Synthesis of Side Chain Substituted 3-Butylisocoumarins and Absolute Configurations of Natural Isocoumarins from Artemisia dracunculus

Article abstract of DOI:10.1007/s00706-003-0046-6

A series of 3-hydroxy- and 3-bromobutyl-substituted isocoumarins was synthesized. The absolute configurations of three isocoumarin derivatives from Artemisia dracunculus, namely (-)-epoxyartemidin, (-)-2′- methoxydihydroartemidin, and (+)-3′-hydroxyartemidin were determined by chemical means via derivatization, kinetic racemate resolution (Horeau method), and comparison of the circular dichroism (CD) spectra.

Full text of DOI:10.1007/s00706-003-0046-6

Monatshefte f€ur Chemie 134, 1195–1206 (2003)
DOI 10.1007/s00706-003-0046-6
Synthesis of Side Chain Substituted
3-Butylisocoumarins and Absolute
Configurations of Natural Isocoumarins
from Artemisia dracunculus
Gerda Lutz-Kutschera1, Doris Engelmeier2, Franz Hadacek2,
,y
,
Andreas Werner1 , Harald Greger2, and Otmar Hofer1 ꢀ
1
Institute of Organic Chemistry, University of Vienna, Wien, Austria
2
Comparative Phytochemistry Department, Institute of Botany, University of Vienna,
Wien, Austria
Received March 17, 2003; accepted March 19, 2003
Published online August 18, 2003 # Springer-Verlag 2003
Summary. A series of 3-hydroxy- and 3-bromobutyl-substituted isocoumarins was synthesized. The
absolute configurations of three isocoumarin derivatives from Artemisia dracunculus, namely (ꢁ)-
epoxyartemidin, (ꢁ)-20-methoxydihydroartemidin, and (þ)-30-hydroxyartemidin were determined by
chemical means via derivatization, kinetic racemate resolution (Horeau method), and comparison of
the circular dichroism (CD) spectra.
Keywords. Epoxyartemidin; 20-Methoxydihydroartemidin; 30-Hydroxyartemidin; Circular dichro-
ism; Chiral resolution; Horeau method.
Introduction
Isocoumarins are metabolites of limited distribution. However, the about 200 until
now known compounds have been isolated from a remarkable manifold of sources
from bacteria, fungi, lichen, and to a less extent also from higher plants and insects
[1, 2]. The biological activities of some isocoumarins [2] have drawn increased
attention on some of the derivatives, e.g., the phytoalexine 6-methoxymellein
(8-hydroxy-6-methoxy-3-methylisocoumarin) from carrots [3–5].
In the course of an investigation of natural constituents of the genus Artemisia
(Compositae, Asteraceae) [6–10] we have now focussed our attention on A. dra-
cunculus, a plant which is not only used as a spice (tarragon) but also well known
for several biological activities, e.g., against worms in the intestinal [11] or as an
ꢀ
Corresponding author. E-mail: otmar.hofer@univie.ac.at
y
Deceased

1196
G. Lutz-Kutschera et al.
insect repellent [12]. Tarragon has always been used in folk medicine, e.g., in case
of stomache troubles [13] or for treatment of rheumatism, gout [13], or toothache
[13, 14].
The genus Artemisia is characterized by polyacetylenes, sesquiterpene lac-
tones, coumarins, flavanoids, lignans, and terpenoid essential oils [15, 16]. How-
ever, especially isocoumarin derivatives represent unique chemical characters of
the A. dracunculus group (A. dracunculus s. str. and closely related species) [17].
Bioassays with several isocoumarins of A. dracunculus showed remarkable anti-
fungal activities. Based on these preliminary results it was of interest to synthesize
a series of isocoumarins, either natural or closely related compounds, for a more
detailed antifungal testing followed by an eventual study of structure-activity rela-
tionship and also for the elucidation of the absolute stereochemistries of some of
the novel compounds.
Results and Discussion
Since (E)-artemidin (7) was the central compound of our synthetic efforts, some
time was expended to optimize the synthetic route to this compound. The methods
for syntheses of isocoumarin derivatives have been reviewed 1997 by Napolitano
[20]. For the synthesis of dihydroartemidin (1) as the starting isocoumarin we
followed generally the method of Batu and Stevenson [21, 22] in the modification
of Liao and Cheng [23]. The former authors reacted the copper acetylide of 1-
hexine with 2-iodobenzoic acid and obtained a mixture of 5-ring lactone
(phthalide) and the desired 6-ring lactone 3-butylisocoumarin. In the modification
of Liao and Cheng the copper salt for the C–C-coupling reaction was substituted
by a zinc salt with Pd(PPh3)4 as catalyst. We obtained yields between 78 and 91%
for the coupling=annelation reaction (Ref. [23] 84%), the amount of the phthalide
side product was small (ca. 5%) and did not disturb the crystallization of dihydro-
artemidin (1). In this reaction we could reduce the amount of catalyst by 50%
without any decrease of the observed yields (2.5 mol%, Ref. [23] 5 mol%).
The next step towards (E)-artemidin (7) was the allylic bromination of 1 with
N-bromosuccinimide (NBS) [21, 24, 25] to 10-bromodihydroartemidin (2) (Scheme
1). Compared to Ref. [21], the use of dibenzoylperoxide (DBPO) allowed to reduce
the reaction time drastically (to about 1=3). The yield of 10-bromodihydroartemidin
depended to a high degree on the purity of 1 and could be increased from 47% to
92% using recrystallized dihydroartemidin (1). Two side products, l0,l0-dibromodi-
hydroartemidin (3) and 10,20-dibromodihydroartemidin (4) (3% each) were also of
interest for our biological testing programme. A further derivative, (E)-10-bromo-
artemidin (5) could be obtained in 36% yield by dehydrohalogenation of com-
pound 4 with DBU [26, 27]. 10- Hydroxydihydroartemidin (6), which was also
needed for the bioassays, was obtained in 100% yield by hydrolysis of the 10-
bromo compound 2 with water=acetone (l h, 90ꢂC) [28, 29].
The dehydrohalogenation of 2 to artemidin (7) by the method described by
Batu and Stevenson [21] gave yields between 35 and 40% (no comments on the
yields were given in Ref. [21]). Absolute tetrahydrofuran instead of benzene or
toluene as solvent, the slow addition of DBU at room temperature, shortening of

Synthesis and Absolute Configuration of Substituted Isocoumarins
1197
Scheme 1
the reaction time from 10 to 2.5 hours, and a modified workup (see Exp.) raised the
yields finally to about 60%. Only the (E) configured product 7 was obtained, in the
1H NMR spectra not even traces of the (Z) product could be detected.
