Enantioselective Synthesis of α-Hydroxy Ketones via Benzaldehyde Lyase-Catalyzed C-C Bond Formation Reaction

Article abstract of DOI:10.1002/1615-4169(200201)344:1<96::AID-ADSC96>3.0.CO;2-Z

(R)-Benzoins and (R)-2-hydroxypropiophenone derivatives are formed on a preparative scale by benzaldehyde lyase (BAL)-catalyzed C-C bond formation from aromatic aldehydes and acetaldehyde in aqueous buffer/ DMSO solution with remarkable ease in high chemical yield and high optical purity. The substrate range of this thiamin diphosphate-dependent enzyme was examined with respect to a broad applicability of this benzoin condensation-type reaction in stereoselective synthesis.

Full text of DOI:10.1002/1615-4169(200201)344:1<96::AID-ADSC96>3.0.CO;2-Z

FULL PAPERS
Enantioselective Synthesis of a-Hydroxy Ketones via Benzaldehyde Lyase-
À
Catalyzed C C Bond Formation Reaction
Ayhan S. Demir,a,* ÷zge SÀesÀenoglu,a Elif Eren,a Birsu Hosrik,a Martina Pohl,b,d
Elena Janzen,b Doris Kolter,c Ralf Feldmann,c Pascal D¸nkelmann,c Michael M¸llerc,*
a
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey,
Fax: ( ‡ 90)-312-2101280, e-mail: asdemir@metu.edu.tr
b
Institut f¸r Enzymtechnologie der Heinrich-Heine Universit‰t D¸sseldorf im Forschungszentrum J¸lich, 52426 J¸lich, Germany
c
Institut f¸r Biotechnologie 2, Forschungszentrum J¸lich GmbH, 52425 J¸lich, Germany,
Fax: ( ‡ 49)-2461-613870, e-mail: mi.mueller@fz-juelich.de
d
Present address: MPB Cologne GmbH, Neurather Ring 1, 51063 Kˆln, Germany
ReceivedMay 21, 2001; ReceivedrevisedNovember 19, 2001; AcceptedNovember 23, 2001
Abstract: (R)-Benzoins and( R)-2-hydroxypropiophenone
derivatives are formed on a preparative scale by benzalde-
diphosphate-dependent enzyme was examined with respect
to a broadapplicability of this benzoin condensation-type
reaction in stereoselective synthesis.
À
hyde lyase (BAL)-catalyzed C C bondformation from
aromatic aldehydes and acetaldehyde in aqueous buffer/
DMSO solution with remarkable ease in high chemical yield
andhigh optical purity. The substrate range of this thiamin
Keywords: benzoin condensation; biocatalyst; carboligation;
hydroxy ketones; thiamin diphosphate.
Introduction
Results and Discussion
The benzoin reaction,[1] one of the oldest C C bond-forming
Benzaldehyde lyase (BAL, EC 4.1.2.38) from Pseudomonas
À
¬
fluorescens Biovar I was first reportedby Gonza les and
reactions in organic chemistry, has been developed for classical
organic synthesis using non-chiral catalysts[2] andfor asym-
metric synthesis using chiral thiazolium andtriazolium salts as
catalyst.[3] Numerous other chemical methods for the enantio-
selective synthesis of 2-hydroxy ketones, which are not based on
[13]
ƒ
Vicuna. They showedthat this strain can grow on benzoin
as a sole carbon andenergy source due to the ability of BAL to
catalyze the cleavage of the acyloin linkage of benzoin yielding
benzaldehyde. The enzyme used in this study was expressed
andpurifiedfrom a recombinant Escherichia coli strain. For
easier purification a hexahistidine tag was cloned to the C-
terminus of the enzyme.[12]
C C bondformation, have been evolved. [4] As an alternative to
À
chemical methods, enantiomerically pure 2-hydroxy ketones
are preparedenzymatically [5] by reduction of the correspond-
ing a-diketone with baker×s yeast[6] or an enzymatic kinetic
resolution of the racemate of either 2-peroxo,[7] 2-hydroxy[8] or
2-acetoxy ketones.[9] In addition to these methods enzymatic
acyloin condensation furnishing a-hydroxy ketone function-
ality in one step has recently gainedincreasing attention. [10]
In our ongoing studies, we established that aromatic aldehydes
can be convertedinto acyloins by a benzoyl formate decarboxy-
lase (BFD)-catalyzedreaction. The reaction affords ( R)-benzoins
and( S)-2-hydroxypropiophenone [(S)-2-HPP] derivatives
with high enantiomeric excess andin goodchemical yields.
À
C
We investigatedthe potential of BAL for catalyzing C
bondformation. As shown in Scheme 1, performing the
carboligation reaction with BAL by using benzaldehyde as a
sole substrate in potassium phosphate buffer [(50 mmol LÀ1,
pH 7.0) containing MgSO4 (2.5 mmol LÀ1) andThDP
(0.15 mmol LÀ1)] at 218C andmonitoring of the reaction by
HPLC using a chiral stationary phase column with authentic
samples as reference showedthe formation of ( R)-benzoin
with an ee >99%, however only in low to moderate yield. The
low solubility of the aromatic substrate in aqueous buffer
solution can be regarded as a fundamental problem. With other
ThDP-dependent enzymes, e.g., benzoyl formate decarboxy-
lase (BFD) from Ps. putida, we observed that addition of
cyclodextrin or DMSO as cosolvent facilitates the formation of
However, only meta- and para-substitutedbenzaldehydes could
[11]
be usedas substrates.
In a preliminary communication we
reported the ability of benzaldehyde lyase (BAL), another thi-
amin diphosphate (ThDP)-dependent enzyme, for the enan-
tioselective formation of (R)- and( S)-benzoins and( R)-2-HPP
[11c]
acyloins in high yieldstarting from hydrophobic substrates.
À
À
derivatives via C C bondcleavage andC
C bondforma-
tion.[12] In this paper we focus on the synthetic potential of BAL
O
À
O
with regardto the ability to catalyze C C bondformation on a
preparative scale for the synthesis of enantiopure 2-hydroxy
R
R
BAL
buffer/DMSO
H
2
ketones. Another aim of this work was to give a broadsurvey of
R
OH
À
the substrate andproduct range of the BAL-catalyzedC
bondformation in oredr to gain information about the
C
1
2
(ee 91% to >99%)
structural importance of substituents of the substrate alde-
hydes with regard to enzyme activity and enantiomeric excess.
Scheme 1. BAL-mediated benzoin condensation.
96
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Adv. Synth. Catal. 2002, 344, No. 1

Enantioselective Synthesis of a-Hydroxy Ketones
FULL PAPERS
Accordingly, addition of DMSO (20%, v/v) to the aqueous
medium containing BAL resulted in the formation of (R)-
benzoin starting from benzaldehyde. This conversion worked
almost quantitatively and( R)-benzoin was obtainedin opti-
cally pure form (ee >99%). During the reaction most of the
benzoin precipitates from the reaction mixture. A small
amount of benzaldehyde was present at the end of the reaction
(1 2%).
drawing properties, and heteroaromatic aldehydes. In contrast
to BFD, BAL accepts aromatic aldehydes substituted at the
ortho-position as well, e.g., compounds 1b e. Only a few
aromatic aldehydes such as pyridine-3- and -4-carbaldehyde, 4-
hydroxybenzaldehyde and pyrrole-2-carbaldehyde as well as
sterically demanding aldehydes like vanillin, isovanillin and
3,4-dimethoxybenzaldehyde gave either very low yield or no
benzoin condensation.
