Three-component coupling approach toward the synthesis of a resorcylic acid lactone framework

Article abstract of DOI:10.1016/j.tet.2011.05.023

A resorcylic acid lactone (RAL) framework was constructed based on a three-component coupling approach. The key step was the intermolecular alkylation of a protected cyanohydrin with an aromatic scaffold, and the subsequent carbonylative esterification of the aryl iodide with an alcohol. This sequence allowed the rapid assembly of three components without extra protection/deprotection steps. This synthetic strategy enables the ketone at the 2′ position to be masked as a protected cyanohydrin during the ester formation, thus avoiding an undesired isocoumarin formation. This method should be widely applicable to the synthesis of various types of RAL frameworks.

Full text of DOI:10.1016/j.tet.2011.05.023

Tetrahedron 67 (2011) 6654e6658
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Tetrahedron
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Three-component coupling approach toward the synthesis of a resorcylic acid
lactone framework
*
Sakae Sugiyama, Shinichiro Fuse, Takashi Takahashi
Department of Applied Chemistry, Tokyo Institute of Technology 2-12-1, Ookayama, Meguro, Tokyo 152-8552, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A resorcylic acid lactone (RAL) framework was constructed based on a three-component coupling ap-
proach. The key step was the intermolecular alkylation of a protected cyanohydrin with an aromatic
scaffold, and the subsequent carbonylative esterification of the aryl iodide with an alcohol. This sequence
allowed the rapid assembly of three components without extra protection/deprotection steps. This
synthetic strategy enables the ketone at the 20 position to be masked as a protected cyanohydrin during
the ester formation, thus avoiding an undesired isocoumarin formation. This method should be widely
applicable to the synthesis of various types of RAL frameworks.
Received 31 March 2011
Received in revised form 6 May 2011
Accepted 7 May 2011
Available online 13 May 2011
Keywords:
Resorcylic acid lactone
Multi-component coupling
Carbonylation
Ó 2011 Elsevier Ltd. All rights reserved.
Cyanohydrin
1. Introduction
Resorcylic acid lactones (RALs) are polyketide natural products
with a large macrocyclic ring fused to resorcylic acid (Fig. 1). RALs
were discovered with the first isolation of radicicol (1) in 1953.1 Al-
though RALs did not attract much attention in the early years, recent
discoveries of potent ATPase and kinase inhibitors amongst the RALs
have revived interest in this family of natural products.2e5 RALs have
various functionalities, such as alkane, alkene, epoxide, and methyl
ketone at the 10 and 20 positions (Fig. 1), and these functionalities do
affect their target selectivities (see RALs 5 and 6 in Fig. 1).2,6
There have been numerous elegant synthetic reports related to
RALs and their analogues.2e21 In the early 1980s, we reported
a zearalenone (2) analogue synthesis through palladium-catalyzed
carbonylative esterification.22e25 Although the carbonylative es-
terification required the activation of the sterically hindered ortho-
disubstituted aryl iodide, the reaction proceeded well to give the
desired benzoate in good yield. We also reported the construction
of the macrolactone ring via intramolecular alkylation using a pro-
tected cyanohydrin.24e26 In 2010, we reported
a divergent,
protection/deprotection-free, short synthetic route for the con-
struction of RAL frameworks based on a three-component coupling
approach.27 The key step was a sequential palladium-catalyzed
coupling reaction using an aromatic scaffold that had two re-
action centers (AreI and AreBr) and a subsequent ring-closing
metathesis (RCM) reaction.28e30
* Corresponding author. Tel.: þ81 3 5734 2120; fax: þ81 3 5734 2884; e-mail
Fig. 1. Structures of naturally occurring RALs. Functionalities at the benzylic position
are emphasized.
address: ttak@apc.titech.ac.jp (T. Takahashi).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.023

S. Sugiyama et al. / Tetrahedron 67 (2011) 6654e6658
6655
Scheme 1. Three-component coupling approach based on the aromatic scaffold 7.
