An Expeditious Route to trans-Configured Tetrahydrothiophenes Enabled by Fe(OTf)3-Catalyzed [3+2] Cycloaddition of Donor–Acceptor Cyclopropanes with Thionoesters

Article abstract of DOI:10.1002/chem.201800957

A synthetic route to trans-configured tetrahydrothiophenes (THTs) through Fe(OTf)₃-promoted [3+2] cycloaddition of donor–acceptor cyclopropanes with thionoesters was developed. The cycloaddition proceeded in high yield with high diastereoselectivity, affording transient α-alkoxy THTs. Not only aromatic and aliphatic thionoesters, but also thionolactone were applicable to the present iron catalysis. Further transformation of the S,O-ketal functionality of the product was achieved in a highly trans diastereoselective manner. Moreover, the utility of our methodology was clearly demonstrated by the synthesis of enantioenriched trans-configured THTs.

Full text of DOI:10.1002/chem.201800957

A Journal of
Accepted Article
Title: An Expeditious Route to trans-Configured Tetrahydrothiophenes
Enabled by Fe(OTf)3-Catalyzed [3+2]-Cycloaddition of Donor-
Acceptor Cyclopropanes with Thionoesters
Authors: Yohei Matsumoto, Daiki Nakatake, Ryo Yazaki, and Takashi
Ohshima
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Chem. Eur. J. 10.1002/chem.201800957
Link to VoR: http://dx.doi.org/10.1002/chem.201800957
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10.1002/chem.201800957
Chemistry - A European Journal
COMMUNICATION
An Expeditious Route to trans-Configured Tetrahydrothiophenes
Enabled by Fe(OTf)3-Catalyzed [3+2] Cycloaddition of Donor-
Acceptor Cyclopropanes with Thionoesters
Yohei Matsumoto, Daiki Nakatake, Ryo Yazaki* and Takashi Ohshima*
Abstract: A synthetic route to trans-configured tetrahydrothiophenes
(THTs) through Fe(OTf)3-promoted [3+2] cycloaddition of donor-
acceptor cyclopropanes with thionoesters was developed. The
cycloaddition proceeded in high yield with high diastereoselectivity,
affording transient a-alkoxy THTs. Not only aromatic and aliphatic
thionoesters, but also thionolactone were applicable to the present
iron catalysis. Further transformation of the S,O-ketal functionality of
the product was achieved in a highly trans diastereoselective
manner. Moreover, the utility of our methodology was clearly
demonstrated by the synthesis of enantioenriched trans-configured
THTs.
readily synthesized from the corresponding esters by treatment
with Lawesson’s reagent, are relatively stable and easy to
handle due to conjugative stabilization by a lone pair at
oxygen.[11] The stable nature of thionoesters makes them useful
for unique transformations that cannot be accessed using a
common carboxylic ester.[12] Previously, Nicolaou et al.
developed several unique transformations of thionoesters and
applied them to the total synthesis of various natural products.[13]
Efficient synthesis of heteroaromatic compounds from
thionoesters is also well investigated.[14] Thus, we focused on
the use of thionoesters for the synthesis of 2,5-trans-configured
THT derivatives through
Lewis
acid-catalyzed
[3+2]
cycloaddition of D-A cyclopropanes. Although the use of
carboxylic ester in the [3+2] cycloaddition of D-A cyclopropanes
is problematic due to instability of the O,O-ketal functionality of
the product (Scheme 1B), thionoesters are a good substrate due
to the higher stability of the corresponding S,O-ketal functionality
under Lewis or Brønsted acid-catalyzed conditions.[13] We also
envisioned that further transformation of the S,O-ketal
functionality through a thionium cation intermediate would
deliver the 2,5-trans-configured THT derivatives in a highly
trans-selective manner to avoid the steric repulsion (Scheme
1C).
