Palladium-catalyzed routes to geranylated or farnesylated phenolic stilbenes: Synthesis of pawhuskin C and schweinfurthin J

Article abstract of DOI:10.1055/s-0032-1316765

Starting from double MOM-protected phloroglucinol, the facile total syntheses of bioactive natural products pawhuskin C and schweinfurthin J were accomplished in good overall yields. The Heck, Stille, or Suzuki coupling reactions of two different electron

Full text of DOI:10.1055/s-0032-1316765

PAPER
▌2895
paper
Palladium-Catalyzed Routes to Geranylated or Farnesylated Phenolic
Stilbenes: Synthesis of Pawhuskin C and Schweinfurthin J
Synthesis of Pawhuskin C and Schweinfurthin J
Mandeep Singh, Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008, India
Fax +91(20)25902629; E-mail: np.argade@ncl.res.in
Received: 07.06.2012; Accepted after revision: 08.07.2012
OH
Abstract: Starting from double MOM-protected phloroglucinol,
the facile total syntheses of bioactive natural products pawhuskin C
HO
and schweinfurthin J were accomplished in good overall yields. The
OH
Heck, Stille, or Suzuki coupling reactions of two different electron-
rich phenolic segments bearing geranylated or farnesylated units
were involved in the decisive step. The Sonogashira coupling reac-
OH
tion followed by palladium-catalyzed chemo- and stereoselective
cis-reduction of an alkyne unit and subsequent isomerization to give
the desired natural products is also described.
pawhuskin C
HO
OH
Key words: total synthesis, natural products, geranylated or farne-
sylated stilbenes, palladium-catalyzed coupling reactions, phloro-
glucinol
OH
schweinfurthin J
OH
A large number of prenylated, geranylated, and farnesyl-
ated phenolic compounds exist in nature and they consti-
tute structurally interesting and biologically important
structural architectures.1–6 A few representative examples
of such naturally occurring bioactive phenolic stilbenes
are depicted in Figure 1.7–10 In the synthesis of these target
compounds holding free prenyl, geranyl, or farnesyl
chains, the formation of benzofurans or benzopyrans, cy-
cloaddition products, regioisomeric mixtures, and poly-
meric gums are common difficulties.1–5 Pawhuskin C (1)
was isolated from Dalea purpurea and exhibits opioid ac-
tivity, while schweinfurthin J (2) was from Macaranga
schweinfurthii and exhibits anticancer activity.7,8 Struc-
tural scrutiny revealed that pawhuskin C could be the
biogenetic precursor of schweinfurthin G, while schwein-
furthin J is the farnesyl derivative of naturally occurring
potent anticancer agent resveratrol.7,11 To date, only one
synthesis of pawhuskin C (1) has been published.12 It was
accomplished using an ortho-lithiation strategy to install
the geranyl chain and subsequent appropriate Horner–
Wadsworth–Emmons condensation to form the desired
trans-stilbene. The palladium-catalyzed C–C coupling re-
actions of substrates bearing prenylated, geranylated, or
farnesylated phenolic segments to form stilbenes are not
known in the literature.13–15 The synthesis of natural prod-
ucts 1 and 2 would be feasible via the uncommon aromatic
Claisen rearrangement of the geranyl or farnesyl unit fol-
lowed by Heck, Stille, Suzuki, or Sonogashira coupling
reactions pathways. Herein we report our results for the
synthesis of these stilbene natural products (Schemes 1
and 2).
HO
OH
OH
mappain
HO
OH
HO
OH
pawhuskin A
OH
O
OH
HO
H
OH
schweinfurthin G
Figure 1 Naturally occurring prenylated, geranylated, or farnesylat-
ed phenolic stilbenes.
The double methoxymethyl-protected (MOM) symmetri-
cal phenol 316 on reaction with geranyl bromide or farne-
syl bromide in the presence of potassium carbonate in
N,N-dimethylformamide provided the expected O-gera-
nylated or O-farnesylated products 4a,b in 76–78% yields
(Scheme 1). The products 4a,b underwent a defined
Claisen rearrangement in refluxing N,N-dimethylaniline
SYNTHESIS 2012, 44, 2895–2902
Advanced online publication: 08.08.2012
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DOI: 10.1055/s-0032-1316765; Art ID: SS-2012-Z0504-OP
© Georg Thieme Verlag Stuttgart · New York

2896
M. Singh, N. P. Argade
PAPER
OMOM
OMOM
OMOM
K2CO3, geranyl bromide/
farnesyl bromide, DMF
DMA, 200 °C
3 h (50–51%)
R1
MOMO
OH
MOMO
O
R1
25 °C, 12 h (76–78%)
HO
OMOM
4a, b
5a, b
3
R3
R2
OMOM
12a, b
PdCl2(PPh3)2, CuI
Tf2O, pyridine
CH2Cl2, –20 °C, 2 h
Pd(OAc)2
KOH, DMF
OMOM
R1
R1
(99–99%)
145 °C, 6 h
(86–86%)
TBAI, DMF–Et3N (5:1)
70 °C, 1.5 h (82–82%)
TfO
OMOM
OMOM
7a, b
6a, b
11a, b, Pd(OAc)2, Ph3P, Et3N, MeCN, 85 °C, 24 h (62–63%) OR
13a, b, Pd(PPh3)4, LiCl, DMF, 120 °C, 8 h (66–67%) OR
15a, b, Pd(PPh3)4, Na2CO3, dioxane–H2O (7:1), 90 °C, 8 h (65–66%)
R3
R3
OMOM
R2
Pd(MeCN)2Cl2
CSA, MeOH
12 h, 25 °C
R2
CH2Cl2, 25 °C, 12 h
R1
OMOM
(55–57%)
(82–85%)
OMOM
R1
8a, b
OMOM
9a, b
OH
HO
HO
a: R1 = Me, R2 = OMOM
3 = OMOM
OH
R
OH
b: R1
2 = OMOM, R3 = H
=
R
OH
schweinfurthin J (2)
OH
pawhuskin C (1)
Scheme 1 Synthesis of bioactive natural and unnatural geranylated or farnesylated phenolic stilbenes.
