Total synthesis of the pyranoisoflavone kraussianone 1 and related isoflavones

Article abstract of DOI:10.1021/np100407n

The first total synthesis of the pyranoisoflavone kraussianone 1 (1) is described. The key steps involved the Suzuki-Miyaura reaction for the construction of the isoflavone core and the regioselective formation of the dimethylpyran scaffolds to the phloroglucinol (ring A) and resorcinol (ring B) moieties of kraussianone 1 (1). This route also provided access to the related isoflavones eriosemaone D (2) and genistein (3) via simple structural modifications.

Full text of DOI:10.1021/np100407n

1680
J. Nat. Prod. 2010, 73, 1680–1685
Total Synthesis of the Pyranoisoflavone Kraussianone 1 and Related Isoflavones
Mamoalosi A. Selepe, Siegfried E. Drewes, and Fanie R. van Heerden*
School of Chemistry, UniVersity of KwaZulu-Natal, PriVate Bag X01, ScottsVille 3209, Pietermaritzburg, South Africa
ReceiVed June 22, 2010
The first total synthesis of the pyranoisoflavone kraussianone 1 (1) is described. The key steps involved the
Suzuki-Miyaura reaction for the construction of the isoflavone core and the regioselective formation of the dimethylpyran
scaffolds to the phloroglucinol (ring A) and resorcinol (ring B) moieties of kraussianone 1 (1). This route also provided
access to the related isoflavones eriosemaone D (2) and genistein (3) via simple structural modifications.
Kraussianone 1 (1) is a pyranoisoflavone that was isolated from
the bark of Eriosema kraussianum Meisn. (Fabaceae), a plant used
traditionally for the treatment of male impotence and urinary
complaints in KwaZulu-Natal, South Africa.1 Preliminary studies
on the biological activity of the compounds isolated from E.
kraussianum revealed 1 to be the most potent metabolite for the
relaxation of carvenosal smooth muscle, an assay used to evaluate
drugs for erectile dysfunction. In this assay, 1 showed an activity
of 85% compared to sildenafil (Viagra) at 78 ng/mL.1,2 Compound
1 further demonstrated significant hypoglycemic and secondary
vasorelaxant effects.3 Therefore, 1 serves as an ideal lead compound
for the development of drugs to combat erectile dysfunction and
related disorders. However, 1 awaits in-depth biochemical studies
to reveal its molecular basis of action for these activities. This has
been hampered by the limited supply of the compound from E.
kraussianum, its sole natural source to date. In order to provide
access to sufficient quantities of 1 for further pharmacological
studies, we have developed a convenient synthetic route for the
preparation of 1 and related compounds, based on the Suzuki-
Miyaura reaction for the construction of the isoflavone core.4 While
the application of the Suzuki-Miyaura reaction in the synthesis of
isoflavones was demonstrated more than two decades ago,4 there
are not many reports on the synthesis of isoflavones with naturally
occurring substitution patterns by this method, especially those with
ring A possessing a phloroglucinol moiety.5,6 Except for the
pyranoisoflavone recently synthesized as a precursor to hirtellanine
A,6 no natural pyranoisoflavones have been reported by this method.
The previous synthetic procedures for pyranoisoflavones were based
on the deoxybenzoin or the chalcone route, which often suffered
from poor regioselectivity in the introduction of the dimethylpyran
ring to the isoflavone skeleton.7-13 We herein report the first
regioselective total synthesis of kraussianone 1 (1), employing the
Suzuki-Miyaura reaction as the key step for the construction of
the isoflavone nucleus.4 This route also gave access to a structurally
related antifungal pyranoisoflavone, eriosemaone D (2),14,15 whose
synthesis has not been disclosed, and to an important phytoestrogen,
genistein (3).
(7). Following this route, a number of related isoflavones can be
synthesized from the same key building blocks. This has been
demonstrated by the synthesis of eriosemaone D (2) from the
kraussianone 1 precursor 4 and by the synthesis of genistein (3)
from the 3-iodochromone 5 (Vide infra).
As illustrated in Scheme 2, the synthesis of the intermediate 5
commenced with regioselective protection of the hydroxy groups
of phloroacetophenone (7) by MOMCl generated from the reaction
16
of dimethoxymethane, AcCl, and catalytic ZnBr2 to give 9 in
50% yield. Condensation of 9 with DMF-DMA gave the enami-
noketone 10 (68%), which was cyclized in the presence of pyridine
and I2 to afford an inseparable mixture of 5 and 11 in the ratio of
1
50:7 (by H NMR), giving 58% and 6% overall yields, respecti-
vely.17-19 3-Iodochromone 5 is thus appropriately functionalized
for the ultimate conversion to an isoflavone via C-C bond
formation by the Suzuki-Miyaura reaction.
Having synthesized the first key building block, 5, the next step
was to prepare its boronic acid partner, 6. This was achieved in a
sequence of steps starting from resorcinol (8) (Scheme 3). Thus,
condensation of 8 with 3-methyl-2-butenoic acid gave chromanone
12 in 92% yield.20 Iodination of 12 with I2 and HIO3 in CH3OH/
H2O21 gave a mixture of the targeted 6-iodochromanone 13 as the
major component in 65% yield together with 8-iodochromanone
14 as a minor component. These compounds were inseparable by
silica gel column chromatography. However, their purification could
be effected by their different solubility properties. The 6-iodoch-
romanone 13 was insoluble in CH2Cl2 and CHCl3, whereas
compound 14 readily dissolved in these solvents. Although
compound 13 was initially obtained in moderate yields under these
conditions, this method was not reproducible on a larger scale.
Therefore, alternative iodinating reagents, KIO3/KI, HIO4/I2, and
ICl, were screened for the regioselective C-6 iodination of chro-
manone 12 under different conditions,22-25 but these mostly gave
the 8-iodo isomer 14 and 7-hydroxy-6,8-diiodo-2,2-dimethyl-4-
chromanone (15). Benzyl protection of the 7-hydoxy group of
Results and Discussion
The retrosynthetic analysis of kraussianone 1 (1) is shown in
Scheme 1. We envisaged that the regioselective aldol-type con-
densation of the pyranoisoflavone 4 with prenal and the subsequent
6π electrocyclization would give the dimethylpyran ring fused to
ring A of kraussianone 1 (1). The isoflavone 4 would in turn be
synthesized by the Suzuki-Miyaura cross-coupling of 3-iodoch-
romone 5 and the boronic acid derivate 6, with the requisite
dimethylpyran scaffold. The latter would be prepared from readily
available resorcinol (8) and the former from phloroacetophenone
* To whom correspondence should be addressed. Tel: +27 33 2605886.
Fax: +27 33 2605009. E-mail: vanheerdenf@ukzn.ac.za.
