Jakob Feldthusen Jensen

Synthesis of Heterocycles through a Ruthenium‐Catalyzed Tandem Ring‐Closing Metathesis/Isomerization/N‐Acyliminium Cyclization Sequence

Olefin metathesis is an extremely powerful and general method for carbon–carbon bond formation in organic synthesis. For example, ruthenium alkylidene catalyzed metathesis has been widely used to construct a variety of alkenes for applications in chemistry, materials science, and chemical biology. A key asset of the metathesis process is the unique olefin functional group selectivity mediated by robust and well-defined catalytic systems. Over the years, however, unexpected nonmetathetic reactions have been observed under metathesis conditions. Although these reactions typically are highly substrate dependent, associated with specific reaction conditions, and possibly caused by ill-defined metal-catalytic species, they represent a unique opportunity for the development of tandem processes. It is well recognized that tandem reactions offer major advantages in the synthesis of valuable target compounds. In this context, metathesis mediated by ruthenium alkylidene catalysts 1 e and 1k (Grubbs firstand second-generation catalysts; Figure 1) has successfully been coupled to nonmetathetic transformations, such as double-bond isomerization, hydrogenation, cyclopropanation, dihydroxylation, 12] keto-hydroxylation, and Kharasch addition reactions. Only a few reports have dealt with the tandem ringclosing metathesis (RCM)/ double-bond isomerization. Notable works by the groups of Snapper and Schmidt have independently shown how cyclic allyl ethers can isomerize into 2,3-dihydropyrans. Schmidt and co-workers have also shown the beneficial effect of added hydride to favor the isomerization step. Inspired by the work of Fustero et al. (RCM/isomerization), and P rez-Castells and co-workers (RCM/isomerization/cyclopropanation), we speculated that enamides generated in the event of a RCM/isomerization sequence could be further isomerized into reactive Nacyliminium intermediates (Scheme 1). The presence of a suitably tethered nucleophile could then bring about a second cyclization step.

On the Mechanism of the Copper-Catalyzed Cyclopropanation Reaction

The selectivity-determining step in enantioselective copper-catalyzed cyclopropanation with diazo compounds has been studied by experimental and computational methods. The addition of the very reactive metallacarbene intermediate in an early transition state to the substrate alkene is concerted but strongly asynchronous, with substantial cationic character on one alkene carbon in the neighborhood of the transition state. Evidence from isotope effects and Hammett studies supports the nature of the transition state. Formation of a metallacyclobutane intermediate by a [2+2] addition is kinetically disfavored. Ligand-substrate interactions influencing the enantio- and diastereoselectivity have been identified, and the preferred orientation of the alkene substrate during the addition is suggested.

Traceless Azido Linker for the Solid-Phase Synthesis of NH-1,2,3-Triazoles via Cu-Catalyzed Azide-Alkyne Cycloaddition Reactions

A broadly useful acid-labile traceless azido linker for the solid-phase synthesis of NH-1,2,3-triazoles is presented. A variety of alkynes were efficiently immobilized on a range of polymeric supports by Cu(I)-mediated azide-alkyne cycloadditions. Supported triazoles showed excellent compatibility with subsequent peptide chemistry. Release of pure material (typically >95%) from the solid support was readily achieved by treatment with aqueous TFA.

Scope and limitations of chiral bis(oxazoline) ligands in the copper-catalysed asymmetric cyclopropanation of trisubstituted alkenes

Abstract A series of derivatives of 3-methyl-2-buten-1-ol has been used to test the scope and limitations of the copper-catalysed asymmetric cyclopropanation of trisubstituted alkenes by ethyl diazoacetate in the presence of C2-symmetric bis(oxazoline) ligands. In the best case, a trans/cis ratio of 91:9, with 92% ee for the major isomer, was obtained from the reaction of the p-methoxybenzoate derivative. The highest ee was 95%, for the trans isomer of a 80:20 diastereomer mixture (acetate derivative).

An Improved Protocol for the Synthesis of 1-(Mesitylenesulfonyl)-3-nitro-1,2,4-triazole (MSNT)

Since the pioneering work of Merrifield,1–5 solid-phase synthesis has become a key technology for the rapid parallel synthesis of polypeptides and other oligomeric compounds for drug discovery and chemical biology research. With an increasing number of peptide and peptide mimetic drug candidates in the pipelines of large pharmaceutical companies, solidphase synthesis will likely continue to have a major impact on pharmaceutical chemistry. For solid-phase synthesis, it is essential that all transformations on the solid support proceed in a quantitative fashion. Until the final step of a synthetic sequence, reaction products remain covalently bound to the support and can only be purified by simple washings and filtrations, rendering any incomplete reaction step along the way a source of decreased yields of products. Solid-phase synthesis typically involves the creation of amideor ester bonds, either as part of the linkage strategy, or to build the final product. In this context, a multitude of coupling reagents has been developed. For example, reagents for esterification on solid support include N,N ′-dicyclohexylcarbodiimide (DCC) in conjunction with 4-(N,N-dimethylamino)pyridine (DMAP)6 or 1-hydroxybenzotriazole (HOBt),7 2,6-dichlorobenzoyl chloride,8 and diethyl azodicarboxylate–triphenylphosphine.9 However, these activators generally result in inferior conversions and product yields. 1-(Mesitylenesulfonyl)-3-nitro-1,2,4-triazole (MSNT) has most often been used for the formation of phosphateand phosphorothiolate esters in oligonucleotide synthesis,10–18 and, to a limited extent for amide-bond formation in peptide synthesis.19,20 Another important application of MSNT is its usefulness to anchor the C-terminal of amino acids to hydroxyl-functionalized supports.21–23 MSNT-based esterification protocols generally proceed with minimal racemization in high yields, and have therefore frequently been

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

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-c]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.

A Linker for the Solid-Phase Synthesis of Hydroxamic Acids and Identification of HDAC6 Inhibitors

We herein present broadly useful, readily available and nonintegral hydroxylamine linkers for the routine solid-phase synthesis of hydroxamic acids. The developed protocols enable the efficient synthesis and release of a wide range of hydroxamic acids from various resins, relying on high control and flexibility with respect to reagents and synthetic processes. A trityl-based hydroxylamine linker was used to synthesize a library of peptide hydroxamic acids. The inhibitory effects of the compounds were examined for seven HDAC enzyme subtypes using a chemiluminescence-based assay.