Stereoselective synthesis of (3R)-3,4-dihydro-6,8-dimethoxy-3-undecyl-1H-[2]benzopyran-1-one and derivatives, metabolites from Ononis natrix

Article abstract of DOI:10.1002/hlca.200390038

A short stereoselective synthesis of (3R)-3,4-dihydro-6,8-dimethoxy-3-undecyl-1H-[2] benzopyran-1-one and derivatives isolated from Ononis natrix has been described. Condensation of dodecanoyl chloride with 3,5-dimethoxyhomophthalic acid afforded 6,8-dime

Full text of DOI:10.1002/hlca.200390038

Helvetica Chimica Acta Vol. 86 (2003)
377
Stereoselective Synthesis of (3R)-3,4-Dihydro-6,8-dimethoxy-3-undecyl-
1H-[2]benzopyran-1-one and Derivatives, Metabolites from Ononis natrix
by Aamer Saeed
Department of Chemistry, Quaid-I-Azam University, 45320-Islamabad, Pakistan
(e-mail: aamersaeed@yahoo.com)
A short stereoselective synthesis of (3R)-3,4-dihydro-6,8-dimethoxy-3-undecyl-1H-[2]benzopyran-1-one
and derivatives isolated from Ononis natrix has been described. Condensation of dodecanoylchloride with 3,5-
dimethoxyhomophthalic acid afforded 6,8-dimethoxy-3-undecylisocoumarin 3, which, on sequentialsaponifi-
cation and esterification, yielded the keto ester 5. Enantioselective reduction of 5 with TarB-NO2/LiBH4
directly furnished the title dihydroisocoumarin 1a in 80% ee (82% yield). Partial as well as complete
demethylation of the latter provided the dihydroisocoumarins 1b and 1c, respectively. Diastereotopy of the CH2
H-atoms on either side of the stereogenic center (C(3)) and the mass-fragmentation pattern of the
dihydroisocoumarins have also been described. All of the compounds synthesized were examined in vitro for
antifungalactivity.
Introduction.
Ononis natrix is a small flowering plant belonging to family
Leguminosae. The infusion of its roots has diuretic, antirheumatic properties, and has
been used for certain disturbances of the urinary tract. During phytochemicalstudies of
this plant, Feliciano et al. had isolated 3,4-dihydro-6,8-dimethoxy-3-undecylisocou-
marin (1a; R1 ˆ R2ˆMe; isocoumarin ˆ 1H-[2]benzopyran-1-one), its 8-hydroxy- (1b;
R1 ˆ Me, R2 ˆ H) and 6,8-dihydroxy- (1c; R1 ˆ R2 ˆ H) derivatives as (R)-antipodes,
from the hexane extract along with some related compounds [1][2]. Kazlauskas et al.
had isolated earlier the related (3R)-3,4-dihydro-8-hydroxy-3-undecylisocoumarin
from the brown alga Caulocystis cephalornithos [3].
We have already reported on the total synthesis of the title dihydroisocoumarins as
racemates [4] by the multistep strategy developed during the synthesis of 6-
methoxymellein, a phytoalexin, and metabolite of several fungi and peniolactol, the
metabolite of the wood attacking fungus Peniophora sanguinea [5]. Title dihydroiso-
coumarins, besides their diuretic, antirheumatic, and antibacterialactivities, are
potential antifungal agents, and a detailed study of their biological profile required a
short synthetic route. Condensation of acid chlorides with homophthalic acids has been
useful for the construction of 3-substituted isocoumarin skeleton, which could easily be
converted into corresponding 3,4-dihydroisocoumarins [6]. Herein, a facile stereo-

378
Helvetica Chimica Acta Vol. 86 (2003)
selective synthesis of title dihydroisocoumarins involving TarB-NO2 as chiral Lewis
acid for enantioselective reduction as a key step, and their antifungal activities are
described.
