Total synthesis of racemosol and de-O-methylracemosol, potent cyclooxygenase (COX) inhibitors and antimalarial agents

Article abstract of DOI:10.1016/j.tetlet.2005.11.016

The total synthesis of antimalarial and cyclooxygenase inhibitors, racemosol and de-O-methylracemosol, is described. The key steps involved the lateral lithiation reaction of ortho-methyl tolulate and the pyran formation via a tandem demethylation-cycliza

Full text of DOI:10.1016/j.tetlet.2005.11.016

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 345–348
Total synthesis of racemosol and de-O-methylracemosol,
potent cyclooxygenase (COX) inhibitors and antimalarial agents
Patcharaporn Sae-Lao,a Prasat Kittakoopb and Shuleewan Rajviroongita,*
aDepartment of Chemistry, Faculty of Science, Mahidol University, Rama VI Rd, Bangkok 10400, Thailand
bNational Center for Genetic Engineering and Biotechnology (BIOTEC), NSTDA, Pathumthani 12120, Thailand
Received 8 September 2005; revised 25 October 2005; accepted 3 November 2005
Available online 22 November 2005
Abstract—The total synthesis of antimalarial and cyclooxygenase inhibitors, racemosol and de-O-methylracemosol, is described.
The key steps involved the lateral lithiation reaction of ortho-methyl tolulate and the pyran formation via a tandem demethyla-
tion–cyclization reaction.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Racemosol (1) and de-O-methylracemosol (2), were iso-
lated from the roots of Bauhinia malabarica Roxb, and
possessed in vitro antimalarial activity.1 Recently we
have discovered that 1 and 2 are potent cyclooxygenase
(COX) inhibitors, showing comparable activity to that
of the standard drug, aspirin.2 Both racemosol (1) and
de-O-methylracemosol (2) were also isolated from B.
racemosa3 and B. rufescens.4 A biosynthetic pathway
for these tetracyclic substances (Fig. 1), involving
stilbene related compounds as precursors, was proposed
by Hostettmann and co-workers.4
O
MeO
OR
OMe
OMe
OMe
OMe
1, 2
OH
MeO
MeO
3
4
OMe
OMe
OH
O
CO2Me
OMe
Br
OH
MeO
OMe
HO
The interesting biological activities of 1 and 2, as well as
the limited amounts obtained from natural sources,
prompted us to investigate their total synthesis. The
retro synthesis of racemosol (1) and de-O-methylrace-
mosol (2) is outlined retrosynthetically in Scheme 1. On
the basis of deprotection and cyclization, the tetracyclic
skeleton of 1, 2 could be obtained from intermediate 3.
5
7
6
OMe
Scheme 1. Retrosynthetic analysis of 1 and 2.
The key intermediate 3 could be prepared from tricyclic
ketone 4 using Grignard reaction. The required tricyclic
ketone 4 can arise from the intramolecular Friedel–
Crafts acylation5 of ester 5. The dihydrostilbene ester
5 could be constructed through C–C bond formation
using the lateral lithiation reaction6 of 2,4-dihydroxy-
3,6-dimethylbenzoic acid (6) and 2,3-dimethoxybenzyl
bromide (7).
2
12
1
11
9
O
10 OR
4
12b
5
HO
8
OH
6
7
The commercially available 2,4-dihydroxy-3,6-dimethyl-
benzoic acid (6) was methylated (K2CO3/MeI) prior to
lithiation. The methoxy protected precursor 8 was trea-
ted with 1.2 equiv LDA at À78 ꢁC and then trapped
with 2,3-dimethoxybenzyl bromide (7)7 to provide
product 5. The regiospecific deprotonation of the
ortho-methyl toluate group led to the desired alkylation
racemosol 1 R = Me
de-O-methylracemosol 2 R = H
Figure 1. Structures for 1 and 2.