(DMA) furnishing only the corresponding p-geranylated dides 14a,b and subsequent conversion into 2-vinyl-
or p-farnesylated trans products 5a,b in 50–51% yields substituted pinacolboranes 15a,b.30,31 The above-men-
along with 30–35% recovery of the starting material. In tioned palladium-catalyzed Heck, Stille, or Suzuki cou-
this reaction, we also noticed the decomposition of the pling reactions of 6a,b with 11a,b, 13a,b, and 15a,b were
starting material to the extent of 10–15%, while under selective and exclusively provided the desired products
forced conditions we noticed excessive decomposition. 9a,b in good yields (62–67%). Interestingly, all of these
To the best of our knowledge, very few examples of such palladium-catalyzed coupling reactions involving elec-
this aromatic Claisen rearrangement to install the geranyl tron-rich substrates were equally efficient in yielding the
or farnesyl unit are known in literature.17–19 The free phe- desired stilbenes. A systematic study of the Sonogashira
nolic groups in compounds 5a,b were transformed to the coupling between 6a and 12a was also planned to provide
good triflyloxy leaving group by treatment with triflic an- selectively both cis- and trans-stilbenes.32–34 Initial at-
hydride/pyridine to obtain 6a,b both in 99% yield. Subse- tempts to couple the phenolic compounds 6a and 12a un-
quently, the Heck, Stille, and Suzuki coupling reactions of der standard coupling conditions resulted in dimerization
the building blocks 6a,b with appropriate coupling part- of the alkyne unit. A literature search revealed that the
ners from Scheme 2 were deliberated to obtain the prod- present observation matches with the report of Boger et
ucts 9a,b.20–25 As depicted in Scheme 2, the Heck and al.35 that such type of electron-rich compounds are rela-
Sonogashira coupling partners 11 and 12 were respective- tively less reactive. An in situ exchange of triflyloxy to
ly prepared from 10a,b by using Wittig or Ohira– iodo using excess tetrabutylammonium iodide was neces-
Bestmann’s reagents;26–28 the radical hydrostannation of sary for Sonogashira coupling reactions of the two elec-
12a,b provided the desired Stille coupling regioisomers tron-rich segments 6a,b and 12a,b; fortunately, these
13a,b;29 and the Suzuki coupling partners were also ob- coupling conditions yielded the desired products 7a,b
tained from 10a,b via Takai olefination to form vinyl io- both in 82% yield. Efforts to convert the alkyne unit in
Synthesis 2012, 44, 2895–2902
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Pawhuskin C and Schweinfurthin J
2897
7a,b into trans-9a,b using diisobutylaluminum hydride In summary, we have demonstrated a new route to bioac-
were unsuccessful and resulted in the recovery of the tive polyene natural products pawhuskin C and schwein-
starting materials.36 At this stage, the recently reported furthin J by using Heck, Stille, Suzuki, or Sonogashira
palladium-catalyzed transfer semihydrogenation condi- coupling reactions as the key steps. The present approach
tions for the reduction of the C≡C bond to the C=C bond provides an easy access to the both geometrically pure cis-
were examined.37 The reaction of alkynes 7a,b with N,N- and trans-stilbene isomers. We feel that Heck, Stille, or
dimethylformamide and potassium hydroxide in the pres- Suzuki coupling reactions will provide access to nerylated
ence of palladium(II) acetate exclusively supplied the cor- trans-stilbenes and the Sonogashira coupling reaction will
responding cis-stilbenes 8a,b both in 86% yield. The cis- provide access to nerylated cis-stilbenes. Hence the de-
geometry of the C=C bond in products 8a,b was con- scribed synthetic strategy is general in nature and will be
firmed on the basis of the chemical shift and coupling con- useful for the preparation of some of the desired natural
stants of the corresponding vinylic protons. Using the and unnatural stilbene analogues, congeners, and the cor-
method reported by Spencer et al.,38a palladium(II)-cata- responding benzofuran or benzopyran architectures for
lyzed cis-to-trans isomerization of the C=C bond in 8a,b structure–activity relationship studies.
formed the required products 9a,b in 82–85% yields. On
the basis of the reports of Sen et al.,38b,c we feel that neryl-
1H NMR spectra were recorded on 200 MHz and 500 MHz spec-
trometers using TMS as an internal standard. 13C NMR spectra were
recorded on 200 (50 MHz), 400 (100 MHz), and 500 (125 MHz)
spectrometers. Mass spectra were recorded on an MS-TOF mass
spectrometer. HRMS (ESI) were recorded on Orbitrap (quadrupole
plus ion trap) and TOF mass analyzer. IR spectra were recorded on
an FT-IR spectrophotometer. Column chromatographic separations
were carried out on silica gel (60–120, 100–200, and 230–400
mesh); petroleum ether = PE. Commercially available n-BuLi,
CrCl2, CHI3, n-Bu3SnH, AIBN, t-BuLi, 2-isopropoxy-4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane, DMA, Tf2O, TBAI, PdCl2(PPh3)2,
Pd(OAc)2, Pd(PPh3)4, Pd(MeCN)2Cl2, and camphorsulfonic acid
(CSA) were used.
substituted analogues of 8a will also form the correspond-
ing product 9a via the Z-to-E C=C bond isomerization (al-
lylic rearrangement). Finally, the acid-catalyzed global
deprotection of methoxymethyl groups in 9a,b delivered
the desired natural products pawhuskin C (1) and sch-
weinfurthin J (2) in 55–57% yields. The obtained analyti-
cal and spectral data for the natural products 1 and 2 were
in complete agreement with the reported data.7,8,12 The
natural products 1 and 2 were obtained via partially sepa-
rate routes in five and seven linear steps with 14–15% and
12–14% overall yields.
1,2-Bis(methoxymethoxy)-4-vinylbenzene (11a); Typical Proce-
dure
R3
R3
To a stirred soln of MePh3PI (2.68 g, 6.63 mmol) in THF (30 mL)
at 0 °C was added 1.60 M n-BuLi in hexane (4.0 mL, 6.41 mmol)
and the mixture was stirred for 45 min under argon. A soln of alde-
hyde 10a39a (500 mg, 2.21 mmol) in THF (10 mL) was added drop-
wise and the mixture was stirred at 25 °C for 24 h. The reaction was
quenched with sat. NH4Cl (5 mL), and THF was removed in vacuo.
The residue was dissolved in EtOAc (25 mL), and EtOAc soln was
washed with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and
concentrated in vacuo. The residue was subjected to column chro-
matography (silica gel, PE–EtOAc, 9:1) to afford pure 11a as a
thick oil;39b yield: 307 mg (62%).
R2
R2
n-BuLi, MePPh3I, THF
CHO
25 °C, 24 h (62–65%)
10a, b
11a, b
Bestmann's
reagent,
K2CO3
CrCl2, CHI3
dioxane–THF (1:1)
0 °C, 2 h (75%)
MeOH, 25 °C
24 h (60–63%)
R3
R3
IR (neat): 1631, 1603 cm–1.
