The first total synthesis of kynapcin-24 by palladium catalysis

Article abstract of DOI:10.1055/s-0028-1087998

The synthesis of kynapcin-24, which can be isolated from the Korean mushroom Polyozellus multiflex Murr, is achieved in 12% overall yield from commercially available 3,4-dihydroxybenzaldehyde by a route in which the longest linear sequence is only 14 step

Full text of DOI:10.1055/s-0028-1087998

PAPER
1175
The First Total Synthesis of Kynapcin-24 by Palladium Catalysis
T
otal
S
ynthesis
i
of
K
yn
n
apcin-24 g-Yi Yang,a Chia-Fu Chang,a Yu-Chao Huang,a Yean-Jang Lee,*a Chao-Chin Hu,b Tsui-Hwa Tsengb
a
Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan
Fax +886(4)7211190; E-mail: leeyj@cc.ncue.edu.tw
School of Applied Chemistry, Chung Shan Medical University, No. 110, Section 1, Chien-Kuo N. Road, Taichung 402, Taiwan
b
Received 11 November 2008; revised 9 December 2008
tin, magnesium, zinc, boron, aluminum, zirconium, and
copper.6,7 The easiest route to 1 was expected to be the
coupling of 3-halobenzofuran and (benzofuranyl)stan-
nane units under palladium catalysis. In previous
Abstract: The synthesis of kynapcin-24, which can be isolated
from the Korean mushroom Polyozellus multiflex Murr, is achieved
in 12% overall yield from commercially available 3,4-dihydroxy-
benzaldehyde by a route in which the longest linear sequence is only
14 steps. The key transformations in the synthesis are copper-medi- projects10 we have achieved such couplings by treating a
ated and palladium-catalyzed coupling reactions of the iodide 3-
mixture of two aryl bromides with a bis(trialkyltin) in the
iodo-5,6-diisopropoxy-2-[(tetrahydropyran-2-yloxy)methyl]benzo-
presence of a palladium catalyst. The reaction proceeds
furan with the corresponding stannane 5,6-diisopropoxy-2-[(tet-
via in situ conversion of one aryl bromide into the corre-
rahydropyran-2-yloxy)methyl]-3-(tributylstannyl)benzofuran, and
sponding stannane followed by coupling of the latter with
a 5-endo-dig iodocyclization of a (hydroxyphenyl)propargyl ether.
the benzofuranyl bromide. Thus, retrosynthetic analysis
Key words: kynapcin-24, copper-mediated, palladium-catalyzed,
suggested the concise route for the synthesis of this natu-
coupling, cyclizations
ral product 1 as shown in Scheme 1. The approach in-
volves the Sonogashira coupling reaction of known11 1-
bromo-2,4,5-trihydroxybenzene (8) and commercially
Prolyl endopeptidase (PEP), a serine protease, is known to
available methyl propynoate under palladium catalysis to
cleave a peptide substrate on the C-terminal side of a pro-
provide the desired propynoate 7; this is followed by the
iodo-mediated 5-endo-dig cyclization of 7 leading to the
expected 3-iodobenzofuran 6. The final step would em-
ploy a transition-metal-catalyzed homocoupling of 6 to
line residue.1 Additionally, the PEP activity of Alzhei-
mer’s patients has been found to be significantly higher
than that of the normal person.2 Therefore, the search for
PEP inhibitors as anti-dementia drugs, which may play a
crucial role in curing Alzheimer’s disease, has attracted
significant attention from the synthetic, biological, and
form the dimer 3,3¢-dibenzofuran 1.
