Rico Petersen

N‐acyliminium intermediates in solid‐phase synthesis

N‐Acyliminium ions are powerful intermediates in synthetic organic chemistry. Examples of their use are numerous in solution‐phase synthesis, but there are unmerited few reports on these highly reactive electrophiles in solid‐phase synthesis. The present review covers the literature to date and illustrates the methods used to generate N‐acyliminium intermediates on solid support and their further elaboration to a range of pharmacologically interesting peptidomimetics, heterocycles, and other small molecules.

Synthesis of oxacyclic scaffolds via dual ruthenium hydride/Brønsted acid-catalyzed isomerization/cyclization of allylic ethers.

A ruthenium hydride/Brønsted acid-catalyzed tandem sequence is reported for the synthesis of 1,3,4,9-tetrahydropyrano[3,4-b]indoles (THPIs) and related oxacyclic scaffolds. The process was designed on the premise that readily available allylic ethers would undergo sequential isomerization, first to enol ethers (Ru catalysis), then to oxocarbenium ions (Brønsted acid catalysis) amenable to endo cyclization with tethered nucleophiles. This methodology provides not only an attractive alternative to the traditional oxa-Pictet-Spengler reaction for the synthesis of THPIs, but also convenient access to THPI congeners and other important oxacycles such as acetals.

Synthesis of hexahydropyrrolo[2,1-a]isoquinoline compound libraries through a Pictet–Spengler cyclization/metal-catalyzed cross coupling/amidation sequence

Molecular libraries of natural product-like and structurally diverse compounds are attractive in early drug discovery campaigns. In here, we present synthetic methodology for library production of hexahydropyrrolo[2,1-a]isoquinoline (HPIQ) compounds. Two advanced HPIQ intermediates, both incorporating two handles for diversification, were synthesized through an oxidative cleavage/Pictet-Spengler reaction sequence in high overall yields. A subsequent metal-catalyzed cross coupling/amidation protocol was developed and its utility in library synthesis was validated by construction of a 20-membered natural product-like molecular library in good overall yields.

Synthesis of 1,4,5 trisubstituted γ-lactams via a 3-component cascade reaction.

A three component one-pot cascade reaction was developed for the synthesis of 1,4,5-trisubstituted γ-lactams. The resulting scaffold can be modified independently at three positions, two of which are conveniently accessed by changing the components of the one-pot reaction. The phases of building block generation, scaffold synthesis and subsequent appendage modification were adapted to library production, which resulted in a screening library of 500 compounds.

A broad range quorum sensing inhibitor working through sRNA inhibition

For the last decade, chemical control of bacterial virulence has received considerable attention. Ajoene, a sulfur-rich molecule from garlic has been shown to reduce expression of key quorum sensing regulated virulence factors in the opportunistic pathogen Pseudomonas aeruginosa. Here we show that the repressing effect of ajoene on quorum sensing occurs by inhibition of small regulatory RNAs (sRNA) in P. aeruginosa as well as in Staphylococcus aureus, another important human pathogen that employs quorum sensing to control virulence gene expression. Using various reporter constructs, we found that ajoene lowered expression of the sRNAs RsmY and RsmZ in P. aeruginosa and the small dual-function regulatory RNA, RNAIII in S. aureus, that controls expression of key virulence factors. We confirmed the modulation of RNAIII by RNA sequencing and found that the expression of many QS regulated genes encoding virulence factors such as hemolysins and proteases were lowered in the presence of ajoene in S. aureus. Importantly, our findings show that sRNAs across bacterial species potentially may qualify as targets of anti-virulence therapy and that ajoene could be a lead structure in search of broad-spectrum compounds transcending the Gram negative-positive borderline.

Synthesis of a Natural Product-Like Compound Collection through Oxidative Cleavage and Cyclization of Linear Peptides†

Massive efforts in molecular library synthesis have strived for the development of synthesis methodology which systematically delivers natural product-like compounds of high spatial complexity. Herein, we present a conceptually simple approach that builds on the power of solid-phase peptide synthesis to assemble precursor peptides (oligomers) designed to undergo oxidative cascade reactions. By harnessing the structural side-chain diversity and inherent stereochemical features offered by readily available amino acids (monomers), a proof-of-concept collection of 54 skeletally and stereochemically diverse compounds was generated, and selected compounds were elaborated into isoform-selective metalloprotease inhibitors.

Tandem Mannich/Diels–Alder reactions for the synthesis of indole compound libraries

A tandem Mannich/Diels–Alder sequence for the synthesis of small-molecule libraries with an indolyl-octahydro-3a,6-epoxy-isoindole core structure is demonstrated in this study. Representative diversification examples based on this scaffold were performed, and a library is being produced within the European Lead Factory (ELF) Consortium.

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

Solvent-Controlled Chemoselectivity in the Photolytic Release of Hydroxamic Acids and Carboxamides from Solid Support

The synthetic utility and theoretical basis of a photolabile hydroxylamine-linker are presented. The developed protocols enable the efficient synthesis and chemoselective photolytic release of either hydroxamates or carboxamides from solid support. The bidetachable mode of the linker unit is uniquely dependent on the solvent. Hydroxamic acids are obtained by performing photolysis in protic solvents, whereas photolysis in aprotic solvents enables the selective release of carboxamides.

Synthesis of Constrained Peptidomimetics via the Pictet-Spengler Reaction

Peptidomimetics offers a solution to the poor pharmacokinetic properties displayed by natural peptides, by providing pharmaceutically useful chemical structures with the ability to mimic the endogenous polyamide structure. This chapter gives an overview of the past decade’s developments in the field of Pictet-Spengler reactions for the synthesis of peptidomimetics, with an emphasis on the applications of constrained heterocycles in mimicry of peptide geometry and biology.