Received: 27 July 2001 / Uploaded 7 August 2001

Recycling may be the key issue, besides from easy workup procedures, for the use of polymer-bound chiral auxiliaries. The employment of chiral auxiliaries in industrial drug discovery processes is limited, due to their price and availability. Reusable auxiliaries on solid support might overcome this drawback. Especially in the high-throughput approaches of compound libraries using solid-phase synthesis, the use of chiral linkers might have an additional impact. 

In 1979 Leznoff et al. (3) reported the synthesis of an immobilized alaninol-auxiliary and its application in the asymmetric a-alkylation of cyclohexanone (Scheme 1). The polymer-bound auxiliary 4, readily prepared by the attachment of N-phthalimide protected alaninol to Merrifield resin under basic conditions and subsequent deprotection, was converted with cyclohexane to its corresponding imine 5. After deprotonation with lithium diiso­propyl­amide (LDA), alkylation with iodo methane or propane at room temperature and acidic hydrolysis, the 2-alkylcyclohexanones 6 were obtained in good yields (80%) and good to excellent enantiomeric excesses (60 and 95%, respectively). The achieved enantiomeric excess of the products was as least as high as for the synthesis in solution. Again, the polymer-bound auxiliary 4 could be reused without any loss of enantioselectivity.

In 1981, the synthesis of a-alkylated esters using a polymer-bound Meyers oxazoline was demonstrated by the group of McManus (4). A chiral oxazoline, derived from hydroxy phenyl alaninol and attached to Merrifield resin, was alkylated with benzyl chloride to provide, after acid catalysed ethanolysis, a-alkylated propionic acid ester. Due to incomplete cleavage from the solid support the chemical yield was poor (43-48%). In addition, the optical purity of the product (ee = 56%) was much lower as reported for the same reaction in solution phase.

These early results clearly showed that asymmetric synthesis on solid support and recycling of the polymer-bound chiral auxiliary is possible. However, up to the early nineties of the last century, no further investigations in this field were done. From that time on, several immobilized auxiliaries, especially Evans oxazolidinones and proline-type auxiliaries, were developed and applied to different reactions.

Kurth and coworkers (5) reported the solid-phase synthesis of 3,5-di-substituted g-butyro­lactones by iodolactonisation of immobilized (S)?prolinol amides. In the first step, N-acylated (S)-prolinol was attached to Merrifield resin under basic conditions followed by deprotonation of the obtained resin 7 with LDA and subsequent addition of methyliodide to furnish polymer-bound C_a-methylated amide 8 (Scheme 2).

Formation of the g-butyro­lactone and cleavage from the solid support was achieved by stirring a THF/water mixture of resin 8 with iodine for three days. After separation of the resin bound (S)-prolinol 10 by filtration, g-butyrolactone (S,R)-9 was obtained in 33% overall yield as a 64:4:31:2 mixture of isomers, representing a 94:6 trans versus cis selectivity and an enantiomeric excess of ee = 35%. The authors were also able to demonstrate the recovery and recyclisation of the chiral auxiliary through the reaction sequence.

This methodology was extended by the development of a second-generation pseudo-C₂-symmetric pyrrolidine-based auxiliary 11 (Scheme 2) (6). Following the procedure described above, the (R)-configured auxiliary 11 furnished g-butyro­lactone (R,S)-9 in 34% overall yield as a single diastereomer with an enantiomeric excess of ee = 81%. In contrast to the (S)-prolinol derived auxiliary 10, the pseudo-C₂-symmetric auxiliary 11 offers an enhanced stereo­selectivity of both the C_a-alkylation step as well as for the iodolactonisation.

Several groups developed polymer-bound oxazolidinones for asymmetric acyl group-based chemistry, including aldol reactions, conjugate addition and enolate alkylations as well as Diels-Alder cyclo­additions. The first example of such an immobilized Evans auxiliary was published by Allin and Shuttleworth and applied in the synthesis of an a-alkylated carboxylic acid (7). Oxazolidinone 12, derived from (S)-serine, was treated with potassium hydride and the resulting alkoxide was attached to Merrifield resin, followed by removal of the BOC protecting group to furnish the polymer-bound auxiliary 13 (Scheme 3).

Treatment of polymer-bound oxazolidinone 13 with propionic anhydride under basic conditions and subsequent a-alkylation with LDA and benzyl bromide at 0°C gave rise to 14, from which a-benzylated propionic acid 15 was released by saponification with lithium hydroxide. The product was obtained in 42% overall yield and excellent enantioselectivity (ee = 96%). The recycling of the auxiliary was not demonstrated. It should be noted at this point, that subsequent work demonstrated some difficulties to reproduce these results (8).

