FLUORINE IN THE LIFE SCIENCE INDUSTRY
104
CHIMIA 2004, 58, No. 3
Chimia 58 (2004) 104–107
© Schweizerische Chemische Gesellschaft
ISSN 0009–4293
Chemo-Enzymatic Synthesis of Chiral
Fluorine-Containing Building Blocks
Richard H. Blaauwa*, Denis R. IJzendoorna, Jozef G.O. Cremersb, Floris P.J.T. Rutjesb,
Quirinus B. Broxtermanc, and Hans E. Schoemakerc
Abstract: Two complementary strategies for the synthesis of optically active fluorine-containing building
blocks have been probed. The first strategy involves either the enzymatic resolution of fluorinated α,α-di-
substituted-α-amino acid amides, or the asymmetric hydrogenation of fluorinated dehydroamino acids. The
second strategy involves the transition metal-catalyzed introduction of fluorine-containing substituents onto
olefin- or acetylene-containing α-H-α-amino acids. These amino acids in turn are made optically active by
enzymatic resolution of the corresponding amides.
Keywords: Asymmetric hydrogenation · Chiral building blocks · Enzymatic resolution ·
Fluorinated amino acids · Transition metal catalysis
Introduction
The facile stereospecific synthesis of a
with DSM Pharma Chemicals in Geleen The First Strategy
(NL).
This paper describes some of the recent
One of our core chiral competences is
variety of multifunctional building blocks efforts of Chiralix and its partners in the de- the enzymatic resolution of amino acid
is an important component of the drug dis- velopment of novel methodologies for the amides by hydrolytic enzyme systems (Fig.
covery toolbox. More specifically, technol- chemo-enzymatic preparation of chiral flu- 2). In general, these enzymes convert L-
ogy for the preparation of fluorine-contain- orine-containing building blocks.
ing building blocks forms a powerful addi-
amino acid amides to the corresponding L-
amino acids, while leaving the D-amino
acid amides untouched. Over the last few
years a set of microorganisms containing
highly stereoselective aminopeptidases and
amidases have been identified, all exhibit-
ing their own specific substrate tolerance
[1]. The aminopeptidase present in
Pseudomonas putida ATCC 12633 was
shown to give excellent results in the hy-
drolysis of α-H-α-amino acid amides, with
a wide variety of amino acid side chains [2].
For the resolution of α,α-disubstituted-α-
amino acid amides, whole cells of My-
cobacterium neoaurum proved to be the
biocatalyst of choice [3], whereas
Ochrobactrum anthropi whole cells could
be applied in a whole range of resolutions,
including those of α-H-α-hydroxy car-
boxylic acids [4].
tion to this toolbox. To this end, Chiralix
aims at the development of novel technolo-
gies for the efficient synthesis of such chi-
ral, densely functionalized compounds by a
synergistic combination of advanced organ-
ic synthesis, homogeneous transition metal
catalysis, and biocatalysis. This is done in
close collaboration with the academic re-
search group of Prof. Floris Rutjes at the
University of Nijmegen (NL), as well as
Two Complementary Approaches
In order to arrive at the desired chiral
fluorinated compounds we envisaged two
possible strategies, depicted in Fig. 1, either
one of which should give access to both
enantiomerically pure forms of a given
building block. The first strategy (counter-
clockwise in Fig. 1) would be to introduce
the desired fluorinated group(s) into a
racemic or prochiral substrate, followed by
an asymmetric transformation to obtain the
molecule in enantiomerically pure form.
The second strategy involves the asymmet-
ric transformation of a non-fluorinated
building block and subsequent installation
of the fluorinated group(s) onto the enan-
tiomerically pure material.
*Correspondence: Dr. R.H. Blaauwa
aChiralix B.V.
Toernooiveld 100
NL-6525 EC Nijmegen, The Netherlands
Tel.: + 31 24 365 2194
Fax: + 31 24 365 3393
E-Mail: richard.blaauw@chiralix.com
bDepartment of Organic Chemistry
University of Nijmegen
In collaboration with the group of Prof.
Burger in Leipzig (Germany) a resolution
protocol was developed for fluorinated
α,α-disubstituted-α-amino acid amides,
using the amidase from Mycobacterium
neoaurum. As can be seen from the results
of these enzymatic conversions depicted in
Table 1, the enzyme performed very well
with the three substrates that were investi-
gated. The astonishing discriminatory pow-
er of the amidase becomes evident from the
In principle, these two strategies are
complementary since they enable us to
choose whether the fluorous substituent
should be introduced prior to or during the
diversification process. Depending on the
substitution pattern and complexity of the
desired building block, one of the two
strategies could prove most advantageous
and we therefore set out to probe both path-
ways.
Toernooiveld 1
NL-6525 ED Nijmegen
cDSM Pharma Chemicals
Advanced Synthesis, Catalysis and Development
P.O. Box 18
NL-6160 MD Geleen