Development of a donor-acceptor concept for enzymatic cross-coupling reactions of aldehydes: The first asymmetric cross-benzoin condensation

Article abstract of DOI:10.1021/ja0271476

Highly enantioenriched mixed benzoins are obtained selectively through a biocatalytical cross-coupling reaction of aromatic aldehydes using ThDP-dependent enzymes. Copyright

Full text of DOI:10.1021/ja0271476

Published on Web 09/24/2002
Development of a Donor-Acceptor Concept for Enzymatic Cross-Coupling
Reactions of Aldehydes: The First Asymmetric Cross-Benzoin Condensation
Pascal Du¨nkelmann,† Doris Kolter-Jung,† Adam Nitsche,† Ayhan S. Demir,†,§ Petra Siegert,‡
Bettina Lingen,‡ Martin Baumann,‡ Martina Pohl,‡,§ and Michael Mu¨ller*,†
Institute of Biotechnology 2, Forschungszentrum Ju¨lich, 52425 Ju¨lich, Germany, and
Institute of Enzyme Technology, Heinrich-Heine UniVersita¨t, Du¨sseldorf, Germany
Received June 3, 2002
Table 1. Combined Enzyme-Substrate Screening
In earlier publications, we showed that enantiopure benzoins can
be efficiently obtained by use of the thiamin diphosphate (ThDP)-
dependent enzymes benzaldehyde lyase (BAL)1 or benzoylformate
decarboxylase (BFD).2 In the present contribution we present
successful and unprecedented results leading to a donor-acceptor
concept for the asymmetric synthesis of mixed benzoins, that is,
benzoins with nonidentical aromatic moieties, using an enzyme-
catalyzed benzoin condensation. An asymmetric variant of this
cross-coupling has not yet been described in the literature.3
The synthesis of mixed benzoins is of interest in many respects
as they are versatile building blocks in organic and pharmaceutical
chemistry.4 In addition to other synthetic routes the racemic
compounds can be synthesized selectively by means of a cyanide-
catalyzed cross-benzoin condensation.5 This selectivity prompted
various scientists to subdivide the aromatic aldehydes into donors,
adding the cyanide ion, and acceptors.6
Although we do not agree completely with the authors’ statements6c
we were inspired by this idea of selective donors and acceptors so
that in an initial experiment 2-chlorobenzaldehyde (2a), 2-methyl-
benzaldehyde (2b), 2-methoxybenzaldehyde (2c), and subsequently
the ortho-substituted benzaldehyde derivatives 2d-f were reacted
with benzaldehyde in the presence of different ThDP-dependent
enzymes. The three substrates 2a-c were chosen because of their
inability to form symmetrical benzoins through the wild-type BFD-
catalyzed reaction,2a assuming that they still might serve as acceptor
substrates although they are not accepted as donors by this enzyme.
Here, the enzymes BFD H281A7 and BAL were identified as potent
catalysts for asymmetric cross-carboligation (Table 1). The absolute
configuration of compound 3a was determined to be R, as expected
(ee > 99%).8 This compound has also been synthesized on a
preparative scale using BFD H281A as well, with pleasing results
concerning conversion and selectivity. Remarkably, the 2,2′-
disubstituted benzoins 5a-c or the mixed benzoins substituted in
2-position 6a-c were not generated in the BFD H281A-catalyzed
reactions while 5d,f and 6d,f were not formed in the BAL-catalyzed
reactions, showing that 2a-d,f react selectively as acceptors in the
presence of the respective biocatalyst.
1
[R ]
2
[R ]
3
[%]
4
5
[%]
6
[%]
1
2
3
enzyme
[%]
a
H
2-Cl
BFD H281A
BAL
BFD H281A
BAL
BFD H281A
BAL
BFD H281A
BAL
BFD H281A
BAL
BFD H281A
BAL
90
70
34
39
40
66
-
10
16
66
30
60
25
-
-
14
-
12
-
10
-
-
1
-
-
-
19
-
-
-
-
-
-
-
-
b
c
d
e
f
H
H
H
H
H
2-Me
2-MeO
2,6-F2
88
53
67
-
12
46
24
-
2,3,5-F3
2,3,4,5,6-F5
9
-
-
90
10
Table 2. Mixed Benzoins Synthesized Chemoselectively and
Asymmetrically on a Preparative Scalea
c
donor 1
[R ]
acceptor 2a
conversion selectivityb
[%]
ee
1
2
3
[R ]
enzyme
[%]
[%]
g
h
i
j
k
l
3-CN
4-Br
4-CF3
3,4-CH2O2
3,4,5-(CH3O)3
3,5-(CH3O)2
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
2-Cl
BFD H281A
BFD H281A
BFD H281A
BAL
BAL
BAL
>99
90
75
98
82
>99
95
>99
83
97
95
90d
95
93
>99
>99
>99
>99
a Experimental procedure: BFD H281A or BAL, ThDP, Mg2+, KPi
buffer, DMSO, 30 °C, 24-48 h. b The selectivity is defined as the percent
ratio of product in relation to the sum of all benzoins obtained. c Determined
by HPLC analysis. d Compound 3g exhibits a strong racemization tendency.
