Practical and efficient entry to isoflavones by Pd(0)/C-mediated Suzuki-Miyaura reaction. Total synthesis of geranylated isoflavones

Article abstract of DOI:10.1016/j.tet.2007.01.062

A scalable synthesis of isoflavones taking advantage of the Suzuki-Miyaura reaction catalyzed by Pd(0)/C is described. The approach developed has been extended to the total synthesis of 7-O-geranylformononetin, griffonianone D, and conrauinone D, which did not display cytotoxicity against human HeLa carcinoma cells. In addition, this study established unambiguously the absolute configuration of natural griffonianone D.

Full text of DOI:10.1016/j.tet.2007.01.062

Tetrahedron 63 (2007) 3010–3016
Practical and efficient entry to isoflavones by Pd(0)/C-mediated
Suzuki–Miyaura reaction. Total synthesis of geranylated
isoflavones
*
Franc¸ois-Xavier Felpin, Cecile Lory, Hawaa Sow and Samir Acherar
ꢀ
´
Universite Bordeaux 1, CNRS, Laboratoire de Chimie Organique et Organometallique, 351 Cours de la Liberation,
´
´
33405 Talence Cedex, France
Received 22 December 2006; revised 16 January 2007; accepted 25 January 2007
Available online 1 February 2007
Abstract—A scalable synthesis of isoflavones taking advantage of the Suzuki–Miyaura reaction catalyzed by Pd(0)/C is described. The
approach developed has been extended to the total synthesis of 7-O-geranylformononetin, griffonianone D, and conrauinone D, which did
not display cytotoxicity against human HeLa carcinoma cells. In addition, this study established unambiguously the absolute configuration
of natural griffonianone D.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of new active compounds. While an impressive
number of isoflavones have been isolated to date,6 we were
interested in their less common geranylated congeners
(Fig. 1). Several reasons motivated us to focus on this family
of products: (1) to date, no total synthesis has been disclosed,
(2) we could take advantage of the chemistry previously de-
veloped in our laboratory, and (3) no information regarding
the anticancer activity has been reported for this class of iso-
flavones.
Isoflavones constitute an important class of natural products
that possess a number of interesting biological activities
including antioxidative,1 antitumor,2 anti-inflammatory,3 or
estrogenic properties.4 The relationship between the con-
sumption of isoflavonoids and the reduction of cardiovas-
cular disease and cancer has been demonstrated in many
reports,5 increasing the interest for the search and the
In this paper we report the total synthesis of 7-O-geranylfor-
mononetin 1, griffonianone D 2, and conrauinone D 3 using
the chemistry of Pd(0)/C.
OCH3
O
O
O
1 : 7-O-Geranylformononetin
2. Results and discussion
OCH3
O
The approach adopted is directly inspired by our studies on
Suzuki–Miyaura cross-coupling using Pd(0)/C, a practical
and inexpensive catalyst (Scheme 1). We recently studied
the Suzuki–Miyaura cross-coupling of 2-iodocycloenones
with boronic acid partners catalyzed both by Pd(0)/C.7 The
O
O
HO
HO
OH
2 : Griffonianone D
O
O
O
Pd/C mediated Suzuki-Miyaura cross-coupling
3 : Conrauinone D
O
O
O
O
R2
R2
Figure 1. Selected examples of geranylated isoflavones.
3
I
(HO)2B
+
R1O
6
THPO
8
Keywords: Pd/C; Suzuki–Miyaura reaction; Isoflavones; 7-O-Geranylfor-
mononetin; Griffonianone D; Conrauinone D.
* Corresponding author. E-mail: fx.felpin@lcoo.u-bordeaux1.fr
5
4
Scheme 1. General retrosynthetic strategy.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.01.062

F.-X. Felpin et al. / Tetrahedron 63 (2007) 3010–3016
3011
Table 1. Synthesis of isoflavones by Pd(0)/C-mediated Suzuki–Miyaura
reaction
optimum conditions feature inexpensive reagents and sol-
vents with low toxicity rendering the method environmen-
tally benign, very practicable, and scalable.8 This catalyst
system would be particularly appropriate for the preparation
of biologically active compounds. The iodochromanone 5
would be an excellent platform for the development of a
small library of isoflavones 4. A number of biologically ac-
tive natural products such as daidzein,9 or glycitin10 possess
this structural scaffold with variously substituted aromatic
rings at C3 and a substituted (or not) hydroxyl at C8.
ArB(OH)2 (2 eq.),
10% Pd/C (5 mol%),
Na2CO3 (1 eq.)
O
O
O
Ar
I
DME/H2O, 45 °C, 1 h
THPO
O
10-15
THPO
5
Entry
ArB(OH)2
Product
Yield (%)a
73
(HO)2B
1
2
3
10
11
12
OCH3
OH
Precursor 5 was prepared in three steps in high yield, starting
from commercially available 2,4-dihydroxyacetophenone 7
(Scheme 2).11 Selective protection of the 4-hydroxyl gave
the THP ether 8, which upon condensation with N,N-di-
methylformamide dimethylacetal provided the 3-(dimethyl-
amino)-20-hydroxyacrylophenone 9. The crude 9 was
directly treated with I2 to furnish the corresponding iodo-
chromanone 5. This optimized sequence, involving three
synthetic operations, required only one chromatographic
purification to give pure 5 in 90% yield over three steps,
on a multigram scale (>11 g).
