Target alcohol/phenol release by cyclative cleavage using glycine as a safety catch linker

The utility of glycine as a safety catch linker for the immobilization of alcohols and phenols to the solid-support is demonstrated by performing a variety of synthetic transformations.     

The reversed Kenner linker: a new safety-catch linker for the preparation of N-alkyl sulfonamides

A new strategy for the solid-phase synthesis of sulfonamides is described. The Kenner safety-catch strategy has been modified such that the carboxylic acid component remains attached to the solid support while the sulfonamide portion is released into solution. An initial demonstration of the scope of this strategy is presented, along with an analysis of the cleavage characteristics and extension to more elaborate products via Suzuki reaction and thiazolidinone synthesis. Reaction: see text.     

Convenient preparation of substituted 5-aminooxazoles via a microwave-assisted Cornforth rearrangement

The preparation of oxazole-4-carboxamides and their subsequent thermal rearrangement to 5-aminooxazole-4-carboxylates is optimized in a high-speed microwave-assisted procedure. The reaction sequence is effective with a variety of substituted oxazoles, and produces products in good yield and high purity.     

Facile solid-phase synthesis of head-side chain cyclothiodepsipeptides through a cyclative cleavage from MeDbz-resin

Head to side-chain cyclothiodepsipeptides were conveniently prepared through a cyclative cleavage using the MeDbz linker. Briefly, the peptide sequence was elongated on a MeDbz-Gly-ChemMatrix resin and reacted with 4-nitrophenyl chloroformate, followed by treatment with DIEA to render an activated cyclic N-acyl-N′-methylurea-resin. Removal of the Cys protecting group and further treatment with DIEA allowed the formation of the thiolactone with the concomitant release of the cyclic peptide from the resin.     

Potent integrin antagonists from a small library of RGD-including cyclic pseudopeptides

[structure: see text]. A small library of cyclic RGD pseudopentapeptides incorporating stereoisomeric 6,5- and 7,5-fused bicyclic lactams was synthesized with the aim of developing active and selective integrin antagonists. The solid-phase synthesis and activity of these RGD derivatives is described. The approach led to two of the most active known inhibitors of alpha(V)beta3 receptor.     

Synthesis of epothilones via a silicon-tethered RCM reaction

[reaction: see text] A short synthesis of epothilone B and D is reported. The key step for generating the C12-13-trisubstituted Z-double bond uses a ring-closing metathesis reaction of a disiloxane to form a nine-membered silicon-tethered ring.     

Optical waveguides for the evanescent wave-induced cleavage of photolabile linker compounds

Functional surfaces and especially the control of surface properties depending on external parameters such as light illumination have gained increasing importance in the last few years. We present the characterization of polymers from the cycloolefin (co)polymer class (COC/COP) functionalized with an aminosilane as a basis for the further immobilization of compounds. In a first step, an assay using AlexaFluor?647 fluorescent dye was used to assess surface homogeneity and reproducibility. A coefficient of variation of less than 15% for dot-to-dot and less than 25% for chip-to-chip could be achieved. The same amino-functionalized surfaces were then used to immobilize a biotinylated photolabile linker compound, binding AlexaFluor?647-labeled streptavidin. The linker was photocleaved with high efficiency at λ = 365 nm and P = 0.15 mW/cm². Fluorescence measurements show that polymers of the COC/COP class can be used as versatile surfaces for the photoinduced release of compounds immobilized via photolabile linkers.     

Benzoylureas as removable cis amide inducers: synthesis of cyclic amides via ring closing metathesis (RCM)

Rapid and high yielding synthesis of medium ring lactams was made possible through the use of a benzoylurea auxiliary that serves to stabilize a cisoid amide conformation, facilitating cyclization. The auxiliary is released after activation under the mild conditions required to deprotect a primary amine, such as acidolysis of a Boc group in the examples given here. This methodology is a promising tool for the synthesis of medium ring lactams, macrocyclic natural products and peptides.     

TRAM linker: a safety-catch linker for the traceless release of acrylamides

[reaction: see text] A novel safety-catch linker for the solid-phase synthesis of small-molecule libraries containing electrophilic reactive groups has been developed. Upon cleavage from solid support, the linker generates a Michael acceptor (an acrylamide) on each library member. Utilization of a two-resin system in the final cleavage step provides crude products in high purity, allowing direct use in biological assays following filtration and evaporation.     

