Synthesis of isoprenyl flavonoids: (+)-Denticulaflavonol, macarangin, and isomacarangin

Article abstract of DOI:10.1055/s-2008-1072734

A straightforward synthesis of two natural C-alkylflavonoids: macarangin, isomacarangin, and the enantiomer of the natural (-)-denticulaflavonol, has been described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072734

LETTER
1149
Synthesis of Isoprenyl Flavonoids: (+)-Denticulaflavonol, Macarangin, and
Isomacarangin
a
a
a
a
a
a
S
P
ynthesis of Is
i
opreny
l
l
F
lavo
a
noids r Basabe,* Mónica de Román, David Diez, Isidro S. Marcos, Olga Bodero, Araceli Blanco,
b
a
Faustino Mollinedo, Julio G. Urones
a
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5,
7008 Salamanca, Spain
3
Fax +34(923)294574; E-mail: pbb@usal.es
Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
b
Received 9 November 2007
3'
4'
OH
Abstract: A straightforward synthesis of two natural C-alkylfla-
vonoids: macarangin, isomacarangin, and the enantiomer of the nat-
ural (–)-denticulaflavonol, has been described.
2'
8
HO
7
9
O
O
2
5'
6'
6
3
Key words: isoprenyl flavonoids, denticulaflavonol, macarangin,
isomacarangin, antitumour activity
15''
10
5
4
OH
16''
1
4'' OH
13''
11''
12''
2
0''
(+)-denticulaflavonol (1)
1
''
A recent approach to bioactive compounds has been de-
9''
17''
1
2''
''
veloped consisting of products, of natural hybrids, or
10''
8''
2
3
4''
bioorganometallic natural product hybrids. As terpenoids
6
''
H
9'' 18''
are known to possess a wide variety of biological
1
3
4
properties and flavonoids possess antioxidant activity,
5
act as anticarcinogens, and express beneficial effects on Figure 1
inflammatory and immunomodulatory systems;6 it
seemed promising to study natural and synthetic com-
pounds that could be considered hybrids of both these
types of natural products, due to their biological activities.
3'
OH
2'
5''
4''
HO
9
O
2
3'
In the latter years a library of natural and synthetic fla-
vonoids has been screened to test their effect on cell pro-
liferation and apoptosis in a human colon cell line (HT-
OH
1
''
2'
1
''
7
10
OH
HO
9
O
O
2
4''
OH
O
2
9). Regarding structural modification of flavonoids, C-
6
5''
10
OH
8
isoprenylation is the most effective modification.
macarangin (2)
OH
7''
In this area, plants of the genus Macaranga have yielded
isopentenylated flavones. Thus, denticulaflavonol, the
first flavonoid with a labdane diterpene moiety, was iso-
isomacarangin (3)
Figure 2
9
lated from Macaranga denticulate; although its absolute
configuration has not been established.
confirm their structures and to carry out antitumour stud-
ies with them and their derivatives.
Besides denticulaflavonol, a geranyl-substituted flavonol,
macarangin (2), has been isolated from Macaranga
All the target structures are flavonol derivatives of
kaempferol that show a diterpenic (denticulaflavonol) or
monoterpenic moiety (macarangin and isomacarangin) in
the A ring of the flavonoid.
9
10
denticulata and Macaranga vedeliana; whereas iso-
macarangin (3), the isomer with the geranyl substituent in
C-8, was isolated from Macaranga schweinfurthii11
(Figure 2).
The required diterpenic framework of denticulaflavonol
Macarangin (2) showed a pronounced antioxidant activi-
was obtained from sclareol (4), as shown in Scheme 1.
9
ty. To the best of our knowledge, the biological activity
12
Sclareol was acetylated in quantitative yield with acetyl
chloride and N,N-dimethylaniline affording the diacetyl
derivative; the isomerisation of which with bis(acetoni-
of denticulaflavonol has not been studied, perhaps due to
the scarce amount isolated.
1
3
In this work we planned the synthesis of denticulaflavonol
trile)palladium (II) chloride and elimination of the ace-
toxy group at C-81 gave the monoacetyl derivative 5.
The hydrolysis of the acetoxy group of 5 gave alcohol 6 in
quantitative yield. Subsequent treatment with CBr and
2b
14
(
1), macarangin (2), and isomacarangin (3) in order to
SYNLETT 2008, No. 8, pp 1149–1152
x
x.
x
x.
2
0
0
8
4
15
Advanced online publication: 16.04.2008
DOI: 10.1055/s-2008-1072734; Art ID: D36807ST
Ph P led to the corresponding bromoderivative 7, also in
3
quantitative yield.
