Simple chemoenzymatic access to enantiopure pharmacologically interesting (R)-2-hydroxypropiophenones

Article abstract of DOI:10.1016/S0957-4166(01)00346-9

A chemoenzymatic synthesis of pharmacological interesting (R)-2-hydroxypropiophenones starting from propiophenone derivatives is described. Manganese(III) acetate-mediated acetoxylation followed by fungus-mediated hydrolysis of propiophenone derivatives affords (R)-2-hydroxypropiophenones in high enantiomeric excess.

Full text of DOI:10.1016/S0957-4166(01)00346-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1953–1956
Simple chemoenzymatic access to enantiopure pharmacologically
interesting (R)-2-hydroxypropiophenones
Ayhan S. Demir,a,b,* Haluk Hamamci,b,c Ozge Sesenoglu,a Feray Aydogan,a Doga Capanoglub and
Rahsan Neslihanoglub
aDepartment of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
bDepartment of Biotechnology, Middle East Technical University, 06531 Ankara, Turkey
cDepartment of Food Engineering, Middle East Technical University, 06531 Ankara, Turkey
Received 28 July 2001; accepted 2 August 2001
Abstract—A chemoenzymatic synthesis of pharmacological interesting (R)-2-hydroxypropiophenones starting from propiophe-
none derivatives is described. Manganese(III) acetate-mediated acetoxylation followed by fungus-mediated hydrolysis of propio-
phenone derivatives affords (R)-2-hydroxypropiophenones in high enantiomeric excess. © 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
been approved as an aid to smoking cessation under the
brand name of Zyban® (Glaxo Wellcome),3 (R)-1-(2,4-
difluorophenyl)-2-hydroxypropan-1-one 1c, a starting
material for Ro 09-33554 and SM 8668/Sch 39304
(anti-fungal agents)5 and (R)-1-(3,5-difluorophenyl)-2-
Chiral a-hydroxy ketones are an important structural
unit in many biologically active natural products and
they are also important synthons for the asymmetric
synthesis of natural products.1 As such, several chemi-
cal methods have been developed for the preparation of
optically active a-hydroxy ketones.1 They are also pre-
pared enzymatically by reduction of the corresponding
a-diketone with baker’s yeast or an enzymatic kinetic
resolution of the racemate of either 2-peroxo-, 2-
hydroxy- or 2-acetoxy ketones.2
hydroxypropan-1-one 1d,
a starting material for
1555U88 (an anti-depressant agent and selective
inhibitor of norepinephrine uptake).6 These hydroxy
ketones have been obtained in enantiomerically pure
form from via the chromatographic separation of enan-
tiomers,5a the kinetic resolution of racemic hydroxy
ketones,5c synthesis from chiral arylepoxides,5e by
asymmetric a-hydroxylation using oxaziridine method-
ology,5d metal salt-induced a-hydroxylation of
ketones,5b Sharpless asymmetric dihydroxylation of the
silylenolether of the corresponding ketone3 and the
recently reported benzaldehyde lyase-catalyzed carboli-
gation of aromatic aldehydes with acetaldehyde.7
The hydroxy ketones 1a–1d are key intermediates for
the synthesis of the pharmacologically interesting 2-
HPP derivatives, (R)-1-(3-chlorophenyl)-2-hydroxy-
propan-1-one 1b, starting material for Bupropion
(active ingredient of Wellbutrin® (Glaxo Wellcome)
marketed for the treatment of depression, it has also
* Corresponding author. E-mail: asdemir@metu.edu.tr
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00346-9

1954
A. S. Demir et al. / Tetrahedron: Asymmetry 12 (2001) 1953–1956
In our ongoing works we have published several papers
about the Mn(OAc)3-mediated direct acetoxylation and
acyloxylation (carried out via metathesis of the acetic
acid by various carboxylic acids) of enones and aro-
matic ketones8 followed by the enzymatic- and fungus-
mediated resolution of acyloxy enones to obtain
optically pure a-hydroxy ketones.9 In the light of these
works, we report herein a simple and efficient chemoen-
zymatic route to the pharmacological interesting 2-
hydroxypropiophenones 1a–1d.
an attractive alternative to the other (multistep) proce-
dures. Based on the preliminary information available
to us from our previous work with fungus-mediated
reactions, a series of fungi were screened for the enan-
tioselective hydrolysis of acetoxy ketones 3a–3d and
two of them gave the desired results (Rhizopus oryzae
(W&P G) and Rhizopus oryzae (NRRL 395) Table 1).
