The synthetic preparation of naturally-occurring aromatase inhibitors, morachalcone A, isogemichalcone B, and isogemichalcone C

Article abstract of DOI:10.1016/j.tet.2013.09.068

A convergent synthesis applicable to the preparation of oxidized prenylchalcones is reported that relies on key Claisen-Schmidt, Mitsunobu, and vinyl/benzyl Stille coupling operations. The synthetic strategy was applied towards the preparation of the natu

Full text of DOI:10.1016/j.tet.2013.09.068

Tetrahedron 69 (2013) 9994e10002
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The synthetic preparation of naturally-occurring aromatase
inhibitors, morachalcone A, isogemichalcone B, and
isogemichalcone C
*
Drew R. Brandt, Kristina M. Pannone, Joseph J. Romano, Eduard G. Casillas
Department of Chemistry, Villanova University, 800 E. Lancaster Ave., Villanova, PA 19085, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2013
Received in revised form 20 September 2013
Accepted 23 September 2013
Available online 27 September 2013
A convergent synthesis applicable to the preparation of oxidized prenylchalcones is reported that relies
on key ClaiseneSchmidt, Mitsunobu, and vinyl/benzyl Stille coupling operations. The synthetic strategy
was applied towards the preparation of the natural products morachalcone A and isogemichalcones B &
C, allowing their preparation in less than 10 steps and 6e8% overall yield.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
Maclura pomifera (the Osage orange tree) and Hypericum Gemini-
florum5 and Broussonetia papyrifera.
Aromatase represents a unique class of enzymes that catalyze
a key oxidative transformation in the biosynthesis of the estrogens,
estrone, and estradiol, through aromatization of their respective
androgen precursors, androstenedione, and testosterone. Through
a sequence of three cytochrome P450-promoted steps, a pendant
methyl (C19) of the androgen A ring is cleaved, allowing for aro-
matization of the resulting enone, providing the phenol charac-
teristic of the estrogens.1
2. Results and discussion
The immediate purpose of this study is to prepare these three
structurally-related naturally-occurring chalcones. The ultimate
intent is to design a synthetic route that would be amenable to
rapid analog preparation in order to effectively explore aromatase
inhibition. In addressing the synthesis, the most readily apparent
disconnections are located at the hydroxycinnamic ester, (for 2 and
3), the aryl-prenyl bond, and the enone (Fig. 1).
Morachalcone A, (1), which does not possess the cinnamate
ester, was prepared with the prenyl and enone disconnections in
mind (Scheme 1). In a previously reported synthesis,6 the phenols
The importance of the estrogens throughout development, be-
ing responsible for the regulation of metabolism, bone growth, the
storage of fat tissue, and secondary sex characteristics, cannot be
overestimated. However, in post-menopausal women, the un-
regulated production and storage of estrogen has been directly
connected with breast cancer.2 Therefore, the inhibition of aro-
matase, as a late focal point in aromatase production, has been used
as attractive therapeutic strategy. Breast cancer treatments target
the enzyme through the use of mechanism-based inactivators, such
as ExemestaneÒ, and competitive inhibitors, such as AnastrozoleÒ.3
As is often the case, natural products can serve as elegant templates
for potential biological activity. As part of a natural product
screening effort for aromatase activity, Kinghorn et al. determined
that the natural products, morachalcone A, isogemichalcone B, and
isogemichalcone C possessed moderate aromatase inhibitory ac-
of commercially available b-resorcylaldehyde (6) were protected as
MOM ethers in 82% yield, while resacetophenone 4 was more
tivity with IC50 values of 4600, 500, and 7100 m
M, respectively.4
Morachalcone A, and isogemichalcones B and C are metabolites of
* Corresponding author. Tel.: þ1 (610) 519 5236; fax: þ1 (610) 519 7167; e-mail
address: eduard.casillas@villanova.edu (E.G. Casillas).
Fig. 1. Morachalcone A and isogemichalcones B and C.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.068

D.R. Brandt et al. / Tetrahedron 69 (2013) 9994e10002
9995
Scheme 1. The synthesis of Morachalcone A.
amenable to monoprotection as a SEM ether, also in 82% yield. That
the peri phenol in the latter example did not readily sustain a pro-
tecting group was advantageous for later, selective prenylation.
After some investigation, it was found that the chalcone core could
be synthesized using a ClaiseneSchmidt condensation of 5 and 7 in
the presence of 150 equiv of ethanolic KOH at room temperature for
18 h.7 Fewer equivalents gave poor conversion, while increased
time or reaction temperatures led to decomposition of the pro-
tecting group. It would be observed repeatedly that only the ther-
modynamically preferred E enone, such as 8 was produced in good
yield (66%), with recovered starting material composing the re-
mainder of the reaction mixture. The simplicity and reliability of
this method would make it a cornerstone of the synthetic strategy.
The free phenol of 8 was envisioned as a handle to install the
prenyl group via a 1,3-prenyl rearrangement, as described by
Talamas8 and Dauben.9 Accordingly, the prenyl ether was prepared
by alkylation of 8 with prenyl chloride in refluxing acetone in 76%
yield. Rearrangement of the O-prenyl ether (9), catalyzed by 10% w/
w FlorisilÒ, in a 100 ꢀC toluene solution for 18 h provided the de-
sired prenylated phenol 10 in a 23% yield that, though modest, was
nevertheless sufficient for the task. Alkylation at the desired ortho
position (10) predominated over the para (w2:1 ratio), with some
accompanying deprenylated material (8). Deprotection of the MOM
and SEM ethers under traditional acid catalysis (1 M HCl in 1:1
isopropanolewater solution) completed the synthesis of mor-
achalcone A (1), in six steps in a 4% overall yield. The spectroscopic
data were consistent with the isolated natural product.10
stannane suitable for a Stille reaction was then identified (Scheme
2).11 In this preparation, diethyl methylmalonate (12) was alkylated
with iodoform to yield a diiodomethyl derivative 13 that was not
isolated, but rather treated with excess NaOH to promote con-
comitant elimination, saponification, and decarboxylation. The re-
sultant vinyl iodide (14) was produced exclusively as the E isomer in
85% yield from the malonate (12). The carboxylic acid was reduced
with LiAlH4 to alcohol 15 that was subsequently protected as a TBS
ether affording iodide 16, both steps proceeding in 87% yield.12 In
this instance, transmetalation of the iodide with n-BuLi, followed
by tributylstannylchloride quench was readily accomplished to give
stannane 17 in 94% yield.13
With the completion of morachalcone A (1), attention then
turned to the preparation of isogemichalcones B and C (2 & 3),
metabolites in which the prenyl group is oxidized on both, but
differ from one another in substitution about the cinnamic ester.
Unfortunately, it was quickly realized that oxidation of the prenyl of
the protected morachalcone A (10) could not be accomplished ef-
ficiently. Though efforts to oxidize the prenyl of 10 using SeO2 were
regioselective for the desired E-allylic alcohol 11, the reaction was
sluggish, poor yielding, and generated equal amounts of over-
oxidized aldehyde.
It was hoped that the Stille coupling would serve as a more
selective, efficient alternative to install the prenyl group. Rather
than attempt a conventional aryl/prenyl coupling, initial efforts
focused on generating the prenyl group via construction of the
benzyl/vinyl bond. A precedented means to prepare a vinyl
Scheme 2. Preparation of vinyl stannane (17) and its subsequent use in
coupling.
a Stille
With protocols for each of the major pieces of the puzzle now
assembled, the next objective was to optimize the order in which
each major fragment (hydroxycinnamate ester, prenyl, resorcinone,
and resorcylaldehyde) was to be installed. Ideally, the synthesis
could be made more convergent by a Stille reaction with an ester-
ified vinyl stannane 23 (Scheme 3) and bromomethylchalcone 27.
To this end, p-coumaric acid (18) was protected in a two-step, one-
pot procedure beginning with exhaustive TBS protection followed
by LiOH-promoted saponification of the resulting TBS-ester to give

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D.R. Brandt et al. / Tetrahedron 69 (2013) 9994e10002
Scheme 3. Protection of cinnamates (20 & 21) and an unsuccessful Stille coupling.
silylated coumaric acid (20) in 90% yield.14 Subsequent attempts to
couple coumarate 20 with iodide 15 under DCC conditions pro-
vided no product, nor was any reaction noted with the corre-
sponding acyl halide or Yamaguchi anhydride. However, Mitsunobu
conditions using a twofold excess of coumarate were successfully
employed to generate the desired ester (22) in 90% yield.15 Pre-
dictably perhaps, the metalation conditions needed to prepare
stannane (23) were shown to be incompatible with the newly
formed ester. Though a method to esterify the coumarate had been
identified, it was determined that the Stille coupling must precede
esterification.