(HO)2B
86
75
OCH3
(HO)2B
(HO)2B
OCH3
OCH3
4
5
13
89
OCH3
O
(HO)2B
(HO)2B
14
15
94
90
O
O
O
NO2
6
DHP, PPTS
CH2Cl2, rt
THPO
OH
HO
OH
a
Yields are for isolated products.
7
8
O
I2, Pyridine
CHCl3, rt
N
DMF-DMA
95°C
We then turned our attention toward the preparation of ger-
anylated isoflavones 1–3 using 10 and 11 as synthetic inter-
mediates. Several geranylated isoflavones have been isolated
from Millettia species14 that are plants essentially found in
Africa. Many species of the genus Millettia exhibit interest-
ing biological activities. For instance, Millettia griffoniana,
found in the central part of Cameroon, is used in traditional
medicine as an oral treatment for boils. It should be noted
that isoflavones 1–3 have never been synthesized and the
configuration of griffonianone D 2 remained unknown at
the time we started our work.
THPO
O
OH
9
I
90% yield over three steps
THPO
O
5
Scheme 2. Preparation of the iodochromanone 5.
Having appreciable quantities of 5 to hand, we focused on the
preparation of a small library by solution-phase Suzuki–
Miyaura12 reaction using Pd/C as heterogenous catalyst.13
Six parallel reactions were conducted on a 1 mmol-scale
(with respect to 5) for only 1 h at 45 ꢀC with Pd(0)/C as a cat-
alyst under ligand free conditions. Excellent yields of cross-
coupled products were obtained as indicated in Table 1. We
particularly focused on the introduction of electron-rich
boronic acids since natural isoflavones are often poly-oxy-
genated. This did not constitute a problem since the method
worked equally well with electron-poor boronic acid (entry
6). These heterogenous conditions compete favorably with
usual homogenous conditions. Indeed, in a similar approach,
Westwell2b described Suzuki–Miyaura reactions of iodo-
chromanones under homogenous conditions (Pd(PPh3)4) in
refluxing benzene for 20 h. Although we did not recycle
the catalyst in this study, we previously showed that it is
possible to reuse it at least five times with good catalytic
efficiency.7 It is important to note that the conditions devel-
oped for the Suzuki–Miyaura reaction using Pd(0)/C as
catalyst could be easily scaled-up since no drop in yields
of cross-coupled products was observed by working on mul-
tigram quantity of 5. Moreover, the heterogenous nature of
the catalyst renders the method particularly well suited for
large-scale applications.
Starting from isoflavone 10, cleavage of the THP protecting
group under acidic conditions followed by an etherification
of the liberated phenol with geranyl bromide furnished 7-
O-geranylformononetin 114a in good yield (six steps from
2,4-dihydroxyacetophenone 7, 53% overall) (Scheme 3).
Then, we turned our attention toward the preparation of
griffonianone D 2 from 7-O-geranylformononetin 1 by a
selective Sharpless asymmetric dihydroxylation (SAD). Un-
fortunately, we obtained griffonianone D 2 with a very low
yield and only under its racemic form. This result was attrib-
uted to the very low solubility of both 1 and 2 in the solvent
system used in this study. We obtained a complex mixture of
compounds where starting material 1 was the major product
recovered (Scheme 4).
Considering that introduction of the chirality on 1 would be
problematic, we reasoned that the chiral diol could be intro-
duced on the geranyl backbone prior to its coupling to the
chromanone core 10 (Scheme 5). Following this pathway,
geraniol 17 was acetylated and selectively dihydroxylated
using the SAD conditions to furnish (S)-18 with good yield

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F.-X. Felpin et al. / Tetrahedron 63 (2007) 3010–3016
OCH3
OCH3
O
O
O
pTsOH
MeOH, THF
Geranyl bromide
K2CO3, Acetone
95%
85%
HO
O
THPO
10
16
OCH3
O
O
O
1 : 7-O-Geranylformononetin
Scheme 3. Synthesis of 7-O-geranylformononetin.
OCH3
OCH3
O
O
AD-mix-α
tBuOH-H2O
< 5%
O
O
O
O
OH
OH
1 : 7-O-Geranylformononetin
Scheme 4. Synthesis of griffonianone D.
2 : (+/-)-Griffonianone D
over two steps (67%).15,16 After two protective group mani-
pulations, alcohol 19 was reacted with isoflavone 16 under
Mitsunobu17 conditions to give the corresponding cross-cou-
pled product. Finally, cleavage of the acetonide furnished
griffonianone D 214e in 93% enantiomeric excess whose
NMR data perfectly match those reported for the natural
product (seven steps, 36% overall). In addition, the value
and sign of the optical rotation were equally in good agree-
ment. Consequently the configuration of natural griffonia-
none D 2 was unambiguously assigned as the (S)-isomer.
protecting group cleaved to afford conrauinone D 3 (six steps
from2,4-dihydroxyacetophenone7, 55% overall) (Scheme6).
As part of a program devoted to the discovery of natural
products with anticancer activity, we evaluated synthetic iso-
flavones 1–3 whose cytotoxicities were unknown. Unfortu-
nately, 7-O-geranylformononetin 1, griffonianone D 2, and
conrauinone D 3 did not exhibit in vitro cytotoxicity against
human HeLa carcinoma cells.