(E)-Artemidin (7) was oxidized to epoxyartemidin (8) by means of 3-chloro-
perbenzoic acid (m-CPBA) [30, 31]. The optical resolution of the resulting race-
mate was achieved by chiral MPLC on triacetyl cellulose [32, 33], giving the
natural (ꢁ)-epoxyartemidin ((ꢁ)-8) [10, 18] and its optical antipode ((þ)-8) in
100% enantiomeric purity.

1198
G. Lutz-Kutschera et al.
Reduction of epoxides to the corresponding optically active secondary alcohols
allowed the determination of absolute configurations using the empirical method of
Horeau via kinetic racemate resolution of racemic 2-phenylbutanoic acid anhy-
dride [34]. For the reduction of the epoxide function of the lactonic isocoumarin
(ꢁ)-8 a relatively mild reducing agent was necessary. NaBH4 failed, however, the
method of Sarmah and Barua [35] using a system of aluminum powder and nickel
chloride in tetrahydrofuran was successful. The yield of the resulting alcohol was
rather low (14%), but 60% of the starting epoxide could be recovered. Pure (þ)-20-
hydroxydihydroartemidin ((þ)-9) was obtained and no 10-hydroxy compound was
present in the reaction product. The expected retention of configuration was in
agreement with the CD spectra showing identical maxima for (ꢁ)-8 and (þ)-9
(see Exp.). Comparison of the optical rotations of (ꢁ)-8 and (þ)-9 at different
wave lenghts showed that the small negative [ꢀ]D value (at ꢁ ¼ 589 nm) of (ꢁ)-8
changes to positive values at lower wavelenghts (365 nm), corresponding to a posi-
tive Cotton effect in the long wave ORD region, which is again in agreement with the
CD data (see Exp.).
A side product of the Al=NiCl2 reduction of (ꢁ)-8, also of interest for the
antifungal testing, was l0-chloro-20-hydroxydihydroartemidin ((ꢁ)-10). This is
presumably the product of a nucleophilic substitution with a chloride ion (from
the NiCl2 reagent) leading to an inversion of configuration at C-l0 (SN2-reac-
tion). Since the CD of (ꢁ)-10 is influenced predominantly by the 10-chloro
substituent which is closer to the isocoumarin chromophore, the CD curve for
(ꢁ)-10 shows almost a mirror image of the corresponding curve for (þ)-9
(and (ꢁ)-8).
Following the procedure of Horeau [36, 37] the secondary alcohol (þ)-9 was
reacted with the anhydride of racemic 2-phenylbutanoic acid. After 20 hours at
room temperature the excessive anhydride was hydrolyzed and the remaining 2-
phenylbutanoic acid separated from the Horeau ester 11. The optical rotation of the
acid had a negative sign, indicating that (þ)-2-phenylbutane acid had reacted
preferentially. This is indicative for an (S) configuration of (þ)-9 and (R,S) con-
l
figuration for (ꢁ)-8. The H NMR spectrum of the diastereomeric ester mixture 8
showed a diastereomeric ratio of 65:35 corresponding to an optical yield of 30%
for the kinetic racemate resolution. This is significantly above the reliability mini-
mum of 20% given by Horeau [36, 37].
The absolute configuration of a further natural isocoumarin derivative, namely
20-methoxydihydroartemidin ((ꢁ)-12) [38] could be correlated with (þ)-9 via
their CD spectra. The entire CD curve of natural (ꢁ)-12 is opposite to the one
of (S)-(þ)-9 (see Exp.) and is therefore only compatible with the (R) configuration.
The optical rotation of (R)-(ꢁ)-12 is rather small and not really significant, how-
ever, the CD spectrum allowed a clear decision.
A further target molecule was the natural (þ)-30-hydroxyartemidin ((þ)-13)
(Scheme 2). To this end, artemidin (7) was reacted with NBS for allylic bromina-
tion to 30-bromoartemidin [24, 25]. The reaction proceeded not very smooth and
the isolation of 30-bromoartemidin was not possible. Dibenzoyl peroxide as a radi-
cal starter and irradiation with a 1000 W halogene lamp was needed to start the
reaction. Chromatography of the raw bromination product on Al2O3 with petrol
ether:ethyl acetate ¼ 1:1 did not yield pure fractions containing the desired

Synthesis and Absolute Configuration of Substituted Isocoumarins
1199
Scheme 2
halogenation product, but already some hydrolized product 13, its acetate 14 as a
result of ester exchange with the eluent ethyl acetate, the ꢀ,ꢂ-unsaturated ketone
15 as oxidation product, and the 10,20-bromo addition product 4; the latter com-
pound has already been isolated as a side product of the NBS bromination of 1 (see
above). Due to the obvious instability of 30-bromoartemidin we resigned on further
attempts to purify this compound. To increase the amount of the mainly desired 30-
hydroxyartemidin (13), the crude bromination product was subjected directly to
hydrolysis with acetone=water at room temperature [28, 29]. The resulting reaction
product was chromatographed carefully to give 5% of 30-hydroxyartemidin (13),
3% of 30-acetoxyartemidin (14), 4% of 30-oxoartemidin (15), and finally 3% of
10,20-dibromodihydroartemidin (4). The unsaturated alcohol 13 was degrading
slowly at room temperature but proved to be fairly stable in the freezer. All side
products (14, 15, 4) were also isolated and characterized because they were of
interest for antifungal screening.
The optical resolution of racemic 13 on triacetyl cellulose [32, 33] gave the two
optically pure enantiomers. Comparison of the CD spectra proved that the (þ)-13
enantiomer was identical with the natural product (þ)-30-hydroxyartemidin
obtained from A. dracunculus in a very small amount [38, 10]. For determination
of the absolute configuration, synthetic (þ)-13 was reacted with racemic 2-phe-
nylbutanoic acid according to the Horeau method [36, 37]. The reaction that pro-
ceeded very slowly (TLC) was interrupted after ca. 50% of (þ)-13 had reacted
(48 hours). After workup, the remaining acid showed a positive rotation, the abso-
lute configuration at C-30 of (þ)-13 was therefore (R). The ratio of the diaste-
reomeric esters 16 was 76:24 corresponding to an unusual high optical yield of
52%.