Tetrahydrothiophene (THT),
a
heavier analog of
tetrahydrofuran, is an important scaffold frequently found in
biologically active natural products.[1] THT is also utilized as a
ligand in synthetic chemistry to harness the preferential
coordination ability to soft metals over hard metals.[2] In contrast
to the methods available for the tetrahydrofuran, methods for the
synthesis of THT remain to be explored, despite its importance;
therefore, multistep reactions involving intramolecular cyclization
are almost inevitable.[1,3,4] An intermolecular [3+2] cycloaddition
reaction of donor-acceptor (D-A) cyclopropanes with
heteroatom-containing dipolarophiles is one of the most powerful
synthetic methods for a five-membered hetero ring system
(Scheme 1A).[5] Although the chemistry of D-A cyclopropanes
has considerably progressed in the last few decades, only a few
A. [3+2] cycloaddition leading to cis-configured five-membered ring
[3+2] Cycloaddition
MeO2C
CO2Me
CO2Me
CO2Me
X
Lewis acid
R3
R2
+
5
2
examples
of
THT
synthesis
using
sulfur-containing
R2
R3
R1
R1
X
dipolarophiles are reported.[6] Furthermore, [3+2] cycloaddition of
D-A cyclopropanes with hetero-dipolarophiles generally provides
a 2,5-cis-configured five-membered ring system through a
common reaction mechanism, and the synthesis of a 2,5-trans-
X = O, NR4, S
R1 and R2: cis
steric hindrance
R2 > R3
B. [3+2] cycloaddition using carboxylic esters
[3+2] Cycloaddition
Lewis acid
configured five-membered ring system has remained
a
formidable task.[7] Herein, we report an expeditious synthetic
route to 2,5-trans-configured THT derivatives through catalytic
[3+2] cycloadditions of D-A cyclopropanes with thionoesters
(Scheme 1C).
MeO2C
CO2Me
CO2Me
CO2Me
O
OR3
R2
+
5
2
R2 OR3
R1
R1
O
unstable
Thiocarbonyls are innately more reactive than the
corresponding carbonyls due to the less efficient p-orbital
overlap of the C-S bond.[8] For example, benzothioaldehyde is
highly unstable, leading to oligomerization even at 110 K, and
thioketones require thermodynamic or kinetic stabilization to be
isolated.[9,10] Among thiocarbonyls, thionoesters, which can be
C. [3+2] cycloaddition using thionoesers for trans-configured THT (This work)
[3+2] Cycloaddition
MeO2C
CO2Me
CO2Me
CO2Me
S
Lewis acid
OR3
R2
+
5
2
R2 OR3
R1
R1
S
stable
(diastereoselective)
MeO2C
CO2Me
Nu
H
R1
transformation
Nu
R2
H
CO2Me
Y. Matsumoto, D. Nakatake, Dr. R. Yazaki, and Prof Dr. T. Ohshima
Graduate School of Pharmaceutical Sciences, Kyushu University
Maidashi Higashi-ku, Fukuoka, 812-8582 (Japan)
E-mail: yazaki@phar.kyushu-u.ac.jp.
5
2
S
R1
S
H
R2
CO2Me
highly diastereoselective
R1 and R2: trans
ohshima@phar.kyushu-u.ac.jp
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Scheme 1. [3+2] Cycloaddition reactions of D-A cyclopropanes and
dipolarophiles.
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10.1002/chem.201800957
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COMMUNICATION
Catalyst
(10 mol%)
MeO2C
CO2Me
Fe(OTf)3
(10 mol%)
CO2Me
S
MeO2C
CO2Me
CO2Me
CO2Me
S
+
OMe
Ph
OR3
R2
CO2Me
+
Ph
OMe
2a
toluene
MS4A, rt, 5 h
Ph
R2 OR3
Ph
R1
S
S
toluene
MS4A, rt, 5 h
R1
1a
3aa
1
2
3
Table 2. Substrate Scope[a]
Table 1. Condition Optimization[a]
R =
H
F
Cl
Br
I
3aa
3ba
3ca
3da
3ea
87% yield (10:1)
86% yield (9.2:1)
89% yield (7.1:1)
91% yield (5.2:1)
83% yield (8.9:1)
MeO2C
S
CO2Me
Entry
1
Catalyst
none
Yield (%)[b]
n.r.
n.r.
n.r.
n.r.
38
dr[b]
OMe
Ph
n.d.
n.d.
n.d.
n.d.
7.0:1
n.d.
10:1
n.d.
n.d.
n.d.
n.d.
