Synthesis and Antimicrobial Activity of Hydroxyalkyl- and Hydroxyacyl-phenols and Their Benzyl Ethers

Article abstract of DOI:10.1002/1521-4184(200203)335:2/3<94::AID-ARDP94>3.0.CO;2-W

New phenolic compounds with hydrophilic side chains were prepared from 4-benzyloxybenzaldehyde and alkenyl magnesium bromides, followed by Sharpless dihydroxylation and hydrogenolytic removal of the benzyl group. The resulting compounds were tested in an agar diffusion assay against gram positive bacteria, gram negative bacteria, and against the fungi Candida glabrata and Aspergillus niger.

Full text of DOI:10.1002/1521-4184(200203)335:2/3<94::AID-ARDP94>3.0.CO;2-W

94
Arch. Pharm. Pharm. Med. Chem. 2002, 2, 94–98
J. Krauß,
D. Unterreitmeier
Synthesis and Antimicrobial Activity of
Hydroxyalkyl- and Hydroxyacyl-phenols and Their
ଝ
Department of Pharmacy,
Ludwig-Maximilians University,
Munich, Germany
Benzyl Ethers
New phenolic compounds with hydrophilic side chains were prepared from 4-ben-
zyloxybenzaldehyde and alkenyl magnesium bromides, followed by Sharpless dihy-
droxylation and hydrogenolytic removal of the benzyl group. The resulting com-
pounds were tested in an agar diffusion assay against gram positive bacteria, gram
negative bacteria, and against the fungi Candida glabrata and Aspergillus niger.
Keywords: Sharpless dihydroxylation; Antimicrobial activity; Hydroxyphenyl
carbinols
Received: August 21, 2001 [FP625]
mide to give the racemic secondary alcohols 2 in good
yields.
Introduction
Since 1867 phenols have been a well-known class of an-
timicrobial substances [1]. Derivatives of phenol, for in-
stance thymol, and chlorophenol, are used as antisep-
tics, disinfectants, and preservatives. Alkyl substituents
often increase the efficieny of antiseptic activity [2]. On
the other hand, many natural products with antibiotic and
antimycotic activity contain hydrophilic side chains, as
do the new class of bengazoles [3].
On the one hand, three of these racemic alcohols were
hydrogenated with Pd/C to remove the benzyl protecting
group.In the course of this reaction the double bond was
also hydrogenated. One side reaction led to the alkyl-
phenols 6. The antimicrobial activity of the resulting
( )-hydroxyalkylphenols 3 was to be compared with the
new more complex phenolic derivatives described be-
low.
On the other hand, the double bond was dihydroxylated
in a Sharpless dihydroxylation reaction [4] with α-AD mix
((K4[Fe(CN)6], OsO4, Na2CO3, (DHQ)2-PHAL) to give the
resulting ( )-dihydroxyketones 4. The α-AD mix dihy-
droxylated the double bond and the secondary alcohol
function was oxidised in the same reaction.The oxidation
of the secondary alcohol depended on the presence of a
surplus of α-AD mix. Under these conditions the α-AD
mix showed no enantioselectivity. The resulting ( )-ke-
tones were debenzylated to give the phenols 5 with trihy-
droxy side chain. During the hydrogenolysis of the pro-
tecting group the ketones were again reduced to the sec-
ondary alcohols, yielding diastereomeric mixtures of 5.
The resulting compounds were tested in an agar diffu-
sion assay (100 µg/disc) for their effects on the gram
positive bacterium Staphylococcus hominis, the gram
negative bacterium Escherichia coli, and the fungi As-
pergillus niger and Candida glabara [5]. The potency of
the substances was compared with the effects of clotrim-
azole (50 µg/disc) and tetracycline (50 µg/disc).Only the
phenol ethers 2a, 4a–e showed poor activity against
gram positive bacteria, gram negative bacteria, and the
fungus Aspergillus niger.
Figure 1
Hybrids of the two classes might be new potent phenolic
antiseptics. Up to now, no phenolic derivatives with ben-
gazole-type side chains have been synthesized and
tested.
Investigations, results, and discussion
Following up this idea, 4-benzyloxybenzaldehyde (1)
was subjected to Grignard reaction with vinyl-, allyl-, but-
3-enyl-, pent-4-enyl-, and hex-5-enyl-magnesium bro-
Correspondence: Jürgen Krauß, Department of Pharmacy,
Ludwig Maximilians University, Butenandt Straße 5–13,
81377 Munich, Germany. Phone: +49 (0)89 2180 7275,
e-mail: hjkra@cup.uni-muenchen.de
Summing up, we could show that a bengazole-like side
chain was not able to increase the antibiotic and antimy-
cotic activity of phenols.