10.1021/np100407n  2010 American Chemical Society and American Society of Pharmacognosy
Published on Web 08/18/2010

Synthesis of the PyranoisoflaVone Kraussianone 1
Journal of Natural Products, 2010, Vol. 73, No. 10 1681
Scheme 2. Synthesis of 3-Iodochromone 5
Scheme 1. Retrosynthetic Analysis of Kraussianone 1 (1)
by the hydrolysis of the boronate ester with an NH4Cl solution
(Scheme 4). The improvement observed with this procedure may
be attributed to the immediate in situ quench of the generated
phenyllithium with triisopropyl borate, thus preventing side reac-
tions of the phenyllithium.30 These optimized reaction conditions
were subsequently employed for the synthesis of the boronic acid
6 in 70% yield from iodochromene 20, as shown in Scheme 3.
chromanone 12 and subsequent iodination of the resulting benzy-
loxychromanone 16 with HIO3/I2 resulted in the formation of
7-benzyloxy-3-iodo-2,2-dimethyl-4-chromanone (17).
21
The Suzuki-Miyaura cross-coupling of 3-iodochromone 5 with
boronic acid 6 using a heterogeneous Pd(C) catalyst19,31 and
subsequent cleavage of the MOM protecting groups with HCl
furnished the pyranoisoflavone 4 in 72% yield. Base-catalyzed
condensation of the pyranoisoflavone 4 with prenal32 gave the
benzyl derivative of kraussianone 1, 23 (74% yield), which was
finally deprotected with BCl313 to afford kraussianone 1 (1) in 69%
yield (Scheme 5).
Eventually, the targeted C-6-iodinated chromanone was success-
fully synthesized by treatment of the CHCl3 solution of 7-benzy-
loxy-2,2-dimethyl-4-chromanone (16) with CF3CO2Ag and I2 at
room temperature.26 This reaction gave 7-benzyloxy-6-iodo-2,2-
dimethyl-4-chromanone (18) as the sole product in 94% yield.
Reduction of 18 with NaBH4 and subsequent dehydration proceeded
smoothly to afford the iodochromene 20 in 96% overall yield.27,28
We envisioned that the boronic acid 6 could be synthesized from
20 by lithium-iodine exchange with n-BuLi, followed by treatment
of the phenyllithium with triisopropyl borate and hydrolysis of the
resulting boronate ester.29 The viability of this method was tested
on p-methoxymethylphenyl iodide (21) (Scheme 4), synthesized
by protection of the hydroxy group of p-iodophenol as the
methoxymethyl ether.16 A solution of phenyl iodide 21 in THF
was therefore sequentially treated with n-BuLi, triisopropyl borate,
and NH4Cl in one pot. Following this procedure, a small amount
of the targeted boronic acid 22 was obtained plus appreciable
quantities of the deiodinated material. It was evident from these
results that the lithium-iodine exchange occurred rapidly as
expected and that the generated aryllithium was very unstable.
Optimum results were obtained by changing the solvent system
to THF/Et2O (1:2) and the sequence in which the reagents were
added, by employing the “in situ quench” procedure developed by
Li and co-workers.30 Accordingly, the boronic acid 22 was prepared
in a one-pot sequence that involved addition of n-BuLi to a solution
of aryl iodide 21 and triisopropyl borate in THF/Et2O (1:2), followed
Having successfully synthesized kraussianone 1 (1), we took
advantage of the available materials and the optimized reaction
conditions to synthesize genistein (3) and eriosemaone D (2).
Eriosemaone D (2) was isolated from E. tuberosum A.Rich,14,15
but its total synthesis has not been disclosed. The synthesis of
genistein (2) by the Suzuki-Miyaura reaction has also not been
published. As shown in Scheme 5, genistein (3) was synthesized
in 66% yield over two steps, by coupling the boronic acid 22 to
3-iodochromone 5,19,31 followed by removal of MOM protecting
groups under similar conditions to those employed for 4. Eriose-
maone D (2) on the other hand was synthesized by benzyl
deprotection of the pyranoisoflavone 4 with BCl3.13 The physical
properties and the spectroscopic data of all the synthesized
compounds were in agreement with those of the isolated natural
compounds. This represents the first total synthesis of kraussianone
1 (1) and eriosemaone D (2) and the first synthesis of genistein
using the Suzuki-Miyaura reaction.
In conclusion, kraussianone 1 (1) and the structurally related
isoflavones eriosemaone D (2) and genistein (3) have been
successfully synthesized by employing the Suzuki-Miyauara
reaction as the key step. The successful synthesis of kraussianone
1 (1), via a route that readily gives entry to analogues, will allow
for further investigations of its pharmacological properties and
structure-activity relationship studies.

1682 Journal of Natural Products, 2010, Vol. 73, No. 10
Scheme 3. Synthesis of Boronic Acid 6
Selepe et al.
The melting points were measured on a Reichert electrothermal
melting point apparatus and are uncorrected. IR spectra were recorded
with a Perkin-Elmer spectrophotometer, and NMR spectra on a Bruker
AVANCE DPX400 spectrometer. 11B NMR spectra were referenced
against an external standard of neat BF3 ·OEt2 containing a capillary
Scheme 4. Model Reaction for Synthesis of Boronic Acid
1
tube of acetone-d6 for deuterium lock. The chemical shifts from H
NMR and 13C NMR spectra are reported in parts per million relative
to the residual protonated or deuterated solvents peaks (CDCl3: δH 7.26,
δC 77.0 and DMSO-d6: δH 2.50, δC 39.5). The spin multiplicities are
given as s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q
(quartet), br (broad), or m (multiplet). The mass spectra were recorded
on a Thermo Finnigan GC-MS ion trap using electron-impact ionization
or on a time-of-flight Waters LCT Premier MS using electrospray
ionization in the positive or negative mode.
Scheme 5. Synthesis of Kraussianone 1 (1), Eriosemaone D (2),
and Genistein (3)
2′-Hydroxy-4′,6′-dimethoxymethoxyacetophenone (9). Catalytic
ZnBr2 was dissolved in dimethoxymethane (2.62 mL, 29.74 mmol)
under an N2 atmosphere, and then AcCl (2.12 mL, 29.74 mmol) was
added dropwise to the stirred solution. The solution was stirred for an
additional 2 h at room temperature and transferred via a cannula to an
ice-cold solution of the predried phloroacetophenone (7) (2.0 g, 11.89
mmol) and DIA (3.6 mL, 23.59 mmol) in CH2Cl2 (100 mL) under an
N2 atmosphere. The mixture was stirred for 3 h, diluted with saturated
NH4Cl solution (40 mL), and stirred for an additional 15 min. The two
phases were partitioned, and the aqueous phase was extracted with
CH2Cl2 (2 × 30 mL). The combined organic extracts were washed
with brine (3 × 100 mL) and dried over anhydrous MgSO4. The solvent
was evaporated to give a yellow oil, which was purified by column
chromatography using Hex/EtOAc (7:3) as eluent to afford 9 as a
colorless oil (1.53 g, 50%): IR (neat) νmax 3100, 2925, 1618 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 13.68 (1H, s, OH), 6.26 (1H, d, J ) 2.4
Hz, H-3′), 6.24 (1H, d, J ) 2.4 Hz, H-5′), 5.25 (2H, s, OCH2O), 5.16
(2H, s, OCH2O), 3.52 (3H, s, OCH3), 3.47 (3H, s, OCH3), 2.65 (3H, s,
COCH3); 13C NMR (CDCl3, 100 MHz) δ 203.1 (C, C-1), 167.3 (C,
C-2′), 163.3 (C, C-4′), 160.5 (C, C-6′), 107.3 (C, C-1′), 97.3 (CH, C-
3′), 94.5 (CH, C-5′), 94.0 (CH2, 2 × OCH2O), 56.7 (CH3, OCH3), 56.4
(CH3, OCH3), 32.9 (CH3, -COCH3); EIMS m/z 225 (10%), 209 (29),
207 (100), 191 (22), 44 (40), 40 (62).