16:1
R
2
Mg(OTf)2
Al(OTf)3
AlCl3
MeO2C
MeO2C
CO2Me
CO2Me
3
OMe
Ph
OMe
Ph
S
S
4
MeO
S
3fa
79% yield (9.3:1)[b]
3ga
5
Sc(OTf)3
Fe(OTf)2
Fe(OTf)3
Cu(OTf)2
Sn(OTf)2
La(OTf)3
Yb(OTf)3
Fe(OTf)3
45% yield (8.5:1)[b]
6
n.r.
95
MeO2C
MeO2C
MeO2C
S
3ia
61% yield (4.5:1)[b]
CO2Me
CO2Me
CO2Me
OMe
Ph
OMe
Ph
7
OMe
Ph
Ph
PhthN
S
S
8
n.r.
5
3ha
3ja
56% yield (5.8:1)[b]
84% yield (>20:1)[b]
9
MeO2C
CO2Me
OMe
MeO2C
CO2Me
OMe
MeO2C
CO2Me
OMe
10
11
12[c]
n.r.
n.r.
38
Ph
Ph
S
S
Ph
2-naphthyl
S
OMe
F
3ab
3ac
3ad
85% yield (10:1)[b]
60% yield (8.9:1)
87% yield (4.0:1)[c]
[a] Conditions: 1a (0.20 mmol), 2a (0.24 mmol), catalyst (0.020 mmol), MS4A
(50 mg), toluene (1.0 ml). [b] Yield and diastereoselectivity were calculated by
1H-NMR analysis using 2-methoxynaphthalene standard. n.r. = no reaction.
n.d. = not determined. [c] Without MS4A.
MeO2C
MeO2C
CO2Me
OMe
CO2Me
OMe
S
Ph
Ph
S
S
S
We began our investigation using cyclopropane 1a and
thionoester 2a as model substrates, and the reactions were
performed with MS4A in toluene at ambient temperature. No
reaction proceeded without a catalyst (entry 1). In addition,
several Lewis acid catalysts, which are commonly used in [3+2]
cycloadditions of D-A cyclopropanes, exhibited no catalytic
activity (entries 2–4). Sc(OTf)3 provided the desired product 3aa
in moderate yield with good diastereoselectivity (entry 5). In
contrast, Fe(OTf)3 exhibited the highest catalytic performance
and 3aa was obtained in 95% yield with high diastereoselectivity,
although Fe(OTf)2 was ineffective (entries 6 and 7). Soft metal
triflates, Cu(OTf)2 and Sn(OTf)2, were less effective, presumably
due to the highly coordinative nature of soft Lewis basic
thionoester 2a (entries 8 and 9). Representative lanthanide
metal catalysts La(OTf)3 and Yb(OTf)3 gave no desired product
3aa (entries 10 and 11). Without MS4A, ring-opening of
tetrahydrothiophene due to water contamination occurred,
resulting in a low chemical yield (entry 12).[15]. TfOH, which can
be generated in situ by decomposing metal triflate with water,
afforded product 3aa in very low yield, suggesting that Lewis
acidic Fe(OTf)3 would be an actual active species.[16]
With the optimal conditions in hand (Table 1, entry 7), we
next investigated the scope with respect to D-A cyclopropanes 1
(Table 2). A range of substituents on the 2-aryl group were
applicable to the present catalysis (3ba–3ea). When less
reactive substrates were used, the use of CH2Cl2 instead of
toluene as a solvent was beneficial for smooth reaction progress.
An electron-rich aromatic group, 4-methoxyphenyl and 2-thienyl,
afforded the products in a synthetically useful yield with high
diastereoselectivity (3fa and 3ga). Although alkyl-substituted
3ae
3af
46% yield (14:1)[b,d]
34% yield (15:1)[b,d,e]
MeO2C
CO2Me
OMe
MeO2C
CO2Me
Ph
S
OiPr
Ph
Ph
S
Fe
3ag
3ah
85% yield (>20:1)[b,f]
63% yield (2.5:1)[c]
No reaction (with 1a)
S
S
O
O
Ph
NMe2
5a
Ph
NMe2
Ph
OMe
Ph
OMe
4a
4b
5b
[a] Reaction Conditions: 1 (0.20 mmol), 2 (0.24 mmol), Fe(OTf)3 (0.020 mmol),
MS4A (50 mg), toluene (1.0 ml). [b] CH2Cl2 was used as a solvent instead of
toluene. [c] Reaction time was 12 h. [d] 30 mol% catalyst was used. [e]
Reaction time was 96 h. [f] Reaction time was 24 h.
