A highly enantioselective synthesis of the odorant, 3-hydroxy-4- phenylbutan-2-one

Article abstract of DOI:10.3184/174751913X13572401996302

An efficient and highly enantioselective synthesis of 3-hydroxy-4- phenylbutan-2-one was developed involving the asymmetric epoxidation of an enone and hydrogenolysis of an α,β-epoxyketone. 1-Phenyl-3-buten-2-one was epoxidised with t-butyl hydroperoxide using a chiral La-BINOL-Ph₃P=O complex as the catalyst to give (3S,4R)- or (3R,4S)- 3,4-epoxy-4-phenylbutan-2- one in ～90% yield and 97% ee. The resultant optically active epoxyketone was reduced in the presence of Pd/C (5 mol%) and H₂ (3 bar) in THF at room temperature to produce (S)- or (R)-3-hydroxy-4-phenylbutan- 2-one in ～80% yield with more than 90% enantiomeric excess.

Full text of DOI:10.3184/174751913X13572401996302

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 105
FEBRUARY, 105–106
A highly enantioselective synthesis of the odorant, 3-hydroxy-4-phenyl-
butan-2-one
Sen Liang, Bao-guo Sun, Hong-yu Tian*, Ya-ling Wang and Yu-mei Sun
School of Food Chemistry, Beijing Key laboratory of Flavour Chemistry, BeijingTechnology and Business University, Beijing 100048,
P. R. China
An efficient and highly enantioselective synthesis of 3-hydroxy-4-phenylbutan-2-one was developed involving the
asymmetric epoxidation of an enone and hydrogenolysis of an α,β-epoxyketone. 1-Phenyl-3-buten-2-one was epoxi-
dised with t-butyl hydroperoxide using a chiral La-BINOL-Ph3P=O complex as the catalyst to give (3S,4R)- or (3R,4S)-
3,4-epoxy-4-phenylbutan-2-one in ~90% yield and 97% ee. The resultant optically active epoxyketone was reduced in
the presence of Pd/C (5 mol%) and H2 (3 bar) in THF at room temperature to produce (S)- or (R)-3-hydroxy-4-phenyl-
butan-2-one in ~80% yield with more than 90% enantiomeric excess.
Keywords: 3-hydroxy-4-phenylbutan-2-one, 3,4-epoxy-4-phenylbutan-2-one, asymmetric epoxidation, hydrogenolysis
The investigation of chiral odorants has recently recieved
attention due to its academic significance and important social
and economic implications. The organoleptic properties of
more stereoisomers of chiral flavour and fragrance compounds
have been examined1 and some chiral odorants have even
entered the market in enantiomerically enriched forms. The
availability of chiral samples in high enantiomeric excess (ee)
is crucial to the investigation of the sensory properties of
stereoisomers. The technique of asymmetric synthesis is a
very efficient approaches to produce enantiomerically enriched
odorants.
and intensity of the two enantiomers have been observed by
gas chromatography-olfactory analysis.14 In order to obtain
more detailed sensory data of the two enantiomers, such
as odour threshold and promote the possible application of
enantiomerically enriched products, a practical and highly
enantioselective method of preparing optically active
3-hydroxy-4-phenylbutan-2-one is still needed. Here we report
the preparation of 3-hydroxy-4-phenylbutan-2-one with high
enantioselectivity by a two-step route, including asymmetric
epoxidation of 1-phenyl-3-buten-2-one and hydrogenolysis
(Scheme 1).
3-Hydroxy-4-phenyl-2-butanone is a flavour compound
with a pleasant, mild, warm and creamy sweet aroma, which
occurs naturally in honey,2,3, wine,4 sherry,5 apple cider6 and
wisteria flower7. It has been identified as one of important bio-
markers for thyme honey.8–10 As one of the important volatile
constituents related to the characteristic odour of wisteria
flowers, it occurs predominantly in the R configuration with
~83.3% ee7. Enantiomerically enriched 3-hydroxy-4-phenyl-
butan-2-one has been prepared in several different ways.
