Catalytic and enantioselective oxa-Piancatelli reaction using a chiral vanadium complex

Article abstract of DOI:10.1039/d0cc02621b

An enantioselective oxa-Piancatelli reaction was established for the first time using a chiral vanadium(v) catalyst. The dual Br?nsted and Lewis acid properties of the vanadium catalyst afforded 4-hydroxycyclopent-2-enone derivatives in up to 90% yields and with 93:7 enantiomeric ratios, as well as >20:1 diastereomeric ratios.

Full text of DOI:10.1039/d0cc02621b

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DOI: 10.1039/D0CC02621B
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Catalytic and Enantioselective oxa-Piancatelli Reaction Using
Chiral Vanadium Complex
Lukas Schober,‡a,b Makoto Sako,‡b Shinobu Takizawa,*b Harald Gröger,*a and Hiroaki Sasai*b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An enantioselective oxa-Piancatelli reaction was established for the decompose the reactants and catalysts in organic reactions.
first time using a chiral vanadium(V) catalyst. The dual Brønsted Furthermore, water is generally an inefficient nucleophile for
and Lewis acid properties of the vanadium catalyst afforded 4- many asymmetric or enantioselective transformations.6
hydroxycyclopent-2-enone derivatives in up to 90% yields and 93:7 Therefore, to achieve an enantioselective oxa-Piancatelli
enantiomeric ratios, as well as >20:1 diastereomeric ratios.
reaction, design and construction of a water-resistant acid-
catalytic system are required.
4-Hydroxycyclopentenones are valuable building blocks for
pharmaceutically relevant compounds, as well as important
precursors of many natural products (Figure 1).1 Among the
synthetic methods for these molecules, the oxa-Piancatelli
reaction, which was first discovered in 1976 by Piancatelli,2 uses
water as a nucleophile to enable the direct transformation of
furfuryl alcohols to 4-hydroxycyclopentenones under acidic
conditions (Scheme 1A).3 Similarly, an aza-Piancatelli reaction
utilizing an amine instead of water was reported in 1977.4
Recently, Rueping, Sun, and Patil independently established
enantioselective aza-Piancatelli reactions using chiral Brønsted
acid catalysts (Scheme 1B).5 Although several aspects of oxa-
and aza-Piancatelli reactions have been investigated by many
synthetic chemists, there have been no reports of an
enantioselective oxa-Piancatelli reaction to date. One difficulty
when using water as a nucleophile is that water is prone to
To address this challenge, we envisioned that a chiral
oxovanadium complex could provide the required catalytic
activity and stability. Vanadium was chosen as the central metal
because of its proven ability to stabilize carbocation moieties
(which are intermediates in the oxa-Piancatelli reaction),7 its
successful applications in enantioselective carbon-carbon bond
formations,8 and its environmental benignity. We previously
developed chiral vanadium complexes9 as acid catalysts for a
Friedel-Crafts reaction9h and as oxidation/acid cooperative
catalysts for a sequential reaction.9f During our subsequent
studies on vanadium catalysis, the vanadium catalysts were also
found to work efficiently in aqueous media for the oxidative
A. oxa-Piancatelli reaction
O
OH
H2O/H
R
O


furnishing racemates:
pioneered in 1976 (ref. 3)
R
O
OH
O
O
1
2
H
X
CO2Me
R1
B. aza-Piancatelli reaction
O
H
OH
O
OH
(CH2)15CH3
H2NR/H
O
OH
R
HO
R2
HO

furnishing racemates:
pioneered in 1977 (ref. 4)
R

punaglandins
(X = I, Br, Cl)
didemnenone A
utenone A
NHR
enantioselective versions:
Rueping, Sun, Patil groups
(ref. 5)
1
3
Figure 1. 4-Hydroxycyclopent-2-enone derivatives.
C. This work
O
OH
a. Faculty of Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld,
Germany.
H2O/chiral vanadium catalyst
Ar
O

