Roger Marti

ENHANCED RESOLUTION IN MAS NMR FOR COMBINATORIAL CHEMISTRY

Abstract We have demonstrated the ability to obtain high resolution NMR spectra from samples on resin using J-resolved 2D NMR. Projection of the non-tilted spectrum onto the chemical shift dimension provides enhanced resolution and virtually complete disappearance of the polymer resonances.

ADIBO-Based "Click" Chemistry for Diagnostic Peptide Micro-Array Fabrication: Physicochemical and Assay Characteristics

Several azide-derivatized and fluorescently-labeled peptides were immobilized on azadibenzocyclooctyne (ADIBO)-activated slide surfaces via a strain-promoted alkyne-azide cycloaddition (SPAAC) reaction revealing excellent immobilization kinetics, good spot homogeneities and reproducible fluorescence signal intensities. A myc-peptide micro-array immunoassay showed an antibody limit-of-detection (LOD) superior to a microtiter plate-based ELISA. Bovine serum albumin (BSA) and dextran covalently attached via “click” chemistry more efficiently reduced non-specific binding (NSB) of fluorescently-labeled IgG to the microarray surface in comparison to immobilized hexanoic acid and various types of polyethylene glycol (PEG) derivatives. Confirmation of these findings via further studies with other proteins and serum components could open up new possibilities for human sample and microarray platform-based molecular diagnostic tests.

Microwave barrel reactor use in trimethylolpropane oleate synthesis by Candida antarctica lipase in a biphasic non-solvent process

A novel microwave barrel reactor (MBR) was constructed and used in lipase catalyzed biolubricant synthesis. The MBR is thought as a versatile process tool for biotransformation and green chemistry that overcomes current size limitations in microwave reactors. A lipase mediated biotransformation in the MBR was compared to a state of the art jacketed reactor with external heat exchanger. Oleic acid and trimethylolpropane converted quantitatively (96%) into biolubricants using microwave induction. The heat dissipation in the MBR was analyzed by thermal imaging and inside thermometry. Conversion rates, rate constants and pseudo reaction orders were in line with conventional processing and no microwave effect was detected. The MBR is a versatile new reactor for non solvent, minimal and common solvent processing in the microwave field. While the subject of investigations was biolubricant synthesis in the MBR, the technology described is of wider potential interest in the field of biomass processing and sustainable chemical manufacture.

Solid-phase synthesis via 5-oxazolidinones. Ring opening reactions with amines and reaction monitoring by single bead FT-IR microspectroscopy

Until recently, large compound libraries produced by solid-phase synthesis have been restricted to those of linear peptides and oligonucleotides, but the need for development and synthesis of libraries of small organic molecules using this method is growing rapidly.1 We are interested in developing strategies and chemistries that would allow entry to combinatorial libraries of peptidomimetic structures on solid support. Our approach to the synthesis of peptide mimetics involves attachment of an essential amino acid residue via its side-chain functionality to the solid support. A similar strategy has been employed by Ellman in creating a peptidomimetic library using the hydroxyethylamino isostere of phenylalanine found in most HIV protease inhibitors anchored via the secondary alcohol.2 Anchoring the amino acid side chain to polymeric supports is now widely used to prepare head-to-tail cyclic peptides via solid-phase-mediated cyclization.3 Typically, Asp or Glu are attached via their ω-carboxyls to hydroxymethyl or aminomethyl resins, with the expectation that the corresponding peptides containing Asp/Glu or Asn/Gln, respectively, will be obtained after final cleavage from the resin. The most widely practiced strategy to obtain head-to-tail cyclic peptides uses the three-dimensional Fmoc/t-Bu/allyl orthogonal protection scheme. Kates et al. developed the use of R-allyl-protected aspartic acid for automated continuous flow synthesis of cyclic peptides containing Asp or Asn residues via side-chain anchoring to the resin followed by on-resin cyclization,4 which is applicable to Gluand Gln-containing sequences. Also, the Fmoc/allyl ester protection scheme was applied to anchor lysine via its -amino group.3e Additionally, side-chain attachment to Merrifield (chloromethylated polystyrene) resin has been applied to cysteine in its unprotected form; this has allowed both Nand C-terminal derivatization.5 In the latter case, C-terminal derivatization to amides and esters required carboxylic acid activation with BOP reagent.

New t-butyl based aspartate protecting groups preventing aspartimide formation in Fmoc SPPS.

