Development of the traceless phenylhydrazide linker for solid-phase synthesis

The hydrazide group is a new oxidatively cleavable traceless linker for solid-phase chemistry. It can be readily introduced by hydrazide formation between a carboxy-functionalized resin and different substituted hydrazines. In order to achieve high yields in this step, new carboxylic acid resins were developed that are not prone to undesired imide formation upon activation of the carboxylic acid. The polymer-bound acyl hydrazides were successfully employed in various transformations, namely Heck, Suzuki, Sonogashira, and Stille couplings, as well as Wittig and Grignard reactions. Traceless release of the coupling products from the solid support is achieved selectively under mild conditions and in high purity by oxidation of the aryl hydrazides to acyl diazenes with Cu(II) salts or N-bromosuccinimide (NBS) and subsequent nucleophilic attack of the acyl diazene intermediates. Traceless cleavage by oxidation with NBS can be carried out as a two-step process in which stable acyl diazenes are first generated by treatment with NBS in the absence of a nucleophile. After removal of the reagents by simple resin washing, the traceless release is effected by the addition of methanol, which leads to products of high purity without any additional separation steps.     

A new versatile linker for the solid-phase synthesis of secondary amines

A novel linker for the solid-phase synthesis of secondary amines based on an intramolecular cyclization was developed. The linker allows for a stepwise built-up of the secondary amines on the support. The feasibility was demonstrated in the parallel synthesis of a small set of different secondary amines.     

Diastereoselective solution and multipin-based combinatorial array synthesis of a novel class of potent phosphinic metalloprotease inhibitors

The solution-phase synthesis and resolution of new phosphinopeptidic building blocks containing a triple bond was realized in high yields and optical purities (units 3 a-d). The absolute configuration of the target compounds was unambiguously established by NMR studies. A post-assembly diversification strategy of these blocks was developed through 1,3-dipolar cycloaddition of a variety of in situ prepared nitrile oxides. This strategy led to the rapid and efficient diastereoselective preparation of a novel class of isoxazole-containing phosphinic peptides (peptides 5 a-i). Solid-phase version of this strategy was efficiently achieved on multipin solid technology, by developing a new protocol for the coupling of P-unprotected dipeptidic blocks with solid supported amino acids in a quantitative and diastereoselective manner. Optimization of dipolar cycloadditions onto pin-embodied phosphinic peptides allowed the convenient preparation of this new class of pseudopeptides. The crude phosphinic peptides (9 a-k) were obtained in high yields and purity as determined by RP-HPLC. Inhibition assays of some of these peptides revealed that they behave as very potent inhibitors of MMPs, outmatching previously reported phosphinic peptides, in terms of potency (K(i) in the range of few nM).     

Efficient solid-phase synthesis of highly functionalized 1,4-benzodiazepin-5-one derivatives and related compounds by intramolecular aza-Wittig reactions

Due to their widespread biological activities and favorable pharmacokinetic properties, benzodiazepines were among the first classes of small molecules to be synthesized on solid supports. Since then, there have been numerous reports on the synthesis of similar skeletons. We have employed the T1 triazene linker to yield 1,4-benzodiazepin-5-one. Starting from various substituted triazene resins, cleavage in the presence of an azide donor, such as trimethylsilylazide, gave rise to aryl azides. Intramolecular aza-Wittig reactions produced the appropriately functionalized N-heterocycles. By using this route, the natural product deoxyvasicinone and related compounds were prepared.     

Solid-phase synthesis: a linker for side-chain anchoring of arginine

A new linker based on a chroman system is described for the side-chain anchoring of Arg and other guanidine-containing molecules. The system is compatible with the Fmoc/tBu solid-phase strategy, because the release of the final product is achieved by treatment with TFA in the presence of scavengers.     

Development of a new traceless aniline linker for combinatorial solid-phase parallel synthesis of rod-shaped liquid crystals with an azomethine linkage

A new traceless linker was developed to synthesize a library of 28 compounds possessing an azomethine linkage using combinatorial solid-phase parallel synthesis. The loading of the substrates on a solid support and cleavage from the solid support were performed by an imine synthesis and by imine-exchanged process in the mild conditions, respectively. Products with a thioester group exhibited liquid crystalline properties with the higher transition temperatures than the others.     