Results and Discussion. 3,5-Dimethoxyhomophthalic acid 2 was prepared from
3,5-dimethoxybenzylbromide via Rh-catalyzed direct carbonylation to corresponding
phenylacetic acid as a key step [7]. Direct condensation of 3,5-dimethoxyhomophthalic
acid with dodecanoyl chloride at elevated temperature afforded the 6,8-dimethoxy-3-
undecylisocoumarin 3 in 65% yield [8] (Scheme 1). It showed the characteristic 1-H
1
singlet of isocoumarin moiety at d 6.07 for HÀC(4) in the H-NMR and signals at d
103.1 (C(4)) and 160.0 (C(3)) in the 13C-NMR spectrum. DEPT 908 and DEPT 1358
experiments confirmed these assignments. Mass spectrum showed the characteristic
isocoumarin fragments at m/z 220, 205, and 177, in addition to the molecular ion, and IR
spectrum showed the lactone CˆO absorption at 1685 cmÀ1.
Scheme 1
a) C11H23COCl, 2008, 4 h; 65%. b) 5% KOH, EtOH, 4 h reflux; 72%. c) MeI, K2CO3, dry acetone, 3 h; 95%.
d) LiBH4, TarB-NO2, 2 h, r.t.; 82%. e) BBr3, CH2Cl2, À788, 10 min; 78%. f) BBr3, CH2Cl2, À788 ! r.t.
overnight; 72%.
Alkaline hydrolysis of the isocoumarin 3 to furnish the 4,6-dimethoxy-2-(2-
oxotridecyl)benzoic acid (4) was accomplished in 78% yield. The keto acid existed in
equilibrium with its cyclic tautomeric lactol form viz. 3,4-dihydro-3-hydroxy-6,8-
1
dimethoxy-3-undecylisocoumarin as evidenced by the H-NMR. Thus, in addition to
the 2-H singlet at d 4.04 for benzylic H-atoms, (HÀC(1'), open-chain form) each of the
H-atoms showed a triplet at d 2.57 2.61 (J ˆ 4.2) and at 2.29 2.40 (J ˆ 4.5) most
4
1
probably by J coupling in H-NMR and signalfor benzyilc C-atom at
d 77.7 in
13C-NMR spectrum was observed.
The keto acid was converted into the corresponding ester, as such keto esters are
known to afford better enantioselectivities in stereoselective reductions. Esterification
with absolute MeOH in presence of a catalytic amount of acid was unsuccessful and
resulted in dehydration back to the parent isocoumarin. The esterification was
successfully achieved by treatment with MeI in presence of anhydrous K2CO3 in dry
acetone to afford the keto ester 5. Keto ester 5 showed the 3-H singlet at 3.66
‡
(COOMe) and 2-H singlet at 3.95 (ArCH2) in 1H-NMR, [M À MeOH] ion at m/z 360

Helvetica Chimica Acta Vol. 86 (2003)
379
in MS, and ester and ketone CˆO absorptions at 1716 and 1694 cmÀ1, respectively, in
IR spectrum.
The crucialstep of the present synthesis was the enantioseel ctive reduction of the
prochiralketo acid 4 or keto ester 5, for which the choice of a chiralreducing agent was
important. The only precedence in literature of the stereoselective reduction of such
keto acids or keto esters is by Krohen et al. [9]. Thus, reduction with Midland×s Alpine-
boranes and enzymes like horse liver dehydrogenase were not successful, whereas more
reactive diisopinocamphenylboranes reduced the acid or ester to dihydroisocoumarin
in 41 and 62% ee, respectively. Higher enantioselectivities were achieved with baker×s
yeast (> 99% ee) but with the opposite (S)-configuration. Other related examples
include the CBS reduction of keto amides to amide alcohols in 15 45% ee (95% ee in
one case), followed by basic hydrolysis to dihydroisocoumarins [10] and the DIBAL-H
reduction of the chiraltricarbonylcompelxes of prochiralketones to homobenzyilc
alcohols as intermediates in the synthesis of dihydroisocoumarins, which gave good
diastereoselection (75% de) [11]. We decided to use the recently reported tartaric acid
derived boronate ester chiral Lewis acid, TarB-NO2 in combination with LiBH4 for
enantioselective reduction of aryl ketones [12]. Thus, with 2 equiv. of TarB-NO2 and
1 equiv. of LiBH4 for 1 equiv. of keto ester 5, the dihydroisocoumarin 1a was obtained
in 80% ee (82% yield) [13][14]. The enantiomeric excesses (ee) were determined by
NMR with chiralshift reagents, and the absolute configuration was checked by the sign
of opticalrotation. The H-atoms of CH groups on either side of the newly created
2
stereogenic center (C(3)) exhibited the diastereotopic effect [15]. The CH2(4) with
restricted motion owing to its incorporation in the heterocyclic ring, and CH2(1') and
CH2(2') groups with free rotation correspond to ABX, ABMNX, and ABMNX2
systems, respectively. The AB H-atoms (CH2(4)) at d 2.73 2.88 showed that the H-
atom cis to side chain located slightly downfield shows a double doublet at d 2.81
2.88 ppm (Jgem ˆ 16.4, Jcis ˆ 3.5 Hz), and the trans-H-atom resonates slightly upfield at
2.73 2.78 ppm (Jgem ˆ 16.2, Jtrans ˆ 11.9 Hz), with a chemicalshift difference of ca.
