Amide chiral resins

The resolution of racemic ethyl 2-chloropropionate with aliphatic and aromatic amines using Candida cylindracea lipase (CCL) [28] was one of the first examples that showed the possibilities of this kind of processes for the resolution of racemic esters or the preparation of chiral amides in benign conditions. Normally, in these enzymatic aminolysis reactions the enzyme is selective toward the (S)-isomer of the ester. Recently, the resolution ofthis ester has been carried out through a dynamic kinetic resolution (DKR) via aminolysis catalyzed by encapsulated CCL in the presence of triphenylphosphonium chloride immobilized on Merrifield resin (Scheme 7.13). This process has allowed the preparation of (S)-amides with high isolated yields and good enantiomeric excesses [29]. 

Piperazine-2,5-diones can be symmetric or asymmetric. Symmetric DKPs are readily obtained by heating amino acid esters,1179-181 whereas asymmetric DKPs are obtained directly from the related dipeptides under basic or, more properly, acid catalysis, or by cyclocondensation of dipeptide esters.1182-185 As an alternative procedure hexafluoroacetone can be used to protect/activate the amino acid for the synthesis of symmetric DKPs or of the second amino acid residue for synthesis of the dipeptide ester and subsequent direct cyclocondensation to DKPs.1186 The use of active esters for the cyclocondensation is less appropriate since it may lead to epimerization when a chiral amino acid is involved as the carboxy component in the cyclization reaction. Resin-bound DKPs as scaffolds for further on-resin transformations are readily prepared using the backbone amide linker (BAL) approach, where the amino acid ester is attached to the BAL resin by its a-amino group and then acylated with a Fmoc-protected amino acid by the HATU procedure, N -deprotection leads to on-resin DKP formation1172 (see Section 6.8.3.2.2.3). 

Majewski and coworkers developed polymer-supported chiral lithium amides and applied them to the aldol reaction (Scheme 33)74. The amide precursor amines were prepared either from the insoluble Merrifield resins or from copolymerized styrene and 4-chloromethylstyrene yielding soluble polymer (SP). 

Crotonates bearing an atropisomeric 1-naphthamide moiety can be reacted in a Sml2-mediated reductive coupling with a variety of aldehydes to yield enantiomerically enriched 7-butyrolactones. The crotonate derived from 2-hydroxy-8-methoxy-Tnaphthamide reacted with pentanal to afford the highest ee of >99% in a combined yield of 90% with a cisltrans-mt o of 90 10. The chiral crotonate can also be linked to a Rink amide resin with the C-8 oxygen, and in the solid-phase reaction the same level of axial-to-central chirality transfer was obtained (Equation 103) <2006JOC2445>. 

Chiral lithium amide bases have been used successfully in the asymmetric deprotonation of prochiral ketones [55, 56]. WUliard prepared polymer-supported chiral amines from amino acid derivatives and Merrifield resin [57]. The treatment of cis-2,6-dimethylcyclohexanone with the polymer-supported chiral lithium amide base, followed by the reaction with TMSCl, gave the chiral silyl enol ether. By using polymeric base 96, asymmetric deprotonation occurred smoothly in tetrahydrofuran to give the chiral sUyl enol ether (, S )-102 in 94% with 82% ee (Scheme 3.28). 

A diastereoselective approach to y-butyrolactones is presented in Scheme 27. 4-Pentenoic acid was coupled to Merrifield resin via prolinol as a chiral linker unit. a-Methyladon and treatment of the amides 103 with iodine in TH F/water mixtures hberated substituted butyrolactones 104a-d as a mixture in which the trans diaster-eomers predominated [42]. 

A re-evaluation of soHd-phase hydantoin synthesis, including aspects of improved retention of chirality, has recently been published [27]. A method with an emphasis on chemical robustness and practical efficiency has been developed, in which the intermediates are anchored on Rink resin through a stable amide bond [28]. 

Trichloro[l,3,5]triazine has also been attached to the Wang resin. Reaction of the resulting supported dichlorinated triazine with 2-(2-aminoethoxy)ethanol and further treatment again with an excess of 2,4,6-trichIoro[l,3,5]triazine afforded resin 65, which has been shown to be effective in the conversion of carboxylic acids into acid chlorides, using triethylamine as base in dichloromethane or acetone as solvent [78]. The obtained acid chlorides can be easily transformed into ester or amides after removal of the resin by filtration and addition of an alcohol or an amine. From the isolated yields of the esters or amides it could be deduced that the yields of the obtained acid chlorides are around 70-90%. However, a chiral amino acid was completely racemized under this resin treatment. 

Successful polymer supported stereoselective Diels-Alder reaction was performed using immobilized enantiopure 4-(3-hydroxy-4,4-dimethyl-2-oxopyrro-lidin-l-yl)benzoic acid 12 as a chiral auxiliary [15]. The corresponding resin-bound acrylate derivate has been applied as the dienophile 13. Preparation of the precursor started with the combination of pantolactone 10 and the sodium salt of 4-aminobenzoic acid. Conversion into the corresponding benzyl ester followed. The obtained racemate was esterified with (lS)-camphanic acid chloride to a dia-stereomeric mixture to gain the enantiopure compounds by chromatographic separation. After subsequent saponification of the camphanic acid moiety and hydrolysis of the benzyl ester the (R)-enantiomer 11 was coupled to Rink amide resin (Scheme 12.6). 

The immobilized Evans chiral auxiliary 56 has also been employed in asymmetric a-alkylation of resin-bound propionic amide [13, 27]. Reductive cleavage afforded the a-benzylated propanol (2-methyl-3-phenylpropanol). 

Polymer-supported chiral p-hydro q amides, derived from the molecular chiral ligand 60, were also successfully used. High yields and enantio-selectivities were obtained with resin 61 (Figure 7.6). The supported ligand was reused 4 times, with a decrease of the enantiomeric excess (from 87 to 80% in the addition of phenylacetylene to benzaldehyde). The same p-hydro q amide was also grafted onto amorphous silica gel and the ligand 62 was reused five times with slight loss of enantioselectivity (from 78 to 75% enantiomeric excesses). ... 

On-resin lactam (amide) formation or cyclization can be achieved via HOBt active esters using a number of reagents. Carbodiimide and phosphonium activation have all been used for ring closure with minimal loss of chiral integrity of the activated amino acid residue. The choice of reagent and auxiliary nucleophile (i.e. HOBt, HOAt) is at the discretion of the operator (see Chapters 2 and 3). However, it is worth noting that successful peptide cyclization is, to an extent, sequence dependent. Nominal ring closure is not uncommon and is due in part to the spatial orientation of the peptide backbone and steric hindrance. 

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