The reaction was carriedout on a semipreparative scale with
different aromatic and heteroaromatic aldehydes and the
corresponding (R)-benzoins 2a s were obtainedin high yield
andmostly in enantiomerically pure form (Table 1). The
enantiomeric excess of the products was determined by HPLC
on a chiral stationary phase column comparedto racemic
products, which were synthesized using classical chemical
benzoin synthesis methodology.[14] The absolute configuration
of the benzoins 2a, b, i, k o, r, s was assignedto be R according
to a correlation of the optical rotation value of benzoins with
data from the literature and to HPLC data of commercially
available enantiomers of benzoins. The absolute configuration
of 2c h, j, p, q was assignedassuming a uniform reaction
mechanism. As can be seen from Table 1, BAL is able to
activate and dimerize a broad range of aromatic aldehydes,
substitutedwith electron-releasing as well as electron-with-
In some cases, e.g., for the halogenatedcompounds, we
observedthe formation of trace amounts of the corresponding
benzils, a known side reaction which is probably due to
oxidation of benzoins by oxygen.[15]
To further demonstrate the usefulness of BAL-catalyzed
reactions on a preparative scale the synthesis of (R)-3,3'-
dimethoxybenzoin (2i) was performedin a repetitive batch
mode. Starting from 2 Â 1.62 g (24 mmol) 3-methoxybenzal-
dehyde and 60 U BAL, after 6 hours at room temperature the
enantiopure product 2i was isolatedin 93% yield.
The BAL-catalyzedtransformation of benzaldehyde in the
presence of acetaldehyde afforded (R)-benzoin (2a) and( R)-2-
HPP 3a in enantiomerically pure form. We observedthat the
benzaldehyde/acetaldehyde ratio is very important for the
product distribution, since excess acetaldehyde resulted in high
yieldformation of ( R)-2-HPP, whereas a 1:1 ratio of benzal-
dehyde/acetaldehyde gave an almost equimolar mixture of
(R)-benzoin and( R)-2-HPP.
As expectedfrom the above-mentionedresults, a wide range
of aromatic aldehydes substituted at ortho-, meta-, and para-
position and heteroaromatic aldehydes were accepted as donor
Table 1. BAL-catalyzed carboligation of aromatic aldehydes to the
corresponding (R)-benzoins 2.
O
substrates for the formation of (R)-2-HPP analogues 3a
p
BAL
buffer/DMSO
Ar
(Table 2). In general ortho-substituted aromatic aldehydes
afforded HPPs 3 in lower yields than the meta-, and para-
substituted aldehydes. 2-Chlorobenzaldehyde and 2-methyl-
benzaldehyde gave no 2-HPP formation. The preference of
BAL for aromatic substrates is underlined by the observation
that 2,2'-disubstituted benzoins were formed with remarkable
ease, e.g., compound 2e, whereas the corresponding 2-HPP
derivative 3c was formedin moedrate yieldeven after
prolongedreaction time. Interestingly, even sterically demand-
ing aromatic aldehydes were accepted as donor substrates in
the presence of acetaldehyde (3m o, Table 2). Enantiomeric
excess of 2-HPP derivatives 3 was determined by chiral phase
2
ArCHO
Ar
OH
2
[a]
(R)-benzoins 2
Ar
yield[%]
ee [%]
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Ph
2-FC6H4
96
68
80
90
87
80
94
94
93
84
89
95
83
95
94
87
98
88
73
> 99
96
97
> 99
> 99[b]
97
> 99
> 99
> 99
n.d.[c]
> 99
> 99
> 99
> 99[d]
> 99
> 99
> 99[e]
92
2-ClC6H4
2-BrC6H4
2-MeOC6H4
3-FC6H4
3-ClC6H4
3-BrC6H4
3-MeOC6H4
3-HOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeOC6H4
4-MeC6H4
2,4-F2C6H3
2-naphthalenyl
2-furanyl
2-thienyl
HPLC analysis using racemic compounds 3c, o[16] or (S)-
[11a, c]
acyloins 3a, d l preparedby BFD-catalyzedreaction
as
references. The absolute configuration of the acyloins 3a, b, d,
e, g, h, j l, p was assignedto be R according to the correlation
of the optical rotation of acyloins with data from the literature
andto HPLC adta of the ( S)-enantiomers. The absolute
O
O
s
91
R
R
BAL
buffer/DMSO
H
[a]
Enantiomeric excess of benzoins 2 was determined by chiral phase
HPLC analysis (Chiralpak AD column, UV detection at 254 nm,
eluent: n-hexane/2-propanol ˆ 90: 10, flow 0.80 mL minÀ1, 208C) using
racemic compounds as references.
OH
acetaldehyde
1
3 (ee 93% to >99%)
[b]
[c]
[d]
[e]
Eluent: n-hexane/2-propanol ˆ 98:2, flow 0.90 mL minÀ1, 208C.
Not determined.
Scheme 2. BAL-mediated carboligation of aromatic aldehydes
and acetaldehyde to the corresponding (R)-2-hydroxypropiophe-
none derivatives 3.
Eluent: n-hexane/2-propanol ˆ 75:25, flow 0.95 mL minÀ1, 208C.
Eluent: n-hexane/2-propanol ˆ 10:90, flow 0.95 mL minÀ1, 208C.
Adv. Synth. Catal. 2002, 344, 96 103
97

Ayhan S. Demir et al.
FULL PAPERS
Table 2. BAL-catalyzed carboligation of aromatic aldehydes and acetal-
dehyde to the corresponding (R)-2-hydroxypropiophenone derivatives 3.
the viewpoint of the organic-preparative chemist, it is impor-
tant to mention that a crude cell extract of the recombinant E.
coli strain overexpressing the BAL gene[21] is sufficient for
catalysis hence purification of the enzyme is not necessary. As
shown for the synthesis of 3k, it is important to remove the
major fraction of protein by ultrafiltration (cut-off 10 kDa) in
order to facilitate product isolation. In doing so, the desired
(R)-2-HPP 3k was isolatedin 65% yieldon a 3-gram scale. As
described for the benzoins, oxidation of acyloins to diketones
was observed in some cases as a side reaction during work-up
or even in aqueous buffer after prolongedreaction time.
The results presentedare in accordwith mechanistic
investigations of other ThDP-dependent enzymes.[11a,22] Since
structural information about BAL is still lacking, a structure-
baseddiscussion of the observedstereocontrol is not yet
possible. Nevertheless, the carboligation must be a conse-
quence of a selective attack of an enamine intermediate to an
acceptor aldehyde yielding (R)-benzoins and( R)-2-HPP
analogues in optically pure form. We expect that our inves-
tigations concerning the substrate andproduct range of this
valuable biocatalyst will be helpful for elucidation of the
catalytic cycle.
O
BAL
buffer/DMSO
Me
ArCHO + CH3CHO
Ar
OH
3
[a]
(R)-2-HPP derivatives 3
Ar
yield[%]
ee [%]
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
Ph
2-FC6H4
2-MeOC6H4
3-FC6H4
3-ClC6H4
3-BrC6H4
3-MeOC6H4
4-ClC6H4
94
64
63
85
94
88
80
88
86
64
65
67
80
90
92
61
>99[b]
97[b]
>99[c]
95
>99[c]
93
>99[d]
>99
>99
>99
97[b]
4-BrC6H4
4-MeOC6H4
2,4-F2C6H3
3,5-F2C6H3
3-HO-4-MeOC6H3
3-MeO-4-HOC6H3
3,4,5-(MeO)3C6H2
2-furanyl
>99
n.d.[e]
n.d.[e]
>99[f]
>99[d]
[a]
Enantiomeric excess of 2-HPP derivatives 3 was determined by chiral
phase HPLC analysis (Chiralcel OB column, UV detection at 254 nm,
eluent:isohexane/2-propanol ˆ 95: 5, flow 0.75 mL minÀ1, 208C) using
racemic compounds or (S)-acyloins (preparedby BFD-catalyzed
reaction) as references.[11]
Conclusion
In conclusion, the methoddescribedhere presents a conven-
ient one-enzyme-catalyzed, highly selective synthesis of (R)-
benzoins and( R)-2-HPP analogues. The reaction works in
organic-aqueous medium, overcomes the solubility problem
with organic substrates, andopens the way for large-scale
preparation. The products are obtained in high yield starting
from simple, easily available aromatic aldehydes and acetal-
dehyde via carboligation reactions. In this way, BAL represents
a valuable alternative to BFD concerning the formation of (R)-
benzoins.[11b] Since these two enzymes are enantiocomplimen-
tary with regardto 2-HPP formation, most members of this
class of substances, except for ortho-substituted( S)-2-HPP
derivatives, can be synthesized in either enantiomeric form
using these two enzymes.