*
Corresponding author. Tel.: +66 2 201 5134; fax: +66 2 354 7151;
e-mail: scsrv@mahidol.ac.th
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.016

346
P. Sae-Lao et al. / Tetrahedron Letters 47 (2006) 345–348
OMe O
OH
OMe
OMe
O
CO2H
CO2Me
CO2Me
a
b
MeO
OMe
HO
MeO
MeO
MeO
9
OMe
OMe
6
8
5
c
O
OR
OR
f
OMe
OMe
OMe
OMe
OH
MeO
e
MeO
4 R = Me
10 R = H
11 R = Bn
3a R = Me
b R = Bn
d
g
O
O
OMe
OMe
h
OMe
OMe
MeO
MeO
12
13
Scheme 2. Reagents and conditions: (a) K2CO3, DMF, MeI (96%); (b) 1.2 equiv LDA, 2,3-dimethoxybenzyl bromide (7), THF, À78 ꢁC (67%); (c)
PPA (92%); (d) 1.0 M BBr3, CH2Cl2, À78 ꢁC (92%); (e) BnBr, K2CO3, reflux acetone (95%); (f) b-methallyl magnesium chloride, THF, À20 ꢁC to rt
(93%); (g) concd HCl/EtOH, reflux 24 h (74%); (h) H2/Pd–C (98%).
product 58 (67%) and the self-coupled isocoumarin 99
(30%). The formation of the isocoumarin from ortho-
toluate coupling has previously been reported10 and in
this case it was suppressed by slow addition of benzyl
bromide 7 to the anion intermediate of 8. Attempts were
made to protect the C–O bond with bulky benzyloxy
and isopropoxy group to decrease the self-coupled prod-
uct, however a poor yield of the desired product was ob-
tained. Intramolecular Friedel–Crafts acylation5 of ester
5 was performed directly in polyphosphoric acid to pro-
vide the seven-membered tricyclic ketone 411 (92%). The
conversion of the ester to the carboxylic acid in this case
is no longer required. Grignard reaction of 4 with b-
methallyl magnesium chloride in toluene:THF (10:1) at
À20 ꢁC gave the corresponding alcohol 3a12 (93%).
Unfortunately, demethylation of 3a with BBr3 prior to
cyclization met with failure. An alternative route using
a benzyloxy protecting group was carried out. Selective
demethylation of 4 with 1.0 M BBr3 at À78 ꢁC in
CH2Cl2 and reprotection of the hydroxy group of 1013
with benzylbromide provided the benzyloxy product
1114 in good yield. Grignard reaction of 11 gave the cor-
responding alcohol 3b15 (75%). Debenzylation, cycliza-
tion and dehydration of compound 3b with concd HCl
in refluxing ethanol provided the desired tetracycle
1216 (74%). Hydrogenation of compound 12 using H2/
Pd–C afforded compound 1317 in excellent yield. This
route should enable us to construct racemosol (1) and
de-O-methylracemosol (2) as well as several analogues
(Scheme 2).
uct 1419 (84%). To our delight, this method had the
advantage of three reactions namely demethylation,
cyclization and dehydration in one pot. The natural
product de-O-methylracemosol (2)20 could be obtained
from hydrogenation (H2/Pd–C) of 14. Racemosol (1)21
was obtained as the major product from methylation
of 2, together with other methylated products, c–9 meth-
oxy (15) and dimethoxy (16),2 as shown in Scheme 3.
The synthetic racemosol (1) and de-O-methylracemosol
(2) were characterized by spectroscopic techniques and
they were identical in all respects to natural products 1
and 2.1,3,4
In conclusion, the bioactive natural products de-O-
methylracemosol (2) and racemosol (1) were successfully
synthesized in 44% and 22% overall yields from the com-
O
OMe
OH
OMe
OMe
a
OH
OH
HO
MeO
3a
14
b
O
O
OR1
OR2
OH
c
HO
OH
HO
2
1: R1 = Me, R2 = H
15: R1 = H, R2 = Me
16: R1 = R2 = Me
In addition, a more efficient method that led to pyran
formation via a tandem demethylation–cyclization18
was applied to our system. Indeed, in the presence of
AlCl3/EtSH in CH2Cl2, compound 3a was smoothly
demethylated and cyclized to deliver a tetracyclic prod-
Scheme 3. Reagents and conditions: (a) AlCl3/EtSH, CH2Cl2, 0 ꢁC to
rt (84%); (b) H2/Pd–C (95%); (c) K2CO3, DMF, MeI (50%).