The bioconversion was performed in DMSO and fun-
gus were incubated in the presence of the a-acetoxy
ketone at 30°C. The optimum pH of the reaction
medium was found to be 6.0–6.5 and the conversions
were monitored by TLC and LC–MS (equipped with a
chiral column using authentic hydroxy ketone as refer-
ence).10a After about 45–50% conversion, the products
were separated using flash column chromatography,
and the hydroxy ketone products 1a–1d were isolated in
40–46% yields with e.e.s of 88 to >99%. Small quanti-
ties of diol were also detected in the crude products by
GC–MS. The configuration of the hydroxy ketones was
assessed by all products as (R) by comparison of its
specific rotation with literature data (Table 1). Under
these conditions less discrimination was observed using
substituted acetoxy ketones 3b–3d. Under similar con-
ditions termination of the reaction after 38–40% con-
2. Results and discussion
In an initial reaction (Scheme 1), the oxidation of
ketones 2a–2d with four equivalents of manganese(III)
acetate in cyclohexane furnished the desired a-acetoxy
ketones 3a–3d in 83–87% yields after purification by
column chromatography. For high yield formation of
the acetoxy ketones, the manganese(III) acetate must be
dried prior to use. The use of benzene as a solvent also
furnished the acetoxy ketones in 76–81% yields with
some side products. The direct synthesis of acyloxy
ketones from ketones using manganese(III) acetate is
Scheme 1.
Table 1. Fungus-mediated hydrolysis of esters
Entry
Substrate
Fungus
Reaction time (h)a
(R)-Alcohol
% e.e.b
% yield
1
2
3
4
5
6
7
8
3a
3a
3b
3b
3c
3c
3d
3d
Rhizopus oryzae (W&P G)c
Rhizopus oryzae (NRRL 395)
Rhizopus oryzae (W&P G)c
Rhizopus oryzae (NRRL 395)
Rhizopus oryzae (W&P G)c
Rhizopus oryzae (NRRL 395)
Rhizopus oryzae (W&P G)c
Rhizopus oryzae (NRRL 395)
48
60
64
72
76
92
72
96
1a
1a
1b
1b
1c
1c
1d
1d
92
\99
94
\99
96
\99
96
97
46
42
39
40
36
37
35
34
a For 38–40% conversions of 1b–1d.
b Enantiomeric excess of 1a–1d was determined by chiral phase HPLC analysis (Chiralpak AD column, UV detection at 254 nm, eluent:
iso-hexane/2-propanol=9:1, flow 0.80 mL min−1 20°C, using racemic compounds as references.10a
c Rhizopus oryzae (Went&Prinsen Geerlings, TUBITAK-72465) the culture was obtained from the Marmara Research Center of Turkish Scientific
and Technical Research Council.

A. S. Demir et al. / Tetrahedron: Asymmetry 12 (2001) 1953–1956
1955
version increases the e.e. to 96 to >99% for 1b–1d
(Table 1). The fungi examined gave comparable results
but with Rhizopus oryzae (W&P G) the conversion was
faster and less selective than that seen with Rhizopus
oryzae (NRRL 395). Slow conversion was observed
with the 2,4-difluoro-substituted derivative 3d. The
hydroxy ketones 1a–1d are stable only when kept in a
cold place under an inert atmosphere and away from
light. The impure acetoxy ketones obtained after bio-
conversion, can be epimerized using DBU in hexane/
THF10b to afford the racemic acetoxy ketones in
81–84% yields after purification by column chromato-
graphy. The recycling of the ester makes this method
for the enantioselective synthesis of hydroxy ketones
quite efficient.
4.3. Representative example for hydrolysis of 2-acetoxy
ketones
Rhizopus oryzae was used for the experiments. It was
cultivated on boiled rice and the fungal spores were
transferred by loopfuls into sterile flasks containing the
medium and grown in rotary shaker at 30°C for 2 days.