3. Conclusion
1. Ac2O, Et3N,
DMAP, CH2Cl2
2. AD-mix-α
67% (2 steps)
OH
OAc
In summary, we have described the first total synthesis of
7-O-geranylformononetin 1, griffonianone D 2, and conraui-
none D 3. The synthetic route developed appears to be ex-
tremely efficient and practical. Notably, we successfully
applied the Pd/C-mediated Suzuki–Miyaura cross-coupling
reaction to the construction of the isoflavone core. Although
these isoflavones did not induce apoptosis of tumoral cells,
the chemistry described herein opens a way for the synthesis
of either natural or non-natural isoflavones with biological
activities.
HO
17
18
OH
1. p-TsOH,
dimethoxypropane
1. DIAD, Ph3P, 16 , THF
OH
2. K2CO3, CH3OH
97% (2 steps)
2. p-TsOH, THF-CH3OH
O
19
O
65% (2 steps)
OCH3
O
O
O
HO
OH
2 : Griffonianone D, 93% ee
4. Experimental
Scheme 5. Synthesis of griffonianone D.
4.1. General procedures
On the other hand, conrauinone D 314c was easily accessed
from isoflavone 11 by a two-step sequence. The free phenol
of the aryl group attached at C3 was geranylated and the THP
Chemical shifts from proton and carbon NMR spectra are
reported in parts per million relative to the CDCl3 peak at
OH
O
1. Geranyl bromide
K2CO3, Acetone
2. pTsOH, MeOH
71% (2 steps)
O
O
O
HO
O
THPO
3 : Conrauinone D
Scheme 6. Synthesis of conrauinone D.

F.-X. Felpin et al. / Tetrahedron 63 (2007) 3010–3016
3013
7.26 ppm (1H) or 77.0 ppm (13C), DMSO at 2.50 ppm (1H)
or 39.52 ppm (13C). Infrared (IR) spectra were recorded as
neat samples on NaCl plates or with KBr pellets. Yields refer
to isolated material determined to be pure by NMR spectros-
copy and thin layer chromatography (TLC), unless specified
otherwise in the text. Chiral HPLC was performed with a
Chiralpak AD-H column, 0.46ꢁ25 cm, flow rate 1 mL/min.
4.3.2. Isoflavone (11). Mp 272–275 ꢀC. IR (KBr) n 1610,
1625, 2952, 3410 cmꢂ1 1H NMR (DMSO, 250 MHz)
.
d 1.59–1.89 (m, 6H), 3.59–3.77 (m, 2H), 5.71 (m, 1H),
6.82 (d, 2H, J¼7.6 Hz), 7.13–7.20 (m, 2H), 7.40 (d, 2H,
J¼7.6 Hz), 8.05 (d, 1H, J¼8.9 Hz), 8.36 (s, 1H), 9.53 (s,
1H). 13C NMR (DMSO, 75 MHz) d 18.3, 24.5, 29.4, 61.7,
95.9, 103.4, 115.0, 115.6, 118.2, 122.3, 123.6, 126.9,
130.0, 153.2, 157.0, 157.2, 160.7, 174.7. HRMS (LSIMS)
calcd for C20H18O5 (M+) 338.1154, found 338.1153.
4.2. Chromanone (5)
A solution of DHP (9 mL, 98.7 mmol) in CH2Cl2 (54 mL)
was added dropwise to a solution of acetophenone (5 g,
32.8 mmol) and PPTS (296 mg) at rt. The resulting mixture
was stirred for 4 h at rt, then washed with saturated aqueous
NaHCO3 solution, and extracted with CH2Cl2 (3ꢁ). The col-
lected organic extracts were dried (MgSO4), filtered, and
concentrated under reduced pressure. The crude was diluted
with DMF/DMA (6.54 mL, 49.3 mmol) and the resulting
mixture was stirred at 95 ꢀC for 3 h. After evaporation
of volatiles, the obtained solid was dissolved in CHCl3
(53 mL) and successively treated with pyridine (2.66 mL,
33 mmol) and I2 (16.7 g, 66 mmol). The resulting mixture
was stirred at rt for 12 h. The reaction was hydrolyzed
with saturated aqueous Na2S2O3 solution and stirred for
30 min at rt. The aqueous phase was extracted with
CH2Cl2 (3ꢁ). The collected organic extracts were dried
(MgSO4), filtered, and concentrated under reduced pressure.
Purification by flash chromatography (20% EtOAc/petro-
leum ether then 40% EtOAc/petroleum ether) gave 5
(11 g, 90% yield) as a colorless solid. Mp 131–133 ꢀC. IR
4.3.3. Isoflavone (12). Mp 151–153 ꢀC. IR (KBr) n 1609,
1627, 1649, 2950 cmꢂ1 1H NMR (CDCl3, 250 MHz)
.
d 1.59–1.80 (m, 3H), 1.88–2.06 (m, 3H), 3.62–3.69 (m,
1H), 3.74 (s, 3H), 3.80–3.89 (m, 1H), 3.89 (s, 3H), 5.55 (m,
1H), 6.92–6.98 (m, 2H), 7.07–7.13 (m, 3H), 7.94 (s, 1H),
7.91 (s, 1H), 8.20 (d, 1H, J¼8.5 Hz). 13C NMR (CDCl3,
75 MHz) d 18.3, 24.9, 29.9, 55.8, 60.6, 61.9, 96.4, 103.3,
112.3, 115.6, 119.0, 121.8, 123.5, 123.7, 126.1, 127.5,
147.3, 152.8, 154.0, 157.7, 161.2, 175.7. HRMS (LSIMS)
calcd for C22H22O6Na (M+Na) 405.1314, found 405.1324.