Herein, we wish to report the efficient synthesis of RAL analogue
13 with a methyl ketone functionality at its 10 and 20 positions
based on a three-component coupling approach (Scheme 1). The
key step was an alkylation/carbonylation sequence using an aro-
matic scaffold 7, which had two reaction centers (AreI and
ArCH2eBr).
We planned to examine two synthetic routes toward the cycli-
zation precursor 12, i.e., routes A and B (Scheme 1). Both routes
include the rapid assembly of three components, 7, 8, and 10,
without extra protection/deprotection steps. At the final stage, the
macrocycle is formed under mild and neutral conditions by an RCM
reaction. It is well known that the proton at the 10 position in 13 is
highly acidic and the ketone is readily enolised to yield an un-
desired isocoumarin.26 Therefore, we decided to employ the
building block 10, in which the ketone at the 20 position was
masked as a protected cyanohydrin. We anticipated that the pro-
tected cyanohydrin would be readily converted into the corre-
sponding ketone by treatment with a weak acid and a diluted base
without forming the undesired isocoumarin.26 The iodo-group at
the 1 position would serve as a masked activated ester and the AreI
bond could be activated by a palladium catalyst to directly form the
desired ester.22e25,31,32 In route A, the carbonylative esterification of
the aromatic scaffold 7 with alcohol 8, followed by intermolecular
alkylation with the protected cyanohydrin 10 afford the desired
coupling product 12. In route B, the order of the carbonylation and
the alkylation is switched. We speculated that the activation of the
AreI bond in the aromatic scaffold 7 (route A) would be easier than
the activation of the more sterically hindered AreI bond in 11
(route B). However, selective alkylation at the 10 position to afford
11 without affecting the AreI bond (route B) seemed easier than
selective carbonylation at the 1 position to afford 9 without
affecting the ArCH2eBr bond (route A). We examined both routes
toward the synthesis of RAL analogue 13.
Scheme 2. Preparation of the pivotal aromatic scaffold 7 and the protected cyanohy-
drin 10.
2. Results and discussion
Syntheses of the aromatic scaffold 7 and the protected cyano-
hydrin 10 are shown in Scheme 2. Iodination at the 1 position in
commercially available, 3,5-dimethoxybenzyl alcohol (14) and the
subsequent conversion of the benzyl alcohol to the corresponding
benzyl bromide afforded the desired product 7 in high yield. The
protected cyanohydrin 10 was readily prepared from geraniol (16)
as shown in Scheme 2. The geraniol was oxidized to the corre-
sponding citral (17), and the aldehyde was converted to the pro-
tected cyanohydrin 10 in two steps.
Scheme 3. Examination of synthetic routes A and B.
was not detected under the employed conditions [5 mol %
PdCl2(PPh3)2, DBU or NEt3, CO (15 atm), DMF, 100 ꢀC]. We con-
cluded that the selective activation of the AreI bond in 7 without
affecting the reactive ArCH2eBr bond is difficult.33
Initially, we examined the carbonylative esterification of 7 with
3-buten-1-ol (Scheme 3, route A). Although the aryl iodide 7 was
consumed, a complex mixture was obtained and the desired ester
Next, we examined route B (Scheme 3). The intermolecular al-
kylation of the protected cyanohydrin 10 with the aromatic scaffold
7 afforded the desired coupling product 11 in good yield.

6656
S. Sugiyama et al. / Tetrahedron 67 (2011) 6654e6658
The crucial palladium-catalyzed carbonylation was examined as
esterification of highly deactivated aryl iodide 11 was achieved by
using a combination of 5 mol % PdCl2(PPh3)2 and DBU. As expected,
the conversion of the protected cyanohydrin to the corresponding
ketone was performed without generating the undesired iso-
coumarin. The desired compound 13 was synthesized via five steps
from the pivotal aromatic scaffold in good yield (total 44% yield).