R2
R2
1H NMR (200 MHz, CDCl3): δ = 3.51 (s, 3 H), 3.53 (s, 3 H), 5.16
(dd, J = 10, 2 Hz, 1 H), 5.23 (s, 2 H), 5.25 (s, 2 H), 5.62 (dd, J = 18,
2 Hz, 1 H), 6.64 (dd, J = 18, 10 Hz, 1 H), 7.01 (dd, J = 8, 2 Hz, 1
H), 7.12 (d, J = 8 Hz, 1 H), 7.25 (d, J = 8 Hz, 1 H).
I
14a, b
12a, b
13C NMR (50 MHz, CDCl3): δ = 56.21, 56.23, 95.4, 95.5, 112.7,
114.2, 116.5, 120.7, 132.5, 136.2, 147.0, 147.3.
MS (ESI): m/z = 247 [M + Na]+.
n-Bu3SnH
AIBN, 80 °C
12 h
O
t-BuLi, THF
–78 °C, 2 h
(78–80%)
iPrO
B
O
R3
R3
1-(Methoxymethoxy)-4-vinylbenzene (11b)
Following the typical procedure for 11a using 10b40a (500 mg, 3.01
mmol), MePh3PI (3.65 g, 9.03 mmol), and 1.60 M n-BuLi in hexane
(5.45 mL, 8.73 mmol) gave 11b as a thick oil;40b yield: 329 mg
(65%).
R2
R2
O
B
SnBu3
O
IR (neat): 1629, 1606 cm–1.
[13a, b]
15a, b
1H NMR (200 MHz, CDCl3): δ = 3.48 (s, 3 H), 5.16 (d, J = 10 Hz,
1 H), 5.18 (s, 2 H), 5.64 (d, J = 18 Hz, 1 H), 6.68 (dd, J = 18, 10 Hz,
1 H), 7.00 (d, J = 8 Hz, 2 H), 7.35 (d, J = 8 Hz, 2 H).
a: R2 = OMOM, R3 = OMOM; b: R2 = OMOM, R3 = H
Scheme 2 Synthesis of Heck, Sonogashira, Stille, and Suzuki cou-
pling blocks.
13C NMR (50 MHz, CDCl3): δ = 56.0, 94.4, 112.1, 116.2, 127.3,
131.5, 136.1, 156.9.
MS (ESI): m/z = 165 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2895–2902

2898
M. Singh, N. P. Argade
PAPER
4-Ethynyl-1,2-bis(methoxymethoxy)benzene (12a); Typical
Procedure
1H NMR ( 200 MHz, CDCl3): δ = (E/Z 93:7):3.47 (s, 3 H), 5.17 (s,
2 H), 6.66 (d, J = 14 Hz, 1 H), 6.94–7.04 (m, 2 H), 7.18–7.29 (m, 2
H), 7.36 (d, J = 16 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 56.1, 74.2, 94.3, 116.3, 127.2,
131.8, 144.2, 157.3.
MS (ESI): m/z = 313 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C10H12IO2: 290.9882; found:
To a stirred soln of 10a (3.00 g, 13.27 mmol) and Ohira–
Bestmann’s reagent (6.41 g, 39.82 mmol) in MeOH (80 mL) was
added K2CO3 (9.17 g, 66.37 mmol) and the mixture was stirred at
25 °C for 24 h under argon. The mixture was concentrated in vacuo,
and EtOAc (50 mL) was added to the residue. The EtOAc soln was
washed with H2O (15 mL) and brine (15 mL), dried (Na2SO4), and
concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel, PE–EtOAc, 9:1) to afford pure 12a as a thick
oil; yield: 1.76 g (60%).
290.9871.
(E)-2-[3,4-Bis(methoxymethoxy)styryl]-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (15a); Typical Procedure
IR (neat): 3286, 2105, 1600 cm–1.
To a stirred soln of vinyl iodide 14a (500 mg, 1.42 mmol) in THF
(10 mL) at –78 °C was added 1.30 M t-BuLi in hexane (1.53 mL,
1.99 mmol) and the mixture was stirred for 45 min under argon. 2-
Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.32 mL,
1.99 mmol) was added dropwise and the mixture was stirred at –78
°C for 2 h. The reaction was quenched with sat. NH4Cl (2 mL) and
THF was removed in vacuo. The obtained residue was dissolved in
EtOAc (25 mL) and the EtOAc soln was washed with H2O (5 mL)
and brine (5 mL), dried (Na2SO4), and concentrated in vacuo. The
residue was purified by column chromatography (silica gel, PE–
EtOAc, 9:1) to afford pure vinyl boronate 15a as a thick oil; yield:
390 mg (78%).
1H NMR (200 MHz, CDCl3): δ = 3.01 (s, 1 H), 3.51 (s, 3 H), 3.52
(s, 3 H), 5.23 (s, 2 H), 5.25 (s, 2 H), 7.09–7.14 (m, 2 H), 7.31 (s, 1
H).
13C NMR (50 MHz, CDCl3): δ = 56.2 (2 C), 76.1, 83.3, 95.1, 95.4,
115.9, 116.0, 120.2, 126.8, 146.7, 148.0.
MS (ESI): m/z = 223 [M + H]+, 245 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H14NaO4: 245.0790;
found: 245.0784.
1-Ethynyl-4-(methoxymethoxy)benzene (12b)
Following the typical procedure for 12a using 10b (3.00 g, 18.07
mmol), Ohira–Bestmann’s reagent (8.72 g, 54.21 mmol), and
K2CO3 (12.48 g, 90.36 mmol) gave 12b as a thick oil;40b yield: 1.84
g (63%).
IR (neat): 3288, 2107, 1604 cm–1.
1H NMR (200 MHz, CDCl3): δ = 3.01 (s, 1 H), 3.47 (s, 3 H), 5.18
(s, 2 H), 6.93–7.03 (m, 2 H), 7.38–7.47 (m, 2 H).
13C NMR (50 MHz, CDCl3): δ = 56.1, 76.0, 83.5, 94.2, 115.3, 116.1,
133.5, 157.5.
IR (neat): 1625, 1602 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.24 (s, 12 H), 3.44 (s, 6 H), 5.16
(s, 2 H), 5.17 (s, 2 H), 5.98 (d, J = 18 Hz, 1 H), 7.04 (s, 2 H), 7.18–
7.32 (m, 2 H).
13C NMR (50 MHz, CDCl3): δ = 24.8, 56.1, 56.2, 83.3, 95.2, 95.5,
115.0, 116.1, 121.9, 132.2, 147.2, 148.0, 148.9.
MS (ESI): m/z = 351 [M + H]+, 373 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C18H27BNaO6: 373.1798;
MS (ESI): m/z = 163 [M + H]+, 185 [M + Na]+.
found: 373.1800.