© WILEY-VCH Verlag GmbH, 69451 Weinheim, 2002
0365-6233/02–03/0094 $ 17.50+.50/0

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 94–98
Synthesis and Antimicrobial Activity 95
Figure 2
Figure 3
Table 1. Antimicrobial activity in the agar diffusion assay (substances:100 µg/disk, references:50 µg/disk (Cl:clotrima-
zole, Te: tetracycline), zone of inhibition: diameter in mm).
Microorganism
2a 2b 2c 2d 2e 3a 3b 3c 4a 4b 4c 4d 4e 5a 5b 5c 5d 5e Cl Te
Aspergillus niger
Candida glabrata
Escherichia coli
Staphylococcus
hominis
7
0
7
8
0
0
0
0
0
0
0
0
0
0
0
6
0
0
0
6
0
0
0
0
0
0
0
0
0
0
0
0
0
0
6
6
0
0
7
6
0
0
7
6
0
0
7
6
0
0
7
6
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
20
35
13 21
10 21
0
0

96
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 94–98
1454, 1386, 1333, 1301, 1243, 1174, 1016, 908, 862. Calcd.:
C: 80.28 H: 7.13 Found: C: 80.36 H: 7.13. C17H18O2 (254.3).
Acknowledgement
We wish to thank Prof.Dr.Franz Bracher for kind support.
( )-1-(4-Benzyloxyphenyl)pent-4-enol (2c)
From 1.5 g (7.0 mmol) 4-benzyloxybenzaldehyde (1) and 1.4 g
(10.5 mmol) but-3-enyl bromide.Yield: 1.03 g (55%) as a white
solid, mp: 62.8°C.
Experimental
Elemental analysis: Heraeus CHN-Rapid, IR Spectra: Perkin-
Elmer FT-IR Paragon 1000, MS: Hewlett Packard MS-Engine;
Electron ionisation (EI) 70 eV, chemical ionisation (CI) with CH4
(300 eV); NMR (400 MHz): Jeol GSX 400 (1H: 400 MHz, 13C:
100 MHz); Melting points: Büchi Melting Point B-540 (not cor-
rected); flash column chromatography (FCC): silica gel 60
(230–400 mesh, E. Merck, Darmstadt).The diastereomeric ra-
tio was determined by 13C-NMR.
1H-NMR (CDCl3) δ (ppm) = 1.70–1.96 (m, 2 H, CH2), 2.03–2.19
(m, 2H, CH2), 4.65 (m, 1H, CH), 4.95–5.08 (m, 2H, =CH2), 5.07
(s, 2H, CH2O), 5.84 (ddt, J = 2.4 Hz, J = 14.8 Hz, J = 27.2 Hz,
1H, –CH=), 6.96 (d, J = 9.3 Hz, 2H, aromat. CH), 7.27 (d, J =
9.3 Hz, 2H, aromat. CH), 7.34–7.43 (m, 5H, aromat. CH). 13C-
NMR (CDCl3) δ (ppm) = 30.23 (CH2), 38.06 (CH2), 70.12
(CH2O), 73.74 (CH), 114.87 (2 aromat. CH), 114.94 (H2C=),
127.26 (2 aromat. CH), 127.55 (2 aromat. CH), 128.06 (aro-
mat. CH), 128.68 (2 aromat. CH), 132.06 (quart. C), 137.10
(–CH=), 138.30 (quart.C), 158.37 (quart.C).MS (CI) m/z = 267
(M– – 1, 7), 251 (100), 213 (20), 185 (15), 161 (25). IR (KBr)
ν (cm–1) = 3335, 2933, 1684, 1605, 1509, 1465, 1454, 1362,
1242, 1005, 825, 700. Calcd.: C: 80.56 H: 7.51 Found: C: 80.13
H: 7.44. C18H20O2 (268.4).
( )-4-Benzyloxyphenylalkenols 2a–e
Magnesium (14.0 mmol) was suspended in 5 mL dry THF, then
5 mL of a solution of alkenyl bromide (10.5 mmol) in dry THF
was added.After stirring for one hour the suspension was heat-
ed under reflux for one hour. The solution of the Grignard rea-
gent was taken up in a syringe and it was added to a solution of
1.5 g (7 mmol) 4-benzyloxybenzaldehyde (1) in 5 mL dry THF.
The mixture was stirred for two hours and heated for one hour
under reflux.Then the mixture was quenched with 10 mL satu-
rated aqueous NH4Cl solution and extracted with diethyl ether
(3 × 20 mL). The combined organic layers were dried over
Na2SO4 and the solvent was evaporated.The residue was puri-
fied by FCC (hexane/ethyl acetate 4:1).
