Solid-Phase Synthesis and Combinatorial Technologies

8.4.2 Supported Reagents

The use of solid-supported materials in organic chemistry became significant with the pioneering work of Fetizon and Golfier in 1968 (137), and this field has been extensively reviewed (135, 138–140). The advent of combinatorial technologies and the renewed interest in solution-phase chemistry for library synthesis have also recently produced a renaissance of interest in supported reagents for application in a wider variety of modern synthetic reactions; potential advantages of supported reagents in terms of reduced pollution and cleaner, more efficient reaction routes have also been recently reviewed (141). A PS-supported distannane as a reagent for radical cyclizations has been developed by Junggebauer and Neumann (142). The well-known perruthenate oxidant for the conversion of alcohols to carbonyl compounds has been transferred to a polymer support by Hinzen and Ley (143). PS-supported HOBt has been used for ester formation and for the protection of amines as carbamates (144). Trifluoromethylaryl ketones supported on Tentagel have been used as in situ sources of polymer-bound dioxiranes for oxidations (145). The applications of PS-bound iodoso diacetate as a reusable iodination and oxidation agent (146) have been expanded. Nicolaou et al. (147) have demonstrated the use of PS–selenium resins able to perform many of the Se-promoted organic transformations common in synthesis. Sylvain et al. (148) have reported the preparation of PS-supported nitroacetate as an intermediate for novel chemical reactions. A PS-supported silyl triflate was reported by Hu and Porco to be capable of supporting enolizable allyl esters as silyl ketene acetals (149). A PS-supported cyclopentadienyl (Cp) phosphazine was prepared by Minutolo and Katzenellenbogen (150) and used as a stable, safe reagent to prepare Cp–tricarbonyl rhenium complexes. PS-supported chiral lithium amides were shown by Majewski et al. (151) to be as efficient as their soluble counterparts in the enantioselective deprotonation of ketones followed by aldol additions. PS-bound electrophilic di(acyloxy)halogenates and diazidohalogenates were prepared by Kirsching et al. and used to 1,2-functionalize glycals (152). Supported Horner-Emmons reagents on a high loading polymer resulting from ring-opening methatesis polymerization (ROMPGEL) were shown to be extremely effective by Barrett et al. (153).

These and many other reported supported reagents are applicable to combinatorial synthetic protocols in solution, and some examples have recently appeared in the literature. For example, Amberlite ion-exchange resin has been used for the construction of an array of aryl/heteroaryl ethers from phenols and alkyl bromides in solution (154) to cyclize and to purify solution arrays of hydroxy quinolinones (155) and to cyclize arrays of oxazoles from aromatic aldehydes and an isocyanide (156). PS-sup- ported HOBt has been employed to to build amide arrays (157, 158). Another array of aryl ethers was prepared from a number of phenols and halides using a PS-supported bicyclic guanidine as a strong base (159). Poly(4-vinylpyridine) was used by Chen (160) to promote the coupling of acyl and sulfonyl chlorides with N-nucleophiles in the synthesis of amide arrays of cathepsin D inhibitors. Polystyrene-bound carbodiimide EDC has been used for the preparation of benzoxazines from anthranilates and isocyanates (161), and the same supported reagent was also employed in the synthesis of an array of acylsulfonamides from benzoic acid and sulfonamides (162). Ley’s

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polymer-supported perruthenate together with a supported Mukayama reagent (163) was successfully employed in the synthesis of a number of pyrazoles from benzyl alcohols and enol ethers; together with a polymer-bound Wittig reagent (164) in the synthesis of an array of β-aminoalcohols from benzyl alcohols and amines; and together with supported borohydride in the synthesis of several alkaloids (165, 166). Ley reported also the use of polymer-supported (diacetoxyiodo) benzene (PSDIB) as a reusable oxidation reagent (167) for solution-phase library synthesis, and the use of supported pyridinium bromide perbromide (PS-PBP) together with supported acids and bases to provide arrys of substituted benzofurans (168), of benzodioxanes and thiazoles (169). An array of aryl ethers was made using PS-supported triphenyl phosphine in a Mitsunobu reaction (170). Arrays of cyanohydrins and highly functionalized amines from PS-supported trimethyl silyl cyanide (171) and PS-supported benzotriazoles (172), respectively, have also been described. Habermann et al. (173) have used supported DMAP, cyanoborohydride, pyridinium bromide perbromide, and various supported scavengers (see Section 8.4.6) in a complex, six-step synthesis to prepare a piperidine–thiomorpholine library without any purification step.