The preparation of benzyl halide 27 necessary for Stille coupling
was also unexpectedly problematic (Scheme 4). Selective MOM
protection of a methyl-substituted acetophenone 24 to give 25 was
straightforward in 94% yield. The earlier success of the Clai-
seneSchmidt condensation was reproduced when 25 was coupled
with benzaldehyde 7 to generate chalcone 26 in good yield (64%) as
the sole stereoisomer. Unfortunately, the normally trustworthy
NBS-promoted radical bromination, using either AIBN in refluxing
CCl4 or benzoyl peroxide initiated by light provided a complex
mixture of halogenated products, in which both the benzylic po-
sition and the acetophenone ring were affected. Having determined
that the assembled chalcone could not be present during the ha-
logenation step, the ClaiseneSchmidt condensation was slotted to
follow the Stille coupling.
Finally, to individually establish the two natural products, the
TBS protecting group was efficiently removed with TBAF to provide
alcohol 31 in 80% yield. The treatment of this alcohol 31 with
coumarate 20 under Mitsunobu conditions was successful in pro-
viding ester 32 in 66% yield. Simultaneous deprotection of the
phenolic TBS and three MOM ethers using 5% HCl in THF proceeded
sluggishly but effectively to provide isogemichalcone B (2) in 52%
yield. Further, there was no evidence of competing isomerization of
the olefin or of cyclization into a flavonoid.
Similarly, ferulic acid (19) was protected using the earlier two-
step exhaustive TBS silylation/saponification strategy to provide
the TBS ether in 95% yield (refer Scheme 3).17 Likewise, the pro-
tected ferulic acid (21) was smoothly converted to the ester (33)
under the same Mitsunobu conditions in 56% yield. The final
deprotection using 5% HCl in THF was selective for the TBS and
MOM ethers, providing isogemichalcone C (3) in high yield (91%),
again without evidence of isomerization or methyl ether removal.
3. Conclusion
Isogemichalcone B (2) was synthesized in 6% overall yield in 10
steps by its longest linear route while isogemichalcone C was
prepared in 8% overall yield in as many steps. Perhaps more im-
portantly, the synthetic approach is convergent and highly ame-
nable to substitution, theoretically providing access to a diverse
Scheme 4. Attempted formation of bromomethylchalcone (27).
Therefore, the optimal ordering of the steps should lead with
Stille coupling to provide the central prenylated acetophenone (29)
to be followed by the ClaiseneSchmidt condensation and finally the
Mitsunobu esterification (Scheme 5). With this in mind, aceto-
phenone 25 was brominated without complication using NBS and
benzoyl peroxide in 97% yield to give the desired benzyl bromide
28. Using a protocol by Peter,16 the pivotal Stille coupling of the
unpurified bromide (28) with vinyl stannane 17 in the presence of
Pd2(dba)3 and AsPh as a co-catalyst successfully generated the
prenylated acetophenone 29 in 52% yield. With the oxidized prenyl
group in place, the ClaiseneSchmidt condensation with MOM-
collection of Isogemichalcone B and C analogs. Further, the three
key reactions (Stille, ClaiseneSchmidt, and Mitsunobu) are com-
patible with a wide range of functional groups. The electronic and
steric requirements of Isogemichalcone B and C can now be probed
by facile modifications to the aryl substituents. Efforts to replace
the phenols of resorcylaldehyde 7 and ferulate 21 with such func-
tionality as eH, eCH3, et-butyl, eCF3, eF, and eCN has begun in the
hopes of creating a small library of analogs that can be used to
explore the structure activity relationships of aromatase inhibition.
4. Materials and methods
protected benzaldehyde
7 (requiring in this instance only
15 equiv of KOH) readily provided the desired chalcone 30 in a re-
Anhydrous reactions were conducted in flame-dried vessels
spectable 61% yield.
under inert atmosphere, using magnetic stirring, and heating

D.R. Brandt et al. / Tetrahedron 69 (2013) 9994e10002
9997
Scheme 5. Completed syntheses of isogemichalcones B and C (2 & 3).
mantles/oil baths, when necessary. Moisture-sensitive reagents
4.2. 2,4-Bis(methoxymethoxy)benzaldehyde (7)
and solvents were added to reaction vessels using oven-dried sy-
ringes through rubber septa. Cited reaction temperatures refer to
sand bath temperatures, not internal reaction temperatures. Unless
otherwise noted, commercially available reagents and solvents
from Aldrich, Acros, Fluka, and Lancaster were used without further
purification. 1H NMR and 13C NMR spectra were recorded on
a Varian NMR spectrophotometer at 300 MHz and 75 MHz, re-
spectively, or a Varian INOVA spectrometer at 400 MHz and
100 MHz, respectively. CDCl3 was used as an internal reference
(7.26 ppm or 77.0 ppm) unless otherwise indicated. Coupling
constants are measured in Hertz. Infrared spectra were recorded on
a PerkineElmer RX1 spectrophotometer. Thin layer chromatogra-
phy analyses were conducted on aluminum-backed Kieselgel 60
A solution of 2,4-dihydroxybenzaldehyde 6 (10.0 g, 72.4 mmol)
in 25 mL THF was cooled to 0 ꢀC, then treated with a 60% sodium
hydride suspension in mineral oil (8.7 g, 217 mmol). After 5 min,
methoxymethyl chloride (17.5 g, 217 mmol) was added and the
mixture was allowed to stir at 65 ꢀC for 18 h. The reaction mixture
was poured onto water, then extracted with EtOAc. The organic
layer was washed with brine and dried over MgSO4. The resulting
orange oil was purified by silica gel chromatography, eluting with
CH2Cl2. Pooled fractions containing product were evaporated to
give 7 as an orange oil that solidified upon standing (13.4 g,
59.2 mmol, 81.8% yield). Structural data was identical to literature
precedents.18 1H NMR (400 MHz, CDCl3)
d 10.35 (s, 1H, CHO), 7.82
F
254 plates, and were visualized by ultraviolet light at 254 nm, or by
(d, J¼8.8 Hz, 1H, H-6), 6.83 (d, J¼1.8 Hz, 1H, H-3), 6.76 (dd, J¼8.7,
treatment with alkaline aq KMnO4, phosphomolybdic acid, or
Hanessian solution. Chromatography was carried out using Baker
60e200 mesh silica gel for columns, silica gel with gypsum on 1, 2,
4, and 6 mm rotors for radial chromatography, an Isco Sg100 using
12, 40 or 120 g prepacked RediSep silica gel cartridges or a Biotage
Horizon HPFC system using 20, 40, 50, 100, or 350 g prepacked
silica gel cartridges.
1.8 Hz, 1H, H-5), 5.28 (s, 2H, OCH2O), 5.22 (s, 2H, OCH2O), 3.53 (s,
3H, OCH3), 3.49 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3):
d 188.3,
163.6, 161.3, 130.3, 120.4, 109.6, 102.8, 94.8, 94.3, 56.5, 56.4; HRMS
(ESI) m/z calcd for
249.0733.
C
11H14O5Na [(MþNa)þ] 249.0739, found
4.3. (2E)-3-(20,40-Bis(methoxymethoxyphenyl))-1-(200-hy-
droxy-400-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)prop-2-
en-1-one (8)
4.1. 1-(2-Hydroxy-4-{[2-(trimethylsilyl)ethoxy]methoxy}phe-
nyl)ethanone (5)
To a solution of aldehyde 7 (3.93 g, 17.4 mmol) and ketone 5
(2.45 g, 8.68 mmol) in 125 mL ethanol was added KOH (73.0 g,
1.30 mol). The resulting mixture was stirred at 25 ꢀC for 18 h, giving
a deep red solution. The reaction mixture was poured onto water
and EtOAc. The organic layer was separated, dried over MgSO4 and
concentrated. The resulting oil was purified by silica gel chroma-
tography, eluting with CH2Cl2, providing 8 as an orange oil (2.81 g,
A solution of 2,4-dihydroxyacetophenone 4 (3.45 g, 22.7 mmol),
and SEMCl (4.54 g, 27.2 mmol) in 22.7 mL of CH2Cl2 was cooled to
0 ꢀC, then treated with diisopropylethylamine (7.03 g, 54.4 mmol).
