Total Synthesis of Asparenydiol by Two Sonogashira Cross-Coupling Reactions Promoted by Supported Pd and Cu Catalysts

Article abstract of DOI:10.1055/s-0039-1690852

Asparenydiol, which is an important natural compound with potential pharmacological activities, was synthesized through two Sonogashira cross-coupling reactions catalyzed by supported Pd and Cu catalysts and by a Mitsunobu etherification. The optimization

Full text of DOI:10.1055/s-0039-1690852

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–I
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G. Casotti et al.
Paper
Synthesis
Total Synthesis of Asparenydiol by Two Sonogashira Cross-Coupling
Reactions Promoted by Supported Pd and Cu Catalysts
Gianluca Casottia
Graziano Fusinia
Matteo Ferreria
Luca Fidia Pardinia
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Claudio Evangelisti*b
Gaetano Angelici*a
Adriano Carpitaa
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a Department of Chemistry and Industrial Chemistry, University
of Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy
gaetano.angelici@unipi.it
b CNR, Istituto di Chimica dei Composti Organometallici
(ICCOM), Via G. Moruzzi 1, 56124, Pisa, Italy
claudio.evangelisti@cnr.it
In loving memory of Prof. Adriano Carpita
Received: 16.01.2020
Accepted after revision: 18.02.2020
Published online: 05.03.2020
After careful retrosynthetic analysis, we envisioned the
possibility of formally applying three main disconnections,
as shown in Scheme 1, which could allow the use of com-
mercially available building blocks or easy to synthesize in-
termediates. Disconnection A could synthetically corre-
spond to a formal etherification, while B and C disconnec-
tions suggest the possibility of building the Asparenydiol
core around its triple bond, using a formal double ethynyl
donor synthon. More specifically, in Scheme 2, the chosen
building blocks are shown based on the disconnections pro-
posed. For disconnection A, we planned an etherification
between a phenol and an allylic alcohol through a Mitsunobu
reaction, which allows neutral conditions and it is compati-
ble with sensitive allylic substrates that are at risk of regio-
isomerization.5,6
DOI: 10.1055/s-0039-1690852; Art ID: ss-2020-t0034-op
Abstract Asparenydiol, which is an important natural compound with
potential pharmacological activities, was synthesized through two
Sonogashira cross-coupling reactions catalyzed by supported Pd and Cu
catalysts and by a Mitsunobu etherification. The optimization of the
Sonogashira couplings allowed the use of catalysts supported on differ-
ent matrices with good results in terms of catalytic efficiency and
yields.
Key words Asparenydiol, Sonogashira cross-coupling, Mitsunobu
etherification, total synthesis, solid-supported palladium catalyst
Asparenydiol is an acetylenic compound that was isolat-
ed for the first time from Asparagus officinalis by Terada
and co-workers in 1995,1 and afterwards found in Aspara-
gus cochinchinensis2 and also in Asparagus racemosus.3
These plants have long been known for their use in ethno-
medicine. Notably, A. cochinchinensis was reported to be
used for treating fever, cough, kidney diseases, and benign
breast tumors in China, and A. racemosus was used to treat
gastric ulcers, diabetes and to improve immunity in India.
Asparenydiol was found to exhibit moderate bioactivity on
some tumoral cell lines (KB, Col-2, LNCaP, Lu-1 and HU-
VEC), with IC50 values between 4 and 20 g/mL.4 Despite
the potential pharmacological applications, the difficult
and low-yielding process of extraction (2 mg of Aspareny-
diol from 5 kg of roots) limits an extensive screening of its
properties. Moreover, to our knowledge, there are still no
examples of synthetic pathways that are suitable for large-
scale production of Asparenydiol.
A
B
OH
C
O
Asparenydiol
HO
OH
C
C
HO
OH
S3
S2
S1
HO
X
O
X
OH
X
OMe
HO
S4 (X = I or Br)
S5 (X = I or Br)
S6 (X = I or Br)
Scheme 1 General retrosynthetic analysis for Asparenydiol
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I
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G. Casotti et al.
Paper
Synthesis
To avoid oligomer formation and homoetherification,
the initial protection of one of the hydroxyl groups of hy-
droquinone and subsequent intermediates is necessary.
Among the most common protecting groups for phenol
protection, we chose to use tert-butyldimethylsilyl ether,
for its chemical stability and the orthogonality compared to
trimethylsilyl ether, necessary for the synthesis of interme-
diate compound 3. We also considered the possibility of us-
ing a two-step Williamson etherification, in which the al-
lylic alcohol is previously transformed into the correspond-
ing chloride, bromide, mesylate or tosylate, followed by
nucleophilic substitution of the phenol under basic condi-
tions. Preliminary results, however, suggested that, in this
case, the Mitsunobu reaction is more reliable. For discon-
nections B and C, we envisioned the use of the Sonogashira
reaction,7 that, in its original version, promotes the alky-
nylation of aryl or alkenyl halides, co-catalyzed by Pd and
Cu(I), in the presence of a base.8
Today, the Sonogashira reaction is commonly performed
under homogeneous catalysis conditions;9 it does not re-
quire preformed organometallic acceptor species in stoi-
chiometric amounts, as in the case of Negishi cross-cou-
pling reactions,10 which is also used for the synthesis of nat-
ural compounds.11 For larger-scale and greener applications
of the Sonogashira reaction, several methods have been de-
veloped, including copper-free reactions, solvent-less reac-
tions, and, notably, Pd-based supported catalysts such as
Pd/C.12 Depending on the order of disconnection between B
and C, the structure of the intermediates could change (12
or 4), even though the building blocks to obtain 8 are essen-
tially the same; 4-tert-butyldimethylsilyl-1-iodobenzene
(2), (E)-3-bromoacrylate (7) and trimethylsilylacetylene
(13). Nevertheless, there is only one example of the synthe-
sis of 12, through a cross-coupling reaction in Pd/Cu homo-
geneous catalysis, reported by Garrais et al. in 2009,13
whereas we had extensive experience in the preparation of
intermediate 4.14 In particular, disconnection B would cor-
respond to a Sonogashira reaction between terminal alkyne
4 and an (E)-1-halo-3-hydroxy-1-propene to yield 8, with
both nascent hydroxy groups protected. Even though there
are several examples of the latter substrate being used suc-
cessfully in homogeneous catalysis at room temperature,15–18
there are none in heterogeneous catalysis, probably due to
the instability at higher temperatures, or to the possibility
to form oxidative addition complexes with palladium.