Since 1-bromo-2,4,5-trihydroxybenzene (8) is known, we
medicinal communities.3 Recently, Song et al. reported
that two novel PEP inhibitors, the benzofuran dimer
kynapcin-24 (1) (IC50, 1.14 mM) and pentacyclic poly-
ozellin (5), as well as related compounds 2–4 (Figure 1),
were isolated from Polyozellus multiflex Murr.4 On the
other hand, although propeptin (IC50, 1.1 mM) has inhibi-
tion similar to 1, it is a hydrophilic and large-molecular-
weight peptide, which may make it difficult to penetrate
the blood–brain barrier. With the difficulty of propeptin as
a PEP inhibitor and the promise shown by drugs such as
1, we undertook the synthesis of 1, since its total synthesis
has not been reported yet.
used it as the starting point of our synthesis, to prepare the
corresponding 3-iodobenzofuran 6 (Scheme 1). However,
attempts at a Sonogashira coupling reaction between 8
and methyl propynoate to give 7 were unsuccessful. The
major product was the recovered starting material methyl
propynoate. This problem could be due to the need for low
temperature, because 8 decomposes above 0 °C.11 These
technical difficulties were overcome by Yang et al.,12 who
O
O
O
OH
MeO2C
O
OH
OH
HO
HO
CO2Me
OH
O
Our research group has had a long-standing interest in the
synthesis and bioassay studies5 of a number of unique nat-
ural products, including coumestans,6 himanimides,7 and
benzofurans.8 The scant prior literature9 on construction
of the parent 3,3¢-dibenzofuran system encouraged the de-
velopment of a strategy involving, as the final step, the
metal-catalyzed homocoupling reaction of 3-bromoben-
zofuran to form 3,3¢-dibenzofuran. Alternatively, the pal-
ladium-catalyzed cross-coupling reaction is well known
for a wide variety of transmetalation reagents including
O
HO
HO
kynapcin-24 (1)
kynapcin-9 (2)
OH
O
O
OH
OH
HO
OAc
HO
HO
HO
OH
O
O
AcO
OH
kynapcin-12 (3)
thelephoric acid (4)
O
AcO
O
OH
OH
HO
HO
OAc
SYNTHESIS 2009, No. 7, pp 1175–1179
x
x
.
x
x
.2
0
0
9
polyozellin (5)
Advanced online publication: 06.03.2009
DOI: 10.1055/s-0028-1087998; Art ID: F22908SS
Figure 1 The structures of kynapcin analogues
© Georg Thieme Verlag Stuttgart · New York

1176
L.-Y. Yang et al.
PAPER
OH
ly, this consisted of the removal of the tetrahydropyran-2-
yl protecting group with pyridinium p-toluenesulfonate in
ethanol, followed by oxidation of the primary alcohol
with 2-iodoxybenzoic acid (IBX) to provide aldehyde 13
in 96% yield. McDonald et al.14 had reported that N-io-
dosuccinimide can oxidize a wide variety of aldehydes to
the corresponding methyl esters with high efficiency in a
single step. In the case of 13, however, the oxidation–
esterification reaction with N-iodosuccinimide or (diacet-
oxyiodo)benzene–iodine to give the desired methyl ester
14 was unsuccessful. The major product was the 2,3-di-
iodobenzofuran, which was produced by hydrolysis, de-
carboxylation, and iodination of methyl ester 14 under
basic conditions. Consequently, we sought to first convert
the aldehyde into the corresponding methyl ester; this pro-
ceeded smoothly by sequential oxidation with silver(I)
oxide and esterification with thionyl chloride and metha-
nol to provide the expected 14.
O
MeO2C
OH
I
iodo-endo-dig
cyclization
HO
HO
Pd coupling
HO
HO
CO2Me
CO2Me
O
O
6
1
CO2Me
Sonogashira
coupling
HO
HO
HO
HO
Br
CO2Me
+
OH
OH
7
8
Scheme 1 Retrosynthetic analysis of kynapcin-24
developed an efficient route from the commercially avail-
able 3,4-dihydroxybenzaldehyde to prepare the corre-
sponding substituted iodobenzene in 72% yield over four
straightforward steps. We prepared 2-iodo-4,5-diisopro-
poxyphenyl acetate (9) (Scheme 2) according to Yang’s
procedures, but failed to obtain the desired product methyl
3-(2-acetoxy-4,5-diisopropoxyphenyl)propynoate under
Sonogashira coupling conditions. With the aim of devel-
oping a successful route to iodobenzofuran 14, an alterna-
tive method of construction was examined (Scheme 2).