The solution was warmed to 25 ꢀC and stirred for 18 h. The reaction
mixture was diluted with dichloromethane before being washed
twice with 5% HCl. The organic layer was washed with satd NaHCO3
then dried with brine and Na2SO4. The resulting colorless oil was
purified by silica gel chromatography (gradient elution: 5e20%
EtOAc in hexanes) providing 5 as a white solid (5.24 g, 18.6 mmol,
5.73 mmol, 66.0% yield). 1H NMR (400 MHz, CDCl3):
d 13.46 (s, 1 H,
OH), 8.20 (d, J¼15.5 Hz, 1H, H-2), 7.83 (d, J¼9.1 Hz, 1H, H-60), 7.61 (d,
J¼9.0 Hz, 1H, H-600), 7.58 (d, J¼15.5 Hz, 1H, H-3), 6.87 (d, J¼2.3 Hz,
1H, H-30), 6.75 (dd, J¼8.7, 2.3 Hz, 1H, H-50), 6.64 (d, J¼2.3 Hz, 1H, H-
300), 6.59 (dd, J¼8.7, 2.3 Hz, 1H, H-500), 5.29 (s, 2H, OCH2O), 5.27 (s,
2H, OCH2O), 5.21 (s, 2H, OCH2O), 3.77 (t, J¼8.4 Hz, 2H, CH2), 3.53 (s,
3H, OCH3), 3.50 (s, 3H, OCH3), 0.97 (t, J¼8.4 Hz, 2H, CH2), 0.01 (s, 9H,
82.0% yield). 1H NMR (400 MHz, CDCl3)
d 12.61 (s, 1H, OH), 7.64 (d,
J¼8.9 Hz, 1H, H-6), 6.59 (d, J¼2.4 Hz, 1H, H-3), 6.54 (dd, J¼8.9,
2.4 Hz, 1H, H-5), 5.24 (s, 2H, OCH2O), 3.75 (t, J¼8.2 Hz, 2H, CH2),
2.56 (s, 2H, COCH3), 0.95 (t, J¼8.2 Hz, 2H, CH2), 0.01 (s, 9H,
Si(CH3)3); 13C NMR (100 MHz, CDCl3):
d
202.9, 165.0, 164.0, 132.6,
Si(CH3)3); 13C NMR (100 MHz, CDCl3):
d 192.6, 166.4, 163.8, 160.8,
114.8, 108.4, 103.9, 92.7, 67.0, 26.5, 18.2, e1.3; HRMS (ESI) m/z calcd
158.1, 139.9, 131.4, 130.2, 118.9, 118.6, 115.2, 109.6, 108.2, 104.1, 103.5,
94.9, 94.5, 92.7, 67.0, 56.6, 56.4, 18.2, e1.2; HRMS (ESI) m/z calcd for
for C14H23O4Si [(MþH)þ] 283.1365, found 283.1360.

9998
D.R. Brandt et al. / Tetrahedron 69 (2013) 9994e10002
C25H34O8Si [(MþH)þ] 491.2085, found 491.2096; Anal. Calcd for
6.36 (dd, J¼8.2, 2.2 Hz, 1H, H-50), 6.34 (d, J¼2.0 Hz, 1H, H-3), 5.23 (t,
J¼7.2 Hz, 1H, H-80), 3.30 (d, J¼7.2 Hz, 1H, H-70), 1.78 (s, 3H, H-100),
C
25H34O8Si: C, 61.20; H, 6.99, found C, 60.82; H, 6.92.
1.66 (s, 3H, H-110); 13C NMR (100 MHz, CD3OD):
d 193.2,163.8,162.1,
4.4. (2E)-3-[20,40-Bis(methoxymethoxy)phenyl]-1-(200-[(3-
methylbut-2-en-1-yl)oxy]-400-{[2-(trimethylsilyl)ethoxy]me-
thoxy}phenyl)prop-2-en-1-one (9)
161.5, 159.5, 140.5, 131.1, 130.6, 128.9, 122.5, 116.7, 115.3, 114.4, 107.8,
106.8, 104.6, 102.3, 24.7, 21.3, 16.7; HRMS (ESI) m/z calcd for
C
20H20O5SiNa [(MþNa)þ] 363.1238, found 363.1203.
To a suspension of enone 8 (0.22 g, 0.45 mmol) and potassium
carbonate (0.14 g, 1.0 mmol) in 10 mL acetone was added prenyl
chloride (0.13 g, 1.3 mmol). The reaction mixture was refluxed for
18 h then concentrated to an orange oil. The product was parti-
tioned between EtOAc and water. The organic layer was separated,
dried over MgSO4 and concentrated. The resulting oil was purified
by silica gel chromatography (gradient elution: 5e30% EtOAc in
hexanes) to provide 9 as a yellow oil (0.190 g, 0.34 mmol, 76% yield).
4.7. (2E)-3-[20,40-Bis(methoxymethoxy)phenyl]-1-(200-hy-
droxy-300-[(2E)-4-hydroxy-3-methylbut-2-en-1-yl]-400-{[2-(tri-
methylsilyl)ethoxy]methoxy}phenyl)prop-2-en-1-one (11)
Chalcone 10 (20 mg, 0.036 mmol) was dissolved in 1 mL of THF.
A catalytic amount of SeO2 (0.40 mg, 0.004 mmol) and tert-butyl
hydroperoxide (6.5 mg, 0.070 mmol, 5.5 M in decane) was added.
The reaction mixture as then stirred for 6 h at 25 ꢀC. After filtration,
the crude reaction mixture was purified by reverse phase HPLC (2:5
to 95:5 MeCN in 0.15% aqueous TFA, 50ꢂ20 mm Phenomenex Luna
1H NMR (400 MHz, CDCl3):
d
8.04 (d, J¼15.9 Hz, 1H, H-2), 7.74 (d,
J¼8.6 Hz, 1H, H-60), 7.58 (d, J¼15.9 Hz, 1H, H-3), 7.56 (d, J¼8.7 Hz,
1H, H-600), 6.84 (d, J¼2.4 Hz, 1H, H-30), 6.70 (dd, J¼8.7, 2.2 Hz, 1H, H-
50), 6.64 (m, J¼2H, H-300, 500), 5.52 (t, J¼6.6 Hz, 1H, ]CH), 5.26 (s, 2H,
OCH2O), 5.23 (s, 2H, OCH2O), 5.19 (s, 2H, OCH2O), 4.59 (d, J¼6.6 Hz,
2H, OCH2), 3.77 (t, J¼8.3 Hz, 2H, CH2), 3.49 (s, 3H, OCH3), 3.49 (s, 3H,
OCH3), 1.78 (s, 3H, CH3), 1.74 (s, 3H, CH3) 0.97 (t, J¼8.3 Hz, 2H, CH2),
C
18 column) to afford 11 as a yellow oil (3.0 mg, 15% yield). 1H NMR
(400 MHz, CDCl3):
d
13.59 (s, 1H, OH), 8.17 (d, J¼15.4 Hz, 1H, H-
b),
7.76 (d, J¼9.1 Hz, 1H, H-6), 7.61 (d, J¼15.4 Hz, 1H, H-
a
), 7.60 (d,
J¼9.1 Hz, 1H, H-60), 6.86 (d, J¼2.3 Hz, 1H, H-3), 6.75 (dd, J¼8.5,
2.3 Hz, 1H, H-5), 6.71 (d, J¼9.1 Hz, 1H, H-50), 5.53 (t, J¼6.8 Hz, 1H, H-
80), 5.32 (s, 2H, OCH2O), 5.28 (s, 2H, OCH2O), 5.21 (s, 2H, OCH2O),
3.99 (s, 2H, H-100), 3.76 (t, J¼8.3 Hz, 2H, CH2), 3.52 (s, 3H, OCH3),
3.50 (s, 3H, OCH3), 3.46 (d, J¼6.8 Hz, 2H, H-70), 1.87 (s, 3H, CH3), 0.01
(s, 9H, Si(CH3)3); HRMS (ESI) m/z calcd for C30H43O9Si [(MþH)þ]
575.2702, found 575.2671.
0.01 (s, 9H, Si(CH3)3); 13C NMR (100 MHz, CDCl3):
d 190.7, 161.9,
160.1, 159.9, 157.7, 138.6, 136.5, 132.9, 128.8. 126.2, 123.6, 119.6,
119.5, 108.6, 108.2, 103.6, 101.4, 94.9, 94.5, 93.0, 66.8, 65.9, 56.5,
56.4, 25.9, 18.5, 18.3, ꢁ1.2; HRMS (ESI) m/z calcd for C30H43O8Si
[(MþH)þ] 559.2713, found 559.2722; Anal. Calcd for C30H42O8Si: C,
64.49; H, 7.58, found C, 64.14; H, 7.20.
4.8. Diethyl 2-(diiodomethyl)-2-methylmalonate (13)19
4.5. (2E)-3-[20,40-Bis(methoxymethoxy)phenyl]-1-(200-hy-
droxy-300-(3-methylbut-2-en-1-yl)-400-{[2-(trimethylsilyl)eth-
oxy]methoxy}phenyl)prop-2-en-1-one (10)
A dispersion of 60% NaH in mineral oil (w/w) (9.21 g, 0.230 mol)
was introduced to a flame-dried round bottom flask under inert
gas. Diethyl ether (120 mL) was added to create a suspension.
