Solid‐Phase Approach for the Synthesis of 2‐Amido‐1,3,4‐oxadiazoles

A new solid‐phase approach for the synthesis of 2‐amido‐1,3,4‐oxadiazoles has been developed. In this synthesis, hydroxypentyl JandaJel polymer support was treated with excess of oxalyl chloride to give resin‐bound 2‐chloro‐2‐oxoacetate, and this intermediate was then coupled with different hydrazides to give resin‐bound 2‐(N′‐acylhydrazinyl)‐2‐oxoacetate. Intramolecular dehydrative cyclization of resulting resin‐bound linear precursor followed by direct amidation using aluminum amide reagent provided 5‐substituted 1,3,4‐oxadiazoles as 2‐carboxamides. To explore the scope of this reaction sequence, we synthesized a small set of library using a combination of hydrazides and amines, and the desired products were obtained in good to high yields.     

Microwave-assisted solid-phase synthesis of hydantoin derivatives

A microwave-assisted synthesis of 3,5- and 1,3,5-substituted hydantoins starting from various resins for solid-phase combinatorial chemistry has been developed. The hydantoins were synthesized from pre-loaded resins with amino acids via treatment with isocyanate or phenylisocyanate and subsequent intramolecular cyclization. Both reactions were performed under microwave irradiation. We studied the cyclative cleavage leading to hydantoin compounds dependent on the nature of the amino acid and the nucleofuge properties of the resin.     

Solid-phase synthesis of a thymidinyl dipeptide urea library

A thymidinyl dipeptide urea library with structural similarity to the nucleoside peptide class of antibiotics was designed and synthesized. To generate the library, a solid-phase synthesis was developed starting from 5'-azidothymidine attached to a polystyrene butyl diethylsilane (PS-DES) resin support. This study describes the prelibrary solid-phase synthesis development including maximum loading capacity optimization, selection of orthogonal functionalized side-chain protection strategies, synthesis of a 64-member test library, and optimization of the final cleavage step. Using the optimized procedures, we synthesized a 1000-member library in a 50 micromol quantity using IRORI-directed sorting technology in MiniKans, producing the target library in good yields and purity.     

Solid-phase synthesis of metal-complex containing peptides

We report the synthesis of Fmoc protected single amino acid chelates (SAAC) and their metal complexes. The modified amino acids are suitable for solid-phase peptide synthesis. The use of 4-hydroxymethylbenzoic acid AM (HMBA-AM) resin allows the nucleophilic cleavage of the peptide-metal complexes from the resin without decomplexation.     

Solid-phase preparation of hydantoins through a new cyclization/cleavage step

An efficient process for the solid-phase synthesis of hydantoins has been developed. The amino acid starting material is anchored to the resin from its carboxylic acid end through formation of a very stable amide bond. After introduction of different functional groups, the cleavage/cyclization step can be performed in acidic or basic conditions.     

2,6-Diketopiperazines from amino acids, from solution-phase to solid-phase organic synthesis

A method to prepare 1,3-disubstituted 2,6-diketopiperazines (2,6-DKP) as useful heterocyclic library scaffolds in the search of new leads for drug discovery is described. The method can be used in solution-phase and solid-phase conditions. In the key step of the synthesis, the imido portion of the new molecule is formed in solution through intramolecular cyclization, under basic conditions, of a secondary amide nitrogen on a benzyl ester. A Wang resin carboxylic ester is used as the acylating agent under solid-phase conditions, allowing the cyclization to take place with simultaneous cleavage of the product from the resin ("cyclocleavage"). The synthetic method worked well with several couples of amino acids, independently from their configuration, and was used for the parallel synthesis of a series of fully characterized compounds. The use of iterative conditions in the solid phase (repeated addition of fresh solvent and potassium carbonate to the resin after filtering out the product-containing solution) allowed us to keep diastereoisomer content below the detection limit by HPLC and (1)H NMR (200 MHz).     