With precursor 14 in hand (Scheme 2), a lithium–iodo ex-
change reaction of 14 with n-butyllithium or tert-butyl-
lithium to give the required benzofuranyllithium was
attempted, but without success. We also failed to obtain 1
by using the palladium-catalyzed reaction of 14 with
bis(trimethyltin). Fortunately, this problem could be over-
come by use of ether 12 instead of ester 14 (Scheme 3).
Lithiation and quenching with tributylstannyl chloride
proceeded smoothly to provide stannane 15 in 73% yield.
The thus available stannane 15 and iodide 12 could then
be subjected to copper-mediated palladium-catalyzed
coupling to give dibenzofuran 16 in 72% yield. As before,
sequential deprotection, oxidation, and oxidation–esterifi-
cation were performed with pyridinium p-toluene-
Coupling of phenyl iodide 9 with protected propargyl al-
cohol 10 instead of methyl propynoate proceeded readily
in dioxane under copper-mediated palladium catalysis to
give the desired 11 in excellent 96% yield (Scheme 2).
According to a procedure of Bew and Knight,13 the acyl
protecting group was removed with hydrazine monohy-
drate; subsequent reaction with N-iodosuccinimide gave
5-endo-dig iodocyclization of the phenol to afford 12 in
76% yield (over two steps). Iodobenzofuran 12 was then
transformed into formylbenzofuran 13 in two steps. Brief-
OTHP
[PdCl2(PPh3)2]
1. NH2NH2⋅H2O
i-PrO
i-PrO
I
I
i-PrO
i-PrO
CuI
100%
i-PrO
2. NIS
76%
OAc
OAc
O
OTHP
i-PrO
I
OTHP
10
96%
9
11
12
I
1. PPTS, EtOH
87%
i-PrO
i-PrO
Ag2O, NaOH
CHO
CO2Me
O
2. IBX, EtOAc
120 oC
SOCl2, MeOH
80%
i-PrO
O
i-PrO
13
14
96%
Scheme 2
THPO
O
Oi-Pr
Oi-Pr
SnBu3
i-PrO
i-PrO
Pd(PPh3)4
n-BuLi
12
i-PrO
CuI, 12
72%
n-Bu3SnCl
73%
O
OTHP
15
O
OTHP
i-PrO
16
O
1. PPTS, MeOH
61%
2. IBX, CH2Cl2
98%
Oi-Pr
Oi-Pr
MeO2C
i-PrO
i-PrO
BCl3
kynapcin-24 (1)
CO2Me
3. Ag2O, NaOH,
then SOCl2, MeOH
75%
0 °C
98%
O
17
Scheme 3
Synthesis 2009, No. 7, 1175–1179 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Kynapcin-24
1177
1H NMR (300 MHz, CDCl3): d = 1.25 (d, J = 6.0 Hz, 6 H), 1.30 (d,
J = 6.0 Hz, 6 H), 2.30 (s, 3 H), 4.41 (sept, J = 6.0 Hz, 2 H), 6.60 (dd,
J = 8.4, 2.1 Hz, 1 H), 6.66 (d, J = 2.1 Hz, 1 H), 6.78 (d, J = 8.4 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 20.7, 21.7, 21.9, 71.6, 72.4, 110.7,
113.4, 118.4, 144.8, 146.3, 149.3, 169.2.
Iodobenzene 9 was prepared, by Yang’s procedure,12 from the ace-
tate prepared as described above (1.10 g, 5.1 mmol); yield: 1.70 g
(96%); white solid; mp 50–52 °C.