A somewhat neglected property of supported reagents is their mutual isolation in heterogeneous reactions, which allows multistep one-pot reaction schemes to be performed on a substrate in solution by simultaneously adding several supported reagents, which in turn react sequentially with only one of the intermediates. Rebek (174) was the first to validate this hypothesis, and subsequently Parlow (175) reported the three-step synthesis of the pyrazole array depicted in Fig. 8.26. In this example, benzylic alcohol 8.44 in solution was treated with three supported reagents. In the first step (a1), it was oxidized to ketone 8.45 by poly(4-vinylpyridinium dichromate), which was then α-brominated to 8.46 with Amberlyst A-26-supported perbromide (step a2). Finally, the bromine of 8.46 was displaced by 4-chloro-1-methyl-5-trifluoromethyl Amberlite IRA-900 (step a3, Fig. 8.26) to give pyrazole 8.47 in a satisfactory 48% overall yield and good purity after filtration of the resins and evaporation of the solvent. The concept of multiple-support isolation could be exploited in combinatorial chemistry because of its attractive features, and efforts to find suitable multistep, diverse transformations coupled with several supported reagents will surely appear in the literature.

a: cyclohexane, 65°C, supported poly(4-vinylpyridinium dichromate) (oxidation a1); supported perbromide on Amberlyst A-26 (bromination a2); supported pyrazole on Amberlite IRA-900 (alkylation a3).

Figure 8.26 Solid-phase site isolation: one-pot, multiple transformation of the benzylic alcohol 8.44 to the pyrazole 8.47.

8.4.3 An Example: Synthesis and Purification of an Amine Library

Ley et al. (176) have recently reported the synthesis of a 96-member library L10 of secondary amines (Fig. 8.27) and the assessment for its further N-functionalization via the seven-member sulfonamide array L11 (Fig. 8.28). The synthetic scheme used employed the sets of benzylic alcohols (M1, 12 representatives, Fig. 8.27), amines (M2, 8 representatives, Fig. 8.27), and arylsulfonyl chlorides (M3, 7 representatives, Fig. 8.26) as monomers and is reported in Figs. 8.27 and 8.28. The authors aimed to fully automate this chemistry using an SP synthesizer and to avoid any purification step apart from filtering off the supported reagents and washing. The commercially available supported reagent 8.50 and the easily prepared reagents 8.48 and 8.49 were selected (Figs. 8.27 and 8.28).

Stock solutions of 12 monomers M1 in dry toluene (0.052 M) were prepared, and 5 mL (0.26 mmol) of each were distributed by the robotic dispenser into 12 reactors. Supported 8.48 (200 mg, 0.26 mmol) was added, the reaction was stirred at 80 °C for 2 h, and after a typical SP work-up/purification protocol, each of the 12 collected organic phases containing the aldehydes was divided into eight portions. Each portion (theoretically 32 mol) was dispensed by the robotic arm into a 96-well reaction block containing the supported reagent 8.49 (35 mg, 35 mol). Stock solutions of eight monomers M2 in methanol were prepared and aliquoted into the reaction block (32mol into each well) to obtain all of the possible combinations of final products, and the block was agitated at rt for 72 h. After the work-up/purification protocol, the organic solutions were recovered in a 96-well plate and evaporated in a centrifuge to afford the array L10. The analytical characterization by HPLC-MS confirmed 9 compounds with <30% purity, 28 compounds with 30–60% purity, and 59 compounds with >60% purity. Only two electron-rich monomers, M1,8 and M2,6 (Fig. 8.29), gave moderate yields of final amines, while the average quality of the library made by the unoptimized synthetic protocol was good. The two-step, polymer-assisted library

M1 : benzyl, heterobenzyl alcohols (12)

M2 : primary, secondary alkyl amines (8)

Figure 8.27 Synthesis and purification of the solution-phase, discrete amine libraryL10 using polymer-supported reagents 8.48 and 8.49.