(E)-2-[4-(Methoxymethoxy)styryl]-4,4,5,5-tetramethyl-1,3,2-di-
oxaborolane (15b)
Following the typical procedure for 15a using vinyl iodide 14b (500
mg, 1.72 mmol), 1.3 M t-BuLi in hexane (1.85 mL, 2.41 mmol), and
2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.49 mL,
2.41 mmol) gave 15b as a thick oil; yield: 400 mg (80%).
(E)-4-(2-Iodovinyl)-1,2-bis(methoxymethoxy)benzene (14a);
Typical Procedure
To a vigorously stirred suspension of CrCl2 (4.35 g, 35.39 mmol) in
THF–dioxane (1:1, 60 mL) at 0 °C was added a soln of aldehyde
10a (1.00 g, 4.42 mmol) in THF–dioxane (1:1, 20 mL) under argon.
After 5 min, CHI3 (6.09 g, 15.48 mmol) in THF–dioxane (1:1, 10
mL) soln was added to the mixture. After 2 h at 0 °C, H2O (80 mL)
and EtOAc (80 mL) were added to the mixture and the organic layer
was separated. The aqueous layer was extracted with EtOAc (2 × 40
mL) and the combined organic layers were washed with brine (15
mL), dried (Na2SO4), and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, PE–EtOAc, 19:1) to
afford pure (E)-vinyl iodide 14a as a thick oil; yield: 1.16 g (75%).
IR (CHCl3): 1626, 1604 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.28 (s, 12 H), 3.44 (s, 3 H), 5.15
(s, 2 H), 6.00 (d, J = 18 Hz, 1 H), 6.97 (d, J = 10 Hz, 2 H), 7.32 (d,
J = 20 Hz, 1 H), 7.40 (d, J = 10 Hz, 2 H).
13C NMR (50 MHz, CDCl3): δ = 24.8, 56.0, 83.2, 94.3, 116.2, 128.4,
130.2, 131.5, 148.9, 157.9.
MS (ESI): m/z = 291 [M + H]+, 313 [M + Na]+.
IR (CHCl3): 1601 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C16H24BO4: 291.1768; found:
291.1750.
1H NMR (200 MHz, CDCl3): δ = (E/Z 94:6): 3.51 (s, 3 H), 3.52 (s,
3 H), 5.23 (s, 4 H), 6.68 (d, J = 14 Hz, 1 H), 6.89 (dd, J = 8, 2 Hz, 1
H), 7.10 (d, J = 8 Hz, 1 H), 7.13 (d, J = 2 Hz, 1 H), 7.33 (d, J = 16
Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 56.2 (2 C), 75.0, 95.3, 95.5, 113.9,
116.4, 120.6, 132.5, 144.2, 147.3, 147.5.
MS (ESI): m/z = 373 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C12H15INaO4: 372.9913;
(E)-1-[(3,7-Dimethylocta-2,6-dienyl)oxy]-3,5-bis(methoxy-
methoxy)benzene (4a); Typical Procedure
To a stirred soln of 3 (2.00 g, 9.34 mmol) and geranyl bromide (4.05
g, 18.69 mmol) in DMF (40 mL) was added K2CO3 (6.45 g, 46.72
mmol) and the mixture was stirred at 25 °C for 12 h under argon. To
the mixture was added EtOAc (100 mL) and the EtOAc soln was
washed with brine (3 × 25 mL), dried (Na2SO4), and concentrated
in vacuo. The residue was purified by column chromatography (sil-
ica gel, PE–EtOAc, 19:1) to afford pure 4a as a thick oil; yield: 2.48
g (76%).
found: 372.9904.
(E)-1-(2-Iodovinyl)-4-(methoxymethoxy)benzene (14b)
Following the typical procedure for 14a using CrCl2 (5.92 g, 48.19
mmol), aldehyde 10b (1.00 g, 6.02 mmol), CHI3 (8.30 g, 21.08
mmol) gave 14b as a thick oil; yield: 1.31 g (75%).
IR (neat): 1602 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.61 (s, 3 H), 1.68 (s, 3 H), 1.73
(s, 3 H), 2.00–2.20 (m, 4 H), 3.47 (s, 6 H), 4.49 (d, J = 8 Hz, 2 H),
5.00–5.20 (m, 1 H), 5.13 (s, 4 H), 5.47 (t, J = 6 Hz, 1 H), 6.27–6.38
(m, 3 H).
IR (CHCl3): 1605 cm–1.
Synthesis 2012, 44, 2895–2902
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Pawhuskin C and Schweinfurthin J
2899
13C NMR (50 MHz, CDCl3): δ = 16.6, 17.7, 25.6, 26.3, 39.5, 56.0,
64.9, 94.5, 96.9, 97.2, 119.3, 123.8, 131.8, 141.3, 158.9, 160.6.
MS (ESI): m/z = 351 [M + H]+, 373 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H31O5: 351.2171; found:
–20 °C for 30 min, which was followed by the addition of Tf2O
(0.18 mL, 1.07 mmol) and the mixture was stirred at –20 °C for a
further 2 h. The reaction was quenched with ice-cooled H2O and the
mixture was extracted with CH2Cl2 (3 × 10 mL). The combined or-
ganic layers were washed with brine (5 mL), dried (Na2SO4), and
concentrated in vacuo. The residue was purified by column chroma-
tography (silica gel, PE–EtOAc, 97:3) to afford pure triflate 6a as a
thick oil; yield: 340 mg (99%).
351.2159.
1,3-Bis(methoxymethoxy)-5-{[(2E,6E)-3,7,11-trimethyldodeca-
2,6,10-trienyl]oxy}benzene (4b)
Following the typical procedure for 4a using 3 (2.00 g, 9.34 mmol),
farnesyl bromide (5.32 g, 18.70 mmol), and K2CO3 (6.45 g, 46.72
mmol) gave 4b as a thick oil; yield: 3.04 g (78%).
IR (neat): 1612 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.56 (s, 3 H), 1.64 (s, 3 H), 1.77
(s, 3 H), 1.85–2.15 (m, 4 H), 3.36 (d, J = 8 Hz, 2 H), 3.46 (s, 6 H),
5.05 (t, J = 6 Hz, 1 H), 5.15 (t, J = 6 Hz, 1 H), 5.18 (s, 4 H), 6.72 (s,
2 H).
13C NMR (50 MHz, CDCl3): δ = 16.0, 17.6, 22.5, 25.6, 26.6, 39.7,
56.1, 94.6, 101.7, 120.3, 121.6, 124.2, 131.4, 135.4, 148.0, 156.0.