Therefore, we opted to use methyl (E)-3-bromoacrylate (7),
which can be easily reduced afterwards with DIBALH at low
temperature without regio-isomerization, as reported by
several groups.19,13 For example, in 2000, Takeuchi et al.
proposed a stereoselective synthesis of 2-alken-4-ynoates
through Sonogashira reaction between arylalkynes and vi-
nyl iodides,20 which looked promising for our purpose. We
A
OTBDMS
OH
OH
+
O
TBDMSO
9
OTBDMS
11
TBDMSO
10
B
C
O
B
I
O
C
OMe
+
OMe
TBDMSO
8
H
2
TBDMSO
12
B
O
H
TMS
+
OMe
O
Br
13
+
Br
OMe
7
TBDMSO
7
4
H
SiMe3
I
C
13
TMS
+
TBDMSO
TBDMSO
3
2
Scheme 2 Retrosynthetic analysis with the proposed building blocks
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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G. Casotti et al.
Paper
Synthesis
also considered alternatives such as an oxidative alkynyla-
tion catalyzed by palladium, as proposed by Nishimura et
al.21 and a cross-coupling between (E)-3-iodoacrylate and
phenylacetylene promoted only by Cu(I), proposed by Bates
et al.22 However, for these two methods, the catalyst load-
ings and the temperatures were too high for our system. In-
terestingly, Ranu et al. studied the reaction between (E)-
1,2-diiodostyrenes and acrylates catalyzed by palladium
nanoparticles in homogeneous catalysis23 and, afterwards,
they minimized the palladium contamination by using pal-
ladium supported on hydroxyapatite,24 and using a low cat-
alyst loading (4.5 × 10–3 mol% of Pd). Unfortunately, this
method is not suitable in our case, because reaction condi-
tions require potassium carbonate and high temperature,
which could potentially lead to deprotection of the phenol
needed in the next step of etherification; furthermore, (E)-
1,2-diiodostyrenes are not directly available.
The first step of the Asparenydiol (15) synthesis was the
protection of 4-iodo-phenol with TBDMSCl, using a slightly
modified version of the reported procedure,25 giving com-
pound 2 in quantitative yield. For the first Sonogashira
cross-coupling, we tested a range of commercially available
supported palladium catalysts [Pd EnCat™40, FibreCat
1007, Pd(PPh3)4PS, and PdCl2(PPh3)2/PS] and two polyvinyl-
pyridine(PVPy)-supported catalysts recently developed by
our research group (Cu/PVPy and Pd-Cu/PVPy).26,27 The
ability of the PVPy resin to promote M–H-type alkenyl-
ations, ensuring also very low metal leaching, was previ-
ously reported.28,29
Table 1 Cross-Coupling Reaction Optimization with 2 and 13
TMS
I
PdEnCatTM40, CuI
+
H
TMS
pyrrolidine, Ar
TBDMSO
TBDMSO
2
13
3
Entry PdEnCatTM40 CuI
Temp. Time Conv.
Yield (%)e
(Pd mol%)
(Cu mol%) (°C)
(h)
(%)d
1a
1
–
1
95
90
3.5
96
73
84
95
44
53
88
28
–
2a
0.5
1
3a
3
–
4a
5
–
5a
0.5
0.5
1
70
90
2.5
1
–
6a
0.25
–
7a
5
–
8a
9
>99
40
–
9b
0.5
0.5
0.25
0.25
90
90
1
5
10b
11c
12c
8
51
<5
25
–
1
–
16
–
a Reaction conditions: 2 (2.0 mmol), 13 (1.5 equiv), pyrrolidine (3.0 equiv),
Pd EnCatTM40, CuI, argon.
b Reaction conditions: 2 (2.0 mmol), 13 (1.5 equiv), pyrrolidine (2.0 equiv),
DMF (3 mL), Pd EnCatTM40, CuI, argon.
c Reaction conditions: 2 (2.0 mmol), 13 (1.5 equiv), pyrrolidine (2 equiv),
toluene (3 mL), Pd EnCatTM40, CuI, argon.
d Apparent conversion based on the disappearance of precursor 2, calculat-
ed by GC analysis as percentage ratio between the sum of the areas of the
product and sub-products and whole addition of the areas.
e Isolated yield of 3 after flash chromatography.
The reaction conditions were initially optimized using
Pd EnCatTM40 as a catalyst (Table 1), because this was al-
ready successfully tested for the synthesis of some natural
compounds.11,30
talysis of copper could be more efficient than the supported
palladium catalysis, we tested a previously described sup-
ported copper species Cu/PVPy. As detected by X-ray ab-
sorption fine structure spectroscopy and high-resolution
transmission electron microscopy, this catalyst contains
Cu(I) nanoparticles (mean diameter of 3.3 nm) in form of
copper oxide (Cu2O).27 Reaction rate and isolated yield
(53%) significantly increased in this case (Table 2, entries 1
and 2), although it was still not satisfactory.
Consequently, other palladium supported catalysts
were tested under the latter conditions, with the best re-
sults being obtained using PdCl2(PPh3)2/PS with a yield of
70% after 1.5 h (Table 2, entry 7). An improvement of the
isolated yield (81%) was obtained by increasing the reaction
time to 3.5 h, even when the amount of catalyst loading was
reduced to 0.25 mol% of Pd, as shown in Table 2, entry 12.
For a direct comparison of efficiency between the support-
ed co-catalyst and its homogeneous version, the reaction
using PdCl2(PPh3)2 and CuI was tested (entry 13). As expect-
ed, the reaction run with homogeneous catalysis led to bet-
ter results in terms of yield (93%), temperature (20 °C), and
reaction time. However, the opportunity to carry out cross-
coupling reactions with supported catalysis can offer several
advantages with respect to the development of sustainable
We initially tried to perform the reaction in the absence
of copper (Table 1, entry 1), however, although the starting
material disappeared after 3.5 h, many different side-prod-
ucts were formed, and a low yield of the desired product
was obtained. The reaction was therefore tested under
more classical Sonogashira conditions with a 2:1 ratio be-
tween palladium and copper, but with reduced catalyst
loading (0.5 mol% of Pd; entries 2–4); also in this case, after
5 h, many collateral reactions took place. In an attempt to
minimize the formation of by-products, the reaction was
performed at 70 °C (entry 5), but a low conversion was ob-
tained, showing that the supported catalysis lost efficiency
below certain temperatures. A decrease of the amount of
copper, instead, led to the formation of lower amounts of
by-products, albeit with longer reaction time (9 h), and al-
lowed the isolation of the product with 40% yield (entries
6–8). The reaction was also tested in the presence of two
different solvents, DMF and toluene (entries 9–12), but ir-
respective of the polarity of the solvent, lower conversions
were obtained. These results suggest that the collateral re-
actions are dependent on the amount of copper iodide that
is soluble in pyrrolidine. Therefore, as the homogeneous ca-
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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G. Casotti et al.