1200
G. Lutz-Kutschera et al.
Experimental
Optical rotation, Perkin-Elmer polarimeter 241; CD, Jobin Yvon Dichrograph CD 6; UV, Hewlett-
Packard 8452A diode array spectrophotometer; IR, Perkin-Elmer 16PC FT-IR; NMR, Bruker AC-250
and Bruker DPX 250, standard pulse sequence programs provided by the spectrometer manufacturer
were used, the HMBC experiments were optimized for a long range coupling constant of 8 Hz, the
spectra were either referenced to internal TMS or to the solvent signal (CDCl3 1H ꢃ ¼ 7.26ppm, 13C
ꢃ ¼ 77.0 ppm, the chemical shifts depended to some degree on the concentrations of the NMR solu-
tions, therefore the concentrations are included in the NMR data); MS, Finnigan MAT 900 S;
PE¼ petrol ether, EE¼ ethyl acetate.
3-Butyl-1H-2-benzopyran-1-one (Dihydroartemidin, 1, C13H14O2)
Pd(PPh3)4 (5.0g, 4.33 mmol, 2.5mol%) and 23.6g (0.173 mol) of ZnCl2 were added under a flow of
N2 to a solution=dispersion of 43.6 g (0.173 mol) of 2-iodobenzoic acid, 42.6g (0.519mol) of 1-hexine,
and 87.5g (0.865 mol) of triethylamine in 180 cm3 of DMF. After 24 h reflux in N2 atmosphere the
clear brown solution was cooled and the solvent was removed at ca. 60ꢂC in vacuo. The remaining
material was prefractionated over Al2O3 (column with 300g Al2O3, PE:EE¼ 90:10) and the seven
fractions of ca. 10 g each were chromatographed over silica gel (160 g SiO2, PE:EE¼ 95:5). The
yellow crystals (30.5 g, 87%) were recrystallized twice from PE:EE¼ 95:5 yielding 20.9g of colour-
less crystals. From the deeply orange colored mother liquors another 6.4 g of 1 could be isolated by
chromatography and recrystallization. Total yield 27.3g (78%); mp 45–47ꢂC (Ref. [21] 49.5–50.5ꢂC);
1H NMR (CDCl3, c ¼ 10mgcmꢁ 3): ꢃ ¼ 8.23 (br.d, J ¼ 8.0 Hz, 8-H), 7.65 (ddd, J ¼ 7.8, ꢃ7.5, 1.3Hz,
6-H), 7.42 (ddd, J ¼ 8.0, ꢃ7.5, 1.0 Hz, 7-H), 7.33 (br.d, J ¼ 7.8 Hz, 5-H), 6.24 (s, 4-H), 2.51
(t, J ¼ 7.6 Hz, 10-H2), 1.68 (br.tt, J ¼ 7.6, 7.5 Hz, 20-H2), 1.39 (tq, J ¼ 7.5, 7.3 Hz, 30-H2), 0.93
(t, J ¼ 7.3 Hz, 40-H3) ppm; 13C NMR (CDCl3): ꢃ ¼ 163.1 (s, C-1), 158.3 (s, C-3), 137.6 (s, C-4a),
134.6 (d, C-6), 129.4 (d, C-8), 127.5 (d, C-7), 125.0 (d, C-5), 120.1 (s, C-8a), 102.8 (d, C-4), 33.2
(t, C-20), 28.9 (t, C-10), 22.1 (t, C-30), 13.7 (q, C-40) ppm.
3-(1-Bromobutyl)-1H-2-benzopyran-1-one (10-Bromodihydroartemidin, 2, C13H13BrO2)
20.4g (101mmol) of Dihydroartemidin (1) and 20.8g (117mmol) of NBS were dissolved in 400cm3
of absolute CCl4 and after adding ca. 0.2g of dibenzoylperoxide (DBPO) the mixture was heated under
reflux. After 1.5h and 2.5 h further portions of 0.1 g of DBPO were added until a change of color to
orange indicated that the reaction had started. After another 1.5h the reaction was complete. The white
precipitate of succinimide was filtered from the yellow solution and the solvent was removed in
vacuum. The dark yellow viscous crude product (35 g) was chromatographed over silica gel (column
d ¼ 10cm, 1 kg SiO2, PE:EE¼ 90:10). The yellowish crystals obtained were recrystallized from
PE:EE¼ 90:10 and a second time from PE:EE ¼ 75:25. Yield 26g (92%); mp 67–69ꢂC (Ref. [21]
69.5–70ꢂC); 1H NMR (CDCl3, c ¼ 10 mg cmꢁ 3): ꢃ ¼ 8.27 (br.d, J ¼ 8.0 Hz, 8-H), 7.71 (ddd, J ¼ 8.0,
7.8, 1.4 Hz, 6-H), 7.51 (ddd, J ¼ 8.0, 7.8, 1.2 Hz, 7-H), 7.42 (br.d, J ¼ 8.0 Hz, 5-H), 6.54 (s, 4-H), 4.70
(t, J ¼ 7.6 Hz, l0-H), 2.20 (dt, J ¼ 7.6, ꢃ7.8 Hz, 20-H2), 1.48 (m, 30-H2), 0.96 (t, J ¼ 7.3 Hz, 40-H3) ppm;
13C NMR (CDCl3): ꢃ ¼ 161.7 (s, C-1), 154.7 (s, C-3), 136.4 (s, C-4a), 134.9 (d, C-6), 129.7 (d, C-8),
128.8 (d, C-7), 126.0 (d, C-5), 120.9 (s, C-8a), 104.1 (d, C-4), 49.0 (d, C-l0), 37.8 (t, C-20), 21.0 (t, C-
30), 13.2 (q, C-40) ppm.
3-(1,1-Dibromobutyl)-1H-2-benzopyran-1-one (10,10-Dibromodihydroartemidin,
3, C13H12Br2O2)
This side product of the NBS bromination above crystallized from earlier chromatographic frac-
tions and was recrystallized from ether. Yield 0.93 g (3%); mp 124–126ꢂC; 1H NMR (CDCl3,

Synthesis and Absolute Configuration of Substituted Isocoumarins
1201
c ¼ 20 mg cmꢁ 3): ꢃ ¼ 8.30 (dm, J ¼ 7.9Hz, 8-H), 7.76 (ddd, J ¼ 7.8, ꢃ7.5, 1.4 Hz, 6-H), 7.58 (ddd,
J ¼ 7.9, ꢃ7.5, 1.2 Hz, 7-H), 7.53 (br.d, J ¼ 7.8 Hz, 5-H), 7.15 (d, J ¼ 0.5 Hz, 4-H), 2.77 (m, 20-H2), 1.63
(m, 30-H2), 1.02 (t, J ¼ 7.4 Hz, 40-H3) ppm; 13C NMR (CDCl3): ꢃ ¼ 160.8 (s, C-1), 153.8 (s, C-3), 136.0
(s, C-4a), 135.1 (d, C-6), 129.8, 129.5 (2d, C-7, C-8), 127.0 (d, C-5), 120.5 (s, C-8a), 105.2 (d, C-4),
61.7 (s, C-l0), 49.8 (t, C-20), 21.1 (t, C-30), 13.1 (q, C-40) ppm; EIMS (70 eV): m=z (%) ¼ 360 (6, Mþ ),
281=279 (100), 199 (70), 171 (49), 159 (35), 145 (93), 89 (96), 86 (50).