©
Georg Thieme Verlag Stuttgart · New York

1
150
P. Basabe et al.
LETTER
CH2OAc
CH2OH
2
CH Br
HO
i
ii
iii
OH
H
H
H
H
4
5
6
7
Scheme 1 Reagents and conditions: (i) a) AcCl, N,N-dimethylaniline, CH Cl , r.t., 24 h, 99%; b) PdCl (MeCN) , THF, r.t., 1 h, 92%; c) SiO ,
2
2
2
2
2
1
00 °C, 1 h, 90%; (ii) K CO , MeOH 3%, r.t., 6 h, 99%; (iii) CBr , Ph P, CH Cl , 0 °C, 10 min, 99%.
2 3 4 3 2 2
Alkylation of the w-benzoyloxyphloroacetophenone 9 from 10, 14 and 15 from 11. Hydrolysis of the benzoate
with the diterpenic bromide 7 or with geranyl bromide (8) groups gave the 4¢-methyl derivatives (purified by column
gave, after protection of the hydroxy groups with p-meth- chromatography) 16 (20%), 17 (14%), 18 (16%); and 19
oxybenzoyl chloride, the key intermediates 10 (50%) and (10%; yields for the three steps). Treatment of 16 with n-
1
7
1
1 (56%), respectively. With these compounds in hand, BuSLi in HMPA at 110 °C led to a compound (in 70%
the synthesis of the flavonoid nucleus was achieved by a yield), whose spectroscopic properties18 are identical to
Baker–Venkataraman rearrangement with NaH to the the natural compound (–)-denticulaflavonol. Neverthe-
1
6
corresponding b-diketones (Scheme 2). These b-dike- less, with regard to the signs of optical rotation of the
1
9
tones were directly submitted, without isolation, to treat- natural and synthesised compounds, it can be concluded
ment with acetic acid to give the cyclised compounds, that the natural compound is the enantiomer of 1
which are the C-6- or C-8-alkylated flavonoids: 12 and 13 (Figure 1) By applying the same reaction conditions to 17,
CH2Br
OMe
HO
OH
O
PMBzO
R
OPMBz
i
ii
PMBzO
R1
OH
O
7
OBz
OBz
H
OBz
+
PMBzO
O
OH
PMBzO
O
iii
9
R1
0 D
1 G
CH2Br
1
1
8
OH
OMe
iv
OMe
R2
R2
R2
HO
R1
O
O
HO
R1
O
PMBzO
R1
O
O
v
OH
OH
OBz
OH
OH
O
PMBzO
R1 R2
R1 R2
R1 R2
1
D
H
G
H
H
D
H
G
16
17
18
19
D
H
G
H
H
D
H
G
12
13
14
15
D
H
G
H
H
D
H
G
2
0
2
3
=
D
=
G
H
Scheme 2 Reagents and conditions: (i) a) K CO , acetone, 74 °C, 3 h; b) p-methoxybenzoyl chloride, K CO , acetone, 74 °C, 3 h, (10, 50%;
2
3
2
3
1
1, 56%); (ii) a) NaH, THF, 40 °C, 6 h; (iii) AcOH, 100 °C, 5 h; (iv) BuNH , benzene, 95 °C, 6 h, (16, 20% and 17, 14% from 10; 18, 16% and
2
19, 10% from 11); (v) n-BuSLi, HMPA, 110 °C, 4 h, (1, 70%; 20, 62%; 2, 65%; 3, 58%).
Synlett 2008, No. 8, 1149–1152 © Thieme Stuttgart · New York

LETTER
Synthesis of Isoprenyl Flavonoids
1151
compound 20 was obtained in 62% yield. In the same
way, treatment of 18 and 19 led to compounds 2 (65%)
and 3 (58%), which are identical to the natural products
macarangin and isomacarangin, respectively. The anti-
tumour activity studies for compounds 1–3 and 20 have
been carried out and will be published elsewhere.
(14) Basabe, P.; Diego, A.; Delgado, S.; Díez, D.; Marcos, I. S.;
Urones, J. G. Tetrahedron 2003, 59, 9173.
(
15) (a) Kang, S. H.; Hong, C. Y. Tetrahedron Lett. 1987, 28,
75. (b) Khan, T. J.; Eilers, M.; Guo, Z.; Ksebati, M. B.;
6
2
0
21
Simon, M.; Scholten, J. D.; Smith, S. O.; Gibbs, R. A. J. Am.