This strategy should be widely applicable to the synthesis of various
kinds of RAL analogues by changing the nucleophiles in the alkyl-
ation/carbonylation sequence.
shown in Table 1. The solution of the aryl iodide 11 and 3-buten-1-
ol in DMF was vigorously stirred under a CO (15 atm) atmosphere at
100 ꢀC. The combination of 5 mol % Pd(Pt-Bu3)2 and DABCO affor-
ded a complex mixture accompanied by a trace amount of desired
ester 12 (Table 1, entry 1). Better yields were observed by
employing DBU (entries 2e4) and K2CO3 (entry 5) as the base. The
combination of 5 mol % PdCl2(PPh3)2 and DBU gave the best result
(entry 4). The yield (61%) was satisfactory considering that the AreI
bond of 11 was highly deactivated by the bulky and electro-
ndonating ortho, para-trisubstituents.
4. Experimental section
4.1. General
Table 1
Palladium-catalyzed carbonylative esterification
NMR spectra were recorded on a JEOL Model EX-270 (270 MHz
for 1H, 67.8 MHz for 13C) or a JEOL Model ECP-400 (400 MHz for 1H,
100 MHz for 13C) instrument in the indicated solvent. Chemical
shifts are reported in units parts per million (ppm) relative to the
signal for internal tetramethylsilane (0 ppm for 1H) for solutions in
CDCl3. NMR spectral data are reported as follows: chloroform
(7.26 ppm for 1H) or chloroform-d (77.1 ppm for 13C). Multiplicities
are reported by the following abbreviations: s; singlet, d; doublet, t;
triplet, q; quartet, m; multiplet, br; broad, J; coupling constants in
Hertz. IR spectra were recorded on a PerkineElmer Spectrum One
FT-IR spectrophotometer. Only the strongest and/or structurally
important absorption is reported as the IR data in cmꢁ1. All re-
actions were monitored by thin-layer chromatography carried out
on 0.25 mm E. Merck silica gel plates (60F-254) with UV light, vi-
sualized by p-anisaldehyde solution, ceric sulfate or 10% ethanolic
phosphomolybdic acid. Merck silica gel 60 (0.063e0.200 mm) was
used for column chromatography. ESI-TOF Mass spectra were
measured with Waters LCT PremierÔ XE. HRMS (ESI-TOF) were
calibrated with leucine enkephalin (SIGMA) as an internal
standard.
HO
OMe O
8
O
Pd cat. base
CO (15 atm)
11
MeO
DMF, 100
EEO
CN
12
Entry
Pd cat.
Base
Yielda (%)
1
2
3
4
5
Pd(Pt-Bu3)2
Pd(Pt-Bu3)2
Pd(OAc)2
PdCl2(PPh3)2
PdCl2(PPh3)2
DABCO
DBU
DBU
DBU
K2CO3
<10
47
24
61
40
a
Isolated yield.
As expected, the conversion of the protected cyanohydrin 12 to
the corresponding ketone 18 was successfully performed without
generating the undesired isocoumarin. Finally, the macrolactone
ring was formed via an RCM reaction using the Grubbs II34 catalyst
in excellent yield without affecting the methyl ketone functionality.
Interestingly, the (E)-isomer was obtained as the sole product
(Scheme 4).
4.1.1. 1-(Bromoethyl)-2-iodo-3,5-dimethoxybenzene (7). To a solu-
tion of 3,5-dimethoxybenzyl alcohol (14) (4.30 g, 25.5 mmol) in
DMF (50.0 mL) was added N-iodosuccinimide (6.90 g, 30.6 mmol)
at 0 ꢀC under Ar. After being stirred at 40 ꢀC for 3 h, the mixture was
poured into Et2O and H2O, and extracted with ethyl acetate. The
extract was washed with 10% aqueous Na2S2O3 solution and brine,
dried over MgSO4, filtered, and concentrated in vacuo. The residue
was used for the next reaction without further purification.
