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.     

Tartric acid-based linker for the solid-phase synthesis of C-terminal peptide alpha-oxo aldehydes

A novel linker, based on the anchoring of (+)-dimethyl 2,3-O-isopropylidene-D-tartrate to PEGA or PEG-PS solid supports, was developed for the solid-phase synthesis of C-terminal peptide alpha-oxo aldehydes. Peptide elongation was performed using the 9-fluorenylmethoxycarbonyl/t-Bu chemistry. The peptide and the 1,2-diol were deprotected on the solid phase. Then, a periodic oxidation of the fully deprotected peptidyl-resin led to the simultaneous cleavage of the product from the solid support and to the generation of the alpha-oxo aldehyde moiety. The methodology allowed the distance between the alpha-oxo aldehyde and the peptide to be easily modulated. The C-terminal peptide alpha-oxo aldehydes synthesized in this study were found to be useful partners in hydrazone, thiazolidine, and oxime chemical ligations.     

Resin-bound 4-phenyl-1,2-dihydroquinoline (DHQ): a new safety-catch linker for solid-phase organic synthesis (SPOS)

A new safety-catch linker has been developed for combinatorial solid-phase chemistry. Azidomethyl-polystyrene, obtained by nucleophilic substitution of chloromethyl-polystyrene, undergoes an acid promoted Schmidt rearrangement. The resulting polymer-bound iminium participates in an aza Diels-Alder cycloaddition, which leads to a supported dihydroquinoline (DHQ resin). The acylated form of the DHQ resin is stable under basic, acidic and mild reducing agents. The cleavage proceeds in two steps (i) oxidative aromatization leading to an activated quinolinium and (ii) nucleophilic displacement of the quinoline resin. The overall process is high yielding and efficient.     

Polymer-supported (2,6-dichloro- 4-alkoxyphenyl)(2,4-dichlorophenyl)methanol: a new linker for solid-phase organic synthesis

An acid and base stable hydroxytetrachlorodiphenylmethyl (HTPM) linker is developed for polymer-supported organic synthesis. The linkers reported here are utilized for loading carboxylic acids, amines, alcohols, and phenols, and are stable to Br?nsted and Lewis acids, Br?nsted bases, and a wide variety of nucleophiles. However, the HTPM linkers can conveniently be cleaved by the solvolytic displacement reactions with 20% TFA. [structure: see text]     

An acid-stable tert-butyldiarylsilyl (TBDAS) linker for solid-phase organic synthesis

[reaction: see text] A new, robust tert-butyldiarylsilyl (TBDAS) linker has been developed for solid-phase organic synthesis. This linker is stable to both protic and Lewis acidic reaction conditions, overcoming a significant limitation of previously reported silyl linkers. Solid-phase acetal deprotection, olefination, asymmetric allylation, and silyl protecting group deblocking reactions have been demonstrated with TBDAS-linked substrates.     

4-Oxoheptanedioic acid: an orthogonal linker for solid-phase synthesis of base-sensitive oligonucleotides

l,6-Dioxaspiro[4,4]nonane-2,7-dione has been found to react readily with alcohols in the presence of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU). The 4-oxoheptanedioic acid tether obtained bears (l) a free carboxy group, which enables anchoring to aminoalkylated resins, and (2) a 4-oxobutanoate structural motif, which allows release of the target alcohol by a mild hydrazinium acetate treatment. To demonstrate the applicability of the procedure, nucleosides have been derivatized with this simple difunctional linker arm, anchored to a solid phase and subjected to synthesis and subsequent release of oligonucleotides bearing a base-sensitive biodegradable phosphate protection.     

