First enantioselective synthesis of daphneticin and its regioisomer

Article abstract of DOI:10.1016/S0957-4166(02)00482-2

An enantioselective total synthesis of chiral daphneticin and its regioisomer is reported for the first time.

Full text of DOI:10.1016/S0957-4166(02)00482-2

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1799–1804
First enantioselective synthesis of daphneticin and its regioisomer
Xinfeng Ren, Xiaochuan Chen, Kun Peng, Xingang Xie, Yamu Xia and Xinfu Pan*
Department of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
Received 9 July 2002; accepted 15 August 2002
Abstract—An enantioselective total synthesis of chiral daphneticin and its regioisomer is reported for the first time. © 2002
Published by Elsevier Science Ltd.
1. Introduction
Coumarinolignoids are a relatively new and rare group
of natural products consisting of C6, C3, C6 units. In
these molecules the coumarin moieties are linked with
the phenyl propanoid units through a 1,4-dioxane
bridge.1 Because of their varied biological activities,
especially their cytotoxicity and antihepatotoxic activi-
ties,2 several efficient syntheses of natural coumarino-
lignoids have been reported.3
Daphneticin
1 has been isolated as a racemic
compound2 from the roots and stems of Daphne
tangutica. As a coumarinolignoid, daphneticin showed4
cytotoxic activity in vitro in the walker-256-carcinosar-
comaascites system. Cordell and Lin3a reported the
synthesis of daphneticin under oxidative reaction condi-
tions (horseradish peroxidase and silver oxide). Later,
Tanaka et al.3g described that daphneticin could also
prepared using Ph2SeO as the oxidizing agent. How-
ever, Cordell and Lin5 recently revised the structure of
daphneticin to have the formula 1 by using the selective
INEPT pulse programme with daphneticin diacetate.
Although Tanaka et al.3c,d synthesized daphneticin 1
and its regioisomer 2 in racemic form, we felt that it
was a pity that a total asymmetric synthesis of daph-
neticin has not yet been reported, and this prompted
the investigations which we report herein.
2. Results and discussion
As shown in Scheme 1, the first half of the convergent
synthesis required preparation of the coumarin 9. Ini-
tially, 7-hydroxycoumarin 3 was easily converted into
7-acetoxycoumarin 4 by acetylation. Treatment of 4
with AlCl3 under 160°C gave 8-acetyl-7-hydroxycou-
marin 5.7 Then, compound 7 was prepared by benzyla-
tion of compound 5 followed by Baeyer–Villiger
oxidation with hydrogen peroxide in alkaline dioxane
solution. On treatment with Ac2O, compound 7 was
converted to the acetate 8, which was then subjected to
catalytic hydrogenation yielding the debenzylation
product 9.
Synthesis of the functionalised aryl unit 16 began from
3,4,5-trimethoxybenzaldehyde 10. Selective demethyla-
tion of 10 with piperidine gave 4-hydroxy-3,5-
dimethoxybenzaldehyde 11.8 Aldehyde 11 was reacted
with monoethyl malonate9 in the presence of pyridine
and piperidine to give an unsaturated ester.10 Protection
of the 4-hydroxyl group with benzyl bromide afforded
the benzyl ether 12, which was reduced with lithium
aluminium hydride/AlCl3 in THF to the corresponding
alcohol 13.11 Asymmetric dihydroxylation of 13 with
In our previous work,6 we reported the first asymmetric
and regioselective synthetic approach to 1,4-benzodiox-
ane lignans. On the basis of this work, we now wish to
report an enantioselective synthesis of daphneticin 1
and its regioisomer 2 from the readily available com-
pound 10 and commercially available 7-hydroxycou-
marin 3.