4.3.4. Isoflavone (13). IR (KBr) n 1623, 2946, 3015,
1
3075 cmꢂ1. H NMR (CDCl3, 250 MHz) d 1.57–1.76 (m,
3H), 1.86–2.04 (m, 3H), 3.59–3.64 (m, 1H), 3.65–3.90 (m,
1H), 3.88 (s, 3H), 3.90 (s, 3H), 5.52 (m, 1H), 6.89 (d, 2H,
J¼8.6 Hz), 7.00–7.08 (m, 3H), 7.20 (m, 1H), 7.92 (s, 1H),
8.18 (d, 1H, J¼9.5 Hz). 13C NMR (CDCl3, 75 MHz)
d 18.2, 24.9, 29.9, 55.8, 55.8, 61.9, 96.4, 103.2, 111.0,
112.4, 115.7, 118.8, 120.9, 124.6, 124.6, 127.4, 148.6,
148.9, 152.3, 157.5, 161.3, 175.8. HRMS (EI) calcd for
C22H23O6 (M+H) 383.1495, found 383.1496.
(KBr) n 1614, 1649, 2930, 2952, 3059 cmꢂ1 1H NMR
.
(CDCl3, 250 MHz) d 1.57–1.80 (m, 3H), 1.87–2.07 (m,
3H), 3.60–3.68 (m, 1H), 3.77–3.87 (m, 1H), 5.53 (m, 1H),
7.07–7.11 (m, 2H), 8.13 (d, 1H, J¼9.5 Hz), 8.21 (s, 1H).
13C NMR (CDCl3, 75 MHz) d 18.2, 24.9, 29.9, 62.0, 86.9,
96.5, 103.1, 116.1, 116.4, 127.8, 157.3, 157.6, 161.7,
172.6. HRMS (LSIMS) calcd for C14H13O4I (M+)
372.9937, found 372.9941.
4.3.5. Isoflavone (14). Mp 298–300 ꢀC. IR (KBr) n 1636,
1
2951 cmꢂ1. H NMR (CDCl3, 250 MHz) d 1.59–1.75 (m,
3H), 1.89–2.06 (m, 3H), 3.63–3.67 (m, 1H), 3.80–3.90 (m,
1H), 5.56 (m, 1H), 6.86 (d, 1H, J¼8.3 Hz), 6.97 (dd, 1H,
J¼1.5, 7.9 Hz), 7.06–7.10 (m, 3H), 7.91 (s, 1H), 8.20 (d,
1H, J¼9.8 Hz). 13C NMR (CDCl3, 75 MHz) d 18.3, 25.0,
30.0, 62.0, 96.5, 101.1, 103.3, 108.3, 109.8, 115.8, 118.9,
122.4, 124.9, 125.7, 127.6, 147.6, 147.7, 152.3, 157.7,
161.4, 175.7. HRMS (LSIMS) calcd for C21H19O6 (M+H)
367.1182, found 367.1176.
4.3. General procedure for the preparation
of isoflavones
General procedure: to a solution of iodoenone (372 mg,
1 mmol) in DME (3 mL) and H2O (3 mL) were added
Na2CO3 (318 mg, 3 mmol), ArB(OH)2 (1.2 mmol), and
Pd/C (53 mg, 5 mol %). The resulting mixture was stirred
for 1 h at 45 ꢀC and then filtered. The catalyst was washed
with H2O (3 mL) and CH2Cl2 (5 mL). The aqueous phase
was extracted twice with CH2Cl2. The collected organic ex-
tracts were dried (MgSO4), filtered, and concentrated under
reduced pressure. The crude was purified by flash chromato-
graphy to give the corresponding cross-coupled product.
4.3.6. Isoflavone (15). Mp 166–168 ꢀC. IR (KBr) n 1602,
1626, 1648, 2953, 3075 cmꢂ1
.
1H NMR (CDCl3,
250 MHz) d 1.30–1.77 (m, 3H), 1.89–2.06 (m, 3H), 3.64–
3.69 (m, 1H), 3.80–3.90 (m, 1H), 5.57 (m, 1H), 7.09–7.14
(m, 2H), 7.60 (t, 1H, J¼8.2 Hz), 7.96 (d, 1H, J¼7.9 Hz),
8.06 (s, 1H), 8.18–8.24 (m, 2H), 8.42 (t, 1H, J¼2.2 Hz).
13C NMR (CDCl3, 62.5 MHz) d 18.3, 24.9, 29.9, 62.0,
96.5, 103.4, 116.2, 118.6, 122.9, 123.2, 123.6, 123.6,
127.6, 129.3, 135.2, 148.3, 153.3, 157.7, 161.8, 175.0.
HRMS (LSIMS) calcd for C20H17NNaO6 (M+Na)
390.0954, found 390.0961.