Nucleotides. Part LV. Synthesis and application of a novel linker for solid-phase synthesis of modified oligonucleotides

Various bifunctional amino-protecting groups such as the phthaloyl, succinyl, and glutaryl group were investigated as potential linker molecules for attachment to solid-support materials. Pentane-1,3,5-tricarboxylic acid 1,3-anhydride ( 16 ) offered the best properties and reacted with the amino groups of differently sugar-protected adenosine (see 20 and 22 ), cytidine (see 29 ), and guanosine derivatives (see 32 ) to the corresponding 2-(2-carboxyethyl)glutaryl derivatives 23 , 24 , 30 , and 33 . The usefulness of the new linker-type molecules was demonstrated by the solid-support synthesis of the potentially antivirally active 3′-deoxyadenylyl-(2′–5′)-2′-adenylic acid 2′-{2-[(adenin-9-yl)methoxy]ethyl} ester ( 38 ) starting from the 2′-end with N⁶,N⁶-[2-(2-carboxyethyl)glutaryl]-9-{{2-[(4,4′-dimethoxytrityl)ethoxy]methyl}adenine ( 12 ).     

A photolabile linker for the solid-phase synthesis of 4-substituted NH-1,2,3-triazoles

This communication presents the synthesis of a novel photolabile azidolinker based on the o-nitroveratryl group. The application of this linker for the synthesis and photolytic release of NH-1,2,3-triazoles is described.     

Expedient synthesis of pseudo-Pro-containing peptides: towards constrained peptidomimetics and foldamers

The reaction of sulfonyl peptides containing L- or D-configured Ser or Thr with bis(succinimidyl) carbonate in the presence of a catalytic amount of a base affords, in solution or in the solid phase, the corresponding peptides with one or two, consecutive or alternate oxazolidin-2-ones (Oxd). The Oxd ring can be regarded to as a pseudo-Pro with an exclusively trans conformation of the preceding peptide bond; homochiral Oxd-containing peptides adopt extended conformations, while the presence of a D-configured Oxd favours folded conformations.     

5-(hydroxymethyl)oxazoles: versatile scaffolds for combinatorial solid-phase synthesis of 5-substituted oxazoles

A scheme combining the preparation of building blocks in solution followed by solid-phase combinatorial chemistry has been developed to side-chain diversify 5-(hydroxymethyl)oxazole scaffold (1) into aryl ethers, thioethers, sulfones, sulfonamides, and carboxamides. Protected heterocyclic scaffolds 2 were linked to the solid phase and N-terminal derivatized using active ester chemistry, providing chemset 4?1-4,1-4?. The free side-chain hydroxyl of 4 was smoothly converted to aryl ethers 6 under Mitsunobu conditions, with a broad range of substituted phenols. Alternatively, quantitative conversion of hydroxyl to bromide followed by displacement with alkyl and aryl thiols gave thioethers 8. Thioethers were optionally oxidized to sulfones 9. Bromide displacement by azide, followed by reduction to amine and acylation with a range of carboxylic acids and sulfonyl chlorides gave carboxamides 11 and sulfonamides 13, respectively. Crude purity at typically >90% was observed for each of the five modifications detailed. A series of 20 compounds, exemplifying each modification, was reprepared, purified, and fully characterized.     

Dioxomolybdenum(VI) complexes of 2-hydroxybenzaldehyde 4-phenyl-S-methylthiosemicarbazone

Mixed ligand complexes of dioxomolybdenum(VI) with 2-hydroxybenzaldehyde 4-phenyl-S-methylthiosemicarbazone (H₂L) were prepared with the formula [MoO₂(L)D] (D = H₂O, methyl, n-butyl, and n-undecyl alcohol, DMF, DMSO, pyridine, 4-picoline, and 3,5-lutidine). The compounds were characterized by elemental analysis, IR and ¹H NMR spectroscopy. The thermal decomposition of the compounds were investigated by using TGA, DTG, and DTA methods in air, and the thermal behavior depending on the second ligand molecule was discussed. A single crystal of the DMF coordinated complex was studied by X-ray diffractometry. The text was submitted by the authors in English.     