Structure based library approach to photosynthesis inhibitors:Combinatorial synthesis of hydrouracil library

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Solid-phase synthesis of a 4-substituted gamma-lactam library

Pyrrolidin-2-one (gamma-lactam) derivatives have shown a wide range of activities as ligands to diverse receptors, e.g., integrin, CCR5, and CCK. Therefore, we have prepared a large library of these derivatives for high-throughput screening against various protein targets, after developing a synthesis of pyrrolidin-2-ones on solid phase. Exploration of the ring formation was key to the success of this synthesis. First, acylation of resin-bound amines with N-Fmoc-protected amino acids and subsequent deprotection of the Fmoc group were accomplished readily. The resulting resin-bound primary amines were treated with beta-monomethyl itaconate under gentle heat in a mixture of methanol and toluene to yield the desired intermediates. Finally, saponification, amide formation, and cleavage from the resin led to the production of a library of 12,000 pyrrolidin-2-one derivatives. These products were isolated as diastereomeric mixtures of high purity and were obtained in good yields.     

The combined solid/solution-phase synthesis of nitrosamines: the evolution of the "libraries from libraries" concept

The generation of diverse chemical libraries using the "libraries from libraries" concept by combining solid-phase and solution-phase methods is described. The central features of the approaches presented are the use of solid-phase synthesis methods for the generation of a combinatorial polyamine library. Following cleavage from the resin with HF, the polyamine library was reacted with ethyl nitrite in the solution phase to yield the desired nitrosamine library in good yield and purity. The approaches described enable the efficient syntheses of individual nitrosamines as well as mixture-based nitrosamine libraries.     

Suzuki cross-coupling of solid-supported chloropyrimidines with arylboronic acids

The utility of the Suzuki cross-coupling to synthesize biaryl compounds is expanded herein to include reactions of resin-supported chloropyrimidines with boronic acids. In particular, an efficient method is described for the synthesis of a library of biaryl compounds from solid-supported chloropyrimidines. The Suzuki reaction was performed in an inert atmosphere using Pd(2)(dba)(3)/P(t-Bu)(3) as catalyst, spray-dried KF as base, and THF as solvent. The reaction was allowed to proceed overnight at 50 degrees C. Upon cleavage with acid, a library of 4-(substituted amino)-6-arylpyrimidines was obtained in moderate yield and high purity.     

Solid-Phase Synthesis of 2,4-diaminopyrimidines via Lewis acid-mediated aromatic nucleophilic substitution

Primary amines were immobilized on (4-formyl-3,5-dimethoxyphenoxy)methylpolystyrene resin via reductive amination. Attachment of two different 4-chloro-2-methylthiopyrimidines, followed by sulfide oxidation, led to their corresponding sulfone intermediates. Aromatic nucleophilic substitution with various anilines or heteroaromatic amines in the presence of trimethyl aluminum afforded the desired 2,4-diaminopyrimidines after acidic cleavage from the resin. The synthetic methodology described herein was validated with the synthesis of a small 162-member library.     

聚苯乙烯基N,O-二酰基磺酰羟胺树脂: 一种双酰基转移试剂在合成酰胺库中的应用

用聚苯乙烯基磺酰羟胺树脂1与酰氯2反应合成了聚苯乙烯基N,O-二酰基磺酰羟胺树脂3. 树脂3作为一种新的双酰基转移试剂可与胺4发生酰基转移反应, 合成了含有24个结构类似的酰胺化合物库. 改变酰氯的种类, 结果发现双对硝基苯甲酰树脂3a的活性较高. 双酰基树脂3胺解结果表明, 由脂肪族胺得到的酰胺收率较芳香族胺高. 当解脱试剂同时含有羟基和氨基时, 双酰基树脂3能选择性地在氨基端发生酰基转移, 而羟基端不受影响.     