4.3.1. Isoflavone (10). Mp 174–175 ꢀC. IR (KBr) n 1608,
1636, 2928, 3059 cmꢂ1 1H NMR (CDCl3, 250 MHz)
.
d 1.59–1.80 (m, 3H), 1.89–2.06 (m, 3H), 3.62–3.71 (m,
1H), 3.81–3.91 (m, 1H), 3.83 (s, 3H), 5.55 (m, 1H), 6.96
(d, 2H, J¼8.8 Hz), 7.08 (d, 2H, J¼6.7 Hz), 7.49 (dd, 2H,
J¼2.2, 6.7 Hz), 7.91 (s, 1H), 8.20 (d, 1H, J¼9.2 Hz). 13C
NMR (CDCl3, 75 MHz) d 18.3, 25.0, 30.0, 55.3, 62.0,
96.4, 103.2, 113.9, 115.7, 118.9, 124.3, 124.7, 127.6,
130.1, 152.1, 157.7, 159.5, 161.3, 175.9. HRMS (LSIMS)
calcd for C21H21O5 (M+H) 353.1389, found 353.1390.
4.3.7. Isoflavone (16). To a solution of 10 (585 mg,
1.66 mmol) in MeOH (30 mL) and THF (30 mL) was added
pTsOH (32 mg, 0.166 mmol) at rt. The resulting mixture was
stirred at 60 ꢀC for 1 h, then Et3N (0.3 mL, 1.66 mmol) was
added, and volatiles were removed under reduced pressure.
Purification by flash chromatography (40% EtOAc/
petroleum ether then 5% MeOH/EtOAc) provided 16
(379 mg, 85%) as a colorless solid. Mp 261–263 ꢀC [lit.18

3014
F.-X. Felpin et al. / Tetrahedron 63 (2007) 3010–3016
264–267 ꢀC]. IR (KBr) n 1609, 1638, 2930, 3132 cmꢂ1. 1H
NMR (DMSO, 250 MHz) d 3.80 (s, 3H), 6.88–7.01 (m,
4H), 7.49–7.54 (m, 2H), 7.98 (d, 1H, J¼8.5 Hz), 8.34 (s,
1H), 10.8 (br s, 1H). 13C NMR (DMSO, 62.5 MHz) d 55.1,
102.1, 113.6, 115.1, 116.6, 123.1, 124.2, 127.3, 130.0,
153.1, 157.4, 158.9, 162.6, 174.6. HRMS (LSIMS) calcd
for C16H12O4 (M+) 268.0736, found 268.0733.
(250 mg, 1.09 mmol) in 2,2-dimethoxypropane (20 mL)
was added pTsOH (72 mg, 0.38 mmol) at rt. After 2 h of stir-
ring at rt, the reaction was quenched with saturated NaHCO3
aqueous solution and extracted with CH2Cl2 (3ꢁ). The col-
lected organic extracts were dried (MgSO4) and concen-
trated under reduced pressure. The oily residue was
dissolved in a mixture of CH3OH (9.3 mL)/H2O (0.7 mL)
and treated with K2CO3 (165 mg, 1.19 mmol). After 2 h of
stirring, solvents were removed under reduced pressure
and the residue was diluted with EtOAc. The organic layer
was washed with brine (1ꢁ), dried (MgSO4), and concen-
trated in vacuo to give 19 (240 mg, 97%), which was pure
enough for the next step. IR (KBr) n 1669, 2860, 2935,
4.3.8. 7-O-Geranylformononetin (1).14a To a solution of 16
(129 mg, 0.48 mmol) and K2CO3 (99 mg, 0.72 mmol) in
acetone (10 mL) was added dropwise geranyl bromide
(0.14 mL, 0.72 mmol) at rt. The resulting mixture was
refluxed for 2 h and then hydrolyzed with H2O (10 mL).
The aqueous phasewas extracted with CH2Cl2 (3ꢁ). The col-
lected organic extracts were dried (MgSO4) and concentrated
under reduced pressure. Purification by flash chromato-
graphy (15% EtOAc/petroleum ether) furnished 1 (172 mg,
95%) as a colorless solid. Mp 113–114 ꢀC. IR (KBr)
1
2982, 3417 cmꢂ1. H NMR (CDCl3, 250 MHz) d 1.09 (s,
3H), 1.24 (s, 3H), 1.32 (s, 3H), 1.41 (s, 3H), 1.41–1.69 (m,
2H), 1.69 (s, 3H), 2.00–2.12 (m, 1H), 2.20–2.32 (m, 1H),
3.66 (dd, 1H, J¼3.4, 9.6 Hz), 4.16 (d, 2H, J¼6.7 Hz), 5.45
(br t, 1H, J¼6.7 Hz). 13C NMR (CDCl3, 62.5 MHz)
d 16.4, 22.9, 26.0, 26.8, 27.5, 28.5, 36.6, 59.3, 80.1, 82.9,
106.6, 123.6, 139.1. HRMS (LSIMS) calcd for C13H24O3
(M+) 228.1725, found 228.1727.
n 1630, 2967, 3052 cmꢂ1 1H NMR (CDCl3, 250 MHz)
.
d 1.61 (s, 3H), 1.67 (s, 3H), 1.77 (s, 3H), 2.11 (br s, 4H),
3.84 (s, 3H), 4.64 (d, 2H, J¼6.7 Hz), 5.09 (br s, 1H), 5.49
(br t, 1H, J¼6.6 Hz), 6.85 (d, 1H, J¼2.1 Hz), 6.95–7.01
(m, 3H), 6.95–7.01 (m, 3H), 7.50 (d, 2H, J¼8.6 Hz), 7.91
(s, 1H), 8.20 (d, 1H, J¼8.6 Hz). 13C NMR (CDCl3,
62.5 MHz) d 55.1, 102.1, 113.6, 115.1, 116.6, 123.1, 124.2,
127.3, 130.0, 153.1, 157.4, 158.9, 162.6, 174.6.