3-(1,2-Dibromobutyl)-1H-2-benzopyran-1-one (10,20-Dibromodihydroartemidin,
4, C13H12Br2O2)
In the bromination reaction of 1, with 1.82 g (9mmol) of 1 and 1.86g of NBS, but without addition of
DBPO and l0h reaction time, the l0,20-bromination product was formed as a side product of the 10-
bromo derivative 2 in the ratio 1:10. The retention time was only a little different from that of 2, but 4
could be crystallized from the earlier (still unpure) fractions of the chromatography (PE:EE¼ 75:25,
1
see above) and recrystallized from PE:EE¼ 80:20. Yield 83 mg (3%); mp 141–143ꢂC; H NMR
(CDCl3, c ¼ 4 mg cmꢁ 3): ꢃ ¼ 8.31 (br.d, J ¼ 8.1 Hz, 8-H), 7.73 (ddd, J ¼ 7.8, ꢃ7.5, 1.2 Hz, 6-H),
7.51 (ddd, J ¼ 8.1, ꢃ7.5, 1.1 Hz, 7-H), 7.45 (br.d, J ¼ 7.8 Hz, 5-H), 6.55 (s, 4-H), 4.84 (d, J ¼
11.3Hz, l0-H), 4.66 (ddd, J ¼ 11.3, 8.0, 2.6Hz, 20-H), 2.43 (ddq, J ¼ 14.6, 7.3, 2.6 Hz, 30-Ha), 2.00
(ddq, J ¼ 14.6, 8.0, 7.3 Hz, 30-Hb), 1.15 (t, J ¼ 7.3 Hz, 40-H3) ppm; 13C NMR (CDCl3): ꢃ ¼ 152.5 (s, C-
3), 135.0 (d, C-6), 129.9 (d, C-8), 129.1 (d, C-7), 126.2 (d, C-5), 121.2 (s, C-8a), 105.8 (d, C-4), 54.8
(d, C-l0), 51.5 (d, C-20), 29.5 (t, C-30), 10.6 (q, C-40) ppm, signals of C-l and C-4a are too weak for
detection; EIMS (70 eV): m=z (%) ¼ 360 (5, Mþ ), 281=279 (25), 201 (49), 200 (54), 189 (100), 159
(43), 131 (31), 89 (46).
(E)-3-(1-Bromo-1-butenyl)-1H-2-benzopyran-1-one ((E)-10-Bromoartemidin,
5, C13H11BrO2)
38mg (0.25 mmol) of DBU were added to a solution of 18mg of 4 in 0.5 cm3 of anhydrous THF under
a flow of N2. After 2.5 h at room temperature the reaction mixture was acidified with 0.5cm3 of 2 M
HCl, saturated with NH4Cl, and extracted with 3 ꢄ 2 cm3 of ether. The combined ether layers were
washed neutral with a solution of saturated aqu. NaCl and dried over MgSO4. After evaporation of the
solvent the remaining yellow oil (15 mg) was purified by repeated preparative TLC (silica gel,
PE:EE¼ 90:10). Yield 5 mg (36%); colourless oil; 1H NMR (CDCl3, c ¼ 2 mgcmꢁ 3): ꢃ ¼ 8.30
(br.d, J ¼ 8.0Hz, 8-H), 7.73 (ddd, J ¼ 7.8, ꢃ7.5, 1.4 Hz, 6-H), 7.53 (ddd, J ¼ 8.0, ꢃ7.5, 1.2 Hz, 7-
H), 7.46 (br.d, J ¼ 7.8 Hz, 5-H), 6.74 (s, 4-H), 6.39 (t, J ¼ 7.8 Hz, 20-H), 2.46 (dq, J ¼ 7.8, 7.5 Hz,
30-H2), 1.11 (t, J ¼ 7.5 Hz, 40-H3) ppm; EIMS (70 eV): m=z (%) ¼ 280=278 (54, Mþ ), 199 (100), 171
(54), 153 (21), 128 (37), 89 (33).
3-(1-Hydroxybutyl)-1H-2-benzopyran-1-one (10-Hydroxydihydroartemidin, 6, C13H14O3)
To a solution of 86mg of 2 in 5 cm3 of acetone 10cm3 of H2O were added under vigorous stirring. The
turbid solution was heated to 90ꢂC for 1 h. Then the reaction mixture was diluted with 10 cm3 of saturated
aqu. NaCl solution and extracted with 5ꢄ5 cm3 of CH2Cl2. The combined organic layers were dried
over MgSO4 and after evaporation practically pure 6 was obtained. Yield 67mg (100%); colorless oil;
1H NMR (CDCl3, c ¼ 20 mg cmꢁ 3): ꢃ ¼ 8.18 (br.d, J ¼ 8.0Hz, 8-H), 7.64 (br.dd, J ¼ 7.8, ꢃ7.5 Hz, 6-H),
7.42 (br.dd, J ¼ 8.0, ꢃ7.5Hz, 7-H), 7.34 (br.d, 1H, J ¼ 7.8 Hz, 5-H), 6.53 (s 4-H), 4.45 (br.t, J ¼ 5.1 Hz,
l0-H), 1.78 (m, 20-Ha þ b), 1.44 (m, 30-H2), 0.92 (t, J ¼ 7.3 Hz, 40-H3), 3.12 (br.s, 10-OH) ppm; 13C NMR
(CDCl3): ꢃ ¼ 162.5 (s, C-1), 158.5 (s, C-3), 136.9 (s, C-4a), 134.8 (d, C-6), 129.4 (d, C-8), 128.0 (d, C-
7), 125.6 (d, C-5), 120.3 (s, C-8a), 102.0 (d, C-4), 70.6 (d, C-l0), 37.1 (t, C-20), 18.5 (t, C-30), 13.7
(q, C-40) ppm; EIMS (70 eV): m=z (%) ¼ 218 (15, Mþ ), 200 (14), 175 (100), 147 (79), 89 (37).