Awano et al. used Sharpless’kinetic resolution of ( )-1-phenyl-
3-buten-2-ol followed by protection of the hydroxyl group,
reduction of the epoxide, oxidation of hydroxyl group formed
from the reduction and deprotection of hydroxyl group to pro-
duce (S)- and (R)-3-hydroxy-4-phenylbutan-2-one with 85.2%
ee and 90.4% ee respectively.7 Fleming et al. reported the
Sharpless’ asymmetric dihydroxylation (Sharpless AD) of the
benzyl substituted allene to give 3-hydroxy-4-phenylbutan-2-
one in 30% yield with 77% ee.11 Enzymatic resolution of acyl-
oins and their esters were investigated to produce optically
active 3-hydroxy-4-phenyl-2-butanone and its butyrate in
>90% ee.12,13 In our previous work, we obtained enantiomeri-
cally enriched 3-hydroxy-4-phenylbutan-2-one ((R)-, 80% ee;
(S)-, 62% ee) by Shi’s asymmetric epoxidation (Shi’s AE) or
Sharpless AD of silyl enol ether. The different odour quality
Results and discussion
Asymmetric epoxidation of α,β-enones could be achieved by
many different methodologies such as asymmetric ligand-
metal catalysis,15,16 asymmetric phase transfer catalysis,17 and
asymmetric organocatalysis.18 Among them, the method devel-
oped by Inanaga et al. is very practical due to the commercial
availability of the required reagents and its high enantioselec-
tivity.15 In this work, asymmetric epoxidation of 1-phenyl-3-
buten-2-one was performed following Inanaga’s protocol with
chiral La-BINOL-Ph3P=O complex as the catalyst and t-butyl
hydroperoxide as the oxidant. Optically active 3,4-epoxy-4-
phenylbutan-2-ones (1a and 1b) were obtained in ~90% yield
and 97% ee.
Torii et al. reported the hydrogenolysis of α,β-epoxykentone
and ester to give aldols in Pd(0)/HCOOH/Et3N and H2/Pd/C
reduction media. However, 3,4-epoxy-4-phenylbutan-2-one
was cleaved selectively at the benzylic position to give the
acyloinundertheconditionofhydrogenolysis.19Thehydrogeno-
lysis of the optically active 3,4-epoxy-4-phenylbutan-2-ones
was carried out by two different methods. One used the Pd/C
(5 mol%), HCOOH (2 equiv.), and Et3N (2 equiv.) in refluxing
THF. Unfortunately, the ee values of the products were not
Scheme 1 Enantioselective synthesis of 3-hydroxy-4-phenylbutan-2-one.
* Correspondent. E-mail: tianhy@btbu.edu.cn

106 JOURNAL OF CHEMICAL RESEARCH 2013
vessel. The reaction mixture was stirred under H2 atmosphere (3 bar)
for 24 h. The Pd/C catalyst was filtered off and the filtrate was concen-
trated by rotary evaporation. The residue was subjected to column
chromatography on silica gel (ethyl acetate-petroleum ether 1:8) to
give the acyloin 2a or 2b. (S)-3-Hydroxy-4-phenylbutan-2-one 2a
(131 mg, 80% yield), light yellow oil, [α]2D0 = +54.2° [c = 1.125, CHCl3
(93.2% ee)]; (R)-3-hydroxy-4-phenylbutan-2-one 2b (133 mg, 81%
yield), light yellow oil, [α]2D0 = –52.7° [c = 1.091, CHCl3 (90.1% ee)].
