Solid-phase synthesis of hydroxypiperazine derivatives using phenethylamine linker by oxidation-Cope elimination

A general method is reported for the parallel solid-phase synthesis of hydroxypiperazine derivatives based on the oxidation-Cope elimination of polymer-bound phenethylamine linker with m-CPBA. The key intermediate of phenethylamine N-oxide resins was separable on solid-phase for subsequent β-elimination, from which the desired hydroxypiperazine products could be obtained in high purities and yields without any significant contamination at 90 °C for 2 h. The utility of the methodology for solid-phase synthesis of general hydroxylamines was also investigated using the same linker. The progress of reactions could be monitored on polymer bound intermediates by ATR-FTIR spectroscopy on single bead. The desired products were obtained in good six-step overall yields upon cleavage from the resins and were characterized by LC/MS, ¹H NMR, and ¹³C NMR spectroscopy.     

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.     

Solid-phase synthesis of substituted guanidines using a novel acid labile linker

A novel acid labile linker for solid-phase synthesis of substituted guanidines has been developed. Its synthetic utility is exemplified by high-yielding pyrazole displacement with structurally and electronically diverse sets of aliphatic and aromatic amines. The final cleavage is achieved by treatment with 95:5 trifluoroacetic acid/water for 1 h. The corresponding guanidines were obtained in high purity (80-95%) and good isolated yields (50-95%). The scope and limitations of this linker were further demonstrated by the solid-phase synthesis of an 880-member library of individual trisubstituted arylguanidines employing pyrazole displacement with a set of 11 anilines and two subsequent Mitsunobu N-alkylations with sets of 10 and 8 alcohols, respectively.     

Solid-phase synthesis of urea and amide libraries using the T2 triazene linker

Starting from Merrifield resin, primary amines were immobilized in two steps by triazene linkage (T2-linker). While reaction with isocyanates gave rise to resin-bound urea derivatives, acylation by acid chlorides or anhydrides furnished amides bound to solid support via the nitrogen atom, therefore representing a novel backbone amide linker. Cleavage from the resin was conducted using dilute trimethylsilyl chloride or trifluoroacetic acid, respectively, to yield ureas and amines/amides in a library format (altogether 60 examples; manual synthesis: 17 ureas, 6 mono-alkylated ureas [including dihydroxylation and ozonolysis/Wittig reaction]; automated synthesis: 15 ureas, 15 amides) in high purities and good overall yields. The synthesis of a small library (4 x 4 member) was successfully conducted on a Bohdan Neptune synthesizer.     

Solid-phase synthesis of the 2-aminobenzoxazole library using thioether linkage as the safety-catch linker

An efficient solid-phase methodology has been developed for the synthesis of 2-aminobenzoxazole derivatives. The key step in this procedure involves preparation of polymer-bound 2-mercaptobenzoxazole resins 3 by reaction of the Merrifield resin with 2-aminophenols and CS(2) in the presence of DIC in MeCN. Oxidation of the resulting resins followed by treatment with amines gives the desired 2-aminobenzoxazole products 5. Further diversification can be introduced to the key resin 11, derived from the nitro group containing resin 3c. This process produces the corresponding amine, which upon reaction with acid chlorides and isocyanates can be used to generate various 6-functionalized 2-aminobenzoxazole analogues 13 and 15.     

Solid-phase synthesis of benzazoles,quinazolines, and quinazolinones using an alkoxyamine linker

An alkoxyamine linker was applied for the solid-phase synthesis of benzazoles, quinazolines, and quinazolinones. Aromatic aldehydes were anchored by aldoxime linkage. After some reactions on a solid support, the products were cleaved with paraformaldehyde under the acidic conditions to afford the corresponding aldehydes, which were subsequently subjected to oxidative coupling with 2-substituted anilines under air atmosphere to give the desired compounds.     

Solid-phase synthesis of neuroactive spider-wasp hybrid toxin analogues using a backbone amide linker

Polyamine toxins isolated from the venoms of spiders and wasps and their synthetic analogues are uncompetitive antagonists of ligand-gated ionotropic receptors in the central- and peripheral nervous systems, and have proved valuable as tools for the investigation of receptor structure and function. In the present letter we describe the efficient solid-phase synthesis (SPS) of novel hybrid toxins using a BAL resin. This strategy enables the bidirectional construction of toxin molecules and has a potential in SPS of chemically diverse libraries of toxin analogues for structure-activity relationship (SAR) studies.     

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.     