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Synthesis
Table 2 Screening of Pd Supported Catalysts under the Optimized
Conditions
cross-coupling, the reaction was previously tested on phe-
nylacetylene (14), to establish optimal reaction conditions.
However, regardless of the catalyst used, when pyrrolidine
was added as a base, an exothermic reaction was observed,
forming (E)-methyl 3-(pyrrolidin-1-yl)acrylate, as the ma-
jor product. Therefore, it was necessary to test several steri-
cally hindered tertiary amines, as bases, using
PdCl2(PPh3)2/PS as a catalyst, under the same conditions de-
scribed above. N-Methyl- and N-butyl-pyrrolidine did not
bring any improvement, whereas DABCO (in 4:1 DMF/H2O
solution) and triethylamine lead mainly to the homodi-
merization of phenylacetylene. The best results were ob-
tained using 2,2,6,6-tetramethylpiperidine as a base, as
shown in Table 3. The use of Pd-Cu/PVPy was particularly
effective, with a yield of 62% in only 3.5 h; therefore, these
conditions were used to optimize the next step.
TMS
I
"Pd", "Cu"
+
H
TMS
pyrrolidine (3 equiv.)
90 °C, Ar
TBDMSO
TBDMSO
2
13
3
Entry ‘Pd’ (mol% Pd)
‘Cu’ (mol% Cu)
Cu/PVPy (0.25)
t (h)
Conv. Yield
(%)c (%)d
1a
PdEnCatTM40 (0.5)
1
85
2a
2
>99
67
53
3a
Pd FibreCat® 1007 (0.5) Cu/PVPy (0.25)
1
4a
2
80
5a
4
95
–
6a
PdCl2(PPh3)2/PS (0.5)
Pd-Cu/PVPy (0.5–0.25)
PdCl2(PPh3)2/PS (0.25)
Cu/PVPy (0.25)
1
89
7a
1.5
1
>99
29
70
Table 3 Cross-Coupling Reaction Optimization with 14 and 7a
8a
O
9a
5
51
H
O
OMe
10a
11a
12a
13b
Cu/PVPy (0.125)
CuI (0.125)
1
54
"Pd", "Cu"
+
Br
OMe
2,2,6,6-tetra-
methylpiperidine
85 °C, Ar
2
89
3.5
2
>99
81
93
14
7
20
PdCl2(PPh3)2 (0.25)
Entry ‘Pd’ (mol% Pd)
‘Cu’
(mol% Cu)
t (h) 2,2,6,6-tetramehyl- Yield
a Reaction conditions: 2 (2.0 mmol), 13 (1.5 equiv), pyrrolidine (3 equiv),
‘Pd’, ‘Cu’, 90 °C, argon.
piperidine (equiv)
(%)b
b Reaction conditions: 2 (2.0 mmol), 13 (1.5 equiv), pyrrolidine (3 equiv),
PdCl2(PPh3)2, CuI, 20 °C, argon.
1
2
3
4
PdCl2(PPh3)2/PS (2)
PdCl2(PPh3)2/PS (2)
CuI (4)
CuI (4)
22
15
6
52
35
62
40
c Apparent conversion based on the disappearance of precursor 2, calculat-
ed by GC analysis as percentage ratio between the sum of the areas of the
product and sub-products and whole addition of the areas.
d Isolated yield of 3 after flash chromatography.
22
Pd-Cu/PVPy (2–1)
Pd-Cu/PVPy (0.5–0.25)
3.5
3.5
6
6
a Reaction conditions: 14 (1.0 mmol), 7 (1.5 equiv), base, ‘Pd’, ‘Cu’, 85 °C,
argon.
synthetic approaches. Indeed, although the reaction mech-
anisms are still under debate and conclusive proof that the
reactions can actually take place at the metal surface with a
real ‘heterogeneous’ mechanism is still lacking,31 the use of
supported catalysts remain a valid alternative to avoid con-
tamination with heavy metals as well as facilitating the re-
action workup in compounds of pharmacological interest.
For the selective deprotection of the trimethylsilyl acet-
ylenic moiety, a reported method14 using silver nitrate (10
mol%) was applied, as shown in Scheme 3, with a yield of
97%.
b Isolated yield of 20 after flash chromatography.
As shown in Table 4, Pd-Cu/PVPy was a good catalyst for
the synthesis of 8, even with a loading of 0.5 mol% in Pd and
0.25 mol% in Cu (entries 1 and 2). These results were unfor-
tunately not comparable with the excellent yield obtained
with homogeneous catalysis (entry 5) and the choice of
supported catalyst is a compromise with the need to devel-
op greener methods.
It is worth noting that, in the first Sonogashira step, the
use of the two separated supported catalysts, PdCl2(PPh3)2/PS
and Cu/PVPy (Table 2, entry 11), was highly effective,
whereas for the synthesis of 8 it was not reactive enough
(Table 4, entry 4). For the second Sonogashira step, it was
necessary to use the supported co-catalyst Pd-Cu/PVPy
(Table 4, entries 1 and 2). Rationalization of this different
behavior is not obvious but can be ascribed to the different
reactivity of the two systems, rather than to instability of
reagents or product, because, in both cases, the correspond-
ing halides could be recovered. Pd-Cu/PVPy is not a simple
mixture of segregated Pd and Cu nanoparticles dispersed
on PVPy.26 In this catalyst, an oxidized Cu(II) phase is
H
TMS
AgNO3 (10 mol%)
pyridine (0.3 equiv.)