cyclopropane did not provide the product, cinnamyl and vinyl-
substituted THT, which could be further transformed through a
cross metathesis reaction, were obtained (3ha and 3ia),
confirming the synthetic utility of the present catalysis for
divergent THT synthesis. Phthalimide-substituted THT 3ja was
also successfully constructed in high yield with excellent
diastereoselectivity.
The scope of thionoesters 2 was also investigated with
cyclopropane 1a. Methyl 4-methoxythionobenzoate (2b) and 4-
fluorothionobenzoate (2c) provided the corresponding THTs 3ab
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10.1002/chem.201800957
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COMMUNICATION
and 3ac in good yield. The initial reaction rate decreased in the
order of 2b > 2a > 2c, suggesting that the reaction was initiated
by nucleophilic attack of the thionoester, the same mechanism
of the common D-A cyclopropane chemistry.[5,16] Time-course
analysis of product 3ac revealed low diastereoselectivity in a
shorter reaction time, and as the reaction progressed, the ratio
of the thermodynamically more stable isomer increased.[16]
2-Naphthyl group could be used as substrate (3ad).
Previously unexplored highly coordinative thiocarbonyls having
heteroaromatic functionality could be applied and products (3ae,
3af) were isolated in moderate yields with high
diastereoselectivities using 30 mol% catalyst.[6d] Useful
intermediate 3ag having ferrocenyl group was obtained in high
yield, verifying synthetic utility of the present catalysis.[17] Inferior
hydride reduction with Et3SiH proceeded smoothly, and a-mono-
substituted product 6 was obtained in 92% yield as a single
diastereomer; this trans-product cannot be accessed from
thioaldehyde due to the instability of the thioaldehyde (Scheme
3a).[9,18a] Although the previously reported [3+2] cycloaddition of
D-A cyclopropanes provided cis-configured five-membered
systems as the major isomer, this transformation proceeded in a
highly trans-selective manner to avoid steric repulsion,[18b]
demonstrating the utility of our synthetic method for trans-
configured THT synthesis. Aside from the reduction,
diastereoselective transformation of the C–O bond to the C–C
bond was achieved using TMSCN, affording a-tetrasubstituted
THT 7 as a single diastereomer, which cannot be synthesized by
conventional SN2 cyclization (Scheme 3b).[3]
reactivity and diastereoselectivity were observed when
a
CO2Me
sterically congested isopropyl thionobenzoate (2h) was used. No
reactions were observed using aromatic/aliphatic carboxylic
esters (4a and 4b) or thioamides (5a and 5b), highlighting the
highly chemoselective nature of the present [3+2] cycloadditions.
Aliphatic thioaldehydes and thioketones are generally
unstable and difficult to use in the intermolecular [3+2]
cycloaddition reaction of D-A cyclopropanes.[8-10] To demonstrate
further synthetic utility of the present catalysis, we next
investigated the scope using aliphatic thionoesters (Scheme 2).
The [3+2] cycloaddition of methyl 3-phenylthionopropionate (2i)
and cyclopropane 1a followed by elimination of methanol
afforded olefinated product 3ai in excellent yield (Scheme 2a).
Sterically-hindered substrate 2j was also applicable to the
present catalysis using 30 mol% Fe(OTf)3 (Scheme 2b). It is
noteworthy that cyclic thionoester, γ-butyrothionolactone (2k),
afforded a hitherto-inaccessible [5,5]-spiro-S,O-ketal ring system
for the first time (Scheme 2c). Although the diastereoselectivity
of 3ak was moderate, those isomers could be separated by
conventional column chromatography.
