New syntheses of dalbergichromene and dalbergin from vanillin via neoflavene intermediate

Article abstract of DOI:10.1016/j.tetlet.2007.01.117

In this Letter, naturally occurring dalbergichromene and dalbergin were synthesized from a common neoflavene intermediate, which was derived from vanillin. The giving neoflavene intermediate was debenzylated with AlCl₃ to yield dalbergichromene in 39% total yield, and it was oxidized by DDQ, and subsequently debenzylated by Pd(OH)₂/C and cyclohexene in refluxing ethanol to give dalbergin in 31% total yield.

Full text of DOI:10.1016/j.tetlet.2007.01.117

Tetrahedron Letters 48 (2007) 2139–2141
New syntheses of dalbergichromene and dalbergin from
vanillin via neoflavene intermediate
Sie-Rong Li,a Liang-Yeu Chen,a Jui-Chi Tsai,a Jing-Yu Tzeng,a
Ian-Lih Tsaia and Eng-Chi Wangb,*
aInstitute of Pharmaceutical Sciences, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
bFaculty of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan
Received 11 December 2006; revised 15 January 2007; accepted 19 January 2007
Available online 26 January 2007
Abstract—In this Letter, naturally occurring dalbergichromene and dalbergin were synthesized from a common neoflavene inter-
mediate, which was derived from vanillin. The giving neoflavene intermediate was debenzylated with AlCl3 to yield dalbergichromene
in 39% total yield, and it was oxidized by DDQ, and subsequently debenzylated by Pd(OH)2/C and cyclohexene in refluxing ethanol
to give dalbergin in 31% total yield.
Ó 2007 Elsevier Ltd. All rights reserved.
Plant Dalbergia species in China are known to be
applied in traditional medicine as a remedy for blood
disorders, ischemia, and inflammation.1 Dalbergichrom-
ene, firstly isolated from the stembark of Dalbergia sis-
soo2 and Dalbergia latifolia,3 belongs to the neoflavene
family. Moreover, Dalbergin isolated from Dalbergia
odorifera,1,4 belongs to neoflavonoids, and was investi-
gated to have tumor-specific cytotoxicity.5 Neoflavenes
attract the attention of chemists because it was not only
found to have various biological activities,6 but also can
be converted into other biological active coumarins.7 In
addition, neoflavenes can be transferred into chroman-
3-ones which were the important intermediates for
various biological and therapeutic agents.8,9 Up to
date, various strategies to deal with the syntheses of
neoflavenes including the coupling reaction of 4-
trifluoromethylsulfonyloxy-2H-chromenes with aryl-
boronic acids,10 a coupling reaction of the ligand with
aryllead triacetates,11 and so on12 have been reported.
However, there is no synthetic method for dalbergi-
chromene disclosed. For the biological and chemical
interest, we design a rational and simple synthetic strat-
egy for both dalbergichromene (8) and dalbergin (11)
through a common neoflavene intermediate 7, which
was prepared from vanillin via 6 steps. In addition,
dihydrodalbergichromene (9) and O-benzyldalbergin
(10) were also obtained in good yield, respectively
(Scheme 1).
As a general procedure, vanillin (1) was treated with
benzyl bromide to provide 2 in 98% yield which was sub-
sequently oxidized with m-CPBA to give 3 in yield of
92%.13 Followed by the reaction with allyl bromide, 4
was given in yield of 98%. Subsequently, 4 was reacted
with benzoyl chloride in the presence of zinc oxide at
room temperature to afford 5 in yield of 61%. Com-
pound 5 was allowed to react with methylene triphenyl-
phosphine to undergo the Wittig reaction to give 6 in
yield of 88%. Then, compound 6 was reacted with
Grubbs’ catalyst (II) to undergo the ring-closing metath-
esis, resulting in the formation of neoflavene 7 in yield of
96% as the key intermediate,14 and which was treated
with AlCl3 to undergo O-debenzylation to give dalbergi-
1
chromene (8) in 85% yield. The H NMR and other
spectroscopic data reported for 8 either from the natural
products2 or semi-synthesis15 were comparable and
coincident with our synthetic one.16 The reaction of
compound 7 with cyclohexene and Pd(OH)2/C in reflux-
ing ethanol gave dihydrodalbergichromene (9)17 in yield
of 95% via O-debenzylation and reduction. Moreover,
the reaction of compound 7 with DDQ in dioxane to
undergo allylic oxidation afforded O-benzyldalbergin
10 in 78% yield.18 After debenzylation of 10
with Pd(OH)2/C and cyclohexene in refluxing ethanol,
Keywords: Neoflavene; Neoflavonoid; Dalbergichromene; Dihydrodal-
bergichromene; Dalbergin.
*
Corresponding author. Fax: +886 7 3125339; e-mail: enchwa@
kmu.edu.tw
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.117