TBDMSO
H2O, acetone
40 °C, 33 h
TBDMSO
3
4
y = 97%
Scheme 3 Selective deprotection of 3
Methyl (E)-3-bromoacrylate (7), which was necessary
for the next cross-coupling reaction, was prepared through
a known two-step synthesis.32 For the second Sonogashira
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Synthesis
Table 4 Cross-Coupling Reaction Optimization with 4 and 7
O
H
O
"Pd", "Cu"
OMe
+
Br
OMe
2,2,6,6-tetra-
methylpiperidine
85 °C, Ar
TBDMSO
TBDMSO
4
7
8
Entry
‘Pd’ (mol% Pd)
‘Cu’ (mol% Cu)
t (h)
2,2,6,6-tetramehylpiperidine (equiv)
Yield (%)d
1a
2a
3b
4c
5a
Pd-Cu/PVPy (2–1)
3.5
3.5
48
7
6
62
57
40
–
Pd-Cu/PVPy (0.5–0.25)
PdCl2(PPh3)2/PS (2)
PdCl2(PPh3)2/PS (0.5)
PdCl2(PPh3)2 (0.5)
6
–
3
Cu/PVPy (0.25)
CuI (0.25)
3
4
Et3N (6 equiv)
92
a Reaction conditions: 4 (2.0 mmol), 7 (1.5 equiv), base, ‘Pd’, ‘Cu’, 85 °C, argon.
b Reaction temperature was increased to 95 °C after 2 h.
c Reaction temperature was increased to 100 °C after 3 h. After 7 h, the reaction reached only 10% of apparent conversion. The product was not isolated.
d Isolated yield of 8 after flash chromatography.
present, forming thin and incomplete shells around the
Pd-rich cores. The specific interaction between Pd and Cu
at the nanoparticle surface was demonstrated to be respon-
sible of the observed marked increase in catalytic efficiency
in Sonogashira-like reactions. Afterwards, the obtained es-
ter 8 was reduced to the corresponding allylic alcohol 9 us-
ing DIBALH as reducing agent, at low temperature, with an
isolated yield of 90% (Scheme 4). Although alkynes can un-
dergo hydroalumination reactions,20,33,34 maintaining a low
temperature, especially during the addition of DIBALH, en-
ables selective reduction of the ester moiety. Moreover,
when only three equivalents of DIBALH were used, the re-
action was compatible with the presence of the TBDMS
protecting group; application of an excess of the reducing
agent led to partial deprotection of the phenol.
For the next step, the monosilylation of hydroquinone
was achieved using a slightly modified reported meth-
od,35,36 with a yield of 10 of 74% (see the experimental sec-
tion). Mitsunobu etherification between 9 and 10 was per-
formed under classical conditions,37,38 using diethyl azodi-
O
DIBALH (3 equiv.)
(1 M in hexane)
OMe
OH
CH2Cl2(6.5 mL/mmol)
from –60 °C to –20 °C
Ar, 1.5 h
TBDMSO
TBDMSO
8
9
y = 90%
Scheme 4 Reduction of the ester moiety of 8 to form the allylic alcohol 9
DEAD (35% in toluene) (1.2 equiv.)
PPh3 (1.2 equiv.)
OH
+
OH
toluene
from 0 °C to 20 °C
Ar, 6 h
TBDMSO
TBDMSO
9
10
(1.2 equiv.)
OH
OTBDMS
TBAF (1 M in THF)
(3 equiv.)
O
O
20 °C, 3 h
TBDMSO
HO
Asparenydiol
y = quant.
11
y = 84%
Scheme 5 Mitsunobu etherification to synthesize intermediate 11 and deprotection to form Asparenedyol (15)
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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G. Casotti et al.
Paper
Synthesis
carboxylate (DEAD) and PPh3, as shown in Scheme 5. The
reaction was monitored by TLC, and reached completion af-
ter 6 h. The crude material was purified by flash chroma-
tography and the intermediate 11 was isolated with a yield
of 84%. The final step involved treatment of 11 with tetra-
n-butylammonium fluoride (TBAF), to deprotect the two
hydroxyl moieties. Asparenydiol (15) was obtained and eas-
ily purified by flash chromatography and isolated in quanti-
tative yield.
In conclusion, the total synthesis of Asparenydiol (15)
was accomplished with an overall yield of 30%, starting
from 4-iodophenol, through two Sonogashira cross-
coupling reactions catalyzed by supported catalysts and a
Mitsunobu etherification (Scheme 6). Therefore, this work
will make possible an extensive screening of its pharmaco-
logical activities. Moreover, it was an interesting applica-
tion of our supported Pd and Cu catalysts, which allowed, in
this case, higher conversions and yield, with respect to most
common commercially available supported catalysts.
agents were directly used without further purification. Dichloro-
methane and triethylamine were dried over calcium hydride and dis-
tilled, whereas hexane and toluene were dried respectively over
LiAlH4 and sodium and then distilled. When specified, solvents were
purged by argon bubbling. Catalysts, PdCl2(PPh3)2 (CAS: 13965-03-2),
PdCl2(PPh3)2/PS (Pd: 1.01 mmol/g), FibreCat™ 1007 (Pd: 0.72
mmol/g), and Pd En Cat™ 40 (Pd: 0.42 mmol/g) where purchased
from Merck–Sigma–Aldrich. 4-Iodophenol (CAS: 540-38-5), tert-bu-
tyldimethylsilylchloride (TBDMSCl; CAS: 18162-48-6), pyrrolidine
(CAS: 123-75-1), AgNO3 (CAS: 7761-88-8), pyridine (CAS: 110-86-1),
propiolic acid (CAS: 471-25-0), diethyl 1,2-hydrazinedicarboxylate
(ca. 40% in toluene; CAS: 1972-28-7), triphenylphosphine (CAS: 603-
35-0), and tetrabutylammonium fluoride (1 M in THF; CAS: 429-41-
4) were purchased by Merck–Sigma–Aldrich and used without fur-
ther purification. Reactions were followed by GC and GC/EI-MS on
small reaction samples. Purification of the crude reaction mixtures
were performed by flash chromatography using Silica Gel 60 (40–63
m, Merck–Sigma–Aldrich), or by fractional distillation. TLC silica gel
plates were purchased from Merck (Merck 60 F254). Gas chromatog-
raphy (GC) analyses were performed with a Dani GC 1000 with PTV
injector, FID detector and two bonded FSOT columns (Alltech, 30 m
0.25 mm i.d., 0.25 mm): AT-5 (column 1) and AT-35 (column 2). Gas
chromatography mass spectrometry (GC/MS) analyses were per-
formed with an Agilent apparatus: mass selective detector 5973 Net-
work, 6890 N Network GC system and HP-5MS bonded column (30 m
0.25 mm i.d., 0.25 mm, column 3). NMR spectra were recorded with
Bruker 400 MHz, Bruker Avance II DRX 400, or Varian INOVA 600 MHz
When not otherwise specified, all reactions were performed under
argon atmosphere; solvents and reagents were handled using hypo-
dermic syringes conveniently stored in a desiccator. Commercial re-
(1.5 equiv.)
