Preparation of 2-Substituted 3-Methoxycarbonyl-4-methoxyfurans that Allow Access to Highly Functionalized Naphthalenes via Regioselective Cycloaddition with Alkoxybenzyne

Article abstract of DOI:10.1055/s-0036-1590825

A facile synthetic method of 2-substituted 3-methoxycarbonyl-4-methoxyfurans has been developed, allowing construction of highly functionalized naphthalene derivatives via (1) regioselective benzyne [4+2] cycloaddition with α-alkoxybenzyne and (2) reductive aromatization.

Full text of DOI:10.1055/s-0036-1590825

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
S. Sato et al.
Letter
Synlett
Preparation of 2-Substituted 3-Methoxycarbonyl-4-methoxyfu-
rans that Allow Access to Highly Functionalized Naphthalenes via
Regioselective Cycloaddition with Alkoxybenzyne
Shogo Sato
OBn
Takuma Kawada
Hiroshi Takikawa
Keisuke Suzuki*
R
OBn
R
R
H+
MeO2C
O
MeO2C
MeO
MeO2C
MeO
HC(OMe)3
O
O
MeOH
1) [4+2]
2) Zn, TiCl4
Department of Chemistry, Tokyo Institute of Technology,
2-12-1 O-okayama, Meguro-ku, Tokyo 152-8551, Japan
ksuzuki@chem.titech.ac.jp
R = Me, CH2NBoc(Me)
Received: 06.05.2017
Accepted after revision: 14.06.2017
Published online: 05.07.2017
(A)
(B)
O
+
O
[4+2]
DOI: 10.1055/s-0036-1590825; Art ID: st-2017-b0332-l
OR
OR
Abstract A facile synthetic method of 2-substituted 3-methoxycar-
bonyl-4-methoxyfurans has been developed, allowing construction of
highly functionalized naphthalene derivatives via (1) regioselective ben-
zyne [4+2] cycloaddition with α-alkoxybenzyne and (2) reductive aro-
matization.
a
RO
O
O
β
RO
III
IV
(C)
reductant
Key words natural products, cycloaddition, furans, benzyne
O
Scheme 2 Three precedents for furan–benzyne cycloaddition
In connection with our ongoing study toward the total
syntheses of tetracenomycin C1 (1) and lactonamycin2 (2)
(Scheme 1), we required a unified approach for the con-
struction of highly functionalized naphthalene scaffold (CD
rings in 1 and DE rings in 2 highlighted in blue).3 The ret-
rosynthetic analysis shown in Scheme 1 suggested a poten-
tial approach by the assembly of alkoxyfuran I and α-
alkoxybenzyne II via [4+2] cycloaddition, which seemed
promising in light of three literature precedents (Scheme
2).
(1) Reactivity: Although furans are generally less reac-
tive dienes in Diels–Alder reactions, their [4+2] reactions
with arynes have been well documented4 thanks to the
high reactivity of the latter species by the unusually low-ly-
ing LUMO (Scheme 2, A).5
(2) Regioselectivity: If one considers substitution pat-
terns of the two alkoxy groups of two reaction partners I
and II (Scheme 1, highlighted in red), one could expect a fa-
vorable regioselectivity by the literature precedent6 of β-
alkoxyfuran III and α-alkoxybenzyne IV (Scheme 2, B).
(3) Ring-opening reductive aromatization: Conversion
of the [4+2] cycloadduct into naphthalene is supported by
several literature precedents (Scheme 2, C).7
To put this plan into practice, however, two challenges
were foreseen: First, since there had been no reports on fu-
ran I with this particular substitution pattern, the prepara-
tive method had to be developed. Second, even if I became
available, complications may arise at the stage of the cyclo-
addition as well as the ring-opening process by the pres-
ence of multifunctional groups on the furan ring, that may
cast steric/electronic influence on the reactivity/selectivity
outcomes.
O
Me
N
Me
D
OH
C
O
B
O
OH
D
O
C
O
OH
O
A
B
F
MeO2C
MeO
O
OMe
A
E
O
OMe HO
OH
OR
O
OH
R = α-L-rhodinosyl
lactonamycin (2)
tetracenomycin C (1)
R'
OR
OR
R'
2
α
R"O2C
R"O2C
3
+
O
4
RO
RO
I
II
Scheme 1 Approach to naphthalene scaffolds characteristic to 1 and 2
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
S. Sato et al.
Letter
Synlett
In this communication, we wish to report the successful
implementation of this scenario, including development of
a facile protocol for preparing trisubstituted furans 5 and
12, and their regioselective cycloaddition reactions with α-
alkoxybenzyne and subsequent reductive ring opening.