1H NMR (300 MHz, CDCl3): d = 1.29 (d, J = 6.0 Hz, 6 H), 1.31 (d,
J = 6.0 Hz, 6 H), 2.30 (s, 3 H), 4.40 (sept, J = 6.0 Hz, 2 H), 6.68 (s,
1 H), 7.27 (s, 1 H).
sulfonate, 2-iodoxybenzoic acid, and silver(I) oxide–
thionyl chloride, with yields of 61, 98, and 75%, respec-
tively. The structure of 17 was confirmed by X-ray crys-
tallography.15 Finally, 17 was deprotected by treatment
with boron trichloride at 0 °C, providing target 1 in 98%
yield. That synthetically prepared 1 was the 3,3¢-dibenzo-
furan was deduced from the X-ray crystallographic struc-
ture of 17. In addition, 1H, 13C, and HMBC NMR spectra
of the synthetic product 1 were in agreement with those
reported for the naturally derived materials.4b
In conclusion, the structure of kynapcin-24 was confirmed
by total synthesis, and kynapcin-24 was obtained in 12%
overall yield by a concise route in which the longest linear
sequence was only 14 steps from commercially available
materials. In addition, the applicability of palladium catal-
ysis and 5-endo-dig iodocyclization could be demonstrat-
ed for the synthesis of a substituted benzofuran of the
2,2¢-substituted-3,3¢-dibenzofuran type.
13C NMR (75 MHz, CDCl3): d = 20.9, 21.7, 21.8, 71.8, 72.8, 78.1,
111.3, 127.0, 145.3, 147.2, 149.7, 168.3.
HRMS (EI): m/z [M+] calcd for C14H19IO4: 378.0328; found:
378.0331.
2-[3-(Tetrahydropyran-2-yloxy)prop-1-ynyl]-4,5-diisopropoxy-
phenyl Acetate (11)
A mixture of iodobenzene 9 (0.50 g, 1.3 mmol), [PdCl2(PPh3)2] (46
mg, 5 mol%), CuI (25 mg, 10 mol%), and 10 (0.30 g, 2.1 mmol) was
added to anhyd MeCN (5.0 mL) and Et3N (4.0 mL); stirring of the
mixture followed for 8 h at 25 °C. The mixture was then filtered
through Celite, which was washed with EtOAc (2 × 5.0 mL), and
the filtrate was evaporated in vacuo. After removal of the solvent,
flash chromatography (silica gel, hexane–EtOAc, 3:1) of the resi-
due gave 11.
Melting points were determined on a Mel Temp II melting-point ap-
paratus and are uncorrected. 1H and 13C NMR spectra were obtained
on Bruker-200 and Varian-300 spectrometers. Chemical shifts are
reported relative to the residual CHCl3 (d = 7.26) peaks. Low-reso-
lution MS and HRMS were carried out on a JEOL JMS-HX 110
mass spectrometer from the National Chung-Tsing University, Tai-
chung. Solvents were freshly distilled from P2O5 or CaH2 prior to
use. THF was distilled over sodium diphenyl ketyl. All reactions
were carried out under a N2 atmosphere unless it is stated otherwise.
Silica gel (silica gel 60, 230–400 mesh, Merck) was used for chro-
matography. Organic extracts were dried over anhyd MgSO4.
Yield: 0.49 g (96%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 1.28, 1.30 (d, J = 6.0 Hz, 12 H),
1.52–1.82 (m, 6 H), 2.28 (s, 3 H), 3.50–3.54 (m, 1 H), 3.79–3.86 (m,
1 H), 4.36, 4.46 (sept, J = 6.0 Hz, 2 H), 4.43 (s, 2 H), 4.86 (s, 1 H),
6.58 (s, 1 H), 6.97 (s, 1 H).
2-Iodo-4,5-diisopropoxyphenyl Acetate (9)
13C NMR (75 MHz, CDCl3): d = 18.9, 20.7, 21.8, 22.0, 25.2, 30.1,
54.4, 61.8, 71.9, 72.9, 80.7, 88.2, 96.3, 108.2, 110.3, 121.6, 146.1,
146.6, 150.4, 168.9.
HRMS (EI): m/z [M+] calcd for C22H30O6: 390.2042; found:
390.2038.
i-PrBr (3.3 mL, 35.2 mmol) was added to a mixture of 3,4-dihy-
droxybenzaldehyde (2.10 g, 15.2 mmol) and K2CO3 (3.00 g, 21.7
mmol) in acetone (50.0 mL) at 55 °C. The reaction mixture was
then refluxed at 70 °C for 8 h (TLC monitoring). After cooling of
the mixture, the soln was evaporated in vacuo, and the brown resi-
due was subjected to flash chromatography (silica gel, hexane–
EtOAc, 4:1) to give the protected 3,4-diisopropoxybenzaldehyde;
yield: 3.08 g (91%).