Diethyl methylmalonate (33.2 g, 0.185 mol) was added slowly over
30 min via syringe, causing gas evolution. After the addition, the
solution was refluxed for 4 h, then cooled to room temperature.
Iodoform (75.0 g, 0.190 mol) was added to the cooled solution. After
the addition, the solution was again refluxed for 36 h. The reaction
mixture was cooled to 0 ꢀC, before 10% aqueous HCl (120 mL) was
added slowly over 20 min. The aqueous layer was extracted three
times with diethyl ether (60 mL). The organic fractions were
combined, dried over MgSO4, filtered and concentrated. The iodide
(13), as a dark brown oil, was used in the next reaction without
purification. 1H NMR spectral data was consistent with that found
To a solution of enone 9 (1.90 g, 3.40 mmol) in 20 mL toluene
was added 60e100 mesh FlorisilÒ (4.50 g). The reaction mixture
was heated at 100 ꢀC for 8 h, then filtered. The filtrate was evapo-
rated then purified by silica gel chromatography (3:1 dichlor-
omethaneehexanes) to give 10 as an orange oil (0.43 g, 0.77 mmol,
23% yield). 1H NMR (400 MHz, CDCl3):
d 13.55 (s, 1H, OH), 8.17 (d,
J¼15.5 Hz, 1H, H- ), 7.75 (d, J¼9.1 Hz, 1H, H-6), 7.61 (d, J¼15.2 Hz,
b
1H, H-
a
), 7.60 (d, J¼9.1 Hz, 1H, H-60), 6.86 (d, J¼2.3 Hz, 1H, H-3),
6.75 (dd, J¼8.6, 2.3 Hz, 1H, H-5), 6.70 (d, J¼9.1 Hz, 1H, H-50), 5.32 (s,
2H, OCH2O), 5.28 (s, 2H, OCH2O), 5.21 (t, J¼7.2 Hz, 1H, H-80), 5.21 (s,
2H, OCH2O), 3.76 (t, J¼8.3 Hz, 2H, CH2), 3.52 (s, 3H, OCH3), 3.49 (s,
3H, OCH3), 3.41 (d, J¼6.8 Hz, 2H, H-70), 1.81 (s, 3H, CH3), 1.67 (s, 3H,
CH3), 0.98 (t, J¼8.3 Hz 2H, CH2), 0.00 (s, 9H, Si(CH3)3); 13C NMR
in the literature.20 1H NMR (300 MHz, CDCl3):
4.22 (q, J¼8.0 Hz, 4H, CH2), 1.80 (s, 3H, CH3), 1.29 (t, J¼8.1 Hz, 6H,
d 5.77 (s, 1H, CHI2),
(100 MHz, CDCl3):
d
193.0, 163.4, 161.0, 160.7, 158.1, 139.6, 131.8,
CH3); 13C NMR (75 MHz, CDCl3):
d 165.9, 62.5 (2), 62.0, 20.2,13.9 (2),
130.2, 128.9, 122.4, 119.3, 118.8, 118.5, 115.3, 109.6, 105.0, 103.5, 94.9,
94.5, 92.5, 66.8, 56.6, 56.5, 26.0, 22.2, 18.3, 18.0, ꢁ1.2; HRMS (ESI) m/
z calcd for C30H43O8Si [(MþH)þ] 559.2710, found 559.2722.
ꢁ26.0; HRMS (EI) (m/z): [Mþ] calcd for C9H14O4I2 439.8982, found,
439.8988.
4.9. (E)-3-Iodo-2-methylacrylic acid (14)19,20
4.6. Morachalcone A, (2E)-1-[200,400-dihydroxy-300-(3-
methylbut-2-en-1-yl)phenyl]-3-(20,40-dihydroxyphenyl)prop-
2-en-1-one (1)
Iodide (13) was dissolved in EtOHeH2O (3:1) (520 mL) then
treated with KOH (28.1 g, 0.500 mol). The solution was refluxed for
24 h, cooled to room temperature, then concentrated to give a red
oil. The oil was treated with 10% aqueous K2CO3 (300 mL) to induce
the precipitation of residual iodoform. The resulting yellow solid
was rinsed with DCM (2ꢂ50 mL) then removed by vacuum filtra-
tion. The filtrate was acidified with concd HCl (130 mL) before being
exhaustively extracted with DCM (5ꢂ35 mL). The combined or-
ganic layers were dried over MgSO4 and concentrated. The crude
product was purified by Biotage flash column chromatography,
eluting with 10% EtOAceHexanes to afford carboxylic acid (14)
(33.5 g, 0.158 mol) as a white solid. The total yield through two
steps was 85.4%. NMR spectral data was consistent with that found
in the literature.12,21 mp¼49.0e50.0 ꢀC; 1H NMR (300 MHz, CDCl3):
The protected chalcone 10 (40 mg, 0.070 mmol) was dissolved in
5 mL of a 1:1 THFei-PrOH solution. Concentrated HCl (0.5 mL) was
added to the solution before stirring for 18 h at 25 ꢀC. EtOAc and
water (15 mL each) were added, the organic layer was separated,
dried over Na2SO4 and concentrated to a red oil. The crude oil was
purified by silica gel chromatography (gradient elution: 2.5e5%
MeOH in CH2Cl2) to provide morachalcone A (1) as an orange
powder (11 mg, 0.032 mmol, 46% yield). Structural data was iden-
tical to literature precedent.4 1H NMR (400 MHz, CD3OD):
d 8.07 (d,
J¼15.6 Hz, 1H, H- ), 7.75 (d, J¼9.0 Hz, 1H, H-6), 7.71 (d, J¼15.4 Hz,
b
1H, H-
a
), 7.50 (d, J¼8.2 Hz, 1H, H-60), 6.40 (d, J¼9.0 Hz, 1H, H-50),

D.R. Brandt et al. / Tetrahedron 69 (2013) 9994e10002
9999
d
d
8.03 (s, 1H, H-3), 2.06 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
169.2, 139.0, 102.0, 19.8; HRMS (EI) (m/z): [Mþ] calcd for C4H7OI
4.13. (E)-3-(40-((tert-Butyldimethylsilyl)oxy)phenyl)acrylic
acid (20)14
197.9542, found, 197.9545.
A solution of p-coumaric acid (4.00 g, 24.4 mmol) (18) and im-
idazole (6.64 g, 97.5 mmol) in DCM (48.0 mL, 0.51 M) was prepared
and cooled to 0 ꢀC then treated with TBSCl (9.12 g, 61.0 mmol). The
solution was allowed to stir for 24 h then quenched with brine
(20.5 mL). The aqueous layer was extracted with EtOAc (2ꢂ25 mL).
The organic fractions were pooled and dried over MgSO4.
4.10. (E)-3-Iodo-2-methylprop-2-en-1-ol (15)12
Carboxylic acid (14) (25.0 g, 118 mmol) was dissolved in diethyl
ether (236 mL, 0.50 M) to produce a pale yellow solution. The so-
lution was cooled to 0 ꢀC. LiAlH4 (4.47 g, 118 mmol) was added in
small portions over 15 min accompanied by hydrogen gas evolu-
tion. The solution was allowed to stir for 4 h at room temperature.
Approximately 0.45 g of additional LiAlH4 (11.8 mmol) was added
and allowed to stir for an additional 30 min to ensure complete
reduction. The mixture was then cooled to 0 ꢀC in an ice/water bath
then quenched by the slow addition of 2 M H2SO4. The aqueous
layer was separated and extracted with DCM (3ꢂ75 mL). The or-
ganics were pooled then washed with 10% aqueous K2CO3 (100 mL).
