Anass Znabet’s research while affiliated with University of Manchester and other places

... Biocatalytic oxidation of meso-pyrrolidines with the monoamine oxidase N (MAO-N) D5 mutant afforded the corresponding bicyclic imines, [4] which were then subjected to a highly diastereoselective Ugi-type three-component reaction (U-3CR) to give bicyclic proline derivatives in high optical purity. [5] This strategy was subsequently exploited in an efficient synthesis of the hepatitis drug, telaprevir (Fig. 1A). [6] The high diastereoselectivity of the U-3CR plausibly results from preferential attack of the isocyanide on the convex face of the constrained bicyclic imine 2. ...

Reference:

Chemoenzymatic Multicomponent Synthesis of Nirmatrelvir

... [21] Beside deracemization, the functionalization of the α-position of cyclic amines was the focus of many research projects including the industrial synthesis of a key intermediate en route to boceprevir. [22] MAOs have been used to generate precursors for multi-component reactions (Ugi-Joullié-and Ugi-Smiles-reactions) [23][24][25][26] and Fischer indole synthesis with aryl-hydrazines [27] in consecutive steps, interrupted by the isolation of the imine intermediate. In contrast, one-pot functionalization of cyclic amines via imines was achieved with cyanide [22,28] and pyrroles [29] as nucleophiles, as well as via gold-catalyzed alkynylation [30] and metal-or enzyme-catalyzed oxidation to the corresponding lactams (Figure 1). ...

Reference:

Chemo‐Enzymatic One‐Pot Two‐Step Functionalization of 1,2,3,4‐Tetrahydroisoquinolines by Monoamine Oxidase‐Ugi‐Joullié Reaction Sequence

... Based on previous work, [93][94] the authors propose a plausible mechanism for a three-component reaction ( Figure 9): Firstly, Pd (0) was generated from the in situ Pd (II) catalyst by oxidizing the CÀ X bond of 2-bromobenzoic acid methyl ester to incorporate Pd (0) to obtain I. Next, polyformaldehyde migration was inserted into the ArÀ Pd bridge to obtain II, and then β- Figure 8. Proposed reaction mechanism. Reproduced with permission. ...

Reference:

C−N Bond Formation Using Paraformaldehyde as C1 Source – Recent Advances

... [19] To our satisfaction, the sequential process occurred with a significantly increased efficiency when stoichiometric amount of the cost-effective TMSOTf was used as Lewis acid promoter (Table 1, entry 11). [20] Conversely, no reaction occurred by replacing TMSOTf with the Brønsted trifluoromethanesulfonic acid (TfOH) (Table 1, entry 12). Notably, regardless the conditions, the reaction was highly diastereoselective leading almost exclusively to the (R,R)/(S,S)-racemic mixture. ...

Reference:

Diastereoselective Synthesis of High Functionalized 4‐Imidazolidinone‐Tetrahydro‐β‐Carboline Hybrids via Divergent Post‐Ugi Transformation

... MCR has emerged as an attractive alternative to multistep linear convergent synthetic approaches and has been successfully applied to the synthesis of active pharmaceutical ingredients (API). [25][26][27][28][29][30] Here, we describe our strategy for the development of a drug-like MCR scaffold stabilizing the 14-3-3σ/ERα complex. The most potent analogs of the series showed efficacy in orthogonal biophysical assays and cell-based PPI stabilization in the low micromolar range. ...

Reference:

Rapid scaffold-hopping for molecular glues: from fragments to cell-active probes targeting the 14-3-3/ERα complex

... This favors catalyst turnover and leaves the C-C bond-forming step as the stereodefining event in the catalytic cycle [193]. Further studies in this area by other authors have shown that other structurally related tripeptides [194][195][196] or smaller dipeptides [197,198] also can catalyze this reaction with success. ...

Reference:

Asymmetric Dual Enamine Catalysis/Hydrogen Bonding Activation

... In 2023, Ruijter, Turner and co-workers reported a remarkable new synthetic approach to nirmatrelvir based on a highly diastereoselective Ugi-type three-component reaction (Scheme 5) [29]. One of the key building blocks, the chiral bicyclic imine 18, was prepared by enantioselective oxidative desymmetrization of meso-pyrrolidine 17 with monoamine oxidase N (MAO-N) [30]. Due to the high volatility of 18, it was isolated in the form of its crystalline bisulfite adduct 19 [31], from which the free imine 18 was generated in situ for the three-component reaction by basic treatment. ...

Reference:

The Design, Synthesis and Mechanism of Action of Paxlovid, a Protease Inhibitor Drug Combination for the Treatment of COVID-19

... Multi-component reactions (MCRs) are an important tool for gathering three or more starting material and converting them into a single product of higher molecular weight in a fast and efficient manner. [4][5][6][7] In recent years, MCRs by high merit of their junction, output, high yields, environmental friendliness, and simplicity of implementation have emerged as a powerful synthetic plan to make "drug-like" diverse structures of heterocyclic moieties. [8][9][10][11] Transition metal catalyzed carbon-carbon and carbon-heteroatom bond-forming reactions are the vital aspects of organic synthesis to give a biologically active organic molecular framework. ...

Reference:

Sc(OTf) 3 catalysed multicomponent synthesis of chromeno[2,3- d ]pyrimidinetriones under solvent-free condition

... 1-Azadienes can participate in cycloaddition reactions both as heterodienes and as dienophiles, dipolarophiles and carbenophiles, which makes them versatile compounds in organic synthesis. [1] 1-Azadienes are commonly used for the preparation of various N-heterocycles, [1] such as di-and tetrahydropyridines, [10][11][12][13] pyrimidines, [14][15][16][17][18] quinolines, thiazines, pyrroles, [19] triazinandiones, and aziridines, as well as amino acids [20,21] and α-aminophosphonates. [22] The enormous synthetic potential of 1-azadienes spurs looking for new efficient methods for their synthesis, especially using available starting compounds and simple catalysts in a pot-atom-step economic manner. ...

Reference:

A Quantum‐Chemical Study of the Mechanism of 1‐Azadienes Formation from Aldimines and Arylacetylenes in the KOBu/DMSO Superbasic Medium