On the basis of these observations, we focused on the identifica-
tion of selective donor substrates and discovered that an appropriate
screening lead us to a broad variety of selectively reacting
benzaldehyde derivatives. This screening was carried out by reacting
2-chlorobenzaldehyde with putative donors in the presence of BFD
H281A and BAL, respectively. Table 2 presents those examples
of selectively obtained mixed benzoins that are likewise synthesized
on a preparative scale (0.2-1.5 g) also with good-to-excellent
conversion and chemoselectivity. Obviously, reactions catalyzed
by these enzymes obey a donor-acceptor selectivity. Notably, the
selectivity exhibited by the enzymes is different to the extent that
BAL has a much broader substrate range concerning aromatic
aldehydes with sterically demanding substituents, while BFD
H281A shows a higher selectivity with aromatic aldehydes with
* To whom correspondence should be addressed. E-mail: mi.mueller@fz-
juelich.de.
† Forschungszentrum Ju¨lich.
‡ Heinrich-Heine Universita¨t, Du¨sseldorf.
§ Present addresses: A. S. Demir, Department of Chemistry, Middle East
Technical University, Ankara, Turkey. Martina Pohl, MPB Cologne GmbH,
Cologne, Germany.
9
12084
J. AM. CHEM. SOC. 2002, 124, 12084-12085
10.1021/ja0271476 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Preliminary Results of the Permutative Donor-Acceptor
and chemical mechanistic concerns. Moreover, we are convinced
that the concept presented here should be transferable to reactions
that proceed in a comparable manner, for example Tishchenko
reactions10,11 or pinacol couplings.11,12 In this case, our work,
stimulated by classic organic chemistry and carried out in the field
of enzymatic synthesis, would lead us to an advanced insight into
general chemical concerns.
Screening Using BAL as Catalysta
1
2
3
donor 1 [R ]
acceptor 2 [R ]
conversion [%]
selectivityb [%]
m
n
o
p
q
r
s
t
u
v
w
x
y
z
Γ
Π
Σ
Ω
3-CN
4-Br
4-CF3
3,4-CH2O2
3,4,5-(CH3O)3
3,5-(CH3O)2
3-CN
4-Br
4-CF3
3,4-CH2O2
3,4,5-(CH3O)3
3,5-(CH3O)2
3-CN
4-Br
4-CF3
3,4-CH2O2
3,4,5-(CH3O)3
3,5-(CH3O)2
2,6-F2
2,6-F2
2,6-F2
2,6-F2
2,6-F2
2,6-F2
2,3,5-F3
2,3,5-F3
2,3,5-F3
2,3,5-F3
2,3,5-F3
2,3,5-F3
2,3,4,5,6-F5
2,3,4,5,6-F5
2,3,4,5,6-F5
2,3,4,5,6-F5
2,3,4,5,6-F5
2,3,4,5,6-F5
>99
98
>99
97
93
>99
89
>99
94
40
71
66
78
72
84
96
66
90
78
94
83
92
-
97
96
Acknowledgment. The skillful technical assistance of Lydia
Walter, Alia Akaouch, Sabine Schu¨ller, and Ralf Feldmann is
gratefully acknowledged. This work was supported by the Deutsche
Forschungsgemeinschaft in the scope of SFB 380. A.S.D. thanks
the DAAD and the Alexander von Humboldt Foundation for a
fellowship.
>99
98
ncc
Supporting Information Available: Experimental data for the
compounds 3a, 3h, 3j, and 3Π (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
>99
76
>99
>99
>99
>99
92
>99
References
(1) (a) Demir, A. S.; Pohl, M.; Janzen, E.; Mu¨ller, M. J. Chem. Soc., Perkin
Trans. 1 2001, 633-635. (b) Demir, A. S.; Sesenoglu, O¨ .; Eren, E.; Hosrik,
B.; Pohl, M.; Janzen, E.; Kolter, D.; Feldmann, R.; Du¨nkelmann, P.;
Mu¨ller, M. AdV. Synth. Catal. 2002, 344, 96-103.
a The selectivity was determined by gaschromatography. b The selectivity
is defined as the percent ratio of product in relation to the sum of all benzoins
obtained. c nc ) no conversion.