Solid-phase oligosaccharide synthesis of a small library of N-glycans

Solid-phase oligosaccharide synthesis is based on a hydroxymethylbenzyl benzoate spacer linker which is connected to the Merrifield resin (1 P). Glycosylation was performed with O-glycosyl trichloroacetimidates of glucosamine, mannose, and galactose permitting chain extension (2e, 5e), branching (4b, 7b, 8b), and chain termination (3t, 6t, 9t) with the use of O-benzyl, O-benzoyl, and N-dimethylmaleoyl as permanent and O-fluorenylmethoxycarbonyl (Fmoc) and O-phenoxyacetyl (PA) as temporary protecting groups. The steps required on solid phase are i) glycosylation under TMSOTf catalysis, ii) selective cleavage of the temporary protecting groups, Fmoc with NEt3 and PA with 0.5 equivalents of NaOMe in CH2Cl2/MeOH, and iii) product cleavage from the resin with 4.0 equivalents of NaOMe in CH2Cl2/MeOH and following O-acetylation for convenient product isolation. Thus a highly successful synthesis of a small library of seventeen N-glycan structures was made possible comprising the N-glycan pentasaccharide core structure 53 and two further chain extended hexa- and heptasaccharide N-glycans with a glucosamine or a lactosamine residue, respectively, which is attached to one of the mannose residues of the core structure (56 and 59).     

Pyrrolo[3,2-e][1,4]diazepin-2-one synthesis: a head-to-head comparison of soluble versus insoluble supports

Aryldiazepin-2-ones are known as "privileged structures", because they bind to multiple receptor types with high affinity. Toward the development of a novel class of aryldiazepin-2-one scaffolds, the synthesis of pyrrolo[3,2-e][1,4]diazepin-2-ones on a support was explored starting from N-(PhF)-4-hydroxyproline and featuring an acid-catalyzed Pictet-Spengler reaction to form the diazepine ring. Three supports [Wang resin, tetraarylphosphonium (TAP) soluble support, and Merrifield resin] were examined in the synthesis of the heterocycle and exhibited different advantages and disadvantages. Wang resin proved effective for exploratory optimization of the synthesis by identification of intermediates after resin cleavage under mild conditions; however, the acidic conditions of the Pictet-Spengler reaction caused premature loss of resin-bound material. Direct monitoring of reactions by TLC, RP-HPLC-MS, and in certain cases NMR spectroscopy was possible with the TAP support, which facilitated purification of intermediates by precipitation; however, incomplete precipitation of material led to overall yields lower than those from solid-phase approaches on resin. Merrifield resin proved stable to the conditions for the synthesis of the pyrrolo[3,2-e][1,4]diazepin-2-one targets and would be amenable to "split-and-mix" chemistry; however, relatively harsh conditions were necessary for final product cleavage. Perspective for the application of different solid-phase approaches in heterocycle library synthesis was thus obtained by demonstration of the respective utility of the three supports for preparation of pyrrolo[3,2-e][1,4]diazepin-2-one.     

Versatile strategies for the solid phase synthesis of small heterocyclic scaffolds: [1,3,4]-thiadiazoles and [1,3,4]-oxadiazoles

New robust protocols for the solid phase synthesis of 5-alkylthio-, 5-alkyl/aryl-, and 5-acylamino-2-alkylamino-[1,3,4]-thiadiazoles are described based on a common resin bound thiosemicarbazide. A protocol for the solid phase synthesis of 2-alkyl/aryl-amino-5-alkylamino-[1,3,4]-oxadiazoles from a resin bound semicarbazide is likewise reported. The protocols have been verified by the preparation of four small libraries that all gave products in good to excellent yields and purity.     

A spiroisoxazolinoproline-based amino acid scaffold for solid phase and one-bead-one-compound library synthesis

An efficient, multigram synthesis of a spiroisoxazolinoproline-based amino acid, 7, requiring minimal purification, delivering good cis:trans diastereoselectivity (approximately 1:4), and providing good yields is reported. Surface-bound studies of the reduction of an arylnitro group in the presence of an isoxazoline ring with tin(II) dichloride dihydrate were undertaken to confirm the stability of the isoxazoline ring. Full derivitization of this spiroisoxazolinoproline-based amino acid scaffold was performed during the synthesis of a sample library with high yields and high purity that validated the efficiency of the chemistry that was employed in resin-bound library synthesis. A 129,600 member one-bead-one-compound (OBOC) library based on the scaffold 7 was synthesized utilizing a dual amino acid encoding method and bifunctionalization of TentaGel resin.     