[b]
[c]
[d]
Chiralpak AD, eluent: isohexane/2-propanol ˆ 90: 10, flow 0.80 mL
minÀ1, 208C.
Chiralcel OB column, eluent: isohexane/2-propanol ˆ 98: 2, flow
0.75 mL minÀ1, 208C.
Chiralcel OB column, eluent: isohexane/2-propanol ˆ 90: 10, flow
0.75 mL minÀ1, 208C.
[e]
[f]
Not determined.
Chiralpak AD column, eluent: isohexane/2-propanol ˆ 95: 5, flow
0.75 mL minÀ1, 208C.
configuration of 3c, f, i, m o was assignedassuming a uniform
reaction mechanism.
Recently, several chiral 2-HPP derivatives became of
interest as starting material for the stereoselective syntheses
of biologically active substances, especially for pharmaceuti-
cals possessing antifungal properties. The 2-HPP derivatives,
(R)-1-(3-chlorophenyl)-2-hydroxypropan-1-one (3e), starting
material for Bupropion,[17] (R)-1-(2,4-difluorophenyl)-2-hy-
droxypropan-1-one (3k), starting material for Ro 09-3355[18]
andSM 8668/Sch 39304,
hydroxypropan-1-one (3l), potential starting material for
1555U88,[20] were synthesizedon a preparative scale. From
Experimental Section
General Methods
[19]
and( R)-1-(3,5-difluorophenyl)-2-
Enzymatic syntheses were performedin standardbuffer consisting of
potassium phosphate (50 mmol LÀ1
,
pH 7.0) containing MgSO4
(2.5 mmol LÀ1) andThDP (0.15 mmol L À1). NMR spectra were recorded
on a Bruker DPX 400 or on a Bruker AMX 300. Chemical shifts d are
reportedin ppm relative to C HCl3 (1H: d ˆ 7.27) and CDCl3 (13C: d ˆ 77.0) or
DMSO (1H: d ˆ 2.49) andDMSO- d6 (13C: d ˆ 39.7) as internal standard.
Column chromatography was conducted on silica gel 60 (40 63 mm). TLC
O
F
O
O
F
was carriedout on aluminium sheets precoatedwith silica gel 60F
254
(Merck), andthe spots were visualizedwith UV light ( l ˆ 254 nm).
Enantiomeric excesses were determined by HPLC analysis using a Thermo
Quest (TSP) GC-LC-MS equippedwith an appropriate optically active
column, as described in the footnotes of the corresponding Tables. GC-mass
spectra were determined on a phenomenex Zebron ZB-5 capillary column
(5% phenylmethylsiloxane, 30 m, 250 mm; TGC (injector) ˆ 2508C, TMS (ion
OH
OH
OH
F
Cl
F
3k
3e
3l
Scheme 3.
source) ˆ 2008C, time program (oven): T0min ˆ 608C, T3min ˆ 608C, T14min ˆ
98
Adv. Synth. Catal. 2002, 344, 96 103

Enantioselective Synthesis of a-Hydroxy Ketones
FULL PAPERS
2808C (heating rate 208C minÀ1), T19min ˆ 2808C, T20min ˆ 3008C (heating
rate 208C minÀ1), T25min ˆ 3008C, MS: EI, 70 eV). Optical rotations were
measuredwith a Bellingham & Stanley P20 polarimeter or a Perkin-Elmer
241 polarimeter. Mps were measuredon a capillary tube apparatus andare
uncorrected. HRMS (EI) and microanalyses were carried out at the
Analytical Department, Chemische Institute der Universit‰t Bonn.
(R)-1,2-Bis(2-bromophenyl)-2-hydroxyethan-1-one (2d)
Semisolid; yield: 90% (>99% ee); [a]2D0: À24.4 (c 1.5, CHCl3); HPLC
(Chiralpak AD): Rt (S) ˆ 23.1 min; Rt (R) ˆ 26.4 min; 1H NMR (400 MHz,
CDCl3/CCl4): d ˆ 6.97 7.93 (m, 8H), 6.22 (d, J ˆ 4.9 Hz, 1H), 4.22 (d, J ˆ
4.9 Hz, 1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 201.6, 138.1, 134.7,
133.7, 133.5, 132.4, 130.5, 129.7, 128.2, 127.9, 127.2, 124.6, 123.6, 77.6.
Preparation of BAL
(R)-2-Hydroxy-1,2-bis(2-methoxyphenyl)ethan-1-one (2e)
Hexahistidine-tagged BAL was obtained from recombinant E. coli SG13009
cells following a procedure described previously.[11a] One unit (U) of activity
is defined as the amount of enzyme which catalyzes the cleavage of 1 mmol
benzoin (1.5 mM) into benzaldehyde in potassium phosphate buffer
Colorless solid; yield: 87% (>99% ee); mp 998C [Lit.[25], mp 98 998C for
racemic compound]; [a]2D0: À125.0 (c 0.9, CHCl3); HPLC (Chiralpak AD, n-
hexane/2-propanol ˆ 98:2, flow 0.90 mL minÀ1, 208C): Rt (R) ˆ 31.2 min.; Rt
1
[50 mmol LÀ1
,
pH 7.0, containing MgSO4 (2.5 mmol LÀ1), ThDP
(S) ˆ 42.2 min; H NMR (400 MHz, CDCl3/CCl4): d ˆ 6.63 7.69 (m, 8H),
5.92 (d, J ˆ 5.1 Hz, 1H), 4.29 (d, J ˆ 5.1 Hz, 1H), 3.71 (s, 3H), 3.69 (s, 3H); 13
C
(0.15 mmol LÀ1) and15% PEG 400 (v/v)] in 1 min at 30 8C.
NMR (100 MHz, CDCl3/CCl4): d ˆ 201.6, 158.4, 157.6, 134.0, 131.1, 130.3,
129.8, 128.2, 125.8, 120.9, 120.8, 111.4, 111.2, 76.1, 55.5, 55.4.
Representative Example for the Synthesis of (R)-Benzoins:
(R)-2-Hydroxy-1,2-diphenylethan-1-one (2a)
(R)-1,2-Bis(3-fluorophenyl)-2-hydroxyethan-1-one (2f)
Colorless solid; yield: 80% (97% ee); mp 70 718C [Lit.[24], mp 73 768C for
racemic compound]; [a]2D0: À38.2 (c 2.5, CHCl3); HPLC (Chiralpak AD): Rt
(R) ˆ 18.9 min; Rt (S) ˆ 23.9 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ
7.67 7.71 (m, 2H), 7.40 7.62 (m, 4H), 6.96 7.32 (m, 2H), 5.77 (d, J ˆ
4.8 Hz, 1H), 4.45 (d, J ˆ 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3/CCl4):
d ˆ 197.2, 163.0 (d, J ˆ 247 Hz), 162.7 (d, J ˆ 248 Hz), 140.9 (d, J ˆ 7 Hz),
135.5 (d, J ˆ 7 Hz), 130.7 (d, J ˆ 8 Hz), 130.4 (d, J ˆ 7 Hz), 124.8 (d, J ˆ
3 Hz), 123.4 (d, J ˆ 3 Hz), 121.1 (d, J ˆ 21 Hz), 115.9 (d, J ˆ 23 Hz), 115.8 (d,
J ˆ 21 Hz), 114.7 (d, J ˆ 21 Hz), 75.7.