( )-1-(4-Benzyloxyphenyl)hex-5-enol (2d)
From 1.5 g (7.0 mmol) 4-benzyloxybenzaldehyde (1) and 1.6 g
(10.5 mmol) pent-4-enyl bromide. Yield: 1.28 g (65%) as a
white solid, mp: 62.8°C.
1H-NMR (CDCl3) δ (ppm) = 1.35–1.49 (m, 2 H, CH2), 1.64–1.85
(m, 2H, CH2), 2.06 (m, 2H, CH2), 4.61 (m, 1H, CH), 4.93–5.01
(m, 2H, =CH2), 5.06 (s, 2H, CH2), 5.77 (m, 1H, –CH=), 6.95 (d,
J = 8.6 Hz, 2H, aromat. CH), 7.25 (d, J = 8.6 Hz, 2H, aromat.
CH), 7.30–7.43 (m, 5H, aromat.CH).13C-NMR (CDCl3) δ (ppm)
= 25.24 (CH2), 33.68 (CH2), 38.46 (CH2), 70.12 (CH2O), 74.22
(CH), 114.76 (=CH2), 114.80 (2 aromat.CH), 127.24 (2 aromat.
CH), 127.56 (2 aromat. CH), 128.06 (aromat. CH), 128.68 (2
aromat. CH), 137.07 (quart. C), 137.31 (quart. C), 138.68
(–CH=), 158.33 (quart. C). MS (CI) m/z = 283 (M+ + 1, 5), 265
(100), 213 (10), 185 (15), 175 (15). IR (KBr) ν (cm–1) = 3309,
3063, 2915, 2860, 1600, 1519, 1240, 1020, 840, 700. Calcd.:
C: 80.28 H: 7.13 Found: C: 80.56 H: 7.05. C19H22O2 (282.4).
( )-1-(4-Benzyloxyphenyl)propenol (2a)
From 1.5 g (7.0 mmol) 4-benzyloxybenzaldehyde (1) and 1.3 g
(10.5 mmol) vinyl bromide.Yield: 1.1 g (65%) as a white solid,
mp: 60.3°C.
1H-NMR (CDCl3) δ (ppm):= 1.97 (s, 1H, OH), 5.05 (s, 2H, CH2),
5.14 (d, J = 6 Hz, 1H, CH), 5.18 (ddd, J = 11.0 Hz, J = 1.5 Hz, J =
1.5 Hz, 1H, HC=), 5.32 (ddd, J = 17.0 Hz, J = 1.5 Hz , J = 1.5 Hz,
1H, HC=), 6.03 (ddd, J = 6.0, Hz, J = 11.0 Hz, J = 17.0 Hz, 1H,
–CH=), 7.0 (d, J = 8.0 Hz, 2H, aromat. CH), 7.3 (d, J = 8.0 Hz,
2H, aromat. CH), 7.31–7.44 (m, 5H, aromat. CH). 13C-NMR
(CDCl3), δ (ppm) = 70.14 (CH2), 74.96 (CH), 114.88 (H2C=),
115.00 (2 aromat. CH), 127.53 (2 aromat. CH), 127.79 (2 aro-
mat. CH), 128.06 (2 aromat. CH), 128.68 (aromat. CH), 135.20
(quart. C), 137.04 (quart. C), 140.43 (CH=), 158.51 (quart. C).
MS (EI): m/z (%) = 240 (M+, 100), 185 (30), 149 (60). IR (KBr)
ν (cm–1) = 3349, 2909, 1638, 1611, 1511, 1421, 1248, 1170,
848, 745. Calcd.: C: 79.97 H: 6.71 Found: C: 80.32 H: 6.88.
C16H16O2 (240.3)
( )-1-(4-Benzyloxyphenyl)hept-6-enol (2e)
From 1.5 g (7.0 mmol) 4-benzyloxybenzaldehyde (1) and 1.7 g
(10.5 mmol) hex-5-enyl bromide.Yield: 1.45 g (70%) as a white
solid, mp: 51°C.
1H-NMR (CDCl3) δ (ppm) = 1.20–1.75 (m, 4H, CH2), 1.81 (m,
2H, CH2), 2.04 (m, 2H, CH2), 4.60 (m, 1H, CH), 4.95 (m, 2H,
=CH2), 5.06 (s, 2H, CH2O), 5.78 (m, 1H, –CH=), 6.95 (d, J = 8.8
Hz, 2H, aromat. CH), 7.25 (d, J = 8.8 Hz, 2H, aromat. CH),
7.27–7.45 (m, 5H, aromat. CH). 13C-NMR (CDCl3) δ (ppm) =
25.38 (CH2), 28.78 (CH2), 33.66 (CH2), 38.77 (CH2), 70.00
(CH2O), 74.19 (CH), 114.34 (H2C=), 114.72 (2 aromat. CH),
127.13 (2 aromat.CH), 127.44 (2 aromat.CH), 127.94 (aromat.