The washes were back-extracted with DCM (3ꢂ50 mL). The com-
bined organics were dried over MgSO4 and concentrated. Vinyl
alcohol (15) (20.3 g, 103 mmol, 87%) was isolated as a clear oil
without the need for purification. Structural data was identical to
The clear concentrate was dissolved in THFeH2O (80 mL/20 mL)
then saponified with LiOH (1.02 g, 24.4 mmol). After stirring for
10 min, the reaction was quenched with 20 mL of 0.1 M HCl. The
solution was extracted with EtOAc (45 mL). The organic layer was
washed with brine, dried over MgSO4 and concentrated. The crude
product was purified by Biotage flash column chromatography,
eluting with 33% EtOAceHexanes to afford (20) (6.10 g, 21.9 mmol,
90%) as a white solid. 1H NMR spectral data was identical to liter-
ature precedent.14 mp¼128.5e130 ꢀC; 1H NMR (300 MHz, CDCl3):
d
7.75 (d, J¼16.1 Hz, 1H, H-2), 7.46 (dt, J¼8.8, 2.5 Hz, 2H, H-20,60),
6.86 (dt, J¼8.8, 2.2 Hz, 2H, H-30,50), 6.32 (d, J¼16.1 Hz, 1H, H-3), 0.99
(s, 9H, SiC(CH3)3), 0.23 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3)
d
172.5,158.3,146.8,130.0,127.4,120.6,114.9, 25.6,18.2, ꢁ4.4; HRMS
literature precedent.12 1H NMR (300 MHz, CDCl3):
H-3), 4.14 (br d, 2H, H-1), 1.85 (br s, 3H, CH3); 13C NMR (300 MHz,
CDCl3)
147.2, 77.3, 67.1, 21.3; HRMS (EI) (m/z): [Mþ] calcd for
d 6.29 (br s, 1H,
(EI) (m/z) [Mþ] calcd for C15H22O3Si 278.1338, found 278.1336.
d
4.14. (E)-3-(40-((tert-Butyldimethylsilyl)oxy)-30-methox-
yphenyl)acrylic acid (21)17
C4H5O2I 211.9335, found, 211.9338.
A solution of ferulic acid (3.00 g, 15.5 mmol) (19) in DCM
(20.0 mL, 0.77 M) was cooled to 0 ꢀC. DIPEA (8.07 mL, 46.3 mmol)
followed by TBSCl (5.82 g, 38.6 mmol) were added to the solution.
After stirring for 24 h, the solution was diluted with EtOAc
(60.0 mL) then quenched with water (15.0 mL). The layers were
separated then the organic layer was washed with 1 M HCl
(2ꢂ30 mL), brine (30.0 mL), then dried over MgSO4 and concen-
trated. The residue was dissolved in THFeH2O (15 mL/5 mL) then
saponified with solid K2CO3 (2.12 g, 15.4 mmol). After 2 h of stirring,
the solution was quenched with 0.1 M HCl (20.0 mL). The solution
was diluted with EtOAc (60.0 mL) then washed with water
(15.0 mL), 1 M HCl (30.0 mL), brine (30.0 mL), then dried over
MgSO4 and concentrated. The crude product was purified by Biot-
age flash column chromatography, eluting with 40%
EtOAceHexanes to provide (21) (4.54 g, 14.7 mmol, 95.0%) as
a white solid. Mp¼150e152 ꢀC; 1H NMR spectral data was identical
4.11. (E)-1-(tert-Butyldimethylsiloxy)-3-iodo-2-methyl-2-
propene (16)
A solution of alcohol (15) (5.00 g, 25.3 mmol) in DCM (85.0 mL,
0.30 M) was cooled to 0 ꢀC in an ice/water bath then treated with
TBSCl (4.18 g, 27.7 mmol). DIPEA (8.80 mL, 50.5 mmol) was then
added slowly over 5 min. The solution was warmed to room tem-
perature then stirred for 18 h. The resulting red solution was
transferred to a separatory funnel and washed with 5% aqueous HCl
(2ꢂ100 mL), NaHCO3 and brine, then dried over MgSO4 and con-
centrated. The crude product was purified by Biotage flash column
chromatography, eluting with 10% Et2OeHexanes to afford silyl
ether (16) (6.90 g, 22.1 mmol, 87%) as a clear yellow oil. 1H NMR
spectral data was identical to that found in the literature.13 1H NMR
(300 MHz, CDCl3):
d 6.20 (s, 1H, H-3), 4.14 (br s, 2H, H-1), 1.78 (s, 3H,
CH3),
d
0.95 (s, 9H, SiC(CH3)3), 0.10 (s, 6H, Si(CH3)2); 13C NMR
to that found in the literature.17 1H NMR (300 MHz, CDCl3):
d 7.73
(75 MHz, CDCl3)
d
147.0, 76.3, 67.1, 29.9, 26.1, 21.4, ꢁ5.2; HRMS (EI)
(d, J¼16.0 Hz, 1H, H-2), 7.06 (dd, J¼8.0, 2.0 Hz, 1H, H-60), 7.05 (d,
J¼1.9 Hz, 1H, H-20), 6.86 (d, J¼8.7 Hz, 1H, H-50), 6.32 (d, J¼16.1 Hz,
1H, H-3), 3.85 (s, 3H, OCH3), 1.00 (s, 9H, SiC(CH3)3), 0.18 (s, 6H,
(m/z): [Mþ] calcd for C10H21OISi 312.0407, found, 312.0412.
4.12. (E)-1-(tert-Butyldimethylsiloxy)-2-methyl-3-(tributyl-
Si(CH3)2); 13C NMR (75 MHz, CDCl3)
d 172.6, 151.2, 148.0, 147.2,
stannyl)-2-propene (17)
127.9, 122.7, 121.1, 114.9, 110.9, 55.4, 25.6, 18.5, ꢁ4.6; HRMS (EI) (m/
z) [Mþ] calcd for C16H24O4Si 308.1444, found 308.1438.
TBS-protected vinyl iodide (16) (3.5 g, 11 mmol) dissolved in
diethyl ether (56.0 mL, 0.20 M) was cooled to ꢁ78 ꢀC. To the cooled
solution, 2.5 M n-BuLi in hexanes (7.18 mL, 17.9 mmol) was added,
followed immediately by addition of tributyltin chloride (4.87 mL,
17.9 mmol). After 3 h of stirring at low temperature, the solution
was gradually warmed to room temperature over 1 h. The solution
was quenched with H2O (8.00 mL). The organic layer was parti-
tioned, washed once with NaHCO3, and brine, then dried over
MgSO4 and concentrated. The crude product was purified by col-
umn chromatography, eluting with 20% EtOAceHexanes to afford
vinyl stannane (17) (5.00 g, 10.5 mmol, 94%) as a clear oil. 1H NMR
spectral data was identical to that found in the literature.13 1H NMR
4.15. (E)-(E)-300-Iodo-200-methylallyl 3-(40-((tert-butyldime-
thylsilyl)oxy)phenyl)acrylate (22)16
DIAD (0.20 mL, 1.0 mmol) was suspended in THF (3.0 mL) and
stirred. Separately, vinyl alcohol (15) (0.10 g, 0.51 mmol), protected
p-coumaric acid (20) (0.28 g, 1.0 mmol), and PPh3 (0.26 g, 1.0 mmol)
were dissolved in THF (7.00 mL). The latter solution was stirred
until all solids were dissolved. The coumarate solution was trans-
ferred to the suspension of DIAD in THF, then stirred at room
temperature. After 70 h, the solution was diluted in EtOAc and
washed with brine. The organic layer was dried over MgSO4 and
concentrated. Purification though silica gel, eluting with 30%
EtOAceHexanes afforded (22) as a yellow oil, 0.21 g (0.46 mmol,
(300 MHz, CDCl3):
d 5.82 (s, 1H, H-3), 4.11 (s, 2H, H-1), 1.70 (s, 3H,
CH3), 1.50 (m, 18H, Sn(CH2)9), 1.35 (m, 9H, CH3), 0.95 (s, 9H,
SiC(CH3)3), 0.10 (s, 6H, Si(CH3)2) 13C NMR (75 MHz, CDCl3):
d
152.8,
90% yield). 1H NMR (300 MHz, CDCl3):
d
7.66 (d, J¼15.4 Hz, 1H, H-2),
120.3, 69.0, 29.2, 27.3, 26.2, 21.0, 18.4, 13.7, 10.1, ꢁ5.3.
7.43 (d, J¼8.8 Hz, 2H, H-20,60), 6.84 (d, J¼8.8 Hz, 2H, H-30,50), 6.38 (br

10000
D.R. Brandt et al. / Tetrahedron 69 (2013) 9994e10002
s, 1H, H-300), 6.31 (d, J¼16.1 Hz, 1H, H-3), 4.69 (s, 2H, H-100), 1.90 (s,
dried over MgSO4 then concentrated to afford 8.0 g of 28 (28 mmol,
97%) as a yellow oil. 1H NMR (300 MHz, CDCl3):
3H, CH3), 0.98 (s, 9H, Si(CH3)3), 0.22 (s, 6H, Si(CH3)2); 13C NMR
d
7.68 (d, J¼9.1 Hz,
(75 MHz, CDCl3)
d
166.6, 158.1, 145.2, 142.7, 129.8, 127.6, 120.6, 115.1,
1H, H-6), 6.66 (d, J¼9.1 Hz, 1H, H-5), 5.35 (s, 2H, OCH2), 4.82 (s, 2H,
79.8, 67.2, 25.6, 21.7, 18.2, ꢁ4.4; IR (neat, cmꢁ1): 2954, 2929, 2857,
1713, 1633, 1599, 1508, 1253, 906, 833; HRMS (EI) (m/z) [(MþH)þ]
calcd for C19H27IO3Si 458.0775, found 458.0781.