* Corresponding author. E-mail: panxf@lzu.edu.cn
0957-4166/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0957-4166(02)00482-2

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X. Ren et al. / Tetrahedron: Asymmetry 13 (2002) 1799–1804
Scheme 1. Reagents and conditions: (i) Ac2O, pyridine, rt, 24 h, 97%; (ii) AlCl3, 160°C, 2 h, 79%; (iii) BnBr, K2CO3, 24 h, 94%;
(iv) H2O2, NaOH, 20 min, 94%; (v) Ac2O, pyridine, rt, 24 h, 90%; (vi) Pd/C (5%), H2, EtOAc, rt, 6 h, 92%; (vii) piperidine, H2O,
reflux, 48 h, 80%; (viii) (1) CO2HCH2CO2Et, pyridine, piperidine, reflux, 6 h; (2) BnBr, K2CO3, 24 h, 80%; (ix) LAH, AlCl3, THF,
0.5 h, 86%; (x) AD-mix-b, MeSO2NH2, t-BuOH, H2O, 0°C, 20 h, 87%; (xi) TsCl, pyridine, 91%; (xii) K2CO3, MeOH, rt, 3 h, 80%;
(xiii) DIAD, Ph3P, THF, rt, 24 h, 65%; (xiv) K2CO3, MeOH, rt, 3 h, 90%; (xv) Pd/C (5%), H2, EtOAc, rt, 6 h, 81%.
AD-mix-b afforded (1R,2R)-14 in 93% e.e.12 Reaction
of (1R,2R)-14 with TsCl in pyridine provided the pri-
mary tosylate (1R,2R)-15. Ring closure of (1R,2R)-15
was promoted by potassium carbonate in methanol,
generating the oxirane (1R,2R)-16.13 Mitsunobu
reaction14 between (1R,2R)-16 and compound 9 gave
the characterized ether (1S,2R)-17, where the absolute
configuration at the C-1 stereogenic centre was inverted
completely from the SN2-type nucleophilic displacement
by 8-acetoxy-7-hydroxycoumarin. Removal of the acet-
yl group of (1S,2R)-17 followed by intramolecular
cyclization using potassium carbonate in methanol
afforded (2S,3S)-18, where nucleophilic attack at C-2
of the oxirane by the phenol hydroxyl group in the
presence of K2CO3 led to complete inversion of the
absolute configuration at C-2 and the formation of the

X. Ren et al. / Tetrahedron: Asymmetry 13 (2002) 1799–1804
1801
1,4-benzodioxane ring.15 The benzyl group was
removed by hydrogenolysis under hydrogen (at atmo-
spheric pressure) in the presence of 5% Pd/C in ethyl
yield 97%). Mp 143–145°C. MS (EI): 204 (M+), 162,
134, 105, 43. H NMR (80 MHz, CDCl3): l 2.36 (s,
3H), 6.42 (d, 1H, J=9.6 Hz), 7.08 (dd, 1H, J=8.1, 2.0
Hz), 7.13 (d, 1H, J=2.1 Hz), 7.52 (d, 1H, J=8.1 Hz),
7.72 (d, 1H, J=9.6 Hz).
1
1
acetate to afford (2S,3S)-1. In the H NMR spectrum
of (2S,3S)-1, H-2 resonated as a doublet signal at l
5.11 with a coupling constant (J=7.9 Hz) which is
typical of a trans-isomer and indicates a threo configu-
ration. The 13C NMR spectrum showed signals at l
61.4, 76.5, 78.6 indicating a six-membered 2-aryl-3-
hydroxymethyl-1,4-benzodioxane skeleton.16
3.3. 8-Acetyl-7-hydroxycoumarin, 5
Compound 4 (3.54 g, 17.3 mmol) and AlCl3 (8.53 g,
63.9 mmol) were mixed together, and the mixture was
heated at 160°C for 2 h. The reaction mixture was
cooled and dilute aqueous hydrochloric acid was
added. The solution was stirred for 1 h at room temper-
ature and then heated under steam bath for 0.5 h. The
solution was cooled and extracted with EtOAc (3×50
mL). The combined organic layer was washed with
brine and dried with Na2SO4. The solvent was distilled
off and the residue was flash chromatographed using
petroleum ether and ethyl acetate (5:1, v/v) as eluent. A
light yellow solid 5 (2.8 g) was obtained in 79% yield.