CH), 128.56 (2 aromat. CH), 136.96 (quart. C), 137.26 (quart.
C), 138.84 (–CH=), 158.20 (quart. C). MS (EI) m/z = 296 (M+,
2), 213 (35), 91 (100). IR (KBr) ν (cm–1) = 3321, 2926, 2854,
1641, 1513, 1454, 1241, 1017, 743, 696. Calcd.: C: 81.04 H:
8.16 Found: C: 81.27 H: 8.16. C20H24O2 (296.4).
( )-1-(4-Benzyloxyphenyl)but-3-enol (2b)
From 1.5 g (7.0 mmol) 4-benzyloxybenzaldehyde (1) and
9.0 mL commercially available allylmagnesium bromide solu-
tion (1 M in THF). Yield: 1.3 g (75%) as a white solid, mp:
68.4°C.
1H-NMR (CDCl3) δ (ppm) = 2.49 (ddd, J = 7.0 Hz, J = 7.0 Hz, J =
1.3 Hz, 2H, CH2), 4.67 (dt, J = 6.4 Hz, J = 2.1 Hz, 1H, CH), 5.06
(s, 2H, CH2O), 5.10–5.18 (m, 2H, H2C=), 5.80 (ddt, J = 7.0 Hz,
J = 10.0 Hz, J = 17.2 Hz, 1H, –CH=), 6.96 (d, J = 8.6 Hz, 2H,
aromat. CH), 7.28 (d, J = 8.6 Hz, 2H, aromat. CH), 7.29–7.45
(m, 5H, aromat. CH). 13C-NMR (CDCl3) δ (ppm) = 43.85 (CH2),
70.11 (CH2O), 73.05 (CH), 114.82 (2 aromat. CH), 118.28
(=CH2), 127.19 (2 aromat. CH), 127.55 (2 aromat. CH), 128.04
(aromat. CH), 128.68 (2 aromat. CH), 134.73 (–CH=), 140.43,
(quart. C), 141.04 (quart. C), 162.27 (quart. C). MS (CI) m/z =
255 (M+ + 1, 2), 237 (100), 213 (20), 185 (15), 147 (21). IR (Na-
Cl film) ν cm–1) = 3321, 3073, 2937, 1640, 1610, 1584, 1512,
( )-4-Hydroxyphenylcarbinols 3a–c
1.0 mmol of the 4-benzyloxyphenyl alcohol 2 was dissolved in
15 mL methanol and 20 mg Pd/C was added. The suspension
was stirred under H2 atmosphere for 10 hours. Then the cata-
lyst was filtered off and the solvent was evaporated.

Arch. Pharm. Pharm. Med. Chem. 2002, 335, 94–98
Synthesis and Antimicrobial Activity 97
( )-1-(4-Benzyloxyphenyl)-3,4-dihydroxybutan-1-one (4b)
( )-1-(4-Hydroxyphenyl)propanol (3a)
From 150 mg (0.6 mmol) of 2b and 2.0 g α-AD mix.Yield: 100
From 150 mg (0.6 mmol) of 2a.Yield: 70 mg (77%) as a colour-
less oil.
mg (58%) as a white solid mp: 90.0°C.
1H-NMR (d4-methanol) δ (ppm) = 3.10 (d, J = 5.9 Hz, 2H, CH2),
3.55 (d, J = 5.9 Hz, 2H, CH2O), 4.22 (tt, J = 5.9 Hz, J = 5.9 Hz,
1H, CH), 5.15 (s, 2H, CH2O), 7.06 (d, J = 8.8 Hz, 2H, aromat.
CH), 7.24–7.25 (m, 5H, aromat. CH), 7.97 (d, J = 8.8 Hz, 2H,
aromat. CH). 13C-NMR (d4-methanol) δ (ppm) = 41.63 (CH2),
65.59 (CH2O), 69.84 (CH2O), 68.97 (CH), 114.41 (2 aromat.