E-mail: harald.groeger@uni-bielefeld.de
first enantioselective
oxa-Piancatelli reaction
Ar

b. The Institute of Scientific and Industrial Research (ISIR), Osaka University,
Mihogaoka, Ibaraki-shi, Osaka 567-0047, Japan.
E-mail: taki@sanken.osaka-u.ac.jp, sasai@sanken.osaka-u.ac.jp
OH
1
2
†
Electronic Supplementary Information (ESI) available: See DOI:
Scheme 1. Oxa- and aza-Piancatelli reactions.
10.1039/x0xx00000x
‡ These authors contributed equally to this work.
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R
coupling of 2-naphthols9g and dehydrogenation of N-
heterocycles.9c Thus, we envisaged that our chiral vanadium
complexes could act as suitable acid catalysts in the presence of
water in an unprecedented enantioselective oxa-Piancatelli
reaction (Scheme 1C).
View Article Online
DOI: 10.1039/D0CtC-B0u2621B
N
V
O
O
O
N
O
V
HO
O
O
O
OH
O
V
O
O
(Ra,S,S)-3a: R = t-Bu
(Ra,S,S)-3b: R = i-Bu
(Ra,S,S)-3c: R = i-Pr
O
O
N
OH
R
(
,
,
)-3a-c
(
Ra S S
S
)-4a
Initially, chiral vanadium(V) catalysts were screened in the
reaction of furfuryl alcohol 1a in a mixed solvent of acetone and
water (Table 1). The dinuclear vanadium catalyst (Ra,S,S)-3a was
promising, giving the desired optically active product 2a in a
60:40 enantiomeric ratio (er) (entry 1). The diastereomeric
catalyst (Sa,S,S)-3a did not show an improved yield or er, but the
opposite enantiomer was obtained (entry 2). The reaction using
(Ra,S,S)-3b having an i-Bu group instead of a t-Bu group, or
(Ra,S,S)-3c with an i-Pr group, led to a decreased er (entries 3
and 4). When the mononuclear vanadium catalyst (Ra,S)-4a
t-Bu
N
V
(Ra,S)-4b : R = H
O
(Ra,S)-4c : R = Ph
O
O
O
(Ra,S)-4d : R = 3,5-Me2C6H3
(Ra,S)-4e : R = 3,5-(CF3)2C6H3
(Ra,S)-4f : R = 3,5-Ph2C6H3
OH
HO
R
(Ra,S)-4c-f
With this proof of concept for an enantioselective oxa-
Piancatelli reaction using (Ra,S)-4e in hand, we investigated the
impact of reaction parameters such as solvent, temperature,
and catalyst loading (for details, see the Supporting
Information). The screening showed that the reaction of 1a (0.1
mmol) with (Ra,S)-4e (5 mol %) in diisopropyl ether (i-Pr2O) at
25 °C provided 2a in 34% yield with 89:11 er (Table 2, entry 1).
Because almost full conversion of 1a was observed, the reason
for the low yield of 2a is likely decomposition of 1a under the
reaction conditions. Although the addition of an excess amount
of water (56 equivalents) was not effective, a smaller excess
amount of water gave 2a in up to 60% yield (entries 2-4). We
were pleased to find that besides water the addition of 3,5-di-t-
butyl-4-hydroxytoluene (BHT) was beneficial for improving the
yield of 2a (67%, entry 5). BHT likely serves as an antioxidant to
suppress a decomposition pathway of 1a. Finally, the reaction
of 1a at 20 °C for 48 h successfully afforded 2a as a single
diastereomer in 84% isolated yield with 93:7 er (entry 6).10
possessing
a naphthyl backbone was examined, results
comparable to that of (Ra,S,S)-3a were observed (entry 5).
Although (Ra,S)-4b bearing a binaphthyl skeleton gave a racemic
mixture of 2a (entry 6), (Ra,S)-4c having a phenyl group on the
binaphthyl improved the enantioselectivity to 73:27 er (entry 7).
After screening variations on the substituent of that catalyst
(entries 8-10), the reaction of (Ra,S)-4e bearing a 3,5-(CF3)2C6H3-
group afforded 2a in 85:15 er but with only 31% NMR yield
(entry 9).
Table 1. Screening of vanadium complexesa
O
OH
chiral vanadium cat.
Ph
O
acetone/H2O (2/1)
10 °C, 40 h, N2
Ph
OH
2a
1a
Table 2. Screening of reaction conditionsa
( >20:1 dr)
H2O (x equiv.)
(Ra,S)-4e (5 mol %)
entry
vanadium cat. (mol %)
(Ra,S,S)-3a (5)
(Sa,S,S)-3a (5)
(Ra,S,S)-3b (5)
(Ra,S,S)-3c (5)
(Ra,S)-4a (10)
(Ra,S)-4b (10)