Benzaldehyde (318 mg, 3 mmol) was dissolved in a mixture of dimethyl
sulfoxide (20 mL) and potassium phosphate buffer [80 mL, 50 mM, pH 7.0,
containing MgSO4 (2.5 mM) and ThDP (0.15 mM)]. After addition of BAL
(20 U) the reaction mixture was allowedto standat 25 8C for 48 h before a
further 20 U of BAL were added. After 62 h no more benzaldehyde was
detected (GC-MS). The reaction mixture was extracted with dichloro-
methane (250 mL) andthe organic layer washedwith water (25 mL) and
brine (25 mL) anddriedover Na 2SO4. Evaporation of the solvent and
purification of the crude product by crystallization afforded (R)-2-hydroxy-
1,2-diphenylethan-1-one as a colorless solid; yield: 305 mg (96%, >99% ee);
mp 133 1348C [Lit.[23], mp 132 1338C for (R)-enantiomer]; [a]2D2: À 113.8
(c 1.5, CH3COCH3); [Lit.[23] [a]D22: À 118.3 (c 2.5, CH3COCH3) for >99% ee];
HPLC: (Chiralpak AD) Rt (R) ˆ 27.1 min; Rt (S) ˆ 34.5 min; 1H NMR
(400 MHz, CDCl3/CCl4): d ˆ 7.92 (d, J ˆ 7.9 Hz, 2H), 7.29 7.52 (m, 8H),
5.97 (d, J ˆ 6.1 Hz, 1H), 4.58 (d, J ˆ 6.1 Hz, 1H); 13C NMR (100 MHz, CDCl3
/CCl4): d ˆ 198.9, 139.6, 134.1, 134.0, 129.5, 129.4, 128.9, 128.8, 128.2, 76.5.
(R)-1,2-Bis(3-chlorophenyl)-2-hydroxyethan-1-one (2g)
Colorless solid; yield: 94% (>99% ee); mp 76 788C [Lit.[30], mp 768C for
racemic compound]; [a]2D0: À31.0 (c 1.2, CHCl3); HPLC (Chiralpak AD): Rt
(R) ˆ 20.2 min; Rt (S) ˆ 26.2 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ
7.09 7.82 (m, 8H), 5.76 (d, J ˆ 5.7 Hz, 1H), 4.32 (d, J ˆ 5.7 Hz, 1H); 13C
NMR (100 MHz, CDCl3/CCl4): d ˆ 197.5, 140.8, 135.7, 135.6, 135.3, 134.4,
130.7, 130.4, 129.5, 129.4, 128.3, 127.5, 126.1, 75.9.
(R)-1,2-Bis(2-fluorophenyl)-2-hydroxyethan-1-one (2b)
Colorless solid; yield: 68% (96% ee); mp 61 628C [Lit.[24], mp 60 628C for
racemic compound]; [a]D20: À264.1 (c 0.5, CH3OH) [Lit.[11b], [a]2D0: À266.0, (c
0.5, CH3OH) for >99% ee]; HPLC (Chiralpak AD): Rt (S) ˆ 17.8 min; Rt
(R)-1,2-Bis(3-bromophenyl)-2-hydroxyethan-1-one (2h)
1
(R) ˆ 20.2 min; H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.80 7.91 (m, 1H),
7.55 7.67 (m, 1H), 6.98 7.30 (m, 6H), 5.91 (d, J ˆ 5.6 Hz, 1H), 4.33 (d, J ˆ
5.6 Hz, 1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 198.6, 164.2 (d, J ˆ
253 Hz), 163.5 (d, J ˆ 251 Hz), 134.7 (d, J ˆ 13 Hz), 134.1 (d, J ˆ 12 Hz),
130.6, 131.2, 129.2, 128.9, 124.4, 123.6, 116.2 (d, J ˆ 24 Hz), 115.4 (d, J ˆ
23 Hz), 75.9.
Colorless solid; yield: 94% (>99% ee); mp 75 778C [Lit.[26], mp 758C for
racemic compound]; [a]2D0: À38.0 (c 2.0, CHCl3); HPLC (Chiralpak AD): Rt
(R) ˆ 22.7 min; Rt (S) ˆ 28.0 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ
7.31 8.30 (m, 8H), 6.01 (d, J ˆ 5.5 Hz, 1H), 4.72 (d, J ˆ 5.5 Hz, 1H); 13C
NMR (100 MHz, CDCl3/CCl4): d ˆ 197.4, 141.1, 137.2, 137.1, 132.9, 132.6,
132.2, 131.1, 130.9, 130.8, 127.8, 126.6, 123.6, 75.9.
(R)-1,2-Bis(2-chlorophenyl)-2-hydroxyethan-1-one (2c)
(R)-2-Hydroxy-1,2-bis(3-hydroxyphenyl)ethan-1-one (2j)
Colorless solid; yield: 80% (97% ee); mp 57 618C [Lit.[30], mp 648C for
racemic compound]; [a]2D0: À46.0 (c 1.0, CHCl3); HPLC (Chiralpak AD): Rt
(S) ˆ 21.7 min; Rt (R) ˆ 24.1 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ
7.19 7.47 (m, 8H), 6.32 (d, J ˆ 5.8 Hz, 1H), 4.35 (d, J ˆ 5.8 Hz, 1H);
13C NMR (100 MHz, CDCl3/CCl4): d ˆ 200.8, 136.2, 135.4, 134.2, 133.0,
132.8, 132.3, 131.2, 130.2, 129.6, 129.3, 127.8, 126.7, 75.6; HRMS: m/z calcd.
Colorless solid; yield: 84% (ee not determined); mp 1508C [Lit.[27], mp. 173
1758C for racemic compound]; [a]2D3: À144.4 (c 1.0, CH3OH); 1H NMR
(300 MHz, DMSO-d6): d ˆ 9.91 (s, 1H), 9.41 (s, 1H), 7.42 (d, J ˆ 7.9 Hz, 1H),
7.30 (s, 1H), 7.24 (t, J ˆ 7.9 Hz, 1H), 7.09 (t, J ˆ 7.7 Hz, 1H), 6.95 (d, J ˆ
8.0 Hz, 1H), 6.79 (t, J ˆ 7.7 Hz, 2H), 6.63 (d, J ˆ 8.0 Hz, 1H), 5.87 (s, 2H); 13
C
‡
for C14H10O2Cl2 [M À Cl]: 245.0375, found: 245.0372; anal. calcd. for C14H10
NMR (75.5 MHz, DMSO-d6): d ˆ 199.1, 157.44, 157.41, 141.2, 136.1, 129.7,
O2Cl2: C, 59.81; H, 3.59%; found: C, 60.07; H, 3.79%.
129.5, 120.3, 119.8, 118.0, 115.1, 114.7, 114.0, 75.7.
Adv. Synth. Catal. 2002, 344, 96 103
99

Ayhan S. Demir et al.
FULL PAPERS
(dd, J ˆ 12, 257 Hz), 162.9 (dd, J ˆ 12, 250 Hz), 161.9 (dd, J ˆ 12, 257 Hz),
160.9 (dd, J ˆ 12, 251 Hz), 132.9 (dd, J ˆ 4, 11 Hz), 130.7 (dd, J ˆ 5, 10 Hz),
121.5 (dd, J ˆ 3, 14 Hz), 118.8 (dd, J ˆ 4, 13 Hz), 112.5 (dd, J ˆ 3, 21 Hz),
111.6 (dd, J ˆ 4, 21 Hz), 105.2 (dd, J ˆ 26 Hz), 104.7 (dd, J ˆ 25 Hz), 72.9 (d,
J ˆ 7 Hz).
(R)-1,2-Bis(4-fluorophenyl)-2-hydroxyethan-1-one (2k)
Colorless solid; yield: 89% (>99% ee); mp 81 828C [Lit.[24], mp 80 828C
for racemic compound]; [a]2D0: À95.2 (c 1.1, CH3OH) [Lit.[3c], [a]Dr:t:: À41.2, (c
1.0, CH3OH) for 44% ee]; HPLC (Chiralpak AD): Rt (S) ˆ 22.5 min; Rt
(R) ˆ 26.5 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.84 (m, 2H), 7.25 (m,
2H), 7.12 (m, 2H), 7.09 (m, 2H), 5.86 (d, J ˆ 5.4 Hz, 1H), 4.12 (d, J ˆ 5.4 Hz,
1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 197.2, 166.7 (d, J ˆ 246 Hz),
165.7 (d, J ˆ 232 Hz), 135.1, 134.9, 132.1 (d, J ˆ 9.6 Hz), 130.2 (d, J ˆ 9.4 Hz),
116.8 (d, J ˆ 22 Hz), 116.1 (d, J ˆ 20 Hz), 75.4.
