Harry C. J. Ottenheijm

Solid-phase organic reactions: A review of the recent literature

Abstract Combinatorial chemistry has emerged as a powerful new technology for chemists to synthesise large numbers of compounds for biological evaluation. One of the techniques used in combinatorial chemistry is polymer supported or “solid-phase” organic synthesis. This article reviews the main chemical reactions reported between 1992-October 1995 using solid-phase support, focusing upon those suitable for synthesising small molecules. The reactions are presented in graphical format in a table according to reaction types. Examples presented include amide bond formation, aromatic substitutions, condensations, cycloadditions, diazotisation, enzymatic coupling, use of Grignard reagents, Michael additions, multiple component reactions, nucleophilic substitution, olefination, oxidations, protection/deprotection, reduction, immobilisation and cleavage. Finally, the information presented is evaluated briefly and some trends are discussed.

Solid-phase organic reactions II: A review of the literature Nov 95–Nov 96

Abstract This Report reviews literature published Nov 1996–Dec 97; it is the third in a series that summarises organic reactions performed on solid supports and is designed as an update to Tetrahedron Reports no. 394 and 418. The reactions are presented in a graphical abstract format and examples are given of the following reactions: amide formation, aromatic substitution (nucleophilic/electrophilic), cleavage, condensation, cycloaddition, deprotection/protection, Grignard and related reactions, heterocycle formation, immobilisation onto resin, Michael addition, miscellaneous, multiple component condensation, olefin formation, oxidation, reduction and substitution (nucleophilic/electrophilic). Solid-phase peptide or other oligomer synthesis and reactions using soluble polymeric supports are not included. This report ends with the discussion of some trends in the domain under consideration. This report summarises literature published during Nov 96 – Dec 97 describing solid-phase organic reactions.

A NEW CLEAVAGE STRATEGY FOR THE SOLID-PHASE SYNTHESIS OF SECONDARY AMINES

Abstract The clean and efficient cleavage of N-benzyl linked tertiary amines from a solid support (e.g. 4 ) by treatment with α-chloroethyl chloroformate (ACE-Cl) / methanol to yield secondary amines 7 is described. This allows the solid-phase synthetic transformation of the secondary amine 2 into 7 . When the Merrifield resin 1 is used the N-tethered amine-polymeric matrix ensemble is stable towards a wide variety of reaction conditions.

Oxidative preparation of optically active n-hydroxy-α-amino acid amides

Abstract Two routes are presented for the conversion of optically active α-amino acid amides into the title compounds. One route(route A) features the formation of the Schiffs base 6 which is subsequently oxidized to the corresponding oxaziridines 7 . Route B is characterized by the formation of an imidazolin 11 which is hydroxylated to compound 12 . Alcoholysis of 7 and 12 in the presence of hydroxylamine hydrochloride yields the title compounds in overall yields ringing from 65 to 85%(route A) and from 14 to 21%(route B).

A one-pot N-protection of L-arginine

A facile, one-pot synthesis of Nα-t-Butyloxycarbonyl,Nδ,Nϖ-di-benzyloxycarbonyl-L-Arginine (3a) and Nα,Nδ,Nϖ-tri-benzyloxycarbonyl-L-Arginine (3b) is reported. Nα-t-Butyloxycarbonyl-L-Arginine (1b) is treated with trimethylsilylchloride and the tri-silylated intermediate 2c is subsequently allowed to react with benzyloxycarbonyl chloroformate to give 3a in 50% overall yield. Starting from 1a or 1c, 3b was prepared according to the same procedure in 72% and 60–85% yield, respectively.

Total synthesis of Cyclotheonamide B, a facile route towards analogues.

A flexible, convergent synthesis of Cyclotheonamide B (1b) was developed, starting from the constituent amino acids, using conventional benzyl-, t-butyl- and allyl-based protecting groups. By modification of the key intermediates, this approach allows the preparation of cyclotheonamide analogues.

Solid and solution phase combinatorial synthesis of ureas

An efficient parallel synthesis of ureas based on amino acids is described, both in solution and on solid phase. 1,1-Carbonylbisbenzotriazole 2 is used as the coupling reagent. The ureas 5 and 10 were obtained in high yield (80-100%) and purity (71-97%)

Interaction of the antibiotic sparsomycin with the ribosome.

Phenol-alanine-sparsomycin, a derivative of sparsomycin carrying a p-hydroxy-benzyl function easily labeled by iodination, has been used to study the interaction of this drug with the ribosome. Our study indicated that the binding of the drug to the ribosome is sensitive to trichloracetic acid and is equally affected by disintegration of the particle after RNase and protease treatments. The ribosome is not irreversibly inactivated, and the chemical structure of the drug is not affected by interaction with the particle. These data are not compatible with the proposed covalent association of sparsomycin with the ribosome by G. A. Flynn and R. J. Ash (Biochem. Biophys. Res. Commun. 114:1-7, 1983); therefore, the antibiotic must inhibit protein synthesis through a reversible interaction with the ribosome. Images

Peptide-derived transition state analogue inhibitors of thrombin; Synthesis, activity and selectivity

In a study to combine the transition state analogue concept with the principle of catalytic site spanning, a series of peptide-derived transition state analogue (TSA) inhibitors of thrombin has been synthesized and tested. In the sequence H-D-Phe-Pro-Arg-Gly-OH (2) the Arg-Gly amide bond has been replaced by three classes of transition state analogues, being the ketomethylene, the hydroxyethylene and the hydroxymethylene amide bond replacements. Compound 12a, in which the amide bond has been replaced by the ketomethylene group, was found to be the most potent thrombin inhibitor of the series studied. Subsequently, penta- and hexapeptide sequences with good affinity for thrombin were developed, i.e. H-D-Phe-Pro-Arg-Gly-Phe-OH (16) and H-D-Phe-Pro-Arg-Gly-Phe-Lys-OH (26). In these sequences the Arg-Gly amide bond was then replaced by the ketomethylene group. The resulting compounds 43a and 47a, respectively, were evaluated in vitro as inhibitors of thrombin and factor Xa. Compound 47a was found to be the most potent thrombin inhibitor of the series studied (Ki = 29 nM). The combination of the transition state analogue concept and the principle of peptide elongation (tetrapeptide-->hexapeptide) yields thrombin inhibitors of high potency and selectivity. The effects of these two alterations reinforce each other indicating a synergistic effect. This might be rationalized by entropy factors.

Pharmacokinetics of the antitumor antibiotic n-pentyl-sparsomycin in beagle dogs

SummaryN-pentyl-sparsomycin (PSm) is a lipophilic analogue of sparsomycin (Sm), which is a well known inhibitor of protein synthesis. This compound was selected for preclinical pharmacokinetic studies because of its high in vitro and in vivo antitumor activity. In this study in which the drug was evaluated in beagle dogs under anaesthesia, the drug concentrations in plasma, urine and bile samples were determined using high performance liquid chromatography (HPLC). Plasma protein binding was approximately 54%. The mean t1/2 β was 0.2 hours (12 minutes) and t1/2 τ was 0.75 ± 0.1 hours (45 ± 6 minutes). During continuous infusions up to 5.25 hours, the steady state was reached in 3 out of 6 experiments, suggesting that in some cases the real t1/2 τ was longer than measured. PSm was actively reabsorbed from the renal tubuli. This process was saturable at the higher doses. Tubular reabsorption played only a minor role in pharmacokinetics as most of the drug (67%) was eliminated by the non-renal clearance. The non-renal clearance was saturable at higher doses of PSm and was the reason for non-linearity of pharmacokinetics.