Page 461 - Cascade_Biocatalysis_Integrating_Stereoselective_and_Environmentally_Friendly_Reactions

19.3 Combination of Substrate Isomerization and their Derivatization 437

In spite of the high elegance of this process shown in Scheme 19.11, the need for
the rather expensive pyridoxal 5-phosphate as a catalyst for racemization represents
a drawback. Furthermore, catalyst loading is relatively high with 20 mol%. Since,
however, for in situ formation of the imine the only required function in principle
is an aldehyde group, more simplified aromatic aldehydes have been studied
[34, 35]. The Beller group [34] identified substituted benzaldehyde in particular
when bearing electron-deficient substituents as an efficient substitute for pyridoxal
phosphate, thus leading to a successful DKR of racemic amino esters. For example,
in the presence of 3,5-dichlorosalicylaldehyde (33) with a decreased catalyst loading
of 5 mol% and alcalase as a biocatalyst, racemic tyrosine ethyl ester (rac-32)was
transformed into (corresponding) l-tyrosine ((S)-34) with 92% yield and 98% ee
(Scheme 19.12) [34]. A very detailed study of the reaction kinetics as well as
modeling of this process technology has been performed by Kragl et al. [35] and,
based on the finding that catalyst deactivation is the limiting factor in this DKR,
optimization was achieved with the formation of the product in a higher yield and
within a decreased reaction time.
Catalyst for
enantioselective
hydrolysis:
alcalase,
water/acetonitrile,
HO pH 7.5, 35 °C HO
NH 2
NH 2
rac
O CH 3
Catalyst for OH
racemization:
O O
O
rac-32 (S)-34
OH 92% yield
98% ee
Cl Cl
33 (5 mol%)
Scheme 19.12 Dynamic kinetic resolution of an α-amino ester based on 3,5-
dichlorosalicylaldehyde-catalyzed racemization and enzymatic ester hydrolysis.

When using amino acid derivatives as substrates bearing a more activated C–H
bond in α-position, even simple commercially available tertiary amines such as
triethylamine turned out to be applicable for racemization in a DKR process.
Such a type of the DKR process has been realized by the Berkessel group [36]
for the enantioselective synthesis of β2-amino acid esters through ring opening
of racemic 5-substituted oxazinones (rac-35) with an alcohol (Scheme 19.13). In
the presence of lipase B from C. antarctica and triethylamine, the enantioselective
enzymatic alcoholysis of rac-35 with allyl alcohol in combination with substrate
racemization gave a broad range of the desired totally protected β-amino acids (R)-
36 in quantitative conversion for all reported examples and with high enantiomeric
excess of up to 96%.