2140
S.-R. Li et al. / Tetrahedron Letters 48 (2007) 2139–2141
iv
CH3O
BnO
OH
CH3O
BnO
O
CH3O
BnO
CHO
CH3O
HO
CHO
iii
i
ii
4
3
2
1
CH3O
O
CH3O
O
CH3O
BnO
O
O
CH3O
BnO
O
vii
vi
v
C6H5
C6H5
HO
BnO
ix
C6H5
C6H5
5
7
viii
8
6
CH3O
HO
O
CH3O
HO
O
O
CH3O
BnO
O
O
x
C6H5
C6H5
C6H5
9
11
10
Scheme 1. Synthesis of dalbergichromene (8), dihydrodalbergichromene (9), O-benzyldalbergin (10), and dalbergin (11). Reagents and conditions:
(i) C6H5CH2Br, K2CO3, acetone, reflux 5 h, 98%; (ii) m-CPBA, CH2Cl2, 12 h, 6 N NaOH–MeOH, 3 h, HCl–H2O, 92%; (iii) allyl bromide, K2CO3,
acetone, reflux, 8 h, 98%; (iv) C6H5COCl, ZnO, rt, 61%; (v) Ph3P+CH3BrÀ, tert-BuOÀK+, 88%; (vi) Grubbs’ cat. (II), CH2Cl2, 96%; (vii) AlCl3,
CH2Cl2, 85%; (viii) Pd(OH)2/C, cyclohexene, EtOH, reflux, 95%; (ix) DDQ, dioxane, 77%; (x) Pd(OH)2/C, cyclohexene, EtOH, reflux, 87%.
dalbergin (11)19 with spectral data identical to that
10. Eguchi, T.; Hoshino, Y.; Ayame, A. Bull. Chem. Soc. Jpn.
reported,1 was produced in 87% yield.
2002, 75, 581–585.
11. Donnelly, D. M. X.; Finet, J. P.; Guiry, P. J.; Nesbitt, K.
Tetrahedron 2001, 57, 413–423.
In conclusion, besides we have disclosed the first and an
12. Pastine, S. J.; Youn, S. W.; Sames, D. Tetrahedron 2003,
efficient method to prepare the naturally occurring dal-
59, 8859–8868.
bergichromene (8) in 39% total yield, the other naturally
13. (a) del Carmen Cruz, M.; Tamariz, J. Tetrahedron 2005,
occurring compound dalbergin (11) was also prepared
from the same common neoflavene (7) intermediate in
31% total yield.
61, 10061–10072; (b) da Silva, A. J. M.; Melo, P. A.; Silva,
N. M. V.; Brito, F. V.; Buarque, C. D.; de Souza, D. V. V.;
Rodrigues, P.; Pocas, E. S. C.; Noel, F.; Albuquerque, E.
X.; Costa, P. R. R. Bioorg. Med. Chem. Lett. 2001, 11,
283–286.
14. Synthesis of 7: A solution of 6 (0.33 g, 0.89 mmol) in
CH2Cl2 (60 mL) was stirred and Grubbs’ catalyst (II)
(0.05 g, 0.06 mmol) was added at rt under dry argon. The
resulting mixture was continually stirred for 8 h. After
work-up as general procedure, and chromatographic
purification process (silica-gel, EtOAc–n-hexane = 1:15),
pure 7 (0.29 g, 96%) was given as colorless liquid, Rf 0.35
(ethyl acetate–n-hexane = 1:10); UV (CH2Cl2) 211, 234,
320 nm; IR (KBr) 2924, 2352, 1612, 1503, 1454, 1379,
Acknowledgments
We are grateful to the NSC (Taiwan) for financial sup-
port. We are also thankful to Professor Hiroki Taka-
hata, Tohoku Pharmaceutical University, Japan, for
his advice and encouragement.
1
1271, 1193, 1017, 808, 747 cmÀ1; H NMR (CDCl3, 200
References and notes
MHz) d 3.85 (s, 3H, OCH3), 4.74 (d, J = 4.0 Hz, 2H, H-2),
4.94 (s, 2H, CH2C6H5), 5.63 (t, 1H, J = 4.0 Hz, H-3), 6.53
(s, 1H, ArH), 6.56 (s, 1H, ArH), 7.16 (m, 2H, ArH), 7.28
(m, 8H, ArH); 13C NMR (CDCl3, 50 MHz) d 55.94
(OCH3), 65.26 (C-2), 71.84 (OCH2C6H5), 100.93, 113.36,
115.42, 117.0, 127.45, 127,56, 127.61, 128.32, 136.93,
137.20, 138.12, 141.79, 149.94, 150.70; EI-MS (70 eV)
m/z (intensity), 344 (M+, 22), 281 (38), 254 (18), 253
(M+À91, 100), 249 (23), 221 (22), 165 (26), 115 (14);
HRMS calcd for C23H20O3: 344.1412. Found: 344.1413.
15. Jurd, L.; Rottman, J. N. Tetrahedron 1978, 27, 57–62.
16. Dalbergichromene 8 was obtained as a colorless crystal,
mp 99–101 °C (petroleum ether) [reported,2 mp 99–
100 °C], Rf 0.36 (EtOAc–n-hexane = 1:4), 1H NMR
(CDCl3, 400 MHz) d 3.86 (s, 3H, OCH3), 4.76 (d,
J = 4.0 Hz, 2H, H-2), 5.21 (s, 1H, OH), 5.69 (t, J =
4.0 Hz, 1H, H-3), 6.51 (s, 1H, ArH), 6.62 (s, 1H, ArH),
7.31 (m, 5H, ArH), 13C NMR (CDCl3, 100 MHz) d 56.02
(OCH3), 65.30 (C-2), 99.96, 111.53, 116.60, 117.52, 127.69,
128.32, 128.52, 137.13, 138.30, 139.59, 146.73, 148.51;
HRMS (ESI) calcd for C16H14O3Na [M+Na]+: 277.0841.
Found: 277.0838.
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Acta, Gene Struct. Expr. 1998, 1400, 29–43; (b) Vlietinck,
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17. Compound 9 was obtained as a colorless crystal, mp 96–
97 °C (n-hexane); UV (CH2Cl2) kmax 232, 300 nm; IR
(KBr) 3500, 1631, 1499, 1451, 1387, 1349, 1261, 1161,
1132, 1063, 1027, 885, 806, 757, 702 cmÀ1 1H NMR
;