3-(N,N-Dimethylamino)-1-(2′-hydroxy-4′,6′-dimethoxymethoxy-
phenyl)propenone (10). DMF-DMA (0.29 mL, 2.19 mmol) was added
to 9 (0.28 g, 1.09 mmol) at 95 °C. The mixture was stirred at the same
temperature for 1.5 h. The volatiles in the orange oil were evaporated
on a rotary evaporator, and the crude solid was subjected to flash
chromatography using Hex/EtOAc (1:1) as eluent. Evaporation of the
solvent gave 10 as a yellow oil, which solidified upon cooling (0.23 g,
68%). The solid was recrystallized to give yellow needle-like crystals
(1:1 Hex/Et2O): mp 85-86 °C; IR (KBr) νmax 3445, 3163, 2913, 1606,
1233 cm-1; 1H NMR (CDCl3, 400 MHz) δ 15.08 (1H, s, OH-2′), 7.92
(1H, d, J ) 12.0 Hz, H-3), 6.29 (1H, d, J ) 12.0 Hz, H-2), 6.26 (1H,
Experimental Section
General Experimental Procedures. Abbreviations: DIA, diisopro-
pylamine; DMF-DMA, N,N-dimethylformamide dimethylacetal; Hex,
hexanes (bp 68-70 °C); p-TSA, p-toluenesulfonic acid. Hex used for
chromatographic purifications was distilled prior to use. Anhydrous
CH2Cl2, CH3CN, THF, and Et2O were obtained from Innovative
Technologies (Newburyport, MA) Pure-Solv 800 solvent purification
system. Reagents used for syntheses were purchased from Fluka, Sigma-
Aldrich, or Merck and were used without further purification unless
otherwise stated. 2′,4′,6′-Trihydroxyacetophenone monohydrate was
dried in an oven at 90 °C for 24 h prior to use. Reactions were
monitored by TLC. The TLC was performed on Merck silica gel plates
(60 F254) and visualized under UV light (254 nm). Alternatively,
detection of spots on the TLC was achieved by heating with a heat
gun after treatment with a solution of anisaldehyde in concentrated
H2SO4 and EtOH prepared in the volume ratio 1:1:18, respectively.
Column chromatography was performed using Merck Kieselgel 60
(230-400 mesh). Centrifugal chromatography was performed on a
Harrison Research Chromatotron model 7924T on glass plates coated
with Merck silica gel with particle size 0.040-0.063 mm, 2-4 mm
thick.

Synthesis of the PyranoisoflaVone Kraussianone 1
Journal of Natural Products, 2010, Vol. 73, No. 10 1683
d, J ) 2.4 Hz, H-3′), 6.17 (1H, d, J ) 2.4 Hz, H-5′), 5.20 (2H, s,
OCH2O), 5.14 (2H, s, OCH2O), 3.51 (3H, s, OCH3), 3.46 (3H, s, OCH3),
3.13 (3H, brs, N(CH3)2), 2.94 (3H, brs, N(CH3)2); 13C NMR (CDCl3,
100 MHz) δ 190.6 (C, C-1), 166.9 (C, C-2′), 161.3 (C, C-4′), 158.9
(C, C-6′), 154.4 (CH, C-3), 107.1 (C, C-1′), 97.9 (CH, C-3′), 97.0 (CH,
C-2), 95.2 (CH2, OCH2O), 94.5(CH, C-5′), 94.1 (CH2, OCH2O), 56.7
(CH3, OCH3), 56.3 (CH3, OCH3), 45.5 (CH3, N(CH3)2), 37.2 (CH3,
N(CH3)2); HRMS-ES m/z [M + Na]+ 334.1267 (calcd for C15H21NO6Na
334.1267).
a stirred solution of chromanone 12 (1.00 g, 5.21 mmol) in dry CH3CN
(30 mL). The reaction mixture was refluxed for 8 h under N2. The
mixture was cooled to room temperature, acidified with 2 M HCl (40
mL), and extracted with EtOAc (3 × 20 mL). The organic extracts
were combined and washed with H2O (25 mL) and brine (25 mL),
then dried over anhydrous MgSO4. The solvent was removed with a
rotary evaporator and the crude product purified on a chromatotron
using a Hex/EtOAc (7:3) solvent mixture. The product 16 was obtained
as white crystals after evaporation of the solvent and recrystallization
from Hex (1.30 g, 88%): mp 55-56 °C; IR (KBr) νmax 3324, 2982,
3-Iodo-5,7-dimethoxymethoxychromone (5). To a solution of
propenone 10 (0.12 g, 0.38 mmol) in CH2Cl2 (20 mL) was added
pyridine (0.06 mL, 0.74 mmol) followed by I2 (0.11 g, 0.44 mmol).
The resulting solution was stirred at room temperature for 12 h. The
reaction was quenched with a saturated Na2S2O3 solution (10 mL), and
the two phases were partitioned. The aqueous phase was extracted with
CH2Cl2 (2 × 20 mL). The organic layers were combined, washed with
H2O (15 mL) and brine (15 mL), and dried over anhydrous MgSO4.
The solvent was evaporated to give a yellow solid. The crude product
was purified on a chromatotron using Hex/EtOAc (7:3) as eluent. The
solvent was evaporated to afford a cream-white solid (94 mg), which
was identified (1H NMR) as a mixture of 5 and 11 in the ratio 50:7,
respectively. Therefore, the percentage yield of compound 5 was 58%:
IR (KBr) νmax 3179, 3099, 3058, 2958, 2904, 1622, 1445, 1275, 1140,
1036, 921, 844 cm1; 1H NMR (CDCl3, 400 MHz) δ 8.09 (1H, s, H-2),
6.75 (1H, d, J ) 2.3 Hz, H-8), 6.71 (1H, d, J ) 2.3 Hz, H-6), 5.29
(2H, s, OCH2O), 5.22 (2H, s, OCH2O), 3.54 (3H, s, OCH3), 3.49 (3H,
s, OCH3); 13C NMR (CDCl3, 100 MHz) δ 171.2 (C, C-4), 161.5 (C,
C-7), 159.2 (C, C-5), 158.3 (C, C-8a), 155.6 (CH, C-2), 108.8 (C, C-4a),
102.1 (CH, C-6), 96.8 (CH, C-8), 95.5 (CH2, OCH2O), 94.4 (CH2,
OCH2O), 89.4 (C, C-3), 56.7 (CH3, OCH3), 56.5 (CH3, OCH3); HRMS-
ES m/z [M + Na]+ 392.9834 (calcd for C13H14O6NaI 392.9835).