Among various methods for furan syntheses, the Feist–
Benary reaction is useful for the preparation of 3-alkoxy-
carbonylfurans (Scheme 3, A):8 Base-promoted reaction of
β-ketoesters with α-chloroketones provides dihydrofuran
V, and acid-catalyzed dehydration gives furan VI bearing 3-
alkoxycarbonyl group. However, this protocol is not directly
applicable to the synthesis of furan I, as the introduction of
the C4 methoxy group is not possible.
For the conversion of 4 into the desired furan 5, we ini-
tially examined basic conditions to form the enolate and
trapping with methylating agents, such as MeOTf and
Me3O+BF4 , which all resulted in failure.
–
On the other hand, acidic conditions provided a promis-
ing result: Upon treatment of furanone 4 (Rf = 0.20, hex-
ane/EtOAc = 2:1) with PPTS in MeOH, the reaction slowly
proceeded (r.t., 24 h), albeit not to full conversion. The for-
mation of a new compound was suggested by TLC analysis
(Rf = 0.70, hexane/EtOAc = 2:1). Chromatographic purifica-
tion (SiO2) gave small amount of furan 5 (9% yield) and 18%
recovery of 4.
After considerable experimentation, the yield of 5 was
improved by three key modifications (Table 1): (1) use of
stronger acids, (2) lower concentration, and (3) use of
trimethyl orthoformate as a dehydrating agent.
(A) Feist–Benary furan synthesis
R'
R'
R'
2
R"O2C
O
R"O2C
R
R"O2C
R
3
base
acid
Table 1 Optimization for the Formation of 5a
+
O
O
–H2O
4
O
HO
Cl
Me
O
Me
O
V
VI
R
acid (0.5 equiv)
HC(OMe)3 (X equiv)
2
MeO2C
O
MeO2C
MeO
(B) This work
MeOH, rt
R'
4
5
R"O2C
R'
R'
2
O
R"O2C
O
R"O2C
base
+
Entry Acid
X
Concentration Time
(M) (h)
5
(%)
4
(%)
O
O
(equiv)
O
MeO
Cl
1
2
3
4
5
6
7e
PPTSb
–
–
–
–
5
5
5
0.1
24
24
24
24
12
22
12
9
18
VII
VIII
Cl
TsOH·H2Oc
TfOHd
0.1
14
18
44
49
87
82
21
18
15
0
Scheme 3 Two approaches to 2,3,4-trisubstituted furans
0.1
To address the issue, we came up with an idea of using
furanone VII, which is readily available from β-ketoesters
and chloroacetyl chloride.9 If viable, this approach would al-
low us to prepare various furans bearing different C2 sub-
stituents (R′) by employing a suitable β-ketoester precursor.
Scheme 4 shows the initial feasibility study on the
preparation of furan 5. According to a literature proce-
dure,9d methyl acetoacetate (3) was treated with Mg(OEt)2
(1.0 equiv) (EtOH, toluene, r.t., 1 h) to form the correspond-
ing magnesium enolate, which reacted with chloroacetyl
chloride (1.1 equiv) (MeCN, 0 °C, 1.5 h) to give furanone 4 in
27% yield.
TfOHd
0.025
0.025
0.025
0.025
TfOHd
TsOH·H2Oc
TsOH·H2Oc
0
0
a 200 mg scale.
bPPTS = pyridinium p-toluenesulfonate.
cTsOH = p-toluenesulfonic acid.
d TfOH = trifluoromethanesulfonic acid.
e 9.0 g scale.
The yield of furan 5 increased slightly by using
TsOH·H2O (Table 1, entry 2), and even more with TfOH (Ta-
ble 1, entry 3). While many unknown products were pro-
duced under these conditions, a clean reaction occurred un-
der more dilute conditions (0.025 M), giving 5 in 44% yield
(Table 1, entry 4). However, we were not able to find suit-
able conditions to complete this reaction. Eventually, how-
ever, we were pleased to find that the use of trimethyl or-
thoformate (5 equiv) allowed full conversion, giving 5 in
49% yield (Table 1, entry 5). Finally, the optimal yield of 5
(87%) was achieved by using TsOH·H2O in the presence of
trimethyl orthoformate (Table 1, entry 6). The robustness of
this reaction was demonstrated by conducting the reaction
on a 9.0 g scale, giving 5 in 82% yield (Table 1, entry 7).
