Chromium-mediated aldol and homoaldol reactions on solid support directed towards an iterative polyol strategy

Chromium-Reformatsky and chromium-homoaldol reactions run under neutral and mild reaction conditions. They are highly chemoselective, tolerant towards most common functional groups, and are not prone to retroaldol reactions. Initial studies directed to transfer these homogeneous chromium-mediated solution-phase reactions to solid phase are presented. The main objective was to develop a methodology to aid a combinatorial iterative strategy to polyols (polyketides) on solid phase. A general reactivity problem was observed with polystyrene based resins compared to the solution-phase reactions, independent if the electrophilic (aldehyde) or nucleophilic (bromide) end of the polyol chain was supported to the resin. A complicated penetration, or loss of the polar solvent environment after penetration into the resin, might be responsible for the reduced reactivity. Application of either a soluble polystyrene resin or a polystyrene resin with a polar polyethylene glycol tether resulted in improved yields.     

Parallel synthesis of unsymmetrically substituted tetraphenyl porphyrins on Wang resin

A method for synthesizing combinatorial libraries of unsymmetrically substituted tetra-meso-phenyl porphyrins on polystyrene based resin is described. Attachment of 5,15-dibromo-10-(4-hydroxyphenyl)-20-(4-nitrophenyl)porphyrin onto brominated Wang resin gave a convenient scaffold for the synthesis of photoactive porphyrin libraries with three points for generating diversity. An array of nine TPP derivatives was prepared by sequential Suzuki coupling/nitro-reduction and acylation protocols.     

Synthesis of novel exocyclic amino nucleosides by parallel solid-phase combinatorial strategy

A versatile parallel solid-phase combinatorial strategy was developed for the synthesis of large nucleoside libraries. Twelve libraries L1-12 of 1152 novel exocyclic triazinylamino nucleosides and one library L13 of 82 new substituted clitocine derivatives were synthesized in high quality as natural product mimic nucleosides on the semi-automated synthesizer. The polystyrene MMT-Cl resin was selected and utilized. The key intermediate resins 5 and 9 loaded with the corresponding scaffolds were prepared and validated with various amines before parallel synthesis. After a variety of amino building blocks were validated, 56 primary amines in 12 groups (building block set A) and 24 secondary amines in 3 groups (building block set B) were selected and utilized to combinatorialize the first and the second reactive sites on scaffold 5 for the synthesis of libraries L1-12. Eighty-two amines (building block set C) were utilized for the synthesis of clitocine library L13. Thirteen libraries of 1234 novel exocyclic amino nucleosides were all analyzed and characterized by high throughput LC-MS. 81.3-100% of the library members in 13 libraries show more than 60% purity, and 65.7-92.7% of the library members in these libraries show 80-100% purity. The strategy can be widely used for the synthesis of other diverse nucleoside libraries.     

Microwave-assisted solid-phase synthesis of 2,5-diketopiperazines: solvent and resin dependence

Solid-phase synthesis of diketopiperazines (DKPs) was preformed using various combinations of resins (polystyrene, TentaGel, ArgoGel, and PEGA) and solvents (toluene, tert-butyl alcohol, water, and toluene/2-butanol (1:4, v/v). The DKPs were synthesized from solid-phase bound dipeptides via intramolecular aminolysis. Both thermal and microwave-assisted solid-phase synthesis of DKPs gave high yields of products independently of resin and organic solvent used; however, only the PEGA resin resulted in high yields of DKPs in water independent of heating method. The short reaction times, high yields, and the possibility to run reactions in water when an appropriate resin is used makes the microwave-assisted solid-phase synthesis the method of choice. The method should be suitable for solid-phase synthesis of diketopiperazine-based libraries.     

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.     

Solid-supported cyclohexane-1,3-dione (CHD): a "capture and release" reagent for the synthesis of amides and novel scavenger resin

[reaction: see text] A three-step synthesis of cyclohexane-1,3-dione (CHD) resin 6 on polystyrene resin is described. Resin 6 was used to prepare an amide library of high purity by microwave-assisted serial "capture and release" and can be recycled for this purpose. High-loading CHD resin 10 was also shown to scavenge allyl cations in solution.     

A straightforward preparation of a polystyrene thiol resin

A mild and efficient two-step synthesis of a polystyrene thiol resin is reported. Firstly, a polystyrene resin was reacted with an activated sulfoxide to afford the resin bound bis-(2-methoxy-carbonylethyl)-sulfonium trifluoromethanesulfonate. Smooth β-elimination based dealkylations afforded the polystyrene thiol resin with good and controlled loading. Its reactivity was assessed through a derivatisation step.     