1202
G. Lutz-Kutschera et al.
(E)-3-(1-Butenyl)-1H-2-benzopyran-1-one ((E)-Artemidin, 7, C13H12O2)
To 10.0g (35.6 mmol) of 2 in 100 cm3 of anhydrous THF a solution of 17.2 g of 1,8-diazabicy-
clo[5.4.0]undec-7-en (DBU) in 85cm3 of anhydrous THF was added slowly under a stream of N2.
The solution changed its color from yellow to green and later to reddish brown. The combined solutions
were heated at reflux in N2 atmosphere for additional 2.5 h. Then the reaction mixture was cooled in
the refrigerator and acidified with a cold (ca. 4ꢂC) buffer of 150 cm3 of saturated aqu. NH4Cl solution
and 25cm3 of conc. HCl. After dilution with 50cm3 of saturated aqu. NaCl solution this mixture was
extracted with 3ꢄ50cm3 of ether. The combined ether phases were washed neutral with 3ꢄ50cm3 of
NaCl solution and dried over MgSO4. Then the dry ether phase was filtered over 20g Al2O3 and the
solvent was evaporated. The remaining crude reddish-yellow crystalline material was chromatographed
over silica gel (600 g SiO2, PE:EE¼ 90:10) to give colourless crystals of racemic 7. Yield 4.1 g (58%);
mp 48–50ꢂC (Ref. [21] 49.5–50.5ꢂC); 1H NMR (CDCl3, c ¼ 20mg cmꢁ 3): ꢃ ¼ 8.18 (br.d, J ¼ 8.0 Hz,
8-H), 7.59 (ddd, J ¼ 7.9, ꢃ7.5, 1.0 Hz, 6-H), 7.36 (br.dd, J ¼ 8.0, ꢃ7.5 Hz, 7-H), 7.30 (br.d, J ¼ 7.9 Hz,
5-H), 6.20 (s, 4-H), 6.62 (dt, J ¼ 15.6, 6.7 Hz, 20-H), 5.97 (dt, J ¼ 15.6, 1.3 Hz, 10-H), 2.20 (qdd,
J ¼ 7.4, 6.7, 1.3 Hz, 3-H2), 1.05 (t, J ¼ 7.4 Hz, 40-H3) ppm; 13C NMR (CDCl3): ꢃ ¼ 162.1 (s, C-1),
152.5 (s, C-3), 137.6 (s, C-4a), 134.5 (d, C-6), 129.4 (d, C-8), 127.5 (d, C-7), 125.4 (d, C-5), 120.4
(s, C-8a), 103.4 (d, C-4), 120.8 (d, C-l0), 138.1 (d, C-20), 25.6 (t, C-30), 12.8 (q, C-40) ppm.
3-(1,2-Epoxybutyl)-1H-2-benzopyran-1-one (Epoxyartemidin, 8, C13H12O3)
A solution of 1.36g of 3-chloroperbenzoic acid (ca. 5.5 mmol of ca. 70% m-CPBA) in 60cm3 of CHCl3
was dropped slowly to a solution of 1.01g (5.05 mmol) of 5 in 50cm3 of CHCl3. After 2 h the resulting
solution was heated to reflux for 4 h. Then further 0.25g of m-CPBA in 10cm3 of CHCl3 were added and
the solution was kept at reflux for further 5 h. After cooling, the acidic products were removed by
extraction with 10% aqu. NaHCO3 and washed neutral with 2ꢄ 25cm3 of aqu. NaCl solution. The
aqueous phases were reextracted with 10cm3 of CHCl3, the combined organic extracts were dried over
MgSO4, and the solvent was removed. The remaining yellow oily product was purified by chromatog-
raphy over silica gel (100 g SiO2, PE:EE ¼ 80:20) to give racemic 8. Yield 0.345 g (32%); colourless oil;
1H NMR (CDCl3, c ¼ 10mgcmꢁ 3): ꢃ ¼ 8.25 (br.d, J ¼ 8.0Hz, 8-H), 7.70 (ddd, J ¼ 7.9, ꢃ7.5, 1.3 Hz, 6-
H), 7.49 (ddd, J ¼ 8.0, ꢃ7.5, 1.1 Hz, 7-H), 7.40 (br.d, J ¼ 7.9 Hz, 5-H), 6.53 (s, 4-H), 3.46 ( d, J ¼ 2.1 Hz,
10-H), 3.29 (td, J ¼ 5.4, 2.1 Hz, 20-H), 1.71 (m, 30-H2), 1.06 (t, J ¼ 7.5 Hz, 40-H3) ppm;13C NMR (CDCl3):
ꢃ ¼ 161.8 (C-l), 152.8 (s, C-3), 136.5 (s, C-4a), 134.9 (d, C-6), 129.6 (d, C-8), 128.4 (d, C-7), 125.5 (d, C-
5), 120.8 (s, C-8a), 103.8 (d, C-4), 54.4 (d, C-l0), 61.5 (d, C-20), 24.7 (t, C-30), 9.5 (q, C-40) ppm.
(R,S)-(ꢁ)-3-(1,2-Epoxybutyl)-1H-2-benzopyran-1-one ((ꢁ)-Epoxyartemidin,
(ꢁ)-8, C13H12O3)
Optical resolution to enantiomerically pure (þ)- and (ꢁ)-8 was achieved by means of cyclic chroma-
tography on triacetyl cellulose [32, 33]. 1H NMR and chiroptical data of (ꢁ)-8 were identical with (ꢁ)-
epoxyartemidin isolated from A. dracunculus [10, 18]. The absolute configurations were determined as
(10R,20S) via correlation with (þ)-9 (Horeau method, see below). Yield 50% (ꢁ)-8 (and 50% of the
20
20
(þ)-enantiomer); colourless oil; ½ꢀꢅD ¼ ꢁ10ꢂ cm3 gꢁ1 dmꢁ1, ½ꢀꢅ ¼ þ 61ꢂ cm3 gꢁ1 dmꢁ1 (EtOH,
c ¼ 0.2); CD (EtOH): ꢁ (D") ¼ 327 (þ0.4), 275 (þ0.5), 266 (þ306.58) nm; UV (EtOH): lmax ¼ 325,
274 (sh), 267 nm.