0.07 ppm, which corresponds to the extent of diastereotopy. The HÀC(3) showed a
dddd pattern at d 4.31, indicating the presence of diastereotopic CH2 groups on either
side. Thus, each of the H-atoms of CH2(1') (HAÀC(1') and HBÀC(1')) also showed a
dddd at d 1.61 and 1.80 with a chemical shift difference of 0.19 ppm, an almost double
extent of diastereotopy compared to that between HAÀC(4) and HBÀC(4). The
diastereotopic effect extends up to the H-atoms of CH2(2') with two sets of multiplets at
d 1.45 and 1.54 ppm, respectively; in this case Dn is reduced to ca. 0.1 ppm due to larger
separation from the stereogenic center. There is no indication of diastereotopy beyond
C(2'), and the rest of H-atoms (CH2(3')ÀCH2(10')) show an 18-H, br. singlet at d
1.23 ppm. 13C-NMR Spectrum showed signals at d 77.6 and 35.0 for C(3) and C(4),
respectively. The lactone CˆO absorption appeared at 1720 cmÀ1 in IR spectrum.
Selective demethylation of the (3R)-3,4-dihydro-6,8-dimethoxy-3-undecylisocou-
marin (1a) was carried out using BBr3 under mild conditions (À 788, 10 min) to furnish
the (3R)-3,4-dihydro-8-hydroxy-6-methoxy-3-undecylisocoumarin (1b). 13C-NMR
Spectrum showed signals at d 79.4 and 34.9 for C(3) and C(4), respectively. IR
Spectrum showed the lactone CˆO absorption at 1665 cmÀ1 due to internalchelation.
Complete demethylation of 1a was achieved with BBr3 at À788 and allowing it to
warm to 48 overnight to yield the (3R)-3,4-dihydro-6,8-dihydroxy-3-undecylisocou-

380
Helvetica Chimica Acta Vol. 86 (2003)
Table 1. NMR Data for the H-Atoms at and around the Stereogenic Center (C(3)) of Dihydroisocoumarins 1a 1c
HÀC(3)
HAÀC(4)
HBÀC(4)
HAÀC(1')
HBÀC(1')
HAÀC(2') HBÀC(2')
1a 4.31 (dddd, J ˆ 10.5, 2.85
7.6, 5.4, 4.6)
1b 4.50 (dddd, J ˆ 11.0, 2.90
7.5, 5.0, 3.7)
(dd, J ˆ 16.5, 11.1) (dd, J ˆ 16.0, 3.7)
1c 4.70 (dddd, J ˆ 11.2, 2.96 2.85
7.4, 5.5, 3.6)
(dd, J ˆ 16.3, 4.0) (dd, J ˆ 16.2, 10.80) 7.5, 5.0)
2.75
1.61 (dddd, J ˆ 13.5, 10.2, 1.80 (dddd, J ˆ 13.7, 10.2, 1.40 (m) 1.54 (m)
(dd, J ˆ 16.4, 3.52) (dd, J ˆ 16.2, 11.92) 5.7, 5.3)
7.4, 5.2)
2.83
1.71 (dddd, J ˆ 14.1, 10.4, 1.85 (dddd, J ˆ 13.5, 10.3, 1.45 (m) 1.54 (m)
5.4, 5.3)
7.6, 5.4)
1.75 (dddd, J ˆ 14.0, 10.1, 1.89 (dddd, J ˆ 13.6, 10.1, 1.47 (m) 1.60 (m)
7.4, 5.0)
marin (1c). The latter was characterized by the complete absence of MeOÀC(8) and
1
MeOÀC(6) singlets both in H- and 13C-NMR spectra, and by the downfield shift of
characteristic signals.