CH2Br), 3.50 (s, 3H, OCH3), 2.60 (s, 3H, COCH3); 13C NMR (75 MHz,
CDCl3):
d 203.1, 162.3, 160.9, 134.3, 130.1, 114.7, 104.8, 93.6, 56.6,
26.3, 21.9; IR (neat, cmꢁ1) 2960.5, 1763.9, 1720.9, 1629.5, 1497.2,
1261.0, 1045.5, 798.1; HRMS (EI) (m/z): [(Mþ)] calcd for C11H13O4Br,
287.9997, found 287.9999.
4.16. 1-(2-Hydroxy-4-(methoxymethoxy))-3-
methylacetophenone (25)
4.19. 1-{3-[(2E)-40-[(tert-Butyldimethylsilyl)oxy]-30-methyl-
but-20-en-10-yl]-2-hydroxy-4-(methoxymethoxy)acetophe-
none (29)16
1-(2,4-Dihydroxy-3-methylphenyl)ethanone
(6.00
g,
36.1 mmol) (24) was dissolved in DCM (110 mL, 0.330 M) to give an
orange solution. DIPEA (15.9 mL, 95.5 mmol) was added causing the
solution to turn a deep red color. Technical grade MOMCl (5.50 mL)
was added, at, which time the solution turned yellow. The solution
was allowed to stir at RT for 18 h before being quenched with H2O.
The aqueous layer was extracted with DCM (2ꢂ30 mL). The organic
fractions were washed once each with NaHCO3, brine, then dried
over MgSO4 and concentrated. The crude product was purified by
Biotage flash column chromatography, eluting with 30%
EtOAceHexanes on a 100 g cartridge to afford (25) (7.14 g,
34.0 mmol, 94%) as white needles. Mp 47.5e49.5 ꢀC; 1H NMR
Pd2(dba)3 (0.635 g, 0.677 mmol) was suspended in anhydrous
THF (7.00 mL, 0.10 M). The subsequent addition of AsPh3 (0.265 g,
0.865 mmol), as a co-catalyst caused the mixture to turn a green
color. After 15 min of stirring, benzyl bromide (28) (2.00 g,
6.92 mmol) was added, followed soon thereafter by a solution of
the vinyl stannane (17) (3.97 g, 8.33 mmol) in THF (1.00 mL) via
syringe. The resulting solution was brought to reflux and stirred for
20 h. The solution was washed with brine (50 mL), satd NaHCO3,
(50 mL), 10% aqueous KF (50 mL) and brine again (50 mL). The or-
ganic solution was passed through a Celite/charcoal pad (1:1 v/v)
that was rinsed with 15% EtOAcehexanes. The eluent was con-
centrated and purified by silica gel chromatography again using 15%
EtOAcehexanes to afford the Stille product (29) (1.41 g, 3.58 mmol,
(300 MHz, CDCl3):
d
7.57 (d, J¼9.1 Hz,1H, H-6), 6.65 (d, J¼9.1 Hz,1H,
H-5), 5.26 (s, 2H, OCH2), 3.48 (s, 3H, OCH3), 2.57 (s, 3H, COCH3), 2.13
(s, 3H, CH3); 13C NMR (75 MHz, CDCl3)
d
203.2, 162.5, 161.3, 129.6,
114.8, 105.0, 105.0, 94.2, 56.4, 26.4, 7.8; IR (neat, cmꢁ1): 2969.0,
2918.4, 1607.0, 1254.8, 1069.5, 798.9; Anal. Calcd for C11H14O4: C,
62.85; H, 6.71, found: C, 62.81; H, 6.81; HRMS (EI) (m/z): [(MþH)þ]
calcd for C11H14O4 210.0892, found, 210.0897.
52%) as a clear oil. 1H NMR (300 MHz, CDCl3):
d 12.75 (s, 1H, OH),
7.56 (d, J¼8.3 Hz, 1H, H-6), 6.63 (d, J¼9.4 Hz, 1H, H-5), 5.49 (tqt,
J¼7.3, 1.8 Hz, 1H, H-20), 5.24 (s, 2H, OCH2), 3.98 (s, 2H, H-40), 3.46 (s,
3H, OCH3), 3.42 (d, J¼7.6 Hz, 2H, H-10), 2.55 (s, 3H, COCH3), 1.78 (s,
3H, CH3), 0.86 (s, 9H, SiC(CH3)3), 0.01 (s, 6H, Si(CH3)2); 13C NMR
4.17. (E)-3-(20,40-Bis(methoxymethoxy)phenyl)-1-(200-hydroxy-
400-(methoxymethoxy)-300-methylphenyl)prop-2-en-1-one (26)
(75 MHz, CDCl3) d 203.0, 162.1, 160.9, 134.7, 129.9, 122.3, 117.8, 114.9,
104.9, 93.9, 68.9, 56.2, 26.3, 25.9, 21.4, 18.4, 13.5, ꢁ5.3; IR (neat,
cmꢁ1) 2955.4, 2929.3, 2855.8, 1628.5, 1256.7, 1046.1, 833.7, 774.9;
HRMS (EI) (m/z): [(MþH)þ] calcd for C21H34O5Si, 395.2254, found
395.2252; Anal. Calcd for C21H34O5Si: C, 63.92; H, 8.69, found C,
63.50; H, 8.69.
Aldehyde (7) (1.0 g, 4.4 mmol) and the protected acetophenone
(25) (1.02 g, 4.85 mmol) were dissolved in EtOH (65.0 mL, 0.070 M).
KOH (4.10 g, 72.9 mmol) was then added to the solution as solid
pellets. As the solution was stirred, the solution color turns to
a deep red color. After 36 h, the reaction mixture was quenched
with 10% aqueous AcOH (60.0 mL) at which time the solution
turned bright yellow. The organic layer was removed, then washed
with NaHCO3 and dried over MgSO4. The residue was crystallized
with Et2Oehexanes to afford 1.18 g (2.82 mmol) of chalcone (26) as
a yellow solid, (64% yield). Mp¼94.5e96.5 ꢀC; 1H NMR (300 MHz,
4.20. (E)-3-(20,40-Bis(methoxymethoxy)phenyl)-1-(300-((E)-1000-
((tert-butyldimethylsilyl)oxy)-900-methylbut-800-en-700-yl)-200-
hydroxy-400-(methoxymethoxy)phenyl)prop-2-en-1-one (30)
Acetophenone (29) (4.74 g, 12.0 mmol) and aldehyde (7) (2.72 g,
12.0 mmol) were dissolved in EtOH (60 mL, 0.20 M). The resulting
solution was treated with KOH (10.1 g, 180 mmol) at which time the
solution turned a dark brown color. After 60 h, the solution was
treated with 10% AcOH until the solution turned bright yellow in
color. The phases were separated and the aqueous phase was
extracted with DCM (3ꢂ20 mL). The pooled organics were washed
with NaHCO3, brine, then dried over MgSO4 and concentrated. The
crude product was purified by Biotage flash column chromatogra-
phy twice, eluting with 5% MeOHeDCM to afford (30) (4.42 g,
CDCl3):
d
8.19 (d, J¼15.7 Hz, 1H, H-2), 7.75 (d, J¼9.1 Hz, 1H, H-60),
7.62 (d, J¼15.4 Hz, 1H, H-3), 7.61 (d, J¼9.1 Hz, 1H, H-600), 6.87 (d,
J¼2.2 Hz, 1H, H-30), 6.75 (dd, J¼8.8, 2.2 Hz, 1H, H-50), 6.69 (d,
J¼9.1 Hz, 1H, H-500), 5.29 (s, 4H, OCH2), 5.21 (s, 2H, OCH2), 3.52 (s,
3H, OCH3), 3.50 (s, 3H, OCH3), 3.50 (s, 3H, OCH3), 2.17 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3)
d 192.7, 163.4, 160.8, 160.4, 157.8, 139.4,
130.0, 128.2, 118.8, 118.4, 114.9, 114.6, 109.3, 104.6, 103.1, 94.6, 94.2,
93.9, 56.4, 56.2, 56.2, 7.8; IR (neat, cmꢁ1) 2956, 2853, 1630, 1603,
1554, 1490, 1259, 1155; Anal. Calcd for C22H26O8: C, 63.15; H, 6.26,
found: C, 63.14; H, 6.29; HRMS (EI) (m/z): [(MþH)þ] calcd for
7.33 mmol, 61%) as a yellow oil. 1H NMR (300 MHz, CDCl3):
d 13.2 (s,
C
22H26O8 418.1628, found, 418.1625.