The medium for fungal growth included glucose syrup
(15.0 g), (NH4)2SO4 (1.0 g), KH2PO4 (0.30 g), MgSO4
(0.12 g) and ZnSO4 (0.02 g) diluted to 500 mL with
distilled water. The medium was divided into five and
sterilized in an autoclave for 15 minutes. Spores from
the main plate were transferred into an Erlenmeyer
flask containing 100 mL sterile medium. The fungus
was inoculated at 30°C for 2 days in the rotary shaker
and a solution of the substrate (2 mmol) in DMSO (3
mL) was added (pH 6.0–6.5). Shaking was resumed
until approximately 38–42% of the racemic acetate was
hydrolyzed. The fungus was removed by filtration,
washed with distilled water and the combined aqueous
phases extracted with ether. The organic extract was
dried, filtered and concentrated and the alcohol and
unhydrolyzed acetate were then separated by flash
column chromatography (EtOAc:hexane, 1:2).
3. Conclusions
The results show that manganese(III) acetate-mediated
acetoxylation of ketones followed by fungus-mediated
hydrolysis of the acetoxy group provides hydroxy
ketones 1a–d, which are important precursors for phar-
macologically interesting compounds, with high enan-
tiomeric excesses and in good yields. The undesired
acetoxy ketones are epimerized in good yield and re-
used. In these conversion reactions the enzymes favor
the (R)-enantiomers.
4.4. 2-Acetoxy-1-phenylpropan-1-one 3a9a
Yellow oil; yield: 84 mg (87%). IR(TF): 1740, 1700
1
cm−1. H NMR (400 MHz, CDCl3): l=7.88–7.92 (m,
2H), 7.41–7.60 (m, 3H), 5.86 (q, J=7.0 Hz, 1H), 2.03
(s, 3H), 1.59 (d, J=7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): l=201.8, 171.3, 134.2, 133.9, 128.8, 128.5,
84.2, 20.2, 17.4.
4. Experimental
4.1. General methods
4.5. 2-Acetoxy-1-(3-chlorophenyl)-propan-1-one 3b
NMR spectra were recorded on a Bruker DPX 400.
Column chromatography was conducted on silica gel
60 (mesh size 40–63 mm). Enantiomeric excesses were
determined by HPLC analysis using a Thermo Quest
(TSP) GC–LC–MS equipped with an appropriate opti-
cally active column, as described in the footnotes of the
corresponding Tables. GC–MS spectra were determined
on a phenomenex Zebron ZB-5 capillary column (5%
phenylmethylsiloxane). Optical rotations were mea-
sured with Bellingham&Stanley P20 polarimeter or
with a Perkin–Elmer 241 polarimeter.
Viscous oil; yield: 97 mg (86%). IR(TF): 1750, 1710
1
cm−1. H NMR (400 MHz, CDCl3): l=7.26–7.44 (m,
2H), 7.78–7.88 (m, 2H), 5.78 (q, J=6.9 Hz, 1H), 2.10
(s, 3H), 1.59 (d, J=6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3): l=198.4, 171.8, 134.7, 133.6, 130.4, 130.2,
129.3, 126.8, 83.9, 21.1, 17.7. Anal. calcd for
C11H11ClO3(226.6): C, 58.29; H, 4.89. Found: C, 58.48;
H, 4.92%.
4.6. 2-Acetoxy-1-(2,4-difluorophenyl)-propan-1-one 3c5f
Yellow oil; yield: 97 mg (85%). IR(TF): 1760, 1710
1
cm−1. H NMR (400 MHz, CDCl3): l=7.93–8.03 (m,
4.2. General procedure for synthesis of 2-acetoxy
ketones 3
1H), 6.82–7.14 (m, 2H), 5.84 (m, 1H), 2.03 (s, 3H), 1.62
(d, J=6.8 Hz, 3H).
A mixture of manganese(III) acetate (5.36 g, 20 mmol)
and the ketone (5 mmol) in cyclohexane (50 mL) was
stirred under reflux (the reaction was monitored by
TLC) using a Dean–Stark trap. The mixture was cooled
to rt, diluted with ethyl acetate and the resulting
organic solution washed successively with 1 M aqueous
HCl solution, saturated aqueous NaHCO3 solution and
brine, and dried over anhydrous MgSO4. The crude
product was chromatographed on flash silica gel in 1:3
ethyl acetate–hexane to afford the acetoxy ketone
product.
