Benzaldehyde lyase-catalyzed enantioselective carboligation of aromatic aldehydes with mono- and dimethoxy acetaldehyde

Article abstract of DOI:10.1021/ol034415b

Matrix presented Benzaldehyde lyase from the Pseudomonas fluorescens catalyzes the reaction of aromatic aldehydes with methoxy and dimethoxy acetaldehyde and furnishes (R)-2-hydroxy-3-methoxy-1-arylpropan-1-one and (R)-2-hydroxy-3,3-dimethoxy-1-arylpropan

Full text of DOI:10.1021/ol034415b

ORGANIC
LETTERS
2
003
Vol. 5, No. 12
047-2050
Benzaldehyde Lyase-Catalyzed
Enantioselective Carboligation of
Aromatic Aldehydes with Mono- and
Dimethoxy Acetaldehyde
2
Ayhan S. Demir* and O2 zge S¸ e s¸ enoglu
Department of Chemistry, Middle East Technical UniVersity, 06531 Ankara, Turkey
Pascal D u1 nkelmann and Michael M u1 ller
Institut f u¨ r Biotechnologie 2, Forschungszentrum J u¨ lich GmbH,
52425 J u¨ lich, Germany
asdemir@metu.edu.tr
Received March 10, 2003
ABSTRACT
Benzaldehyde lyase from the Pseudomonas fluorescens catalyzes the reaction of aromatic aldehydes with methoxy and dimethoxy acetaldehyde
and furnishes (R)-2-hydroxy-3-methoxy-1-arylpropan-1-one and (R)-2-hydroxy-3,3-dimethoxy-1-arylpropan-1-one in high yields and enantiomeric
excess via acyloin linkage. Aromatic aldehydes and benzoins are converted into enamine-carbanion-like intermediates prior to carboligation.
Enantiopure 2,3-dioxygenated aryl propanones are highly
valuable chiral synthons useful for the synthesis of various
biologically active molecules such as the 1,4-benzodioxane
framework, which has often been found in biologically active
There are several methods in the literature for the synthesis
of rac-2,3-dioxygenated aryl propanone derivatives, but
there are few examples of the enantioselective synthesis of
these compounds. Yuen et al. synthesized (R)-2,3-dihydroxy-
1-phenylpropan-1-one by the addition of a phenylmetallic
reagent to 1,2-isopropylidene-D-glyceraldehyde followed by
4
1
natural products. These compounds are important starting
materials for the synthesis of cytoxazone (a novel cytokine
2
modulator), the side chain of taxol, and 5′-methoxyhydno-
3
carpin, which has multidrug pump inhibitor activity (Scheme
1).
Scheme 1
(
1) (a) Gu, W.; Chen, X.; Pan, X.; Chan, A. S. C.; Yang, T.-K.
Tetrahedron: Asymmetry 2000, 11, 2801. (b) Merlini, L.; Zanarotti, A.;
Pelter, A.; Rochefort, M. P.; Hansel, R. J. Chem. Soc., Perkin Trans. 1
1
980, 775. (c) She, X. G.; Jing, X. B.; Pan, X. F.; Chan, A. C.; Yang, T.
K. Tetrahedron Lett. 1999, 40, 4567. (d) Ward, R. S. Nat. Prod. Rep. 1997,
4, 43. (e) Ward, R. S. Nat. Prod. Rep. 1999, 16, 75. (f) Hansel, R.; Shulz,
J.; Pelter, A. J. Chem. Soc., Chem. Commun. 1972, 195.
2) (a) Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 1915. (b) Kakeya,
1
(
H.; Morishita, M.; Koshino, H.; Morita, T.; Kobayashi, K.; Osada, H. J.
Org. Chem. 1999, 64, 1052. (c) Sakamoto, Y.; Shiraishi, A.; Seonhee, J.;
Nakata, T. Tetrahedron Lett. 1999, 40, 4203. (d) Seki, M.; Mori, K. Eur.
J. Org. Chem. 1999, 2965. (e) Hamersak, Z.; Ljubovic, E.; Mercep, M.;
Mesic, M.; Sunjic, V. Synthesis 2001, 1989. (f) Madhan, A.; Kumar, A.
R.; Rao, B. V. Tetrahedron: Asymmetry 2001, 12, 2009. (g) Carda, M.;
Gonzalez, F.; Sanchez, R.; Marco, J. A. Tetrahedron: Asymmetry 2002,
1
3, 1005.
1
0.1021/ol034415b CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/15/2003