CH), 127.48 (2 aromat. CH), 127.77 (aromat. CH), 127.98
(quart. C), 128.26 (2 aromat. CH), 130.74 (2 aromat. CH),
138.01 (quart. C), 164.37 (quart. C), 199.59 (CO). MS (CI) m/z
= 287 (M+ + 1, 20), 269 (40), 227 (100).IR (KBr) ν (cm–1) = 3376,
2925, 1676, 1602, 1509, 1254, 1174, 1016, 821. Calcd.: C:
71.31 H: 6.34 Found: C: 70.97 H: 6.38 C17H18O4 (286.3).
1H-NMR (d6-acetone) δ (ppm) = 0.77 (t, J = 7.4 Hz, CH3), 1.61
(m, 1H, CH2), 1.71 (m, 1H, CH2), 4.40 (t, J = 6.8 Hz, 1H, CH),
6.70 (d, J = 8.5 Hz, 2H, aromat.CH), 7.05 (d, J = 8.5 Hz, 2H, ar-
omat.CH).13C-NMR (d6-acetone) δ (ppm) = 10.21 (CH3), 31.83
(CH2), 75.44 (CH), 115.13 (2 aromat. CH), 127.05 (2 aromat.
CH), 136.09 (quart. C), 156.12 (quart. C). All data were in full
accordance with the values given in [8]. C9H12O2 (152.19).
( )-1-(4-Hydroxyphenyl)pentanol (3b)
From 150 mg (0.5 mmol) of 2c.Yield: 65 mg (72%) as a colour-
less oil.
1H-NMR (CDCl3) δ (ppm) = 0.87 (t, J = 7.0 Hz, 3H, CH3), 1.33
(m, 4H, CH2), 1.70 (m, 1H, CH2), 1.82 (m, 1H, CH2), 4.60 (t, J =
6.7 Hz, 1H, CH), 6.77 (d, J = 8.6 Hz, 2H, aromat. CH), 7.18 (d,
J = 8.6 Hz, 2H, aromat.CH).13C-NMR (CDCl3) δ (ppm) = 13.99
(CH3), 22.54 (CH2), 28.01 (CH2), 38.43 (CH2), 74.55 (CH),
115.45 (2 aromat. CH), 127.41 (2 aromat. CH), 136.55 (quart.
C), 155.19 (quart. C). MS (EI) m/z = 180 (M+, 5), 123 (100).
Calcd.: C: 73.30 H: 8.95 Found: C: 72.95 H: 8.91. C11H16O2
(180.25).All data were in full accordance with those given in [6].
( )-1-(4-Benzyloxyphenyl)-4,5-dihydroxypentan-1-one (4c)
From 200 mg (0.8 mmol) of 2c and 2.0 g α-AD mix.Yield: 135
mg (57%) as a white solid, mp: 80.1°C.
1H-NMR (CDCl3) δ (ppm) = 1.20 (m, 2H, CH2), 1.81 (m, 2H,
CH2), 3.06 (dd, 1H, CH), 3.42 (dd, 1H, CH), 3.59 (dd, 1H, CH),
3.61 (m, 1H, CH), 5.06 (s, 2H, CH2), 6.93 (d, J = 8.8 Hz, 2H, ar-
omat. CH), 7.19–7.35 (m, 5H, aromat. CH), 7.89 (d, J = 8.8 Hz,
2H, aromat. CH). 13C-NMR (CDCl3) δ (ppm) = 27.17 (CH2),
34.44 (CH2), 66.81 (CH2O), 70.15 (CH2O), 71.73 (CH), 73.89
(CH), 74.38 (CH), 114.33 (2 aromat. CH), 127.01 (2 aromat.
CH), 127.47 (2 aromat.CH), 128.26 (2 aromat.CH), 128.70 (ar-
omat. CH), 131.99 (quart. C), 136.20 (quart. C), 162.99 (quart.
C), 199.59 (CO). MS (CI) m/z (%) = 301 (M+ + 1, 10), 283 (20),
91 (100). IR (KBr) ν (cm–1) = 3364, 2925, 1676, 1601, 1509,
1454, 1379, 1302, 1254, 1168, 1016, 916, 862.Calcd.:C:71.98
H: 7.71 Found: C: 71.88 H: 7.53. C18H20O4 (300.4)
( )-1-(4-Hydroxyphenyl)hexanol (3c)
From 760 mg (2.7 mmol) of 2d.Yield: 510 mg (96%) as a col-
ourless oil.
1H-NMR (CDCl3) δ (ppm) = 0.88 (t, J = 8.2 Hz, 3H, CH3), 1.15–
1.79 (m, 6 , CH2), 4.53 (dd, J = 7.5 Hz, J = 13.5 Hz, 1H, CH),
6.79 (d, J = 8.9 Hz, 2H, aromat.CH), 7.18 (d, J = 8.9 Hz, 2H, ar-
omat. CH). 13C-NMR (CDCl3) δ (ppm) = 14.32 (CH3), 23.18
(CH2), 39.66 (CH2), 74.26 (CH), 115.71 (2 aromat. CH), 128.11
(2 aromat. CH), 137.54 (quart. C), 156.83 (quart. C). MS (EI)
m/z = 176 (M+ – 18, 15), 137 (40), 107 (100).IR (KBr) ν (cm–1) =
3333, 3024, 2956, 2931, 1614, 1598, 1454, 1240, 1171, 1109,
1005, 949, 895. C12H18O2 (194.28).