(R)-2-Hydroxy-1,2-di(2-naphthalenyl)ethan-1-one (2q)
Colorless solid; yield: 98% (>99% ee); mp 1278C [Lit.[31], mp 125 1268C
for racemic compound]; [a]2D0: 21.0 (c 1.1, CHCl3); HPLC (Chiralpak AD, n-
hexane/2-propanol ˆ 10:90, flow 0.95 mL minÀ1, 208C): Rt (R) ˆ 18.5 min; Rt
(S) ˆ 30.0 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 6.71 7.76 (m, 14H),
5.92 (d, J ˆ 6.1 Hz, 1H), 4.86 (d, J ˆ 6.1 Hz, 1H); 13C NMR (100 MHz, CDCl3
/CCl4): d ˆ 198.9, 137.3, 136.5, 134.5, 134.4, 132.9, 131.5, 129.7, 129.2, 128.9,
128.3, 127.9, 127.2, 126.4, 124.7, 122.9, 76.7.
(R)-1,2-Bis(4-chlorophenyl)-2-hydroxyethan-1-one (2l)
Colorless solid; yield: 95% (>99% ee); mp 898C [Lit.[28,30], mp 87 888C for
racemic compound]; [a]D20: À29.0 (c 0.1, CH3OH) [Lit.[3c], [a]rD:t:: À12.3, (c 1.0,
CH3OH) for 29% ee; Lit.[3b], [a]D: 32.0, (CH3OH) for 76% ee (S)]; HPLC
(Chiralpak AD): Rt (R) ˆ 26.7 min; Rt (S) ˆ 31.5 min; 1H NMR (400 MHz,
CDCl3/CCl4): d ˆ 7.75 (d, J ˆ 8.5 Hz, 2H), 7.31 (d, J ˆ 8.5 Hz, 2H), 7.22 (d,
J ˆ 8.5 Hz, 2H), 7.15 (d, J ˆ 8.5 Hz, 2H), 5.75 (d, J ˆ 5.2 Hz, 1H), 4.32 (d, J ˆ
5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 197.5, 141.1, 137.7,
135.2, 132.0, 130.8, 129.8, 129.5, 129.4, 75.8.
(R)-1,2-Di(2-furanyl)-2-hydroxyethan-1-one (2r)
Brown solid; yield: 88% (92% ee); mp 1368C [Lit.[2c], mp 135 1368C for
racemic compound]; [a]D20: À21.6 (c 0.1, CH3OH) [Lit.[32], [a]2D0: À22.0, (c
0.01, CH3OH) for 94% ee]; HPLC (Chiralpak AD): Rt (S) ˆ 22.8 min; Rt
(R)-1,2-Bis-(4-bromophenyl)-2-hydroxyethan-1-one (2m)
1
(R) ˆ 28.6 min; H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.90 7.91 (m, 1H),
7.51 7.52 (m, 1H), 7.44 (d, J ˆ 3.6 Hz, 1H), 6.60 (dd, J ˆ 1.5, 3.6 Hz, 1H),
6.32 6.36 (m, 2H), 5.84 (d, J ˆ 5.6 Hz, 1H), 3.98 (d, J ˆ 5.6 Hz, 1H); 13C
NMR (100 MHz, DMSO-d6): d ˆ 185.2, 152.6, 149.9, 148.5, 143.3, 120.6,
112.7, 110.9, 108.8, 69.7.
Colorless solid; yield: 83% (>99% ee); mp 85 878C [Lit.[29], mp 95 988C
for racemic compound]; [a]2D0: À13.0 (c 0.5, CH3OH) [Lit.[3c], [a]Dr:t:: À2.3, (c
1.0, CH3OH) for 20% ee; Lit.[11b], [a]D20: À12.0, (c 0.5, CH3OH) for >99% ee];
HPLC (Chiralpak AD): Rt (R) ˆ 32.4 min; Rt (S) ˆ 36.5 min; 1H NMR
(400 MHz, CDCl3/CCl4): d ˆ 7.65 (d, J ˆ 8.5 Hz, 2H), 7.49 (d, J ˆ 8.5 Hz,
2H), 7.38 (d, J ˆ 8.5 Hz, 2H), 7.10 (d, J ˆ 8.5 Hz, 2H), 5.72 (d, J ˆ 6.1 Hz,
1H), 4.29 (d, J ˆ 6.1 Hz, 1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 197.6,
138.1, 132.7, 132.5, 132.0, 130.6, 129.8, 129.7, 123.4, 75.8.
(R)-1,2-Di(2-thienyl)-2-hydroxyethan-1-one (2s)
Colorless solid; yield: 73% (91% ee); mp 1078C [Lit.[33], mp 108 1098C for
racemic compound]; [a]D20: À392.0 (c 0.1, CHCl3) [Lit.[32], [a]D20: À380.0, (c
0.1, CHCl3) for 95% ee]; HPLC (Chiralpak AD): Rt (R) ˆ 35.0 min; Rt (S) ˆ
(R)-2-Hydroxy-1,2-bis(4-methoxyphenyl)ethan-1-one (2n)
1
40.6 min; H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.10 7.40 (m, 4H), 6.41
Colorless solid; yield: 95% (>99% ee); mp 1128C [Lit.[2c], mp 109 1108C
for racemic compound]; [a]2D0: À90.4 (c 1.0, CH3OH) [Lit.[3c], [a]Dr:t:: À76.2, (c
1.1, CH3OH) for 86% ee]; HPLC (Chiralpak AD, n-hexane/2-propanol ˆ
75:25, flow 0.95 mL mL minÀ1, 208C): Rt (R) ˆ 25.4 min; Rt (S) ˆ 30.2 min;
1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.85 (d, J ˆ 8.6 Hz, 2H), 7.24 (d, J ˆ
8.6 Hz, 2H), 7.16 (d, J ˆ 8.6 Hz, 2H), 6.82 (d, J ˆ 8.6 Hz, 2H), 5.84 (d, J ˆ
5.7 Hz, 1H), 4.46 (d, J ˆ 5.7 Hz, 1H), 3.85 (s, 3H), 3.76 (s, 3H); 13C NMR
(100 MHz, CDCl3/CCl4): d ˆ 197.3, 164.2, 159.9, 132.4, 131.9, 129.4, 126.8,
114.8, 114.7, 75.5, 55.5, 55.3.
6.60 (m, 2H), 5.81 (d, J ˆ 5.8 Hz, 1H), 4.14 (d, J ˆ 5.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3/CCl4): d ˆ 196.2, 148.1, 143.5, 124.7, 119.6, 119.2, 113.1,
112.1, 110.2, 75.4.