3-Iodo-5,6-diisopropoxy-2-[(tetrahydropyran-2-yloxy)meth-
yl]benzofuran (12)
H2NNH2·H2O (60 mL, 1.3 mmol) was added to a soln of 11 (63 mg,
0.16 mmol) in THF (10.0 mL), and the mixture was stirred at 25 °C
for 20 min. The reaction mixture was first diluted with Et2O (10.0
mL), and then filtered through a silica gel pad and eluted with Et2O.
The eluate was concentrated in vacuo, and the residue was subjected
to flash chromatography (silica gel, hexane–Et2O, 1:2); this gave
the desired phenol; yield: 56 mg (100%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 1.27 (d, J = 6.0 Hz, 6 H), 1.34 (d,
J = 6.0 Hz, 6 H), 1.54–1.86 (m, 6 H), 3.56–3.60 (m, 1 H), 3.89–3.96
(m, 1 H), 4.23 (sept, J = 6.0 Hz, 1 H), 4.45–4.52 (m, 3 H), 4.90 (d,
J = 3.3 Hz, 1 H), 6.01 (br s, 1 H), 6.49 (s, 1 H), 6.88 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 19.1, 22.0, 22.2, 25.3, 30.4, 55.5,
62.3, 71.2, 73.9, 80.6, 91.1, 97.8, 99.7, 102.6, 122.6, 141.6, 152.4,
153.9.
HRMS (EI): m/z [M+] calcd for C20H28O5: 348.1937; found:
348.1934.
A soln of the protected 3,4-diisopropoxybenzaldehyde (2.00 g, 9.0
mmol) in MeOH (35.0 mL) was stirred for 10 min at r.t.; this was
followed by slow addition of concd H2SO4 (0.4 mL) with stirring
over 5 min. Subsequently, 30% H2O2 (7.2 mL, 69.3 mmol) was
poured in one portion into the acidic soln at r.t. The mixture was
stirred for 5 h (TLC monitoring). After the reaction was completed,
the resulting mixture was quenched by the addition of sat. aq
NaHCO3 (5.0 mL), and then extracted with CH2Cl2 (3 × 30.0 mL).
The organic layers were concentrated in vacuo, and the residue was
subjected to flash chromatography (silica gel, hexane–Et2O, 3:1);
this gave the desired 3,4-diisopropoxyphenol; yield: 1.70 g (91%);
yellow oil.
A mixture of 3,4-diisopropoxyphenol (1.01 g, 4.8 mmol) and
K2CO3 (0.99 g, 7.1 mmol) in acetone (15.0 mL) was refluxed at
100 °C (oil bath) for 1 h, and then AcCl (0.40 mL, 5.8 mmol) was
added dropwise at r.t. The resulting mixture was heated to reflux for
5 h, and the resultant mixture was cooled and filtered and the solid
was washed with acetone (3 × 5 mL). The combined organic por-
tions were dried (Na2SO4) and then concentrated in vacuo. The res-
idue was purified by flash column chromatography (silica gel,
hexane–Et2O, 3:1); this gave the desired acetate product.
A mixture of the phenol prepared as described above (40 mg, 0.11
mmol) and NIS (31 mg, 0.14 mmol) in CH2Cl2 (6.0 mL) was stirred
for 15 min at 25 °C. The reaction was quenched by the addition of
sat. aq Na2S2O3 (3.0 mL), and the mixture was extracted with
CH2Cl2 (3 × 10.0 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The residue was purified by
Yield: 1.00 g (90%); colorless oil.
Synthesis 2009, No. 7, 1175–1179 © Thieme Stuttgart · New York

1178
L.-Y. Yang et al.
PAPER
5,6-Diisopropoxy-2-[(tetrahydropyran-2-yloxy)methyl]-3-
flash column chromatography (silica gel, hexane–Et2O, 3:1); this
gave 12; yield: 40 mg, 76%); yellow oil.