Mp 165–167°C. MS (EI): 204 (M+), 189, 161, 133, 105,
We also synthesized daphneticin’s regioisomer 2. Mit-
sunobu reaction14 between compound 7 and compound
16 gave the ether (1S,2R)-19. The two benzyl groups of
compound (1S,2R)-19 were removed by catalytic
hydrogenation, leaving the epoxide ring intact, to
afford (1S,2R)-20.17 Cyclization of (1S,2R)-20 with
potassium carbonate in methanol then afforded
(2S,3S)-2.
In summary, we have carried out the enantioselective
synthesis of daphneticin 1 and its regioisomer 2 in 17
and 14% yield, respectively. All spectral data were in
agreement with those found in the literature.2,3c,3d This
is the first enantioselective total synthesis of these
coumarinolignoids.
1
77, 43. H NMR (80 MHz, CDCl3): l 2.98 (s, 3H), 6.29
(d, 1H, J=9.4 Hz), 6.91 (d, 1H, J=8.3 Hz), 7.54 (d,
1H, J=8.5 Hz), 7.66 (d, 1H, J=9.6 Hz), 13.65 (s, 1H).
3.4. 8-Acetyl-7-benzyloxycoumarin, 6
A mixture of compound 5 (1.8 g, 8.8 mmol), benzyl
bromide (2 mL) and anhydrous potassium carbonate
(1.9 g) in acetone (100 mL) was stirred overnight at
room temperature. The reaction mixture was evapo-
rated in vacuo. The crude products were dissolved in
water and then extracted with ethyl acetate (3×50 mL).
The combined organic layer was washed with brine and
dried with Na2SO4. The solvent was distilled off and
the residue was flash chromatographed using petroleum
ether and ethyl acetate (4:1, v/v) as eluent. The product
6 was obtained as white solid (2.44 g, yield 94%). Mp
113–115°C. MS (EI): 294 (M+), 276, 252, 189, 160, 91,
43. 1H NMR (200 MHz, CDCl3): l 2.61 (s, 3H), 5.20 (s,
2H), 6.26 (d, 1H, J=9.4 Hz), 6.91 (d, 1H, J=8.6 Hz),
7.37 (m, 5H), 7.41 (d, 1H, J=8.6 Hz), 7.62 (d, 1H,
J=9.6 Hz).
3. Experimental
3.1. General
Melting points were measured on a Kofler apparatus
1
and were uncorrected. The H and 13C NMR data were
recorded with Bruker AM-80 and Avance-200 MHz
spectrometers. The chemical shifts are reported in ppm
relative to TMS. Mass spectra were recorded on a
ZAB-HS spectrometer. Elemental analyses were per-
formed on a Carlo–Erba 1106 instrument. Optical rota-
tions were determined on
a
Perkin–Elmer 341
polarimeter. Chrial analysis was performed on Varian
Dynamax SD-300 using chiralcel column CDMPC
(150×4.6 mm D) with hexane/isopropyl alcohol as elu-
ant (n-hexane:isopropyl alcohol, 20:1, 0.5 mL/min,
25°C). Flash column chromatography was generally
performed on silica gel (200–300 mesh) eluting with
petroleum ether:ethyl acetate and TLC inspections on
silica gel GF254 plates with petroleum ether:ethyl acet-
ate, if not noted especially below.
3.5. 7-Benzyloxy-8-hydroxycoumarin, 7
A solution of 30% aqueous H2O2 (30 mL) was added
dropwise to a mixture of 6 (1 g, 3.4 mmol) in dioxane
(30 mL) and 1N NaOH (20 mL) at 10°C, and stirred at
the same temperature for more than 20 min. The
reaction mixture was poured into ice-water and neutral-
ized with 5% HCl, then extracted with ethyl acetate
(3×30 mL). The combined organic layer was washed
with brine, dried over Na2SO4 and evaporated. The
crude product was flash chromatographed using
petroleum ether and ethyl acetate (3:1, v/v) as eluent.