P. Sae-Lao et al. / Tetrahedron Letters 47 (2006) 345–348
347
3.67, 3.72, 3.82, 3.92 (4s, 12H, 4 · OCH3), 6.40 (s, 1H,
ArH), 6.52 (s, 1H, ArH), 6.60 (s, 1H, ArH); 13C NMR
(75 MHz, CDCl3): d 8.7, 20.2, 55.5, 55.8, 61.4, 61.7, 101.7,
107.7, 107.8, 116.9, 119.8, 121.7, 136.7, 139.2, 152.0, 157.7,
159.2, 159.6, 160.7, 163.59; IR (KBr): mmax 3422, 2933,
2845, 1717, 1656, 1595, 1467, 1131, 988 cmÀ1; MS (EI):
m/z (relative intensity) 385 ([M+H]+, 21), 384 (M+, 100),
341 (70), 325 (47). Anal. Calcd for C22H24O6: C, 68.74; H,
6.29%. Found: C, 68.93; H, 6.47%.
mercially available 2,4-dihydroxy-3,6-dimethyl benzoic
acid (6). Structure modification as well as the asymmet-
ric synthesis of racemosol and related compounds are
under investigation.
Acknowledgements
Financial support originated from the Postgraduate
Education and Research Program in Chemistry
(PERCH) and the Biodiversity Research and Training
Program (BRT). We are grateful to the Department of
Chemistry, Faculty of Science, Mahidol University,
and The Medicinal Chemistry and Natural Product
Laboratory at Chulabhorn Research Institute (CRI),
for research facilities.
10. (a) Hauser, F. M.; Rhee, R. P.; Prasanna, S.; Weinreb, S.
M.; Dodd, J. H. Synthesis 1980, 72–74; (b) Thasana, N.;
Ruchirawat, S. Synlett 2003, 1037–1039.
1
11. Compound 4: colourless solid; mp 120–122 ꢁC; H NMR
(300 MHz, CDCl3): d 2.13 (s, 3H, ArCH3), 3.12 (2dt, 4H,
J = 4.9, 5.5 Hz, 2 · CH2), 3.73, 3.82, 3.90, 3.95 (4s, 12H,
4 · OCH3), 6.48 (s, 1H, H-9), 6.80 (d, 1H, J = 8.8 Hz, H-
3), 7.81 (d, 1H, J = 8.8 Hz, H-4); 13C NMR (75 MHz,
CDCl3): d 8.7, 28.9, 32.8, 55.6, 55.7, 59.8, 62.1, 104.7,
109.8, 118.2, 126.8, 127.8, 133.1, 135.9, 138.5, 146.2, 155.2,
157.1, 159.9, 195.5; IR (KBr): mmax 3448, 2934, 1650, 1595,
1587, 1446, 1349, 1284, 1129, 1085 cmÀ1; MS (EI): m/z
(relative intensity) 343 ([M+H]+, 20), 342 (M+, 2), 327 (5),
326 (30), 325 (100). Anal. Calcd for C20H22O5: C, 70.16;
H, 6.48%. Found: C, 70.34; H, 6.12%.
References and notes
1. Kittakoop, P.; Kirtikara, K.; Tanticharoen, M.; The-
btaranonth, Y. Phytochemistry 2000, 55, 349–352.
2. Songarsa, S.; Rajviroongit, S.; Tang, D.; Hannongbua, S.;
Kirtikara, K.; Kittakoop, P. Chem. Biodiversity, in press.
3. (a) Anjaneyulu, A. S. R.; Reddy, A. V. R.; Reddy, D. S.
K.; Cameron, T. S.; Roe, S. P. Tetrahedron 1986, 42,
2417–2420; (b) Prabhakar, P.; Gandhidasan, R.; Raman,
V. N.; Krishnasamy, N. R.; Nanduri, S. Phytochemistry
1994, 36, 817–818; (c) Jain, R.; Alam, S.; Saxena, U.
Indian J. Chem., Sect. B 2002, 41, 1321–1322.