7-Hydroxy-2,2-dimethyl-4-chromanone (12). Resorcinol (8) (1.0
g, 9.1 mmol) and 3-methyl-2-butenoic acid (0.91 g, 9.1 mmol) were
added simultaneously under N2 to a stirred mixture of CH3SO3H (14.5
mL, 218.2 mmol) and P2O5 (0.7 g, 5.1 mmol) at 70 °C. The reaction
mixture was stirred at the same temperature for 30 min, cooled to room
temperature, and poured into ice-water (150 mL). The aqueous phase
was extracted with Et2O (3 × 25 mL), and the combined organic
extracts were washed with H2O (2 × 50 mL) and brine (25 mL) and
dried over anhydrous MgSO4. The solvent was evaporated to afford a
yellow solid. The solid was purified by flash chromatography using
Hex/EtOAc (3:2) as mobile phase to give chromanone 12 as a light
yellow solid (1.61 g, 92%). Recrystallization of the solid afforded white
crystals (9:1 CH2Cl2/Et2O): mp 170.0-171.5 °C (lit.20 172-174 °C);
2964, 2890, 1672, 1604, 1441, 1319, 1258, 1164, 1000, 988, 840 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 7.81 (1H, d, J ) 8.4 Hz, H-5),
7.32-7.43 (5H, m, PhCH2), 6.62 (1H, dd, J ) 1.9 and 8.4 Hz, H-6),
6.46 (1H, d, J ) 1.9 Hz, H-8), 5.08 (2H, s, PhCH2), 2.66 (2H, s, H-3),
1.45 (6H, s, 2 × CH3); 13C NMR (CDCl3, 100 MHz) δ 191.2 (C, C-4),
165.7 (C, C-7), 161.8 (C, C-8a), 136.2 (PhCH2), 128.7 (PhCH2), 128.3
(CH, C-5), 128.2 (PhCH2), 127.5 (PhCH2), 113.1 (C, C-4a), 109.8 (CH,
C-6), 102.2 (CH, C-8), 79.6 (C, C-2), 70.2 (CH2, PhCH2), 48.6 (CH2,
C-3), 26.7 (2 × CH3); HRMS-ES m/z [M + Na]+ 305.1149 (calcd for
C18H18O3Na 305.1154).
7-Benzyloxy-6-iodo-2,2-dimethyl-4-chromanone (18). CF3CO2Ag
(94 mg, 0.426 mmol) was added to a solution of 16 (100 mg, 0.355
mmol) in CHCl3 (10 mL). The mixture was stirred for 5 min, and then
a solution of I2 (90 mg, 0.355 mmol) in CHCl3 (20 mL) was added
dropwise to the stirred suspension. The resulting mixture was stirred
at room temperature for 12 h. The solution was filtered to remove the
AgI, and the filtrate was washed with Na2S2O3 solution (10%, 30 mL),
NaHCO3 solution (5%, 30 mL), H2O (50 mL), and brine (30 mL). The
organic phase was dried over anhydrous MgSO4, and the solvent was
evaporated to give a cream-white solid. The solid was purified by flash
chromatography using Hex/EtOAc (6:4) as eluent to afford iodochro-
manone 18 as a white solid (136 mg, 94%). Recrystallization of the
solid from CH3OH gave colorless needles: mp 128-130 °C; IR (KBr)
ν
max 2983, 1661, 1583, 1262 cm1; 1H NMR (CDCl3, 400 MHz) δ 8.28
(1H, s, H-5), 7.48 (2H, d, J ) 7.5 Hz, PhCH2), 7.41 (2H, t, J ) 7.5
Hz, PhCH2), 7.34 (1H, t, J ) 7.3 Hz, PhCH2), 6.40 (1H, s, H-8), 5.14
(2H, s, PhCH2), 2.65 (2H, s, H-3), 1.44 (6H, s, 2 × CH3); 13C NMR
(CDCl3, 100 MHz) δ 194.2 (C, C-4), 162.8 (C, C-7), 162.1 (C, C-8a),
137.3 (CH, C-5), 135.6 (PhCH2), 128.7 (PhCH2), 128.2 (PhCH2), 127.0
(PhCH2), 116.0 (C, C-4a), 101.3 (CH, C-8), 80.1 (C, C-2), 77.2 (C,
C-6), 71.1 (CH2, PhCH2), 48.2 (CH2, C-3), 26.6 (2 × CH3); HRMS-
ES m/z [M + Na]+ 431.0118 (calcd for C18H17O3NaI 431.0120).
7-Benzyloxy-6-iodo-2,2-dimethyl-4-chromanol (19). To a solution
of 18 (0.295 g, 1.05 mmol) in THF (5 mL) was added NaBH4 (0.20 g,
5.25 mmol) in EtOH (20 mL). The resulting solution was refluxed for
3 h. The reaction mixture was cooled to room temperature, quenched
with saturated NH4Cl solution (40 mL), and extracted with EtOAc (3
× 20 mL). The organic phases were combined, washed with saturated
NaHCO3 solution (20 mL), brine (20 mL), and H2O (20 mL), and dried
over anhydrous MgSO4. The organic layer was concentrated, and the
product was purified by flash chromatography using a Hex/EtOAc (1:
1) solvent system to afford chromanol 19 as a colorless oil (0.282 g,
95%), which eventually solidified. The solid was recrystallized from
Hex/Et2O (3:2) to give white crystals: mp 90-92 °C; IR (KBr) νmax
IR (KBr) νmax 3129, 2967, 2837, 1578, 1252, 1169, 1126, 854 cm-1
;
1H NMR (DMSO-d6, 400 MHz) δ 7.58 (1H, d, J ) 8.4 Hz, H-5), 6.43
(1H, dd, J ) 1.9 and 8.4 Hz, H-6), 6.24 (1H, d, J ) 1.9 Hz, H-8), 2.65
(2H, s, H-3), 1.36 (6H, s, 2 × CH3); 13C NMR (DMSO-d6, 100 MHz)
δ 190.1 (C, C-4), 164.7 (C, C-7), 161.4 (C, C-8a), 127.9 (CH, C-5),
112.8 (C, C-4a), 109.8 (CH, C-6), 102.8 (CH, C-8), 79.3 (C, C-2),
47.8 (CH2, C-3), 26.2 (2 × CH3); HRMS-ES m/z [M + Na]+ 215.0687
(calcd for C11H12O3Na 215.0684).