Chem. Soc. 2000, 122, 7153.
16) (a) Thasana, N.; Ruchirawat, S. Tetrahedron Lett. 2002, 43,
(
4
515; and references cited therein. (b) Krohn, K.; Vidal, A.;
In conclusion, we have accomplished the synthesis of two
natural products: macarangin (2) and isomacarangin (3).
We have also synthesised (+)-denticulaflavonol, the enan-
tiomer of the natural product. The absolute configuration
of (–)-denticulaflavonol has been established as well.
Vitz, J.; Westermann, B.; Abbas, M.; Green, I. Tetrahedron:
Asymmetry 2006, 17, 3051. (c) Pinto, D. C. G. A.; Silva, A.
M. S.; Cavaleiro, J. A. S. Synlett 2007, 1897.
(
(
17) Katoh, T.; Nakatani, M.; Shikita, S.; Sampe, R.; Ishiwata,
A.; Ohmori, O.; Nakamura, M.; Terashima, S. Org. Lett.
2001, 3, 2701; and references cited therein.
18) Physical Data of (+)-Denticulaflavonol (1)
Acknowledgment
22
[
1
a]D +15.0 (c 0.10, CHCl ). IR (film): 3392, 2921, 2850,
3
–
1 1
648, 1609, 1463, 1367, 1261, 1178, 1090 cm . H NMR
The authors are grateful to Dr. A. M. Lithgow and Dr. C. Raposo for
the NMR and mass spectra, respectively. The authors also thank the
FSE, CICYT (CTQ2005-04406), Junta de Castilla y León
(
700 MHz, CDCl ): d = 12.10 (1 H, s, 5-OH), 8.12 (2 H, d,
3
J = 8.8 Hz, H-2¢, H-6¢), 6.96 (2 H, d, J = 8.8 Hz, H-3¢, H-5¢),
6
.56 (1 H, s, 3-OH), 6.47 (1 H, s, H-8), 6.16 (1 H, s, 7-OH),
(
SA063A07) for financial support and the latter for a doctoral fel-
5
.27 (1 H, t, J = 7.6 Hz, H-14¢¢), 5.07 (1 H, s, 4¢-OH), 4.80
lowship to M.deR., O.B. and A.B.
(
1 H, s, H -17¢¢), 4.48 (1 H, s, H -17¢¢), 3.48 (2 H, d, J = 7.6
A
B
Hz, H-15¢¢), 2.35 (1 H, m, H -7¢¢), 2.19 (1 H, m, H -12¢¢),
1
1
A
A
.90 (1 H, m, H -7¢¢), 1.87 (1 H, m, H -12¢¢), 1.84 (3 H, s, H-
6¢¢), 1.72 (1 H, m, H -1¢¢), 1.69 (1 H, m, H -6¢¢), 1.60 (1 H,
References and Notes
B
B
A
A
(
(
(
1) Tietze, L. F.; Bell, H. P.; Chandrasekhar, S. Angew. Chem.
m, H -11¢¢), 1.56 (1 H, m, H -2¢¢), 1.55 (1 H, m, H-9¢¢), 1.47
A
A
Int. Ed. 2003, 42, 3996.
2) Sierra, M. A.; Torres, M. R.; de la Torre, M. C.; Álvaro, E.
J. Org. Chem. 2007, 72, 4213.
(1 H, m, H -2¢¢), 1.44 (1 H, m, H -11¢¢), 1.38 (1 H, m, H -
B
B
A
3¢¢), 1.30 (1 H, m, H -6¢¢), 1.15 (1 H, m, H -3¢¢), 1.05 (1 H,
B
B
m, H-5¢¢), 0.98 (1 H, m, H -1¢¢), 0.85 (3 H, s, H-18¢¢), 0.78 (3
B
1
3
3) (a) Singh, M.; Pal, M.; Sharma, R. P. Planta Medica 1999,
H, s, H-19¢¢), 0.66 (3 H, s, H-20¢¢) ppm. C NMR (175 MHz,
65, 2. (b) Cichewicz, R. H.; Kenyon, V. A.; Whitman, S.;
CDCl ): d = 175.3 (C-4), 161.7 (C-7), 157.7 (C-5), 157.2 (C-
3
Morales, N. M.; Arguello, J. F.; Holman, T. R.; Crews, P. J.