The NMR data for the H-atoms at and around the stereogenic center (C(3)) of the
dihydroisocoumarins 1a 1c are collected in Table 1. It is evident that the substituents
R1 and R2 have no significant effect on splitting pattern and J values, except for slight
variation of d values. Thus, CH2(4) H-atoms show a consistent Jgem value of 16.2 Æ
0.3 Hz and two different Jvic values for cis and trans H-atoms with a ratio of ca. 1:3, the
one resonating downfield and showing lower J value, but the order may be reversed.
Similarly, the CH2(1') H-atoms couple to different extent with their vicinal counter-
parts.
Scheme 2 delineates the mass fragmentation pattern of the EI mass spectra of
dihydroisocoumarins 1a 1c, which is consistent with the generalmass-fragmentation
mechanism for dihydroisocoumarins. The major peaks correspond to a-cleavage, loss of
CO, and retro-DielsÀAlder cleavage products.
Scheme 2

Helvetica Chimica Acta Vol. 86 (2003)
381
The isocoumarin, keto acid, keto ester, and dihydroisocoumarin 3, 4, 5, and 1a 1c,
respectively, were examined in vitro for antifungalactivities against some human,
animal, and plant pathogenic molds [16] (Table 2). It is evident from Table 2 that 5 is
more potent than 4, and 1a shows more antifungalactivity compared to the
corresponding isocoumarin 3. Among dihydroisocoumarins 1a 1c, 8-hydroxy and
6,8-dihydroxy derivatives, 1b and 1c, respectively, are more active compared to
dimethoxy compound 1a, possibly due to internal chelation between OH and lactone
CˆO groups [17].
Table 2. Antifungal Activity (antifungal activity determined by agar-dilution method and the results reported as
linear-growth inhibition (LGI) [%] at 400 mg/ml[%] of media SDA; standard drugs: miconazoel and
ketoconazole)
Pathogens
3
4
5
1a
1b
1c
Standard
drugs
Trichophyton schoenleinii
Candida albicans
23
17.5
27
19.4
25.0
26.3
70
79
Aspergillus niger
Microsporum canis
Fusarium solani
47.9
48.6
24.8
12.5
46.2
31
16.8
6.9
54
55
29.0
21
50
56
34
13.2
54
60
32
15
55
64
31
12.7
20
98.4
73.5
100
Pseudallescheria boydii
In summary, an efficient stereoselective synthesis of the principal dihydroisocou-
marins of Ononis natrix has been accomplished. It involves three linear steps and
proceeds with an overall yield of 40%.
Experimental Part
General. THF was dried over Na/benzophenone under N2 and CH2Cl2 over CaH2 under Ar and distilled
fresh before use. Flash column chromatography (FC): Merck Kieselgel 60 (230 400 mesh). Opticalrotations: in
CHCl3 on a Perkin-Elmer 341 polarimeter. IR Spectra were recorded on a Bruker Vector 22. 1H- and the
13C-NMR spectra were determined in CDCl3 solns. at 400 (Bruker AM-400) and 100 MHz (Bruker AM-100),
resp. EI-MS (70 eV): MAT 312 instrument. Elemental analyses: CHN-Rapid Heraeus. Enantiomeric excesses
1
(ee) were determined by H-NMR with (‡)-[Eu(hfc)3] as optically active shift reagent.
6,8-Dimethoxy-3-undecyl-1H-[2]benzopyran-1-one (3). A stirred mixture of 3,5-dimethoxyhomophthalic
acid (2; 0.5 g, 2.08 mmol) and dodecanoyl chloride (1.82 g, 8.33 mmol) was heated on an oil bath at 200 8 for 4 h.