TMS
H
TMS
AgNO3 (10 mol%)
TBDMSCl (1.1 equiv.)
Et3N (1.2 equiv.)
PdCl2(PPh3)2 (0.25 mol% Pd)
Cu/PvPy (0.125 mol% Cu)
I
I
pyridine (0.3 equiv.)
H2O, acetone
40 °C, 33 h
TBDMSO
pyrrolidine (3 equiv.)
TBDMSO
CH2Cl2 (1.5 mL/mmol)
reflux, 18 h
HO
TBDMSO
90 °C, Ar
(4)
y = 70% (3 steps)
2
1
3
O
O
MeOH, H2SO4 conc.
HBr (48%)
100 °C, 2 h
Br
OMe
COOH
propiolic acid
Br
OH
reflux, 24 h
y = 35% (2 steps)
(7)
(6)
(5)
Pd-Cu/PvPy
(0.5 mol% Pd, 0.25 mol% Cu)
2,2,6,6-tetramethylpiperidine (3 equiv.)
85 °C, Ar
OH
(10)
1) DIBALH (3 equiv.)
O
TBDMSO
CH2Cl2 (6.5 mL/mmol)
from –60 °C to –20 °C
Ar, 1.5 h
OH
(1.2 equiv.)
OMe
DEAD (38% w/w in toluene)
(1.2 equiv)
PPh3 (1.2 equiv.)
toluene, from 0 °C to 20 °C
Ar, 6 h
2) MeOH, then HCl 2M
TBDMSO
TBDMSO
(9)
y = 90%
(8)
y = 57%
OTBDMS
OH
O
TBAF (1 M in THF) (3 equiv.)
20 °C, 3 h
O
TBDMSO
HO
Asparenydiol (15)
y = quant.
overall yield = 30%
(11)
y = 84%
Scheme 6 Optimized total synthesis of Asparenydiol
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

G
G. Casotti et al.
Paper
Synthesis
spectrometers. HPLC-ESI-Q/ToF flow injection analyses (FIA) were
carried out with a 1200 Infinity HPLC (Agilent Technologies, USA),
coupled with a quadrupole–time of flight tandem mass spectrometer
(6530 Infinity Q-TOF; Agilent Technologies) through a Jet Stream ESI
interface (Agilent). Mass Hunter Workstation Software (B.04.00) was
used to control the HPLC and the mass spectrometer, for data acquisi-
tion, and for data analysis.
hexane) and the product was isolated as a colorless oil with a yield of
97% (2.25 g) (purity > 99% by GC). Spectroscopic data were consistent
with reported values.14
1H NMR (CDCl3, 400 MHz):  = 7.4 (d, J = 8.6 Hz, 2 H), 6.8 (d, J = 8.7 Hz,
2 H), 3.0 (s, 1 H), 1.0 (s, 9 H), 0.2 (s, 6 H).
13C NMR (CDCl3, 100 MHz):  = 156.3, 133.6, 127.1, 120.2, 114.8, 83.7,
75.9, 25.6, 18.2, –4.4.
MS (EI): m/z (%) = 232 [M]+ (19), 177 (6), 176 (24), 175 (100), 159 (3),
145 (5), 115 (4).
tert-Butyldimethylsilyloxy-4-iodobenzene (2)
In a 250 mL two-necked, round-bottom flask, equipped with a reflux
condenser, under an inert atmosphere, 4-iodophenol (1; 6.6 g, 30.0
mmol) was dissolved in anhydrous CH2Cl2 (40 mL). Freshly distilled
triethylamine (5.00 mL, 36.0 mmol) and TBDMSCl (5.00 g, 33.0 mmol)
were added to the solution, and the mixture was stirred at reflux
temperature for 22 h. The reaction was quenched with HCl 2 M and
extracted with CH2Cl2 (3 × 30 mL). The combined organic phases were
washed with a saturated solution of NaHCO3 and a saturated solution
of NaCl until neutrality was reached. The solution was dried over
Na2SO4, filtered and concentrated under reduced pressure. The prod-
uct was obtained as a yellow oil (9.36 g) with a yield of 93% and a GC
purity > 98%. The intermediate was used without further purification
for the next steps. Spectroscopic data were consistent with reported
values.25
Methyl (E)-3- Bromoacrylate (7)
In a 500 mL three-necked, round-bottom flask, equipped with a re-
flux condenser and mechanical stirrer, under an inert atmosphere,
were introduced propiolic acid (25 g, 357 mmol) and HBr (48% solu-
tion, 150 mL). The resulting mixture was stirred at 100 °C for 2 h. The
reaction flask was cooled to r.t. and, subsequently, cooled in an ice
bath to induce crystallization of (E)-3-bromoacrylic acid. The precipi-
tate was filtered, washed with cool water and dried. The product was
obtained as a crystalline white solid with a yield of 74% (40.3 g) and
identified as (E)-3-bromoacrylic acid. Spectroscopic data were consis-
tent with reported values.32
M.p. = 117–118 °C (lit.32 117.5–118.5 °C).
1H NMR (CDCl3, 600 MHz):  = 11.0 (s, 1 H), 7.7 (d, J = 14.3 Hz, 1 H),
6.5 (d, J = 14.3 Hz, 1 H).
MS (EI): m/z (%) = 152 (98), 150 (100) [M]+, 135 (57), 133 (58), 124
(14), 107 (35), 105 (36), 71 (76), 45 (28).
1H NMR (CDCl3, 600 MHz):  = 7.5 (dd, J = 6.8, 2.1 Hz, 2 H), 6.6 (dd, J =
6.6, 2.1 Hz, 2 H), 0.9 (s, 9 H), 0.18 (s, 6 H).