Synthesis and application of polytetrahydrofuran-grafted polystyrene (PS-PTHF) resin supports for organic synthesis

Cross-linked polystyrene (PS) with polytetrahydrofuran (PTHF) chains were prepared for use in solid phase organic synthesis (SPOS). The resins were prepared from styrene, styrene-PTHF macromonomers and cross-linkers 1,4-bis[4-vinylphenoxy]butane or divinylbenzene by suspension polymerization. The styrene-PTHF macromonomers were prepared by cationic polymerization of 4-vinylbenzyl bromide and 4-(4-vinylphenoxy)butyl iodide activated by silver hexafluoroantimonate and 4-(5-hydroxypentyl)styrene activated by triflic anhydride. Alternatively, polytetrahydrofuran-grafted polystyrene (PS-PTHF) resins could also be directly prepared from 5-hydroxypentyl JandaJel by cationic polymerization using triflic anhydride as the initiator. These PS-PTHF resins exhibited good swelling characteristics across a wide spectrum of polar and non-polar solvents. These resins were used in the synthesis of 3-methyl-1-phenyl-2-pyrazolin-5-one, which requires β-ketoester formation at low temperature (−78 °C), resulting in good yield and product purity; whereas the same synthesis carried out on PEG-grafted PS (PS-PEG) resin resulted in incomplete synthesis.     

Synthesis of new 3'-, 5-, and N(4)-modified 2'-O-methylcytidine libraries on solid support

A versatile solid phase combinatorial approach was developed and utilized for the rapid synthesis of new 2'-O-methylcytidine nucleoside libraries 1-7 containing 672 compounds with 3'-deoxy-3'-C-methyl, 3'-deoxy-3'-C-hydroxymethyl, and 5-alkyl/alkynyl modifications. The modified uridine scaffolds 8-10, 23-25, and 31 were loaded onto the 4-methoxytrityl chloride (MMT-Cl) polystyrene resin through the hydroxyl groups at the 5'-position as well as on the substituents at the 3'- and 5-positions. The scaffolds loaded on the resin were orthogonally protected by MMT group on the resin itself and TBDMS or acetyl protecting groups. The 4-position of the uridine derivatives was activated by 2,4,6-triisopropyl benzene sulfonyl chloride for further derivatization. The resins 14-16, 28-30, and 32 loaded with the corresponding activated scaffolds were reacted with the selected and validated amino building blocks in the 96 well format on the semiautomated synthesizer. The high-quality 2'-O-methylcytidine libraries 1-7 were thus generated and characterized by liquid chromatography-mass spectrometry (LC-MS) analysis with 63-99% successful rates.     

Lewis base‐catalyzed electrophilic lactonization of selenyl bromide resin and facile solid‐phase synthesis of furan‐2(5H)‐one derivatives

A facile solid‐phase synthesis approach was developed for the rapid synthesis of multi‐substituted furan‐2(5H)‐one derivatives libraries. The synthetic strategy included the selenyl bromide resin‐induced electrophilic lactonization catalyzed by Lewis base, lithiation, nucleophilic substitution and oxidation–elimination of the selenium resins. The advantages of the new method are good yields, high purity, straightforward operations and high diversity of the products, lack of odor, and good stability of the selenium resins. Copyright © 2014 John Wiley & Sons, Ltd.     

Macroporous polystyrene-supported palladium catalyst containing a bulky N-heterocyclic carbene ligand for Suzuki reaction of aryl chlorides

Macroporous polystyrene (MPS)-supported 1-mesitylimidazolium chloride resin was prepared by reacting macroporous chloromethyl polystyrene with 1-mesitylimidazole as a supported N-heterocyclic carbene (NHC) precursor for the immobilization of a palladium catalyst. This MPS-supported NHC precursor readily formed a stable complex with Pd(OAc)2, which effectively catalyzed the Suzuki reaction of aryl iodide and bromides at room temperature and even aryl chlorides at elevated temperatures (100 degrees C). This catalyst showed reusability in the Suzuki reaction of aryl bromide.     

Solution- and soluble-polymer supported asymmetric syntheses of six-membered ring prostanoids

An asymmetric synthesis of prostanoids containing a six-membered ring core structure (11a-homoprostaglandins), both in solution and using non-cross-linked polystyrene (NCPS) as a soluble support, was developed. Target molecule 1 was generated in a convergent fashion using a three-component coupling strategy, wherein chiral enone (R)-2 was the precursor of the central ring and the cuprate 3 and triflate 4 were used to introduce the side chains. The chiral center of (R)-2 directed the facial selectivity of the conjugate addition reaction which then dictated the stereochemical outcome of the subsequent alpha alkylation. Attachment of a six-membered ring scaffold to NCPS facilitated purification without compromising synthetic yields, still allowed 1H-NMR analysis of the intermediates in the synthesis, and provided an avenue for the construction of six-membered ring prostanoid libraries.     

