Biomimetic Transamination of R-Alkyl â-Keto Carboxylic Esters
J . Org. Chem., Vol. 63, No. 6, 1998 1879
Sch em e 1
of the amino acid critically involved in the design of
carbapenem antibiotics and other biologically relevant
compounds.1,10
Key stages of our chemoenzymatic approach involve
diastereoselective synthesis of the targeted amino acids
and their biocatalytic resolution to the enantiomerically
pure compounds. The first stage, a methodologically new
diastereoselective biomimetic transamination of the flu-
orinated â-keto carboxylic ester with benzylamine was
shown to proceed under mild reaction conditions afford-
ing the corresponding Schiff base of the targeted amino
acid of either (2R*,3S*) or (2R*,3R*) stereochemistry,
depending on the base-catalyst employed. The second
stage, a biocatalytic resolution of the diastereomerically
pure amino acids to the pairs of enantiomers was
efficiently accomplished via penicillin acylase-catalyzed
highly enantioselective hydrolysis of the corresponding
N-phenylacetyl derivatives. The whole process providing
access to all four optical isomers [(2S,3S), (2S,3R),
(2R,3S), (2R,3R)] of the hitherto unknown R-methyl-â-
(trifluoromethyl)-â-alanine would be methodologically
useful for the development of more general approaches
to this class of biologically interesting fluorinated amino
acids.
as [1,3]-Proton Shift Reaction (PSR),11,12 for preparing
various fluorine-containing amino compounds of biome-
dicinal and synthetic importance (Scheme 1).13 A key
reaction stage of the method is the base-catalyzed [1,3]-
proton shift within 1,3-azaallylic system of imines 1, 2,
an azomethine-azomethine isomerization, which pro-
vides an intramolecular reduction-oxidation process via
biomimetic14 transposition of the imine functionality.
Desired amino compounds 3 can be easily released from
Schiff bases 2 by an acidic hydrolysis under mild reaction
conditions. Synthetic potential of the method has been
demonstrated with the efficient preparation of various
fluoroalkyl-, fluoroarylamines,11 R- and â-amino acids12
3 (R ) Alk, Ar, COOH, CH2COOH, respectively) starting
with appropriate carbonyl compounds and benzylamine,
picolylamines, or enantiopure R-phenylethylamines (asym-
metric PSR).11g,12g However, the azomethine-azomethine
isomerizations of imines containing a stereogenic center
in the R-position to the imine carbon atom have not been
studied so far. Accordingly, apart from the synthetic
targets, the present study gains also an additional
impetus when considering methodologically new stereo-
Resu lts a n d Discu ssion
Recently we have developed biomimetic, reducing
agent-free, reductive amination methodology, referred to
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