MS (EI): m/z (%) = 335 (8), 334 [M]+ (44), 279 (7), 278 (34), 277 (100),
151 (8), 150 (49), 149 (6), 135 (34).
In a 500 mL three-necked, round-bottom flask, equipped with a re-
flux condenser and mechanical stirrer, under an inert atmosphere,
(E)-3-bromoacrylic acid (19.2 g, 128 mmol) was dissolved in anhy-
drous MeOH (200 mL) and 15 drops of concentrated H2SO4 were add-
ed. The reaction mixture was stirred at reflux temperature for 24 h.
The solvent was removed through distillation under reduced pressure
and the residue was poured on a saturated solution of NaHCO3 (50
mL). The mixture was extracted with Et2O (3 × 50 mL) and the com-
bined organic phases dried over Na2SO4, filtered and concentrated un-
der reduced pressure. Spectroscopic data were consistent with re-
ported values.
4-tert-Butyldimethylsilyloxyphenylethynyltrimethylsilane (3)
In a 5 mL Schlenk flask, equipped with a two-neck connection, with a
reflux condenser, under an inert atmosphere, Pd and Cu catalysts
were added in the amounts indicated in Table 2. Pyrrolidine (300 or
500 L, 4.00 or 6.00 mmol), 2 (0.668 g, 2.00 mmol) and trimethylsily-
lacetylene (13) (415 L, 3.00 mmol) were added to the solution. The
mixture was stirred at 90 °C for 3.5 h (Table 2, entry 12), then the re-
action was quenched with a saturated solution of NH4Cl. The mixture
was extracted with Et2O (3 × 50 mL) and the combined organic phases
were dried over Na2SO4, filtered and concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel (pure hexane). The product was obtained as a yellowish oil with
81% yield (0.492 g) (purity > 95% by GC). Spectroscopic data were con-
sistent with reported values.14
B.p. = 72–75 °C, 70 mbar (lit.39 69 °C, 55 mbar).
1H NMR (CDCl3, 600 MHz):  = 7.6 (d, J = 12.0 Hz, 1 H), 6.5 (d, J =
12.0 Hz, 1 H), 3.7 (s, 3 H).
MS (EI): m/z (%) = 166 (24), 164 (24), 135 (99), 133 (100), 107 (28),
105 (28), 85 (45), 54 (5), 53 (5).
1H NMR (CDCl3, 400 MHz):  = 7.4 (d, J = 8.0 Hz, 2 H), 6.8 (d, J = 8.0 Hz,
2 H), 1.0 (s, 9 H), 0.3 (s, 9 H), 0.2 (s, 6 H).
13CNMR (CDCl3, 100 MHz):  = 156.1, 133.5, 130.4, 120.1, 116.0, 105.3,
92.6, 25.7, 18.2, 0.11, –4.4.
MS (EI): m/z (%) = 305 (10), 304 [M]+ (34), 289 (13), 249 (12), 248 (33),
Methyl 5-(E)-4-tert-Butyldimethylsilyloxy-phenyl-pent-2-en-4-
yn-1-ate (8)
In a 10 mL Schlenk flask, equipped with a two-neck connection, with
a reflux condenser, under inert atmosphere, Pd and Cu catalysts were
added in the amounts indicated in Table 4. 2,2,6,6-Tetramethylpiperi-
dine (1 or 2 mL, 6.00 or 12.0 mmol), 4 (0.696 g, 3.00 mmol) and 7
(0.330 g, 2.00 mmol) were added to the solution. In the best condition
found (Table 4, entry 2) the mixture was stirred at 85 °C for 3.5 h and
the reaction was quenched with a saturated solution of NH4Cl. The
mixture was extracted with Et2O (3 × 15 mL) and the combined or-
ganic phases were dried over Na2SO4, filtered and concentrated under
reduced pressure. The residue was purified by flash chromatography
on silica gel (Hex/EtOAc, 95:5). The product was obtained as a yellow-
ish oil with 57% yield (0.360 g).
247 (100), 233 (11), 116 (8), 73 (12).
4-tert-Butyldimethylsilyloxy-1-ethynylbenzene (4)
In a 250 mL two-necked, round-bottom flask, equipped with a reflux
condenser, under inert atmosphere, 3 (3.04 g, 10.0 mmol), acetone
(75 mL), pyridine (243 mL, 0.30 mmol), and a solution of AgNO3
(0.170 g, 1.00 mmol) in H2O (10.8 mL) were stirred at 40 °C for 33 h.
The reaction was quenched with a saturated solution of NaCl and ex-
tracted with Et2O (3 × 50 mL). The combined organic phases were
dried over Na2SO4, filtered and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel (pure
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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G. Casotti et al.
Paper
Synthesis
1H NMR (CDCl3, 400 MHz):  = 7.3 (d, J = 8.7 Hz, 2 H), 6.9 (d, J =
15.8 Hz, 1 H), 6.8 (d, J = 8.7 Hz, 2 H), 6.2 (d, J = 15.8 Hz, 1 H), 3.7 (s,
3 H), 0.9 (s, 9 H), 0.2 (s, 6 H).
13C NMR (CDCl3, 100 MHz):  = 166.7, 157.1, 133.8, 128.7, 125.9,
120.5, 115.0, 99.2, 85.8, 52.0, 25.8, 18.4, –4.4.
ed solution of NH4Cl (15 mL), and extracted with CH2Cl2 (3 × 10 mL).
The combined organic phases were dried over Na2SO4, filtered and
concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (Hex/toluene, 75:25). Collected
fractions containing intermediate 11 were concentrated under re-
duced pressure with a yield of 84%.
1H NMR (CDCl3, 400 MHz):  = 7.3 (d, J = 8.5 Hz, 2 H), 6.8 (m, 8 H), 6.3
(dt, J = 15.9, 5.3 Hz, 1 H), 6.0 (d, J = 15.9 Hz, 1 H), 4.6 (dd, J = 5.4,
1.6 Hz, 2 H), 1.0 (s, 18 H), 0.22 (s, 6 H), 0.19 (s, 6 H).
MS (EI): m/z (%) = 317 (10), 316 (42) [M]+, 285 (8), 261 (8), 260 (30),
259 (100), 227 (8), 199 (7), 73 (6).