At the same time, Burgess and Lim (9) examined the stereochemical outcome of the same alkylation with a similar oxazolidinone derived from (S)-tyrosine. For the immobilization of the auxiliary, N-acylated oxazolidinone 16 was coupled under Mitsunobu conditions to Wang and TentaGel resin or by nucleophilic substitution to Merrifield resin (Scheme 4).

After deprotonation with LDA and alkylation with benzyl bromide at 0°C, alcohol 18 was obtained by reductive cleavage from the solid support with lithium borohydride in different yields and enantiomeric excesses, depending on the nature of the solid support. While Merrifield resin, in contrast to the results published by Allin and Shuttleworth, showed poor stereoselectivity (ee up to 56%), the best results were obtained with the Wang resin (ee up to 90%). Poorer yields (12-39%) and enantio­selectivities (ee = 71-88%) were observed for the alkylation with benzyloxymethyl chloride (BOMCl) and aliphatic alkyl bromides.

The first asymmetric aldol reaction on a solid support was performed by Purandare and Natarajan (10). They used a tyrosine based oxazolidinone 19 immobilized on Wang resin, prepared by the protocol reported by Burgess et al., for the synthesis of a-substitutedb-hydroxy ester 22 (Scheme 5).

The polymer-bound auxiliary 19 was acylated with hydrocinnamoyl chloride and the following aldol reaction with isovaler­aldehyd was investigated under several conditions, i. e. changing of reaction temperature, number of equivalents of boron reagent and Hünig base. Under optimized reaction conditions, ester 22 was obtained along with hydrocinnamoyl ester 23, derived from unreacted starting material, in a 90 : 10 ratio by detachment from the polymeric support using sodium methoxide. HPLC and ¹H-NMR studies revealed that the product was predominantly a single syn diastereo­mer (20:1), but either enantiomeric excess nor chemical yield of the reaction sequence were given.

A high reproducibility of the aldol reaction in solution to the solid support in respect to stereoselectivity and chemical yield has been demonstrated by Poon and Abell (11). Oxazolidinone 24, immobilized on hydroxymethyl polystyrene resin, was acylated with propionyl chloride after deprotonation with n-butyl­lithium and enolised using n-dibutylboron triflate/triethylamine (Scheme 6). 

Subsequent aldol reaction at -78°C with benzaldehyde furnished a polymer-bound aldol adduct. After cleavage from the polymeric support with lithium hydroxide in THF, b-hydroxy acid 25 was obtained as a clean product (94% purity) in 63% overall yield and with excellent diastereo- and enantioselectivity (de, ee > 98%). The authors also investigated the conjugate addition of the propionated oxazolidinone 26 to acrylonitrile (Scheme 6). After enolisation with TiCl₃(Oi-Pr) and diisopropylamine, acrylonitrile was added and the resulting product cleaved from the solid support using lithium hydroxide in THF to furnish a-methylated 3-cyano butyric acid 27 in 52% overall yield, but with lower enantiomeric excess (ee = 78%) as observed for the aldol reaction. 

A different approach for the asymmetric aldol reaction on solid support was reported by Reggelin et al. (12). A polymer-bound aldehyde, obtained from the oxidation of Wang resin, was treated with the boron enolate of an acylated Evans oxazolidinone at -78°C. After treatment with trimethyl aluminium and N,O-dimethylhydroxylamine, the aldol adduct was cleaved from the solid support and isolated in 65% overall yield and with a syn to anti ratio of 87:13. The resulting polymer-bound Weinreb amide was then transformed into its corresponding aldehyde and reused in the aldol reaction. This methodology could be extended by the employment of a fluoride ion labile silyl linker on Merrifield resin ([i]) or a soluble polymeric support (14). By this improvements, the cyclic reestablishment of the aldehyde functionality allowed the iterative synthesis of di- and triketides in diastero- and enantiomerically pure form. 

Cycloadditions are one of the most versatile reactions in organic synthesis on solid support because of their ability to build up cyclic ring systems. Winkler and McCoull (15) described the application of the tyrosine-based oxazolidinone system 24 to the asymmetric Diels-Alder cyclo­addition. Oxazolidinone 24, prepared by attachment of N-BOC-(S)-tyrosine methyl ester to hydroxymethyl Merrifield resin under Mitsunobu conditions and subsequent formation of the oxazolidinone moiety, underwent acylation with in situ generated trans-crotonic anhydride to furnish resin 28 (Scheme 7). 