(tributylstannyl)benzofuran (15)
A soln of 12 (0.31 g, 0.66 mmol) in anhyd THF (10.0 mL) was
cooled to –78 °C in an acetone–dry ice bath. A 1.6 M soln of n-BuLi
in hexane (0.54 mL, 0.86 mmol) was added slowly (1 drop/2 s), dur-
ing which time the soln changed its color from colorless to pale yel-
low. The soln was stirred for 10 min at –78 °C, and then the reaction
was quenched at this temperature with neat n-Bu3SnCl (0.2 mL,
0.73 mmol). The soln was removed from the dry ice bath and al-
lowed to reach r.t. The reaction was quenched with H2O (0.3 mL)
and the soln was concentrated in vacuo. The residue was further pu-
rified by column chromatography (alumina, hexane–Et2O, 4:1); this
gave 15; yield: 0.31 g (73%); colorless oil.
1H NMR (300 MHz, acetone-d6): d = 1.29 (d, J = 5.1 Hz, 6 H), 1.31
(d, J = 5.1 Hz, 6 H), 1.44–1.80 (m, 6 H), 3.49–3.53 (m, 1 H), 3.85–
3.92 (m, 1 H), 4.48 (sept, J = 5.1 Hz, 1 H), 4.58 (sept, J = 5.1 Hz, 1
H), 4.63 (d, J = 12.7 Hz, 1 H), 4.73 (br t, J = 3.3 Hz, 1 H), 4.78 (d,
J = 12.7 Hz, 1 H), 6.87 (s, 1 H), 7.13 (s, 1 H).
13C NMR (75 MHz, acetone-d6): d = 18.7, 21.3, 21.5, 25.1, 29.9,
59.8, 61.2, 65.6, 71.6, 72.5, 97.1, 100.1, 109.8, 123.3, 146.6, 149.3,
149.6, 153.5.
HRMS (EI): m/z [M+] calcd for C22H27IO5: 474.0903; found:
474.0905.
1H NMR (300 MHz, acetone-d6): d = 0.88 (t, J = 7.2 Hz, 9 H), 1.23–
1.80 (m, 36 H), 3.48–3.53 (m, 1 H), 3.85–3.91 (m, 1 H), 4.36 (sept,
J = 7.2 Hz, 1 H), 4.49 (d, J = 12.6 Hz, 1 H), 4.55 (sept, J = 7.2 Hz,
1 H), 4.68 (d, J = 12.6 Hz, 1 H), 4.73 (br t, J = 3.3 Hz, 1 H), 7.06 (s,
1 H), 7.12 (s, 1 H).
13C NMR (75 MHz, acetone-d6): d = 9.7, 13.0, 18.9, 21.5, 21.6,
25.3, 27.1, 30.3, 61.3, 61.9, 71.5, 72.5, 97.0, 100.1, 111.3, 111.9,
127.2, 145.5, 148.0, 151.0, 158.6.
2-Formyl-3-iodo-5,6-diisopropoxybenzofuran (13)
A soln of 12 (0.27 g, 0.57 mmol) in EtOH (5.0 mL) was stirred for
5 min at 25 °C, and then PPTS (14 mg, 0.06 mmol) was added. The
mixture was heated to 50 °C for 4 h, and the solvent was evaporated
in vacuo. The residue was purified by flash column chromatography
(silica gel, hexane–Et2O, 3:1); this afforded the corresponding alco-
hol; yield: 0.19 g (87%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 1.35 (d, J = 6.0 Hz, 12 H), 3.01 (br
s, 1 H), 4.45 (sept, J = 6.0 Hz, 2 H), 4.75 (s, 2 H), 6.81 (s, 1 H), 6.93
(s, 1 H).
5,5¢,6,6¢-Tetraisopropoxy-2,2¢-bis[(tetrahydropyran-2-yl-
oxy)methyl]-3,3¢-dibenzofuran (16)
13C NMR (75 MHz, CDCl3): d = 21.9, 22.0, 57.1, 64.2, 72.4, 73.4,
100.4, 110.2, 123.4, 146.3, 148.9, 149.5, 154.9.