To a solution of the residue in THF (132 mL) were added PPh3
(6.36 g, 24.3 mmol) and CBr4 (10.1 g, 30.6 mmol) at 0 ꢀC under Ar.
After being stirred at 0 ꢀC for 3 h, the mixture was poured into
Et2O and H2O, and extracted with ethyl acetate. The extract was
washed with saturated aqueous NaHCO3 and brine, dried over
MgSO4, filtered, and concentrated in vacuo. The residue was pu-
rified by column chromatography on silica gel, and eluted with 5%
ethyl acetate in hexane to afford 1-(bromoethyl)-2-iodo-3,5-
dimethoxybenzene (7) (7.79 g, 21.8 mmol, 85%) as a white solid.
Mp 126e128 ꢀC; 1H NMR (400 MHz, CDCl3)
1H), 6.36 (d, J¼2.9 Hz, 1H), 4.63 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H);
13C NMR (67.8 MHz, CDCl3)
161.0, 159.2, 141.8, 107.0, 98.8, 81.5,
56.5, 55.6, 39.4; FT-IR (solid) 2940, 1586, 1471, 1322, 1200, 1084,
942, 824 cmꢁ1; HRMS (ESI-TOF); [MþH]þ calcd for C9H11O2BrI,
356.8987; found 356.8984.
d
6.69 (d, J¼2.9 Hz,
d
Scheme 4. Total synthesis of RAL analogue 13.
3. Conclusion
4.1.2. Protected cyanohydrin 10. To a solution of citral (17)35 (1.30 g,
8.54 mmol) were added TMSCN (1.4 mL, 11.3 mmol) and a catalytic
amount of DC-18-crown-6 KCN complex at 0 ꢀC. After being stirred
at room temperature for 1 h, the reaction mixture was diluted with
THF and 1 M HCl was carefully added at 0 ꢀC (caution: HCN is
generated). After being stirred at the same temperature for 30 min,
the reaction mixture was extracted with Et2O. The extract was
In summary, the synthesis of RAL analogue 13 was accomplished
with a methyl ketone functionality at the 10 and 20 positions based
on a three-component coupling approach. The RAL framework was
rapidly assembled via an alkylation/carbonylation sequence with-
out extra protection/deprotection steps. The crucial carbonylative

S. Sugiyama et al. / Tetrahedron 67 (2011) 6654e6658
6657
washed with brine, dried over MgSO4, filtered, and concentrated in
vacuo. The residue was used for the next reaction without further
purification.
1424, 1330, 1275, 1161, 1097, 1048 cmꢁ1; HRMS (ESI-TOF); [MþH]þ
calcd for C24H33O5, 401.2328; found 401.2326.
To a solution of the crude cyanohydrin in CH2Cl2 (10.0 mL) were
added ethyl vinyl ether (1.64 mL, 17.1 mmol) and CSA (132 mg,
0.568 mmol) at 0 ꢀC under Ar. After being stirred at room tem-
perature for 1 h, the reaction mixture was poured into saturated
aqueous NaHCO3 and extracted with Et2O. The extract was washed
with brine, dried over MgSO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel,
and eluted with 5% ethyl acetate in hexane to afford the protected
cyanohydrin 10 (1.78 g, 7.08 mmol, 83%) as a colorless oil (di-
astereomeric mixture).