Synthetic studies toward macrocidins: an RCM approach for the construction of the central cyclic core

The central macrocyclic core of the macrocidins was constructed using RCM as the key reaction. A preliminary investigation dealing with the key reactions, that is, the Dieckmann cyclization and the RCM, revealed that RCM of the β-ketoamide is better than RCM of the corresponding acyltetramic acid.     

Dual linker with a reference cleavage site for information rich analysis of polymer-supported transformations

Two dual linker systems with specific reference cleavage sites were designed and synthesized to accelerate and simplify development and optimization of reaction conditions for solid-phase synthesis. The dual linker allows simple evaluation of cleavage rate of polymer-supported compounds from the linker and, at the same time, ensures that all resin-bound components are cleaved from the solid support. The dual linker 4 was assembled from two Wang linkers connected by a three carbon spacer. The linker 9 was synthesized using the PAL and HMPB linkers.     

Stereoselective synthesis of cyclic ether compounds via reductive cleavage of bicyclic ketals

Bicyclic ketals in the 6,8-dioxabicyclo[3.2.1]octane system readily reacted with triethylsilane-boron tri-fluoride etherate at room temperature to give only the cis-tetrahydropyranol derivatives via C₅-O₆ bond cleavage. Three- and erythro-alcohols were prepared selectively from the endo- and exo-ketal, respectively. Dehydrated products also formed when the tertiary alcohol was involved under these reaction conditions. However, the cleavage reaction with aluminum hydride gave the trans-tetrahydropyranol as the major product without dehydration.     

A novel direct method for preparation of aromatic polyimides via microwave-assisted polycondensation of aromatic dianhydrides and diisocyanates

Possibility of imide structure formation under microwave irradiation of molecules containing anhydride and isocyanate functional groups was investigated. The microwave-assisted polycondensation of aromatic diisocyanates and dianhydrides for preparation of polyimides was studied. The effect of microwave irradiation time and power, solvent nature, solid content of monomers, effect of catalyst, effect of polymerization reactor material and possibility of pressure development during polymerization, on the inherent viscosity of prepared polyimides were discussed. Experimental results showed that polymers obtained via this method had superior inherent viscosity and yield in comparison to the polymers obtained via conventional solution method.     

Development of a concise and diversity-oriented approach for the synthesis of plecomacrolides via the diene-ene RCM

[reaction: see text] A concise synthesis of the core structures of plecomacrolide with ring sizes varying from 16 to 19 atoms was achieved for the first time by the diene-ene ring-closing olefin metathesis reaction. This approach should allow access to the structurally diverse analogues of plecomacrolide.     

Synthesis of a thioester linker precursor for a general preparation of peptide C-terminal thioacids

A general procedure to prepare peptide thioacids by solid-phase peptide synthesis is presented. The method involves the synthesis of 4-[α-(S-acetyl)mercaptobenzyl]phenoxyacetic acid as general precursor. This reagent once attached to a solid support is derivatized with the Boc-amino acid of choice after deprotection of the thiol.     

Synthesis of 2-phosphonopyrroles via a one-pot RCM/oxidation sequence

A four-step synthesis of 2-phosphonopyrroles is presented starting from suitable aldehydes. The key step in the synthesis involves a one-pot ring-closing metathesis/oxidation sequence of a functionalized alpha-aminoalkenyl phosphonate. Notwithstanding the presence of a nucleophilic nitrogen atom and high substitution patterns in the substrate, the results of the RCM reaction are excellent using mild reaction conditions. Furthermore, a synergism is observed between the RCM catalyst and the oxidizing agent, causing higher oxidation rates and allowing reaction for substrates that normally fail to ring close under standard RCM conditions.     

Use of a Baylis-Hillman adduct in the stereoselective synthesis of syributins via a RCM protocol

The total synthesis of syributins 1 and 2 using the Baylis-Hillman adduct of 2,3-O-isopropylidene-R-glyceraldehyde-ethyl acrylate as starting material followed by ring closing metathesis (RCM) of the acrylate derivative of the ensuing diol as the key step is reported.