Synthesis of (R)-2-Hydroxy-1,2-bis(3-methoxyphenyl)ethan-
1-one (2i) on a Preparative Scale
To a suspension of 3-methoxybenzaldehyde (1.62 g, 12 mmol) in dimethyl
sulfoxide (40 mL) and potassium phosphate buffer [160 mL, 50 mM, pH 7.0,
containing MgCl2 (2.5 mM) andThDP (0.15 mM)] BAL (0.3 U/mL) was
added and the reaction-mixture stirred at 218C. After a reaction-time of 3 h
(R)-2-Hydroxy-1,2-bis(4-methylphenyl)ethan-1-one (2o)
Colorless solid; yield: 94% (>99% ee); mp 908C [Lit.[30], mp 898C for
racemic compound]; [a]D20: À150.0 (c 0.7, CH3OH) [Lit.[3c], [a]rD:t:: À130.8, (c
1.0, CH3OH) for 82% ee; Lit.[3b], [a]D: 107.0, (CH3OH) for 82.5% ee (S)];
HPLC (Chiralpak AD): Rt (R) ˆ 30.2 min; Rt (S) ˆ 36.0 min; 1H NMR
(400 MHz, CDCl3/CCl4): d ˆ 7.83 (d, J ˆ 8.1 Hz, 2H), 7.18 7.22 (m, 4H),
7.16 (d, J ˆ 8.1 Hz, 2H), 5.88 (d, J ˆ 5.8 Hz, 1H), 4.52 (d, J ˆ 5.8 Hz, 1H), 2.36
(s, 3H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 198.5, 144.7,
138.3, 136.9, 131.5, 130.0, 129.7, 129.6, 128.1, 76.1, 22.1, 21.6.
the product, which accumulates as
a yellow oil, was separated by
centrifugation and 3-methoxybenzaldehyde (1.62 g, 12 mmol) was added
to the buffer solution. The reaction-mixture was stirred for an additional 3 h
at 218C before extraction with dichloromethane (3 x 50 mL) was carried out.
After drying the collected organic phase over Na2SO4, removal of thesolvent
under reduced pressure gave the crude product. Crystallization at
À 188C from isohexane/ethyl acetate afforded the pure product as a white
solid; yield: 3.03 g (93%, >99% ee); mp 558C [Lit.[34], mp 558C for racemic
compound]; [a]D20: À156.0 (c 1.0, CH3OH) [Lit.[3c], [a]Dr:t:: À105.9, (c 1.0, CH3
OH) for 66% ee]; HPLC (Chiralpak AD, n-hexane/2-propanol ˆ 90:10, flow
(R)-1,2-Bis(2,4-difluorophenyl)-2-hydroxyethan-1-one (2p)
0.90 mL minÀ1
,
208C): Rt (R) ˆ 41.0 min; Rt (S) ˆ 54.1 min; 1H NMR
(300 MHz, CDCl3): d ˆ 7.46 7.51 (m, 2H), 7.22 7.34 (m, 2H), 7.07 (d,
J ˆ 8.4 Hz, 1H), 6.94 (d, J ˆ 6.9 Hz, 1H), 6.86 (t, J ˆ 2.4 Hz, 1H), 6.82 (d, J ˆ
8.4 Hz, 1H), 5.90 (d, J ˆ 6.1 Hz, 1H), 4.54 (d, J ˆ 6.1 Hz, 1H), 3.81(s, 3H), 3.77
(s, 3H); 13C NMR (75.5 MHz, CDCl3): d ˆ 198.9, 160.3, 159.9, 140.6, 134.9,
130.4, 129.9, 122.0, 120.7, 120.3, 114.3, 113.5, 113.3, 76.4, 55.6, 55.4.
Semisolid; yield: 87% (>99% ee); [a]2D0: À102.4 (c 2.0, CHCl3); HPLC
(Chiralpak AD): Rt (R) ˆ 17.3 min; Rt (S) ˆ 18.3 min; 1H NMR (400 MHz,
CDCl3/CCl4): d ˆ 7.82 7.97 (m, 2H), 6.86 7.10 (m, 4H), 5.87 (s, 1H), 4.18
(br.s, 1H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 195.2 (d, J ˆ 5 Hz), 166.3
100
Adv. Synth. Catal. 2002, 344, 96 103

Enantioselective Synthesis of a-Hydroxy Ketones
FULL PAPERS
Representative Example for the Synthesis of (R)-2-Hydroxy-
1-phenylpropan-1-one Derivatives: (R)-2-Hydroxy-1-
phenylpropan-1-one [(R)-2-HPP] (3a)
(R)-1-(3-Bromophenyl)-2-hydroxypropan-1-one (3f)
Viscous oil; yield: 88%; (93% ee); [a]2D0: 22.1 (c 1.5, CHCl3); HPLC (Chiralcel
OB, isohexane/2-propanol ˆ 95:5, flow 0.75 mL minÀ1, 208C): Rt (S) ˆ
23.0 min; Rt (R) ˆ 33.7 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 8.04
8.05 (m, 1H), 7.82 7.84 (m, 1H), 7.73 7.75 (m, 1H), 7.36 7.40 (m, 1H), 5.09
(q, J ˆ 6.9 Hz, 1H), 3.78 (br.s, 1H), 1.41 (d, J ˆ 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3/CCl4): d ˆ 200.3, 141.3, 136.7, 132.0, 130.4, 126.4, 123.4, 69.8,
24.2.
Benzaldehyde (212 mg, 2 mmol) was dissolved in a mixture of dimethyl
sulfoxide (20 mL) and potassium phosphate buffer [80 mL, 50 mM, pH 7.0,
containing MgSO4 (2.5 mM) andThDP (0.15 mM)]. To this solution 88 mg
(2 mmol) acetaldehyde was added. After addition of BAL (20 U) the
reaction mixture was allowedto standat 25 8C. After 24 h 20 U of BAL and
176 mg (4 mmol) of acetaldehyde were added. This was repeated every 24 h.
After 96 h the conversion was determined as 97% (GC-MS). Work-up
according tothe formerprocedure afforded(R)-2-HPP as a viscous oil; yield:
285 mg (94%, >99% ee); [a]D22: 85.1 (c 2.0, CHCl3), [Lit.[9a] [a]2D0: 82.2 (c 2.0,
CHCl3) for 96% ee; Lit.[35] [a]D20: À80.9 (c 2.0, CHCl3) for >95% ee (S)];
(R)-2-Hydroxy-1-(3-methoxyphenyl)propan-1-one (3g)
HPLC (Chiralpak AD, isohexane/2-propanol ˆ 90:10, flow 0.80 mL minÀ1
,
Viscous oil; yield: 80% (>99% ee); [a]2D0: 67.8 (c 1.0, CHCl3) [Lit.[11c], [a]D20
:
208C): Rt (S) ˆ 12.1 min; Rt (R) ˆ 14.3 min; 1H NMR (400 MHz, CDCl3/
CCl4): d ˆ 7.90 (dd, J ˆ 1.4, 8.2 Hz, 2H), 7.40 7.60 (m, 3H), 5.13 (q, J ˆ
6.0 Hz, 1H), 3.80 (br.s, 1H), 1.41 (d, J ˆ 6.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3/CCl4): d ˆ 202.7, 134.4, 134.0, 128.9, 128.7, 69.2, 22.0.
À65.2 (c 1.1, CHCl3) for 96% ee (S)]; HPLC (Chiralcel OB, isohexane/2-
propanol ˆ 90:10, flow 0.75 mL minÀ1, 208C): Rt (S) ˆ 12.9 min; Rt (R) ˆ
14.4 min; 1H NMR (300 MHz, CDCl3): d ˆ 7.15 7.47 (m, 4H), 5.14 (q, J ˆ
6.8 Hz, 1H), 3.89 (s, 3H), 3.78 (d, J ˆ 6.8 Hz, 1H), 1.45 (d, J ˆ 6.8 Hz, 3H); 13
C
NMR (100 MHz, CDCl3/CCl4): d ˆ 201.9, 160.2, 135.2, 130.1, 121.9, 121.6,
113.4, 69.5, 55.5, 22.5.
(R)-1-(2-Fluorophenyl)-2-hydroxypropan-1-one (3b)
Viscous oil; yield: 64% (97% ee); [a]2D0: 105.3 (c 0.5, CHCl3); HPLC
(Chiralpak AD, isohexane/2-propanol ˆ 90:10, flow 0.80 mL minÀ1, 208C):
Rt (S) ˆ 9.7 min; Rt (R) ˆ 11.1 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ
7.81 7.90 (m, 1H), 7.56 7.67 (m, 1H), 7.12 7.31 (m, 2H), 4.96 (q, J ˆ
6.8 Hz, 1H), 3.72 (br.s, 1H), 1.29 (d, J ˆ 6.8 Hz, 3H); 13C NMR (100 MHz,
CDCl3/CCl4): d ˆ 198.2, 163.8 (d, J ˆ 251 Hz), 134.5 (d, J ˆ 12 Hz), 131.3,
129.9, 124.5, 115.9 (d, J ˆ 23 Hz), 72.2, 21.1.