Novel tocopheryl compounds. Part 15: One-pot formation of furotocopheryl derivatives

Reaction of tocopheryl bromide 2a or chromanyl bromide 2b with triphenyl phosphine produced phosphomium salt intermediates (3a-b), which further reacted with acyl chlorides to novel furotocopherol compounds 4-11 in good yields. The cyclization proceeded according to a two step esterification-Wittig mechanism. Similarly, furotocopheryl dimer 12 was prepared starting from oxalyl chloride. The coupling of tocopheryl phosphonium salt 3a onto modified polystyrene provided a new, vitamin E-loaded resin.     

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.     

A Practical,Water‐Soluble,Ionic Scavenger for the Solution‐Phase Syntheses of Amides

A new ionic, water‐soluble scavenger for acyl chlorides, 1‐(2‐aminoethyl)pyridinium bromide ( 1 ), has been investigated. Compound 1 was used for the rapid and simple purification of a series of benzamides and sulfonamides (Table) obtained by solution‐phase synthesis from the corresponding amines (Scheme). The inexpensive scavenger, which can be prepared on large scale, was shown to readily ‘eliminate’ excess acyl chlorides (reagent) by simple aqueous extraction. The amides purified in this way were obtained in excellent yields and purities (Table), which makes 1 a versatile new reagent, especially for the combinatorial solution‐phase synthesis of amide libraries.     

Efficient loading of primary alcohols onto a solid phase using a trityl bromide linker

The Letter describes an improved, rapid and mild strategy for the loading of primary alcohols onto a polystyrene trityl resin via a highly reactive trityl bromide linker. This protocol facilitates an efficient resin loading even of acid-sensitive or heat-labile alcohols, which otherwise require expensive or non-commercial resin types. Secondary alcohols were only attached in moderate to low yields, while attempts to load a tertiary alcohol expectedly failed. Importantly, selective attachment of diols via a primary alcohol group in the presence of more hindered alcohol groups proved possible. The effects of activation time and reagent excess as well as alcohol structure were investigated. This improved method provides a convenient access to O-linked resin-bound N-Fmoc-protected amino alcohols that may be employed in SPS of peptides with C-terminal alcohol functionalities. In the case of a sensitive alcohol containing an activated aziridine functionality, the use of the trityl bromide linker proved superior to a recently described silver triflate-assisted trityl chloride resin-based procedure.     

Synthesis and olefination of carbonyl compounds using solid-supported reagents

The development and application of three new solid-supported reagents for use in the synthesis or olefination of carbonyl compounds are described. The reagents include the Weinreb amide, Mukaiyama's S-2-pyridyl thioate and a Peterson methylenation reagent. As solid-supports p-benzyl alcohol resin, Wang resin and Merrifield resin (1-2% crosslinked polystyrene) have been used.     

A new method for the preparation of 2-chlorotrityl resin and its application to solid-phase peptide synthesis

2-Chlorotritylchloride (2-CTC) resin was prepared efficiently from 1% DVB-crosslinked polystyrene resin and 1-chloro-2-(dichloro(phenyl)methyl)benzene, which was easily obtained from 2-chlorobenzophenone. This 2-CTC resin showed excellent properties as a support for solid-phase peptide synthesis. Four peptide fragments were obtained in high purity using the resin.     

Solid-phase synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition

The solid-phase synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition of polymer-bound azides to various alkynes is reported. Polymer-bound azides were synthesized from polymer-bound halides and sodium azide and reacted with alkynes to produce polymer-bound 1,2,3-triazoles. Cleavage of the triazoles was performed with trifluoroacetic acid. A traceless synthesis of 1,2,3-triazoles was developed using 2-methoxy-substituted resin (polymer-bound 4-hydroxy-2-methoxybenzyl alcohol). In addition, a synthesis of 4-hydroxybenzyl-substituted 1,2,3-triazoles from the bromo-Wang resin (4-(bromomethyl)phenoxymethyl polystyrene) was achieved.     

聚苯乙烯我—1，2—亚乙基多胺树脂催化合成正丁基苯基醚

由氯甲基聚苯乙烯和多－1,2－亚乙基多胺反应合成了聚苯乙烯我－1,2－亚乙基多胺树脂,并通过质量变化,分析,交换量和红外光谱进行了表征,研究了利用该树脂催化合成正丁基苯基醚的反应,催化剂能够回收并重复使用,4次后其质量未损失,活性未下降。