Jan H. van Maarseveen

1,2,3-Triazoles as peptide bond isosteres: synthesis and biological evaluation of cyclotetrapeptide mimics

Since the discovery of Cu(I)-catalysed click chemistry, the field of peptidomimetics has expanded to include 1,4-connected 1,2,3-triazoles as useful peptide bond isosteres. Here, we report the synthesis of triazole-containing analogues of the naturally occurring tyrosinase inhibitor cyclo-[Pro-Val-Pro-Tyr] and show that the analogues retain enzyme inhibitory activity, demonstrating the effectiveness of a 1,4-connected 1,2,3-triazole as a trans peptide bond isostere.

Selective Enrichment of Azide-Containing Peptides from Complex Mixtures

A general method is described to sequester peptides containing azides from complex peptide mixtures, aimed at facilitating mass spectrometric analysis to study different aspects of proteome dynamics. The enrichment method is based on covalent capture of azide-containing peptides by the azide-reactive cyclooctyne (ARCO) resin and is demonstrated for two different applications. Enrichment of peptides derived from cytochrome c treated with the azide-containing cross-linker bis(succinimidyl)-3-azidomethyl glutarate (BAMG) shows several cross-link containing peptides. Sequestration of peptides derived from an Escherichia coli proteome, pulse labeled with the bio-orthogonal amino acid azidohomoalanine as substitute for methionine, allows identification of numerous newly synthesized proteins. Furthermore, the method is found to be very specific, as after enrichment over 87% of all peptides contain (modified) azidohomoalanine.

Enantioselective Copper‐Catalysed Propargylic Substitution: Synthetic Scope Study and Application in Formal Total Syntheses of (+)‐Anisomycin and (−)‐Cytoxazone

A copper catalyst with a chiral pyridine-2,6-bisoxazoline (pybox) ligand was used to convert a variety of propargylic esters with different side chains (R=Ar, Bn, alkyl) into their amine counterparts in very high yields and with good enantioselectivities (up to 90% enantiomeric excess (ee)). Different amine nucleophiles were applied in the reactions and the highest enantioselectivities were obtained for aniline and its analogues. Interestingly, some carbon nucleophiles could also be used and with indoles excellent ee values were obtained (up to 98% ee). The versatility of the propargylic amines obtained was demonstrated by their further elaboration to formal total syntheses of the antibiotic (+)-anisomycin and the cytokine modulator (-)-cytoxazone.

Conformationally homogeneous heterocyclic pseudotetrapeptides as three-dimensional scaffolds for rational drug design: receptor-selective somatostatin analogues.

A would-be amide: A 1,4-disubstituted 1,2,3-triazole was used as a surrogate for a trans amide bond to create a library of 16 diastereomeric pseudotetrapeptides as beta-turn mimetics. High-resolution structural analysis indicated that these scaffolds adopt distinct, rigid, conformationally homogeneous beta-turn-like structures (see example), some of which bind somatostatin receptor subtypes selectively, and some of which show broad-spectrum activity.

Ring‐Closing Metathesis of Allylic O,O‐ and N,O‐Acetals

A variety of allylic O,O -a ndN,O-acetals were synthesized using a mild palladium-catalyzed coupling of an alcohol or sulfonamide with an alkyl or aryl 1,2-propadienyl ether. The resulting linear acetals were used for the synthesis of unsaturated rings via ring-closing metathesis, in which the acetal carbon ± a precursor for oxycarbenium or N-sulfonyliminium ions, respectively ± served as a reactive center for further introduction of functional groups. The prod- ucts ± unsaturated oxygen and nitrogen heterocyclic scaffolds ± offer multiple opportunities for derivatiza- tion as illustrated with the synthesis of substituted dihydropyrans, chromenes, enantiopure tetrahydro- pyridines and an enantiomerically pure quinolizidine amino acid.

Total Synthesis of (+)-Yohimbine via an Enantioselective Organocatalytic Pictet–Spengler Reaction

The binolphosphoric acid-catalyzed Pictet-Spengler reaction of an N-(5-oxy-2,4-pentadienyl)tryptamine derivative with methyl 5-oxo-2-(phenylseleno)pentanoate leads to the tetrahydro-β-carboline in a 92:8 enantiomeric ratio. This product is easily converted into the substrate for a stereoselective intramolecular Diels-Alder reaction of the type earlier reported by Jacobsen. These two key steps constitute the basis for a nine-step total synthesis of (+)-yohimbine from tryptamine. A similar asymmetric Pictet-Spengler reaction was applied to the synthesis of an intermediate in the recent total synthesis of corynantheidine by Sato.

In situ quantitative measurement of concentration profiles in a microreactor with submicron resolution using multiplex CARS microscopy

In situ quantitative imaging of concentration profiles of reactants and products inside a microfluidic reactor is achieved, with submicron spatial resolution with mM sensitivity and on ms time scales, for a given position. The label-free approach relies on quantitative vibrational spectroscopy, using Coherent Anti-Stokes Raman scattering microscopy in a spectrally resolved fashion, and is demonstrated on an elementary acid-base reaction.

Expedient pyrrolizidine synthesis by propargylsilane addition to N-acyliminium ions followed by gold-catalyzed α-allenyl amide cyclization

A reaction sequence, involving the addition of (substituted) propargylsilanes to lactam-derived N-acyliminium ions followed by gold-catalyzed cyclization of the resulting alpha-allenyl amide, is applied in expedient syntheses of pyrrolizidine alkaloids heliotridine and ent-retronecine in five steps from (S)-malic acid.

Organocatalytic Enantioselective Pictet–Spengler Reactions for the Syntheses of 1-Substituted 1,2,3,4-Tetrahydroisoquinolines

A series of 1-substituted 1,2,3,4-tetrahydroisoquinolines was prepared from N-(o-nitrophenylsulfenyl)phenylethylamines through BINOL-phosphoric acid [(R)-TRIP]-catalyzed asymmetric Pictet-Spengler reactions. The sulfenamide moiety is crucial for the rate and enantioselectivity of the iminium ion cyclization and the products are readily recrystallized to high enantiomeric purity. Using this methodology we synthesized the natural products (R)-crispine A, (R)-calycotomine and (R)-colchietine, the synthetic drug (R)-almorexant and the (S)-enantiomer of a biologically active (R)-AMPA-antagonist.

Synthesis of Water-Soluble Scaffolds for Peptide Cyclization, Labeling, and Ligation

The synthesis and applications of water-soluble scaffolds that conformationally constrain side chain unprotected linear peptides containing two cysteines are described. These scaffolds contain a functionality with orthogonal reactivity to be used for labeling and ligation. This is illustrated by the chemical ligation of two dissimilar constrained peptides via oxime ligation or strain-promoted azide-alkyne cycloaddition in aqueous media.