4. Maillard, M. P.; Iglesisas, M. C.; Saadou, M.; Evans, H.
S.; Hostettmann, K. Helv. Chim. Acta 1991, 74, 791–799.
5. (a) Budhram, S. R.; Palaniswamy, A. V.; Eisenbraun, J. E.
J. Org. Chem. 1986, 51, 1402–1406; (b) Anderson, L. C.;
Horton, J. W.; Walker, E. F.; Weiler, R. M. J. Am. Chem.
Soc. 1955, 77, 598–601; (c) Corey, J. E.; Behforouz, M.;
Ishiguro, M. J. Am. Chem. Soc. 1979, 101, 1608–1609.
6. (a) Leeper, F. J.; Staunton, J. J. Chem. Soc., Chem.
Commun. 1978, 406–407; (b) Evans, G. E.; Leeper, F. J.;
Murphy, J. A.; Staunton, J. J. Chem. Soc., Chem.
Commun. 1979, 205–206; (c) Leeper, F. J.; Staunton, J.
J. Chem. Soc., Chem. Commun. 1979, 206–207; (d) Dodd,
J. H.; Weinreb, S. M. Tetrahedron Lett. 1979, 38, 3593–
3596.
12. Compound 3a: viscous oil; 1H NMR (300 MHz, CDCl3): d
1.53 (s, 3H, CH3), 2.17 (s, 3H, ArCH3), 2.90–3.50 (m, 4H,
2 · CH2), 2.98, 3.15 (2d, 2H, J = 14.3 Hz, 2 · CH2), 3.80,
3.80, 3.85, 3.88 (4s, 12H, 4 · OCH3), 4.56, 4.68 (2s, 2H,
2 · CH), 6.45 (s, 1H, H-9), 6.80 (d, 1H, J = 9.0 Hz, H-3),
7.83 (d, 1H, J = 9.0 Hz, H-4); 13C NMR (75 MHz,
CDCl3): 9.5, 23.9, 25.1, 35.5, 53.0, 55.3, 55.4, 60.2, 61.9,
79.4, 79.4, 108.7, 108.7, 114.1, 117.8, 122.8, 128.8, 132.9,
137.6, 138.2, 142.6, 145.4, 150.9, 157.7; IR (neat): mmax
3446, 2935, 2834, 1735, 1598, 1486, 1282, 1220, 1128,
1090 cmÀ1; MS (EI): m/z (relative intensity) 398 (M+, 1),
380 (47), 374 (53), 349 (64), 343 (47), 342 (72), 136 (100).
Anal. Calcd for C24H30O5: C, 72.34; H, 7.59%. Found: C,
72.79; H, 7.84%.
13. Compound 10: yellow solid; mp 167–170 ꢁC; 1H NMR
(300 MHz, CDCl3): d 2.05 (s, 3H, ArCH3), 3.02 (d, 2H,
J = 10.1 Hz, CH2), 3.12 (d, 2H, J = 10.1 Hz, CH2), 3.70,
3.75, 3.78 (3s, 9H, 3 · OCH3), 6.20 (s, 1H, H-9), 6.82 (d,
1H, J = 8.8 Hz, ArH), 7.90 (d, 1H, J = 8.8 Hz, ArH),
14.55 (s, 1H, ArOH); 13C NMR (75 MHz, CDCl3): d 7.7,
25.2, 37.4, 55.4, 55.7, 60.9, 103.4, 109.7, 111.5, 114.1,
128.9, 132.8, 137.2, 143.8, 144.9, 155.8, 162.1, 165.4, 195.9;
IR (KBr): mmax 3448, 3089, 2919, 1607, 1582, 1488, 1413,
1144, 1090 cmÀ1; MS (EI): m/z (relative intensity) 329
([M+H]+, 28), 328 (M+, 100), 313 (13), 310 (26), 297 (14).
Anal. Calcd for C19H20O5: C, 69.50; H, 6.14%. Found: C,
69.41; H, 6.20%.