Am. Chem. Soc. 2004, 126, 14910. (c) Nakagawa-Goto, K.;
Yamanda, K.; Nakamura, S.; Chen, T.-H.; Chiang, P.-C.;
Bastow, K. F.; Wang, S.-C.; Spohn, B.; Hung, M.-C.; Lee,
F.-Y.; Lee, F.-C.; Lee, K.-H. Bioorg. Med. Chem. Lett. 2007,
4’), 155.0 (C-9), 148.5 (C-8¢¢), 145.3 (C-2), 140.8 (C-13¢¢),
135.4 (C-3), 129.6 (C-2¢, C-6¢), 123.6 (C-1¢), 120.5 (C-14¢¢),
115.6 (C-3¢, C-5¢), 109.3 (C-6), 106.2 (C-17¢¢), 103.5 (C-10),
94.3 (C-8), 56.0 (C-9¢¢), 55.5 (C-5¢¢), 42.1 (C-3¢¢), 39.6 (C-
10¢¢), 39.0 (C-1¢¢), 38.5 (C-12¢¢), 38.3 (C-7¢¢), 33.6 (C-18¢¢),
33.5 (C-4¢¢), 24.4 (C-6¢¢), 21.7 (C-11¢¢, C-19¢¢), 21.4 (C-15¢¢),
19.4 (C-2¢¢), 16.4 (C-16¢¢), 14.5 (C-20¢¢) ppm. TOFMS: m/z
calcd for C H O Na: 581.2874; found: 581.2903.
17, 5204.
(
4) (a) Pietta, P. G. J. Nat. Prod. 2000, 63, 1035. (b) Nijveldt,
R. J.; van Nood, E.; van Hoorn, D. E. C.; Boelens, P. G.;
van Norren, K.; van Leeuwen, P. A. M. Am. J. Clin. Nutr.
3
5
42
6
2
6
(19) The authors quote [a]D –131.8 (c 0.05, CHCl ) for the
3
9
2
001, 74, 418. (c) Miliauskas, G.; van Beek, T. A.;
natural (–)-denticulaflavonol. Compound 1 has a value of
2
2
de Waard, P.; Venskutonis, R. P.; Sudhölter, E. J. R. J. Nat.
Prod. 2005, 68, 168. (d) Šmejkal, K.; Grycová, L.; Marek,
R.; Lemière, F.; Jankovská, D.; Forejtníková, H.; Vančo, J.;
Suchý, V. J. Nat. Prod. 2007, 70, 1244.
[a]D +15.0 (c 0.10, CHCl ) and some derivatives have
22
3
similar values and the same sign, for instance 16 [a] +13.6
D
2
2
(c 0.14, CHCl ), 17 [a] +14.4 (c 0.09, CHCl ), and 20
3
D
3
2
2
[a]D +12.0 (c 0.65, CHCl ), so it can be concluded that 1 is
3
(
(
5) Yanling, L.; Fang, H.; Wenfang, X. Mini-Rev. Med. Chem.
the enantiomer of the natural (–)-denticulaflavonol. The
difference in the values could be attributed to the small
amount of the natural compound isolated.
2
007, 7, 663.
6) (a) Harbone, J. B.; Williams, C. A. Phytochemistry 2000, 55,
81. (b) Nakatsuka, T.; Tomimori, Y.; Fukuda, Y.; Nukaya,
4
(20) Spectroscopic Data of Macarangin (2)
H. Bioorg. Med. Chem. Lett. 2004, 14, 3201.
IR (film): 3380, 2925, 1650, 1608, 1555, 1513, 1484, 1444,
–
1 1
(
7) Daskiewicz, J.; Depeint, F.; Viornery, L.; Bayet, C.; Comte-
Sarrazin, G.; Comte, G.; Gee, M. G.; Johnson, I. T.; Ndjoko,
K.; Hostettmann, K.; Barron, D. J. Med. Chem. 2005, 48,
1371, 1315, 1256, 1181, 1087, 1031 cm . H NMR (400
MHz, CDCl ): d = 12.10 (1 H, s, 5-OH), 8.13 (2 H, d, J = 9.0
3
Hz, H-2¢, H-6¢), 6.97 (2 H, d, J = 9.0 Hz, H-3¢, H-5¢), 6.57 (1
H, s, 3-OH), 6.48 (1 H, s, H-8), 6.19 (1 H, s, 7-OH), 5.30 (1
H, t, J = 7.0 Hz, H-2¢¢), 5.11 (1 H, s, 4¢-OH), 5.06 (1 H, m,
H-7¢¢), 3.49 (2 H, d, J = 7.0 Hz, H-1¢¢), 2.10 (4 H, s, H-5¢¢, H-
6¢¢), 1.84 (3 H, s, H-4¢¢), 1.68 (3 H, s, H-10¢¢), 1.60 (3 H, s,
2790.