Iodobenzofuran 12 (0.16 g, 0.34 mmol), CuI (16 mg, 16 mol%),
Pd(PPh3)4 (31 mg, 8 mol%), and stannane 15 (0.28 g, 0.44 mmol)
were introduced into a sealable tube containing anhyd dioxane (5.0
mL), and the mixture was degassed. The tube was sealed and heated
for 15 h at 160 °C; after cooling, the mixture was filtered and evap-
orated in vacuo. The residue was subjected to flash chromatography
(silica gel, hexane–Et2O, 4:1); this gave 16; yield: 0.17 g (72%);
yellow oil.
1H NMR (300 MHz, acetone-d6): d = 1.20–1.77 (m, 36 H), 3.34–
3.37 (m, 2 H), 3.70–3.82 (m, 2 H), 4.38–4.80 (m, 10 H), 7.01 (s, 1
H), 7.03 (s, 1 H), 7.04 (s, 1 H), 7.07 (s, 1 H).
The thus obtained primary alcohol was directly oxidized with IBX
in EtOAc. To a soln of the alcohol (31 mg, 0.08 mmol) in EtOAc
(4.0 mL) was added IBX (23 mg, 0.16 mmol) at 25 °C; this was fol-
lowed by reflux at 120 °C (oil bath) for 5 h. The resulting suspen-
sion was cooled, excess IBX was removed by filtration, and the
filtrate was concentrated in vacuo. After removal of the solvent, the
residue was subjected to flash chromatography (silica gel, hexane–
Et2O, 4:1); this gave 13; yield: 30 mg (96%); yellow solid: mp 97–
99 °C.
13C NMR (75 MHz, acetone-d6): d = 18.9, 19.0, 21.4, 21.5, 21.5,
21.6, 21.6, 25.2, 25.2, 30.2, 59.3, 59.6, 61.3, 61.4, 71.5, 71.6, 72.4,
72.5, 97.7, 98.0, 100.2, 100.3, 109.4, 109.6, 110.0, 110.1, 110.2,
121.1, 146.2, 146.3, 148.8, 148.9, 150.2, 150.3, 151.1, 151.3.
HRMS (EI): m/z [M+] calcd for C40H54O10: 694.3717; found:
694.3711.
1H NMR (300 MHz, acetone-d6): d = 1.32 (d, J = 6.0 Hz, 6 H), 1.36
(d, J = 6.0 Hz, 6 H), 4.55 (sept, J = 6.0 Hz, 1 H), 4.72 (sept, J = 6.0
Hz, 1 H), 6.99 (s, 1 H), 7.21 (s, 1 H), 9.73 (s, 1 H).
13C NMR (75 MHz, acetone-d6): d = 21.1, 21.4, 71.5, 72.6, 78.7,
98.2, 109.6, 122.9, 147.7, 149.1, 151.1, 153.5, 177.7.
HRMS (EI): m/z [M+] calcd for C15H17IO4: 388.0172; found:
388.0172.
5,5¢,6,6¢-Tetraisopropoxy-2,2¢-bis(methoxycarbonyl)-3,3¢-
dibenzofuran (17)
3-Iodo-2-(methoxycarbonyl)-5,6-diisopropoxybenzofuran (14)
To a mixture of 13 (74 mg, 0.19 mmol) and Ag2O (60 mg, 0.10
mmol) in THF (4.0 mL) was introduced 0.5 N NaOH in EtOH (2.0
mL) at 25 °C. The mixture was heated to 50 °C for 30 min. The re-
sulting suspension was filtered and the solid was washed with THF
(5 × 1.5 mL); the combined filtrate and wash were concentrated in
vacuo. The crude product was dissolved in MeOH (8.0 mL), and
then SOCl2 (30 mL, 0.38 mmol) was added dropwise at 25 °C. The
mixture was heated to reflux at 110 °C (oil bath) for 4 h, and the re-
sulting soln was evaporated in vacuo. The residue was neutralized
with sat. aq NaHCO3 (2.0 mL), extracted with EtOAc (3 × 7.0 mL),
and purified by flash chromatography (silica gel, hexane–EtOAc,
3:1); this gave 14; yield: 64 mg (80%); white solid; mp 85–87 °C.