FC of the residue (petroleum ether/AcOEt 9 :2) afforded 3 (0.48 g, 1.35 mmol, 65%). Colorless prisms. IR
(KBr): 2913, 2849, 1685, 1645, 1625, 1575, 1510, 860, 835, 810. 1H-NMR (400 MHz, CDCl3): 0.87 (t, J ˆ 7.12,
Me(11')); 1.25 (br. s, CH2(3') CH2(10')); 1.65 (q, J ˆ 8.4, CH2(2')); 2.44 (t, J ˆ 7.0, CH2(1')); 3.87
(s, MeOÀC(6)); 3.95 (s, MeOÀC(8)); 6.07 (s, HÀC(4)); 6.30 (s, HÀC(5)); 6.41 (s, HÀC(7)). 13C-NMR
(100 MHz, CDCl3): 165.5 (C(1)); 163.5 (C(8)); 160.0 (C(3)); 159.5 (C(6)); 142.6 (C(4a)); 103.1 (C(4)); 99.6
(C(5)); 98.3 (C(7)); 56.4 (MeOÀC(8)); 55.7 (MeOÀC(6)); 33.9 (C(1')); 32.0 (C(9')); 29.74, 29.72, 29.6, 29.55,
‡
29.51, 29.4 (C(4') C(8')); 26.9 (C(2')); 24.7 (C(3')); 22.8 (C(10')); 14.2 (C(1')). EI-MS (70 eV): 360 (63, M ),
220 (43), 206 (17), 205 (100), 177 (52), 149 (38). Anal. calc. for C22H32O4: C 73.30, H 8.95; found: C 73.21,
H 8.98.
4,6-Dimethoxy-2-(2-oxotridecyl)benzoic Acid (or 3,4-Dihydro-3-hydroxy-6,8-dimethoxy-3-undecyl-1H-
[2]benzopyran-1-one; 4). A stirred soln. of 3 (0.4 g, 1.11 mmol) in EtOH (15 ml) was treated with 5% KOH
(30 ml), and the mixture was refluxed for 4 h. After cooling the mixture, most of the EtOH was evaporated.
Cold H2O (15 ml) was added, and the mixture was acidified with dil. HCl and extracted with AcOEt (2 Â 30 ml).
The org. phase was dried (MgSO4), and the solvent was evaporated under vacuum to leave a solid.

382
Helvetica Chimica Acta Vol. 86 (2003)
Recrystallization from AcOEt/petroleum ether afforded 4 (0.30 g, 0.80 mmol, 72%). White scales. IR (KBr):
1
3011, 2949, 1716, 1683, 1601, 1202, 1162. H-NMR (400 MHz, CDCl3)1): 0.86 (t, J ˆ 6.38, Me(11')); 1.23 (br. s,
CH2(2') CH2(10')); 1.53 1.62 (m, CH2(1')); 2.29 2.40 (t, J ˆ 4.5, 1 HÀC(4)); 2.57 2.61 (t, J ˆ 4.2,
1 HÀC(4)); 3.84 (s, MeO); 3.98 (s, MeO); 6.39 (d, J ˆ 2.0, HÀC(7)); 6.47 (d, J ˆ 2.2, HÀC(5)); 11.22 (br. s,
COOH). 13C-NMR (100 MHz, CDCl3): 195.5 (C(3), CˆO); 168.3 (COOH); 132.7 (C(5)); 131.8 (C(6)); 127.4
(C(7)); 77.7 (C(4)); 55.6 (2 MeO); 42.9 (C(1')); 32.1 (C(9')); 29.8, 29.79, 29.77, 29.71, 29.68, 29.65, 29.6 (C(2')
‡
C(8')); 22.8 (C(10')); 14.2 (C(11')). EI-MS: 378 (27.8, M ), 360 (51), 220 (53), 195 (46), 178 (70), 150 (32).
Anal. calc. for C22H34O5: C 69.81, H 9.05; found: C 69.78, H 9.08.
Methyl 4,6-Dimethoxy-2-(2-oxotridecyl)benzoate (5). A mixture of 4 (0.25 g, 0.66 mmol) and anh. K2CO3
(0.5 g) in dry acetone (10 ml) was treated with MeI (56 mg, 24.7 ml, 0.78 mmol) and refluxed for 3 h. The
mixture was filtered while hot, the filter cake was washed with warm dry acetone, and the solvent was
evaporated to yield 5 (0.26 g, 0.66 mmol, 100%). Oil. IR (film): 3011, 2949, 1725, 1710, 1694, 1601, 1162.
1H-NMR (400 MHz, CDCl3; numbering according to cyclic form): 0.87 (t, J ˆ 6.52, Me(11')); 1.26 (br. s,
CH2(2') CH2(10')); 1.68 (m, CH2(1')); 2.27 2.35 (t, J ˆ 4.2, 1 HÀC(4)); 2.39 2.52 (t, J ˆ 4.5, 1 HÀC(4)); 3.66
(s, COOMe), 3.81 (s, MeO); 3.88 (s, MeO); 3.95 (s, ArCH2); 6.30 (d, J ˆ 2.0, HÀC(7)); 6.41 (d, J ˆ 2.24,
‡
HÀC(5)). EI-MS: 392 (42.0, M ), 237 (17.80), 220 (53), 209 (43.8), 178 (70). Anal. calc. for C23H36O5: C 70.38,
H 9.24; found: C 70.33, H 9.21.
