Racemization during esterification

Standard solid-phase peptide synthesis requires the first (C-terminal) amino acid to be esterified with a polymeric alcohol. Partial racemization can occur during the esterification of N-protected amino acids with Wang resin or hydroxymethyl polystyrene [200,201]. /V-Fmoc amino acids are particularly problematic because the bases required to catalyze the acylation of alcohols can also lead to deprotection. A comparative study of various esterification methods for the attachment of Fmoc amino acids to Wang resin [202] showed that the highest loadings with minimal racemization can be achieved under Mitsunobu conditions or by activation with 2,6-dichloroben-zoyl chloride (Experimental Procedure 13.5). iV-Fmoc amino acid fluorides in the presence of DMAP also proved suitable for the racemization-free esterification of Wang resin (Entry 1, Table 13.13). The most extensive racemization was observed when DMF or THF was used as solvent, whereas little or no racemization occurred in toluene or DCM [203]. 

Racemization occurring during esterification of protected amino acids to hydroxymethyl polymers is a well-recognized problem.PP l This reaction is promoted by the use of DMAP as catalyst,P l and racemization is particularly pronounced in the case of cysteine.P By the use of optimized esterification methods racemization can be reduced, but not totally sup-pressed.P l When starting with halomethyl-functionalized resins, such as 2-chlorotrityl chloride resin,P l bromo-SASRIN resin,P l or 4-(bromomethyl)phenoxyacetamide res-in,P l racemization levels are significantly lowered. Alternatively, racemization is largely prevented by using the TDO esters without DMAP,f P°l or PyAOP in the presence of DIPEA at low temperature.P l... 

R)-3-Phenoxybutanoic acid and the corresponding butyl (S)-ester were obtained by Burkholderia cepacia lipase-catalyzed enantioselective esterification of the racemic acid with 1-butanol in hexane containing anhydrous sodium sulfate to remove the water produced during the reaction (Figure 6.17) [64]. 

Attachment of carboxylic acids to supports as trityl esters is achieved by treatment of the corresponding trityl chloride resin with the acid in the presence of an excess of a tertiary amine (Figure 3.5 see also Section 13.4.2). This esterification usually proceeds more quickly than the acylation of benzyl alcohol linkers. Less racemization is generally observed during the esterification of A-protected a-amino acids with trityl linkers than with benzyl alcohol linkers [47], If valuable acids are to be linked to insoluble supports, quantitative esterification can be accomplished by using excess 2-chlorotrityl chloride resin, followed by displacement of the remaining chloride with methanol [64]. 

Lipases have been extensively used for the kinetic resolution of racemic alcohols or carboxylic acids in organic solvents. Chiral alcohols are usually reacted with achiral activated esters (such as vinyl, isopropenyh and trichloroethyl esters) for shifting the equilibrium to the desired products and avoiding problems of reversibility. For the same reasons, chiral acids are often resolved by using acidolysis of esters. In both cases, the overall stereoselectivity is affected by the thermodynamic activity of water of water favors hydrolytic reactions leading to a decrease in the optical purity of the desired ester. Direct esterifications are therefore difficult to apply since water formed during the reaction may increase the o of the system, favors reversibiUty, and diminishes the overall stereoselectivity. 

Of those in common usage, the 2-chlorotrityl 28 [74] and 4-carboxytrityl 29 [75] linkers give the least stabilized cations and are suitable for immobilization of carboxylic acids. They are ideal for Fmoc/tBu-based SPPS as their use avoids many of the side reactions that occur with standard benzyl-based linkers. Firstly, race-mization does not occur during loading of the resin with the C-terminal residue [79], as is the case with esterification to hydroxy-functionalized resins. Secondly, the bulky trityl cation does not cause alkylation side reactions with nucleophilic amino-acid side-chains. Thirdly, cysteine does not undergo racemization [80, 81]... 

As shown in Scheme 2.8, the racemic starting acetate (A/B) is hydrolyzed to give alcohols (P/Q) in an organic medium containing a minimum amount of water, which in turn, by the action of the same lipase, are re-esterified with cyclohexanoic acid present in the mixture. Thus, the alcohol moiety of the substrate has to enter the active site of the lipase twice during the course of its transformation into the final product ester (R/S). An apparent selectivity of = 4(X) was achieved in this way, whereas the corresponding isolated single-step resolutions of this process were 1 = 8 for the hydrolysis of acetate A/B, and 2 = 97 for the esterification of alcohol P/Q with cyclohexanoic acid. 

Trifluoroacetaldehyde, generated from l-ethoxy-2,2,2-trifluoroethanol (4 mmol) by treatment with polyphosphoric acid (PPA), was passed into a toluene solution of (Ry BIN0L-Ti(0-/-Pr)2 (1 mmol) at -78 °C in the presence of 2-propanol (2 mmol) coproduced during the preparation of the catalyst from Ti(0-/-Pr)4 and (i )-binaphthol (BINOL). The resulting hemiacetal was treated with benzoyl chloride, triethylamine and 4-dimethylaminopyridine (DMAP) at -78 °C to afford 2,2,2-trifluoro-l-isopropoxyethyl benzoate (80% ee) in 85% yield. When the esterification was carried out at higher temperatures, % ee of the product considerably decreased due probably to racemization of the intermediate hemiacetal. 

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