(2) (a) Iding, H.; Du¨nnwald, T.; Greiner, L.; Liese, A.; Mu¨ller, M.; Siegert,
P.; Gro¨tzinger, J.; Demir, A. S.; Pohl, M. Chem. Eur. J. 2000, 6, 1483-
1495. (b) Demir, A. S.; Du¨nnwald, T.; Iding, H.; Pohl, M.; Mu¨ller, M.
Tetrahedron: Asymmetry 1999, 10, 4769-4774.
small substituents. Thus, the complementary substrate ranges of
different enzymes enable the synthesis of a large diversity of mixed
benzoins.
Evidence that the aldehydes used do not serve as selective
acceptors only in the presence of one special donor, and vice versa,
could be provided by an additional test series combining identified
selective donors with selective acceptors in the presence of BAL
(Table 3). In most of these attempts the mixed benzoin 3 was
obtained with high-to-excellent selectivity.
To obtain access to the (S)-enantiomer of the mixed benzoins,
we employed the kinetic racemic resolution via C-C bond cleavage
established for the BAL-catalyzed (S)-benzoin formation (Scheme
1).1a In doing so the enantiopure mixed (S)-benzoin (S)-3h was
obtained with more than 49% conversion (ee > 99%). Thus, both
enantiomers of the mixed benzoins are accessible through this
enzyme-catalyzed reaction.
(3) Cf. Enders, D.; Breuer, K. In ComprehensiVe Asymmetric Catalysis;
Jacobson, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. 2, pp 1093-1102.
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1996, 61, 2129-2136. (b) Pettit, G. R.; Lippert, J. W.; Herald, D. L. J.
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(6) (a) Semerano, G. Gazz. Chim. Ital. 1941, 71, 447-461. (b) Merz, K. W.;
Plauth, D. Chem. Ber. 1957, 90, 1747-1757. (c) We assume that at least
in some cases the selective formation of one mixed benzoin might result
from an isomerization, leading to the thermodynamically more stable
product. In our case the observed enantioselectivity clearly proves the
selective formation of the respective mixed benzoins. Cf. (d) Corrie, J. E.
T. Tetrahedron 1998, 54, 5407-5416. (e) Rozwadowska, M. D. Tetra-
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(7) Polovnikova, L. S.; McLeish, M. J.; Sergienko, E. A.; Burgner, J. T.;
Anderson, N. L.; Jordan, F.; Kenyon, G. L.; Hasson, M. S. Submitted for
publication. We thank Dr. McLeish for kindly providing us with the BFD
H281A gene.
Scheme 1. Generation of the Mixed (S)-Benzoin (S)-3h by Kinetic
Racemic Resolution
(8) Since symmetric benzoins generated through wild-type BAL- and wild-
type BFD-catalyzed reactions are of R-configuration, we assumed that
the mixed benzoins 3 possess R-configuration, too.1,2 To scrutinize the
absolute configuration of the mixed benzoins, (R)-2′-chlorobenzoin 3a
was prepared nonenzymatically starting from (R)-(2-chlorophenyl)-2-
trimethylsilyloxy-acetonitrile9a by means of a Grignard reaction with
phenylmagnesium bromide.
(9) (a) Hayashi, M.; Matsuda, T.; Oguni, N. J. Chem. Soc., Chem. Commun.
1990, 1364-1365. (b) McKenzie, A.; Kelman, A. L. J. Chem. Soc. 1934,
412-418.
(10) (a) Tishchenko, W. Chem. Zentralbl. 1906, 77, 1309-1311. (b) Lin, I.;
Day, A. R. J. Am. Chem. Soc. 1952, 74, 5133-5135.
In summary, we have shown that mixed benzoins can be
synthesized enantioselectively through an enzymatic cross-benzoin
condensation by ThDP-dependent enzymes taking advantage of the
aldehydes donor-acceptor behavior. This one-step synthesis starting
from cheap and commercially available aldehydes represents an
outstanding improvement in comparison to the costly and tedious
synthesis based on the conversion of chiral cyanohydrines with
phenyl-Grignard derivatives.4a-c,9 Essential for the realization of
this concept was a successful implementation of both enzymatic
(11) The transfer of our result to these types of reaction is plausible, as both
reactions proceed in two steps, of which the first is the generation of an
activated species by conversion of one substrate with a catalyst and since
racemic cross-couplings have already been described for both reactions.
(12) (a) Robertson, G. M. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Flemming, I., Pattenden, G., Eds.; Pergamon: Oxford, 1991; Vol. 3, pp
563-611. (b) Clerici, A.; Porta, O. J. Org. Chem. 1983, 48, 1690-1694.
(c) Freudenberger, J. H.; Konradi, A. W.; Pederson, S. F. J. Am. Chem.
Soc. 1989, 111, 8014-8016.
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