Henk Hiemstra

Intramolecular reactions of N-acyliminium intermediates

Generation des ions N-acyliminiums et syntheses de leurs precurseurs; amidoalkylations intramoleculaires avec des π-nucleophiles aromatiques; reactions de π-nucleophiles non aromatiques; utilisation des composes a methylene actif; reactions pericycliques

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.

Enantioselective BINOL-Phosphoric Acid Catalyzed Pictet-Spengler Reactions of N-Benzyltryptamine

Optically active tetrahydro-beta-carbolines were synthesized via an ( R)-BINOL-phosphoric acid-catalyzed asymmetric Pictet-Spengler reaction of N-benzyltryptamine with a series of aromatic and aliphatic aldehydes. The tetrahydro-beta-carbolines were obtained in yields ranging from 77% to 97% and with ee values up to 87%. The triphenylsilyl-substituted BINOL-phosphoric acid proved to be the catalyst of choice for the reaction with aromatic aldehydes. For the aliphatic aldehydes, 3,5-bistrifluoromethylphenyl-substituted BINOL-phosphoric acid was identified as the best catalyst.

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.

Organocatalytic Enantioselective Total Synthesis of (−)-Arboricine

The tetracyclic indole alkaloid (-)-arboricine has been prepared using an asymmetric organocatalytic Pictet-Spengler reaction as the key step followed by a diastereoselective Pd-catalyzed iodoalkene/enolate cyclization. The absolute stereochemistry was unequivocally proven by X-ray crystallographic analysis and appeared to be opposite to the published structure in the original paper.

Synthesis of statine from (S)-malic acid ; stereocontrol via radical cyclization

Abstract Highly stereoselective syntheses of enantiomerically pure γ-amino acids statine and 4- epi -statine from ( S )-malic acid are described by using, respectively, an intramolecular α-acylamino radical reaction and an intermolecular N -acyliminium allylsilane coupling.

Tomato-produced 7-epizingiberene and R-curcumene act as repellents to whiteflies

How whiteflies (Bemisia tabaci) make the choice for a host plant prior to landing, is not precisely known. Here we investigated whether they respond to specific volatiles of tomato. Zingiberene and curcumene were purified from Solanum habrochaites (PI127826), characterised by NMR and X-ray analysis and identified as 7-epizingiberene and R-curcumene. In contrast, oil from Zingiber officinalis contained the stereoisomers zingiberene and S-curcumene, respectively. Using a combination of free-choice bio-assays and electroantennography, 7-epizingiberene and its dehydrogenated derivative R-curcumene were shown to be active as semiochemicals to B. tabaci adults, whereas the stereoisomers from ginger were not. In addition, R-curcumene elicited the strongest electroantennographic response. Bio-assays showed that a cultivated tomato could be made less attractive to B. tabaci than its neighbouring siblings by the addition of the tomato stereoisomer 7-epizingiberene or its derivative R-curcumene. These sesquiterpenes apparently repel adult whiteflies prior to landing, presumably because it informs them that after landing they, or their offspring, may be exposed to higher and lethal concentrations of the same compounds.

4.5 – Additions to N-Acyliminium Ions

The addition of strongly polarized carbon-carbon double bonds (enols) to simple iminium ions, known as the Mannich reaction (equation 1), is a fundamentally important route to amines, especially in biosynthetic processes.1,2 This reaction type is less synthetically useful if weakly polarized or unpolarized carbon-carbon π-bonds are used as nucleophiles (equation 2).3 Because of the low electrophilic reactivity of the iminium moiety, the reverse reaction, known as the Grob fragmentation (equation 2), is often the more important process.4 However, if the iminium moiety has a carbonyl substituent on nitrogen, its electrophilicity is strongly enhanced, and reactions with CC bonds are irreversible and synthetically useful (equation 3).

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.