(
(
8) Comte, G.; Daskiewicz, J.; Bayet, C.; Conseil, G.; Viornery-
Vanier, A.; Dumontet, C.; Di Pietro, A.; Barron, D. J. Med.
Chem. 2001, 44, 763.
9) Sutthivaiyakit, S.; Unganont, S.; Sutthivaiyakit, P.;
Suksamrarn, A. Tetrahedron 2002, 58, 3619.
10) Hnawia, E.; Thoison, O.; Guéritte-Voegelein, F.; Bourret,
D.; Sévenet, T. Phytochemistry 1990, 29, 2367.
11) Beutler, J. A.; McCall, K. L.; Boyd, M. R. Nat. Prod. Lett.
1
3
H-9¢¢) ppm. C NMR (100 MHz, CDCl ): d = 175.2 (C-4),
3
161.7 (C-7), 158.0 (C-5), 157.4 (C-4¢), 155.0 (C-9), 145.5
(C-2), 140.0 (C-3¢¢), 132.2 (C-3), 132.1 (C-8¢¢), 129.6 (C-2¢,
C-6¢), 123.6 (C-1¢), 123.3 (C-7¢¢), 120.9 (C-2¢¢), 115.3 (C-3¢,
C-5¢), 109.2 (C-6), 103.8 (C-10), 94.4 (C-8), 39.6 (C-5¢¢),
25.6 (C-10¢¢), 26.4 (C-6¢¢), 21.4 (C-1¢¢), 17.6 (C-9¢¢), 16.2 (C-
4¢¢) ppm. TOFMS: m/z calcd for C H O Na: 445.1659;
(
(
(
1
999, 13, 29.
12) (a) Ruzicka, L.; Janot, M. M. Helv. Chim. Acta 1931, 14,
45. (b) Urones, J. G.; Marcos, I. S.; Basabe, P.; Gomez, A.;
2
5
26
6
6
found: 445.1639.
Estrella, A.; Lithgow, A. M. Nat. Prod. Lett. 1994, 5, 217.
(21) Spectroscopic Data of Isomacarangin (3)
(
13) Overman, L. E.; Knoll, F. M. Tetrahedron Lett. 1979, 4, 321.
IR (film): 3388, 2918, 1648, 1608, 1561, 1509, 1438, 1374,
Synlett 2008, No. 8, 1149–1152 © Thieme Stuttgart · New York

1
152
P. Basabe et al.
315, 1241, 1176, 1114 cm . H NMR (400 MHz, CDCl ):
LETTER
–
1 1
1
NMR (100 MHz, CDCl ): d = 175.5 (C-4), 161.0 (C-7),
159.0 (C-5), 157.4 (C-4¢), 153.8 (C-9), 145.4 (C-2), 139.4
(C-3¢¢), 132.2 (C-3), 132.1 (C-8¢¢), 129.9 (C-2¢, C-6¢), 123.6
(C-1¢, C-7¢¢), 121.0 (C-2¢¢), 115.7 (C-3¢, C-5¢), 105.0 (C-8),
103.8 (C-10), 99.2 (C-6), 39.6 (C-5¢¢), 26.5 (C-6¢¢), 25.6 (C-
10¢¢), 21.8 (C-1¢¢), 17.6 (C-9¢¢), 16.3 (C-4¢¢) ppm. TOFMS:
m/z calcd for C H O : 421.1616; found: 421.1642.
3
3
d = 11.74 (1 H, s, 5-OH), 8.12 (2 H, d, J = 8.9 Hz, H-2¢, H-
6
6
¢), 6.98 (2 H, d, J = 8.9 Hz, H-3¢, H-5¢), 6.61 (1 H, s, 3-OH),
.32 (1 H, s, H-6), 6.14 (1 H, s, 7-OH), 5.31 (1 H, t, J = 6.9
Hz, H-2¢¢), 5.08 (1 H, s, 4¢-OH), 5.04 (1 H, m, H-7¢¢), 3.62 (2
H, d, J = 6.9 Hz, H-1¢¢), 2.09 (4 H, s, H-5¢¢, H-6¢¢), 1.85 (3 H,
1
3
s, H-4¢¢), 1.65 (3 H, s, H-10¢¢), 1.57 (3 H, s, H-9¢¢) ppm.
C
2
5
25
6
Synlett 2008, No. 8, 1149–1152 © Thieme Stuttgart · New York

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