(S)-(þ)-3-(2-Hydroxybutyl)-1H-2-benzopyran-1-one ((þ)-20-Hydroxydihydroartemidin,
(þ)-9, C13H14O3)
Under N2 3.85g (16.2mmol) of NiCl2 ꢆ 6H2O were mixed with 292 mg (10.82 mmol) of Al powder
and a solution of 70 mg (0.324mmol) of (ꢁ)-8 in 12cm3 of anhydrous THF was added rapidly. If

Synthesis and Absolute Configuration of Substituted Isocoumarins
1203
the reaction did not start for itself, the mixture was heated to 40–45ꢂC with a hot gun until strong
bubbling indicated the start of the reduction. After about 15min of heating the mixture was stirred
for further 18h at room temperature. Then all solids were filtered off, the solvent was removed in
vacuum, and the crude product chromatographed over silica gel (15 g SiO2, PE:EE ¼ 80:20). Yield
10mg (14%, 42 mg of the starting material were also recovered, therefore 35% yield with respect
20
20
to reacted material); colourless oil; ½ꢀꢅD ¼ þ69ꢂ cm3 gꢁ1 dmꢁ1, ½ꢀꢅ365 ¼ þ565ꢂ cm3 gꢁ1 dmꢁ1
(EtOH, c ¼ 0.2); CD (EtOH): ꢁ (D") ¼ 325 (þ0.8), 273 (þ1.0), 263 (þ1.5)nm; UV (EtOH):
lmax ¼ 326, 273 (side max.), 265 (max.), 257 (side max.) nm; H NMR (CDCl3, c ¼ 5 mgcmꢁ 3):
1
ꢃ ¼ 8.25 (br.d, J ¼ 8.1 Hz, 8-H), 7.68 (ddd, J ¼ 7.9, ꢃ7.5, 1.3 Hz, 6-H), 7.47 (dd, J ¼ 8.1, ꢃ7.5,
1.1 Hz, 7-H), 7.37 (br.d, J ¼ 7.9 Hz, 5-H), 6.37 (s, 4-H), 4.04 (m, 20-H), 2.74 (br.dd, J ¼ 14.6, 3.9Hz,
l0-Ha), 2.58 (dd, J ¼ 14.6, 8.5 Hz, l0-Hb), 1.60 (m, 30-Ha þ b), 1.01 (t, J ¼ 7.4 Hz, 40-H3) ppm; 13C
NMR (CDCl3): ꢃ ¼ 162.8 (s, C-1), 155.1 (s, C-3), 137.3 (s, C-4a), 134.8 (d, C-6), 129.6 (d, C-8),
127.9 (d, C-7), 125.2 (d, C-5), 120.3 (s, C-8a), 102.8 (d, C-4), 70.6 (d, C-20), 41.3 (t, C-l0), 30.1
(t, C-30), 9.8 (q, C-40) ppm; EIMS (70 eV): m=z (%) ¼ 218 (6, Mþ ), 160 (100), 136 (20), 131 (39),
118 (20),89 (50), 59 (33).
(S,S)-(ꢁ)-3-(1-Chloro-2-hydroxybutyl)-1H-2-benzopyran-1-one
((ꢁ)-10-Chloro-20-hydroxydihydroartemidin, (ꢁ)-10, C13H13ClO3)
This compound was a side product of the reaction above. Further chromatograpy (20 g SiO2,
PE:EE¼ 80:20) yielded colorless crystals of (ꢁ)-10. Yield 8 mg (9% or 25% based on reacted
20
20
material); mp 122–124ꢂC; ½ꢀꢅD ¼ ꢁ40ꢂ cm3 gꢁ1 dmꢁ1, ½ꢀꢅ365 ¼ ꢁ330ꢂ cm3 gꢁ1 dmꢁ1 (EtOH, c ¼
0.1); CD (EtOH): ꢁ (D") ¼ 318 (ꢁ1.2), 278 ( ꢁ 1.7, side min.), 268 (ꢁ2.2), 260 (ꢁ2.1, sh.), 235
(þ5.5) nm; UV (EtOH): ꢁmax ¼ 322, 276 (side max.), 268 (max.), 260 (sh.), 233 nm; 1H NMR (CDCl3,
c ¼ 4 mgcmꢁ 3): ꢃ ¼ 8.25 (br.d, J ¼ 8.0 Hz, 8-H), 7.73 (ddd, J ¼ 7.8, ꢃ7.5, 1.4 Hz, 6-H), 7.53 (ddd,
J ¼ 8.0, ꢃ7.5, 1.2 Hz, 7-H), 7.45 (br.d, J ¼ 7.8 Hz, 5-H), 6.68 (s, 4-H), 4.57 ( d, J ¼ 7.0 Hz, 10-H), 4.17
(ddd, J ¼ 8.5, 7.0, 3.0 Hz, 20-H), 2.29 (br.s, 20-OH), 1.91 (ddq, J ¼ 14.0, 7.3, 3.1 Hz, 3-Ha), 1.61 (m, 3-
Hb), 1.06 (t, 3H, J ¼ 7.4 Hz, 40-H3) ppm; 13C NMR (CDCl3): ꢃ ¼ (s, C-1 not detected), 152.4 (s, C-3),
136.3 (s, C-4a), 135.0 (d, C-6), 129.8 (d, C-8), 129.0 (d, C-7), 126.1 (d, C-5), 121.1 (s, C-8a), 106.7 (d,
C-4), 61.7 (d, C-10), 73.9 (d, C-20), 26.2 (t, C-30), 9. 7 (q, C-40) ppm; EIMS (70 eV): m=z
(%) ¼ 254=252 (2=6, Mþ ), 281=279 (25), 196 (32), 194 (100), 160 (27), 159 (24).
Determination of the Absolute Configuration of (þ)-9 (Horeau Esters 11, C23H24O4)
Racemic 2-phenylbutanoic acid anhydride (22 mg, 0.07mmol) was dissolved in 0.6 cm3 of dry
pyridine and poured over 5 mg (0.023mmol) of (þ)-9. The mixture was stirred for 20h at room
temperature. Then 1 cm3 of 10% aqu. NaHCO3 solution was added and stirring was continued for 1
additional h. After adding 4 cm3 of H2O, the reaction mixture was extracted with 4 ꢄ 2 cm3 of ether,
the combined ether solutions were dried over Na2SO4, and the solvent was evaporated in vacuo to
give the diastereomeric mixture of esters of the alcohol (þ)-9 with (þ)- and (ꢁ)-2-phenylbutanoic
acid. The aqu. phase was acidified with 10cm3 of 2M HCl and extracted with 3 ꢄ 2 cm3 of benzene.