HPLC (Chiralcel OD, 2-propanol-hexane 10:90, 1 mL min−1): tR
((R)-) 7.9 min; tR ((S)-) 9.9 min. 1H NMR δ 2.21 (s, 3H, Me), 2.88 (dd,
J = 14.1, 7.2 Hz, 1H, H-4), 3.14 (dd, J1 = 14.1, 4.5 Hz, 1H, H-4), 3.38
(d, J = 5.4 Hz, 1H, OH), 4.43 (m, 1H, H-3), 7.27(m, 5H, ArH). 13C
NMR δ 209.1, 136.4, 129.2, 128.5, 126.9, 77.6, 39.9, 25.8. GC/MS
(EI) m/z (%) 164 (1, M+), 146 (30), 121 (58), 103 (66), 91 (100), 77
(21).
reproducible. This might be due to the racemisation of the
acyloins under acidic conditions. The other was carried out in
the presence of Pd/C (5 mol%) and H2 (3 bar) in THF at room
temperature. (S)- and (R)-3-Hydroxy-4-phenylbutan-2-one (2a
and 2b) were obtained in ~80% yield with more than 90% ee.
In summary, optically active 3-hydroxy-4-phenylbutan-2-
ones were produced with high ee values by the asymmetric
epoxidation of 1-phenyl-3-buten-2-one using chiral La-BINOL
complex as the catalyst and t-BuOOH as the oxidant followed
the hydrogenolysis in the presence of Pd/C and H2. Compared
with the previously reported methods, this route is more
practical, efficient and enantioselective.
Experimental
4-Phenyl-3-buten-2-one and triphenylphosphine oxide were purchased
from Beijing Bailingwei Science and Technology Company. (R)-
and (S)-1,1′-bi-2-naphthol (BINOL), t-butyl hydroperoxide (TBHP,
~5.5 M soulution in decane), and La(O-i-Pr)3 were purchased from
Sigma-Aldrich Chemical Co., and the other compounds were
purchased from the Beijing Huaxue Shiji Company.
The NMR spectra were obtained on a Bruker AV300 MHz NMR in
CDCl3 and chemical shifts were referenced to residual protons in
CDCl3. Enantiomeric excesses were determined by high-performance
liquid chromatography (HPLC) with an Agilent 1200 HPLC using a
Chiralcel OD chiral column (0.46 cm diameter × 15 cm). Optical rota-
tions were measured on an Autopol IV digital automatic polarimeter.
Absolute configuration of the products was determined by comparing
their retention times or specific rotations with the literature data.
Financial support from the National Natural Science Founda-
tion of P. R. China (No. 31071610 and 31271932), Beijing
Natural Science Foundation Program and Scientific Research
Key Program of Beijing Municipal Commission of Education
(KZ201110011015), the National Key Technology R&D Pro-
gram (2011BOD-H23B01) and PHR (IHLB) (No. PHR2010
08244) is gratefully acknowledged.
Received 2 December 2012; accepted 20 December 2012
Paper 1201654 doi: 10.3184/174751913X13572401996302
Published online: 13 February 2013
References
Synthesis of (3S,4R)- or (3R,4S)-3,4-epoxy-4-phenylbutan-2-one (1a
or 1b)
1
2
J.C. Leffingwell, Http://www.leffingwell.com/olfaction.htm, 2012/12/02.
B.R. D’Arcy, G.B. Rintoul, C.Y. Rowland, and A.J. Blackman, J. Agric.
Food Chem., 1997, 45, 1834.
A solution of (R)- or (S)-BINOL (174 mg, 0.6 mmol) and triphe-
nylphosphine oxide (507 mg, 1.8 mmol) in THF (40 mL) was added
to a mixture of La(O-i-Pr)3 (195 mg, 0.6 mmol) and activated MS 4A
(300 mg). The mixture was stirred for 1 h at room temperature under
nitrogen. After the addition of TBHP (0.8 mL, 5.5M, 4.5 mmol), the
mixture was then stirred for 30 min and then a solution of 4-phenyl-3-
buten-2-one (447 mg, 3 mmol) in THF (10 mL) was added. The whole
mixture was stirred for 30 min at room temperature to complete the
reaction. Silica gel was added and the insoluble materials were filtered
through Celite. After concentration of the filtrate, the residue was
subjected to column chromatography on silica gel (ethyl acetate-
petroleum ether 1:30) to give the epoxy ketone 1a or 1b. (3S,4R)-3,4-
Epoxy-4-phenylbutan-2-one 1a (442 mg, 91% yield), colourless oil,
[α]2D0 = +99.5° [c = 1.088, CHCl3 (97.1% ee)]; (3R,4S)-3,4-epoxy-4-
3
4
5
A. Bouseta, V. Scheirman, and S. Collin, J. Food Sci., 1996, 61, 683.
Y. Kotseridis and R. Baumes, J. Agric. Food Chem., 2000, 48, 400.
F. Neuser, H. Zorn, and R.G. Berger, J. Agric. Food Chem., 2000, 48,
6191.
