Oxidative Kinetic Resolution of cis -Fused Tricyclic 1-Tetralone Derivatives by Guanidine-Bisurea Bifunctional Organocatalyst

Article abstract of DOI:10.1055/s-0036-1588151

We present an enantioselective synthesis of cis -fused tricyclic 1-tetralones via oxidative kinetic resolution in the presence of cumene hydroperoxide (CHP) and guanidine-bisurea bifunctional organocatalyst. This reaction affords the corresponding α-hydroxylation products together with unreacted tetralones in good to high enantioselectivity, with s values as high as 42. The reaction was successfully applied for the synthesis of the core structure of a kainoid derivative, 4-(2-methoxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (MFPA).

Full text of DOI:10.1055/s-0036-1588151

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
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A
M. Odagi et al.
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Oxidative Kinetic Resolution of cis-Fused Tricyclic 1-Tetralone
Derivatives by Guanidine–Bisurea Bifunctional Organocatalyst
CF3
Minami Odagi*
(CH2)17CH3
Cl
HN
Keisuke Hosoya
Ar =
H
H
H
H
N
N
N
N
Yoshiharu Yamamoto
Kazuo Nagasawa*
Ar
O
N
N
Ar
CF3
H
H
O
Ph
Ph
O
(5 mol%)
O
O
Department of Biotechnology and Life Science, Tokyo University
of Agriculture and Technology, 2-24-16, Naka-cho, Koganei city,
184-8588, Tokyo, Japan
odagi@cc.tuat.ac.jp
knaga@cc.tuat.ac.jp
CO2t-Bu
CO2t-Bu
CO2t-Bu
CHP (0.75 equiv)
K2CO3 (1.0 equiv)
OH
H
X
X
X
H
H
+
toluene (0.025 M)
0 °C, 72 h
H
H
H
( )n
s = up to 42
( )n
( )n
n = 1 or 2
racemic substrate
cis-fused tricyclic 1-tetralone derivatives were obtained with up to 99% ee
Received: 28.12.2016
Accepted after revision: 02.02.2017
Published online: 24.02.2017
cis-fused 3,4-cyclopenta- and 3,4-cyclohexa-1-tetralone
derivatives enantioselectively with
a
broad substrate
scope.8–11
DOI: 10.1055/s-0036-1588151; Art ID: st-2016-b0880-c
OH
Me
O
OH
Me
O
Abstract We present an enantioselective synthesis of cis-fused tricy-
clic 1-tetralones via oxidative kinetic resolution in the presence of cu-
mene hydroperoxide (CHP) and guanidine–bisurea bifunctional or-
ganocatalyst. This reaction affords the corresponding α-hydroxylation
products together with unreacted tetralones in good to high enantiose-
lectivity, with s values as high as 42. The reaction was successfully ap-
plied for the synthesis of the core structure of a kainoid derivative, 4-(2-
methoxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (MFPA).
CO2Me
OH
O
R
Br
Br
O
N
Me
Me
H
Me
Me
H
H
HO
Me
Me
10-ketomorphinan
hamigeran A
hamigeran B
Figure 1 Examples of 3,4-cyclopenta- and 3,4-cyclohexa-1-tetralone
structures in biologically active compounds
Key words tetralone, oxidative kinetic resolution, guanidine, urea
cis-Fused tricyclic 1-tetralone derivatives are useful
building blocks in organic synthesis and privileged struc-
ture motifs in a broad range of natural products, such as ha-
migerans and morphinans, as well as pharmaceuticals (Fig-
ure 1).1–4 In spite of the synthetic significance of the struc-
ture, only a limited range of strategies is available for the
construction of tricyclic 1-tetralones, and substrate scope is
often very narrow, focusing on particular natural products
and their core structures. In 2001, Nicolaou et al. reported
construction of tricyclic 1-tetralone structures by means of
photoenolization of benzaldehyde and subsequent intra-
molecular Diels–Alder reaction.5 In their reaction, trans-
fused 3,4-cyclopenta- and 3,4-cyclohexa-1-tetralone deriv-
atives were obtained in high yield (75–95% yield), and they
successfully applied this strategy for the synthesis of ha-
migerans A and B.6 In 2005, Studer and Ryu et al. reported a
synthesis of 3,4-cyclopenta-1-tetralones in moderate yield
by applying a TEMPO-based radical cyclization of 1-aryl-5-
hexenyloxyamine derivatives. In this reaction, the ratio of
the fused cis and trans structures was 1:1 to 1:2.7 Although
these representative preceding studies were successful,
there is still a need for efficient methodology to construct
We recently developed oxidative kinetic resolution of 3-
or 4-substituted tetralones rac-2a and rac-2b using guani-
dine–bisurea bifunctional organocatalyst 1a (Scheme
1).12,13 This reaction efficiently provides the corresponding
hydroxylation products 3, while unreacted 2 is recovered
with high enantiomeric excess. Here, we planned to apply
this oxidative kinetic resolution strategy to 3,4-cyclopenta-
and 3,4-cyclohexa-1-tetralone derivatives. Since these sub-
strates can be regarded as 3,4-disubstituted 1-tetralones,
we were interested to see whether the oxidative kinetic res-
olution under guanidine–bisurea bifunctional organocatal-
ysis conditions could be extended to these new types of
substrates.
