mann elimination, upon treatment with Me2NH, to furnish vinyl sulfone resin 20 and release in solution the desired tertiary amine with general structure 19 in a 25% average yield for the six-step sequence. However, all of the final compounds had to be purified by reversed phase high-performance liquid chromatography (HPLC) owing to a minor 3-chlorobenzoic acid impurity. This problem can be circumvented by extended washing of the activated resin with 2 N HCl in tetrahy-drofuran (THF), presumably exchanging the anions of the ammonium salt for chloride. The advantage of the sulfide safety-catch resin is the decreased sensitivity of the alkylated product to b-elimination, which could be utilized to increase the yield or extend the scope of alkylating agents to less activated systems. However, oxidation of the sulfide resin prior to amine synthesis would be necessary for more oxidation-sensitive systems. Via a Hydroxylamine Resin

A Hofmann-type elimination has also been utilized independently by both Grigg (Scheme 10.5, route a) and Andersson (Scheme 10.5, route b) in the synthesis of tertiary methylamines using an extremely robust and versatile traceless linker [12]. Polystyrene resin (21) with a hydroxylamine linker attached can be converted to resin-bound tertiary hydroxylamine 22. Quaternization of 22 with MeOTf resulted in the alkoxyammonium intermediate 23, which upon treatment with NEt3 in CH2Cl2 furnished the resin-bound aldehyde 25 and released into solution the tertiary methylamine with the general structure 24. An alternative route involving the exposure of 23 to much milder reagents such as lithium iodide (in dioxane or ace-

Me m

21 22 23 24 25

a: 1) BOC anhydride, DIEA, THF; 2) NaH/DMF then F^Br; 3) 20% TFA/CH2CI2; 4) R2CHO/NaBH(OAc)3,THF. b: 1) R,CHO, AcOH, MeOH; 2) BH3.Py, HCI/Dioxane; 3) R2CHO, PPTS, BH3.Py, MeOH-THF.

Scheme 10.5. Hofmann elimination on a hydroxylamine resin.

tonitrile) or samarium iodide (in THF) also resulted in highly efficient cleavage delivering tertiary methylamines of high purity in good overall yields.

The quaternization works only with methyl triflate as the alkylating reagent, thus limiting the diversity of the produced library. Although other triflates prepared in situ via AgOTf/alkyl halide exchange gave the corresponding quaternary salts in solution, this approach is unsuitable for the solid-phase sequence because of interference of reaction kinetics from the silver halide precipitate. Both routes are amenable to solution-phase parallel synthesis by careful selection of reaction conditions and work-up methods starting from O-benzylhydroxylamine. Although this hydroxylamine resin (22) is more stable than the ester REM resin (2) toward a variety of nucleophilic reagents, it limits a library design to tertiary methylamines. Furthermore, this resin cannot be recycled once it is used - an advantage of the REM resins. Alternative Cleavage Techniques

A major challenge associated with the cleavage of amines from resins is the removal of any excess cleavage reagents and byproducts from the reaction mixture. The process generally requires extraction or chromatography, which could render the synthesis of large libraries cumbersome. The pursuit of other cleavage strategies that would allow for the direct isolation of pure compounds has become necessary. Murphy and coworkers introduced a novel two-resin system in which the resin-bound quaternary ammonium compounds were treated with an excess of a second resin-bound amine such as the weakly basic ion-exchange resin Amber-lite IRA-95 in dimethylformamide (DMF) and a catalytic amount of Et3N (Scheme 10.6) [13]. Under these conditions, highly pure products were recovered with good yields after filtration and evaporation of the solvent.



Scheme 10.6. Proposed mechanism for the two-resin system-promoted Hofmann elimination.

Similar results were obtained by treating the resin-bound quaternary ammonium compounds with Amberlite weakly basic ion-exchange resin in DMF in the absence of any additional base. The basic resin is sufficient to achieve cleavage and avoid the need for an aqueous work-up. These surprising two-resin results may be explained by a thermal elimination of the amine from the resin as the HBr salt.

The basic resin then desalts the amine to catalyze the ¿-elimination. Alternatively, it may also be due to trace amounts of base, present either from previous steps or from trace dimethylamine in the DMF. It was found that yield was a function of reaction time with an optimal length of 18 h for a 14-member library production. Identical results generating highly pure products were obtained using a depro-tected Rink amide resin, albeit at lower yield [13].

A novel Wang resin-bound piperazine base (26) that resembles Murphy's two-resin system was introduced by Yamamoto et al. (Scheme 10.7) [14]. It was used successfully (2 equiv., loading 1.62 mmol g-1), in the absence of any other external base, to cleave N-aryl-N'-benzylpiperazines from the resin by treating the quaternary ammonium compounds with resin 26 in CH2Cl2 for 16 h at room temperature. However, the caveat of this reagent and the ion-exchange resin is that they complicate the reusability of the REM resin since at the end of the sequence both resins are mixed together.