( )-1-(4-Benzyloxyphenyl)-5,6-dihydroxyhexan-1-one (4d)
From 250 mg (1.3 mmol) of 2d and 2.0 g α-AD mix. Yield:
175 mg (42%) as a white solid: mp: 120.6°C.
1H-NMR (CDCl3) δ (ppm) = 1.18 (m, 2H, CH2), 1.44 (m, 2H,
CH2), 1.80 (m, 2H, CH2), 3.40 (dd, J = 11.2, Hz, J = 8.1 Hz, 1H,
CH), 3.59 (dd, J = 3.4 Hz, J = 11.2 Hz, 1H, CH), 3.64 (m, 1H,
CH), 5.07 (s, 2H, CH2), 6.94 (d, J = 10.0 Hz, 2H, aromat. CH),
7.23–7.38 (m, 5H, aromat. CH), 7.88 (d, J = 10.0 Hz, 2H, aro-
mat. CH). 13C-NMR (CDCl3) δ (ppm) = 19.81 (CH2), 32.71
(CH2), 37.76 (CH2), 66.71 (CH2O), 70.14 (CH2O), 71.65 (CH),
114.61 (aromat. CH), 127.46 (aromat. CH), 128.25 (aromat.
CH), 128.70 (aromat.CH), 130.35 (aromat.CH), 136.15 (quart.
C), 162.67 (quart. C), 199.41 (CO). MS (CI): m/z (%) = 315
(M+ + 1, 100), 297 (50), 249 (55). IR (NaCl film) ν (cm–1) =
3289, 2923, 1675, 1602, 1508, 1455, 1413, 1377, 1303, 1253,
1172, 1109, 1051, 1009, 916. Calcd.: C: 72.59 H: 7.05 Found:
C: 72.47 H: 7.52. C19H22O4 (314.4).
( )-4-Benzyloxyphenyldihydroxyalkanones 4a–e
1.0 mol of the alkene 2a–e was dissolved in 20 mL of a mixture
of tert-butanol and water (1:1) and 2.0 g α-AD mix were added.
The suspension was cooled to 0°C and stirred for 12 hours.
Then it was quenched with 20 mL 10% Na2SO3 solution and ex-
tracted with ethyl acetate (3 × 50 mL). The combined organic
layers were evaporated.The residue was purified by FCC (ethyl
acetate).
( )-1-(4-Benzyloxyphenyl)-2,3-dihydroxypropan-1-one (4a)
From 200 mg (0.8 mmol) of 2a and 2.0 g α-AD mix. Yield:
140 mg (65%) as a white solid, mp: 140.1°C.
( )-1-(4-Benzyloxyphenyl)-6,7-dihydroxyheptan-1-one (4e)
1H-NMR (CDCl3) δ (ppm) = 3.82 (dd, J = 5.1 Hz, J = 11.3 Hz,
1H, CH), 3.96 (dd, J = 3.8 Hz, J = 11.3 Hz, 1H, CH), 5.19 (m,
1H, CH), 5.26 (m, 2H, CH2O), 7.09 (d, J = 8.9 Hz, 2 H, aromat.
CH), 7.24–7.60 (m, 5H, aromat. CH), 7.99 (d, J = 8.9 Hz, 2H,
aromat. CH). 13C-NMR (CDCl3) δ (ppm) = 65.95 (CH2O), 71.16
(CH2O), 75.57 (CH), 115.88 (2 aromat. CH), 128.60 (2 aromat.
CH), 129.09 (2 aromat. CH), 129.56 (aromat. CH), 132.06
(2 aromat. CH), 133.20 (quart. C), 164.60 (quart. C), 210.31
(CO). MS (CI) m/z = 273 (100), 243 (70), 211 (75). IR (KBr)
ν (cm–1) = 3376, 2925, 1672, 1605, 1575, 1509, 1453, 1381,
1244, 1176, 1122, 1056, 1019, 974. Calcd.: C: 70.58 H: 5.92
Found: C: 70.70 H: 6.17. C16H16O4 (274.3).
From 500 mg (1.7 mmol) of 2e and 2.0 g α AD mix. Yield:
510 mg (90%) as a white solid mp: 145°C.