the oxidation of the newly formed hydroxy group by Moffat’s
reagent.
On the basis of the preliminary information available to
us from our previous work with BAL-mediated carboligation
reactions of aromatic aldehydes with acetaldehyde, we tried
a series of acetaldehyde derivatives for the enantioselective
carboligation reaction of aromatic aldehydes (Scheme 3).
5
In this context, the enantioselective C-C bond-forming
reaction using an enzyme, i.e., a ThDP-dependent enzyme,
appears to be a highly promising process. Thiamin-dependent
enzymes have been used for various carbon-carbon bonding
6a
reactions. Transketolases transfer an active glycolaldehyde
group from a ketose donor to an R-hydroxyaldehyde
Scheme 3
6
b
acceptor. Pyruvate decarboxylase (PDC), benzoyformate
decarboxylase (BFD), and phenylpyruvate decarboxylase
enzymes are capable of catalyzing acyloin-type condensation
7
reaction leading to formation of chiral R-hydroxy ketones.
None of the above-mentioned enzymes are capable of
catalyzing the carboligation reaction of aromatic aldehydes
with derivatives of acetaldehyde.
In our ongoing studies, we reported the ability of benz-
aldehyde lyase (BAL), a novel thiamin diphosphate (ThDP)-
dependent enzyme from Ps. fluorescens BioVar I, to catalyze
the enantioselective formation of (R)- and (S)-benzoins and
Neither halogenated acetaldehyde derivatives nor glyoxal
gave positive results, but methoxy and dimethoxy acetalde-
hydes were found to be good choices from among the readily
available functionalized acetaldehyde derivatives.
Benzaldehyde (1a) was dissolved in potassium phosphate
4
buffer (80 mL, 50 mM, pH 7.0, containing MgSO (2.5 mM)
and ThDP (0.15 mM)) containing 20% DMSO and methoxy
acetaldehyde. After the addition of BAL, the reaction was
allowed to stand at room temperature. The reaction was
monitored by HPLC with a chiral column. After 48 h no
more change was observed and purification of the crude
product by column chromatography gave (R)-2-hydroxy-3-
methoxy-1-phenylpropan-1-one (2a) in 94% yield (ee >
(R)-2-hydroxypropiophenone ((R)-2-HPP) derivatives via
C-C bond cleavage and C-C bond formation. (R)-2-HPP
derivatives are formed in preparative scale by benzaldehyde
lyase (BAL)-catalyzed C-C bond formation from aromatic
aldehydes and acetaldehyde in buffer/DMSO solution with
remarkable ease in high chemical yields and high optical
8
purity (Scheme 2).
9
8%) (Table 1). A similar reaction was carried out with
Scheme 2
dimethoxy acetaldehyde, and the corresponding (R)-2-
hydroxy-3,3-dimethoxy-1-phenylpropan-1-one (3a) was ob-
tained in 91% yield and ee >98%.
