Esters enantioselective aminolysis

Studies of the ability of the lipase B from Candida antarctica (CAL-B) to catalyse the enantioselective aminolysis of esters by cis- and firms-2-phenylcycloalkanamines (54 n = 1, 3, 4) have been followed up by molecular modelling approaches in order to probe the lipase-catalysed aminolysis mechanism. CAL-B possesses a typical serine-dependent triad, so it was possible, with access to an X-ray crystal structure of CAL-B, to model a series of phosphonamidates (55 n = 1, 3, 4) as analogues of the tetrahedral intermediate (TI) resulting from attack of the amine on the carbonyl of the acyl-enzyme. The results suggested as the most plausible intermediate for the CAL-B-catalysed aminolysis a zwitterionic TI resulting from the direct His-assisted attack of the amine on to a C=0 group of the acyl-enzyme.80... 

A very straightforward approach as compared with the existing one (Fig. 3) would have been the direct enzyme-catalyzed peptide formation (cf. Chen et al. [30]) by enantioselective aminolysis of ester 2 with histidine methylester 4 or even racemic histidine ester, as it would resolve the objectives of resolution and coupling in one step. Orientating experiments in which 20 proteases adsorbed on porous glass beads (SIKUG 041/02/120/A, Schott) were in contact with EtOH solutions of 2 and 4 with various water contents, however, did not reveal any reaction. 

A very straightforward approach in route C (Fig. 2) would have been the direct enzyme-catalyzed peptide formation (cf. Chen et al. [18]) by enantioselective aminolysis of diester 9 with (S)-tert-leucine methylamide 13 or even racemic 13. This would combine three synthetic objectives the resolution of (rac)-9, the resolution of (roc)-13 and the coupling step. In orientating experiments monoester 10 was tested as a model substrate. It was contacted with an equal amount of (S)-amine 13 in the presence and absence of an organic solvent. Solid or liquid subtilisin Carlsberg preparations (Alcalase 2.0 T or Alcalase 2.5 L, respectively) were used as the catalyst. Only with the liquid enzyme preparation was the formation of minor amounts of one of two possible diastereoisomeric peptides observed [19], whereas most of the ester was hydrolyzed to the acid. Likewise, a few selected lipases also provided negative results. 

A chemoenzymatic approach has been employed to synthesize enantioneriched P-amino acid esters. The aza-Michael addition of benzyl amine to P-alkyl substituted enoates, under solvent-free conditions, and subsequent hpase-catalyzed resolution via enantioselective aminolysis afforded the corresponding p-amino esters in moderate yields (19-36% yield) and with high enantioselectivities (93-99% ee) [96]. 

Figure 39 Enantioselective aminolysis of various racemic 3-hydroxy esters.

Although the aminolysis of esters to amides is auseful synthetic operation, usually it presents some disadvantages in terms of drastic reaction conditions, long reaction times or strong alkali metal as catalyst, which are usually not compatible with other functional groups in the molecule [6]. For this reason, enzymatic aminolysis of carboxylic acid derivatives offers a clean and ecological way for the preparation of different kind of amines and amides in a regio-, chemo-, and enantioselective manner. 

Apart from aminolysis and olefin metathesis the photoactivation of aminocar-bene complexes offers another nonconventional entry into peptide synthesis. Irradiation into the hypsochromic MLCT-band of chromium aminocarbenes such as 201 generates a ketene-like intermediate 204 that is trapped by amino acid esters such as 202 or 205 to produce dipeptides 203 or 206 after enantioselective protonation (Scheme 11.49) [106]. This photochemical protocol generally combines good yields with high diastereoselectivities and is especially attractive for the incorporation of a-alkyl a-amino acid esters into peptides that may be hampered in conventional peptide synthesis methodologies due to steric hindrance [106c]. 

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