1H-NMR (CDCl3) δ (ppm) = 1.24–1.75 (m, 6H, CH2), 2.88 (t, J =
7.1 Hz, 2H, CH2), 3.36 (m, 2H, CH), 3.54 (m, 1H, CH), 5.08 (s,
2H, CH2), 6.96 (d, J = 8.8 Hz, 2H, aromat. CH), 7.36 (m, 5H,
aromat. CH), 7.89 (d, J = 8.8 Hz), 2 H, aromat. CH). 13C-NMR
(CDCl3) δ (ppm) = 29.12 (CH2), 30.23 (CH2), 37.80 (CH2), 43.78
(CH2), 69.75 (CH2O), 73.02 (CH2O), 75.08 (CH), 117.74 (2
aromat. CH), 130.12 (2 aromat. CH), 130.46 (2 aromat. CH),
130.96 (aromat.CH), 131.57 (2 aromat.CH), 139.94 (quart.C),
140.20 (quart.C), 167.56 (quart.C), 204 (CO).MS (CI):m/z (%)

98
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 94–98
= 329 (M+ + 1, 40), 313 (100), 213 (85).IR (NaCl film):ν (cm–1) =
3367, 2935, 1677, 1600, 1510, 1454, 1377, 1240, 1173, 1015,
911.Calcd.:C:73.15 H:7.37 Found:C:72.75 H:7.38.C20H24O4
(328.4).
6-(4-Hydroxyphenyl)hexane-1,2,6-triol (diastereomeric mixture)
(5d)
From 100 mg (0.3 mmol) of 4d.Yield: 43 mg (60%) as a colour-
less oil.
1H-NMR (d4-methanol) δ (ppm) = 1.29 (m, 2H, CH2), 1.40–1.69
(m, 2H, CH2), 1.69–2.00 (m, 2H, CH2), 3.51 (m, 2H, CH2), 3.66
(m, 1H, CH), 6.88 (d, J = 8.8 Hz, 2H, aromat. CH), 7.92 (d, J =
8.8 Hz, 2H, aromat. CH). 13C-NMR (d4-methanol) δ (ppm) =
20.74 (CH2), 32.62 (CH2), 37.62 (CH2), 66.24 (CH2O), 71.86
(CH), 71.89 (CH), 73.61 (CH), 114.93 (2 aromat. CH), 128.69
(quart. C), 130.52 (2 aromat. CH), 162.43 (quart. C). MS (CI)
m/z = (225, M– – 1, 100), 207 (55). Calcd.: C: 63.70 H: 8.02
Found: C: 64.00 H: 8.00. C12H18O4 (226.3). Diastereomeric
ratio: 1:1.
4-Hydroxyphenylalkanetriol 5a–e
0.5 mmol of the benzyloxy derivatives were dissolved in 15 mL
methanol and 20 mg Pd/C was added. The suspension was
stirred for 10 h under H2 atmosphere.Then the catalyst was fil-
tered off and the solvent was evaporated.The residue was puri-
fied by FCC (ethyl acetate/methanol).
1-(4-Hydroxyphenyl)propane-1,2,3-triol (diastereomeric mix-
ture) (5a)
From 200 mg (0.7 mmol) of 4a.Yield: 84 mg (65%) as a white
solid.
7-(4-Hydroxyphenyl)hepane-1,2,7-triol (diastereomeric mixture)
(5e)
1H-NMR (d3-acetonitrile) δ (ppm) = 3.42–3.73 (m, 3H, CH),
4.57 (d, J = 6.2 Hz, 1H, CH), 6.87 (d, J = 8.4 Hz, 2H, aromat.
CH), 7.29 (d, J = 8.4 Hz, 2H, aromat. CH).
From 200 mg (0.6 mmol) of 4e.Yield: 110 mg (75%) as a col-
ourless oil.
1H-NMR (d6-acetone) δ (ppm) = 1.15–1.39 (m, 6H, CH2),
1.40–1.70 (m, 2H, CH2), 3.32 (dd, J = 6.8 Hz, J = 10.8 Hz, 1H,
CH), 3.41 (dd, J = 4.1 Hz, J = 10.8 Hz, 1H, CH), 3.52 (m, 1H,
CH), 4.49 (t, J = 7.2 Hz, 1H, CH), 5.55 (s, 1H, OH), 6.73 (d, J =
8.5 Hz, 2H, aromat. CH), 7.11 (d, J = 8.5 Hz, 2H, aromat. CH).
13C-NMR (d6-acetone) δ (ppm) = 25.53 (CH2), 26.00 (CH2),
33.46 (CH2), 39.61 (CH2), 66.52 (CH2O), 71.84 (CH), 73.23
(CH), 114.86 (2 aromat. CH), 127.14 (2 aromat. CH), 137.12
(quart. C), 156.35 (quart. C). MS (CI) m/z = (223, M+ – 17,100),
187 (20), 107 (60). IR (NaCl film) ν (cm–1) = 3320, 2924, 2854,
1597, 1512, 1454, 1245, 1164, 1066, 828, 735, 698. Calcd.: C:
64.98 H: 8.39 Found: C: 64.64 H: 8.83. C13H20O4 (240.3).
Diastereomeric ratio: 1:1.
