Synthesis of Bicyclic Hemiacetals Catalyzed by Unnatural Densely Substituted γ-Dipeptides

The asymmetric synthesis of bicyclic highly substituted tetrahydropyrans is described. The reaction is catalyzed by unnatural γ-dipeptides based on densely substituted l- and d-proline derivatives. This organocatalytic one-pot reaction takes place among a ketone, a nitroalkene, and an aldehyde to yield an octahydro-2H-chromene scaffold. Monomeric species, from which the corresponding γ-dipeptides are synthesized, cannot catalyze the reaction, thus confirming the emergent nature of the catalytic behavior of these dimeric species.Financial support for this work was provided by the Spanish Ministerio de Ciencia, Innovación y Universidades (MICINNFEDER, Grants PID2019-104772GB-I00 and RED2018-102387-T) and the Gobierno Vasco/Eusko Jaurlaritza (GV/EJ, Grant IT-1553-22). M.d.G.R. thanks the DIPC and UPV/EHU for her postdoctoral contract. M.A. thanks the Gobierno Vasco/Eusko Jaurlaritza for her Ph.D. grant. J.Z. thanks the China Scholarship Council for his Ph.D. grant (CSC 201908390051). The authors also thank the SGI/IZO-SGIker of the UPV/EHU and the DIPC for the generous allocation of analytical and computational resources

Dehydroamino acids: chemical multi-tools for late-stage diversification

α,β-Dehydroamino acids (dhAAs) are noncanonical amino acids that are found in a wide array of natural products and can be easily installed into peptides and proteins. dhAAs exhibit remarkable synthetic flexibility, readily undergoing a number of reactions, such as polar and single-electron additions, transition metal catalyzed cross-couplings, and cycloadditions. Because of the relatively mild conditions required for many of these reactions, dhAAs are increasingly being used as orthogonal chemical handles for late-stage modification of biomolecules. Still, only a fraction of the chemical reactivity of dhAAs has been exploited in such biorthogonal applications. Herein, we provide an overview of the broad spectrum of chemical reactivity of dhAAs, with special emphasis on recent efforts to adapt such transformations for biomolecules such as natural products, peptides, and proteins. We also discuss examples of enzymes from natural product biosynthetic pathways that have been found to catalyze many similar reactions; these enzymes provide mild, regio- and stereoselective, biocatalytic alternatives for future development. We anticipate that the continued investigation of the innate reactivity of dhAAs will furnish a diverse portfolio dhAA-based chemistries for use in chemical biology and drug discovery

Palladium Complexes of Chelating Carbenes for Catalytic Heck Reactions and 1,4-conjugate Addition Reactions

Activities of a series of modular palladium Chugaev-type carbene complexes were investigated in catalytic Heck and 1,4-conjugate addition reactions. Significant variations of catalytic activity with ligand structure were observed in the Heck reaction. A methyl hydrazine-derived palladium dicarbene dibromide complex was recognized as the most effective precatalyst for the Heck reaction. The best precatalyst selected mediated the Heck reaction of electron-poor aryl chlorides and a range of aryl bromides with styrene in high yields at 120 C. Heck reactions performed under air showed limited air tolerance. The modular nature of the palladium Chugaev-type carbene complexes also allowed optimization of the catalytic 1,4-conjugate addition reaction of organoboranes. A methyl hydrazine-derived palladium dicarbene dichloride complex was identified as the most promising precatalyst for the addition of phenylboronic acid to acyclic and cyclic enones at 40�C. Monitoring the 1,4-conjugate addition reactions revealed the need to optimize the reaction time, because the yield of the product decreased in most cases as the reaction was allowed to proceed for longer durations.Chemistry Departmen

Higher-Order Cyclopropenimine Superbases: Direct Neutral Brønsted Base Catalyzed Michael Reactions with α‑Aryl Esters

The synthesis and characterization of six new classes of higher-order superbases, including five that incorporate cyclopropenimine functionality, has been achieved. We propose a nomenclature that designates these as the CG₂, GC₂, PC₃, PC₁, C₃, and GP₂ classes of superbases. The p<i>K</i>_BH+ values were measured to be between 29.0 and 35.6 in acetonitrile. Linear correlations of ten superbase basicities vs that of their substituents demonstrated the insulating effect of the cyclopropenimine core. The molecular structures of several of these materials were obtained by single-crystal X-ray analysis, revealing interesting aspects of conformational bias and noncovalent organization. The types of superbasic cores and substituents were each reliably shown to affect selectivity for deprotonation over alkylation. Higher-order cyclopropenimine and guanidine superbase stability to hydrolysis was found to correlate to basicity. Finally, a GC₂ base was found to catalyze conjugate additions of α-aryl ester pronucleophiles, representing the first report of a neutral Brønsted base to catalyze such reactions

Higher-Order Cyclopropenimine Superbases: Direct Neutral Brønsted Base Catalyzed Michael Reactions with α‑Aryl Esters

The synthesis and characterization of six new classes of higher-order superbases, including five that incorporate cyclopropenimine functionality, has been achieved. We propose a nomenclature that designates these as the CG₂, GC₂, PC₃, PC₁, C₃, and GP₂ classes of superbases. The p<i>K</i>_BH+ values were measured to be between 29.0 and 35.6 in acetonitrile. Linear correlations of ten superbase basicities vs that of their substituents demonstrated the insulating effect of the cyclopropenimine core. The molecular structures of several of these materials were obtained by single-crystal X-ray analysis, revealing interesting aspects of conformational bias and noncovalent organization. The types of superbasic cores and substituents were each reliably shown to affect selectivity for deprotonation over alkylation. Higher-order cyclopropenimine and guanidine superbase stability to hydrolysis was found to correlate to basicity. Finally, a GC₂ base was found to catalyze conjugate additions of α-aryl ester pronucleophiles, representing the first report of a neutral Brønsted base to catalyze such reactions