The product, 7 was obtained as a white solid (0.8 g,
94%). Mp 163–164°C. MS (EI): 268 (M+), 211, 177,
3.2. 7-Acetoxycoumarin, 4
To a stirred solution of 7-hydroxycoumarin 3 (3.1 g,
19.1 mmol) in CH2Cl2 (50 mL), Ac2O (2 mL) and
pyridine (one drop) were added. After the solution was
stirred overnight at room temperature, it was evapo-
rated in vacuo. The crude products were dissolved in
water and then extracted with EtOAc (3×50 mL). The
combined organic layer was washed with brine, and
then dried with Na2SO4. The solvent was distilled off
under reduced pressure and the residue was flash chro-
matographed using petroleum ether and ethyl acetate
(3:1, v/v) as eluent to afford 4 as a white solid (3.84 g,
1
125, 91, 65. H NMR (200 MHz, CDCl3): l 5.22 (s,
2H), 5.8 (s, 1H), 6.26 (d, 1H, J=9.4 Hz), 6.88 (d, 1H,
J=8.6 Hz), 6.96 (d, 1H, J=8.8 Hz), 7.37 (m, 5H), 7.60
(d, 1H, J=9.6 Hz).

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X. Ren et al. / Tetrahedron: Asymmetry 13 (2002) 1799–1804
3.6. 8-Acetoxy-7-benzyloxycoumarin, 8
6.79 (s, 2H), 7.62 (d, 1H, J=15.8 Hz). A mixture of
ethyl 4-hydroxy-3,5-dimethoxy cinnamate (1.6 g, 6.35
mmol), benzyl bromide (1.8 mL) and anhydrous potas-
sium carbonate (1.6 g) in acetone (100 mL) were stirred
overnight at room temperature. The reaction mixture
was evaporated in vacuo. The crude products were
dissolved in water and then extracted with ethyl acetate
(3×50 mL). The combined organic layer was washed
with brine and dried with Na2SO4. The solvent was
distilled off and the residue was flash chromatographed
using petroleum ether and ethyl acetate (4:1, v/v) as
eluent. The product 12 was obtained as a white solid
(2.02 g, 93%). Mp 71–73°C. MS (EI): 342 (M+), 297,
A mixture of 7 (0.85 g, 3.17 mmol), acetic anhydride (5
mL) and pyridine (0.5 mL) in CH2Cl2 was stirred
overnight at room temperature. The reaction mixture
was poured into water and extracted with ethyl acetate
(3×30 mL). The combined organic layer was washed
with brine, dried over Na2SO4 and evaporated to dry-
ness. The residue was flash chromatographed using
petroleum ether and ethyl acetate (3:1, v/v) as eluent to
afford 8 as a white solid (0.88 g, 90%). Mp 127–128°C.
MS (EI): 310 (M+), 268, 177, 149, 121, 91, 43. 1H NMR
(200 MHz, CDCl3): l 2.39 (s, 3H), 5.19 (s, 2H), 6.26 (d,
1H, J=9.6 Hz), 6.92 (d, 1H, J=8.6 Hz), 7.27 (d, 1H,
J=8.6 Hz), 7.37 (m, 5H), 7.62 (d, 1H, J=9.6 Hz).
1
251, 177, 135, 91, 65. H NMR (200 MHz, CDCl3): l
1.34 (t, 3H, J=7.2 Hz), 3.85 (s, 6H), 4.27 (q, 2H,
J=7.2 Hz), 5.05 (s, 2H), 6.35 (d, 1H, J=16.0 Hz), 6.74
(s, 2H), 7.31–7.50 (m, 5H), 7.60 (d, 1H, J=16.0 Hz).