To examine the oxidative kinetic resolution of cis-fused
tricyclic 1-tetralones, we commenced by applying the pre-
viously developed conditions to rac-4a bearing 3,4-cyclo-
pentane structure (Table 1). The hydroxylation product 5a
was obtained in 38% yield with 69% ee, and 4a was recov-
ered in 31% yield with 97% ee; the s value was 22 (Table 1,
entry 1). Then, we carried out general structure–activity
relationship studies of catalyst 1 focusing on the substitu-
ents of the guanidine moiety, R1, R2, and chiral spacer R3
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
M. Odagi et al.
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Oxidative kinetic resolution of 3-substituted 1-tetralone
(CH2)17CH3
Ar = 3,5-(CF3)2C6H3
Cl
HN
H
H
H
N
H
N
N
N
Ar
N
N
Ar
H
H
O
Ph
Ph
O
1a (5 mol%)
CHP (0.75 equiv)
K2CO3 (1.0 equiv)
O
O
O
CO2t-Bu
CO2t-Bu
CO2t-Bu
OH
Ph
+
3
toluene (0.033 M)
0 °C, 48 h
Ph
Ph
rac-2a
3a
2a
42%, 97% ee
49%, 83% ee
s = 44
Oxidative kinetic resolution of 4-substituted 1-tetralone
1a (5 mol%)
CHP (0.75 equiv)
K2CO3 (1.0 equiv)
O
O
O
CO2t-Bu
OH
CO2t-Bu
CO2t-Bu
+
4
toluene (0.033 M)
0 °C, 48 h
Ph
Ph
Ph
2b
44%, 99% ee
3b
51%, 89% ee
rac-2b
s = 89
Scheme 1 Previous work: oxidative kinetic resolution of 3- or 4-substituted tetralones
(Table 1, entries 2–6). When the R1 and R2 groups were
changed to afford disubstituted guanidine (1b and 1c), the
enantioselectivity decreased drastically, and the s values
were found to be 1 and 3, respectively (Table 1, entries 2
and 3). Next, the effect of the R3 group in catalyst 1a was
examined. The R3 group was varied among benzyl, isopro-
pyl, and methyl. In the case of a benzyl group, the enantio-
selectivity of 5a and 4a was slightly decreased to 54% ee
and 95% ee, respectively (Table 1, entry 4). On the other
hand, aliphatic groups (isopropyl and methyl groups) dras-
Table 1 Optimizations of the Reaction Conditions with rac-4aa
R1
R2
Ar = 3,5-(CF3)2C6H3
Cl
N
H
H
H
H
N
N
N
N
Ar
N
H
N
H
Ar
O
R3
R3
O
1 (5 mol%)
CHP (0.75 equiv)
K2CO3 (1.0 equiv)
O
O
O
CO2t-Bu
CO2t-Bu
CO2t-Bu
OH
H
+
H
H
toluene (0.033 M)
0 °C, 48 h
H
H
H
rac-4a
5a
4a
Entry
Catalyst 1
5a
4a
sd
R1
R2
R3
Yield (%)b
ee (%)c
Yield (%)b
ee (%)c
1
2
3
4
5
6
7e
1a
1b
1c
1d
1e
1f
H
(CH2)17CH3
Ph
Ph
Ph
Bn
i-Pr
Me
Ph
38
36
27
58
43
4
69
–10
41
31
61
50
39
57
96
52
97
–6
16
95
56
1
22
–(CH2)4–
1
3
–(CH2)5–
H
H
H
H
(CH2)17CH3
(CH2)17CH3
(CH2)17CH3
(CH2)17CH3
54
12
7
62
31
2
1a
44
87
83
37
a Reaction conditions: rac-4a (0.1 mmol), CHP (0.075 mmol), and K2CO3 (0.1 mmol) in the presence of 1 (5 mol%) in toluene (0.033 M) at 0 °C for 48 h.