1H NMR (300 MHz, CDCl3): d = 1.35 (d, J = 6.0 Hz, 6 H), 1.40 (d,
J = 6.0 Hz, 6 H), 3.98 (s, 3 H), 4.48 (sept, J = 6.0 Hz, 1 H), 4.55
(sept, J = 6.0 Hz, 1 H), 6.96 (s, 1 H), 7.06 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.8, 22.0, 52.2, 72.2, 73.4, 74.4,
99.0, 110.8, 124.0, 143.0, 147.5, 150.2, 152.3, 159.4.
Compound 17 was prepared (by the procedure described above for
14 from 12 via 13) from 16 (80 mg, 0.12 mmol) and PPTS (6.0 mg,
0.02 mmol) in MeOH (8.0 mL) at 50 °C for 5 h. A mixture of the
free alcohol (80 mg, 0.16 mmol) and IBX (0.17 g, 0.60 mmol) was
heated in CH2Cl2 (10.0 mL) at reflux for 7 h, and the thus formed
aldehyde (54 mg, 0.09 mmol) was oxidized with Ag2O (66 mg, 0.42
mmol) in THF (6.0 mL). The resulting acid in MeOH (15 mL) was
treated with SOCl2 (21 mL, 0.30 mmol) at 110 °C for 4 h. This gave
17. (The products of the three steps were isolated in 61, 98, and 75%
yield, respectively.)
White solid; mp 156–157 °C.
1H NMR (300 MHz, CDCl3): d = 1.27, 1.42 (d, J = 6.0 Hz, 24 H),
3.77 (s, 6 H), 4.31, 4.58 (sept, J = 6.0 Hz, 4 H), 6.85 (s, 2 H), 7.17
(s, 2 H).
13C NMR (75 MHz, CDCl3): d = 21.8, 21.8, 21.9, 22.0, 51.9, 72.0,
73.3, 99.1, 109.8, 118.6, 120.0, 141.0, 146.8, 150.7, 151.6, 159.7.
HRMS (EI): m/z [M+] calcd for C32H38O10: 582.2465; found:
582.2471.
HRMS (EI): m/z [M+] calcd for C16H19IO5: 418.0277; found:
418.0279.
Synthesis 2009, No. 7, 1175–1179 © Thieme Stuttgart · New York

PAPER
Total Synthesis of Kynapcin-24
1179
5,5¢,6,6¢-Tetrahydroxy-2,2¢-bis(methoxycarbonyl)-3,3¢-dibenzo-
furan (1, Kynapcin-24)
BCl3 (0.24 mL, 0.24 mmol) was added dropwise to a soln of 17 (17
mg, 0.03 mmol) in CH2Cl2 (3.0 mL) at 0 °C. The reaction was mon-
itored by TLC and quenched by treatment with MeOH. The solvent
was removed and the residue was subjected to flash chromatogra-
phy (silica gel, EtOAc–hexane, 3:1); this gave 1.
References
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Yield: 12 mg (98%); yellow solid; mp 300 °C (dec).
1H NMR (300 MHz, acetone-d6): d = 3.69 (s, 6 H), 6.77 (s, 2 H),
7.12 (s, 2 H), 9.30 (br s, 2 H), 9.57 (br s, 2 H).
13C NMR (75 MHz, acetone-d6): d = 51.0, 97.7, 104.9, 118.4, 119.5,
140.6, 143.7, 148.0, 149.6, 159.3.
HRMS (EI): m/z [M+] calcd for C20H14O10: 414.0587; found:
414.0584.
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Acknowledgment
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This work was financially supported by the National Science
Council of the Republic of China (Research Grant NSC 96-2113-
M-018-001-MY2). We thank Professor T. Ross Kelly for valuable
proofreading and the revised manuscript. We also acknowledge
with appreciation the NSC-supported HRMS spectrometry facility
for providing high-resolution mass spectra.
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(15) The X-ray data for 17 have been deposited at CCDC under
the number CCDC701406.
Synthesis 2009, No. 7, 1175–1179 © Thieme Stuttgart · New York