7-Hydroxy-6-iodo-2,2-dimethyl-4-chromanone (13). A solution of
chromanone 12 (0.15 g, 0.78 mmol), HIO3 (0.03 g, 0.17 mmol), and I2
(0.08 g, 0.32 mmol) in CH3OH/H2O (3:1, 10 mL) was heated to 85 °C
for 12 h. The CH3OH was evaporated to give a yellow residue, which
was diluted with EtOAc (20 mL) and H2O (25 mL). The two phases
were partitioned, and the aqueous phase was extracted with EtOAc (2
× 20 mL). The combined organic extracts were washed with saturated
Na2S2O3 solution (20 mL), H2O (40 mL), and brine (30 mL) and dried
over anhydrous MgSO4. Evaporation of solvent gave a yellow solid,
which was washed with hot CH2Cl2, cooled, and filtered. The residue
was recrystallized from CH2Cl2/EtOAc (8:2) to give pure 13 (0.16 g,
65%). The mother liquor, which contained mostly 7-hydroxy-8-iodo-
2,2-dimethyl-4-chromanone (14), was evaporated to give a yellow solid
(49 mg). Compound 13 had mp 195-197 °C; IR (KBr) νmax 2978,
3782, 3467, 2982, 2929, 1579, 1460, 1278, 1163, 1129, 1035 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 7.83 (1H, s, H-5), 7.49 (2H, d, J ) 7.5
Hz, PhCH2), 7.39 (2H, t, J ) 7.6 Hz, PhCH2), 7.32 (1H, t, J ) 7.3 Hz,
PhCH2), 6.36 (1H, s, H-8), 5.07 (2H, s, PhCH2), 4.75 (1H, brq, J )
7.5 Hz, H-4), 2.17 (1H, brd, J ) 7.3 Hz, OH-4), 2.10 (1H, dd, J ) 6.0
and 13.6 Hz, H-3b), 1.80 (1H, dd, J ) 8.5 and 13.6 Hz, H-3a), 1.43
(3H, s, CH3), 1.30 (3H, s, CH3); 13C NMR (CDCl3, 100 MHz) δ 157.8
(C, C-7), 154.9 (C, C-8a), 138.0 (CH, C-5), 136.6 (PhCH2), 128.5
(PhCH2), 127.9 (PhCH2), 127.0 (PhCH2), 119.5 (C, C-4a), 101.8 (CH,
C-8), 76.2 (C, C-2), 75.2 (C, C-6), 70.8 (CH2, PhCH2), 62.9 (C, C-4),
42.6 (CH, C-3), 28.8 (CH3), 25.9 (CH3); HRMS-ES m/z [M + Na]+
433.0280 (calcd for C18H19O3NaI 433.0277).
1
2922, 2702, 1641, 1563, 1327, 1259, 849 cm1; H NMR (DMSO-d6,
7-Benzyloxy-6-iodo-2,2-dimethylchromene (20). p-TSA (0.012 g,
0.058 mmol) was added to a solution of chromanol 19 (0.12 g, 0.29
mmol) in THF (15 mL) under N2. The resulting solution was refluxed
under N2 for 2 h. A NaOH solution (10%, 15 mL) was added to the
cooled reaction mixture, and the mixture was extracted with Et2O (3
× 15 mL). The combined organic extracts were washed with H2O (40
mL) and brine solution (30 mL) and dried over anhydrous MgSO4.
Evaporation of the solvent afforded a colorless oil, which solidified
upon cooling. The solid was successively recrystallized from Hex and
400 MHz) δ 7.96 (1H, s, H-5), 6.40 (1H, s, H-8), 2.67 (2H, s, H-3),
1.36 (6H, s, 2 × CH3); 13C NMR (DMSO-d6, 100 MHz) δ 189.2 (C,
C-4), 163.1 (C, C-7), 161.1 (C, C-8a), 136.3 (CH, C-5), 114.9 (C, C-4a),
102.8 (CH, C-8), 79.8 (C, C-2), 76.4 (C, C-6), 47.4 (CH2, C-3), 26.1
(2 × CH3); HRMS-ES m/z [M + Na]+ 340.9656 (calcd for C11H11O3NaI
340.9651).
7-Benzyloxy-2,2-dimethyl-4-chromanone (16). K2CO3 (2.16 g,
15.63 mmol) and BnBr (1.2 mL, 10.42 mmol) were added under N2 to

1684 Journal of Natural Products, 2010, Vol. 73, No. 10
Selepe et al.
CH3OH to give iodochromene 20 as white fluffy crystals (0.112 g,
97%): mp 63-65 °C; IR (KBr) νmax 3032, 2972, 2924, 1713, 1602,
organic layers were combined, washed with 1 M HCl (40 mL), H2O
(40 mL), and brine (40 mL), and dried over anhydrous MgSO4.
Evaporation of the solvent followed by column chromatography gave
23 as a yellowish oil (70 mg, 74%): IR (KBr) νmax 3422, 3034, 2974,
1
1480, 1454, 1358, 1158, 736 cm-1; H NMR (CDCl3, 400 MHz) δ
7.49 (2H, d, J ) 7.3 Hz, PhCH2), 7.40 (2H, t, J ) 7.3 Hz, PhCH2),
7.37 (1H, s, H-5), 7.32 (1H, t, J ) 7.2 Hz, PhCH2), 6.41 (1H, s, H-8),
6.22 (1H, d, J ) 9.9 Hz, H-4), 5.48 (1H, d, J ) 9.9 Hz, H-3), 5.10
(2H, s, PhCH2), 1.42 (6H, s, 2 × CH3); 13C NMR (CDCl3,100 MHz)
δ 157.9 (C, C-7), 154.6 (C, C-8a), 136.5 (PhCH2), 136.0 (CH, C-5),
128.7 (CH, C-3), 128.5 (PhCH2), 127.9 (PhCH2), 127.0 (PhCH2), 120.9
(CH, C-4), 117.0 (C, C-4a), 102.0 (CH, C-8), 76.8 (C, C-2), 74.8 (C,
C-6), 70.9 (CH2, PhCH2), 28.0 (2 × CH3); HRMS-ES m/z [M + Na]+
415.0176 (calcd for C18H17O2NaI 415.0171).
1
2927, 1651,1615, 1496, 1463, 1287, 1146, 1058, 828, 696 cm-1; H
NMR (CDCl3, 400 MHz) δ 13.22 (1H, s, OH-5), 7.79 (1H, s, H-2),
7.27-7.34 (5H, m, PhCH2), 6.96 (1H, s, H-6′), 6.73 (1H, d, J ) 10.0
Hz, H-4′′′), 6.52 (1H, s, H-3′), 6.31 (1H, s, H-8), 6.28 (1H, d, J ) 9.8
Hz, H-4′′), 5.61 (1H, d, J ) 10.0 Hz, H-5′′′), 5.49 (1H, d, J ) 9.8 Hz,
H-5′′), 5.04 (2H, s, PhCH2), 1.47 (6H, s, H-7′′′ and H-8′′′), 1.44 (6H,
s, H-7′′ and H-8′′); 13C NMR (CDCl3,100 MHz) δ 180.9 (C, C-4), 159.3
(C, C-7), 157.5 (CH, C-2′), 157.3 (C, C-8a), 156.9 (C, C-5), 154.7 (C,
C-4′), 154.4 (CH, C-2), 136.8 (PhCH2), 129.1 (CH, C-6′), 128.5
(PhCH2), 128.1 (CH, C-5′′), 128.0 (CH, C-5′′′), 127.8 (PhCH2), 127.2
(PhCH2), 121.6 (CH, C-4′′), 120.6 (C, C-3), 115.6 (CH, C-4′′′), 114.5
(C, C-5′), 112.2 (C, C-1′), 106.2 (C, C-4a), 105.5 (C, C-6), 101.8 (CH,
C-3′), 94.8 (CH, C-8), 77.9 (C, C-6′′′), 76.8 (C, C-6′′), 70.8 (CH2,
PhCH2), 28.3 (2 × CH3, C-7′′′ and C-8′′′), 28.2 (2 × CH3, C-7′′ and
C-8′′); HRMS-ES m/z [M + Na]+ 531.1782 (calcd for C32H28O6Na
531.1784).