(R)-1-(4-Chlorophenyl)-2-hydroxypropan-1-one (3h)
Viscous oil; yield: 88% (>99% ee); [a]2D0: 18.3 (c 0.5, CHCl3) [Lit.[9c], [a]2D0
:
15.2 (c 1.0 2.0, CHCl3) for 83% ee]; HPLC (Chiralcel OB, isohexane/2-
propanol ˆ 95:5, flow 0.75 mL minÀ1, 208C): Rt (S) ˆ 17.5 min; Rt (R) ˆ
28.9 min.; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.83 (d, J ˆ 8.3 Hz, 2H),
7.48 (d, J ˆ 8.3 Hz, 2H), 4.98 (q, J ˆ 6.7 Hz, 1H), 3.59 (br.s, 1H), 1.42 (d, J ˆ
6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ 199.5, 134.6, 132.5,
130.9, 129.1, 69.5, 22.1.
(R)-2-Hydroxy-1-(2-methoxyphenyl)propan-1-one (3c)
Viscous oil; yield: 63% (>99% ee); [a]2D0: 143.0 (c 0.8, CHCl3); HPLC
(Chiralcel OB, isohexane/2-propanol ˆ 98:2, flow 0.75 mL minÀ1, 208C): Rt
(S) ˆ 34.9 min; Rt (R) ˆ 42.7 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ
7.70 7.78 (m, 1H), 7.39 7.51 (m, 1H), 6.91 7.01 (m, 2H), 5.05 (q, J ˆ
6.8 Hz, 1H), 3.89 (s, 3H), 3.68 (br.s, 1H),1.42 (d, J ˆ 6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3/CCl4): d ˆ 203.7, 158.2, 134.5, 131.3, 125.1, 121.1, 111.3,
(R)-1-(4-Bromophenyl)-2-hydroxypropan-1-one (3i)
Viscous oil; yield: 86% (>99% ee); [a]2D0: 61.3 (c 0.5, CHCl3); HPLC
(Chiralcel OB, isohexane/2-propanol ˆ 95:5, flow 0.75 mL minÀ1, 208C): Rt
(S) ˆ 19.2 min; Rt (R) ˆ 27.6 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ
7.73 (d, J ˆ 8.5 Hz, 2H), 7.58 (d, J ˆ 8.5 Hz, 2H), 4.96 (q, J ˆ 7.0 Hz, 1H), 3.57
(br.s, 1H), 1.40 (d, J ˆ 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3/CCl4): d ˆ
200.4, 137.1, 133.0, 131.4, 129.4, 71.4, 22.4.
‡
72.9, 55.2, 20.7; HR-MS: m/z: calcd. for C10H12O3 [M C2H5O]: 135.0454;
found: 135.0450; anal. calcd. for C10H12O3: C, 66.65; H, 6.71%; found: C,
66.27; H, 6.64%.
(R)-1-(3-Fluorophenyl)-2-hydroxypropan-1-one (3d)
(R)-2-Hydroxy-1-(4-methoxyphenyl)propan-1-one (3j)
Viscous oil; yield: 85%; (95% ee); [a]2D0: 107.5 (c 0.5, CHCl3); (Chiralcel OB,
isohexane/2-propanol ˆ 95:5, flow 0.75 mL minÀ1, 208C): Rt (S) ˆ 16.5 min;
Rt (R) ˆ 25.8 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.71 7.76 (m, 1H),
7.59 7.66 (m, 1H), 7.41 7.50 (m, 1H), 7.22 7.31 (m, 1H), 4.92 (q, Jˆ 6.8 Hz,
1H), 3.71 (br.s, 1H), 1.41 (d, J ˆ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3/
CCl4): d ˆ 198.8, 164.1 (d, J ˆ 246 Hz), 134.2 (d, J ˆ 7 Hz), 130.2 (d, J ˆ 7 Hz),
124.3 (d, J ˆ 3 Hz), 114.1 (d, J ˆ 23 Hz), 113.8 (d, J ˆ 22 Hz), 71.8, 21.4.
Viscous oil; yield: 64% (>99% ee); [a]2D0: 43.4 (c 1.0, CH3OH) [Lit.[4f], [a]2D0
:
32.8 (c 1.4, CH3OH) for 99% ee; Lit.[36], [a]D20: À33.4 (c 1.05, CH3OH) for
98% ee (S); Lit.[4h], [a]D28: À 41.1 (c 1.12, CH3OH) for 92% ee (S)]; HPLC
(Chiralcel OB, isohexane/2-propanol ˆ 95:5, flow 0.75 mL minÀ1, 208C): Rt
(S) ˆ 26.9 min; Rt (R) ˆ 36.4 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ
7.92 (d, J ˆ 8.6 Hz, 2H), 6.97 (d, J ˆ 8.6 Hz, 2H), 5.11 (q, J ˆ 7.0 Hz, 1H), 3.89
(s, 3H), 3.52 (br.s, 1H), 1.44 (d, J ˆ 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3/
CCl4): d ˆ 200.6, 164.1, 130.9, 125.9, 114.0, 68.8, 55.5, 22.6.
(R)-1-(3-Chlorophenyl)-2-hydroxypropan-1-one (3e)
Viscous oil; yield: 94% (>99% ee); [a]2D0: 73.0 (c 1.1, CH2Cl2); HPLC
(Chiralcel OB, isohexane/2-propanol ˆ 98:2, flow 0.75 mL minÀ1, 208C): Rt
(S) ˆ 28.5 min; Rt (R) ˆ 48.2 min; 1H NMR (300 MHz, CDCl3): d ˆ 7.91 (s,
1H), 7.69 (d, J ˆ 8.0 Hz, 1H), 7.56 (d, J ˆ 8.0 Hz, 1H), 7.43 (dd, J ˆ 8.0 Hz,
1H), 5.12 (q, J ˆ 7.0 Hz, 1H), 3.70 (br. s, 1H), 1.41 (d, J ˆ 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3/CCl4): d ˆ 200.9, 135.7, 133.8, 130.6, 130.3, 129.1,
(R)-1-(3,5-Difluorophenyl)-2-hydroxypropan-1-one (3l)
Viscous oil; yield: 67% (>99% ee); [a]2D0: 71.0 (c 1.0, CHCl3); HPLC
(Chiralcel OB, isohexane/2-propanol ˆ 95:5, flow 0.75 mL minÀ1, 208C): Rt
(S) ˆ 12.7 min; Rt (R) ˆ 16.7 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ
7.78 8.18 (m, 1H), 6.70 7.31 (m, 2H), 4.99 (q, J ˆ 6.6 Hz, 1H), 3.36 (br.s,
1H), 1.42 (d, J ˆ 6.6 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): d ˆ 201.3, 163.5
(d, J ˆ 252 Hz), 136.5, 112.0 (d, J ˆ 17 Hz), 109.6 (t, J ˆ 25 Hz), 70.1, 22.3.
‡
126.9, 69.7, 22.2; HR-MS m/z calcd. for C9H9O2Cl [M ]: 184.0291, found:
184.0272; anal. calcd. for C9H9O2Cl: C, 58.55; H, 4.91%; found: C, 58.23; H,
5.16%.
Adv. Synth. Catal. 2002, 344, 96 103
101

Ayhan S. Demir et al.