Synthesis and evaluation of 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid as a linker in solid-phase synthesis monitored by gel-phase (19)F NMR spectroscopy

Gel-phase (19)F NMR spectroscopy is a useful monitoring technique for solid-phase organic chemistry due to the high information content it delivers and swift acquisition times, using standard NMR spectrometers. This paper describes the synthesis of the novel linker 2-(2-fluoro-4-hydroxymethyl-5-methoxy-phenoxy)acetic acid in 29% yield over seven steps, using nucleophilic aromatic substitutions on 2,4,5-trifluorobenzonitrile as key steps. Following standard solid-phase synthesis a peptide could be cleaved from the linker using 20% TFA in CH(2)Cl(2) in 30 minutes, in contrast to a previously described monoalkoxy linker that requires 90% TFA in water at elevated temperature. A resin-bound peptide could be successfully glycosylated using only two equivalents of a thioglycoside donor, activated with N-iodosuccinimide and trifluoromethanesulfonic acid, and subsequent cleavage and deprotection gave the target glycopeptide. Direct glycosylation of the linker itself followed by mild acidic cleavage gave a fully protected hemiacetal for further chemical manipulation.     

Solid-phase synthesis of a library of C-terminal agmatine dipeptides using a backbone amide linker (BAL) strategy

In this Letter, we report a novel solid-phase strategy using a backbone amide linker (BAL) attached to a polystyrene support for the synthesis of C-terminal agmatine dipeptides. Our method eliminates the need to purify intermediates by column chromatography and enables us to build rapidly an 18-member library of C-terminal agmatine dipeptides which are subsequently screened for inhibitory activity against a viral enzyme.     

Selenium-based safety-catch linker: solid-phase synthesis of vinyl-substituted oxadiazoles and triazoles

Vinyl-substituted oxadiazoles and triazoles were prepared through hydrazinolysis, acylation, cyclocondensation, and elimination of selenium resins. The polystyrene-supported resins used here not only facilitate separation of products but also serve as a pro-vinyl safety-catch linker.     

Combinatorial synthesis of heterocycles: solid-phase synthesis of 2-amino-4(1H)-quinazolinone derivatives

A new solid-phase synthesis of various substituted 2-amino-4(1H)-quinazolinones from a resin bound amine component is described. The amine was readily converted to the corresponding polymer bound S-methylthiopseudourea. Condensation with different substituted isatoic anhydrides afforded 2-amino-4(1H)-quinazolinone derivatives. The method is amenable for combinatorial library generation.     

Thioester-isocyanides: versatile reagents for the synthesis of cycle-tail peptides

A novel class of reagents, thioester isocyanides, have been prepared and applied in the synthesis of peptide macrocycles. The isocyanide part of the molecule is deployed in a multicomponent macrocyclization step. This step is followed by chemoselective peptide ligation at the thioester part of the macrocycle. Our method can now be used for rapid assembly and evaluation of cycle-tail peptides.     

The sulfone linker in solid-phase synthesis: preparation of 3,5-disubstituted cyclopent-2-enones

The preparation of functionalized 3,5-disubstituted cyclopent-2-enones via a solid-phase sulfone linker strategy is described. Polystyrene/divinylbenzene sulfinate 1 underwent S-alkylation followed by alpha,alpha-dialkylation with cis-1,4-dichloro-2-butene to form polymer-bound 3-phenylsulfonylcyclopentenes 8. Subsequent epoxidation of the cyclopentene moiety in 8 was accomplished by treatment of mCPBA, and the resulting oxirane ring in resin 9 was opened with various nucleophiles, i.e., Grignard and cuprate reagents, azide ion, and amines. To complete the sulfone-based linker strategy, Swern or TPAP oxidation of 10 gave a transient gamma-ketosulfone, which underwent sulfinate elimination, thus cleaving the sulfone linker. Eleven 3,5-disubstituted cyclopent-2-enones (11) were prepared with this five-step process in 18-40% overall yield from solid-phase benzene sulfinate 1.     

Efficient and versatile COMU-mediated solid-phase submonomer synthesis of arylopeptoids (oligomeric N-substituted aminomethyl benzamides)

The development of a highly efficient methodology for solid-phase synthesis of para- and meta-arylopeptoids (oligomeric N-substituted aminomethyl benzamides) with free acids or free amides at the C-terminus is described. The arylopeptoids were synthesised by means of a convenient submonomer protocol in which the arylopeptoid residues were created in an iterative manner on the growing chain using an acylation-substitution cycle. The uronium salt COMU was found to be the most efficient reagent for ensuring fast and clean couplings of the benzoic acid building blocks.