MS (ESI): m/z = 505 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C21H29F3NaO7S: 505.1484;
IR (neat): 1603 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.60 (s, 6 H), 1.68 (s, 3 H), 1.73
(s, 3 H), 1.90–2.20 (m, 8 H), 3.47 (s, 6 H), 4.49 (d, J = 6 Hz, 2 H),
5.00–5.20 (m, 2 H), 5.13 (s, 4 H), 5.47 (t, J = 8 Hz, 1 H), 6.27–6.38
(m, 3 H).
13C NMR (50 MHz, CDCl3): δ = 16.0, 16.6, 17.7, 25.7, 26.2, 26.7,
39.5, 39.7, 56.0, 64.9, 94.4, 96.8, 97.2, 119.2, 123.7, 124.3, 131.3,
135.4, 141.3, 158.9, 160.6.
found: 505.1498.
MS (ESI): m/z = 419 [M + H]+, 441 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C25H38NaO5: 441.2617;
3,5-Bis(methoxymethoxy)-4-[(2E,6E)-3,7,11-trimethyldodeca-
2,6,10-trienyl]phenyl Trifluoromethanesulfonate (6b)
Following the typical procedure for 6a using 5b (250 mg, 0.59
mmol), pyridine (0.09 mL, 1.19 mmol), and Tf2O (0.15 mL, 0.89
mmol) gave 6b as a thick oil; yield: 325 mg (99%).
found: 441.2607.
(E)-4-(3,7-Dimethylocta-2,6-dienyl)-3,5-bis(methoxymeth-
oxy)phenol (5a); Typical Procedure
IR (neat): 1612 cm–1.
DMA (5 mL) was added to 4a (500 mg, 1.43 mmol) and the mixture
was refluxed for 3 h under argon. The mixture was allowed to attain
r.t. To the mixture was added EtOAc (40 mL) and the soln was
washed with dil HCl (2 × 10 mL), H2O (3 × 10 mL), and brine (10
mL), dried (Na2SO4), and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, PE–EtOAc, 4:1) to
afford pure 5a as a thick oil; yield: 250 mg (50%).
1H NMR (200 MHz, CDCl3): δ = 1.57 (s, 6 H), 1.68 (s, 3 H), 1.77
(s, 3 H), 1.85–2.20 (m, 8 H), 3.37 (d, J = 6 Hz, 2 H), 3.46 (s, 6 H),
5.00–5.25 (m, 3 H), 5.18 (s, 4 H), 6.72 (s, 2 H).
13C NMR (50 MHz, CDCl3): δ = 16.0, 16.1, 17.6, 22.5, 25.7, 26.6,
26.7, 39.7, 39.8, 56.1, 94.6, 101.7, 120.4, 121.6, 124.1, 124.3,
131.3, 135.0, 135.2, 135.5, 148.0, 156.0.
MS (ESI): m/z = 573 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C26H38F3O7S: 551.2290;
IR (CHCl3): 3394, 1603 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.57 (s, 3 H), 1.65 (s, 3 H), 1.76
(s, 3 H), 1.85–2.20 (m, 4 H), 3.30 (d, J = 8 Hz, 2 H), 3.46 (s, 6 H),
5.00–5.25 (m, 2 H), 5.14 (s, 4 H), 5.48 (br s, 1 H), 6.31 (s, 2 H).
13C NMR (50 MHz, CDCl3): δ = 16.0, 17.6, 22.1, 25.7, 26.7, 39.8,
55.9, 94.3, 96.0, 112.4, 123.2, 124.4, 131.2, 134.2, 154.8, 156.2.
found: 551.2296.
(E)-5-{[(3,4-Bis(methoxymethoxy)phenyl]ethynyl}-2-(3,7-di-
methylocta-2,6-dienyl)-1,3-bis(methoxymethoxy)benzene (7a);
Typical Procedure
To a stirred soln of triflate 6a (300 mg, 0.62 mmol), PdCl2(PPh3)2
(43 mg, 10 mol%), CuI (35 mg, 30 mol%), and TBAI (689 mg, 1.86
mmol) in DMF–Et3N (5:1, 8 mL) under argon at 70 °C was added
alkyne 12a (193 mg, 0.87 mmol) in DMF–Et3N (5:1, 4 mL) over a
period of 1 h. The mixture was allowed to stir for an additional 30
min and then it was cooled to 25 °C. The mixture was diluted with
EtOAc (50 mL) and the EtOAc soln was washed with brine (3 × 20
mL), dried (Na2SO4), and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, PE–EtOAc, 4:1) to
afford pure 7a as a thick oil; yield: 282 mg (82%).
MS (ESI): m/z = 373 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C20H31O5: 351.2171; found:
351.2172.
3,5-Bis(methoxymethoxy)-4-[(2E,6E)-3,7,11-trimethyldodeca-
2,6,10-trienyl]phenol (5b)
Following the typical procedure for 5a using 4b (500 mg, 1.19
mmol) gave 5b as a thick oil; yield: 255 mg (51%).
IR (neat): 3398, 1606 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.57 (s, 3 H), 1.59 (s, 3 H), 1.67
(s, 3 H), 1.76 (s, 3 H), 1.85–2.15 (m, 8 H), 3.31 (d, J = 6 Hz, 2 H),
3.46 (s, 6 H), 5.00–5.25 (m, 3 H), 5.14 (s, 4 H), 6.31 (s, 2 H).
13C NMR (50 MHz, CDCl3): δ = 15.9, 16.0, 17.7, 22.1, 25.7, 26.66,
26.71, 39.7, 39.8, 55.9, 94.3, 96.0, 112.4, 123.2, 124.3, 124.4,
131.3, 134.2, 134.8, 154.8, 156.2.
IR (CHCl3): 2401, 1597 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.57 (s, 3 H), 1.65 (s, 3 H), 1.78
(s, 3 H), 1.85–2.15 (m, 4 H), 3.40 (d, J = 8 Hz, 2 H), 3.48 (s, 6 H),
3.52 (s, 3 H), 3.54 (s, 3 H), 5.06 (t, J = 6 Hz, 1 H), 5.13–5.25 (m, 1
H), 5.20 (s, 4 H), 5.25 (s, 4 H), 6.95 (s, 2 H), 7.05–7.20 (m, 2 H),
7.33 (s, 1 H).
MS (ESI): m/z = 419 [M + H]+, 441 [M + Na]+.