FULL PAPERS
1
10.9 min; H NMR (400 MHz, CDCl3/CCl4): d ˆ 7.91 8.05 (m, 1H), 6.83
7.10 (m, 2H), 5.02 (q, J ˆ 6.5 Hz, 1H), 3.76 (br. s, 1H), 1.42 (d, J ˆ 6.5 Hz, 3H);
13C NMR (75.5 MHz, CDCl3): d ˆ 199.5, 166.4 (d, J ˆ 259 Hz), 162.2 (d, J ˆ
259 Hz), 133.2, 118.7, 113.0 (d, J ˆ 21 Hz), 105.1 (dd, J ˆ 27 Hz), 72.7, 20.8;
(R)-2-Hydroxy-1(3-hydroxy-4-methoxyphenyl)propan-1-one
(3m)
Colorless oil; yield: 80%; (ee not determined); [a]2D0: 40.9 (c 1.0, CHCl3); 1H
NMR (300 MHz, CDCl3): dˆ7.52 (s, 1H), 7.47 (d, J ˆ 8.1 Hz, 1H), 6.92 (d,
J ˆ 8.1 Hz, 1H), 5.82 (br.s, 1H), 5.11 (q, J ˆ 7.1 Hz, 1H), 3.97 (s, 3H), 3.80
(br.s, 1H), 1.44 (d, Jˆ7.1 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): d ˆ 201.6,
153.5, 146.6, 131.5, 124.8, 114.8, 113.2, 71.9, 56.3, 23.8; HR-MS: m/z: calcd. for
‡
HR-MS: m/z calcd. for C9H8O2F2 [M ]: 186.0493, found: 186.0520.
Acknowledgements
‡
C10H12O4 [M ]: 196.0735; found: 196.0735.
Financial support by the Deutsche Forschungsgemeinschaft in the scope of
SFB 380 is gratefully acknowledged. We thank Alexander von Humboldt
Foundation, DAAD, Turkish Scientific and Technical Research Council
(TUBITAK) and Turkish State Planning Organisation (for GC-LC-MS). E.
J. is recipient of a Konrad Adenauer Stiftung fellowship. The authors thank
Prof. R. Vicunƒa for providing the BAL gene.
(R)-2-Hydroxy-1(4-hydroxy-3-methoxyphenyl)propan-1-one
(3n)
Colorless oil; yield: 90%; (ee not determined); [a]2D0: 42.3 (c 1.0, CHCl3); 1H
NMR (300 MHz, CDCl3): d ˆ 7.58 (s, 1H), 7.42 (d, J ˆ 8.4 Hz, 1H), 6.96 (d,
J ˆ 8.4 Hz, 1H), 6.35 (br.s, 1H), 5.10 (q, J ˆ 7.0 Hz, 1H), 3.93 (br. s, 4H), 1.44
(d, J ˆ 7.0 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): d ˆ 201.4, 151.9, 147.6,
126.5, 124.7, 114.8, 111.1, 69.5, 56.8, 23.6; HR-MS: m/z: calcd. for C10H12O4
References and Notes
‡
[M ]: 196.0736; found: 196.0741; anal. calcd. for C10H12O4: C, 61.22, H,
[1] a) F. Wˆhler, J. Liebig, Ann. Pharm. 1832, 3, 249 282; b) H.
Staudinger, Ber. Dtsch. Chem. Ges. 1913, 46, 3535 3538.
6.16%; found: C, 61.00, H, 5.95%.
[2] a) T. Ukai, R. Tanaka, S. Dokawa, J. Pharm. Soc. Jpn. 1943, 63, 296
300; b) R. Breslow, J. Am. Chem. Soc. 1958, 80, 3719 3726; c) H.
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(R)-2-Hydroxy-1(3,4,5-trimethoxyphenyl)propan-1-one (3o)
¬
Castells, F. Lopez-Calahorra, L. Domingo, J. Org. Chem. 1988, 53,
4433 4436; e) T. Matsumoto, M. Ohishi, S. Inoue, J. Org. Chem.
1985, 50, 603 606.
Colorless oil; yield: 92% (>99% ee); [a]2D0: 54.3 (c 1.0, CHCl3); HPLC
(Chiralpak AD, isohexane/2-propanol ˆ 95:5, flow 0.75 mL minÀ1, 208C): Rt
[3] a) J. C. Sheehan, T. Hara, J. Org. Chem. 1974, 39, 1196 1199; b) R. L.
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Catalysis, Vol. 2 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, Berlin, 1999, pp. 1093-1102.
1
(S) ˆ 28.5 min; Rt (R) ˆ 36.4 min; H NMR (300 MHz, CDCl3): dˆ7.11 (s,
2H), 5.07 (q, J ˆ 7.1 Hz, 1H), 3.81 (s, 9H), 3.72 (br. s, 1H), 1.45 (d, J ˆ 7.1 Hz,
3H); 13C NMR (75.5 MHz, CDCl3): d ˆ 201.5, 153.5, 143.5, 128.9, 106.4, 69.4,
‡
56.6, 56.4, 23.6; HR-MS: m/z: calcd. for C12H16O5 [M ]: 240.0992; found:
240.0995; anal. calcd. for C12H16O5: C, 59.99, H, 6.71%; found: C, 59.84, H,
6.76%.
[4] For some recent examples see: a) W. Adam, M. M¸ller, F. Prechtl, J.
Org. Chem. 1994, 59, 2358 2364; b) W. Adam, R. T. Fell, V. R.
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(R)-1-(2-Furanyl)-2-hydroxypropan-1-one (3p)[37]
Viscous oil; yield: 61%; (>99% ee); [a]2D0: 18.0 (c 0.2, CHCl3); HPLC
(Chiralcel OB, isohexane/2-propanol ˆ 90:10, flow 0.75 mL minÀ1, 208C): Rt
(S) ˆ 13.7 min; Rt (R) ˆ 16.9 min; 1H NMR (400 MHz, CDCl3/CCl4): d ˆ
7.40 (m, 1H), 6.55 (d, J ˆ 3.4 Hz, 1H), 6.36 (dd, J ˆ 1.7, 3.4 Hz, 1H), 5.01 (q,
J ˆ 6.7 Hz, 1H), 3.66 (br.s, 1H), 1.45 (d, J ˆ 6.7 Hz, 3H); 13C NMR (100 MHz,
CDCl3/CCl4): d ˆ 196.2, 150.3, 144.1, 111.6, 110.4, 71.2, 21.8.
√
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Representative Example for the Synthesis of (R)-2-Hydroxy-
1-phenylpropan-1-one Derivatives on a Preparative Scale:
(R)-1-(2,4-Difluorophenyl)-2-hydroxypropan-1-one (3k)
2,4-Difluorobenzaldehyde (4.2 g, 29.7 mmol) was dissolved in a mixture of
dimethyl sulfoxide (100 mL) and potassium phosphate buffer [380 mL,
50 mM, pH 7.0, containing MgSO4 (2.5 mM) andThDP (0.15 mM)]. After
addition of acetaldehyde (2.6 g, 60.0 mmol) the reaction was started by
adding 480 U of BAL (7.5 g of wet cells of E. coli recBAL,[21] suspended in
20 mL standard buffer, were disrupted by sonification and centrifuged to
afford20 mL of a solution containing 480 U BAL) andthe reaction mixture
was smoothly stirredat 25 8C. Conversion was monitoredby GC-MS by
extracting analytical samples with dichloromethane followed by phase
separation by centrifugation. After 38 h (99% conversion) the reaction
mixture was filteredusing a foldedfilter andan ultrafiltration membrane
(cut-off 10 kDa, Sartocon Micro module, Sartorius AG, Gˆttingen). Then,
100 g sodium chloride and 200 mL ethyl acetate were added to the permeate.
The organic layer was separated, dried with Na2SO4 andconcentratedunder
vacuum to give 3k as a yellow oil; yield: 3.6 g (65%, 97% ee); [a]2D0: 66.9 (c 1.0,
CHCl3) [Lit.[19c], [a]D20: 73.0 (c 1.0, CHCl3) for >98% ee; Lit.[19f], [a]D25: À67.1
(c 1.17, CHCl3) for >99.5% ee (S)]; HPLC (Chiralpak AD, isohexane/2-
propanol ˆ 90:10, flow 0.80 mL minÀ1, 208C): Rt (S) ˆ 8.8 min; Rt (R) ˆ
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102
Adv. Synth. Catal. 2002, 344, 96 103

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103