Anal. Calcd. for C18H24N3Si: C 68.32, H 7.64. Found: C 68.27, H 7.61.
13C NMR (CDCl3, 100 MHz):  = 156.0, 152.9, 149.7, 137.2, 133.0,
120.7, 120.2, 116.0, 115.6, 112.5, 90.6, 86.0, 68.4, 25.7, 25.6, 18.23,
18.19, –4.40, –4.47.
HRMS (TOF MS ES+): m/z [M + Na]+ calcd for C29H42O3Si2: 517.2565;
found: 517.2553. Analytical HPLC purity 91%.
5-(E)-4-tert-Butyldimethylsilyloxy-phenyl-pent-2-en-4-yn-1-ol
(9)
In a 250 mL two-necked, round-bottom flask, under an inert atmo-
sphere, 8 (3.16 g, 10.0 mmol) was dissolved in anhydrous CH2Cl2 (65
mL). The solution was cooled to –60 °C and DIBALH (1 M in hexane,
30 mL) was slowly dropped into the well-stirring mixture. The mix-
ture was stirred for 1.5 h and the temperature was allowed to warm
up to –20 °C. The reaction was quenched, at low temperature, by
slowly dropping in MeOH (20 mL), followed by HCl (1 M 20 mL) and a
saturated solution of Rochelle salt (50 mL). The resulting mixture was
extracted with CH2Cl2 (3 × 30 mL) and the combined organic phases
were washed again with Rochelle salt (30 mL) and dried over Na2SO4,
filtered and concentrated under reduced pressure. The residue was
purified by flash chromatography on silica gel (Hex/EtOAc, 1:1) and
the product 9 was isolated as a yellowish oil with a yield of 90% (2.59
g) (purity > 99% by GC).
Asparenedyol (15)
A solution of 11 was transferred to a 25 mL two-necked, round-bot-
tom flask and TBAF (1 M in THF, 11 mL, 2.5 equiv) was added. The
mixture was stirred at r.t. for 2.5 h, then the reaction was quenched
with a saturated solution of NH4Cl (20 mL) and the mixture was ex-
tracted with CH2Cl2 (3 × 15 mL). The combined organic phases were
concentrated under reduced pressure, dissolved in acetone, filtered
on silica and concentrated. The residue was purified by flash chroma-
tography on silica gel (CHCl3/acetone, 9:1). Asparenedyol was isolated
as a white solid with a yield of 84% (0.448 g).
1H NMR (CDCl3, 400 MHz):  = 7.3 (d, J = 8.5 Hz, 2 H), 6.7 (m, 2 H), 6.3
(dt, J = 15.8, 5.3 Hz, 1 H), 5.9 (m, 1 H), 4.2 (m, 2 H), 0.9 (s, 9 H), 0.2 (s,
6 H).
1H NMR (acetone-d6, 400 MHz):  = 8.7 (bs, 1 H), 7.9 (bs, 1 H), 7.3 (m,
2 H), 6.8 (m, 6 H), 6.3 (dt, J = 15.9, 5.3 Hz, 1 H), 6.1 (dt, J = 15.9, 1.7 Hz,
1 H).
13C NMR (CDCl3, 100 MHz):  = 156.0, 141.0, 133.0, 120.2, 116.0,
13C NMR (acetone-d6, 100 MHz):  = 205.5, 157.8, 151.8, 151.6, 137.8,
110.8, 90.2, 86.2, 63.0, 25.6, 18.2, –4.4.
133.0, 115.8, 115.6, 114.0, 111.9, 90.5, 85.4, 68.1.
MS (EI): m/z (%) = 289 (11), 288 (50) [M]+, 233 (7), 232 (23), 231 (100),
HRMS (TOF MS ES+): m/z [M – H]– calcd for C17H14O3: 265.0870;
229 (8), 128 (8), 75 (16), 73 (8).
found: 265.0864.
Anal. Calcd. for C17H24O2Si: C 70.78, H 8.39. Found: C 70.75, H 8.41
Analytical HPLC purity 99%.
4-tert-Butyldimethylsilyloxy-1-phenol (10)
Funding Information
In a 250 mL two-necked, round-bottom flask, under an inert atmo-
sphere, hydroquinone (2.20 g, 20.0 mmol) was dissolved in EtOAc
(100 mL). Imidazole (3.40 g, 50.0 mmol) and TBDMSCl (3.31 g, 22.0
mmol) were added to the solution and the resulting mixture was
stirred for 4 h at 20 °C. The reaction was quenched with a saturated
solution of NaCl (50 mL) and the mixture was extracted with EtOAc
(3 × 30 mL). The reunited organic phases were dried over Na2SO4, fil-
tered and concentrated under reduced pressure. The residue was pu-
rified by flash chromatography on silica gel (Hex/EtOAc, 8:2) and the
product 10 was isolated as a white solid with a yield of 74% (3.31 g)
(purity > 99% by GC). Spectroscopic data were consistent with report-
ed data.36
Financial support from the University of Pisa (PRA 2018_23) is grate-
fully acknowledged.
U
n
i
v
ersità
d
iP
i
sa(P
R
A
2
0
1
8
_
2
3)
Acknowledgment
G.A. is grateful to Prof. Ilaria Degano of the Department of Chemistry
and Industrial Chemistry of the University of Pisa, for HPLC–HRMS
analysis.
1H NMR (CDCl3, 400 MHz):  = 6.7 (m, 4 H), 0.9 (s, 9 H), 0.1 (s, 6 H).
MS (EI) m/z (%) = 225 (4), 224 (20) [M]+, 169 (6), 168 (22), 167 (100),
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690852.
153 (2), 137 (3), 75 (5), 73 (3).