The benzene phases were washed neutral with water, dried over Na2SO4, and the solvent was
evaporated. The remaining 2-phenylbutanoic acid, dissolved in a minimum amount of benzene,
showed a negative optical rotation (ꢀD ¼ ꢁ0.028ꢂ) indicating (S) configuration for (þ)-9. The
1
ester mixture of the ether phase was analyzed by H NMR showing that the ratio of diastereomers
was (S,S):(S,R) ¼ 65:35 corresponding to an optical yield of 30%. 1H NMR (CDCl3,
c ¼ 2 mgcmꢁ 3): ꢃ (S,S)=(S,R) ¼ 8.19=8.24 (8-H), 7.62=7.66 (6-H), 7.44=7.46 (7-H), ꢃ7.2=7.2
(5-H), ꢃ7.2=7.2 (Ph), 5.84=6.12 (4-H), ꢃ5.15=5.15 (20-H), 3.39=3.40 (200-H), ꢃ2.7=2.7(10-H),
ꢃ2.05=2.05 (300-Ha), ꢃ1.7= 1.7 (30-H), ꢃ1.7= 1.7(300-Hb), ꢃ0.85=0.85 (40-H), ꢃ0.85=0.85 (400-H)
ppm; FDMS: m=z ¼ 364 (Mþ , C23H24O4).

1204
G. Lutz-Kutschera et al.
Absolute Configuration of (ꢁ)-3-(2-Methoxybutyl)-1H-2-benzopyran-1-one
((ꢁ)-20-Methoxydihydroartemidin, 12, C14H16O3)
(ꢁ)-12 has been isolated in very low yield from A. dracunculus [10, 38]. The CD spectrum of
the natural compound was practically a mirror image of the CD spectra of compounds (ꢁ)-8 and
20
20
(þ)-9, the absolute configuration at C-20 was therefore (R). ½ꢀꢅD ¼ ꢃꢁ15ꢂ cm3 gꢁ1 dmꢁ1, ½ꢀꢅ365
¼
ꢁ80ꢂ cm3 gꢁ1 dmꢁ1 (EtOH, c ¼ 0.03); CD (EtOH): ꢁ (D") ¼ ꢃ320 (ꢁ1.0), ꢃ270 (ꢁ0.7), ꢃ250 (ꢁ0.6,
sh.) nm; UV (EtOH): ꢁmax ¼ 327, 273 (side max.), 264, 257 (sh.) nm; 1H NMR (CDCl3,
c ¼ 2 mgcmꢁ 3): ꢃ ¼ 8.26 (br.d, J ¼ 8.0 Hz, 8-H), 7.68 (ddd, J ¼ 7.8, ꢃ7.5, 1.3 Hz, 6-H), 7.46 (ddd,
J ¼ 8.0, ꢃ7.5, 1.2 Hz, 7-H), 7.37 (br.d, J ¼ 7.8 Hz, 5-H), 6.34 (s, 4-H), 3.62 (tdd, J ¼ ꢃ7.0, 7.2, 5.7Hz,
20-H), 3.35 (s, 20-OCH3), 2.71 (dd, J ¼ 14.7, 7.2 Hz, 10-Ha), 2.63 (dd, J ¼ 14.7, 5.7 Hz, 10-Hb), 1.62 (m,
30-H2), 0.96 (t, J ¼ 7.4 Hz, 4 -H3) ppm; 13C NMR (CDCl3): ꢃ ¼ (s, C-1 not detected), 155.4 (s, C-3),
0
140.3 (s, C-4a), 134.7 (d, C-6), 129.5 (d, C-8), 127.7 (d, C-7), 125.2 (d, C-5), (s, C-8a not detected),
104.9 (d, C-4), 79.3 (d, C-20), 57.2 (q, OCH3), 38.2 (t, C-10), 26.3 (t, C-30), 9.2 (q, C-40) ppm.
Bromination of (E)-Artemidin (7) with NBS
NBS (0.6g) was added to a solution of 0.6g of 7 in 6 cm3 of anhydrous CCl4 and the mixture was
heated to reflux. Then ca. 5 mg of dibenzoylperoxide (DBPO) were added and the mixture was
irradiated with a 1000 W halogene lamp. TLC indicated very slow progress of the reaction. Therefore
further 5 mg of DBPO were added after 1.5 h, and again after 5.5 h. After 10h of irradiation the lamp
was removed and the mixture heated to reflux for further 12h. Then the mixture was cooled, filtered,
and the solvent was removed to leave 0.92g of crude oily product. Several attempts to obtain the
obviously rather instable 30-bromo derivative were not successful. However, the desired 30-hydroxy
derivative 13 and two further 30- derivatives, 14 and 15, were obtained as pure compounds by
chromatography. The 10,20-dibromo product 4, also present in the reaction mixture, had already been
obtained by NBS bromination of 1 (see above).
(E)-3-(3-Hydroxy-1-butenyl)-1H-2-benzopyran-1-one ((E)-30-Hydroxyartemidin,
13, C13H12O3)
The crude bromination product (735 mg) was chromatographed on Al2O3 (100 g Al2O3, gradient
PE:EE¼ 75:25 ! 50:50) and the remaining material (120mg) was subjected to MPLC with the same
gradient. Finally pure racemic 13 could be obtained which proved to be fairly stable in the refrigerator.
Yield 27mg (5%); slightly yellow oil; 1H NMR (CDCl3, c ¼ 10mg cmꢁ 3): ꢃ ¼ 8.24 (br.d, J ¼ 8.0 Hz,
8-H), 7.66 (ddd, J ¼ 7.8, ꢃ7.5, 1.4 , 6-H), 7.44 (br.dd, J ¼ 8.0, ꢃ7.5 Hz, 7-H), 7.37 (br.d, J ¼ 7.8 Hz, 5-
H), 6.33 (s, 4-H), 6.66 (dd, J ¼ 15.6, 5.0 Hz, 20-H), 6.28 (dd, J ¼ 15.6, 1.5 Hz, 10-H), 4.53 (qdd, J ¼ 7.3,
5.0, 1.5Hz, 3-H), 1.37 (d, J ¼ 7.3 Hz, 40-H3) ppm; 13C NMR (CDCl3): ꢃ ¼ 162.0 (s, C-1), 152.0 (s, C-
3), 137.4 (s, C-4a), 134.8 (d, C-6), 129.7 (d, C-8), 128.1 (d, C-7), 25.7 (d, C-5), 120.8 (s, C-8a), 105.2
(d, C-4), 120.4 (d, C-l0), 138.7 (d, C-20), 67.7 (t, C-30), 23.4 (q, C-40) ppm.