This reaction was carried out with a wide range of aromatic
aldehydes and heteroaromatic aldehydes, and the correspond-
Table 1. Synthetic (R)-2-HPP Derivatives
(R)-2a -j
(R)-3a -c
ARCHO
1
yield (%)a ee (%)b yield (%)a ee (%)b
In this paper, we focus on the synthetic potential of BAL
with regard to its ability to catalyze C-C bond formation
with aromatic aldehydes and functionalized acetaldehyde
derivatives to obtain the functionalized derivatives of HPP.
No such reaction was observed when using an aliphatic
aldehyde other than acetaldehyde (propanal, butanal, etc.).
Carboligation with functionalized acetaldehyde derivatives
may be a new and efficient way to obtain important chiral
polyoxo compounds.
a
b
c
d
e
f
g
h
i
ph
94
81
87
91
90
94
72
70
<5h
>98c
91
87
79
>98i
c
89j
2,4-F2C6H3
4-MeOC6H4
2-MeOC6H4
2-furanyl
94
92c
>98k
94c
95d
95e
ndf
91g
4-HOC6H4
3-OH-4-MeOC6H3
3,5-F2C6H3
3- pyridinyl
4-pyridinyl
<5h
<5
h
h
j
<5
a
(
3) Stermitz, F. R.; Lorenz, P.; Tawara, J. N.; Zenewicz, L. A.; Lewis,
K. Proc. Natl. Acad. Sci. 2000, 97, 1433.
4) (a) Krueger, K. H. Chem. Ber. 1956, 89, 1016. (b) Smith, L. I.;
Acetaldehyde derivatives were used in excess amounts, and yields are
b
based on aromatic aldehydes. Ee value is measured immediately after
workup. c Chiral HPLC analysis, Chiralcel OD column, UV detection at
(
d
Anderson, R. H. J. Org. Chem. 1951, 16, 963. (c) Guillot, G. Bull. Soc.
Chim. Fr. 1972, 2393. (d) Cahnmann, F. Bull. Soc. Chim. Fr. 1937, 226.
e) Beracierta, A. P.; Whiting, D. A. J. Chem. Soc., Perkin Trans. 1 1978,
254 nm, 95:5 hexane/2-propanol, flow 0.6 mL/min. Chiralcel OD column,
UV detection at 254 nm, 90:10 hexane/2-propanol, flow 0.5 mL/min.
e
(
1
Chiralpak AD, UV detection at 254 nm, 90:10 hexane/2-propanol, flow
0.7 mL/min. Not determined. g Chiralpak AD, UV detection at 254 nm,
f
257.
h
i
(5) Delton, M. H.; Yuen, G. U. J. Org. Chem. 1968, 33, 2473.
6) (a) Sch o¨ rken, U.; Sprenger, G. A. Biochim. Biophys. Acta 1998, 1385,
80:20 hexane/2-propanol, flow 0.7 mL/min. Detected by GC-MS. Chiral-
cel OD column, UV detection at 254 nm, 85:15 hexane/2-propanol, flow
0.8 mL/min. Chiralcel OD column, UV detection at 254 nm, 95:5 hexane/
2-propanol, flow 0.8 mL/min. Chiralcel OD column, UV detection at 254
nm, 97:3 hexane/2-propanol, flow 0.8 mL/min.
(
j
2
29. (b) Turner, N. J. Curr. Opin. Biotechnol. 2000, 11, 527.
7) (a) Ward, O. P.; Singh, A. Curr. Opin. Biotechnol. 2000, 11, 520.
b) Ward, O. P.; Baev, M. In StereoselectiVe Biocatalysis; Patel, R. N.,
Ed.; Marcel Dekker, Inc.; New York: 2000; p 487.
k
(
(
2048
Org. Lett., Vol. 5, No. 12, 2003