3.7. 8-Acetoxy-7-hydroxycoumarin, 9
A suspension of 8 (137 mg, 0.44 mmol) and 5% Pd–C
(13 mg) in ethyl acetate (10 mL) was stirred under a H2
atmosphere. The reaction mixture was filtered and the
filtrate was concentrated. The residue was flash chro-
matographed using petroleum ether and ethyl acetate
(2:1, v/v) as eluent to afford 9 as a white solid (89 mg,
92%). Mp 160–162°C. MS (EI): 220 (M+), 178, 150,
3.10. 4-Benzyloxy-3,5-dimethoxycinnamyl alcohol, 13
To a suspension of LiAlH4 (0.274 g, 7.2 mmol) in dry
THF (50 mL), AlCl3 (0.32 g, 2.4 mmol) was added
portionwise at room temperature. After the suspension
was stirred for 10 min, a solution of compound 12 (0.82
g, 2.4 mmol) in dry THF was added dropwise to the
suspension. The reaction mixture was stirred at room
temperature for 0.5 h. Then the reaction was quenched
with ice-water, extracted with ethyl acetate and the
combined organic layers were washed with brine, and
then dried with Na2SO4. The solvent was distilled off
and the residue was flash chromatographed using
petroleum ether and ethyl acetate (2:1, v/v) as eluent.
Compound 13 was obtained as a colorless oil (0.62 g,
1
138, 81, 69. H NMR (200 MHz, acetone-d6): l 2.36 (s,
3H), 6.21 (d, 1H, J=9.4 Hz), 6.95 (d, 1H, J=8.6 Hz),
7.43 (d, 1H, J=8.6 Hz), 7.91 (d, 1H, J=9.6 Hz), 9.38
(br s, 1H).
3.8. 4-Hydroxy-3,5-dimethoxybenzaldehyde, 11
A solution of 3,4,5-trimethoxybenzaldehyde 10 (3.48 g,
17.7 mmol) in piperidine (35 mL) and water (35 mL)
was heated under reflux for 48 h and the cooled mixture
was poured into 4N aqueous hydrochloric acid. The
mixture was extracted with ethyl acetate (3×50 mL).
The combined organic layer was washed with 2N
hydrochloric acid, water, dried over Na2SO4. The sol-
vent was distilled off and the residue was flash chro-
matographed using petroleum ether and ethyl acetate
(4:1, v/v) as eluent to afford 11 as a white solid (2.58 g,
80%). Mp 113–114°C. MS (EI): 182 (M+), 167, 139,
86%). MS (EI): 300 (M+), 209, 177, 149, 121, 91, 65. H
1
NMR (200 MHz, CDCl3): l 3.81 (s, 6H), 4.28 (d, 2H,
J=5.4 Hz), 5.01 (s, 2H), 6.26 (dt, 1H, J=15.8 Hz, 5.6
Hz), 6.51 (d, 1H, J=15.8 Hz), 6.59 (s, 2H), 7.27–7.52
(m, 5H).
3.11. (1R,2R)-1-(4-Benzyloxy-3,5-dimethoxyphenyl)-2,3-
dihydroxypropanol, (1R,2R)-14
To a stirred solution of tert-BuOH (25 mL) and H2O
(25 mL), AD-mix-b (7 g) and MeSO2NH2 (475 mg) was
added, the mixture was stirred at room temperature
until both phases were clear, and then cooled to 0°C,
compound 13 (1.5 g, 5 mmol) was added immediately,
the mixture was stirred vigorously at 0°C until TLC
revealed the absence of 13. The reaction was quenched
at 0°C by addition of Na2SO3 (7.5 g), then warmed to
room temperature and stirred for 0.5 h. The reaction
mixture was extracted with ethyl acetate (3×50 mL).
The combined organic layer was washed with a 2N
KOH solution, water and dried over Na2SO4. The
solvent was distilled off and the residue was flash
chromatographed using petroleum ether and ethyl ace-
tate (1:3, v/v) as eluent. A white powder of (1R,2R)-14
(1.45 g, 87%) was obtained in 93% e.e. (retention times
18.5 min). Mp 77–79°C. [h]2D5 −18 (c 1.60, CHCl3). MS
1
111, 96, 65. H NMR (80 MHz, CDCl3): l 3.97 (s, 6H),
6.12 (br s, 1H), 7.17 (s, 2H), 9.83 (s, 1H).