Combinatorial library of low molecular-weight organo- and hydrogelators based on glycosylated amino acid derivatives by solid-phase synthesis

A combinatorial approach for the synthesis of supramolecular gelators as new organic materials is described herein. In the course of the development of a convenient and flexible solid-phase synthesis of the artificial glycolipids, some of these compounds were accidentally found to act as low molecular-weight gelators toward organic solvents. Using this combinatorial solid-phase synthesis of glycosylated amino acetates, screening and optimization of low molecular-weight organo/hydro-gelators were efficiently carried out. We found that an N-acetyl-galactosamine-appended amino acid ester (GalNAc-aa) efficiently gelates a broad spectrum of organic solvents. More interestingly, some GalNAc-aa derivatives displayed an excellent hydrogelation capability. Transmission electron microscopy, scanning electron microscopy, confocal laser scanning microscopy, and FT-IR were used for characterization of the gel structure. It is indicated that supramolecular fibers supported by strong hydrogen-bonding networks are entangled so that the resulting spaces can immobilize a number of solvent molecules effectively. In addition, the supramolecular hydrogel consisting of GalNAc-suc-glu(O-methyl-cyc-pentyl)(2) is stable even under high salt concentrations probably due to its nonionic character and as a result, a native protein is successfully entrapped in the gel matrix without denaturation.     

Synthesis of functionalized 1,3-thiazine libraries combining solid-phase synthesis and post-cleavage modification methods

The solid-phase synthesis of diverse sets of 1,3-thiazine-5-carboxylates on Wang resin is described. Acetoacetylation, followed by Knoevenagel condensation and an acid-promoted ring-closure reaction with thioureas furnished polymer-bound 1,3-thiazines. As an alternative to transesterification, a de-novo synthesis of beta-keto esters, starting from polymer-bound malonic acid through reaction with acyl imidazoles, was applied to increase the diversity. To reduce contamination, an on-bead purification of resin-bound 1,3-thiazines that makes use of differences in the reactivity of ester bonds toward alkoxides is reported. A final four-step post-cleavage modification of thiazine-5-carboxylates, derived by TFA cleavage from the Wang linker, leads to esters or amides. Twenty 1,3-thiazines were obtained in yields of up to 61 % over either 9 or 13 steps.     

Solid-phase combinatorial synthesis of benzothiazoles, benzimidazoles, and benzoxazoles using a traceless linker

New methodology for the solid-phase synthesis of benzothiazoles, benzimidazoles, and benzoxazoles has been developed by using a traceless 4-alkoxy-aniline linker. The desired products were released from the polymer support by imine-exchange process coupled with air oxidation. Combinatorial library consisting of 36 members has been synthesized using this linker. The yields are low to good, which highly depend on the building blocks. Recycling of the polymer support was also investigated.     

Chemical synthesis of a glycolipid library by a solid-phase strategy allows elucidation of the structural specificity of immunostimulation by rhamnolipids

The first synthesis of a glycolipid library by hydrophobically assisted switching phase (HASP) synthesis is described. HASP synthesis enables flexible switching between solution-phase steps and solid-supported reactions conducted with molecules attached to a hydrophobic silica support. A library of glycolipids derived from the lead compound 1-a strongly immunostimulatory rhamnolipid--with variations in the carbohydrate part, the lipid components, and the stereochemistry of the 3-hydroxy fatty acids was designed and synthesized. The enantioselective synthesis of the 3-hydroxy fatty acid building blocks was achieved by employing asymmetric hydrogenation of 3-oxo fatty acids. Glycolipids were prepared by this approach without any intermediary isolation steps, mostly in excellent yields. Final deprotection to the carboxylic acids was accomplished by enzymatic ester cleavage. All prepared rhamnolipids were tested for their immunostimulatory properties against human monocyte cells by assaying the secretion of the cytokine tumor necrosis factor alpha (TNFalpha) into the medium. The observed structure-activity relationships of rhamnolipids indicate a specific, recognition-based mode of action, with small structural variations in the rhamnolipids resulting in strong effects on the immunostimulatory activities of the rhamnolipids at low micromolar concentrations.     

Development of a new traceless aniline linker for solid-phase synthesis of azomethines. Application to parallel synthesis of a rod-shaped liquid crystalline library

A new traceless linker was developed to synthesize a library of 42 compounds possessing an azomethine linkage using combinatorial solid-phase parallel synthesis. The loading of the substrates on a solid support and cleavage from the solid support were performed by an imine synthesis and by imine-exchanged process under mild conditions, respectively. Thioesters with a hydroxy group on the central core exhibited liquid crystalline properties with the widest transition temperatures in the library.     

Solid-phase synthesis of benzothiazoles using an alkoxyamine linker

An alkoxyamine linker was applied for the solid-phase synthesis of benzothiazoles. The substrate was anchored by aldoxime linkage and products were cleaved from the solid-support by aldoxime-imine exchange coupled with air-oxidation under the weakly acidic conditions. The tether is highly robust under Mitsunobu reaction, nucleophilic substitution reaction, and Pd-catalyzed reaction conditions.