Obtaining homogenous aspartyl‐containing peptides via Fmoc/tBu chemistry is often an insurmountable obstacle. A generic solution for this issue utilising an optimised side‐chain protection strategy that minimises aspartimide formation would therefore be most desirable. To this end, we developed the following new derivatives: Fmoc‐Asp(OEpe)‐OH (Epe = 3‐ethyl‐3‐pentyl), Fmoc‐Asp(OPhp)‐OH (Php = 4‐n‐propyl‐4‐heptyl) and Fmoc‐Asp(OBno)‐OH (Bno = 5‐n‐butyl‐5‐nonyl). We have compared their effectiveness against that of Fmoc‐Asp(OtBu)‐OH and Fmoc‐Asp(OMpe)‐OH in the well‐established scorpion toxin II model peptide variants H‐Val‐Lys‐Asp‐Asn/Arg‐Tyr‐Ile‐OH by treatments of the peptidyl resins with the Fmoc removal reagents containing piperidine and DBU at both room and elevated temperatures. The new derivatives proved to be extremely effective in minimising aspartimide by‐products in each application. Copyright

Efficient and scalable total synthesis of calcitroic acid and its 13C-labeled derivative

Calcitroic acid, the deactivated form of the physiological active vitamin D3 metabolite calcitrol, and its 13C labeled derivative has been synthesized starting from the commercially available Inhoffen-Lythgoe diol in 11 steps with an overall yield of 21%. The key steps in the synthesis were the formation of the C1-homologated nitrile with KCN and K13CN as well as the Horner–Wittig reaction with the ring A phosphine oxide reagent.

Organocatalytic oxa-Diels–Alder reaction of α,β-unsaturated ketones under non-classical conditions

Non-classical reaction conditions are compatible with organocatalysis and can often improve reaction course. Oxa-Diels–Alder reaction of acyclic α,β-unsaturated ketones with aldehydes is a challenging transformation that affords valuable pyranone products. Application of microwave irradiation and solvent-free conditions during ball-milling had the best influence on this reaction, in terms of shortened reaction times and increased product yields. Other factors, such as aqueous conditions, ultrasound and flow conditions also bring notable improvements. Unfortunately, a range of chiral organocatalysts provided only small enantioselectivity of the reaction of up to e.r. 63 : 37.

One-Pot Synthesis of Trifluoromethylated Quinazolin-4(3H)-ones with Trifluoroacetic Acid as CF3 Source

A novel and convenient one-pot sequential cascade method for the preparation of 2-trifluoromethylquinazolin-4(3 H)-ones is described. Trifluoroacetic acid (TFA) was employed as inexpensive and readily available CF3 source, which in the presence of T3P was condensed with a variety of anthranilic acids and amines to provide the products in up to 75% yield. The protocol was proved to be robust on 80 g scale, and the synthetic versatility of the prepared quinazolinon-4-ones was demonstrated by derivatization to further useful building blocks.

Energy-related chemical research at the Universities of Applied Sciences.

An overview of current activities in the field of energy-related chemical research at the Swiss Universities of Applied Sciences is presented.

4-epi-Isofagomine derivatives as pharmacological chaperones for the treatment of lysosomal diseases linked to β-galactosidase mutations: Improved synthesis and biological investigations

(5aR)-5a-C-pentyl-4-epi-isofagomine 1 is a powerful inhibitor of lysosomal β-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B. We report herein an improved synthesis of this compound and analogs (5a-C-methyl, pentyl, nonyl and phenylethyl derivatives), and a crystal structure of a synthetic intermediate that confirms its configuration resulting from the addition of a Grignard reagent. These compounds were evaluated as glycosidase inhibitors and their potential as chaperones for mutant lysosomal galactosidases determined. Based on these results and on docking studies, the 5-C-pentyl derivative 1 was selected as the optimal structure for further investigations: this compound induces the maturation of mutated β-galactosidase in fibroblasts of a GM1-gangliosidosis patient and promote the decrease of keratan sulfate and oligosaccharide load in patient cells. Compound 1 is clearly capable of restoring β-galactosidase activity and of promoting maturation of the protein, which should result in significant clinical benefit. These properties strongly support the development of compound 1 for the treatment of GM1-gangliosidosis and Morquio disease type B patients harboring β-galactosidase mutations sensitive to pharmacological chaperoning.