7. To a solution of 2,3-dimethoxybenzylalcohol (0.25 g,
1.48 mmol) in 10 mL of dry CH2Cl2 at 0 ꢁC was added
PBr3 (1.5 mL, 1.5 mmol). After stirring for 2 h, the
reaction was quenched with water and extracted with
CH2Cl2 (3 · 20 mL). The combined organic solution was
washed with saturated NaHCO3 and water, dried
(MgSO4), filtered and concentrated in vacuo. Chromato-
graphy on silica gel (hexanes) gave 7 as a colourless oil
(0.24 g, 71%).
14. Compound 11: white solid; mp 145–148 ꢁC; 1H NMR
(300 MHz, CDCl3): d 2.05 (s, 3H, ArCH3), 2.94–3.14 (m,
4H, 2 · CH2), 3.70, 3.80, 3.83 (3s, 9H, 3 · OCH3), 4.75 (s,
2H, OCH2), 6.40 (s, 1H, H-9), 6.78 (d, 1H, J = 8.8 Hz,
ArH), 7.19–7.35 (m, 5H, 4 · ArH), 7.70 (d, 1H,
J = 8.8 Hz, ArH); 13C NMR (75 MHz, CDCl3): d 9.0,
28.9, 32.8, 55.6, 55.7, 59.8, 76.3, 104.8, 109.9, 118.6, 126.8,
126.9, 127.6, 127.8, 128.0, 128.3, 128.5, 133.1, 135.9, 137.5,
138.5, 146.2, 155.2, 155.6, 159.9, 195.5; IR (KBr): mmax
1
8. Compound 5: viscous oil; H NMR (300 MHz, CDCl3): d
2.14 (s, 3H, ArCH3), 2.89 (m, 4H, 2 · CH2), 3.78, 3.81,
3.84, 3.89, 3.96 (5s, 15H, 5 · OCH3), 6.46 (s, 1H, H-5),
6.78 (m, 2H, ArH), 7.00 (t, 1H, J = 7.9 Hz, ArH); 13C
NMR (75 MHz, CDCl3): d 8.7, 32.1, 35.1, 52.1, 55.5, 55.6,
60.6, 61.8, 107.1, 110.3, 117.5, 120.7, 122.0, 123.8, 135.3,
138.6, 147.1, 152.7, 156.3, 159.3, 168.9; IR (neat): mmax
2998, 2942, 2835, 1727, 1602, 1583, 1481, 1268, 1224, 1152,
1010 cmÀ1; MS (EI): m/z (relative intensity) 375 ([M+H]+,
15), 374 (M+, 53), 343 (52), 342 (66), 327 (44), 324 (18),
136 (100). Anal. Calcd for C21H26O6: C, 67.36; H, 7.00%.
Found: C, 67.74; H, 6.89%.
3447, 2941, 1649, 1597, 1454, 1292, 1223, 1131, 1085 cmÀ1
;
MS (EI): m/z (relative intensity) 418 (M+, 19), 417 (17),
402 (25), 401 (100), 400 (21), 135 (41). Anal. Calcd for
C26H26O5: C, 74.62; H, 6.26%. Found: C, 74.95; H, 5.93%.
