesis-generating approach to prioritize candidates for further biological evaluation. These findings highlight I-MCRs as promising synthetic tools for expanding natural product-related chemical space and generating structurally novel semisynthetic analogs.

The new polyheterocyclic compound, 2-benzyl-7-(4-chlorophenyl)-3-morpholino-6-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one, was synthesized by a sequential combination of 4-chlorobenzaldehyde, (1-phenyl-1H-1,2,3-triazol-4-yl)methanamine, 2-isocyano-1-morpholino-3-phenylpropan-1-one, and maleic anhydride under a microwave-assisted one-pot process [Ugi-Zhu/aza Diels-Alder cycloaddition/N-acylation/decarboxylation/dehydration] with a 28% overall yield. The synthesized compound was fully characterized by 1D (¹H, ¹³C) and 2D (COSY, HSQC, and HMBC) NMR, FT-IR, and HRMS.

The synthesis and characterization of three tridentate ligands for new MOFs are described. A triple aminolysis of the 1,3,5-tribenzoyl chloride with p-aminobenzoic acid gave the tricarboxylic acid 3 in 90% yield. Moreover, the same reaction, also from the 1,3,5-tribenzoyl chloride, but using p-aminobenzonitrile gave the new tris-benzonitrile 5 in 85% yield. Finally, this later one was treated with sodium azide and a Lewis acid to synthesize the new tris-tetrazole-based ligand 7 in 72% yield through a [3 + 2] azide-nitrile cycloaddition. It is noteworthy that the isosterism between carboxylic acids and tetrazoles may be considered to design and fabricate new MOFs with similar properties.

We herein report the synthesis and characterization of six α,β-unsaturated dicarboxylic acid ligands with different phenyl spacers, and two ligands with a biphenyl and anthraquinone spacers. All these dimaleamic acids were synthesized in 16 to 99% yields via a base-catalyzed maleimide ring opening in water (ligand 2), or by a di-N-acylation from the corresponding diamines and maleic anhydride in acetic acid (ligands 4, 6, 8, 10, 12, 14 and 16). These reactions were performed using green solvents, while requiring minimal work up procedures, making them suitable alternatives to access these types of bidentate ligands quickly, which can be used to fabricate new metal-organic frameworks (MOFs).

The synthesis and characterization of three new bis 1-substituted 1H-tetrazoles are described. Two products were synthesized in a single step via a direct heterocyclization of primary amines, methyl orthoester (trymethyl orthoformate), and sodium azide in 30% and 91% yields, respectively. Besides, another one was prepared via a three-step synthetic strategy: S_NAr (32%), nitro-group reduction (66%), and primary amine heterocyclization (83%), yielding 18%, overall. The aim behind the synthesis of new tetrazole-containing products is to construct novel MOF-like structures to evaluate their gas capture properties (CO₂, CO, and SO₂) under relative humidity conditions.

The synthesis and characterization of one symmetrical bis-1-substituted-1H-tetrazole (69%) via a Huisgen-type 1,3-dipolar cycloaddition, as well as, one symmetrical aza-linked bis-5-substituted-1H-tetrazole (57%) via a classic Huisgen 1,3-dipolar cycloaddition followed by a reductive aza-coupling under greener reaction conditions are described. The main reason behind these tetrazole-based ligands is to construct novel Metal-Organic Framework (MOF) architectures to evaluate their CO₂ capture properties under relative humidity conditions. It is worthy to note that both herein reported products have not been synthesized nor isolated, anywhere. Besides, the synthesis of new ligands to fabricate novel MOFs with potential application in environmental remediation has become a highly valued field of opportunity for synthetic chemists and materials engineers.