(3R)-3,4-Dihydro-6,8-dimethoxy-3-undecyl-1H-[2]benzopyran-1-one (1a). A soln. of 5 (0.23 g, 0.6 mmol)
in dry THF (40 ml) was added slowly via syringe to a stirred soln. of TarB-NO2 (30 mlof 0.4 m in THF,
0.12 mmol) under Ar. The mixture was stirred for 30 min at r.t. LiBH4 (3 ml, 2m in THF, 0.6 mmol) was added
dropwise over 10 min, and the mixture was further stirred for 2 h (TLC). The mixture was quenched with H2O
(5 ml), acidified with 2n HCl, and extracted with Et2O (3 Â 50 ml). The combined org. layer was washed with
brine (30 ml), dried (MgSO4), and concentrated. FC (petroleum ether/AcOEt 7:1) afforded 1a (0.178 g,
0.49 mmol, 82%). Colorless scales. [a]2D5 ˆ À59 (c ˆ 0.96, CHCl3). IR (film): 2924, 2853, 1720, 1710, 1604, 1583,
1572, 1464, 1198, 832. 1H-NMR (400 MHz, CDCl3): 0.86 (t, J ˆ 6.0, Me(11')); 1.23 (br. s, CH2(2') CH2(10'));
1.40 (m, 1 HÀC(2')); 1.54 (m, 1 HÀC(2')); 1.61 (dddd, J ˆ 13.5, 10.2, 5.7, 5.3, 1 HÀC(1')); 1.80 (dddd, J ˆ 13.7,
10.2, 7.4, 5.2, 1 HÀC(1')); 2.73 2.75 (dd, Jgem ˆ 16.2, Jtrans ˆ 11.92, 1 HÀC(4)); 2.88 2.96 (dd, Jgem ˆ 16.4, Jcis
ˆ
3.52, 1 HÀC(4)); 3.85 (s, MeOÀC(6)); 3.91 (s, MeOÀC(8)); 4.28 4.31 (dddd, J ˆ 10.5, 7.6, 5.4, 4.6, HÀC(3));
6.28 (d, J ˆ 2.12, HÀC(7)); 6.37 (d, J ˆ 2.4, HÀC(5)). 13C-NMR (100 MHz, CDCl3): 164.8 (C(1), CO); 163.0
(C(8)); 162.8 (C(6)); 144.0 (C(4a)); 107.2 (C(8a)); 103.9 (C(5)); 97.8 (C(7)); 77.6 (C(3)); 56.2 (MeOÀC(8));
55.6 (MeOÀC(6)); 35.0 (C(4)); 34.8 (C(1')); 32.0 (C(9')); 29.74, 29.71, 29.68, 29.65, 29.6, 29.52, 29.5 (C(3')
‡
C(8')); 25.0 (C(2')); 22.8 (C(10')); 14.2 (C(11')). EI-MS (70 eV): 362 (39, M ), 207 (100), 178 (52), 179 (31), 151
(42). Anal. calc. for C22H34O4: C 72.85, H 9.45; found: C 72.81, H 9.44.
(3R)-3,4-Dihydro-8-hydroxy-6-methoxy-3-undecyl-1H-[2]benzopyran-1-one (1b). A 1m soln. of BBr3 in
CH2Cl2 (0.44 ml, 0.44 mmol) was injected to a stirred soln. of 1a (80 mg, 0.22 mmol) in dry CH2Cl2 (3 ml) at
À788, under Ar. After stirring for 10 min, the mixture was poured into ice-water (20 ml) and stirred for 10 min.