Scheme 4
ing acyloin derivatives 2a-j and 3a-c were obtained in high
afforded (R)-2a, (R)-3a, and (S)-benzoin in optically pure
form after separation of the products by column chroma-
tography (Scheme 4). To obtain full conversion of (R)-
benzoin into (R)-HPP derivatives, methoxy and dimethoxy
acetaldehydes have to be used in excess and should be added
to the reaction mixture at fixed time intervals. Some
representative examples of the synthesis of benzoins are
shown in Table 2.
enantiomeric excess, as summarized in Table 1. The optical
purity of the products was determined using HPLC with a
chiral column, and the data were compared with those from
racemic products synthesized either using classical chemical
4a
synthesis methodology or by racemization of chiral com-
9
pounds. Since HPP generated through wild-type BAL-
catalyzed reaction is of (R)-configuration, we assumed that
HPP derivatives also possess (R)-configuration. To determine
the absolute configurations of the products, (R)-2-hydroxy-
3
-methoxy-1-phenylpropan-1-one (2a) was converted chemi-
Table 2. Synthetic (S)-Benzoins and (R)-2-HPP Derivatives
5
cally to the known (R)-2,3-dihydroxy-1-phenylpropan-1-one
by means of a selective cleavage of ether functionality.
1
0
(S)-4a -e
(R)-2
yield (%)a
rac 4
Ar
yield (%)a
ee (%)b
ee (%)b
As shown in Table 1, BAL is able to bind a broad range
of different aromatic and heteroaromatic aldehydes to C2-
ThDP prior to ligation. The yield of the reaction depends
on the structure of the aldehyde. Fluorine substitution on
the 3,5- and 2,4-positions of the phenyl ring decreased the
yield of the reaction. Pyridine carbaldehyde also furnished
a low yield, but furfural and o-methoxy benzaldehyde gave
the products in high yields. The steric and electronic demand
of the substituent putatively plays a decisive role in the
conversion rate.
>98c
>98f
93
94f
96f
92g
a
b
c
d
e
ph
47
44
46
39
48
>98c
38.5
45.5
45
f
2,4-F2C6H3
4-MeOC6H4
2-MeOC6H4
2-furanyl
d
>98
>98
e
c
45.5
92
44
a
Acetaldehyde derivatives were used in excess amounts, and yields are
b
based on benzoin. Ee value is measured immediately after workup.
c
Chiralpak AD, UV detection at 254 nm, 90:10 hexane/2-propanol, flow
0.8 mL/min. d Chiralpak AD, UV detection at 254 nm, 75:25 hexane/2-
propanol, flow 0.95 mL/min. e Chiralpak AD, UV detection at 254 nm, 98:2
f
hexane/2-propanol, flow 0.90 mL/min. Chiralcel OD column, UV detection
8
at 254 nm, 95:5 hexane/2-propanol, flow 0.6 mL/min. g Chiralcel OD
column, UV detection at 254 nm, 90:10 hexane/2-propanol, flow 0.5 mL/
min.
In our previous communications, we showed that BAL
is also able to accept benzoin as a substrate to catalyze C-C
bond cleavage followed by carboligation in the presence of
acetaldehyde (Scheme 2). Accordingly, (R)-benzoin was
reacted with BAL in the presence of methoxy and dimethoxy
acetaldehyde; the reaction was monitored by HPLC. Addition
of the corresponding acetaldehyde derivative resulted in the
formation of (R)-2-hydroxy-3-methoxy-1-phenylpropan-1-
one (2a) and (R)-2-hydroxy-3,3-dimethoxy-1-phenylpropan-
The results presented here are in accord with the mecha-
nistic investigation of other ThDP-dependent enzymes. Since
structural information about BAL is still lacking, a structure-
based discussion of the observed stereocontrol is not yet
possible.
1
-one (3a) in high yields and almost optically pure form
The method described herein presents the first enzyme-
catalyzed highly enantioselective synthesis of (R)-2-hydroxy-
(Scheme 4). As anticipated, the same reaction starting from
(S)-benzoin failed. Repeating this reaction with rac-benzoin
3
-methoxy-1-arylpropan-1-one and (R)-2-hydroxy-3,3-di-
methoxy-1-arylpropan-1-one via acyloin linkage. The reac-
tion works in organic-aqueous medium, overcomes the
solubility problem with organic substrates, and paves the way
for large-scale preparation. The products are obtained in high
yields starting from simple, easily available aromatic alde-
hydes, benzoins, and methoxy and dimethoxy acetaldehyde
via C-C bond cleavage and carboligation reactions. This
(
8) (a) Demir, A. S.; Pohl, M.; Janzen, E.; M u¨ ller, M. J. Chem. Soc.,
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S.; Pohl, M. Chem. Eur. J. 2000, 6, 1483.
(
9) Demir, A. S.; Hamamci, H.; Sesenoglu, O.; Neslihanoglu, R.;
Asikoglu, B.; Capanoglu, D. Tetrahedron Lett. 2002, 43, 6447.
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Kunitama, Y.; Numazawa, M. J. Org. Chem. 1991, 56, 334.
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(12) Kochetkov, N. K.; Nifant’ev, E. E. J. Gen. Chem. 1960, 30, 1848.
(13) (a) Enders, D.; Breuer, K.; Teles, J. H. HelV. Chim. Acta 1996, 79,
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3499763, 1970; Chem. Abstr. 1970, 73, 89166.
(
(
Pharm. Bull. 1987, 35, 570.
Org. Lett., Vol. 5, No. 12, 2003
2049

type of polyoxygenated products in optically pure form can
be used for the synthesis of many biologically active
compounds.
tion (DPT), and the Deutsche Forschungsgemeinschaft in the
scope of SFB 380 is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. Financial support from Middle East
Technical University (BAP-2002), the Scientific and Techni-
cal Research Council of Turkey (TUBITAK), the Turkish
Academy of Science, the Turkish State Planning Organiza-
OL034415B
2050
Org. Lett., Vol. 5, No. 12, 2003