Solid-phase parallel synthesis of 17alpha-substituted estradiol sulfamate and phenol libraries using the multidetachable sulfamate linker

We report an application of the multidetachable sulfamate linker in the synthesis of two model libraries of N-derivatized 17alpha-piperazinomethyl estradiols (phenols and sulfamates) by solid-phase parallel chemistry. The solid-phase precursor, a 3-sulfamoyl-17alpha-(N-trifluoroacetyl-piperazinomethyl) estradiol, was synthesized in solution from estrone and loaded efficiently onto trityl chloride resin as polymeric support. After cleavage of the trifluoroacetyl protecting group, sequential acylation reactions with five Fmoc-protected amino acids and five carboxylic acids were performed to introduce two levels of molecular diversity. Finally, the resins were split into two parts, and acidic (5% trifluoroacetic acid in dichloromethane) and nucleophilic (piperazine in tetrahydrofuran) cleavages were used to generate libraries A (5 x 5 sulfamates) and B (5 x 5 phenols) members in overall yields of 18-66% and high HPLC purities (87-96%) without purification steps. A preliminary screening test for inhibition of steroid sulfatase showed that the phenols were clearly weaker inhibitors, as compared to their sulfamate analogues. The most potent inhibitors were those with suitable hydrophobic amino acid and carboxylic acid substituents. Thus, compounds with a phenylalanine residue as the first element of diversity inhibited over 90% of steroid sulfatase activity at a concentration of 1 nM in homogenates of HEK-293 transfected cells, being as potent as the leading inhibitor 17alpha-tert-butylbenzyl estradiol 3-O-sulfamate previously reported. These results suggest that the steroid sulfatase inhibitory potency of estradiol derivatives, sulfamoylated or not, can be increased by the hydrophobic effect of a suitable substituent introduced in the proximity of the D ring of the steroid. The present work also demonstrated the efficiency and the cleavage versatility of the sulfamate linker to generate libraries of compounds with relevant biological importance, phenols and sulfamates.     

Solid-phase synthesis of monocyclic beta-lactam derivatives

Liquid-phase studies concerning the solid-phase synthesis of monocyclic beta-lactams via the ester-enolate imine condensation route have been conducted utilizing triazene esters 1 and 2 as model compounds. Esters were attached to benzylamine resin 6 by a triazene linker employing the respective diazonium salts. Immobilized ester-enolates 8 and 10 were reacted with various imines and imine precursors to give polymer-bound beta-lactams 14 and 17 in different substitution patterns. Traceless cleavage from the triazene linker yields the desired beta-lactams 16 and 19.     

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.     

Solid-phase organic synthesis of polyisoprenoid alcohols with traceless sulfone linker

Solid-phase organic synthesis of polyprenols with a traceless sulfone linker is described. The polymer-bound benezenesulfinate is first linked with the "tail" building blocks of isoprenyl chlorides via S-alkylation. With use of dimsyl anion as an appropriate base, the polymer-bound alpha-sulfonyl carbanion is generated and coupled with other "body" building blocks in an efficient manner. After repeated processes and a global palladium-catalyzed desulfonation with LiEt 3BH as the reducing agent, the desired polyprenols with various chain lengths and geometrical configurations are obtained in 32-59% overall yields. The solid-phase synthesis offers the advantage in facile isolation of polyprenols without tedious operation or time-consuming purification.     

Solid-phase synthesis of unsymmetrical ureas through the use of Kenner safety-catch linker

A new strategy for the solid-phase synthesis of unsymmetrical ureas is described. Upon treatment of Kenner safety-catch linker with an isocyanate, followed by TMSCHN₂ or iodoacetonitrile and an amine, the corresponding unsymmetrical ureas are released in solution.     

Solid-phase synthesis of lidocaine and procainamide analogues using backbone amide linker (BAL) anchoring

New solid-phase strategies have been developed for the synthesis of lidocaine (1) and procainamide (2) analogues, using backbone amide linker (BAL) anchoring. Both sets were prepared starting from a common resin-bound intermediate, followed by four general steps: (i) attachment of a primary aliphatic or aromatic amine to the solid support via reductive amination (as monitored by a novel test involving reaction of 2,4-dinitrophenylhydrazine with residual aldehyde groups); (ii) acylation of the resultant secondary amine; (iii) displacement of halide with an amine; and (iv) trifluoroacetic acid-mediated release from the support. A manual parallel strategy was followed to provide 60 novel compounds, of which two dozen have not been previously described. In most cases, initial crude purities were >80%, and overall isolated yields were in the 40-88% range.     

Solid-phase synthesis of palmitoylated and farnesylated lipopeptides employing the fluoride-labile PTMSEL linker

Acid- and base-labile S-palmitoylated and S-farnesylated lipopeptides can be synthesized in high overall yield employing the (2-phenyl-2-trimethylsilyl) ethyl (PTMSEL) linker for anchoring to and release under almost neutral conditions from the solid support.     

Solid-phase synthesis of 3,4-dihydro-1H-pyrimidine-2-ones using sodium benzenesulfinate as a traceless linker

The facile preparation of 3,4-dihydropyrimidine-2-one derivatives with traceless solid-phase sulfone linker strategy is described. Key steps involved in the solid-phase synthetic procedure include (i) sulfinate acidification, (ii) condensation of urea or thiourea with aldehydes and sulfinic acid, and (iii) traceless product release via a one-pot cyclization-dehydration process. A library of 18 compounds was synthesized.     

Solid-phase synthesis of N-substituted 3,4-dihydroquinazolinone derivatives

An efficient solid-phase synthetic approach for the synthesis of N-substituted 3, 4-dihydroquinazolinone derivatives has been developed. Four different 2-nitrobenzoic acids and three different 2-phenylacetyl chlorides were employed in the synthesis of this library. After purification, all products were obtained in good yields.