The layers were separated, and the aq. layer was extracted with CH2Cl2 (2 Â 25 ml) and then with AcOEt
(30 ml). The combined org. phases were dried (MgSO4) and concentrated. FC (petroleum ether/AcOEt 8 :2)
afforded 1b (60 mg, 0.17 mmol, 78%). Colorless prisms. [a]2D5 ˆ À18.2 (c ˆ 0.31, CHCl3). IR (film): 3435, 2956,
2924, 2855, 1727, 1665, 1627, 1461, 1461, 1271, 1249, 1121, 1072, 741. 1H-NMR (400 MHz, CDCl3): 0.87 (t, J ˆ 7.0,
Me(11')); 1.25 (br. s, CH2(2') CH2(10')); 1.45 (m, 1 HÀC(2')); 1.55 (m, 1 HÀC(2')); 1.71 (dddd, J ˆ 14.1, 10.4,
5.4, 5.3, 1 HÀC(1')); 1.85 (dddd, J ˆ 13.5, 10.3, 7.6, 5.4, 1 HÀC(1')); 2.81 2.85 (dd, Jgem ˆ 16.5, Jcis ˆ 11.1,
1 HÀC(4)); 2.84 2.96 (dd, Jgem ˆ 16.0, Jtrans ˆ 3.7, 1 HÀC(4)); 3.81 (s, MeO); 4.45 4.54 (dddd, J ˆ 11.0, 7.5, 5.0,
3.7, HÀC(3)); 6.24 (d, J ˆ 2.76, HÀC(7)); 6.36 (d, J ˆ 2.64, HÀC(5)); 11.25 (br., OH). 13C-NMR (100 MHz,
CDCl3): 170.0 (C(1), CO); 165.9 (C(6)); 164.7 (C(8)); 141.2 (C(4a)); 106.3 (C(5)); 103.9 (C(8a)); 99.5 (C(7));
78.9 (C(3)); 55.6 (MeO); 34.9 (C(4)); 32.5 (C(1')); 32.0 (C(9')); 29.70, 29.69, 29.66, 29.64, 29.60, 29.54, 29.5
‡
(C(3') C(8')); 24.9 (C(2')); 22.8 (C(10')); 14.1 (C(11')). EI-MS (70 eV): 348 (39, M ), 207 (100), 178 (52), 179
(31), 151 (42). Anal. calc. for C21H32O4: C 72.38, H 9.26; found: C 72.35, H 9.28.
(3R)-3,4-Dihydro-6,8-dihydroxy-3-undecyl-1H-[2]benzopyran-1-one (1c). A 1m soln. of BBr3 in CH2Cl2
(0.88 ml, 0.88 mmol) was added dropwise to a stirred soln. of 1a (80 mg, 0.22 mmol) in dry CH2Cl2 (3 ml) at
À788 under Ar. The mixture was gradually allowed to warm to r.t. and stirred overnight. The mixture was
poured into ice-coolH 2O, stirred for 10 min, and extracted with CH2Cl2 (3 Â 30 ml) and then with AcOEt
(30 ml). The combined org. phases were washed with H2O, dried (MgSO4), and concentrated. FC (petroleum
1
)
To avoid confusion and for direct comparison, C-atom numbering is considered same as in 3.

Helvetica Chimica Acta Vol. 86 (2003)
383
ether/AcOEt 7:3) afforded 1c (53 mg, 0.16 mmol, 72%). Colorless scales. [a]2D5 ˆ À14.3 (c ˆ 1.12, CHCl3). IR
1
(film): 3435, 2956, 1727, 1669, 1627, 1461, 1461, 1271, 1249, 1121, 1072, 741. H-NMR (400 MHz, CDCl3): 0.88
(t, J ˆ 6.5, Me(11')); 1.26 (br. s, CH2(2') CH2(10')); 1.47 (m, 1 HÀC(2')); 1.60 (m, 1 HÀC(2')); 1.75 (dddd, J ˆ
14.0, 10.1, 7.5, 5.0, 1 HÀC(1')); 1.89 (dddd, J ˆ 13.6, 10.1, 7.4, 5.0, 1 HÀC(1')); 2.81 2.85 (dd, Jgem ˆ 16.2, Jtrans
ˆ
10.8, 1 HÀC(4)); 2.84 2.96 (dd, Jgem ˆ 16.3, Jtrans ˆ 10.80, 1 HÀC(4)); 4.54 4.70 (dddd, J ˆ 10.5, 7.6, 5.4, 4.6,
HÀC(3)); 6.24 (d, J ˆ 2.76, HÀC(7)); 6.36 (d, J ˆ 2.64, HÀC(5)). 13C-NMR (100 MHz, CDCl3): 170.3 (C(1),
CO); 164.9 (C(6)); 162.6 (C(8)); 142.0 (C(4a)); 106.9 (C(5)); 102.7 (C(8a)); 102.2 (C(7)); 79.9 (C(3)); 34.9
(C(4)); 33.2 (C(1')); 32.0 (C(9')); 29.73, 29.71, 29.67, 29.65, 29.60, 29.55, 29.52 (C(3') C(8')); 24.9 (C(2')); 22.6
‡
(C(10')); 14.2 (C(11')). EI-MS (70 eV): 334 (49, M ), 179 (97), 151 (37), 150 (40), 122 (34). Anal. calc. for
C20H30O4: C 71.82, H 9.04; found: C 71.86, H 9.01.