Kraussianone 1 (1). BCl3 (0.5 mL, 1 M in heptane) was added to
a solution of 23 (50 mg, 0.1 mmol) in CH2Cl2 (5 mL) cooled to -80
°C. The mixture was stirred under N2 at a temperature below -68 °C
for 30 min. The reaction was quenched with H2O and extracted with
CH2Cl2 (2 × 15 mL). The combined organic extracts were washed
with H2O (20 mL) and brine (20 mL) and dried over anhydrous MgSO4.
Evaporation of the solvent gave a yellow oil, which was purified on a
chromatotron using CH2Cl2 to give 1 (24 mg, 69%) as a yellow solid.
The solid was recrystallized from Hex/CH3OH (4:1): mp 186-188 °C
(lit.1 185-187 °C); IR (KBr) νmax 3336, 2975, 2872, 1649, 1615, 1460,
1132, 773 cm-1; 1H NMR (CDCl3, 400 MHz) δ 12.55 (1H, s, OH-5),
8.27 (1H, s, OH-2′), 7.73 (1H, s, H-2), 6.75 (1H, s, H-6′), 6.74 (1H, d,
J ) 10.0 Hz, H-4′′′), 6.53 (1H, s, H-3′), 6.40 (1H, s, H-8), 6.28 (1H,
d, J ) 9.8 Hz, H-4′′), 5.65 (1H, d, J ) 10.0 Hz, H-5′′′), 5.52 (1H, d,
J ) 9.8 Hz, H-5′′), 1.49 (6H, s, H-7′′′ and H-8′′′), 1.44 (6H, s, H-7′′
and H-8′′); 13C NMR (CDCl3,100 MHz) δ 182.0 (C, C-4), 160.4 (C,
C-7), 157.2 (CH, C-2′), 157.1 (C-8a), 156.4 (C, C-5), 155.7 (C, C-4′),
154.7 (CH, C-2), 128.8 (CH, C-5′′), 128.6 (CH, C-5′′′), 127.1 (CH,
C-6′), 123.1 (C, C-3), 121.3 (CH, C-4′′), 115.28 (CH and C, C-4′′′ and
C-5′), 112.1 (C, C-1′), 107.3 (CH, C-3′), 106.1 (C, C-6), 105.5 (C,
C-4a), 95.0 (CH, C-8), 78.5 (C, C-6′′′), 77.2 (C, C-6′′), 28.4 (2 × CH3,
C-7′′′ and C-8′′′), 28.2 (2 × CH3, C-7′′ and C-8′′); HRMS-ES m/z [M
+ Na]+ 441.1317 (calcd for C25H22O6Na 441.1314).
7-Benzyloxy-2,2-dimethylchromene-6-boronic acid (6). Triiso-
propyl borate (1.8 mL, 7.65 mmol) was added to a stirred solution of
20 (1.0 g, 2.55 mmol) in THF/Et2O (1:2, 75 mL) under N2. The solution
was cooled to -100 °C using a liquid N2 and CH3OH bath, and then
n-BuLi (2.4 mL of a 1.6 M solution in hexanes) was added slowly
with stirring. After 1 h of stirring at a temperature below -78 °C,
saturated NH4Cl solution was added (50 mL). The solution was stirred
for an additional 1 h at room temperature, and the aqueous phase was
extracted with Et2O (3 × 30 mL). The combined organic phases were
washed with H2O (2 × 60 mL) and brine (60 mL) and dried over
anhydrous MgSO4. The solvent was evaporated to give a white solid,
which was purified by column chromatography using Hex/EtOAc (4:
1) as the mobile phase. Evaporation of the solvent gave boronic acid
6 as a fluffy white solid (0.55 g, 70%): IR (KBr) νmax 3367, 3027,
2969, 2928, 1643, 1607, 1567, 1449 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 7.47 (1H, s, H-5), 7.36-7.42 (5H, m, PhCH2), 6.46 (1H, s, H-8),
6.32 (1H, d, J ) 10.1 Hz, H-4), 5.54 (2H, s, B(OH)2), 5.49 (1H, d, J
) 10.1 Hz, H-3), 5.08 (2H, s, PhCH2), 1.44 (6H, s, 2 × CH3); 13C
NMR (CDCl3,100 MHz) δ 165.6 (C, C-7), 157.4 (C, C-8a), 135.8
(PhCH2), 134.8 (CH, C-5), 128.9 (PhCH2), 128.6 (PhCH2), 127.9 (C,
C-3), 127.8 (PhCH2), 121.8 (CH, C-4), 114.9 (C, C-4a), 100.1 (CH,
C-8), 77.1 (C, C-2), 70.9 (CH2, PhCH2), 28.3 (2 × CH3) (C-6 signal
not observed); 11B NMR (CDCl3, 128 MHz) δB 28.74.
2′-Benzyloxy-5,7-dihydroxy-6′′,6′′-dimethylpyrano[2′′,3′′:4′,5′]isofla-
vone (4). To a solution of 5 (0.5 g, 1.28 mmol) in DME/H2O (1:1, 60
mL) were added K2CO3 (0.52 g, 3.82 mmol), boronic acid 6 (0.55 g,
1.77 mmol), and 10% Pd(0)/C (68 mg, 5 mol %). The reaction mixture
was stirred at 40-45 °C for 12 h. The catalyst was filtered and washed
with Et2O and H2O. The organic solvents were evaporated, and the
crude product was diluted with CH3OH (25 mL) and HCl (3 M, 10
mL). The resulting solution was stirred at 50 °C for 18 h. CH3OH was
evaporated, and the reaction mixture was diluted with CH2Cl2 (15 mL)
and H2O (10 mL). The two phases were partitioned, and the aqueous
phase was extracted with CH2Cl2 (2 × 15 mL). The combined organic
phases were washed with NaHCO3 solution (10%, 50 mL), H2O (50
mL), and brine (50 mL). The organic layer was dried over anhydrous
MgSO4. Evaporation of the solvent with a rotary evaporator gave a
yellow oil, which was subjected to column chromatography using Hex/
EtOAc (3:2) as eluent. The solvent was evaporated to give 4 as a
yellowish oil, which solidified upon cooling (0.41 g, 72%). Recrystal-
lization of the solid from Hex/Et2O (1:1) gave white crystals: mp 93-95
°C; IR (KBr) νmax 3255, 2974, 2929, 1650, 1615, 1497, 1277, 1151,
Eriosemaone D (2). Compound 4 (10 mg, 0.023 mmol) was
debenzylated under similar conditions to those applied for 1, and the
product was purified on a chromatotron to give 2 as a yellow solid (6
1
mg, 75%): H NMR (CDCl3, 400 MHz) δ 12.32 (1H, s, OH-5), 8.21
(1H, brs, OH-7 or OH-2), 7.96 (1H, s, H-2), 6.76 (1H, s, H-6′), 6.53
(1H, s, H-3′), 6.44 (1H, d, J ) 2.3 Hz, H-8), 6.37 (1H, d, J ) 2.3 Hz,
H-6), 6.27 (1H, d, J ) 9.8 Hz, H-4′′), 5.53 (1H, d, J ) 9.8 Hz, H-5′′),
1.44 (6H, s, H-7′′ and H-8′′); LRMS-ES m/z [M - H]+ 351.0.