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O S

O R3

L11

7 discretes sulfonamide library

Figure 8.28 Synthesis and purification of the solution-phase, discrete sulfonamide libraryL11 using the polymer-supported reagent 8.50.

synthesis in solution was easily automated, and an expansion of the library size was proposed by the authors.

The same chemical route was further exploited by dispensing monomer set M3 (0.4 mmol) into seven reactors and treating it with PS-supported 8.50 (0.4 mmol) to give in situ polymer-bound sulfonylpyridinium chlorides 8.51. After stirring at rt for 30 min, stock solutions of dibenzylamine (theoretically 0.25 mmol), prepared as in L10 from benzyl alcohol and benzylamine with >90% yield and purity, were added and stirred at rt (TLC monitoring) for 30–60 min (Fig. 8.28). After the usual work-up and purification, reasonably pure sulfonamides L11 (>90%, HPLC-MS and NMR) were recovered.

8.4.4 Supported Catalysts and Ligands

The use of solid-supported catalysts or ligands in organic synthesis is also widespread on both a laboratory and an industrial scale, and these species have been extensively reviewed (135, 177, 178). The preparation of cheap, reusable solid-supported catalysts with high turnover numbers and similar catalytic properties to their homogeneous counterparts has proved to be a challenging goal, because supported catalysts often exhibit less effective catalytic properties. The reduced accessibility to inner catalytical sites in a support, the vicinity of catalytic sites in high-loading supports, and the disruption of symmetry in the catalyst by introduction of a bond with the solid support have all been advocated as possible explanations of the lower reactivities and/or specificities often encountered with these species. However, the advantages of recoverable, stable, solid-phase catalysts have stimulated research despite the drawbacks mentioned above, and some significant contributions have been reported over the last

Figure 8.29 Synthesis and purification of the solution-phase, discrete amine libraryL10 using polymer-supported reagents 8.48 and 8.49: structure of the monomer sets M1–M2.

few years. Ion-exchange resin-supported lanthanides have been shown by Yu et al. (179) to be effective catalysts for a wide variety of reactions. Seebach and co-workers (180, 181) has reported a polymer-bound TADDOL (α,α,α′,α′-tetraaryl-1,3-dioxo- lane-4,5-dimethanol) prepared from dendritic building blocks that compared favorably in reactivity with soluble TADDOLs in the stereoselective addition of diethylzinc to benzaldehyde. A second C2-symmetric catalyst has also been described for the same reaction (182), and Sung et al. (183) have studied the influence of various supports on the efficiency in asymmetric catalysis for supported ephedrine and camphor derivatives in the same reaction. A ROMPGEL-supported catalyst (184) for the same reaction had similar performances with its soluble counterpart in terms of efficiency and enantioselectivity. Silica-supported phenolates have been found to be efficient catalysts for Michael reactions (185). Nagayama (186) have reported a safer and cleaner PS-mi- croencapsulated version of osmium tetraoxide. Kobayashi has reviewed the use of supported rare earth catalysis in organic synthesis (187). A copolymer between