b Yield of isolated product.
c Determined by HPLC analysis using a chiral stationary phase.
d The selectivity factor (s) was calculated as follows: s = kfast/kslow = In[1 − C(1+ee5a)]/In[1 − C(1 − ee5a)] = In[(1 − C)(1 − ee4a)]/In[(1 − C)(1+ee4a)]; C = ee4a
/(ee4a+ee5a).
e Reaction was performed in toluene (0.025 M) for 72 h; CHP = cumene hydroperoxide.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

C
M. Odagi et al.
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tically reduced the selectivity. Especially in the case of the
methyl group as R3, conversion was very low, and 4a was
recovered almost quantitatively in racemic form (Table 1,
entry 6). Thus further optimization of the reaction condi-
tions were carried out with catalyst 1a. We found that the s
value was improved to 37 by diluting the reaction mixture
(0.025 M) and extending the reaction time to 72 h (Table 1,
entry 7). Under these conditions, the hydroxylation product
5a was obtained in 44% yield with 87% ee, while unreacted
4a was obtained in 52% yield with 83% ee.
With the optimal conditions in hand, we investigated
the substrate scope for the oxidative kinetic resolution of
tricyclic 1-tetralones 4 (Scheme 2). In the case of 3,4-cyclo-
penta-1-tetralones rac-4b and rac-4c, which have an elec-
tron-donating group on the aromatic ring at C6, oxidative
kinetic resolution proceeded smoothly, and the corre-
sponding hydroxylation products 5b and 5c were obtained
with high enantioselectivity (85% ee and 86% ee, respec-
tively), while unreacted 4b and 4c were each recovered
with 91% ee. On the other hand, very low reactivity was ob-
served for rac-4d bearing a methoxy group at C5, and a
poor s value was obtained (s = 2). This is probably because
of serious steric repulsion in 4d between the methoxy
group at C5 and the cyclopentane moiety, producing a tran-
sition state (TS) conformer that is unfavorable for α-hydrox-
ylation.14 In the case of rac-4e–g bearing an electron-with-
drawing group at C6 or C8, good to high s values were ob-
served (s = 15–24), and hydroxylation products 5e–g were
obtained with 51–78% ee, while unreacted 4e–g were re-
covered with 87–99% ee. This oxidative kinetic resolution
was applicable to 3,4-cyclohexa-1-tetralone rac-4h, and the
corresponding hydroxylation product 5h and unreacted 4h
were obtained in 80% ee and 89% ee, respectively (s = 27).
This kinetic resolution reaction was also successfully ap-
plied to the acyclic substrate rac-4i. In this case, hydroxyl-
ation product 5i was obtained in 39% yield with 90% ee,
while unreacted 4i was recovered in 58% yield with 68% ee
(s = 39). Interestingly, the oxidation reaction did not pro-
ceed at all with the trans isomer of rac-4j, and the starting
product rac-4j was recovered quantitatively.