4-Methoxymethoxy-1-iodobenzene (21). AcCl (1.94 mL, 27.27
mmol) was added dropwise to the stirred solution of dimethoxymethane
(2.40 mL, 27.27 mmol) and catalytic ZnBr2 under N2. The solution
was stirred for an additional 2 h at room temperature and transferred
via a cannula to an ice-cold solution of 4-iodophenol (2.0 g, 9.09 mmol)
and DIA (4.16 mL, 27.27 mmol) in CH2Cl2 (100 mL) under an N2
atmosphere. The mixture was stirred for 4 h, diluted with saturated
NH4Cl solution (40 mL), and stirred for an additional 15 min. The two
phases were partitioned, and the aqueous phase was extracted with
CH2Cl2 (2 × 30 mL). The combined organic extracts were washed
with brine (3 × 100 mL) and dried over anhydrous MgSO4. The solvent
was evaporated, and the product was purified with column chroma-
tography using Hex/EtOAc (8:2) to afford 21 as a colorless oil (1.8 g,
75%): IR (neat) νmax 2954, 2901, 2825, 1585, 1483, 1231, 1147, 987,
1
1038, 832, 699 cm-1; H NMR (CDCl3, 400 MHz) δ 12.79 (1H, s,
OH-5), 7.77 (1H, s, H-2), 7.22-7.34 (5H, m, PhCH2), 6.92 (1H, s,
H-6′), 6.50 (1H, s, H-3′), 6.23 (1H, d, J ) 9.8 Hz, H-4′′), 6.21 (1H, d,
J ) 2.2 Hz, H-8), 6.19 (1H, d, J ) 2.2 Hz, H-6), 5.44 (1H, d, J ) 9.8
Hz, H-5′′), 5.03 (2H, s, PhCH2), 1.40 (6H, s, H-7′′ and H-8′′); 13C
NMR (CDCl3,100 MHz) δ 181.0 (C, C-4), 163.0 (C, C-7), 162.5 (C,
C-5), 158.0 (C, C-8a), 157.5 (C, C-2′), 154.8 (C, C-4′), 154.6 (CH,
C-2), 136.6 (PhCH2), 129.2 (CH, C-6′), 128.5 (PhCH2), 128.2 (CH,
C-5′′), 127.9 (PhCH2), 127.3 (PhCH2), 121.5 (CH, C-4′′), 120.8 (C,
C-3), 114.6 (C, C-5′), 112.0 (C, C-1′), 105.8 (C, C-4a), 101.8 (CH,
C-3′), 99.6 (CH, C-6), 94.1 (CH, C-8), 76.8 (C, C-6′′), 70.9 (CH2,
PhCH2), 28.2 (2 × CH3, C-7′′ and C-8′′); HRMS-ES m/z [M + Na]+
465.1312 (calcd for C27H22O6Na 465.1314).
2′-O-Benzylkraussianone 1 (23). 3-Methyl-2-butenal (0.18 mL, 1.85
mmol) was added under an N2 atmosphere to a stirred mixture of
Ca(OH)2 (55 mg, 0.74 mmol) and 4 (82 mg, 0.185 mmol) in CH3OH
(10 mL). The mixture was stirred for 3 days at room temperature.
CH3OH was evaporated, and the reaction mixture was diluted with
EtOAc (15 mL) and H2O (20 mL). The two phases were partitioned,
and the aqueous phase was extracted with EtOAc (2 × 15 mL). The
1
818 cm-1; H NMR (CDCl3, 400 MHz) δ 7.56 (2H, d, J ) 9.0 Hz,
H-2 and H-6), 6.82 (2H, d, J ) 9.0 Hz, H-3 and H-5), 5.14 (2H, s,
OCH2O), 3.46 (3H, OCH3); 13C NMR (CDCl3, 100 MHz) δ 157.0 (C,
C-4), 138.2 (CH, C-2 and C-6), 118.5 (CH, C-3 and C-5), 94.3 (CH2,
OCH2O), 84.3 (C, C-1), 55.9 (CH3, OCH3).
4-Methoxymethoxyphenylboronic acid (22). Triisopropyl borate
(2.21 mL, 9.47 mmol) was added in one portion to the stirred solution
of iodobenzene 21 (1.0 g, 3.79 mmol) in THF/Et2O (60 mL, 1:2) under
N2. The solution was cooled to -100 °C using a liquid N2 and CH3OH
bath, and then n-BuLi (3.79 mL of a 1.5 M solution in hexanes) was

Synthesis of the PyranoisoflaVone Kraussianone 1
Journal of Natural Products, 2010, Vol. 73, No. 10 1685
(2) Drewes, S. E.; Horn, M. M.; Khan, F.; Munro, O. Q.; Dhlamini,
J. T. B.; Rakuambo, C.; Marion Meyer, J. J. Phytochemistry 2004,
65, 1955–1961.
added with stirring over 5 min. After 1 h of stirring at a temperature
below -78 °C, a saturated NH4Cl (30 mL) solution was added. The
mixture was stirred for an additional 1 h, and the two phases were
partitioned. The aqueous phase was extracted with Et2O (2 × 20 mL).
The organic phases were combined, washed with H2O (40 mL) and
brine (40 mL), and dried over anhydrous MgSO4. The solvent was
evaporated to give a white solid, which was subjected to column
chromatography using Hex/EtOAc (4:1) as the mobile phase. The
solvent was evaporated to give boronic acid 22 as a white solid (0.59
(3) Ojewole, J. A. O.; Drewes, S. E.; Khan, F. Phytochemistry 2006, 67,
610–617.
(4) Hoshino, Y.; Miyaura, N.; Suzuki, A. Bull. Chem. Soc. Jpn. 1988,
61, 3008–3010.
(5) Wei, G.; Yu, B. Eur. J. Org. Chem. 2008, 3156–3163.
(6) Zheng, S.-Y.; Shen, Z.-W. Tetrahedron Lett. 2010, 51, 2883–2887.
(7) Jain, A. C.; Jain, S. M. Tetrahedron 1972, 28, 5063–5067.
(8) Jain, A. C.; Sharma, B. N. J. Org. Chem. 1974, 39, 2215–2217.