1H, OH), 8.17 (d, J¼15.8 Hz, 1H, H-3), 7.75 (d, J¼9.4 Hz, 1H, H-600),
7.61 (d, J¼15.5 Hz, 1H, H-2), 7.60 (d, J¼8.8 Hz, 1H, H-60), 6.86 (d,
J¼2.4 Hz, 1H, H-30), 6.75 (dd, J¼8.6, 2.2 Hz, 1H, H-50), 6.68 (d,
J¼9.1 Hz,1H, H-500) 5.52 (br t, 1H, J¼8.1 Hz, H-800), 5.28 (s, 2H, OCH2),
5.27 (s, 2H, OCH2), 5.21 (s, 2H, OCH2), 4.00 (br s, 2H, H-1000), 3.52 (s,
3H, OCH3), 3.50 (s, 6H, OCH3), 3.48 (d, 2H, H-700), 1.80 (s, 3H, H-1100),
0.87 (s, 9H, Si(CH3)3), 0.02 (s, 6H, Si(CH3)2); 13C NMR (75 MHz,
4.18. 1-(3-(Bromomethyl))-2-hydroxy-4-(methoxymethoxy)
acetophenone (28)
A solution of acetophenone (25) (6.00 g, 28.5 mmol) in CCl4
(190 mL, 0.15 M) was placed round bottomed flask fitted with
a reflux condenser. The solution was treated with NBS (5.10 g,
28.7 mmol) and benzoyl peroxide (0.700 g, 2.89 mmol) to form
a yellow solution. The solution was irradiated from a tungsten
lamp, causing the solvent to reflux. After 4 h, the cloudy white
suspension was placed in an ice/water bath to precipitate the spent
solid succinimides. The mixture was filtered and the filtrate was
CDCl3)
d 192.8, 163.3, 160.6, 160.5, 157.9, 139.5, 134.6, 130.1, 128.8,
122.5, 119.1, 118.5, 117.9, 115.2, 109.4, 104.6, 103.3, 94.7, 94.3, 93.8,
68.9, 56.5, 56.3, 56.3, 25.9, 21.4, 18.4, 13.5, ꢁ5.3; HRMS (EI) (m/z):
[(MþH)þ] calcd for C32H47O9Si 603.2989, found 603.2983; IR (neat,
cmꢁ1) 2951.3, 2927.5, 2853.9, 1631.3, 1608.0, 1562.0, 1492.9, 1255.6,
1236.4, 1044.8, 995.4, 834.0; UV (MeCN) (lmax, nm) 202, 210, 242,

D.R. Brandt et al. / Tetrahedron 69 (2013) 9994e10002
10001
370; Anal. Calcd for C32H46O9Si: C, 63.76; H, 7.69, found: C, 63.67; H,
7.47.
4.23. (E)-(E)-1-(3-((E)-
b
0-(2,4-Bis(methoxymethoxy)phenyl)
acryloyl)-(20-hydroxy-4 -(methoxymethoxy)phenyl)-30-meth-
ylbut-90-en-80-yl-(110-(400-(tert-butyldimethylsilyl)oxy)-300-me-
thoxyphenyl)acrylate (33)
4.21. (E)-3-(20,40-Bis(methoxymethoxy)phenyl)-1-(200-hy-
droxy-300-((E)-1000-hydroxy-900-methylbut-800-en-700-yl)-400-(me-
thoxymethoxy)phenyl)prop-2-en-1-one (31)
Chalcone (31) (0.200 g, 0.409 mmol), protected ferulic acid (21)
(0.252 g, 0.817 mmol), and PPh3 (0.215 g, 0.820 mmol) were dis-
solved in THF (5.0 mL) providing a yellow solution. The chalcone
solution was then added to a DIAD (0.16 g, 0.16 mL, 0.81 mmol)
solution in THF (2.0 mL). The resulting solutionwas allowed to stir at
room temperature for 72 h, at which time the solution was diluted
in EtOAc (5 mL) and quenched with brine. The organic layer was
dried over MgSO4 and concentrated. The crude product was purified
by Biotage flash column chromatography, eluting with 40%
EtOAceHexanes on a 50 g cartridge to provide ferulate ester 33
(0.18 g, 0.23 mmol, 56%) as an orange solid. 1H NMR (300 MHz,
Chalcone (30) (1.31 g, 2.17 mmol) was dissolved in THF
(4.45 mL, 0.49 M) producing a yellow solution. The solution was
treated with 1.0 M TBAF in THF (2.60 mL, 2.6 mmol) causing the
solution to turn deep red in color. The solution was stirred for 18 h,
then quenched with H2O. The aqueous phase was extracted with
DCM (3ꢂ10 mL). The organic fractions were pooled then washed
with NaHCO3, brine, then dried over MgSO4 and concentrated. The
crude product was purified by Biotage flash column chromatog-
raphy, eluting with 50% EtOAceHexanes on a 50 g cartridge to
afford alcohol 31 (0.85 g, 1.7 mmol, 80%) as a yellow solid.
CDCl3):
d
8.18 (d, J¼15.4 Hz,1H, H-
b
), 7.77 (d, J¼8.8 Hz,1H, H-60), 7.60
(d, J¼8.8 Hz,1H, H-6), 7.60 (d, J¼15.4 Hz,1H, H- ), 7.60 (d, J¼16.1 Hz,
a
Mp¼90.5e91.5 ꢀC; 1H NMR (300 MHz, CDCl3):
d
8.18 (d, J¼15.8 Hz,
1H, H-700), 7.00 (m, 2H, H-200, H-600), 6.86 (d, J¼2.2 Hz, 1H, H-3), 6.83
(d, J¼8.8 Hz, 1H, H-500), 6.75 (dd, J¼8.1, 2.2 Hz, 1H, H-5), 6.69 (d,
J¼8.8 Hz,1H, H-50), 6.30 (d, J¼15.4 Hz,1H, H-800), 5.65 (br t, J¼6.6 Hz,
1H, H-80), 5.29 (s, 4H, OCH2), 5.21 (s, 2H, OCH2), 4.58 (s, 2H, H-110),
3.83 (s, 3H, OCH3), 3.52e3.47 (m, 11H, H-70& 3ꢂOCH3), 1.90 (s, 3H,
H-100), 0.99 (s, 9H, SiC(CH3)3), 0.16 (s, 6H, Si(CH3)2); 13C NMR
1H, H-3), 7.76 (d, J¼9.2 Hz, 1H, H-600), 7.60 (d, J¼15.8 Hz, 1H, H-2),
7.60 (d, J¼8.8 Hz, 1H, H-60), 6.86 (d, J¼2.6 Hz, 1H, H-30), 6.75 (dd,
J¼8.8, 2.6 Hz, 1H, H-50), 6.68 (d, J¼9.2 Hz, 1H, H-500) 5.54 (br t,
J¼6.6 Hz, 1H, H-800), 5.28 (s, 4H, OCH2), 5.21 (s, 2H, OCH2), 4.00 (d,
J¼5.3 Hz, 2H, H-1000), 3.52 (s, 3H, OCH3), 3.49 (s, 3H, OCH3), 3.49 (s,
3H, OCH3), 3.47 (d, 2H, H-700), 1.87 (s, 3H, H-1100); 13C NMR
(75 MHz, CDCl3) d 192.9, 167.1, 163.3, 160.7, 160.6, 158.0, 151.2, 147.5,
(75 MHz, CDCl3):
d
192.8, 163.3, 160.5, 160.5, 157.9, 139.7, 135.0,
144.7, 139.7, 130.4, 130.2, 129.0, 128.4, 127.2, 122.2, 121.1, 119.1, 118.6,
117.3, 116.0, 115.3, 110.9, 109.5, 104.7, 103.4, 94.8, 94.4, 93.9, 70.2,
56.5, 56.3, 56.3, 55.5, 25.7, 21.7, 18.5, 14.1, ꢁ4.6; IR (neat, cmꢁ1):
3328, 2929, 2855, 1720, 1605, 1505, 156, 1232, 995; Anal. Calcd for
130.1, 128.9, 123.8, 118.9, 118.4, 117.5, 115.2, 109.4, 104.7, 103.3, 94.6,
94.2, 93.8, 69.0, 56.5, 56.3, 56.3, 21.5, 13.8; IR (neat, cmꢁ1) 3327.6,
2971.1, 2907.5, 2826.6, 1630.4, 1605.7, 1563.6, 1492.1, 1272.7,
1234.9, 1154.0, 991.7, 976.2; HRMS (EI) (m/z): [(MþH)þ] calcd for
C
42H54O12Si: C, 64.76; H, 6.99, found: C, 65.22; H, 6.90; HRMS (EI)
C
26H33O9489.2125, found 489.2113; UV (CHCl3) (lmax, nm) 248,
(m/z): [(MþH)þ] calcd for C42H55O12Si 779.3463, found, 779.3448.