TMSOTf
Et3SiH
MeO2C
CO2Me
CO2Me
MeO2C
CO2Me
Ph
Ph
OMe
Ph
+
(a)
CH2Cl2
MS4A
rt, 24 h
Ph
S
Ph
S
S
6
3aa (10:1)
H
Ph
92% yield
single diastereomer
unstable
H
Ph
H
S
ꢀ trans configuration
ꢀꢀinaccessible from thioaldehyde
CO2Me
Nu
H
Ph
CO2Me
TMSOTf
Me3SiCN
MeO2C
MeO2C
CO2Me
CO2Me
(b)
OMe
Ph
CN
Ph
CH2Cl2
MS4A
rt, 24 h
Ph
Ph
S
S
7
3aa (10:1)
85% yield
single diastereomer
Scheme 3. TMSOTf mediated diastereoselective transformation of 3aa.
MeO2C
CO2Me
Fe(OTf)3
(10 mol%)
S
1a
+
(a)
Ph
Fe(OTf)3
(10 mol%)
S
Ph
OMe toluene (0.20 M)
MS4A, rt, 5 h
MeO2C
CO2Me
CO2Me
CO2Me
S
Ph
+
OMe
Ph
2i
3ai
98% yield
(single isomer)
Ph OMe
toluene
MS4A, rt, 6 h
Ph
Ph
S
(R)-1a
>99% ee
2a
chiral 3aa
80% yield (10:1)
95% ee
Fe(OTf)3
(30 mol%)
MeO2C
CO2Me
S
a
b
(b)
1a
+
OMe
Ph
CH2Cl2 (0.20 M)
MS4A, rt, 5 h
S
MeO2C
MeO2C
MeO2C
CO2Me
CO2Me
Ph
CO2Me
Ph
3aj
95% yield
[O]
c
2j
S
CN
Ph
Ph
Ph
Ph
S
S
S
O
O
MeO2C
CO2Me
Fe(OTf)3
(20 mol%)
chiral 7
83% yield
single diastereomer
95% ee
8
chiral 6
85% yield
87% yield
single diastereomer
95% ee
O
+
1a
(c)
O
Ph
S
CH2Cl2 (0.20 M)
MS4A, rt, 5 h
2k
3ak
Scheme 4. Chiral THT synthesis using (R)-1a. Reaction conditions: a)
TMSOTf (30 mol%), Et3SiH (3.0 equiv.), MS4A, CH2Cl2, 0°C to RT, 24 h. b)
TMSOTf (50 mol%), TMSCN (5.0 equiv.), MS4A, CH2Cl2, 0°C to RT, 24 h. c)
mCPBA (2.0 equiv), CH2Cl2, RT, 6 h.
75% yield
(2.3:1)
Scheme 2. [3+2] Cycloaddition reactions of cyclopropane 1a and aliphatic
thionoester 2i and 2j and thionolactone 2k.
Finally, we applied our method to chiral THT synthesis
using readily available chiral cyclopropane (R)-1a (Scheme 4).
The enantioenriched THT was isolated in high yield with 95% ee.
Further elaboration of the obtained chiral 3aa provided chiral
We next turned our attention to transformations of the
S,O-ketal functionality (Scheme 3). A Lewis acid-mediated
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10.1002/chem.201800957
Chemistry - A European Journal
COMMUNICATION
Xu, Org. Lett. 2012, 14, 1090; h) F. J. Robertson, J. Wu, J. Am. Chem.
Soc. 2012, 134, 2775.
products 6 and 7 without decreasing the enantioselectivity.
Absolute stereochemistry of oxidized sulfone 8 was confirmed
by X-ray crystallographic analysis, where stereochemical
inversion was observed, supporting the predominance of SN2
nucleophilic attack of the thionoester rather than the carbocation
pathway.
[5]
[6]
For reviews on donor-acceptor cyclopropanes: a) T. F. Schneider, J.
Kaschel, D. B. Werz, Angew. Chem. Int. Ed. 2014, 53, 5504; Angew.
Chem. 2014, 126, 5608; b) M. A. Cavitt, L. H. Phun, S. France, Chem.
Soc. Rev. 2014, 43, 804.
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Chai, Org. Biomol. Chem. 2013, 11, 7859; c) S.-W. Wang, W.-S. Guo,
L.-R. Wen, M. Li, RSC Adv. 2015, 5, 47418. Very recently, Werz at al
reported elegant [3+2] cycloaddition of D-A cyclopropanes using
relatively stable thioketones such as thiobenzophenone. When the
unsymmetrical thioketones were used, 2,5-cis-configured THTs were
obtained in moderate diastereoselectivity. See, d) A. U. Augustin, M.