S.-R. Li et al. / Tetrahedron Letters 48 (2007) 2139–2141
2141
(CDCl3, 400 MHz) d 2.05 (m, 1H, H-3a), 2.28 (m, 1H, H-
3b), 3.85 (s, 3H, OCH3), 4.07 (d, J = 6.4 Hz, 1H, H-4),
4.13 (m, 2H, H-2), 5.11 (s, 1H, OH), 6.37 (s, 1H, ArH),
6.42 (s, 1H, ArH), 7.11 (m, 2H, ArH), 7.21 (m, 1H, ArH),
7.28 (m, 2H, ArH); 13C NMR (CDCl3, 100 MHz) d 31.97,
40.58, 51.91, 63.97, 99.73, 115.16, 116.25, 126.41, 128.41,
128.55, 139.36, 145.69, 146.09, 148.47; EI-MS (70 eV) m/z
(intensity), 257 (M++1, 19), 256 (M+, 100), 240 (8), 239
(8), 228 (24), 227 (32); HRMS (ESI) calcd for C16H16O3Na
[M+Na]+: 279.0997. Found: 279.0996. Anal. Calcd for
C16H16O3: C, 74.98; H, 6.29. Found: C, 74.71; H, 6.29.
18. Synthesis of 10: 7 (0.15 g, 0.44 mmol) dissolved in 1,4-
dioxane (5 mL) was reacted with DDQ (0.2 g, 0.88 mmol)
at rt for 1 h. After usual work-up and chromatographic
purification process (silica-gel, EtOAc–n-hexane = 1:4), 10
was produced (0.12 g, 77%) as pale yellow crystals, mp
119–120 °C (n-hexane), Rf = 0.68 (ethyl acetate–n-hex-
ane = 1:2), 1H NMR (CDCl3, 200 MHz) d 3.98 (s, 3H,
OCH3), 5.04 (s, 2H, OCH2C6H5), 6.20 (s, 1H, H-3), 6.84
(s, 1H, H-5), 6.92 (s, 1H, H-8), 7.27 (m, 7H, ArH), 7.47 (m,
3H, ArH); 13C NMR (CDCl3, 50 MHz) d 56.38 (OCH3),
71.45 (OCH2C6H5), 100.44, 110.97, 111.23, 112.12, 127.33,
128,00, 128.19, 128.57, 128.81 129.44, 135.51, 136.31,
144.53, 150.32, 153.57, 155.46, 161.30; EI-MS (70 eV) m/z
(intensity), 358 (M+, 5), 268 (20), 267 (100), 236 (30), 235
(69), 209 (24), 208 (21), 207 (45), 91 (72). Anal. Calcd for
C23H18O4: C, 77.08; H, 5.06. Found: C, 77.10; H, 5.09.
19. Dalbergin 11 was obtained as pale yellow crystals, mp
210–211 °C (EtOAc–n-hexane = 1:1) [reported,1 mp 211–
212 °C], Rf = 0.58 (ethyl acetate–n-hexane = 1:1), The
spectral data such as 1H NMR, 13C NMR, EI-MS are
all coincident to the reported dalbergin.