4.1.6. The RAL analogue 13. To a solution of the cyclization pre-
cursor 18 (47.6 mg, 0.119 mmol) in CH2Cl2 (24.0 mL) was added
Grubbs II catalyst (10.0 mg, 0.0119 mmol) at room temperature
under Ar. After being stirred at the same temperature for 3 h, the
mixture was filtered and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (20% in ethyl ac-
etate in hexane) to afford the RAL analogue 13 (39.8 mg,
0.115 mmol, 97%) as a white solid. Mp 117e118 ꢀC; 1H NMR
(400 MHz, CDCl3)
d
6.38 (s, 2H), 5.90 (s, 1H), 5.38 (dt, J¼15.5, 6.8 Hz,
2H), 5.30 (ddd, J¼15.5, 6.3, 5.8 Hz, 2H), 4.34 (t, J¼5.3 Hz, 2H), 3.81
(s, 3H), 3.79 (s, 3H), 3.56 (s, 2H), 2.41 (dt, J¼5.8, 5.3 Hz, 2H),
4.1.3. Aryl iodide 11. To a solution of the protected cyanohydrin 10
(98.9 mg, 0.393 mmol) in THF (5.00 mL) was added dropwise
LiN(TMS)2 (0.454 mL, 1.00 M in toluene, 0.454 mmol) at ꢁ78 ꢀC
under Ar. After being stirred at the same temperature for 30 min,
a solution of 1-(bromoethyl)-2-iodo-3,5-dimethoxybenzene (7)
(108 mg, 0.303 mmol) in THF (3.00 mL) was added to the reaction
mixture at ꢁ78 ꢀC. After being stirred at 0 ꢀC for 30 min, the mix-
ture was poured into Et2O and 1 M HCl, and extracted with Et2O.
The extract was washed with saturated aqueous NaHCO3 and brine,
dried over MgSO4, filtered, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel, and eluted
with 25% Et2O in hexane to afford the aryl iodide 11 (133 mg,
0.252 mmol, 83%) as a colorless oil (diastereomeric mixture).
2.17e2.08 (m, 7H); 13C NMR (67.8 MHz, CDCl3)
d 197.2, 168.2, 161.4,
158.2, 157.6, 134.9, 131.8, 128.0, 123.9, 117.6, 105.7, 97.7, 64.2, 55.9,
55.4, 48.7, 39.7, 31.6, 29.4, 19.8; FT-IR (solid) 2948, 1720, 1675, 1587,
1453, 1381, 1264, 1198, 1069, 961, 635 cmꢁ1; HRMS (ESI-TOF);
[MþH]þ calcd for C20H25O5, 345.1702; found 345.1704.
Acknowledgements
We thank Prof. Takayuki Doi (Tohoku University) for his fruitful
discussions.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.023. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
4.1.4. Ester 12. In a glass vessel, to a suspension of the aryl iodide 11
(283 mg, 0.535 mmol) and 3-butene-1-ol (8) (0.136 mL, 1.60 mmol)
in DMF (3.00 mL) were added PdCl2(PPh3)2 (18.7 mg, 26.6 mmol)
and DBU (0.160 mL, 1.07 mmol) under Ar. The vessel was placed in
an autoclave, which was purged with CO three times before ap-
plication of pressure (15 atm). After it was stirred at 100 ꢀC for 12 h,
the reaction mixture was poured into Et2O and saturated aqueous
NH4Cl, and extracted with Et2O. The extract was washed with
saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel, and eluted with 30% Et2O in hexane
to afford the ester 12 (163 mg, 0.326 mmol, 61%) as a colorless oil
(diastereomeric mixture).
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m
mol) (31.7 mg, 79.2
m
mol, 2
steps 90%) as a colorless oil. 1H NMR (400 MHz, CDCl3)
d
6.38 (d,
J¼2.4 Hz, 1H), 6.32 (d, J¼2.4 Hz, 1H), 6.07 (s, 1H), 5.84 (ddt, J¼17.4,
10.1, 6.8 Hz, 1H), 5.13 (d, J¼17.4 Hz, 1H), 5.08e5.00 (m, 2H), 4.31 (t,
J¼6.8 Hz, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.72 (s, 2H), 2.46 (dt, J¼6.8,
6.3 Hz, 2H), 2.13e2.11 (m, 7H), 1.67 (s, 3H), 1.58 (s, 3H); 13C NMR
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d 196.8, 167.6, 161.6, 159.9, 158.8, 135.9, 134.2,
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