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
>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.
(4) (a) Pirrung, M. C.; Fallon, L.; Lever, D. C.; Shuey, S. W. J. Org. Chem.
1996, 61, 2129-2136. (b) Pettit, G. R.; Lippert, J. W.; Herald, D. L. J.
Org. Chem. 2000, 65, 7438-7444. (c) Ager, D. J.; Prakash, I.; Schaad,
D. R. Chem. ReV. 1996, 96, 835-875. (d) Jackson, W. R.; Jacobs, H. A.;
Jayatilake, G. S.; Matthews, B. R.; Watson, K. G. Aust. J. Chem. 1990,
43, 2045-2062. (e) Shirai, R.; Takayama, H.; Nishikawa, A.; Koiso, Y.;
Hashimoto, Y. Bioorg. Med. Chem. Lett. 1998, 8, 1997-2000.
(5) Buck, J. S.; Ide, W. S. In Organic Reactions; Adams, R., Bachmann, W.
E., Blatt, H. A., Fieser, L. F., Johnson, J. R., Snyder, H. R., Eds.; Wiley:
New York, 1949; Vol. 4, pp 269-304 and references therein.
(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-
hedron 1985, 41, 3135-3140.
(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.
JA0271476
9
J. AM. CHEM. SOC. VOL. 124, NO. 41, 2002 12085