O
Cl
(1.1 equiv)
Me
O
Mg(OEt)2
(1.0 equiv)
Cl
MeO2C
O
Me
MeO2C
EtOH, toluene
rt, 1 h
MeCN
0 °C, 1.5 h
O
27%
3
4
Me
O
PPTS
(0.5 equiv)
MeO2C
MeO
3
MeOH, rt, 24 h
9%
5
(18% recov.)
Scheme 4 Two-step preparation of furan 5
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
S. Sato et al.
Letter
Synlett
It turned out that furan 5, once obtained as hygroscopic
white solid, was stable enough to be stored in a tightly
sealed container over one week (r.t.). A precaution is the
tight sealing, in that storage in an open vial (r.t., 12 h) led to
decomposition, giving a yellow sticky oil (Figure 1).
This highly regioselective cycloaddition could be inter-
preted as follows (Figure 2). The starting point of discussion
is the long-known12 and well-exploited13 polarization of α-
alkoxybenzyne IX in that a higher electrophilicity is dis-
played at the carbon distal from the α-alkoxy group (Figure
2, A).13c,f,g,i,14 Given the case, a prototype of the present case
is Sargent’s report on the reaction of α-methoxybenzyne
(X) with β-methoxyfuran (XI), where the cycloaddition
mode shown in Figure 2 (B) is favored (selectivity 86:14).6
Considering the polarization of furan XI by electron dona-
tion from the methoxy group, this outcome could be ratio-
nalized by the HOMO–LUMO interaction as shown in Figure
2 (B). Turning attention to the present case, furan 5 could be
regarded as a derivative of β-methoxyfuran (XI) with two
extra groups, that is, 2-methyl and 3-methoxycarbonyl
groups (Figure 2, C). Prior to the experiment, we wondered
how these extra groups affect the reactivity and the regio-
selectivity of furan 5. A DFT calculation showed that the
HOMO of 5 also has the largest coefficient at C5 (Figure 2, C,
right),15 suggesting the preferred mode of cycloaddition A
(Figure 2, D) from the view of the frontier orbital interac-
tion. Despite the methyl group would discourage the mode
A by the steric effect, the observed high regioselectivity
suggests how decisive the orbital interaction is, overriding
the steric effect.
Figure 1 Property of furan 5
Experimental procedure for synthesis of furan 5 is as
follows: To a mixture of furanone 4 (200 mg, 1.28 mmol)
and trimethyl orthoformate (0.70 mL, 6.4 mmol) in MeOH
(51 mL) was added TsOH·H2O (121 mg, 0.636 mmol) at
room temperature. After stirring for 22 hours at room tem-
perature, the reaction was quenched by adding Et3N (0.5
mL). The resulting mixture was poured into saturated aque-
ous NaHCO3, and the products were extracted with EtOAc
(4×). The combined organic extracts were dried (Na2SO4)
and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel, hexane, EtOAc =
4:1) to afford furan 510 (189 mg, 87% yield) as a white solid.
With the requisite furan 5 in hand, the utility in the
[4+2] cycloaddition was examined by the reaction with the
α-alkoxybenzyne species, generated from o-iodoaryl tri-
flate 6 (Scheme 5): Upon treatment of a mixture of furan 5
(1.4 equiv) and o-iodoaryl triflate 6 in THF with n-BuLi (1.2
equiv, –95 °C, 20 min),11 the cycloaddition smoothly pro-
ceeded in a regioselective manner to give the desired cy-
cloadduct 7 in 80% yield and a small amount of regioisomer
8 (5% yield). Structures of cycloadducts 7 and 8 were con-
firmed by HMBC experiments (Scheme 5, A).