(Ra,S)-4c (10)
(Ra,S)-4d (10)
(Ra,S)-4e (10)
(Ra,S)-4f (10)
yield (%)b
erc
1
8
60:40
41:59
50:50
59:41
58:42
50:50
73:27
68:32
85:15
80:20
1a
2a
(>20:1 dr)
additive
i-Pr2O (0.5 M)
25 °C, 24 h, N2
2
10
6
(0.1 mmol)
3
entry
H2O (equiv.)
additive
yield (%)b
erc
4
9
5
17
20
20
20
31
22
1
—
—
34
43
58
60
67
84e
89:11
87:13
90:10
91:9
91:9
93:7
6
2
56
—
7
3
14
—
8
4
2.8
2.8
2.8
—
9
5
6d
BHT (1 equiv.)
BHT (1 equiv.)
10
aThe reaction of 1a (0.12 mmol) was conducted in 0.3 mL of the solvent. bYields
were determined via 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as
an internal standard. cHPLC (Daicel Chiralpak IE) was used to determine er
values.
aThe reaction of 1a with (Ra,S)-4e was conducted in 0.2 mL of solvent. bYields were
determined via 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an
internal standard. cHPLC (Daicel Chiralpak IE) was used to determine er values.
dPerformed at 20 °C for 48 h. eIsolated yield. BHT: 3,5-di-t-butyl-4-hydroxytoluene.
With the optimized conditions in hand, we next explored the
substrate scope (Scheme 2). Furfuryl alcohols 1b-f bearing a
para-substituent such as an electron-withdrawing group (F, Cl,
Br, or I) or an electron-donating group (methyl) on the phenyl
moiety underwent the reaction to afford the corresponding
products 2b-f in moderate to good yields with high
enantioselectivities (90:10–93:7 er). Substrates 1g and 1h
having a meta-substituted aryl group furnished 2g (62% yield,
2 | J. Name., 2012, 00, 1-3
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91:9 er) and 2h (90% yield, 89:11 er), respectively. When 1i and which is then cleaved during formation of the intermediate C,
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1j were employed in the reaction, the yields and which bears an aldehyde moiety and anDeOnI:o1l0a.t1e03b9o/Du0nCdC0to26t2h1Be
enantioselectivities were diminished, probably because of the Lewis acidic vanadium center. The final rearrangement is an
steric effect of the ortho-substituent on the phenyl group. The intramolecular aldol reaction, enantioselectively leading to the
reaction of 1k or 1l possessing a 2-naphthyl group or 1-naphthyl desired product as a result of the chirality of the vanadium
group also proceeded to give the product 2k and 2l in 62% yield catalyst.
with 89:11 er and 55% yield with 71:29 er, respectively. Thienyl- To clarify the role of the phenolic hydroxy group in vanadium
substituted 1m smoothly reacted at 0 °C to provide 2m in 71% catalyst (Ra,S)-4e, catalysis by methyl ether-type vanadium
yield with 88:12 er. In all cases, a single trans diastereomer was complex (Ra,S)-4g was attempted using the optimized
formed. The absolute configuration of synthesized compound conditions. Both the yield and er of 2a were reduced (66% NMR
2b was determined to be (S,S) form by comparison of the yield and 77:23 er; Scheme 4). In addition, vanadium catalyst
specific rotation with that of the reported compound11 after TBS (Ra,S)-4h that did not contain an aryl substituent exhibited a
protection and reduction (for details, see the Supporting similar catalytic activity to (Ra,S)-4g, affording 2a in 65% NMR
Information).
yield with 73:27 er. These results indicate that the phenolic
hydroxy group in the catalyst is crucial for improving yield as
well as enantioselectivity, supporting the proposed cooperative
effect of the vanadium catalyst on intermediate C in Scheme 3.
The 3,5-bis(trifluoromethyl)phenyl group in the catalyst
increases the acidity of the phenolic hydroxy group and also acts
as a bulky substituent.
H2O (5 L, ca. 2.8 equiv.)
(Ra,S)-4e (5 mol %)
2
1
BHT (1.0 equiv.)
i-Pr2O (0.5 M)
20 °C, 48 h, N2
(>20:1 dr)
(0.10 mmol)
O
O
O
F
Cl
Br
OH
N
N
(Ra,S)-4e
O
V
O
V