HRMS (ESI): m/z [M + H]+ calcd for C25H39O5: 419.2797; found:
13C NMR (50 MHz, CDCl3): δ = 16.0, 17.6, 22.7, 25.6, 26.7, 39.8,
56.0, 56.2 (2 C), 88.3, 88.5, 94.4, 95.2, 95.4, 111.1, 116.2, 117.3,
119.6, 121.1, 121.5, 122.2, 124.3, 126.2, 131.2, 134.9, 146.8, 147.5,
155.4.
419.2798.
MS (ESI): m/z = 555 [M + H]+, 577 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C32H42NaO8: 577.2777;
(E)-4-(3,7-Dimethylocta-2,6-dienyl)-3,5-bis(methoxymeth-
oxy)phenyl Trifluoromethanesulfonate (6a); Typical Procedure
To a stirred soln of 5a (250 mg, 0.71 mmol) in CH2Cl2 (5 mL) at
–20 °C was added pyridine (0.11 mL, 1.42 mmol) in a dropwise
fashion under an argon atmosphere and the mixture was stirred at
found: 577.2770.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2895–2902

2900
M. Singh, N. P. Argade
PAPER
1,3-Bis(methoxymethoxy)-5-{[4-(methoxymethoxy)phe-
nyl]ethynyl}-2-[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-tri-
enyl]benzene (7b)
Following the typical procedure for 7a using triflate 6b (300 mg,
0.54 mmol), PdCl2(PPh3)2 (38 mg, 10 mol%), CuI (31 mg, 30
mol%), TBAI (604 mg, 1.63 mmol), and alkyne 12b (123 mg, 0.76
mmol) gave 7b as a thick oil; yield: 251 mg (82%).
5-[(E)-3,4-Bis(methoxymethoxy)styryl]-2-[(E)-3,7-dimethyloc-
ta-2,6-dienyl]-1,3-bis(methoxymethoxy)benzene (9a); Typical
Procedures
C=C Bond isomerization: To a stirred soln of the cis-stilbene 8a
(100 mg, 0.18 mmol) in CH2Cl2 (0.4 mL) was added PdCl2(MeCN)2
(4.6 mg, 10 mol%) and the mixture was stirred at 25 °C for 12 h un-
der argon. The mixture was diluted with Et2O (20 mL), filtered
through a short pad of Celite and washed with Et2O (10 mL), and
the filtrate was concentrated in vacuo. The residue was subjected to
column chromatography (silica gel, PE–EtOAc, 4:1) to afford pure
trans-stilbene 9a as a thick oil; yield: 82 mg (82%).
IR (CHCl3): 2401, 1598 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.57 (s, 3 H), 1.59 (s, 3 H), 1.67
(s, 3 H), 1.78 (s, 3 H), 1.85–2.50 (m, 8 H), 3.40 (d, J = 8 Hz, 2 H),
3.48 (s, 9 H), 5.08 (t, J = 6 Hz, 1 H), 5.10–5.25 (m, 2 H), 5.19 (s, 2
H), 5.20 (s, 4 H), 6.94 (s, 2 H), 6.95–7.05 (m, 2 H), 7.40–7.50 (m, 2
H).
13C NMR (50 MHz, CDCl3): δ = 16.0, 16.1, 17.7, 22.7, 25.7, 26.6,
26.7, 39.7, 39.8, 56.0, 56.1, 88.4, 88.5, 94.3, 94.4, 111.1, 116.1,
116.7, 121.0, 121.7, 122.2, 124.2, 124.4, 131.3, 133.0, 135.0, 155.4,
157.1.
Heck coupling: Triflate 6a (100 mg, 0.20 mmol) and styrene 11a
(69 mg, 0.31 mmol) were dissolved in MeCN (2 mL). Et3N (1 mL),
Pd(OAc)2 (4.6 mg, 10 mol%), and Ph3P (27 mg, 50 mol%) were
added to the stirred mixture. The mixture was heated at 85 °C for 24
h under argon. The mixture was concentrated in vacuo and the res-
idue was subjected to column chromatography (silica gel, PE–
EtOAc, 4:1) to afford pure trans-stilbene 9a as a thick oil; yield: 71
mg (62%).
MS (ESI): m/z = 585 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C35H46NaO6: 585.3192;
found: 585.3191.
Stille coupling: Triflate 6a (100 mg, 0.20 mmol) and stannate 13a
(159 mg, 0.31 mmol) were dissolved in DMF (2 mL) in a thick-
walled Pyrex screw-cap tube (10 mL) under argon. Pd(PPh3)4 (12
mg, 5 mol%) and LiCl (44 mg, 1.031 mmol) were added to this mix-
ture and the capped tube was heated in an oil bath at 120 °C with
stirring for 8 h. To the mixture was added EtOAc (20 mL) and the
EtOAc soln was washed with brine (3 × 10 mL), dried (Na2SO4),
and concentrated in vacuo. The residue was purified by column
chromatography (silica gel, PE–EtOAc, 4:1) to afford pure trans-
stilbene 9a as a thick oil; yield: 76 mg (66%).
5-[(Z)-3,4-Bis(methoxymethoxy)styryl]-2-[(E)-3,7-dimethyloc-
ta-2,6-dienyl]-1,3-bis(methoxymethoxy)benzene (8a); Typical
Procedure
Compound 7a (200 mg, 0.36 mmol), KOH (30 mg, 0.54 mmol),
Pd(OAc)2 (4.0 mg, 5 mol%), and DMF (2 mL) were placed in a
thick-walled Pyrex screw-cap tube (10 mL) under argon and the
capped tube was heated in an oil bath at 145 °C under stirring for 6
h. The mixture was cooled to 25 °C and diluted with EtOAc (25
mL). The EtOAc soln was washed with brine (3 × 10 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, PE–EtOAc, 4:1) to afford pure
cis-stilbene 8a as a thick oil; yield: 172 mg (86%).
Suzuki coupling: To a mixture of triflate 6a (100 mg, 0.20 mmol)
and boronate 15a (108 mg, 0.31 mmol) in dioxane–H2O (2 mL, 7:1)
were added Pd(PPh3)4 (12 mg, 5 mol%) and Na2CO3 (109 mg, 1.037
mmol) in a thick-walled Pyrex screw-cap tube (10 mL). The mix-
ture was heated at 90 °C for 8 h and then concentrated in vacuo to
give a residue. EtOAc (20 mL) was added to the residue and the or-
ganic layer was washed with H2O (5 mL) and brine (5 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, PE–EtOAc, 4:1) to afford pure
trans-stilbene 9a as a thick oil; yield: 74 mg (65%).