4.7. 2-Acetoxy-1-(3,5-diflurophenyl)-propan-1-one 3d
Yellow oil; yield: 95 mg (83%). IR(TF): 1750, 1710
1
cm−1. H NMR (400 MHz, CDCl3): l=7.76–8.15 (m,
1H), 6.74–7.32 (m, 2H), 5.80 (m, 1H), 2.01 (s, 3H), 1.58
(d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
l=198.9, 172.3, 165.2 (d, J=248 Hz), 138.2, 112.4,
111.7 (d, J=20 Hz), 109.1 (d, J=25 Hz), 83.9, 20.4,
17.1. Anal. calcd for C11H10F2O3 (228.2): C, 57.90; H,
4.42. Found: C, 58.12; H, 4.62%.

1956
A. S. Demir et al. / Tetrahedron: Asymmetry 12 (2001) 1953–1956
4.8. (R)-2-Hydroxy-1-phenylpropan-1-one 1a
(f) Enders, D.; Breuer, K. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H.,
Eds.; Springer: Berlin, 1999; Vol. 2, pp. 1093–1102; (g)
Koike, T.; Murata, K.; Ikariya, T. Org. Lett. 2000, 2,
3833; (h) Lee, J. C.; Jin, Y. S.; Choi, J. H. Chem.
Commun. 2001, 956.
Viscous oil, e.e. >99%; [h]2D2=+85.3 (c 2.0, CHCl3),
[lit.9a [h]D20=+82.2 (c 2.0, CHCl3) for 96% e.e.; HPLC
(Chiralpak AD): Rt (R)=14.3 min, Rt (S)=12.1 min;
1H NMR (400 MHz, CDCl3): l=7.89–7.92 (m, 2H),
7.40–7.62 (m, 3H), 4.99 (q, J=6.0 Hz, 1H), 3.80 (br.s,
1H), 1.41 (d, J=6.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3): l=201.6, 134.2, 134.0, 128.7, 128.3, 69.2, 22.0.
2. (a) Adam, W.; Lazarus, M.; Saha-Mo¨ller, C. R.; Schreier,
P. Acc. Chem. Res. 1999, 32, 837 and references cited
therein; (b) Demir, A. S.; Hamamci, H.; Tanyeli, C.;
Akhmedov, I. M.; Doganel, F. Tetrahedron: Asymmetry
1998, 9, 1673; (c) Kajiro, H.; Mitamura, S.; Mori, A.;
Hiyama, T. Tetrahedron: Asymmetry 1998, 9, 907; (d)
Zhu, Y.; Shu, L.; Tu, Y.; Shi, Y. J. Org. Chem. 2001, 66,
1818.
3. Fang, Q. K.; Han, Z.; Grover, P.; Kessler, D.;
Senanayake, C. H.; Wald, S. A. Tetrahedron: Asymmetry
2000, 11, 3659.
4. Leuenberger, H. G.; Matzinger, P. K.; Wirz, B. Chimia
1999, 53, 536.
5. (a) Monteith, M. J. Spec. Chem. 1999, 19, 276–278; (b)
Gala, D.; DiBenedetto, D. J. Tetrahedron: Asymmetry
1997, 8, 3047; (c) Gala, D.; DiBenedetto, D. J.; Clark, J.
E.; Murphy, B. L.; Schumacher, D. P.; Steinman, M.
Tetrahedron Lett. 1996, 37, 611; (d) Gala, D.;
DiBenedetto, D. J.; Mergelsberg, I.; Kugelmann, M. Tet-
rahedron Lett. 1996, 37, 8117; (e) Gala, D.; DiBenedetto,
D. J. Tetrahedron Lett. 1994, 35, 8299; (f) Konosu, T.;
Miyaoka, T.; Tajima, Y.; Oida, S. Chem. Pharm. Bull.
1991, 39, 2241; (g) Kitazaki, T.; Tasaka, A.; Hosono, H.;
Matsushita, Y.; Itoh, K. Chem. Pharm. Bull. 1999, 47,
360.