O
(Ra,S)-4e
O
O
Ph
1a
OH
O
OH
2b
OH
OH
-H2O
O
OH
O
Ph
2c
2d
1a
OH
87% yield, 90:10 er
73% yield, 90:10 er
75% yield, 90:10 er
O
A
O
O
O
N
I
Me
Vanadium
O
OH
O
Ph
V
promoted
O
Ph
HO
F
resonance
O
Ph
O
H
O
OH
2e
65% yield, 91:9 er
OH
OH
2g
62% yield, 91:9 er
N
V
OH
2f
2a
57% yield, 93:7 er
O
O
O
C
O
O
Ph
O
O
O
OH
O
N
V
OMe
OH
O
Me
OH
2j
F
OH
OH
2i
O
N
V
2h
O
Ph
Ph
H2O
90% yield, 89:11 er
45% yield, 75:25 er
52% yield, 72:28 er
O
OH
O
O
H
Hemiacetal
formation
O
OH
O
O
O
O
S
O
OH
HO
B
OH
OH
OH
Scheme 3. Plausible catalytic cycle.
V cat. (5 mol %)
optimal conditions
2k
2l
2ma
62% yield, 89:11 er
55% yield, 71:29 er
71% yield, 88:12 er
aAt 0 °C for 24 h
1a
2a
Scheme 2. Substrate scope of the enantioselective oxa-Piancatelli reaction.
t-Bu
t-Bu
t-Bu
N
V
N
N
V
O
O
O
V
O
O
O
O
O
O
A
plausible catalytic cycle for the vanadium-catalyzed
O
O
O
OH
OH
OH
HO
MeO
MeO
enantioselective oxa-Piancatelli reaction of 1 is shown in
Scheme 3. Initially, the vanadium catalyst (Ra,S)-4e reacts with
furfuryl alcohol 1a with dehydration to give intermediate A. It is
noteworthy that vanadium is capable of activating alcohols,
formally removing the hydroxy group as an anion and stabilizing
the carbocation, as known for other analogous processes.7
Stabilizing the carbocation and the addition of water at the
furan moiety carbon furnishes the corresponding hemiacetal B,
F3
C
F3C
(Ra,S)-4e
(Ra,S)-4g
(Ra,S)-4h
2a: 65% yielda
73:27 er
CF3
CF3
2a: 84% yield
2a: 66% yielda
93:7 er
77:23 er
aNMR yield using 1,3,5-trimethoxybezene as an internalstandard.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Scheme 4. Control experiments.
Hanada, N. Fujiwara, Y. Kita, and M. Egi, Org. Lett., 2010, 12,
View Article Online
4900–4903. (d) S. Akai, K. TanimotoD, OYI.: 1K0a.1n0a39o/,DM0C.CE02g6i,21TB.
Yamamoto, and Y. Kita, Angew. Chem. Int. Ed., 2006, 45,
2592–2595.
In summary, the first enantioselective catalytic oxa-Piancatelli
reaction was developed. Using a bifunctional vanadium catalyst,
the target molecules were obtained in yields of up to 70% and
enantiomeric ratios of up to 93:7. In all cases the diastereomeric
ratios were >20:1.
8
9
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Kaphan, C. L. Marshall, P. C. Stair, A. P. Sattelberger, and M.
Delferro, Chem. Rev., 2019, 119, 2128−2191. (b) S. Takizawa,
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(a) M. Sako, T. Aoki, N. Zumbrägel, L. Schober, H. Gröger, S.
Takizawa, and H. Sasai, J. Org. Chem., 2019, 84, 1580–1587.
(b) M. Sako, A. Sugizaki, and S. Takizawa, Bioorg. Med. Chem.
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2017, 19, 3867–3870. (e) M. Sako, K. Ichinose, S. Takizawa, H.
Sasai, Chem. Asian. J., 2017, 12, 1305–1308. (f) M. Sako, Y.
Takeuchi, T. Tsujihara, J. Kodera, T. Kawano, S. Takizawa, H.
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S. Takizawa, Y. Yoshida, H. Sasai, Tetrahedron: Asymmetry,
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This work was supported by the German Academic Exchange
Service (DAAD) and Japan Society for the Promotion of Science
(JSPS) within the joint DAAD-JSPS funding program “DAAD PPP
Japan 2017/2018” (DAAD grant no. 57345562), JSPS KAKENHI
Grant Numbers 18K14220 in Early-Career Scientists,
JP16K08163 in Grant-in-Aid for Scientific Research (C),
JP18H04412 in Middle Molecular Strategy, JP18KK0154 in
Promotion of Joint International Research (Fostering Joint
International Research(B), The Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan Society for the
Promotion of Science (JSPS), Daiichi Sankyo Foundation of Life
Science, and Hoansha Foundation. We acknowledge the
technical staff of the Comprehensive Analysis Center of ISIR,
Artificial Intelligence Research Center of ISIR, and the analytical
department of Bielefeld University.
10 Although other metals and chiral phosphoric acid, which is
effective for the enantioselective aza-Piancatelli reaction5,
were also tested, vanadium complexes showed better
catalytic activity regarding the yield and enantioselectivity of
2a.
11 K. Nakata, Y. Kiyotsuka, T. Kitazume, Y. Kobayashi, Synlett,
2011, 2872–2874.
Conflicts of interest
There are no conflicts of interest to declare.
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