Ultrasound-assisted diastereoselective green synthesis of spiro-fused-γ-lactams functionalized with an amide bond heterocyclic bioisostere via the Ugi azide/domino process coupled strategy.

A series of linked-type 1,5-disubstituted tetrazoles (1,5-DS-Ts) were synthesised via an isocyanide-based multicomponent reaction (IMCR) and used as synthetic platforms to access bound-type polyheterocycles containing an epoxyisoindol-1(6H)-one scaffold under green conditions. This rapid sonochemical synthetic strategy includes a double domino process using an orthogonal heterocyclic input in the Ugi-azide (UA) reaction. DFT calculations and NBO analysis were performed to understand the pseudopericyclic reaction involved in the 1,5-electrocyclization of the UA mechanism.

Isocyanide-Based Multicomponent Reactions Coupled One-Pot Process: Efficient Tools to Diversity-Oriented Synthesis of Structural Peptidomimetics.

Multicomponent diversity-oriented synthesis (DOS) of conformationally anchored structural peptidomimetics like 2,5-diketopiperazines (2,5-DKP) containing heterocyclic bioisosteres of the amide bond, such as 1,2,3-triazoles and 1,5-disubstituted tetrazoles (1,5-DS-T) is described. Structural peptidomimetics are synthesized from similar available starting materials, via a strategy based on isocyanide-based multicomponent reactions (IMCRs): Ugi-4CR and Ugi-Azide (UA), followed by a one-pot process: SN2/intramolecular alkyne-azide cycloaddition (IAAC). The sequential aligning of two powerful synthetic tools (IMCR and IAAC) has parallelly contributed to generate anchored conformation and complexity in target molecules, which are considered structural peptidomimetics of 2,5-DKP. Herein, the 1,2,3-triazole ring plays a key role in the preference for the boat conformation. Furthermore, the use of UA reaction generates scaffold diversity at the N-1 α-carbon of the pyrazinone ring, replacing a linear amide bond with a heterocyclic bioisostere such as 1,5-DS-T leading to the synthesis of novel tricyclic peptidomimetics. The DFT calculations confirmed the boat conformation of the synthesized molecules.

Synthesis of Polyheterocyclic Dimers Containing Restricted and Constrained Peptidomimetics via IMCR-Based Domino/Double CuAAC Click Strategy.

A novel strategy via the triple process (multicomponent reactions (MCR)-domino)/tandem was developed for the synthesis of restricted and constrained bis-1,2,3-triazole-linked pyrrolo[3,4-b]pyridine peptidomimetics dimers in overall yields of 20-55%. This strategy allows the construction of six heterocycles in two stages of the reaction.

Synthesis of Tris-Heterocycles via a Cascade IMCR/Aza Diels-Alder + CuAAC Strategy.

6-Triazolylmethyl-pyrrolo[3,4-b]pyridin-5-one tris-heterocycles were synthesized in 43-57% overall yields. The two-stage synthesis involved a cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization) followed by a copper-assisted alkyne-azide [3+2] cycloaddition (CuAAC). This efficient and convergent strategy proceeded via complex terminal alkynes functionalized with a fused bis-heterocycle at the α-position. The final products are ideal candidates for SAR studies as they possess two privileged scaffolds in medicinal chemistry: 4-substituted or 1,4-substituted 1H-1,2,3-triazoles and pyrrolo[3,4-b]pyridin-5-ones.

An efficient Ugi-3CR/aza Diels-Alder/Pomeranz-Fritsch protocol towards novel aza-analogues of (±)-nuevamine, (±)-lennoxamine and magallanesine: a diversity oriented synthesis approach.

A rapid and efficient synthesis of a series of (±)-nuevamine, (±)-lennoxamine and magallanesine aza analogues is described. The synthetic strategy involves Ugi-3CR and two further condensation processes, aza-Diels-Alder cycloaddition and the Pomeranz-Fritsch reaction. The variation of the chain-size in aldehyde moieties provided structural diversity in only two operational reaction steps.