IR (CHCl3): 1638 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.50 (s, 3 H), 1.58 (s, 3 H), 1.69
(s, 3 H), 1.80–2.05 (m, 4 H), 3.29 (d, J = 8 Hz, 2 H), 3.33 (s, 9 H),
3.42 (s, 3 H), 4.96 (s, 4 H), 4.99 (s, 2 H), 5.05–5.25 (m, 2 H), 5.13
(s, 2 H), 6.40 (s, 2 H), 6.59 (s, 2 H), 6.75–7.00 (m, 3 H).
IR (CHCl3): 1599 cm–1.
13C NMR (50 MHz, CDCl3): δ = 16.0, 17.6, 22.6, 25.6, 26.7, 39.8,
55.8, 56.0, 56.1, 94.5, 95.4 (2 C), 108.7, 116.4, 117.6, 119.3, 122.7,
123.3, 124.4, 129.5, 129.7, 131.2, 131.9, 134.5, 136.0, 146.3, 146.8,
155.4.
MS (ESI): m/z = 557 [M + H]+, 579 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C32H44NaO8: 579.2934;
1H NMR (200 MHz, CDCl3): δ = 1.57 (s, 3 H), 1.65 (s, 3 H), 1.79
(s, 3 H), 1.85–2.15 (m, 4 H), 3.40 (d, J = 8 Hz, 2 H), 3.50 (s, 6 H),
3.53 (s, 3 H), 3.56 (s, 3 H), 5.00–5.15 (m, 1 H), 5.15–5.30 (m, 1 H),
5.24 (s, 4 H), 5.25 (s, 2 H), 5.29 (s, 2 H), 6.92 (s, 2 H), 6.90–7.18
(m, 4 H), 7.33 (s, 1 H).
13C NMR (50 MHz, CDCl3): δ = 16.0, 17.6, 22.7, 25.6, 26.7, 39.8,
56.0, 56.16, 56.19, 94.4, 95.4 (2 C), 106.0, 114.2, 116.5, 119.7,
120.9, 122.5, 124.3, 127.6, 127.7, 131.2, 132.1, 134.6, 136.7, 146.8,
147.4, 155.8.
found: 579.2924.
1,3-Bis(methoxymethoxy)-5-[(Z)-4-(methoxymethoxy)styryl]-2-
[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienyl]benzene (8b)
Following the typical procedure for 8a using 7b (200 mg, 0.35
mmol), KOH (30 mg, 0.53 mmol), and Pd(OAc)2 (4.0 mg, 5 mol%)
gave 8b as a thick oil; yield: 172 mg (86%).
MS (ESI): m/z = 579 [M + Na]+.
1,3-Bis(methoxymethoxy)-5-[(E)-4-(methoxymethoxy)styryl]-
2-[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienyl]benzene (9b)
C=C Bond isomerization: Following the typical procedure for 9a
using cis-stilbene 8b (150 mg, 0.26 mmol), PdCl2(MeCN)2 (6.8 mg,
10 mol%) gave 9b as a thick oil; yield: 127 mg (85%).
IR (CHCl3): 1604 cm–1.
1H NMR (200 MHz, CDCl3): δ = 1.57 (s, 3 H), 1.59 (s, 3 H), 1.67
(s, 3 H), 1.77 (s, 3 H), 1.85–2.15 (m, 8 H), 3.36 (d, J = 6 Hz, 2 H),
3.39 (s, 6 H), 3.46 (s, 3 H), 5.01 (s, 4 H), 5.05–5.27 (m, 3 H), 5.15
(s, 2 H), 6.42 (d, J = 12 Hz, 1 H), 6.50 (d, J = 12 Hz, 1 H), 6.67 (s,
2 H), 6.90 (d, J = 8 Hz, 2 H), 7.22 (d, J = 8 Hz, 2 H).
13C NMR (50 MHz, CDCl3): δ = 15.9, 16.1, 17.7, 22.6, 25.7, 26.65,
26.71, 39.7, 39.8, 55.8, 55.9, 94.3, 94.4, 108.8, 115.9, 119.3, 122.7,
124.3, 124.4, 129.2, 129.5, 130.2, 131.0, 131.2, 134.6, 134.8, 136.0,
155.4, 156.2.
Heck coupling: Following the typical procedure for 9a using triflate
6b (100 mg, 0.18 mmol), styrene 11b (45 mg, 0.27 mmol), Et3N (1
mL), Pd(OAc)2 (4.0 mg, 10 mol%), and Ph3P (24 mg, 50 mol%)
gave 9b as a thick oil; yield: 64 mg (63%).
Stille coupling: Following the typical procedure for 9a using triflate
6b (100 mg, 0.18 mmol), stannate 13b (123 mg, 0.27 mmol),
Pd(PPh3)4 (10 mg, 5 mol%), and LiCl (39 mg, 0.90 mmol) gave 9b
as a thick oil; yield: 68 mg (67%).
MS (ESI): m/z = 565 [M + H]+, 587 [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C35H48NaO6: 587.3349;
Suzuki coupling: Following the typical procedure for 9a using tri-
flate 6b (100 mg, 0.18 mmol), boronate 15b (79 mg, 0.27 mmol),
found: 587.3352.
Synthesis 2012, 44, 2895–2902
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Pawhuskin C and Schweinfurthin J
2901
Pd(PPh3)4 (10 mg, 5 mol%), and Na2CO3 (96 mg, 0.90 mmol) gave
9b as a thick oil; yield: 67 mg (66%).
References
(1) Nicolaou, K. C.; Evans, R. M.; Roecker, A. J.; Hughes, R.;
Downes, M.; Pfefferkorn, J. A. Org. Biomol. Chem. 2003, 1,
908; and references cited therein.
(2) Mondal, M.; Argade, N. P. Synlett 2004, 1243.
(3) Mondal, M.; Puranik, V. G.; Argade, N. P. J. Org. Chem.
2006, 71, 4992.
IR (CHCl3): 1601 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.59 (s, 3 H), 1.60 (s, 3 H), 1.68
(s, 3 H), 1.81 (s, 3 H), 1.92–2.00 (m, 4 H), 2.00–2.11 (m, 4 H), 3.43
(d, J = 5 Hz, 2 H), 3.50 (s, 3 H), 3.52 (s, 6 H), 5.06–5.14 (m, 2 H),
5.20 (s, 2 H), 5.22–5.28 (m, 1 H), 5.25 (s, 4 H), 6.94 (d, J = 15 Hz,
1 H), 6.94 (s, 2 H), 7.02 (d, J = 15 Hz, 1 H), 7.03 (d, J = 10 Hz, 2
H), 7.45 (d, J = 10 Hz, 2 H).
(4) Mondal, M.; Puranik, V. G.; Argade, N. P. J. Org. Chem.
2007, 72, 2068.