4.3.12. Protected griffonianone D. To a solution of alcohol
19 (53 mg, 0.233 mmol) and isoflavone 16 (52 mg,
0.194 mmol) in THF (2 mL) was added at rt Ph3P
(102 mg, 0.388 mmol) and DIAD (78 mL, 0.388 mmol).
The resulting mixture was stirred for 6 h at 50 ꢀC in a sealed
tube. Solvents were removed under reduced pressure and the
crude was purified by flash chromatography (20% EtOAc/
petroleum ether) to give the title compound contaminated
4.3.9. Geranyl acetate.19 To a solution of geraniol (2 g,
12.99 mmol) in CH2Cl2 (130 mL) was added, at rt, Et3N
(5.42 mL, 38.96 mmol), Ac2O (3.07 mL, 32.47 mmol), and
DMAP (cat.). The resulting mixture was stirred 8 h at rt
and then washed with water. Purification by flash chromato-
graphy (5% EtOAc/petroleum ether) gave the title compound
(2.44 g, 96%) as a colorless oil. IR (KBr) n 1670, 1742, 2925,
2968 cmꢂ1. 1H NMR (CDCl3, 300 MHz) d 1.58 (s, 3H), 1.66
(s, 3H), 1.68 (s, 3H), 2.03–2.09 (m, 4H), 2.03 (s, 3H), 4.57 (d,
2H, J¼7.1 Hz), 5.06 (m, 1H), 5.32 (br t, 1H, J¼7.1 Hz). 13C
NMR (CDCl3, 75 MHz) d 16.4, 17.6, 21.0, 25.6, 26.2, 39.5,
61.3, 118.2, 123.7, 131.8, 142.2, 171.0.
1
by DIAD residues. H NMR (CDCl3, 250 MHz) d 1.10 (s,
3H), 1.24 (s, 3H), 1.31 (s, 3H), 1.41 (s, 3H), 1.46–1.76 (m,
2H), 1.80 (s, 3H), 2.09–2.21 (m, 1H), 2.28–2.40 (m, 1H),
3.66 (dd, 1H, J¼3.4, 9.2 Hz), 3.83 (s, 3H), 4.64 (d, 2H,
J¼6.7 Hz), 5.54 (br t, 1H, J¼6.4 Hz), 6.84 (d, 1H,
J¼2.5 Hz), 6.94–7.00 (m, 3H), 7.49 (d, 2H, J¼8.6 Hz),
7.91 (s, 1H), 8.19 (d, 1H, J¼9.2 Hz).
4.3.13. Griffonianone D (2).14e A solution of the impure
protected griffonianone D (w0.233 mmol) in MeOH
(6 mL) and H2O (0.2 mL) was treated with pTsOH
(22 mg) at rt and the mixture was stirred for 5 h at 50 ꢀC.
The solution was neutralized with Et3N, concentrated under
reduced pressure, and purified by flash chromatography
(60% EtOAc/petroleum ether) to give griffonianone D 2
(66 mg, 65% yield, two steps). ee: 92%, determined by chi-
ral HPLC (hexane/i-PrOH¼70/30, 32.2 min for (R)-griffo-
nianone and 37.3 min for (S)-griffonianone). [a]2D2 ꢂ11.1
(c 0.45, CHCl3) [lit.14e [a]D23 ꢂ7.97 (c 0.042, CHCl3)]. Mp
128–130 ꢀC [lit.12e 128–129 ꢀC]. IR (KBr) n 1609, 1636,
4.3.10. (S,E)-6,7-Dihydroxy-3,7-dimethyloct-2-enyl ace-
tate (18). To a stirred solution of AD-mix a (3.60 g) in a
mixture of t-BuOH (13 mL) and H2O (13 mL) was added
successively CH3SO2NH2 (2.55 mmol) and geranyl acetate
(500 mg, 2.55 mmol) at 0 ꢀC. The resulting mixture was
stirred at 0 ꢀC for 48 h and then quenched with solid
Na2SO3. After 30 min of stirring at rt, the reaction was
diluted with CH2Cl2 and the aqueous phase was extracted
with CH2Cl2 (3ꢁ). The collected organic extracts were dried
(MgSO4) and concentrated under reduced pressure. Purifica-
tion by flash chromatography (70% EtOAc/petroleum ether)
gave 18 (410 mg, 70%) as a colorless oil. IR (KBr) n 1668,
1
2926, 3375 cmꢂ1. H NMR (CDCl3, 250 MHz) d 1.17 (s,
3H), 1.21 (s, 3H), 1.39–1.71 (m, 2H), 1.65 (br s, 1H), 1.79
(s, 3H), 2.11–2.17 (m, 1H), 2.20–2.45 (m, 1H), 2.35 (br s,
1H), 3.36 (d, 1H, J¼10.4 Hz), 3.84 (s, 3H), 4.64 (d, 2H,
J¼6.4 Hz), 5.55 (br t, 1H, J¼6.7 Hz), 6.85 (d, 1H,
J¼2.5 Hz), 6.95–7.01 (m, 3H), 7.49 (d, 2H, J¼8.9 Hz),
7.91 (s, 1H), 8.19 (d, 1H, J¼8.8 Hz). 13C NMR (CDCl3,
75 MHz) d 16.8, 23.3, 26.5, 29.4, 36.5, 55.3, 65.4, 73.0,
78.0, 100.9, 113.9, 115.0, 118.3, 118.8, 124.2, 124.8,
127.7, 130.1, 142.3, 152.0, 157.9, 159.5, 163.2, 175.9.