OBn
Me
MeO2C
I
n-BuLi (1.2 equiv)
O
+
THF, –95 ° C, 20 min
TfO
MeO
6
5 (1.4 equiv)
Me
O
OBn
OBn
MeO2C
MeO
Figure 2 Rationale for the regioselectivity
O
+
MeO
MeO2C
Scheme 6 shows the further conversion of cycloadduct 7
for the model construction of the CD rings in tetracenomy-
cin C (1), which was realized by reductive aromatization by
exploiting a low-valent titanium species as a reductant:7a
Upon treatment of 7 with TiCl4 (5 equiv) and Zn (10 equiv)
in THF (0 °C, 1 h), the reaction proceeded nicely to give
naphthalene 9 in 71% yield.
Having established this protocol, we became interested
in the application to the construction of the DEF rings of
lactonamycin (2, Scheme 7). By setting the pyrrolidone-
fused naphthalene 15 as the target, the model study started
Me
7 (80%)
8 (5%)
(A)
Me
O
OBn
OBn
MeO2C
MeO
MeO
O
: key HMBC
MeO2C
C 91.7 Me
δ
C 80.1
δ
H
H
δ
H 7.09
δH 6.93
7
8
Scheme 5 Regioselective [4+2] benzyne cycloaddition to furan 5
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
S. Sato et al.
Letter
Synlett
amount of its regioisomer. Due to the line broadening of the
1H NMR spectra, the structure assignment of the cycload-
duct 13 was not possible at this stage. However, it was as-
signed as such by the successful conversion into the target-
ed pyrrolidone 15 as described in the following. After re-
ductive aromatization (TiCl4, Zn, THF, r.t., 8 h), acid-
mediated detachment of the N-Boc group (TFA, CH2Cl2, r.t.,
1 h) triggered the lactamization3d to afford 15 in 89% yield.
The structure of 15 was unambiguously confirmed by
HMBC experiments (Scheme 7, A).
Me
O
OBn
Me
D
OBn
C
TiCl4 (5 equiv)
Zn (10 equiv)
MeO2C
MeO2C
THF, 0 °C, 1 h
MeO
MeO
7
71%
9
Me
D
OH
C
O
O
OH
MeO2C
MeO
B
A
OMe
OH
OH
O
tetracenomycin C (1)
In retrospect, the high regioselectivity of the cycloaddi-
tion of furan 12 is notable: In spite of the increased steric
demand around the C2 position by the presence of an ami-
nomethyl group, the selectivity was even better than that
observed in the reaction of furan 5 (cf. Scheme 5).
In summary, we have developed a viable method to pre-
pare 2-substituted 3-methoxycarbonyl-4-methoxyfurans,
which allowed the construction of highly functionalized
naphthalene derivatives via (1) regioselective benzyne
[4+2] cycloaddition with α-alkoxybenzyne and (2) reduc-
tive aromatization. Further works on the application to nat-
ural product synthesis are under way in our laboratory.
Scheme 6 Reductive aromatization
with β-ketoester 1016 having a γ-amino group. In the reac-
tion of 10 with chloroacetyl chloride, choice of the base
proved decisive: The initial attempt using Mg(OEt)2 (vide
supra) resulted in no reaction. After screening various bas-
es, the use of NaH (1.0 equiv, CH2Cl2, r.t., 0.5 h) proved effec-
tive, giving furanone 11 in 31% yield.17 The next step was
the acid-mediated formation of the furan: Treatment of 11
with TsOH·H2O (0.5 equiv) and trimethyl orthoformate (5
equiv, 0.025 M in MeOH, r.t., 72 h) gave furan 12 in 86%
yield. Notably, the reaction proceeded without touching the
N-Boc group.
Funding Information
This work was supported by Grant-in-Aid for Scientific Research (S)
(No. 16H06351), Grant-in-Aid for Young Scientists (B) (No. 26750363)
from Japan Society for the Promotion of Science (JSPS), and Grant-in-
Aid for Scientific Research on Innovative Areas ‘Advanced Molecular
O
Boc(Me)N
Cl
NaH
(1.0 equiv)
Cl
Boc(Me)N
MeO2C
MeO2C
γ
(1.1 equiv)
O
β
CH2Cl2
rt, 0.5 h
–30 °C, 30 h
Transformations by Organocatalysts’ from MEXT, Japan.
a
Jp
an
S
o
ecity
o
f
r
hte
P
or
m
o
itn
of
S
ecince
,
Gra
n
-ti-A
d
i
o
f
r
Secnifit
Reseacrh
S()
1(
6
H
0
6
3
5
1aJ)p
a
n
S
o
ecity
o
f
r
hte
Pro
m
o
itn
of
S
ecince
,
Gra
n
-ti-A
d
i
o
f
r
Y
o
u
n
g
Secinsti
B()
2(
6
7
5
0
3
6
3)
O
O
31%
10
11
OBn
I
Acknowledgment
Boc(Me)N
Boc(Me)N
MeO2C
OBn
TsOH·H2O
HC(OMe)3
We are grateful for Mr. Yasuyuki Ueda for DFT calculations.