13C NMR (125 MHz, CDCl3): δ = 15.9, 16.1, 17.6, 22.7, 25.6, 26.6,
26.7, 39.7, 39.8, 55.9 (2 C), 94.4, 94.5, 106.0, 116.4, 119.7, 122.6,
124.2, 124.4, 127.2, 127.6, 127.7, 131.2, 131.3, 134.6, 134.8, 136.5,
155.9, 156.8.
MS (ESI): m/z = 565 [M + H]+.
HRMS (ESI): m/z [M + Na]+ calcd for C35H48NaO6: 587.3349;
(5) Nicolaou, K. C.; Lister, T.; Denton, R. M.; Gelin, C. F.
Angew. Chem. Int. Ed. 2007, 46, 7501.
(6) Qi, J.; Porco, J. A. Jr. J. Am. Chem. Soc. 2007, 129, 12682.
(7) Belofsky, G.; French, A. N.; Wallace, D. R.; Dodson, S. L.
J. Nat. Prod. 2004, 67, 26.
(8) Klausmeyer, P.; Van Q, N.; Jato, J.; McCloud, T. G.;
Beutler, J. A. J. Nat. Prod. 2010, 73, 479.
found: 587.3358.
(9) (a) Neighbors, J. D.; Buller, M. J.; Boss, K. D.; Wiemer, D.
F. J. Nat. Prod. 2008, 71, 1949. (b) van der Kaaden, J. E.;
Hemscheidt, T. K.; Mooberry, S. L. J. Nat. Prod. 2001, 64,
103. (c) Treadwell, E. M.; Cermak, S. C.; Wiemer, D. F.
J. Org. Chem. 1999, 64, 8718.
(10) (a) Topczewski, J. J.; Kodet, J. G.; Wiemer, D. F. J. Org.
Chem. 2011, 76, 909. (b) Yoder, B. J.; Cao, S.; Norris, A.;
Miller, J. S.; Ratovoson, F.; Razafitsalama, J.;
Andriantsiferana, R.; Rasamison, V. E.; Kingston, D. G. I.
J. Nat. Prod. 2007, 70, 342.
(11) Jang, M.; Cai, L.; Udeani, G. O.; Slowing, K. V.; Thomas,
C. F.; Beecher, C. W. W.; Fong, H. H. S.; Farnsworth, N. R.;
Kinghorn, A. D.; Mehta, R. G.; Moon, R. C.; Pezzuto, J. M.
Science (Washington, D.C.) 1997, 275, 218.
(12) Neighbors, J. D.; Salnikova, M. S.; Wiemer, D. F.
Tetrahedron Lett. 2005, 46, 1321.
4-{(E)-4-[(E)-3,7-Dimethylocta-2,6-dienyl}-3,5-dihydroxy-
styryl}benzene-1,2-diol (Pawhuskin C, 1); Typical Procedure
To a stirred soln of trans-stilbene 9a (80 mg, 0.14 mmol) in MeOH
(10 mL) was added CSA (5 mg, cat.) and the mixture was stirred at
25 °C for 12 h under an argon atmosphere. The reaction was
quenched by addition of sat. NaHCO3 and concentrated in vacuo. To
the residue was added EtOAc (20 mL) and the EtOAc soln was
washed with brine (5 mL), dried (Na2SO4), and concentrated in vac-
uo. The residue was purified by column chromatography (silica gel,
PE–EtOAc, 1:1) to afford pure pawhuskin C (1) as a yellow solid;
yield: 30 mg (55%); mp 144–146 °C (Lit.7 148–152 °C).
IR (CHCl3): 3423, 1619 cm–1.
1H NMR (200 MHz, acetone-d6): δ = 1.57 (s, 3 H), 1.62 (s, 3 H),
1.78 (s, 3 H), 1.90–2.15 (m, 4 H), 3.37 (d, J = 8 Hz, 2 H), 5.09 (t,
J = 6 Hz, 1 H), 5.33 (t, J = 6 Hz, 1 H), 6.58 (s, 2 H), 6.70–6.92 (m,
4 H), 7.04 (d, J = 2 Hz, 1 H), 7.75–8.15 (br s, 4 H).
13C NMR (100 MHz, acetone-d6): δ = 16.4, 17.9, 23.2, 26.0, 27.6,
40.8, 105.8, 113.8, 115.4, 116.4, 119.9, 124.4, 125.4, 127.1, 128.5,
131.0, 131.7, 134.7, 137.4, 146.1, 146.3, 157.2.
(13) Morales-Serna, J. A.; Zúñiga-Martínez, A.; Salmón, M.;
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MS (ESI): m/z = 381 [M + H]+, 403 [M + Na]+.
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5-[(E)-4-Hydroxystyryl]-2-[(2E,6E)-3,7,11-trimethyldodeca-
2,6,10-trienyl]benzene-1,3-diol (Schweinfurthin J, 2)
Following the typical procedure for 1 using 9b (100 mg, 0.17 mmol)
gave 2 as a yellow solid; yield: 43 mg (57%); mp 118–120 °C.
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IR (CHCl3): 3423, 1630, 1605 cm–1.
1H NMR (500 MHz, CD3OD): δ = 1.56 (s, 6 H), 1.63 (s, 3 H), 1.77
(s, 3 H), 1.90 (t, J = 10 Hz, 2 H), 1.96 (q, J = 10 Hz, 2 H), 2.01 (t,
J = 10 Hz, 2 H), 2.07 (q, J = 10 Hz, 2 H), 3.30 (d, J = 10 Hz, 2 H),
5.03–5.10 (m, 1 H), 5.08 (t, J = 10 Hz, 1 H), 5.26 (t, J = 10 Hz, 1
H), 6.46 (s, 2 H), 6.75 (d, J = 15 Hz, 1 H), 6.76 (d, J = 10 Hz, 2 H),
6.90 (d, J = 15 Hz, 1 H), 7.32 (d, J = 10 Hz, 2 H).
13C NMR (125 MHz; CD3OD): δ = 16.1, 16.3, 17.8, 23.2, 25.9,
27.6, 27.8, 40.8, 41.0, 105.7, 115.8, 116.5, 124.7, 125.5, 125.6,
127.3, 128.2, 128.6, 130.7, 131.9, 134.7, 135.8, 137.6, 157.2, 158.1.
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MS (ESI): m/z = 433 [M + H]+, 455 [M + Na]+.
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Acknowledgment
M.S. thanks CSIR, New Delhi for the award of research fellowship.
N.P.A. thanks Department of Science and Technology, New Delhi,
for financial support.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
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nfomartit
© Georg Thieme Verlag Stuttgart · New York
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M. Singh, N. P. Argade
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