1731, 2974, 3426 cmꢂ1 1H NMR (CDCl3, 300 MHz)
.
d 1.15 (s, 3H), 1.20 (s, 3H), 1.37–1.50 (m, 1H), 1.55–1.66
(m, 1H), 1.71 (s, 3H), 2.04 (s, 3H), 2.04–2.15 (m, 2H),
2.27–2.35 (m, 2H), 3.33 (dm, 1H, J¼10.5 Hz), 4.58 (d, 2H,
J¼6.8 Hz), 5.38 (br t, 1H, J¼7.1 Hz). 13C NMR (CDCl3,
62.5 MHz) d 16.4, 21.0, 23.1, 26.4, 29.4, 36.5, 61.3, 73.0,
78.0, 118.6, 142.0, 171.3. MS (CI/NH3) m/z 248 (M+NH4),
188 (MꢂCH3CO).
4.3.11. (E)-3-Methyl-5-((S)-2,2,5,5-tetramethyl-1,3-di-
oxolan-4-yl)pent-2-en-1-ol (19). To a solution of 18
4.3.14. Protected conrauinone D. To a solution of 11
(64 mg, 0.19 mmol) and K2CO3 (39 mg, 0.28 mmol) in

F.-X. Felpin et al. / Tetrahedron 63 (2007) 3010–3016
3015
Vasselin, D. A.; Westwell, A. D.; Matthews, C. S.; Bradshaw,
T. D.; Stevens, M. F. G. J. Med. Chem. 2006, 49, 3973–3981.
3. Chacko, B. K.; Chandler, R. T.; Mundhekar, A.; Khoo, N.;
Pruitt, H. M.; Kucik, D. F.; Parks, D. A.; Kevil, C. G.;
Barnes, S.; Patel, R. P. Am. J. Physiol. Heart Circ. Physiol.
2005, 289, H908–H915.
acetone (3.5 mL) was added dropwise geranyl bromide
(56 mL, 0.28 mmol) at rt. The resulting mixture was refluxed
for 2 h and then hydrolyzed with H2O (3 mL). The aqueous
phase was extracted with CH2Cl2 (3ꢁ). The collected or-
ganic extracts were dried (MgSO4) and concentrated under
reduced pressure. Purification by flash chromatography
(10% EtOAc/petroleum ether) furnished the title compound
(81 mg, 90%) as a colorless solid. Mp 130–133 ꢀC. IR (KBr)
ꢀ
4. (a) Bennetau-Pelissero, C.; Le Houerou, C.; Lamothe, V.; Le
Menn, F.; Babin, P.; Bennetau, B. J. Agric. Food Chem. 2000,
n 1637, 2842, 2932, 3052 cmꢂ1
.
1H NMR (CDCl3,
ꢀ
48, 305–311; (b) Le Houerou, C.; Bennetau-Pelissero, C.;
Lamothe, V.; Le Menn, F.; Babin, P.; Bennetau, B.
Tetrahedron 2000, 56, 295–301; (c) Doerge, D. R.; Sheehan,
D. M. Environ. Health Perspect. 2002, 110, 349–353.
5. Duncan, A. M.; Phipps, W. R.; Kurzer, M. S. Best Pract. Res.
Clin. Endocrinol. Metab. 2003, 17, 253–271.
6. Boland, G. M.; Donnelly, D. M. X. Nat. Prod. Rep. 1998, 15,
241–260.
7. Felpin, F.-X. J. Org. Chem. 2005, 70, 8575–8578.
8. For a review, see: Felpin, F.-X.; Ayad, T.; Mitra, S. Eur. J. Org.
Chem. 2006, 2679–2690.
250 MHz) d 1.61 (s, 3H), 1.68 (s, 3H), 1.75 (s, 3H), 1.61–
1.74 (m, 3H), 1.89–2.13 (m, 7H), 3.63–3.67 (m, 1H),
3.81–3.91 (m, 1H), 5.10 (br s, 1H), 5.51 (br t, 1H,
J¼6.1 Hz), 5.55 (br s, 1H), 6.98 (d, 2H, J¼8.6 Hz), 7.06–
7.10 (m, 2H), 7.49 (d, 1H, J¼8.6 Hz), 7.92 (s, 1H), 8.21
(s, 1H, J¼9.5 Hz). 13C NMR (CDCl3, 75 MHz) d 16.7,
17.7, 18.3, 25.0, 25.7, 26.3, 30.0, 39.5, 62.0, 64.9, 96.5,
103.2, 114.7, 115.7, 118.9, 119.4, 123.8, 124.1, 124.8,
127.6, 130.0, 131.8, 141.3, 152.1, 157.1, 158.9, 161.3,
175.9. HRMS (LSIMS) calcd for C30H34O5 (M+)
474.2406, found 474.2403.
9. Hosny, M.; Rosazza, J. P. N. J. Nat. Prod. 1999, 62, 853–858.
10. Chang, Y.; Nair, M.; Santell, R.; Helferich, W. J. Agric. Food
Chem. 1994, 42, 1869–1871.