Scheme 10.7. Polymer-supported bases used in Hofmann elimination.

A soluble noncrosslinked polystyrene-bound basic reagent (NCPS-NEt2) (27) has been developed recently by Janda and coworkers (Scheme 10.7) [15]. Use of base 27 (3 equiv., loading 0.85 mmol g-1) in CH2Cl2 eliminates the need for purification and allows the direct isolation of a library of pure tertiary amines through simple filtration and concentration operations. The advantage of this method over the ion-exchange resin and the polymer-supported base methods is that it allows for the recycling of the REM resin by taking advantage of the insolubility of cleavage reagent 27 in methanol. Once the cleavage is complete, filtration of the reaction mixture separates the REM resin from the tertiary amine and the soluble reagent 27. Concentration of the filtrate followed by trituration with cold MeOH results in precipitation of 27. Filtration of the resulting slurry effectively separates the noncrosslinked polystyrene reagent and evaporation of the filtrate leaves behind the tertiary amine in good yields and high purity. However, a large amount of MeOH might be required to triturate the soluble reagent 27, which could render the synthesis of large libraries cumbersome.

Alternatively, Brown has reported a vapor-phase elimination approach as a rapid method for the cleavage of tertiary amines from REM resins 2 and 12 in Irori

MacroKans™ [16]. The MacroKans™ were placed in a glass peptide vessel, which was then sealed under a slight positive pressure of ammonia gas. Products were isolated cleanly in good yields after evaporation, resin sorting, and washing with CH3CN or dimethylsulfoxide (DMSO). This is a particularly suitable method of parallel processing for the synthesis of large libraries, thus minimizing or eliminating the impurities due to the cleavage reagent.

b-Elimination on Selenyl Resins

The oxidation of selenides to selenoxides and their thermal elimination to alkenes has been studied extensively and has found numerous applications in synthesis [17]. The chemistry was first adapted to solid phase in 1976 when Heitz and co-workers prepared a polymer-supported selenide and oxidatively eliminated it to release an a, b-unsaturated ketone [18]. However, its application in solid-phase synthesis as a cleavage method was realized with the advent of the polymer-bound selenium reagents used in cyclization reactions to construct resin-bound carbo-cyclic scaffolds [19]. Recently, Nicolaou et al. utilized it in a strategy to generate a 10,000-compound benzopyran library by a solid-phase split-and-pool technique using Irori's NanoKan™ technology [20].

This novel strategy involves immobilization of an o-prenylated phenol (28) through cycloloading with a polystyrene-based selenyl bromide resin [21] to give resin-bound benzopyran scaffold 29 via a precedented 6-endo-trig cyclization (Scheme 10.8) [22]. Further elaboration of 29 to 30 and subsequent cleavage from solid support via oxidation and spontaneous syn-elimination of the selenoxide tether provides benzopyran 31. This is an example of a traceless release from solid support where functionality is generated at the released molecule instead of any linker residue being incorporated at the cleavage site.

Rs 31

Rs 31

Scheme 10.8. Release of benzopyrans via a resin-bound selenoxide elimination.

Indeed, the newly formed double bond can serve as a starting point for the generation of secondary libraries or more focused libraries, thus introducing additional elements of diversity. For example, epoxidation of the released benzopyran 31 followed by ring opening of the intermediate epoxide 32 with a variety of nu-cleophiles provides access to a new series of benzopyran derivatives with the general structure 33. Additionally, benzopyrans with the general structure 34 can result from further elaboration of the secondary hydroxyl group of 33 with a series of electrophiles [20c]. Taking into consideration the current advances in asymmetric epoxidation of olefinic substrates, this sequence could provide entry to chiral benzopyran libraries starting from chiral benzopyran epoxides [23].

The loading to the selenium solid support is compatible with a great variety of prenylated phenols except for substrates with electron-withdrawing groups adjacent to the prenyl group or adjacent to the phenol hydroxyl group participating in the cyclization step. Therefore, these scaffolds have to be loaded with the electron-withdrawing groups masked. The elimination of the selenoxide resin tether proceeds smoothly at room temperature and seems to be independent of the substitution pattern of the benzopyran scaffold.