13C-NMR (d3-acetonitrile) δ (ppm) = 63.98 (CH2O), 75.30 (CH),
75.70 (CH), 115.37 (2 aromat. CH), 128.93 (2 aromat. CH),
134.26 (quart. C), 156.91 (quart. C). MS (CI) m/z = 167 (M+ +
1–18, 100), 149 (70), 107 (48). IR (NaCl film) ν (cm–1) = 3358,
1613, 1514, 1449, 1238, 1027, 825, 530. Calcd.: C: 58.69 H:
6.57 Found: C: 58.94 H: 6.58. C9H12O4 (184.2). Diastereomeric
ratio: 1:1.
4-(4-Hydroxyphenyl)butane-1,2,4-triol (diastereomeric mixture)
(5b)
From 80 mg (0.28 mmol) of 4b.Yield: 20 mg (36%) as a yellow
oil.
1H-NMR (d4-methanol) δ (ppm) = 1.71–1.90 (m, 2H, CH2),
2.54–3.48 (m, 3H, CH, CH2O), 4.68 (m, 1H, CH), 6.64 (m, 2H,
aromat. CH), 7.09 (m, 2H, aromat. CH). 13C-NMR (d4-metha-
nol) δ (ppm) = 42.81 (CH2), 43.24 (CH2), 66.92 (CH2O), 67.38
(CH2O), 70.34 (CH), 71.18 (CH), 71.60 (CH), 73.21 (CH),
116.01 (2 aromat. CH), 116.24 (2 aromat. CH), 128.06 (2
aromat. CH) 128.52 (2 aromat. CH), 136.74 (quart. C), 137,71
(quart. C), 157,61 (quart. C), 157,71 (quart. C). MS (CI) m/z =
181 (M + 1–18, 100)163 (55), 147 (55), 121 (85). IR (NaCl film)
ν (cm–1) = 3349, 2940, 1614, 1599, 1514, 1238, 1056, 835.
Calcd.: C: 60.59 H: 7.12 Found: C: 60.41 H: 7.05. C10H14O4
(198.2). Diastereomeric ratio: 1:1.3.
References
ଝ
Dedicated to Prof. Dr. E. Reimann on occasion of his 65th
birthday.
[1] Ullmann’s Encyclopedia of Industrial Chemistry, Vol. A 8,
A 19, VCH, Weinheim 1991.
[2] H. Bechthold, P. Ehrlich, Z. Physiol. Chem. 1906, 47, 173.
[3] R. Fernandez, M. Dherbomez, Y. Letourneux, M. Nabil, J.
5-(4-Hydroxyphenyl)pentane-1,2,5-triol (diastereomeric mix-
ture) (5c)
F. Ve r b i s t , J. F. B i a r d , J. Nat. Prod. 1999, 678.
[4] H.Becker, K.B.Sharpless:Angew.Chem.1996, 108, 447.
From 150 g (0.5 mmol) of 4c.Yield: 67 mg (63%) as a colour-
less oil.
[5] W.H.Gerwick, M.F.Moghaddam, S.K.Agarwal, Experien-
tia 1989, 45, 115.
1H-NMR (d4-methanol) δ (ppm) = 1.2–1.93 (m, 4H, CH2), 3.48
(m, 3H, CH, CH2), 4.52 (m, 1H, CH), 6.83 (d, J = 8.8 Hz, 2H,
aromat.CH), 7.89 (d, J = 8.8 Hz, 2H.aromat.CH).13C-NMR (d4-
methanol) δ (ppm) = 28.24 (CH2), 34.20 (CH2), 66.38 (CH2O),
72.32 (CH), 74.11 (CH), 115.11 (2 aromat. CH), 127.38 (2 aro-
mat. CH), 132.37 (quart. C), 162.73 (quart. C). Calcd.: C: 60.59
H: 7.12 Found: C: 60.37 H: 7.28. C11H16O4 (212.2). Diastereo-
meric ratio: 1:1.
[6] L. N. Lungren, Z. Shen, O.Theander, Acta. Chem. Scand.,
Ser. B 1985, 39, 241.
[7] M. Wieser, H. Furukawa, H. Morita, T. Yoshida, T. Na-
gasawa, Tetrahedron, Asymmetry 1999, 10, 1627.
[8] G. C. Bramanti, P. Bianchini, G. Cerbai, L. Turbanti, N.
Tellini, Chim. Ther. 1967, 2, 415.