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
(E)-tert-Butyl(4-(5-(4-((tert-butyldimethylsilyl)oxy)phenoxy)-
pent-3-en-1-yn-1-yl)phenoxy)dimethylsilane (11)
References
In a 25 mL two-necked, round-bottom flask, under an inert atmo-
sphere, 9 (0.576 g, 2 mmol) was dissolved in anhydrous toluene (10
mL), then 10 (0.539 g, 2.4 mmol) and PPh3 (0.629 g, 2.4 mmol) were
added to the solution. The mixture was cooled to 0 °C and DEAD (38%
w/w in toluene, 1.15 mL, 2.4 mmol) was added. The mixture was
stirred at 0 °C for 6 h, then the reaction was quenched with a saturat-
(1) Terada, K.; Honda, C.; Suwa, K.; Takeyama, S.; Oku, H.; Kamisako,
W. Chem. Pharm. Bull. (Tokyo) 2011, 43, 564.
(2) Zhang, H. J.; Sydara, K.; Tan, G. T.; Ma, C.; Southavong, B.;
Soejarto, D. D.; Pezzuto, J. M.; Fong, H. H. S. J. Nat. Prod. 2004, 67,
194.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

I
G. Casotti et al.
Paper
Synthesis
(3) Jayashree, G. V.; Kumar, K. H.; Krupashree, K.; Rachitha, P.;
Khanum, F. Ind. Crops Prod. 2015, 78, 102.
(25) Ogawa, T.; Ohta, K.; Iijima, T.; Suzuki, T.; Ohta, S.; Endo, Y.
Bioorg. Med. Chem. 2009, 17, 1109.
(4) Dembitsky, V. M. Lipids 2006, 41, 883.
(26) Evangelisti, C.; Balerna, A.; Psaro, R.; Fusini, G.; Carpita, A.;
Benfatto, M. ChemPhysChem 2017, 18, 1921.
(27) Balerna, A.; Evangelisti, C.; Tiozzo, C. X-ray Spectrom. 2017, 46,
82.
(5) Fletcher, S. Org. Chem. Front. 2015, 2, 739.
(6) Swamy, K. C. K.; Kumar, N. N. B.; Balaraman, E.; Kumar, K. V. P. P.
Chem. Rev. 2009, 109, 2551.
(7) Doucet, H.; Hierso, J. C. Angew. Chem. Int. Ed. 2007, 46, 834.
(8) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874.
(9) Plenio, H. Angew. Chem. Int. Ed. 2008, 47, 6954.
(10) Krascsenicsová, K.; Kasák, P.; Putala, M.; Walla, P.; Uray, G.;
Kappe, C. O. Chem. Commun. 2004, 10, 2606.
(11) Fusini, G.; Barsanti, D.; Angelici, G.; Casotti, G.; Canale, A.;
Benelli, G.; Lucchi, A.; Carpita, A. Tetrahedron 2018, 74, 4381.
(12) Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133.
(13) Garrais, S.; Turkington, J.; Goldring, W. P. D. Tetrahedron 2009,
65, 8418.
(14) Carpita, A.; Mannocci, L.; Rossi, R. Eur. J. Org. Chem. 2005, 1859.
(15) Newton, S.; Carter, C. F.; Pearson, C. M.; De C. Alves, L.; Lange,
H.; Thansandote, P.; Ley, S. V. Angew. Chem. Int. Ed. 2014, 53,
4915.
(16) Sabitha, G.; Das, S. K.; Ankireddy, P.; Yadav, J. S. Tetrahedron Lett.
2013, 54, 1097.
(17) Vaz, B.; Pereira, R.; Pérez, M.; Álvarez, R.; De Lera, A. R. J. Org.
Chem. 2008, 73, 6534.
(18) Hulot, C.; Blond, G.; Suffert, J. J. Am. Chem. Soc. 2008, 130, 5046.
(19) Hashmi, A. S. K.; Graf, K.; Ackermann, M.; Rominger, F. Chem-
CatChem 2013, 5, 1200.
(20) Takeuchi, R.; Tanabe, K.; Tanaka, S. J. Org. Chem. 2000, 65, 1558.
(21) Nishimura, T.; Araki, H.; Maeda, Y.; Uemura, S. Org. Lett. 2003, 5,
2997.
(22) Bates, C. G.; Saejueng, P.; Venkataraman, D. Org. Lett. 2004, 6,
1441.
(28) Evangelisti, C.; Panziera, N.; Pertici, P.; Vitulli, G.; Salvadori, P.;
Battocchio, C.; Polzonetti, G. J. Catal. 2009, 262, 287.
(29) Jumde, R. P.; Marelli, M.; Scotti, N.; Mandoli, A.; Psaro, R.;
Evangelisti, C. J. Mol. Catal. A: Chem. 2016, 414, 55.
(30) Laudadio, G.; Fusini, G.; Casotti, G.; Evangelisti, C.; Angelici, G.;
Carpita, A. J. Flow Chem. 2019, 9, 133.
(31) Biffis, A.; Centomo, P.; Del Zotto, A.; Zecca, M. Chem. Rev. 2018,
118, 2249.
(32) Weir, J. R.; Patel, B. A.; Heck, R. F. J. Org. Chem. 1980, 45, 4926.
(33) Sauerberg, P.; Bury, P. S.; Mogensen, J. P.; Deussen, H. J.;
Pettersson, I.; Fleckner, J.; Nehlin, J.; Frederiksen, K. S.;
Albrektsen, T.; Din, N.; Svensson, L. A.; Ynddal, L.; Wulff, E. M.;
Jeppesen, L. J. Med. Chem. 2003, 46, 4883.
(34) Bellina, F.; Carpita, A.; Corradi, C.; Rossi, R. Synth. Commun.
1996, 26, 3297.
(35) Li, L.; Shen, X.; Xu, Q. H.; Yao, S. Q. Angew. Chem. Int. Ed. 2013,
52, 424.
(36) López-Pelegrín, J. A.; Wentworth, P.; Sieber, F.; Metz, W. A.;
Janda, K. D. J. Org. Chem. 2000, 65, 8527.
(37) Sauerberg, P.; Mogensen, J. P.; Jeppesen, L.; Bury, P. S.; Fleckner,
J.; Olsen, G. S.; Jeppesen, C. B.; Wulff, E. M.; Pihera, P.; Havranek,
M.; Polivka, Z.; Pettersson, I. Bioorg. Med. Chem. Lett. 2007, 17,
3198.
(38) Kiuchi, H.; Takahashi, D.; Funaki, K.; Sato, T.; Oi, S. Org. Lett.
2012, 14, 4502.
(39) Rossi, R.; Carpita, A.; Lippolis, V.; Benetti, M. Gazz. Chim. Ital.
1990, 120, 783.
(23) Ranu, B. C.; Chattopadhyay, K. Org. Lett. 2007, 9, 2409.
(24) Ranu, B. C.; Adak, L.; Chattopadhyay, K. J. Org. Chem. 2008, 73,
5609.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I