A similar resin-bound selenoxide elimination on 2-seleno carbohydrates (35) was utilized by Nicolaou et al. in the synthesis of a small library of carbohydrate orthoesters representing novel regions of the potent antibiotic everninomicin (Scheme 10.9) [24]. Oxidation of glycoside 35 with meta-chloroperbenzoic acid (m-CPBA) gave the corresponding resin-bound selenoxide, which underwent a thermal syn-elimination. This thermal selenoxide elimination to the intermediate ke-tene acetal 36 introduces the desired functionality for the formation of orthoesters 37 and 38 and can release the desired products in a traceless manner from solid support. Orthoester 37 is formed from glycoside 35a and 2,3-allyl orthoester 38 is formed from deprotected glycoside 35b. However, unlike the solution-phase selenoxides, it was observed that the resin-bound selenoxide was more prone to eliminate at room temperature and therefore necessitated the use of lower temperatures in the oxidation step. Thus, treatment of selenide 35 with m-CPBA in CH2Cl2 at —78 °C, followed by rapid filtration and transfer to a sealed tube, was found to give the best results. Although the chemistry has been developed in both solution- and solid-phase chemistry, it is well suited to the solid-phase synthesis of novel semi-synthetic everninomicins and other carbohydrate libraries.

Scheme 10.9. Carbohydrate orthoesters via a resin-bound selenoxide elimination.

288 | 10 Elimination Chemistry in the Solution- and Solid-phase Synthesis of Combinatorial Libraries 10.2.3

/-Elimination on Sulfone Resins

Sulfone elimination has the potential to be a preferred strategy for solid-phase compound cleavage. While no linker and cleavage strategy can be stable to the full range of conditions available to the synthetic chemist, the oxidative activation-elimination strategy promises to increase substantially the variety of options. Schwyzer et al. first described a 2-(4-carboxyphenylsulfonyl)ethanol linker for the synthesis of peptides and oligonucleotides [25]. However, the application and utility of a sulfone-type linker in peptide synthesis was demonstrated in 1992 by Katti et al. with the introduction of a new and readily available linker in the solidphase synthesis of C-terminal peptides (Scheme 10.10) [26]. For example, Leu-enkephalin (40) was released from resin 39 in 54% or 60% overall yields, using either Boc or Fmoc chemistries respectively, after cleavage from the solid support with dioxane/MeOH/4 N NaOH followed by re-acidification.

H f^if^ HO-Leu-Phe-Gly-Gly-Tyr-Boc


Scheme 10.10. Release of C-terminal peptides via a b-elimination from a sulfone resin.

Apart from being used successfully in the area of peptide chemistry, sulfone linkers have gained favor in the solid-phase synthesis of small molecules. For example, 4-aminobenzenesulfonamides with the general structure 44 were prepared from 2-mercaptoethanol resin 42 (Scheme 10.11) [27]. Resin 42 was converted to sulfone 43, which underwent a facile b-elimination to release the desired

44 45

a) 4-(chlorosulfonyl)phenylisocyanate, dibutyltinlaurate; b) RNH2, pyridine; c) mCPBA, CH2CI2; d) 10 % NH4OH in CF3CH2OH.

44 45

a) 4-(chlorosulfonyl)phenylisocyanate, dibutyltinlaurate; b) RNH2, pyridine; c) mCPBA, CH2CI2; d) 10 % NH4OH in CF3CH2OH.

Scheme 10.11. Release of arylsulfonamides via a b-elimination from a sulfone resin.

4-aminobenzenesulfonamides, in good yields and purities, upon treatment with aqueous NH4OH.

A small library of seven dehydroalanine derivatives has been prepared by a b-elimination of a sulfinate resin (Scheme 10.12). Anchoring of cysteine onto Merri-field resin through the side-chain thiol group gave a resin-bound sulfide (46). Modification of both C- and N-termini and oxidation of the sulfide with m-CPBA followed by a b-elimination of the sulfinate resin 48 furnished the dehydroalanine derivatives 47 in 31-86% yields with high purities after aqueous work-up [28].

h2n co2h 46

modification h2n co2h 46

1) mCPBA, CH2CI2

2) DBU, CH2CI2

R2: OMe, OBn, NHBn Scheme 10.12. Dehydroalanine derivatives via a sulfone elimination.

Elimination of a sulfinate resin has also been utilized in heterocyclization chemistry for the synthesis of a few 2-substituted-4-piperidone derivatives (50) from resin-bound sulfone 49, which serves as a divinyl ketone synthon (Scheme 10.13). The amine reagent can act both as a nucleophile and as a base, thus promoting a Michael addition to resin 49 and inducing elimination of the sulfinate resin followed by a second Michael addition to the newly formed enone [29].

Scheme 10.13. 2-Substituted-4-piperidones via a sulfone elimination.

b-Elimination on Silyl Resins b-Elimination was utilized in the cleavage of several silyl amide linkers (SAL) and trimethylsilylethyl ester linkers for the facile release of peptide fragments from the solid support (Scheme 10.14). Stabilization of a carbocation by a b-trialkylsilyl group, as shown in intermediate 52, seems to facilitate the release of C-terminal mct^ i

0 SiMe3 51

90% TFA Scavenger



CF3C02" Me3si

Scheme 10.14. Release of peptides via a b-silyl elimination on silyl amide linkers.

amides (53) from silyl resin 51 [30]. b-Elimination of the trialkylsilyl group neutralizes the transient carbocation to give a stable styrene derivative (54). These silyl amide linkers gave improved yields of C-terminal tryptophan amides over conventional linkers since an irreversible alkylation of the tryptophan indole nucleus by such carbocations is suppressed. However, acid scavengers (1,2-ethanedithiol/ phenol/thioanisole, 5:3:2) were needed as the styrene moiety is sensitive to protonation. Therefore, purification of the final product is required in order to remove the scavenger byproducts.