15. Compound 3b: viscous oil; 1H NMR (300 MHz, CDCl3): d
1.50 (s, 3H, CH3), 2.25 (s, 3H, ArCH3), 2.92–3.25 (m, 4H,
2 · CH2), 3.25, 3.65 (2d, 2H, J = 11.0 Hz, 2 · CH2), 3.78,
3.84, 3.87 (3s, 9H, 3 · OCH3), 4.52, 4.67 (2s, 2H, 2 · CH),
4.76 (d, 1H, J = 10.8 Hz, OCH2), 4.89 (d, 1H, J = 10.8 Hz,
9. Compound 9: white solid; mp 128–130 ꢁC; 1H NMR
(300 MHz, CDCl3): d 2.13, 2.23, 2.33 (3s, 9H, 3 · ArCH3),

348
P. Sae-Lao et al. / Tetrahedron Letters 47 (2006) 345–348
1
OCH2), 6.50 (s, 1H, H-9), 6.80 (d, 1H, J = 9.0 Hz, H-3),
7.38–7.56 (m, 5H, PhH), 7.86 (d, 1H, J = 9.0 Hz, H-4); 13
19. Compound 14: yellowish solid; mp 224–226 ꢁC; H NMR
(300 MHz, DMSO-d6): d 1.36 (s, 6H, 2 · gem-CH3), 1.91
(s, 3H, ArCH3), 2.84 (m, 4H, 2 · CH2), 5.50 (s, 1H, H-1),
6.14 (s, 1H, H-6), 6.56 (m, 2H, ArH), 8.20, 9.22, 9.30, (3s,
3H, 3 · ArOH); 13C NMR (75 MHz, DMSO-d6): d 8.6,
23.8, 26.6, 35.2, 74.6, 109.2, 109.3, 112.5, 113.0, 118.9,
127.9, 128.5, 132.2, 135.1, 136.1, 140.4, 144.8, 152.1, 154.8;
IR (KBr): mmax 3505, 3354, 3254, 2924, 1616, 1592, 1499,
1363, 1274, 1098, 810 cmÀ1; MS (EI): m/z (relative
intensity) 324 (M+, 9), 310 (22), 309 (100). Anal. Calcd
for C20H20O4: C, 74.06; H, 6.21%. Found: C, 73.82; H,
6.41%.
C
NMR (75 MHz, CDCl3): 9.7, 23.8, 25.5, 35.1, 53.2, 55.4,
55.5, 60.0, 76.3, 79.5, 108.8, 109.0, 114.1, 118.0, 122.3,
127.5, 128.0, 128.2, 128.4, 128.7, 128.8, 132.2, 136.0, 138.1,
138.5, 142.7, 145.8, 150.9, 155.9, 156.8; IR (neat): mmax
3387, 2935, 2832, 1597, 1480, 1274, 1124 cmÀ1; MS (EI):
m/z (relative intensity) 419 (59), 365 (48), 327 (95), 91
(100). Anal. Calcd for C30H34O5: C, 75.92; H, 7.22%.
Found: C, 75.89; H, 6.90%.
1
16. Compound 12: viscous oil; H NMR (300 MHz, CDCl3):
d 1.40 (s, 6H, 2 · gem-CH3), 2.00 (s, 3H, ArCH3), 3.00
(m, 4H, 2 · CH2) 3.70, 3.74, 3.80 (3s, 9H, 3 · OCH3),
5.52 (s, 1H, H-1), 6.11 (s, 1H, H-6), 6.62 (d, 1H,
J = 8.0 Hz, ArH), 7.00 (d, 1H, J = 8.4 Hz, ArH); 13C
NMR (75 MHz, CDCl3): d 8.3, 24.8, 26.8, 36.2, 55.6,
61.0, 74.9, 104.9, 109.5, 112.0, 114.6, 124.2, 129.8, 134.2,
135.1, 135.6, 136.3, 144.3, 152.2, 152.3, 157.1; IR (neat):
1
20. Compound 2: yellowish solid; mp 230–233 ꢁC; H NMR
(300 MHz, CDCl3 + acetone-d6): d 1.25 (s, 3H, gem-CH3),
1.45 (s, 3H, gem-CH3), 1.88 (dd, 1H, J = 13.0, 6.0 Hz, H-
1), 1.93 (s, 3H, ArCH3), 2.30 (t, 1H, J = 12.9, 12.6 Hz, H-
1), 2.82–3.25 (m, 4H, 2 · CH2), 4.45 (dd, 1H, J = 12.1,
5.9 Hz, H-12b), 5.22 (s, 1H, ArOH), 6.02 (s, 1H, H-6), 6.55
(d, 1H, J = 8.5 Hz, ArH), 6.65 (d, 1H, J = 8.5 Hz, ArH);
m
max 3008, 2961, 2929, 2855, 1597, 1492, 1465, 1359, 1283,
1270, 1135, 1088, 908 cmÀ1; MS (EI): m/z (relative
intensity) 366 (M+, 5), 365 (12), 352 (26), 351 (100), 321
(10). Anal. Calcd for C23H26O4: C, 75.38; H, 7.15%.
Found: C, 75.64; H, 7.11%.