(E)-3-(3-Acetyloxy-1-butenyl)-1H-2-benzopyran-1-one ((E)-30-Acetoxyartemidin,
14, C15H14O4)
The crude bromination product (184mg) was subjected to chromatography on Al2O3 (15 g Al2O3,
1
PE:EE¼ 95:5). Yield 4 mg (3%); colorless oil; H NMR (CDCl3, c ¼ 3 mgcmꢁ 3): ꢃ ¼ 8.27 (br.d,
J ¼ 8.0 Hz, 8-H), 7.69 (ddd, J ¼ 8.0, ꢃ7.5, 1.4 Hz, 6-H), 7.48 (ddd, J ¼ 8.0, ꢃ7.5, 1.2 Hz, 7-H), 7.40
(br.d, J ¼ 8.0 Hz, 5-H), 6.38 (s, 4-H), 6.56 (dd, J ¼ 15.6, 6.2 Hz, 20-H), 6.23 (dd, J ¼ 15.6, 1.3 Hz, 10-
H), 5.53 (qdd, J ¼ 6.6, 6.2, 1.3 Hz, 30-H), 2.09 (s, COCH3), 1.40 (d, J ¼ 6.6 Hz, 40-H3) ppm; 13C
NMR (CDCl3): ꢃ ¼ 134.8 (d, C-6), 129.8 (d, C-8), 128.3 (d, C-7), 125.8 (d, C-5), 105.9 (d, C-4),
122.6 (d, C-l0), 134.0 (d, C-20), 70.0 (t, C-30), 20.2 (q, C-40), 20.2 (q, COCH3) ppm, no s detected;

Synthesis and Absolute Configuration of Substituted Isocoumarins
1205
EIMS (70 eV): m=z (%) ¼ 258 (64, Mþ ), 216 (95), 199 (32), 187 (39), 173 (100), 155 (31), 145
(26), 115 (28), 89 (52).
(E)-3-(3-Oxo-1-butenyl)-1H-2-benzopyran-1-one ((E)-30-Oxoartemidin, 15, C13H10O3)
This oxidation product was obtained during the chromatography for the isolation of 13 from earlier
main fractions of the MPLC separation as yellowish crystalline material (18 mg); recrystallized from
PE:EE¼ 65:35. Yield 12mg (2%); colourless crystals, mp 173–175ꢂC; 1H NMR (CDCl3,
c ¼ 20 mg cmꢁ 3): ꢃ ¼ 8.28 (dm, J ¼ 8.0Hz, 8-H), 7.72 (ddd, J ¼ 7.8, ꢃ7.5, 1.4 Hz, 6-H), 7.54 (ddd,
J ¼ 8.0, ꢃ7.5, 1.2, 7-H), 7.47 (br.d, J ¼ 7.8 Hz, 5-H), 6.68 (s, 4-H), 7.07 (d, J ¼ 15.5 Hz, 20-H), 6.96
(d, J ¼ 15.5 Hz, l0-H), 2.34 (s, 40-H3) ppm; 13C NMR (CDCl3): ꢃ ¼ 197.0 (s, C-30), 160.8 (s, C-1), 152.3
(s, C-3), 136.2 (s, C-4a), 135.0 (d, C-6), 132.4 (d, C-20), 130.0 (d, C-8), 129.7 (d, C-7), 126.6 (d, C-5),
121.9 (s, C-8a), 111.7 (d, C-4), 128.5 (d, C-l0), 29.3 (q, C-40) ppm; EIMS (70 eV): m=z (%) ¼ 214
(78, Mþ ), 199 (100), 158 (15), 144 (32), 115 (66), 89 (67), 63 (29).
(R)-(þ)-3-(3-Hydroxybutyl)-1H-2-benzopyran-1-one ((þ)-30-Hydroxyartemidin,
(þ)-13, C13H12O3)
Optical resolution to enantiomerically pure (þ)- and (ꢁ)-13 was achieved by cyclic chromatography
1
on triacetyl cellulose [32, 33]. H NMR and chiroptical data of (þ)-13 were identical with (þ)-30-
hydroxyartemidin isolated from A. dracunculus [10, 18]. The absolute configuration was determined as
(R) by means of the Horeau method (see below). Yield 50% (þ)-13 (and 50% of the (ꢁ)-enantiomer);
20
20
colourless oil; ½ꢀꢅD ¼ þ18ꢂ cm3 gꢁ1 dmꢁ1, ½ꢀꢅ436 ¼ þ 54ꢂ cm3 gꢁ1 dmꢁ1 (EtOH, c ¼ 0.2); CD (EtOH):
ꢁ (D") ¼ 341 (þ0.5), ꢃ300 (ꢁ0.1), 227 (ꢁ0.8)nm; UV (EtOH): ꢁmax ¼ 343, 302, 288, 283 (sh),
231 nm.
Determination of the Absolute Configuration of (þ)-13 (Horeau Esters 16, C23H22O4)
Procedure in analogy to the Horeau esters 11:12 mg (0.04 mmol) of racemic 2-phenylbutanoic acid
anhydride in 0.5 cm3 of dry pyridine were poured over 3 mg (0.014 mmol) of (þ)-13; 48h at room
temperature; after workup, the remaining 2-phenylbutanoic acid, in a minimum amount of benzene,
showed an optical rotation of ꢀD ¼ þ0.030ꢂ indicating (R) configuration for (þ)-13. The diastereomeric
ester mixture was analyzed by 1H NMR showing that the ratio of diastereomers was (R,R):(R,S) ¼ 76:24
corresponding to an optical yield of 52%. 1H NMR (CDCl3, c ¼ 1 mgcmꢁ 3): ꢃ (R,R)=(R,S) ¼ 8.24=8.29
(8-H), 7.67=7.76 (6-H), 7.45=ꢃ7.47 (7-H), ꢃ7.37=7.37 (5-H), ꢃ7.3=7.3 (Ph), 6.07=6.29 (4-H),
6.46=6.55 (20-H), 5.75=6.11 (10-H), 5.54=5.52 (30-H), ꢃ2.1=2.1 (30-Ha), ꢃ1.8=1.8 (300-Hb), ꢃ1.3=1.3
(40-H), 0.92=0.92 (400-H3) ppm; FDMS: m=z ¼ 362 (Mþ , C23H22O4).
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