2
TfO
MeO2C
6
O
O
MeOH
rt, 72 h
n-BuLi
MeO
MeO
THF, –95 °C
25 min
Supporting Information
86%
71%
12
13
Me
Supporting information for this article is available online at
Boc(Me)N
MeO2C
OBn
N
OBn
D
https://doi.org/10.1055/s-0036-1590825.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
F
O
TiCl4, Zn
TFA
E
THF, rt, 8 h
CH2Cl2
rt, 1 h
MeO
MeO
References and Notes
75%
89%
14
15
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O
(A)
Me
N
Me
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OH
D
O
C
O
OBn
O
A
F
O
OMe
O
E
B
O
HO
MeO
H 7.09
OR
δ
C 120.0
H
δ
R = α-L-rhodinosyl
lactonamycin (2)
15
: key HMBC
Scheme 7 Construction of the DEF-ring system of lactonamycin
Furthermore, the benzyne [4+2] cycloaddition of 12
with α-alkoxybenzyne proceeded in a regioselective man-
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
S. Sato et al.
Letter
Synlett
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(9) (a) Gelin, R.; Galliaud, A.; Chantegrel, B.; Gelin, S. Bull. Soc. Chim.
Fr. 1974, 5, 1043. (b) Gelin, S.; Hartmann, D. J. Heterocycl. Chem.
1976, 13, 521. (c) Moorthie, V. A.; McGarrigle, E. M.; Stenson, R.;
Aggarwal, V. K. ARKIVOC 2007, (v), 139. (d) Ünsal-tan, O.;
Özden, K.; Rauk, A.; Balkan, A. Eur. J. Med. Chem. 2010, 45, 2345.
(e) Ponoandian, T.; Muthusubramanian, S. Tetrahedron 2013, 69,
527.
(14) For a recent interpretation of the regioselectivity, see:
(a) Medina, J. M.; Mackey, J. L.; Garg, N. K.; Houk, K. N. J. Am.
Chem. Soc. 2014, 136, 15798. (b) Picazo, E.; Houk, K. N.; Garg, N.
K. Tetrahedron Lett. 2015, 56, 3511.
(15) The density functional theory (DFT) calculation was performed
using Jaguar (version 8.8, Schrödinger Inc., LLC. New York,
2015). The HOMO of 5 was calculated at the B3LYP/6-31G (d)
level.
(16) (a) Guinn, D. E.; Summers, J. B.; Heyman, H. R.; Conway, R. G.;
Rhein, D. A.; Albert, D. H.; Magoc, T.; Carter, G. W. J. Med. Chem.
1992, 35, 2055. (b) Sasaki, I.; Toyoda, T.; Yoshinaga, H.;
Natsutani, I.; Takahashi, Y. WO 2012008528, 2012. (c) Dockerty,
P.; Edens, J. G.; Tol, M. B.; Angeles, D. M.; Domenech, A.; Hirsch,
A. K. H.; Veening, J.-W.; Scheffers, D.-J.; Witte, M. D. Org. Biomol.
Chem. 2017, 15, 894.
(10) Analytical Data for Compound 5
1
White solid; mp 57–59 °C. H NMR (600 MHz, CDCl3): δ = 2.51
(s, 3 H), 3.76 (s, 3 H), 3.85 (s, 3 H), 6.94 (s, 1 H). 13C NMR (150
MHz, CDCl3): δ = 14.7, 51.4, 58.4, 106.6, 121.3, 148.9, 159.7,
163.8. IR (ATR): 3144, 2952, 1698, 1616, 1446, 1288, 1105 cm–1
.
ESI-HRMS: m/z calcd for C8H10NaO4 [M + Na]+: 193.0471; found:
193.0466.
(17) Use of 2 equiv of NaH gave lower yield of 11 (27% yield).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E