Similarly, linker 55 was designed to be cleaved by a b-elimination mechanism based on the 2-(trimethylsilyl)ethylester protecting group (Scheme 10.15) [31]. Fluoridolysis or dilute acid cleavage enabled the preparation of protected peptide fragments such as 56. C-Terminal tryptophans or prolines could be successfully anchored with this linker and no undesired alkylation or diketopiperazine formation was observed upon cleavage.

0 SiMe3




Scheme 10.15. Release of peptides via b-silyl elimination on 2-(trimethylsilyl)ethyl ester linkers.

A b-elimination mechanism is also involved in the release of olefins 60 from resin-bound allyl silanes such as 59, the product of a solid-phase cross-olefin metathesis between allylsilane 58 and an olefin (Scheme 10.16) [32].



Scheme 10.16. Release of olefins from an allyl silane resin via a b-silyl elimination.

b-Elimination on Fluorenyl Resins b-Elimination was also implemented in the cleavage of several fluorene-based linkers for the facile release of peptide fragments from solid support (Scheme 10.17) [33]. Quantitative cleavage of the Merrifield peptide 62 and peptide 63, which corresponds to the sequence 31-38 of uteroglobin, was achieved from the fluorene resin 61 in good yields and high purities with 20% morpholine in DMF or 10% piperidine in DMF. Resin 61 proved to be superior to other fluorene-derived resins where incomplete removal of the protected peptide from the resin has been described [33b]. Also, slight lability to N,N-diisopropylethylamine, which was used at the neutralization step after Boc deprotection in peptide synthesis, and basic amino groups of the growing peptide has been detected occasionally in other fluorene-derived resins [33c]. The fluorene nucleus in resin 61 has been conveniently substituted with an electron-donating N-amide group to fine-tune its base lability in order to prevent any premature cleavage of the growing peptide chain.

20% Morpholine RC02H

DMF 62 R = Boc-Leu-Ala-Gly-Val

63 R = Boc-Asp(OcHx)-Asp(OcHx)-Thr(Bzl)-Met-Lys(CIZ)-Asp(OcHx)-Ala-Gly

Scheme 10.17. Release of C-terminal peptides via a b-elimination from a fluorenyl resin.

b-Elimination on 2-(2-Nitrophenyl)ethyl Resins b-Elimination was also utilized with 2-(2-nitrophenyl)ethyl (NPE) linkers. Release of 3'-hydroxy-and 3'-phosphateoligonucleotides 66 and 67 from CPG (controlled pore glass) support was achieved through carbonate and phosphate linkers 64 and 65 respectively (Scheme 10.18) [34]. The conditions used were either 0.5 M 1,8-diazabicyclo[5.4.0]undecene-7 (DBU) in dioxane, pyridine for 1 h, and ammonia for 5 h at 55 °C or 20% piperidine in DMF for 3 h. The linkage was found to be resistant to 40% Et3N in pyridine for 16 h, conditions commonly used to remove the 2-cyanoethylphosphate protecting group. An important application of 2-(2-nitrophenyl)ethyl linkages is that these supports can be used together with p-

nitrophenylethyl-protected nucleoside 2-cyanoethylphosphoramidites for the preparation of oligonucleotides without using ammonia during the final deblocking, because all protecting groups will be cleaved by DBU. This strategy will be of interest for the preparation of oligonucleotides containing ammonia-sensitive compounds such as base analogs, fluorescent compounds, and so on.

0.5 DBU



Scheme 10.18. Release of oligonucleotides via a b-elimination.

Radical-based b-Eliminations b-C,O Bond Scission

Peukert and Giese devised the original photolabile linker (68) based on the radical-induced b-C,O bond scission of a 2-pivaloylglycerol group for the release of immobilized acids (Scheme 10.19) [35]. Upon irradiation, an a-hydroxyalkyl radical intermediate (69) is generated via a Norrish type I reaction with release of carbon monoxide and a t-butylradical that leads to isobutene. Elimination then takes place where the glycerol radical is converted into an enolate radical (70) and a carboxylic acid (71) is released. The reaction is not solvent dependent but selection of the irradiation wavelength is crucial. The pivaloyl linker 68 was found to cleave aromatic

HOvX Hi cOtNbu O^A

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