4.3.15. Conrauinone D (3).14c To a solution of protected
conrauinone D (72 mg, 0.15 mmol) in a mixture of THF
(3 mL) and MeOH (3 mL) was added pTsOH (3 mg,
0.015 mmol). The resulting mixture was stirred for 4 h at
60 ꢀC. pTsOH was neutralized with Et3N, solvents were
removed under reduced pressure, and the crude was purified
by flash chromatography (70% EtOAc/petroleum ether) to
give conrauinone D 3 (46 mg, 79%) as a white solid. Mp
186–188 ꢀC [lit.14c 188–190 ꢀC]. IR (KBr) n 1618, 2964,
11. Gammil, R. B. Synthesis 1979, 901–903.
12. For the synthesis of isoflavones by Suzuki–Miyaura cross-
coupling, see: (a) Hoshino, Y.; Miyaura, N.; Suzuki, A. Bull.
Chem. Soc. Jpn. 1988, 61, 3008–3010; (b) Yokoe, I.; Sugita,
Y.; Shirataki, Y. Chem. Pharm. Bull. 1989, 37, 529–530; (c)
Joo, Y. H.; Kim, J. K.; Kang, S.-H.; Noh, M.-S.; Ha, J.-Y.;
Choi, J. K.; Lim, K. M.; Lee, C. H.; Chung, S. Bioorg. Med.
Chem. Lett. 2003, 13, 413–417; (d) Ding, K.; Wang, S.
Tetrahedron Lett. 2005, 46, 3707–3709; (e) Ito, F.; Iwasaki,
M.; Watanabe, T.; Ishikawa, T.; Higuchi, Y. Org. Biomol.
Chem. 2005, 3, 674–681; (f) Eisnor, C. R.; Gossage, R. A.;
Yadav, P. N. Tetrahedron 2006, 62, 3395–3401.
13. For leading examples of Suzuki–Miyaura reactions with Pd/C
as catalyst, see: (a) Marck, G.; Villiger, A.; Buchecker, R.
Tetrahedron Lett. 1994, 35, 3277–3280; (b) Gala, D.;
Stamford, A.; Jenkins, J.; Kugelman, M. Org. Process Res.
Dev. 1997, 1, 163–164; (c) Ennis, D. S.; McManus, J.;
Wood-Kaczmar, W.; Richardson, J.; Smith, G. E.; Carstairs,
A. Org. Process Res. Dev. 1999, 3, 248–252; (d) LeBlond,
C. R.; Andrews, A. T.; Sun, Y.; Sowa, J. R., Jr. Org. Lett.
2001, 3, 1555–1557; (e) Dyer, U. C.; Shapland, P. D.; Tiffin,
P. D. Tetrahedron Lett. 2001, 42, 1765–1767; (f) McClure,
M. S.; Roschangar, F.; Hodson, S. J.; Millar, A.; Osterhout,
M. H. Synthesis 2001, 1681–1685; (g) Organ, M. G.; Mayer,
S. J. Comb. Chem. 2003, 5, 118–124; (h) Tagata, T.; Nishida,
M. J. Org. Chem. 2003, 68, 9412–9415; (i) Gruber, M.;
Chouzier, S.; Koheler, K.; Djakovitch, L. Appl. Catal., A:
1
3232 cmꢂ1. H NMR (CDCl3, 300 MHz) d 1.61 (s, 3H),
1.69 (s, 3H), 1.74 (s, 3H), 2.10 (m, 4H), 4.56 (d, 2H,
J¼6.8 Hz), 5.10 (m, 1H), 5.50 (br t, 1H, J¼6.0 Hz), 6.34
(m, 1H), 6.86 (d, 1H, J¼2.3 Hz), 6.92 (dd, 1H, J¼2.3,
9.1 Hz), 6.98 (dm, 2H, J¼6.8 Hz), 7.48 (d, 2H, J¼9.0 Hz),
1
7.92 (s, 1H), 8.19 (d, 1H, J¼8.6 Hz). H NMR (DMSO,
250 MHz) d 1.57 (s, 3H), 1.63 (s, 3H), 1.70 (s, 3H), 2.07
(m, 4H), 4.57 (d, 2H, J¼6.4 Hz), 5.07 (m, 1H), 5.44 (br t,
1H, J¼6.4 Hz), 6.87 (d, 1H, J¼2.2 Hz), 6.92 (d, 1H,
J¼2.2), 6.97 (d, 2H, J¼8.9 Hz), 7.49 (d, 2H, J¼8.5 Hz),
7.97 (d, 1H, J¼8.9 Hz), 8.33 (s, 1H). 13C NMR (DMSO,
62.5 MHz) d 16.4, 17.6, 25.5, 25.8, 38.9, 64.4, 102.1,
114.3, 115.2, 116.6, 119.7, 123.2, 123.8, 124.1, 127.3,
130.0, 131.0, 140.2, 153.1, 157.4, 158.1, 162.6, 174.6.
Acknowledgements
The University of Bordeaux 1 and the Centre National de la
Recherche Scientifique (CNRS) are gratefully acknowl-
edged for financial support. F.-X.F. thanks Mr. Edouard God-
ineau (University Bordeaux 1), Mrs. Geraldine Rousseau
(University Bordeaux 1) and M. Soumya Mitra (The Ohio
State University) for helpful discussions. Mrs. Muriel Ber-
lande (University Bordeaux 1) is acknowledged for technical
assistance with HPLC.
ꢀ
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