C NMR (75 MHz, DMSO-d6): d 8.7, 22.9, 23.4, 30.6,
32.7, 34.8, 38.9, 73.7, 110.0, 110.2, 112.4, 114.8, 116.2,
130.2, 135.8, 137.4, 142.3, 143.8, 153.3, 154.4; IR (KBr):
13
m
max 3404, 2972, 2927, 1596, 1578, 1501, 1451, 1411, 1365,
17. Compound 13: white solid; mp 148–150 ꢁC; 1H NMR
(300 MHz, CDCl3): d 1.34 (s, 3H, gem-CH3), 1.60 (s, 3H,
gem-CH3), 2.02 (dd, 1H, J = 12.8, 6.0 Hz, H-1), 2.02
(s, 3H, ArCH3), 2.43 (t, 1H, J = 12.8 Hz, H-1), 2.93–
3.47 (m, 4H, 2 · CH2), 3.74, 3.85, 3.86 (3s, 9H, 3 · OCH3),
4.58 (dd, 1H, J = 12.6, 5.9 Hz, H-12b), 6.14 (s, 1H, H-6),
6.72 (d, 1H, J = 8.7 Hz, ArH), 7.04 (d, 1H, J = 8.7 Hz,
ArH); 13C NMR (75 MHz, CDCl3): d 8.3, 22.7, 23.2, 30.5,
32.2, 35.2, 38.4, 55.3, 55.6, 61.1, 73.1, 105.1, 109.2, 111.7,
114.8, 120.3, 135.6, 136.2, 136.8, 145.5, 151.3, 152.3, 156.2;
IR (KBr): mmax 3448, 2970, 2936, 2836, 1601, 1578, 1490,
1466, 1273, 1129, 1078, 810 cmÀ1; 369 ([M+H]+, 17), 368
(M+, 65), 353 (24), 351 (20), 313 (32), 312 (100), 283 (79).
Anal. Calcd for C23H28O4: C, 74.97; H, 7.66%. Found:
C, 74.69; H, 7.43%.
1283, 1164, 1131, 1104, 1084, 1009, 908 cmÀ1; MS (EI):
m/z (relative intensity) 327 ([M+H]+, 9), 326 (M+, 38), 311
(11), 309 (16), 271 (31), 270 (100). Anal. Calcd for
C20H22O4: C, 73.60; H, 6.79%. Found: C, 73.44; H, 7.00%.
1
21. Compound 1: yellowish solid; mp 129–132 ꢁC; H NMR
(300 MHz, CDCl3): d 1.25 (s, 3H, gem-CH3), 1.45 (s, 3H,
gem-CH3), 1.89 (dd, 1H, J = 13.0, 6.0 Hz, H-1), 1.93
(s, 3H, ArCH3), 2.33 (t, 1H, J = 12.9 Hz, H-1), 2.80–3.30
(m, 4H, 2 · CH2), 3.79 (s, 3H, OCH3), 4.47 (dd, 1H, J =
12.1, 5.9 Hz, H-12b), 4.43 and 5.63 (2s, 2H, 2 · ArOH),
6.01 (s, 1H, H-6), 6.58 (d, 1H, J = 8.6 Hz, ArH), 6.75 (d,
1H, J = 8.5 Hz, ArH); 13C NMR (75 MHz, CDCl3): d
8.2, 22.1, 23.3, 30.3, 32.1, 34.0, 38.1, 55.9, 73.3, 107.4,
109.1, 109.3, 114.6, 115.6, 128.4, 135.9, 137.0, 141.7, 145.0,
152.1, 152.4; IR (KBr): mmax 3423, 2973, 2928, 1594, 1492,
1459, 1442, 1273, 1107, 1089 cmÀ1; 341 ([M+H]+, 12), 340
(M+, 53), 323 (16), 285 (28), 284 (100). Anal. Calcd for
C21H24O4: C, 74.09; H, 7.11. Found: C, 74.11; H, 7.40.
18. Gopalakrishnan, G.; Kasinath, V.; Pradeep, S. N. D.;
Thirumurugan, S. S.; Raj, S.; Shanmugan, G. Molecules
2000, 5, 880–885.