292.
4.24. Isogemichalcone B (2)
4.22. (E)-(E)-1-(3-((E)-
b
-(2,4-Bis(methoxymethoxy)phenyl)
Protected isogemichalcone B (32) (0.17 g, 0.23 mmol) was dis-
solved in 1.5 mL of a 5% HCl/THF (1:1 v/v) solution. The solution was
brought to reflux. After 8 h, the solution was cooled to room tem-
perature and diluted with EtOAc. The organic fractions were washed
with NaHCO3, brine, then dried over MgSO4 and concentrated.
When the reaction was found to be incomplete, the reaction mix-
ture was reintroduced to the same conditions for an additional 3 h,
then worked up in the same manner. The crude product was puri-
fied by flash column chromatography, eluting with 100% EtOAc on
a 40 g cartridge to afford (2) (0.06 g, 0.12 mmol, 52%) as an orange
solid. Structural data was identical to that of the isolated natural
acryloyl)-20-hydroxy-40-(methoxymethoxy)phenyl)-30-methyl-
but-90-en-80-yl-(110-(400-((tert-butyldimethylsilyl)oxy)phenyl))
acrylate (32)
Chalcone (31) (0.600 g, 1.23 mmol), protected p-coumaric acid
(20) (0.684 g, 2.46 mmol), and PPh3 (0.645 g, 2.46 mmol) were
stirred in THF (12.3 mL) until all the solids dissolved to give a yellow
solution. This mixture was added to a solution of DIAD (0.485 mL,
0.498 g, 2.46 mmol) in THF (0.50 mL) before being allowed to stir at
room temperature. After 72 h, the solution was diluted in EtOAc
(5 mL) then quenched with brine. The organic layer was dried over
MgSO4 and concentrated. The crude product was purified by Biot-
age flash column chromatography, eluting with 40%
EtOAceHexanes on a 50 g cartridge to provide ester 32 (0.61 g,
product reported in the literature.5
d
1H NMR (300 MHz, acetone-
d6):
d
8.22 (d, J¼15.4 Hz,1H, H-
b
), 7.92 (d, J¼9.5 Hz,1H, H-60), 7.79 (d,
J¼15.4 Hz, 1H, H-
a
), 7.69 (d, J¼8.8 Hz, 1H, H-6), 7.59 (d, J¼15.4 Hz,
1H, H-700), 7.55 (d, J¼8.8 Hz, 2H, H-200, H-600), 6.87 (d, J¼8.8 Hz, 2H, H-
300, H-500), 6.53 (d, J¼8.7 Hz, 1H, H-50), 6.51 (d, J¼2.2 Hz, 1H, H-3),
6.45 (dd, J¼8.8, 2.2 Hz, 1H, H-5), 6.35 (d, J¼16.1 Hz, 1H, H-800), 5.67
(br t, J¼7.0 Hz, 1H, H-90), 4.54 (s, 2H, H-110), 3.46 (d, J¼7.1 Hz, 2H, H-
0.81 mmol, 66%) as a yellow oil. 1H NMR (300 MHz, CDCl3):
d 8.18 (d,
J¼15.4 Hz, 1H, H-
b
), 7.78 (d, J¼9.5 Hz, 1H, H-60), 7.62 (d, J¼16.1 Hz,
1H, H-
a
), 7.61 (d, J¼16.1 Hz, 1H, H-800), 7.60 (d, J¼8.8 Hz, 1H, H-6),
7.40 (d, J¼8.1 Hz, 2H, H-200, 600), 6.86 (d, J¼2.2 Hz, 1H, H-3), 6.83 (d,
J¼8.1 Hz, 2H, H-300, 500), 6.74 (dd, J¼8.8, 2.2 Hz, 1H, H-5), 6.69 (d,
J¼8.8 Hz,1H, H-50), 6.30 (d, J¼15.4 Hz,1H, H-700), 5.64 (br t, J¼7.3 Hz,
1H, H-80), 5.29 (s, 4H, OCH2O), 5.21 (s, 2H, OCH2O), 4.57 (s, 2H, H-
110), 3.52 (s, 3H, OCH3), 3.49 (s, 3H, OCH3), 3.48 (s, 3H, OCH3), 3.46
(d, J¼6.6 Hz, 2H, H-70), 1.90 (s, 3H, H-100), 0.98 (s, 9H, SiC(CH3)3)
70),1.86 (s, 3H, H-100); 13C NMR (75 MHz, CDCl3)
d 193.6,167.3,165.2,
162.5,162.3,160.6,160.0,145.3,141.0,131.8,131.2,130.9,130.9,130.2,
127.7, 127.1, 117.7, 116.7, 116.7, 115.8, 115.5, 115.2, 114.9, 109.3, 108.0,
103.6, 70.2, 22.1,14.2; HRMS (EI) (m/z): [(MþH)þ] calcd for C29H27O8
503.1706, found, 503.1707.
0.21 (s, 6H, Si(CH3)2); 13C NMR (75 MHz, CDCl3):
d
192.9, 167.1,
4.25. Isogemichalcone C (3)
163.3, 160.7, 160.6, 158.0, 157.8, 144.4, 139.7, 130.5, 130.2, 129.6,
129.0, 127.1, 120.5, 119.2, 118, 116.0, 115.4, 109.6, 104.7, 103.5, 94.8,
94.4, 93.9, 77.2, 76.0, 70.1, 56.5, 56.3, 56.3, 25.6, 21.8, 18.2, 14.1, ꢁ4.4;
IR (neat, cmꢁ1) 2955, 2930, 2857, 1709, 1630, 1601, 1563, 1509, 1258,
1080, 1004; Anal. Calcd for C41H52O11Si: C, 65.75; H, 7.00, found: C,
65.56; H, 6.96; HRMS (EI) (m/z) [(MþH)þ] calcd for C41H53O11Si
749.3357, found, 749.3347.
Protected isogemichalcone C (33) (0.18 g, 0.23 mmol) was dis-
solved in a 1.5 mL of a 5% HCl/THF (1:1 v/v) solution. The solution
was brought to reflux. After 8 h, the solution was cooled to room
temperature and diluted with EtOAc. The organic layer was washed
with NaHCO3, brine, then dried over MgSO4 and concentrated. The
crude product was purified by Biotage flash column

10002
D.R. Brandt et al. / Tetrahedron 69 (2013) 9994e10002
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chromatography, eluting with 100% EtOAc on a 20 g cartridge to
afford (3) (0.11 g, 0.21 mmol, 91%) as an orange solid. 1H NMR
spectral data was identical to that of the isolated natural product.4a
1H NMR (300 MHz, acetone-d6):
d
8.21 (d, J¼15.4 Hz, 1H, H-
b
), 7.94
(d, J¼8.9 Hz, 1H, H-60), 7.80 (d, J¼15.4 Hz, 1H, H-
a
), 7.70 (d, J¼8.5 Hz,
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1H, H-6), 7.60 (d, J¼16.0 Hz, 1H, H-700), 7.35 (d, J¼2.3 Hz, 1H, H-200),
7.15 (d, J¼8.7 Hz, 1H, H-600), 6.86 (d, J¼8.5 Hz, 1H, H-500), 6.54 (d,
J¼15.8 Hz, 1H, H-50), 6.52 (br s, 1H, H-3), 6.44 (d, J¼8.4 Hz, 1H, H-5),
6.45 (br d, J¼8.2 Hz, 1H, H-5), 6.35 (d, J¼16.0 Hz, 1H, H-800), 5.70 (br
t, J¼7.0 Hz, 1H, H-80), 4.55 (s, 2H, H-110), 3.99 (s, 3H, OCH3), 3.48 (d,
J¼7.1 Hz, 2H, H-70), 1.91 (s, 3H, H-100); 13C NMR (75 MHz, CDCl3)
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d
193.6, 167.3, 165.2, 162.5, 162.3, 159.9, 150.1, 148.8, 145.6, 141.0,
131.8, 131.3, 130.2, 127.8, 127.6, 124.0, 117.8, 116.1, 116.1, 115.5, 115.2,
114.7, 111.5, 109.3, 108.0, 103.8, 70.3, 56.5, 22.1, 14.2; HRMS (ESI) (m/
z): [(MþH)þ] calcd for C30H29O9 533.1812, found, 503.1799.
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Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.09.068.
References and notes
1. Di Nardo, G.; Gilardi, G. Biotechnol. Appl. Biochem. 2013, 60, 92e101.