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N-phenylmaleimide and an organotin chloride was reported by Chemin et al. (188) as a suitable supported source of tin hydride catalyst with reduced tin leaking. Uozumi et al. (189), Uozumi and Watanabe (190), and Zhang and Allen (191) have supported respectively onto Tentagel, Argogel and Deloxan THP II resins several palladium catalysts that performed successfully in C–C coupling reactions; a PS-supported chiral π-allylPd catalyst for the allylation of amines with a high stability and a high turnover has also been reported recently (192). A PS-supported, recyclable ruthenium Grubbs catalyst was reported by Ahmed et al. (193) as being better than its soluble counterpart in terms of stability and lack of Ru contamination for reaction products. A PS-sup- ported piperidine was reported as an efficient catalyst for the Knoevenagel condensation by Simpson et al. (194), with significantly reduced contamination, compatibility and side reaction problems when compared with free piperidine. Two silica-supported copper (I) complexes of imines were reported by Clark et al. (195) as smooth and effective catalysts for radical atom-transfer polymerization reactions with a variety of substrates. A comprehensive study on supported Al-based catalysts for the Diels–Alder reaction was reported by Altava et al. (196), which explored several supports and drew interesting conclusions regarding efficiency and stereoselectivity as related to the polymeric matrix. None of these examples have been applied to combinatorial library synthesis so far; two examples of successful combinatorial applications of polymersupported catalysts are reported below.

Kobayashi and Nagayama has described a supported scandium reagent 8.52 (Fig. 8.30) as an effective catalyst for the preparation of a quinoline library L12 in solution (Fig. 8.28, top) (197) and also for three-component reactions involving aldehydes, amines, and silyl nucleophiles (198) in the preparation of two small arrays of β-amino ketones and esters (L13, Fig. 8.30, bottom) or nitriles (L14, Fig. 8.30, bottom). The supported catalyst showed a high efficiency and turnover number and provided the products with good yields and purities.

Another recent example by Peukert and Jacobsen (199) took advantage of the first polymer supported Jacobsen’s catalyst 8.53 (Fig. 8.31) comparable with the soluble catalyst in asymmetric epoxidation and its full characterization (200, 201). The supported catalyst, prepared from the activated carbonate of hydroxymethyl PS and from a soluble phenolic catalyst (201), was used to catalyze the opening of racemic alkyl epoxides (M1, Fig. 8.31) with substituted phenols and yielded the 50-member aryloxy alcohol library L15 with good enantiomeric purity (average >90%, never below 80% e.e.). 8.53 was also used to produce the chiral intermediate monomer set M3 (Fig. 8.31) which was used to make two 50-member chiral libraries L16 (1,4-diary- loxy 2-propanols) and L17 (3-aryloxy-2-hydroxy propanamines) with excellent enantiomeric excess following the straightforward synthetic schemes reported in Fig. 8.31.

8.4.5 Supported Scavengers

In 1996, Kaldor et al. (202) introduced a new application for functionalized resins in solution-phase library synthesis. In this method, the SP was used as a chemoselective reagent toward the excess of reagent in solution (needed to drive the reaction to completion) which was scavenged by the support and gave clean product in solution

Figure 8.30 Synthesis and purification of the solution-phase, discrete librariesL12–L14 using polymer-supported catalyst 8.52.

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Figure 8.31 Synthesis and purification of the solution-phase discrete librariesL15–L17 using the polymer supported catalyst 8.53.

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Figure 8.33 Solid-supported scavengers: tagging reagents 8.54–8.57 and supported, covalent scavengers 8.58–8.63.

bottom) are reported along with classes of molecules that they scavenge. The limitations of the method usually depend on the absence of the scavenged chemical and similarly reactive groups in the product. However, even mixtures of compounds with similar reactivity have been successfully purified using carefully selected scavenging conditions; for example, the reaction of supported 8.62 with an excess of amine in solution did not affect the hydroxyl-containing reaction product 8.64 (Fig. 8.34) (202), which was recovered pure.

A recent approach involving in situ tagging of excess reagents or by-products that would otherwise be difficult to scavenge (Fig. 8.32, path E) has been developed. In this method the reagent C is tagged with a so-called sequestration-enabling reagent X to give CX, which is scavenged by a supported reagent that interacts both with CX and with the excess of X itself, leaving product P in solution. Examples of such reagents are provided in Fig. 8.35. The diamine 8.65 and the amino phenol 8.66 were both used to tag isocyanates, and the tagged molecules were removed with acidic and basic supports, respectively (212). The acidic thiourea 8.67 was used as a tag for α-bromoketones, which were removed by basic supports. Similarly, the sulfonylisocyanate 8.68 (213) and the anhydride 8.69 (223) were used to tag anilines, alcohols,