3.9. Ethyl 4-benzyloxy-3,5-dimethoxycinnamate, 12
Monoethyl malonate (1.523 g, 11.54 mmol) was added
to the solution of compound 11 (1.05 g, 5.77 mmol) in
pyridine (15 mL) and piperidine (0.25 mL). The mixture
was heated under reflux at 120°C for 6 h, then the
pyridine was evaporated. The crude product was dis-
solved in ethyl acetate and the solution was washed
with 5% sodium bicarbonate and water, dried over
Na2SO4. The solvent was distilled off and the residue
was flash chromatographed using petroleum ether and
ethyl acetate (3:1, v/v) as eluent. Ethyl 4-hydroxy-3,5-
dimethoxycinnamate was obtained as a white solid (1.3
g, 89%). Mp 59–61°C. MS (EI): 252 (M+), 224, 207,
1
(EI): 334 (M+), 273, 183, 123, 91, 65. H NMR (200
1
180, 140, 121, 65, 53. H NMR (80 MHz, CDCl3): l
MHz, CDCl3): l 3.48 (m, 2H), 3.76 (m, 1H), 3.77 (s,
6H), 4.55 (d, 1H, J=6.6 Hz), 4.96 (s, 2H), 6.55 (s, 2H),
7.29–7.48 (m, 5H).
1.35 (t, 3H, J=7.1 Hz), 3.93 (s, 6H), 4.28 (q, 2H,
J=7.1 Hz), 5.77 (br s, 1H), 6.31 (d, 1H, J=15.9 Hz),

X. Ren et al. / Tetrahedron: Asymmetry 13 (2002) 1799–1804
1803
3.12. (1R,2R)-1-(4-Benzyloxy-3,5-dimethoxyphenyl)-2,3-
dihydroxypropyl tosylate, (1R,2R)-15
(1S,2R)-17 (110 mg, 0.21 mmol) in methanol (10 mL)
and the solution was stirred vigorously for 2 h at
room temperature. The methanol in the reaction mix-
ture was evaporated in vacuo and 2N HCl (2 mL) was
added. The mixture was extracted with ethyl acetate
(3×20 mL) and the combined organic layer was
washed with brine and dried over Na2SO4. The solvent
was distilled off and the residue was flash chro-
matographed using petroleum ether and ethyl acetate
(2:1, v/v) as eluent. A white solid of (2S,3S)-18 (91
mg, 90%) was obtained in 93% e.e. (retention times
23.6 min). Mp 182–185°C. [h]2D5 +28 (c 0.7, CHCl3).
Compound (1R,2R)-14 (0.55 g, 1.65 mmol) in pyridine
(15 mL) was cooled to 0°C under N2, then TsCl (0.345
g, 1.8 mmol) was added. The reaction mixture was
stirred at room temperature for 20 h, diluted with
ethyl acetate (50 mL) and extracted with 1N HCl
(3×20 mL). The organic phase was dried with Na2SO4,
concentrated in vacuo, and the residue was flash chro-
matographed using petroleum ether and ethyl acetate
(1:2, v/v) as eluent to yield (1R,2R)-15 as a white
powder (0.73 g, 91%) in 96% e.e. (retention times 13.7
min). Mp 121–122°C. [h]2D5 −10 (c 2.90, CHCl3). MS
(EI): 488 (M+), 470, 424, 345, 334, 300, 172, 107, 91.
1H NMR (200 MHz, CDCl3): l 2.44 (s, 3H), 3.79 (s,
6H), 3.88 (m, 1H), 3.97 (m, 2H), 4.61 (d, 1H, J=5.8
Hz), 4.97 (s, 2H), 6.54 (s, 2H), 7.29–7.77 (m, 9H).
1
MS (EI): 476 (M+), 385, 299, 277, 207, 91. H NMR
(200 MHz, CDCl3): l 3.65 (m, 2H), 3.82 (s, 6H), 4.28
(m, 1H), 5.01 (s, 2H), 5.15 (d, 1H, J=8.1 Hz), 6.31 (d,
1H, J=9.4 Hz), 6.62 (s, 2H), 6.73 (d, 1H, J=8.6 Hz),
7.17 (d, 1H, J=8.8 Hz), 7.28–7.46 (m, 5H), 7.61 (d,
1H, J=9.6 Hz).
