Tandem Ring-Closing Metathesis/Isomerization Reactions for the Total Synthesis of Violacein

A series of 5-substituted 2-pyrrolidinones was synthesized through a one-pot ruthenium alkylidene-catalyzed tandem RCM/isomerization/nucleophilic addition sequence. The intermediates resulting from RCM/isomerization showed reactivity toward electrophiles in aldol condensation reactions which provided a new entry for the total synthesis of the antileukemic natural product violacein

Solid-Phase Synthesis of Peptide Thioureas and Thiazole-Containing Macrocycles through Ru-Catalyzed Ring-Closing Metathesis

N-Terminally modified α-thiourea peptides can selectively be synthesized on solid support under mild reaction conditions using <i>N,N</i>′-di-Boc-thiourea and Mukaiyama’s reagent (2-chloro-1-methyl-pyridinium iodide). This N-terminal modification applies to the 20 proteinogenic amino acid residues on three commonly used resins for solid-phase synthesis. Complementary methods for the synthesis of α-guanidino peptides have also been developed. The thiourea products underwent quantitative reactions with α-halo ketones to form thiazoles in excellent purities and yields. When strategically installed between two alkene moieties, said thiazole core was conveniently embedded in peptide macrocycles via Ru-catalyzed ring-closing metathesis reactions. Various 15–17 membered macrocycles were easily accessible in all diastereomeric forms using this methodology. The developed “build/couple/pair” strategy is well suited for the generation of larger and stereochemically complete screening libraries of thiazole-containing peptide macrocycles

A Photolabile Linker for the Solid-Phase Synthesis of Peptide Hydrazides and Heterocycles

A photolabile hydrazine linker for the solid-phase synthesis of peptide hydrazides and hydrazine-derived heterocycles is presented. The developed protocols enable the efficient synthesis of structurally diverse peptide hydrazides derived from the standard amino acids, including those with side-chain protected residues at the C-terminal of the resulting peptide hydrazide, and are useful for the synthesis of dihydro­pyrano­[2,3-<i>c</i>]­pyrazoles. The linker is compatible with most commonly used coupling reagents and protecting groups for solid-phase peptide synthesis

Combining the Petasis 3‑Component Reaction with Multiple Modes of Cyclization: A Build/Couple/Pair Strategy for the Synthesis of Densely Functionalized Small Molecules

A <i>build/couple/pair</i> strategy for the synthesis of complex and densely functionalized small molecules is presented. The strategy relies on synthetically tractable building blocks (build), that is, diversely substituted hydrazides, α-hydroxy aldehydes, and boronic acids, which undergo Petasis 3-component reactions (couple) to afford densely functionalized <i>anti</i>-hydrazido alcohols. The resulting scaffolds can subsequently be converted via chemoselective cyclization reactions (pair), including intramolecular Diels–Alder or Ru-alkylidene catalyzed ring-closing metathesis, into sets of structurally diverse heterocycles in good yields in only 3–4 steps

Build/Couple/Pair Strategy Combining the Petasis 3-Component Reaction with Ru-Catalyzed Ring-Closing Metathesis and Isomerization

A “build/couple/pair” pathway for the systematic synthesis of structurally diverse small molecules is presented. The Petasis 3-component reaction was used to synthesize <i>anti</i>-amino alcohols displaying pairwise reactive combinations of alkene moieties. Upon treatment with a ruthenium alkylidene-catalyst, these dienes selectively underwent ring-closing metathesis reactions to form 5- and 7-membered heterocycles and cyclic aminals via a tandem isomerization/<i>N</i>-alkyliminium cyclization sequence

Ruthenium Hydride/Brønsted Acid-Catalyzed Tandem Isomerization/<i>N</i>‑Acyliminium Cyclization Sequence for the Synthesis of Tetrahydro-β-carbolines

This paper describes an efficient tandem sequence for the synthesis of 1,2,3,4-tetrahydro-β-carbolines (THBCs) relying on a ruthenium hydride/Brønsted acid-catalyzed isomerization of allylic amides to <i>N</i>-acyliminium ion intermediates which are trapped by a tethered indole nucleophile. The methodology provides not only a convenient “aldehyde-free” alternative to the classical Pictet–Spengler reaction but also attractive possibilities for total synthesis, including rapid generation of molecular complexity and formation of quaternary stereogenic centers. TBHCs can also be accessed by harnessing the Suzuki cross-coupling reaction to the isomerization/<i>N</i>-acyliminium cyclization sequence. Finally, diastereo- and enantioselective versions of the title reaction have been examined using substrate control (with dr >15: 1) and asymmetric catalysis (ee up to 57%), respectively

Pharmacologically relevant PPARγ ligands.

<p>Pharmacologically relevant PPARγ ligands.</p

Ruthenium Hydride/Brønsted Acid-Catalyzed Tandem Isomerization/<i>N</i>‑Acyliminium Cyclization Sequence for the Synthesis of Tetrahydro-β-carbolines

This paper describes an efficient tandem sequence for the synthesis of 1,2,3,4-tetrahydro-β-carbolines (THBCs) relying on a ruthenium hydride/Brønsted acid-catalyzed isomerization of allylic amides to <i>N</i>-acyliminium ion intermediates which are trapped by a tethered indole nucleophile. The methodology provides not only a convenient “aldehyde-free” alternative to the classical Pictet–Spengler reaction but also attractive possibilities for total synthesis, including rapid generation of molecular complexity and formation of quaternary stereogenic centers. TBHCs can also be accessed by harnessing the Suzuki cross-coupling reaction to the isomerization/<i>N</i>-acyliminium cyclization sequence. Finally, diastereo- and enantioselective versions of the title reaction have been examined using substrate control (with dr >15: 1) and asymmetric catalysis (ee up to 57%), respectively

Synthesis and biological evaluation of dihydropyrano-[2,3-c]pyrazoles as a new class of PPARγ partial agonists

<div><p>Peroxisome proliferator-activated receptor γ (PPARγ) is a well-known target for thiazolidinedione antidiabetic drugs. In this paper, we present the synthesis and biological evaluation of a series of dihydropyrano[2,3-<i>c</i>]pyrazole derivatives as a novel family of PPARγ partial agonists. Two analogues were found to display high affinity for PPARγ with potencies in the micro molar range. Both of these hits were selective against PPARγ, since no activity was measured when tested against PPARα, PPARδ and RXRα. In addition, a novel modelling approach based on multiple individual flexible alignments was developed for the identification of ligand binding interactions in PPARγ. In combination with cell-based transactivation experiments, the flexible alignment model provides an excellent analytical tool to evaluate and visualize the effect of ligand chemical structure with respect to receptor binding mode and biological activity.</p></div

The ligands 4 (orange) and 10ag (green) shown on top of each other from alignment on CID-10229498.

<p>The altered ligand structure induces a relocation of the ligand in the receptor, allowing the phenyl-substituent on the dihydropyrano[2,3-c]pyrazole N1 in 10ag to participate in several stabilizing hydrophobic interactions in the β-sheet regions.</p