4.9. (R)-1-(3-Chlorophenyl)-2-hydroxypropan-1-one 1b
Viscous oil; e.e. >99%; [h]2D0=+73.3 (c 1.0, CH2Cl2);
HPLC (Chiralpak AD): Rt (R)=13.3 min, Rt (S)=11.4
min, 1H NMR (CDCl3): l=7.26–7.46 and 7.76–7.91
(m, 4H), 4.96 (q, J=6.9 Hz, 1H), 3.81 (br.s, 1H), 1.42
(d, J=6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3):
l=197.6, 134.9, 133.4, 130.3, 130.1, 129.1, 126.8, 70.2,
21.4; Anal. calcd for C9H9O2Cl: C, 58.55; H, 4.91%;
found: C, 58.26; H, 5.21%.
4.10. (R)-1-(2,4-Difluorophenyl)-2-hydroxypropan-1-one
1c5c,f
Yellow oil; e.e.=97%; [h]2D0=+66.7 (c 1.0, CHCl3), [lit.5f
[h]2D0=−67.1 (c 1.0, CHCl3) for >99.5% e.e. (S); HPLC
(Chiralpak AD): Rt (R)=10.9 min, Rt (S)=8.8 min, 1H
NMR (CDCl3): l=7.92 (m, 1H), 6.82–7.14 (m, 2H),
5.01 (m, 1H), 3.75 (br s, 1H), 1.42 (d, J=6.6 Hz, 3H).
4.11. (R)-1-(3,5-Difluorophenyl)-2-hydroxypropan-1-one
1d6
6. Boswell, G. E.; Musso, D. L.; Davis, A. O.; Kelley, J. L.;
Soroko, F. E.; Cooper, B. R. J. Heterocycl. Chem. 1997,
34, 1813.
Viscous oil; e.e. >99%; [h]2D0=+70.2 (c 1.1, CHCl3);
HPLC (Chiralpak AD): Rt (R)=10.8 min, Rt (S)=8.9
7. (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; (b) Demir, A. S.;
Du¨nnwald, T.; Iding, H.; Pohl, M.; Mu¨ller, M. Tetra-
hedron: Asymmmetry 1999, 10, 4769; (c) Du¨nnwald, T.;
Demir, A. S.; Siegert, P.; Pohl, M.; Mu¨ller, M. Eur. J.
Org. Chem. 2000, 2161; (d) Demir, A. S.; Pohl, M.;
Janzen, E.; Mu¨ller, M. J. Chem. Soc., Perkin Trans. 1
2001, 633.
8. (a) Demir, A. S.; Camkerten, N.; Gercek, Z.; Duygu, N.;
Reis, O.; Arikan, E. Tetrahedron 1999, 55, 2441; (b)
Demir, A. S.; Jeganathan, A. Synthesis 1992, 235; (c)
Demir, A. S.; C¸ amkerten, N.; Akgu¨n, H.; Tanyeli, C.;
Mahasneh, A. S.; Watt, D. S. Synth. Commun. 1990, 20
(15), 2279.
1
min; H NMR (CDCl3): l=7.78–8.17 (m, 1H), 6.71–
7.31 (m, 2H), 4.99 (m,1H), 3.36 (br.s, 1H), 1.42 (d,
J=6.7 Hz, 3H).
Acknowledgements
Financial support by the Turkish Scientific and Techni-
cal Research Council (TUBITAK), Turkish State Plan-
ning Organization (for GC–LC–MS) and Middle East
Technical University (AFP 2001) is gratefully
acknowledged.
9. (a) Demir, A. S.; Hamamci, H.; Tanyeli, C.; Akhmedov,
I. M.; Doganel, F. Tetrahedron: Asymmetry 1998, 9,
1673; (b) Demir, A. S.; Hamamci, H.; Doganel, F.;
Ozgul, E. J. Mol. Cat. B Enzymatic 1999, 1, 347.
10. (a) rac-1a–d are synthesized from rac-3a–d using K2CO3/
MeOH: Zhu, Y.; Tu, Y.; Yu, H.; Shi, Y. Tetrahedron
Lett. 1998, 39, 7819–7822 or MeOH (80 mL), 40% (v/v)
H2SO4 (15 mL) rt 12 h; (b) Hexane/THF (10/1), 0.3
mol% DBU, 35°C, 20–24 h.
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