Busse, P. G. Jones, D. B. Werz, Angew. Chem. Int. Ed. 2017, 56,
14293; Angew. Chem. 2017, 129, 14481; e) A. U. Augustin, M. Sensse,
P. G. Jones, D. B. Werz, Org. Lett. 2018, 20, 820.
In summary, we developed a catalytic [3+2] cycloaddition
of D-A cyclopropanes with thionoesters for the synthesis of
trans-configured THTs. Aromatic and aliphatic thionoesters were
applicable to the present catalysis. Thionolactone provided the
hitherto-inaccessible
[5,5]-spiro-S,O-ketal
ring
system.
Transformation mediated by TMSOTf delivered trans-configured
THT derivatives with excellent diastereoselectivity. The present
methodology was applied to an enantioenriched THT synthesis
using chiral cyclopropane. Further applications of this trans-
configured THT synthetic method to biologically active
compounds are in progress.
[7]
a) D. P. Patrick, S. J. Jeffrey, J. Am. Chem. Soc. 2005, 127, 16014; b)
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Chem. Soc. 2009, 131, 3122; d) T. P. Andrew, G. S. Austin, J. N.
Andrew, S. J. Jeffrey, J. Am. Chem. Soc. 2010, 132, 9688; e) F. de
Nanteuil, E. Serrano, D. Perrotta, J. Waser, J. Am. Chem. Soc. 2014,
136, 6239.
Acknowledgements
[8]
[9]
For reviews on thiocarbonyl compounds: a) P. Metzner, Synthesis
1992, 1185; b) P. Metzner, Top. Curr. Chem. 1999, 204, 127.
a) H. G. Giles. R. A. Marty. P. de Mayo, Can. J. Chem. 1976, 54, 537;
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This work was financially supported by JSPS KAKENHI Grant
Number JP15H05846
in
Middle
Molecular Strategy,
JP16H01032 in Precisely Designed Catalysts with Customized
Scaffolding and Platform for Drug Discovery, Informatics, and
Structural Life Science from MEXT. Drs. Kazuteru Usui and
Yasufumi Fuchi are gratefully acknowledged for analytical
measurement assistance. We are grateful to Prof. Hirai’s group
for the use of polarimeter.
[10] a) J. Kaschel, C. D. Schmidt, M. Mumby, D. Kratzert, D. Stalke, D. B.
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Keywords: cycloaddition • thionoester • iron •
tetrahydrothiophene • stereoselectivity
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[15] Without strict drying technique, by-product was observed via water
substitution followed by ring opening reaction.
MeO2C
Lewis acid
H2O
CO2Me
MeO2C
MeO2C
CO2Me
CO2Me
[2]
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Ph
O
OMe
Ph
OH
Ph
–MeOH
Ph
S
Ph
S
S
Ph
[16] See Supporting Information for details.
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10.1002/chem.201800957
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
CO2Me
MeO2C
MeO2C
CO2Me
R2
CO2Me
Y. Matsumoto, D. Nakatake, R. Yazaki*
and T. Ohshima*
Fe(OTf)3
“Nu”
CO2Me
R2
R1
R1
S
R1
S
OR3
Nu
+
Page No. – Page No.
20 examples
up to 98% yield
S
An Expeditious Route to trans-
Configured Tetrahydrothiophenes
Enabled by Fe(OTf)3-Catalyzed [3+2]
Cycloaddition of Donor-Acceptor
Cyclopropanes and Thionoesters
Thionoesters
OR3
Tetrahydrothiophenes
• Stereoselective
R2
• Stable but reactive
• Easily available
• R1 and R2: trans
A
synthetic route to trans-configured tetrahydrothiophenes (THTs) through
Fe(OTf)3-promoted [3+2] cycloaddition of donor-acceptor cyclopropanes with
thionoesters was developed. The cycloaddition proceeded in high yield with high
diastereoselectivity, affording transient THTs bearing S,O-ketal functionality.
Further transformation of the S,O-ketal functionality was achieved in a highly trans
diastereoselective manner.
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