(9) Jain, A. C.; Kumar, A.; Gupta, R. C. J. Chem. Soc., Perkin Trans. 1
1979, 279–282.
(10) Rao, K. S. R. M.; Iyer, C. S. R.; Iyer, P. R. Tetrahedron 1987, 43,
3015–3019.
(11) Tsukayama, M.; Horie, T.; Iguchi, Y.; Nakayama, M. Chem. Pharm.
Bull. 1988, 36, 592–600.
(12) Tsukayama, M.; Kawamura, Y.; Tamaki, H.; Kubo, T.; Horie, T. Bull.
Chem. Soc. Jpn. 1989, 62, 826–832.
(13) Tsukayama, M.; Kawamura, Y.; Tamaki, H.; Horie, T. Chem. Pharm.
Bull. 1991, 39, 1704–1706.
g, 85%): IR (KBr) νmax 3436, 3359, 1651, 1606, 1235, 1016, 773 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 8.16 (2H, d, J ) 8.6 Hz, H-2 and H-6),
7.15 (2H, d, J ) 8.6 Hz, H-3 and H-5), 5.27 (2H, s, OCH2O), 3.52
(3H, OCH3); 13C NMR (CDCl3, 100 MHz) δ 160.9 (C, C-4), 137.5
(CH, C-2 and C-6), 115.6 (CH, C-3 and C-5), 94.1 (CH2, OCH2O),
56.1 (CH3, OCH3) (C-1 signal not observed); 11B NMR (128 MHz,
CDCl3) δ 28.52.
Genistein (3). 4-Methoxymethoxyphenylboronic acid (22) (42 mg,
0.23 mmol), K2CO3 (51 mg, 0.37 mmol), and catalytic 10% Pd/C were
added to a solution of 3-iodochromone 5 (50 mg, 0.13 mmol) in DME
(2 mL) and H2O (2 mL). The resulting mixture was stirred at 40-45
°C for 12 h. The catalyst was filtered and washed with H2O and Et2O.
The organic solvents were evaporated, and the crude product was diluted
in CH3OH (10 mL) and HCl (3 M, 5 mL). The resulting solution was
refluxed for 30 min. CH3OH was evaporated, and the aqueous phase
was extracted with EtOAc (3 × 15 mL). The combined organic layers
were washed with H2O (30 mL) and brine (30 mL) and dried over
anhydrous MgSO4. The solvent was evaporated, and the crude product
was purified by column chromatography using Hex/EtOAc (3:2) and
recrystallized from EtOH to give the isoflavone 3 as a yellow solid
(23 mg, 66%): mp 300-303 °C (lit.33 301-302 °C); IR (KBr) νmax
(14) Hostettmann, K.; Marston, A. Pure Appl. Chem. 1994, 66, 2231–2234.
(15) Ma, W. G.; Fuzzati, N.; Li, Q. S.; Yang, C. R.; Stoeckli-Evans, H.;
Hostettmann, K. Phytochemistry 1995, 39, 1049–1061.
(16) Berliner, M.; Belecki, K. Org. Synth. 2007, 84, 102.
(17) Gammill, B. R. Synthesis 1979, 901–903.
(18) Hong, R.; Feng, J.; Hoen, R.; Lin, G.-Q. Tetrahedron 2001, 57, 8685–
8689.
(19) Felpin, F.-X.; Lory, C.; Sow, H.; Acherar, S. Tetrahedron 2007, 63,
3010–3016.
(20) Camps, F.; Coll, J.; Messeguer, A.; Pericas, M. A.; Ricart, S. Synthesis
1980, 725–728.
(21) Mujahidin, D.; Doye, S. Eur. J. Org. Chem. 2005, 2689–2693.
1
3434, 3181, 3069, 2922, 1652, 1621, 1176, 809, 784 cm-1; H NMR
(DMSO-d6, 400 MHz) δ 12.93 (1H, s, OH-5), 9.65 (1H, brs, OH-4′),
8.29 (1H, s, H-2), 7.36 (2H, d, J ) 8.8 Hz, H-2′ and H-6′), 6.81 (2H,
d, J ) 8.8 Hz, H-3′ and H-5′), 6.38 (1H, d, J ) 2.1 Hz, H-6), 6.22
(1H, d, J ) 2.1 Hz, H-8); 13C NMR (DMSO-d6, 100 MHz,) δ 182.3
(C, C-4), 166.0 (C, C-7), 163.9 (C, C-5), 159.8 (C, C-4′), 158.9 (C,
C-8a), 154.8 (CH, C-2), 131.2 (CH, C-2′ and C-6′), 124.8 (C, C-1′),
123.3 (C, C-3), 116.8 (CH, C-3′ and C-5′), 106.3 (C, C-4a), 100.1 (CH,
C-6), 94.8 (CH, C-8); HRMS-ES (m/z) [M - H]- 269.0452 (calcd for
C15H9O5 269.0450).
(22) Adimurthy, S.; Ramachandraiah, G.; Ghosh, P. K.; Bedekar, A. V.
Tetrahedron Lett. 2003, 44, 5099–5101.
(23) Aslam, S. N.; Stevenson, P. C.; Phythian, S. J.; Veitch, N. C.; Hall,
D. R. Tetrahedron 2006, 62, 4214–4226.
(24) Hossain, M. M.; Tokuoka, T.; Yamashita, K.; Kawamura, Y.;
Tsukayama, M. Synth. Commun. 2006, 36, 1201–1211.
(25) Weitl, F. L. J. Org. Chem. 1976, 41, 2044–2045.
(26) Haszeldine, R. N.; Sharpe, A. G. J. Chem. Soc. 1952, 993–1001.
(27) Lichtenfels, A. R.; Coelho, A. L.; Costa, R. R. J. Chem. Soc., Perkin
Trans. 1 1995, 949–951.
(28) Lim, J.; Kim, H.-I.; Kim, H. H.; Ahn, K.-S.; Han, H. Tetrahedron
Lett. 2001, 42, 4001–4003.
(29) Brown, H. C.; Cole, T. E. Organometallics 1983, 2, 1316–1319.
Acknowledgment. We are grateful to the National Research
Foundation (South Africa) for financial assistance.
Supporting Information Available: Copies of NMR spectra of
kraussianone 1 (1), eriosemaone D (2), genistein (3), and synthetic
intermediates 4, 5, 6, 10, 13, 18, 19, 20, and 23. This material is
available free of charge via the Internet at http://pubs.acs.org.
(30) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Cai, D.; Larsen,
R. D.; Reider, P. J. J. Org. Chem. 2002, 67, 5394–5397.
(31) Felpin, F.-X. J. Org. Chem. 2005, 70, 8575–8578.
(32) Mondal, M.; Puranik, G. V.; Argade, N. P. J. Org. Chem. 2006, 71,
4992–4995.
References and Notes
(33) Bradbury, R. B. J. Chem. Soc. 1951, 3447–3449.
(1) Drewes, S. E.; Horn, M. M.; Munro, O. Q.; Dhlamini, J. T. B.; Meyer,
J. J. M.; Rakuambo, N. C. Phytochemistry 2002, 59, 739–747.
NP100407N