6
7
Y. Xu, W. Fan, and M.C. Qian, J. Agric. Food Chem., 2007, 55, 3051.
K. Awano, T. Yanai, I. Watanabe, Y. Takagi, T. Kitahara, and K. Mori,
Biosci Biotech. Bioch., 1995, 59, 1251.
8
9
E. Alissandrakis, P.A. Tarantilis, P.C. Harizanis, and M. Polissiou, J. Agric.
Food Chem., 2007, 55, 8152.
K.A. Aliferis, P.A. Tarantilis, P.C. Harizanis, and E. Alissandrakis, Food
Chem., 2010, 121, 856.
10 E. Alissandrakis, P.A. Tarantilis, C. Pappas, P.C. Harizanis, and
M. Polissiou, Eur. Food Res. Technol., 2009, 229, 365.
11 S.A. Fleming, R. Liu, and J.T. Redd, Tetrahedron Lett., 2005, 46, 8095.
12 G. Scheid, W. Kuit, E. Ruijter, R.V.A. Orru, E. Henke, U.T. Bornscheuer,
and L.A. Wessjohann, Eur. J. Org. Chem., 2004, 1063.
13 P. Oedman, L.A. Wessjohann, and U.T. Bornscheuer, J. Org. Chem., 2005,
70, 9551.
14 H. Tian, H. Ye, B. Sun, Y. Liu, M. Huang, and H. Chen, Flavour Frag. J.,
2011, 26, 385.
15 K. Daikai, T. Hayano, R. Kino, H. Furuno, T. Kagawa, and J. Inanaga,
Chirality, 2003, 15, 83.
16 H. Wang, Z. Wang, and K. Ding, Tetrahedron Lett., 2009, 50, 2200.
17 W. Adam, P.B. Rao, H.-G. Degen, and C.R. Saha-Moller, Tetrahedron:
Asymmetry, 2001, 12, 121.
18 A. Russo and A. Lattanzi, Synthesis, 2009, (9), 1551.
19 S. Torii, H. Okumoto, S. Nakayasu, and T. Kotani, Chem. Lett., 1989, 18,
1975.
phenylbutan-2-one 1b (428 mg, 88% yield), colourless oil, [α]2D0
=
–99.8° [c = 1.059, CHCl3 (97.3% ee)]. HPLC (Chiralcel OD, 2-propa-
nol-hexane 10:90, 1 mL min−1): tR ((3S,4R)-) 13.8 min; tR ((3R,4S)-)
12.6 min. 1H NMR δ 2.19 (s, 3H, Me), 3.49 (d, J = 1.8 Hz, 1H, H-3),
4.00 (d, J = 1.8 Hz, 1H, H-4), 7.26 (m, 2H, ArH), 7.36 (m, 3H, ArH).
13C NMR δ 203.9, 134.8, 128.7, 128.4, 125.5, 63.2, 57.4, 24.5. GC/
MS (EI) m/z (%) 162 (25, M+), 120 (40), 91 (100), 77 (16), 43 (51).
Synthesis of (S)- or (R)-3-hydroxy-4- phenylbutan-2-one (2a or 2b)
The solution of (3S,4R)- or (3R,4S)-3,4-epoxy-4-phenylbutan-2-one
(1a or 1b) (162 mg, 1 mmol) in THF (15 mL) and a catalytic amount
of Pd (10% on charcoal, 50 mg) was added to a 100 mL pressure

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