3.13. (1R,2R)-2,3-Expoxy-1-(4-benzyloxy-3,5-
dimethoxyphenyl)propanol, (1R,2R)-16
3.16. Daphneticin, (2S,3S)-1
A solution of (2S,3S)-18 (210 mg, 0.44 mmol) in ethyl
acetate (10 mL) was hydrogenated over 5% Pd–C (20
mg) under a H2 atmosphere. The reaction mixture was
filtered and the filtrate was concentrated. The residue
was flash chromatographed using petroleum ether and
ethyl acetate (1:1, v/v) as eluent. A white solid of
(2S,3S)-1 (138 mg, 81%) was obtained with 92% e.e.
Retention times: (2S,3S)-1 27.6 min, (2R,3R)-1 25.8
min. [h]2D5 +11 (c 1.40, CHCl3). Mp 229–231°C. MS
(EI): 386 (M+), 368, 353, 277, 209, 177, 167, 149, 43.
1H NMR (200 MHz, acetone-d6): l 3.74 (m, 2H), 3.88
(s, 6H), 4.25 (m, 1H), 5.11 (d, 1H, J=7.9 Hz), 6.27 (d,
1H, J=9.4 Hz), 6.67 (s, 2H), 7.14 (d, 1H, J=8.6 Hz),
7.35 (d, 1H, J=8.8 Hz), 7.68 (d, 1H, J=9.6 Hz). 13C
NMR (50 MHz, acetone-d6): l 56.6, 61.4, 76.5, 78.6,
106.1, 114.6, 121.5, 125.1, 130.7, 138.9, 144.6, 145.9,
148.9, 160.5. IR (KBr/cm−1): 3449, 1713, 1609, 1456,
1334, 1271, 1130, 1063, 835. Found: C, 62.23; H, 4.68.
C20H18O8 requires C, 62.17; H, 4.66%.
K2CO3 (0.146 g, 1.06 mmol) was added to a solution
of (1R,2R)-15 (0.47 g, 0.96 mmol) in MeOH (20 mL).
The suspension was vigorously stirred at room temper-
ature for 3 h under Ar and was poured into water (30
mL). The layers were separated and the aqueous layer
was extracted with ethyl acetate (3×20 mL). The com-
bined organic phase was dried over Na2SO4, concen-
trated in vacuo and purified by flash chromatography
using petroleum ether and ethyl acetate (1:1, v/v) as
eluent gave (1R,2R)-16 as a white solid (0.35 g, 80%)
with 90% e.e. (retention time 9.2 min). Mp 98–100°C.
[h]2D5 −8 (c 1.60, CHCl3). MS (EI): 316 (M+), 225, 195,
1
153, 139, 91. H NMR (200 MHz, CDCl3): l 2.86 (m,
2H), 3.23 (m, 1H), 3.81 (s, 6H), 4.43 (d, 1H, J=5.6
Hz), 5.00 (s, 2H), 6.64 (s, 2H), 7.31–7.51 (m, 5H).
3.14. (1S,2R)-8-Acetoxy-7-[2,3-epoxy-1-(4-benzyloxy-
3,5-dimethoxyphenyl)propoxy]coumarin, (1S,2R)-17
A solution of PPh3 (136 mg, 0.52 mmol) and (1R,2R)-
16 (150 mg, 0.47 mmol) in dry THF (10 mL) was
added dropwise to a solution of 8-acetoxy-7-hydroxy-
coumarin (114 mg, 0.52 mmol) and DIAD (105 mg,
0.52 mmol) in dry THF at room temperature under
nitrogen. After stirring the mixture overnight at room
temperature, the mixture was evaporated in vacuo.
The residue was flash chromatographed using
petroleum ether and ethyl acetate (2:1, v/v) as eluent.