The author gratefully acknowledges a Georg Forster research fellowship from the Alexander von
Humboldt-Foundation Germany. The author is indebted to the InstrumentalResearch Services, Institut f¸r
Organische Chemie, Universit‰t Hannover, Germany, for the spectralanayl ses.
REFERENCES
[1] A. San Feliciano, A. F. Barrero, M. Medarde, J. M. Miguel del Corral, M. V. Calle, Phytochemistry 1983, 22,
2031.
[2] A. San Feliciano, J. M. Miguel del Corral, L. M. Canedo, M. Medarde, Phytochemistry 1990, 29, 945.
[3] R. Kazlauskas, J. Mulder, P. T. Murphy, R. J. Wells, Aust. J. Chem. 1980, 33, 2097.
[4] N. H. Rama, A. Saeed, C. W. Bird, Liebigs Ann. Chem. 1993, 1331.
[5] N. H. Rama, A. Saeed, C. W. Bird, Liebigs Ann. Chem. 1995, 711; N. H. Rama, R. Iqbal, A. Saeed, S.
Hameed, J. Chem. Soc. Pak. 1992, 14. 138.
[6] A. Saeed, Monatsh. Chem. 2002, in press; A. Saeed, J. Chin. Chem. Soc. 2002, in press; N. H. Rama, R.
Iqbal, Kh. Zamani, A. Saeed, M. Z. Iqbal, M. I. Chaudary, Indian J. Chem. 1998, 37 B, 365; A. Saeed, N. H.
Rama, Arabian J. Sci. Eng. 1996, 21, 403.
[7] A. Giroux, C. Nadeau, Y. Han, Tetrahedron Lett. 2000, 41, 7601.
[8] K. Nozawa, M. Yamada, Y. Tsuda, K. I. Kawai, S. Nakajima, Chem. Pharm. Bull. 1981, 29, 2491, 3486; H.
Kaji, M. Yamada, K. Nozawa, K. I. Kawai, S. Nakajima, Org. Prep. Proced. Int. 1986, 18, 253.
[9] K. Krohen, R. Bahramsari, U. Flˆrke, K. Ludewig, C. Nakajima, A. Klichespory, H.-J. Aust Michel, S.
Raeger, B. Schulz, S. Antus, Phytochemistry 1997, 45, 313.
[10] A. Arnoldi, A. Bassoli, L. Merlini, E. Ragg, Gazz. Chim. Ital. 1992, 122, 403.
[11] R. Thangarasa, J. R. Green, T. Nadasdi, J. Chem. Soc., Chem. Commun. 1994, 501.
[12] J. T. Suri, T. Vu, A. Hernandez, J. Congdon, B. Singaram, Tetrahedron Lett. 2002, 43, 3649.
[13] P. Bovicelli, P. Lupattelli, B. Crescenzi, A. Saetti, R. Bernini, Tetrahedron 1999, 55, 14719.
[14] K. Uchida, H. Watanabe, K. Mori, Biosci. Biotech. Biochem. 1997, 61, 1564.
[15] J. K. Kendall, T. H. Fisher, H. P. Schultz, T. P. Schultz, J. Org. Chem. 1989, 54, 4218.
[16] U. Kazmi, S. N. Ali, S. A. Jamal, A. Rehaman, J. Pharm. Sci. 1991, 4, 113; Atta-ur-Rahman, M. I.
Choudhary, W. J. Thomsen in −Bioassay Techniques for Drug Development×, Harwood Academic
Publishers, The Netherlands, 2001, p. 22.
[17] K. Nozawa, S. Nakajima, M. Yamada, K. I. Kawai, Chem. Pharm. Bull. 1980, 28, 1622.
Received July 23, 2002