Diethyl aluminium chloride catalyzed Diels-Alder reaction of dienophile 28 and cyclopentadiene at low temperature gave the bicycle 29, which up­on exposure to lithium benzylate released Diels-Alder adduct 30 from the solid support in 26% overall yield. The 21:1 endo/exo ratio and the enantiomeric excess of ee = 86% compares favourably with the selectivities obtained from the solution phase reaction (>20:1 endo/exo ratio, ee = 88% ). 

Recently, another group reported the asymmetric 1,3-dipolar cycloaddition of resin 28 with mesitonitrile oxide and diphenylnitrone (16). After reductive cleavage of the cycloaddition aducts from the solid support, 4,5-dihydro isoxazoles and isoxazolidines were obtained in good chemical yields (up to 62%) and enantiomeric excesses (up to 89%). However, the long reaction times (up to 40 days) and the formation of regioisomers are a significant problem in this procedure. 

A combinatorial approach to a-substituted glycine amides via Ugi four-component condensation (4-CC) on a solid support was developed by Kunz et al. (17). The chiral O-pivaloyl protected galactosylamine auxiliary 31 was prepared by the attachment of a galactosylazide via a heptanedioic acid-based spacer to Wang resin, followed by reduction of the azide moiety to generate the amino functionality. This strategy allows, after cleavage of the ester linkage to the resin, the direct determination of the diastereomeric excesses of the released amino acid derivative 33 (Scheme 8). 

The stereoselective Ugi four-component condensation, performed with five equivalents of each aldehyde, isonitrile and formic acid under lewis acid conditions, led to the formation of polymer-bound glycine amides 32. Acidic detachment from the resin with trifluoracetic acid (TFA) in dichloro methane furnished amino acid derivatives 33 in 20-59% overall yield and diastereomeric excesses of de = 71-88%. After separation of the diastereomers by preparative HPLC and cleavage of the N-glycoside bond with hydrochloric acid in methanol, enantiomerically pure a-substituted glycine amides 34 were obtained. The generality of the method was demonstrated with a set of five different aldehydes and three isonitriles. The employment of hydroxymethyl polystyrene resin instead of Wang resin leads to a more acid stabile ester linkage, which allows the direct cleavage of the glycine amides 34 from the solid support under the conditions described above. 

The oxidative cleavage of polymer-bound sulfoximines to their corresponding sulfones was reported by Hachtel and Gais (18) (Scheme 9). 

Starting from sulfoximine 35, readily available from Merrifield resin and the potassium salt of (S)-S-methyl-S-phenylsulfoximine, deprotonation in a-position with n-butyllithium at -78°C in THF and subsequent hydroxyalkylation with benzaldehyde or propanal led to the formation of b-hydroxy sulfoximines 36. Oxidative cleavage with m-chloroperbenzoic acid proceeded smoothly to afford b-hydroxy sulfones 37 in 81 and 84% overall yield, respectively. As already expected from the results of the hydroxyalkylation of lithiosulfoximines in solution phase, the asymmetric inductions are low and sulfones 37 were obtained with ee values of 26 and 24%. 

Recently, Enders et al. (19) reported the development of two novel chiral hydrazine resins and their application in the asymmetric synthesis of a-branched primary amines. The enantiopure b-methoxy­amino auxiliaries, easily derived from amino acids trans-4-hydroxy-(S)-proline and (R)-leucine, were attached to Merrifield resin and transformed into their corresponding hydrazines 38 (SAMP-resin) and 39 (RAML-resin), representing immobilized analogues of the well-known SAMP and (R)-methoxyleucinol auxiliaries (Scheme 10). 

Immobilisation of various aldehydes, followed by nucleophilic 1,2-addition of aliphatic and aromatic organolithium reagents at -100°C in THF to the resulting hydrazones and subsequent reductive cleavage from the solid support with borane-tetrahydrofuran complex, furnished a series of a-branched primary amines in 50-70% purity after extraction procedures. Further purification was achieved by acylation of the amine moiety and chromatography of the resulting amides 40, which were isolated in 24-51% overall yield and with enantiomeric excesses of up to 86%. By choosing either the SAMP-resin 38 or the RAML-resin 39, the (R)- or (S)-amide 40 can be synthesized. In addition, this protocol shows great flexibility regarding aliphatic and aromatic substrates and allows the synthesis of the acylated a-branched amines from commercially available substrates.