A white solid of (1S,2R)-17 (150 mg, 65%) was
obtained in 92% e.e. (retention times 12.6 min). Mp
69–71°C. [h]2D5 −44 (c 3.2, CHCl3). MS (EI): 518 (M+),
3.17. (1S,2R)-7-Benzyloxy-8-[2,3-epoxy-1-(4-benzyloxy-
3,5-dimethoxyphenyl)propoxy]coumarin, (1S,2R)-19
A solution of PPh3 (292 mg, 1.11 mmol) and (1R,2R)-
17 (320 mg, 1.01 mmol) in dry THF (10 mL) was
added dropwise to a solution of 7-benzyloxy-8-hydroxy-
coumarin (298 mg, 1.11 mmol) and DIAD (225 mg,
1.11 mmol) in dry THF at room temperature under
nitrogen. After stirring of the mixture overnight at
room temperature, the mixture was evaporated in
vacuo. The residue was flash chromatographed using
petroleum ether and ethyl acetate (2:1, v/v) as eluent.
A white solid of (1S,2R)-19 (344 mg) was obtained in
92% e.e. (retention times 15.1 min) and 60% yield. Mp
47–49°C. [h]2D5 +31 (c 2.0, CHCl3). MS (EI): 566 (M+),
1
476, 397, 385, 367, 355, 299, 91. H NMR (200 MHz,
CDCl3): l 2.43 (s, 3H), 2.84 (m, 2H), 3.33 (m, 1H),
3.82 (s, 6H), 4.99 (s, 2H), 5.09 (d, 1H, J=3.8 Hz),
6.27 (d, 1H, J=9.4 Hz), 6.58 (s, 2H), 6.69 (d, 1H,
J=8.8 Hz), 7.15 (d, 1H, J=8.8 Hz), 7.30–7.49 (m,
5H), 7.59 (d, 1H, J=9.6 Hz).
1
475, 445, 385, 358, 322, 299, 91. H NMR (200 MHz,
CDCl3): l 2.83 (m, 2H), 3.45 (m, 1H), 3.74 (s, 6H),
4.95 (s, 2H), 5.16 (s, 2H), 5.27 (d, 1H, J=5.4 Hz),
6.23 (d, 1H, J=9.6 Hz), 6.73 (s, 2H), 6.85 (d, 1H,
J=8.8 Hz), 7.09 (d, 1H, J=8.6 Hz), 7.28–7.46 (m,
5H), 7.56 (d, 1H, J=9.6 Hz).
3.15. (2S,3S)-18
K2CO3 (73 mg, 0.53 mmol) was added to a solution of

1804
X. Ren et al. / Tetrahedron: Asymmetry 13 (2002) 1799–1804
3.18. (1S,2R)-7-Hydroxy-8-[2,3-epoxy-1-(4-hydroxy-3,5-
dimethoxyphenyl)propoxy]coumarin, (1S,2R)-20
tion of China (No. 29972015; 20172023) is gratefully
acknowledged.
A solution of (1S,2R)-19 (500 mg, 0.88 mmol) in
ethyl acetate (10 mL) was hydrogenated over 5% Pd–
C (50 mg) under a H2 atmosphere. The reaction mix-
ture was filtered and the filtrate was concentrated.
The residue was flash chromatographed using
petroleum ether and ethyl acetate (1:1, v/v) as eluent.
A white solid (1S,2R)-20 (255 mg, 75% yield, 92%
e.e., retention times 21.3 min) was obtained. [h]2D5 +17
(c 1.40, CHCl3). Mp 121–123°C. MS (EI): 386 (M+),
References
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1
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3.19. Daphneticin’s regioisomer, (2S,3S)-2
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(106 mg, 89% yield, 92% e.e.) as a white solid. Reten-
tion times: (2S,3S)-2 30.7 min, (2R,3R)-2 27.4 min.
[h]2D5 −8 (c 1.10, CHCl3). Mp 242–244°C. MS (EI):
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1
386 (M+), 368, 328, 219, 210, 191, 167. H NMR (200
MHz, CDCl3): l 3.58 (m, 2H), 3.93 (s, 6H), 4.07 (m,
1H), 5.07 (d, 1H, J=8.4 Hz), 6.31 (d, 1H, J=9.4
Hz), 6.66 (s, 2H), 6.94 (d, 1H, J=8.8 Hz), 7.03 (d,
1H, J=8.6 Hz), 7.67 (d, 1H, J=9.6 Hz). 13C NMR
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Acknowledgements
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Support from the National Natural Science Founda-