Synthesis of spirohydantoins and spiro-2,5-diketopiperazines via resin-bound cyclic alpha,alpha-disubstituted alpha-amino esters

A seven-step solid-phase synthesis of spirohydantoins and an eight-step solid-phase synthesis of spiro-2,5-diketopiperazines is reported. Key intermediate in the synthesis of both compound libraries is the resin-bound cyclic alpha,alpha-disubstituted alpha-amino ester, which can be obtained after selective homogeneous reduction of the aliphatic nitro ester using tin(II) chloride dihydrate. Nitro ester, in turn, is synthesized by a high-pressure-assisted [4 + 2] cycloaddition of resin-bound nitro alkene and butadiene, whereas nitro alkene is obtained by a Knoevenagel condensation of resin-bound nitro acetate with an imine. Novel spirohydantoins are obtained by isocyanate coupling with the resin-bound amino ester 5, followed by cyclization cleavage using a base. Novel spiro-2,5-diketopiperazines are obtained by PyBOP coupling of a Fmoc-protected amino acid with resin-bound amino ester, followed by Fmoc deprotection and an acid-assisted cyclization cleavage. After preparation of seven different resin-bound alpha,alpha-disubstituted alpha-amino esters, a 7 x 8 compound library of spirohydantoins was synthesized using eight different isocyanates, and a 7 x 8 compound library of spiro-2,5-diketopiperazines was synthesized using eight different Fmoc amino acids.     

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.     

Synthesis and high performance liquid chromatography/electrospray mass spectrometry single-bead decoding of split-pool structural libraries of polyamines supported on polystyrene and polystyrene/ethylene glycol resins

Natural polyamines are ubiquitous biomolecules present in all living cells. These cationic compounds play essential roles in both cell growth and differentiation and are known to interact in complex ways with polyanionic biomolecules. Consequently, there is significant interest in expanding nature's polyamine diversity using combinatorial synthesis and screening strategies. This article describes an efficient split-pool solid-phase synthetic strategy toward the generation of encoded libraries of polyamines via the exhaustive borane-promoted reduction of trityl-linked, resin-bound polyamides. Model structural libraries of tetra- and pentaamines were designed from a set of geometrically diverse amino acid building blocks. To encode the libraries, a partial termination synthesis approach was employed at the polyamide stage, allowing each library to be analyzed from single beads by HPLC/ESMS under two sets of conditions featuring both pH extremes. Determination of the sequence of polyamine residues was simply achieved by the mass differences observed between the full oligomers and the terminated ones. Both polystyrene- and TentaGel-supported libraries, including a library of 4913 pentaamines, were prepared and successfully decoded. For the TentaGel-supported libraries, suitable for on-bead aqueous screening of biomolecules, a novel trityl-derivatized resin was prepared in which the trityl group is anchored to the poly(ethylene glycol) chains via a methylene group. The resulting resin is much more resistant than other commercially available polystyrene-poly(ethylene glycol) trityl resins to the harsh borane reduction conditions required. Two workup conditions for the cleavage of the resultant borane-amine adducts were evaluated on the TentaGel bound polyamide 14. Although the two methods showed a comparable efficiency when using the polystyrene support, with 14 it was found that the piperidine-exchange method afforded polyamines of higher purity than the iodine-based oxidative method previously developed in our laboratory.     

碳酸酯把手改构Wang树脂及其性能

基于碳酸酯结构易于亲核脱除的原理, 使用氯甲酸氯甲酯改构Wang树脂, 并探究了改构树脂与首位氨基酸的缩合效率. 实验结果表明, 改构后的Wang树脂与20种Fmoc保护氨基酸均能达到70%以上的缩合效率; 且对于带有较大侧链基团的Fmoc保护氨基酸, 通过降低树脂取代度或延长反应时间可提高其连接率. 为了验证改构后的碳酸酯型树脂在裂解时侧链未受到影响, 设计合成了3种模型肽, 并用温和裂解剂3-吡啶甲醛肟铯盐进行裂解. 实验结果表明, 利用改构树脂能得到侧链全保护的肽片段, 可初步应用到长链困难肽的合成中.