The difference of reactivity between the cis- and trans-
isomers 4i and 4j can be plausibly explained in terms of the
transition state (TS) for the oxidation with CHP.15 Thus, in
the case of 4i, there is no significant steric repulsion in TS-
(CH2)17CH3
Ar = 3,5-(CF3)2C6H3
Cl
HN
H
H
H
N
H
N
N
N
Ar
N
N
Ar
H
H
O
Ph
Ph
O
1a (5 mol%)
CHP (0.75 equiv)
K2CO3 (1.0 equiv)
O
O
O
8
5
CO2
CO2t-Bu
CO2t-Bu
OH
H
+
X
6
X
X
H
H
toluene (0.025 M)
0 °C, 72 h
H
H
H
(
)
(
)
(
)
n
n
n
rac-4
n = 1 or 2
5
4
O
O
O
CO2t-Bu
CO2t-Bu
CO2t-Bu
H
H
H
MeO
BnO
H
H
H
MeO
5b: 39%, 85% ee
4b: 47%, 91% ee
s = 39
5c: 44%, 86% ee
4c: 43%, 91% ee
s = 42
5d: 7%, 27% ee
4d: 88%, 13% ee
s = 2
O
O
F
O
CO2t-Bu
CO2t-Bu
CO2t-Bu
H
H
H
Br
Cl
F
H
H
H
5g: 59%, 51% ee
4g: 39%, 99% ee
s = 15
5e: 43%, 76% ee
4e: 46%, 92% ee
s = 24
5f: 45%, 78% ee
4f: 50%, 87% ee
s = 23
O
O
O
CO2t-Bu
CO2t-Bu
CO2t-Bu
H
Me
Me
H
Me
Me
5j: n.d.
5h: 45%, 80% ee
4h: 54%, 89% ee
s = 27
5i: 39%, 90% ee
4i: 58%, 68% ee
s = 39
4j: 99%, 0% ee
s = n.d.
Scheme 2 Oxidative kinetic resolution of tricyclic 1-tetralones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
M. Odagi et al.
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F
CF2
H
O
O
a)
b)
Me Me
Me Me
Me Me
N
steric
repulsion
N
H
N
H
O
O
Ph
O
Ph
N
O
Ph
N
CF3
steric
repulsion
steric
repulsion
N
H
HO
H
HO
O
HO
H
H
N
H
Ar
Me
H
Ph
O
HO
O
O
3
CO2t-Bu
O
3
H
Me
H
CO2t-Bu
H
CO2t-Bu
Me
Me
H
Me
Me
Ot-Bu
H
H
Me
Me
TS-cis-II
Me
TS-cis-I
TS-trans-I
TS-trans-II
Me
Me Me
Me Me
Me Me
Me Me
steric
repulsion
steric
repulsion
steric
repulsion
steric
repulsion
O
Ph
O
Ph
O
Ph
O
Ph
HO
HO
HO
O
HO
O
H
Me
Me
Me
O
O
CO2t-Bu
Me
CO2t-Bu
Me
H
Me
CO2t-Bu
CO2t-Bu
H
Me
H
H
H
Me
H
H
TS-cis-III
TS-cis-IV
TS-trans-III
TS-trans-IV
Scheme 3 Plausible transition-state models for oxidative kinetic resolution of a) rac-4i and b) rac-4j. The catalyst structure in TS-cis-II–IV and TS-trans-
I–IV are omitted to clarify.
cis-I for 4i among the four possible TS models (Scheme 3,
a), and highly efficient oxidative kinetic resolution reaction
takes place from the cis-isomer rac-4i.
On the other hand, all four possible TS models for the
trans isomer rac-4j have significant steric repulsions be-
tween CHP and the methyl group (TS-trans-I, TS-trans-III,
and TS-trans-IV) or the carbon atom at C3 (TS-trans-II,
Scheme 3, b).
Next we applied the oxidative kinetic resolution of tri-
cyclic 1-tetralone derivatives to the synthesis of optically
active 6 bearing a heterocyclic cis-fused moiety in the 1-te-
tralone. Optically active tetralone 6 would be useful for the
synthesis of (+)-8, which is a core structure of 4-(2-me-
thoxyphenyl)-2-carboxy-3-pyrrolidineacetic acid (MFPA,
9), a kainoid derivative with potent neuroexcitatory activity
(Scheme 4).16
Thus, oxidative kinetic resolution of rac-6 was exam-
ined under the optimal reaction conditions. The hydroxyl-
ation product 7 was obtained in 57% yield with 69% ee,
while unreacted 6 was recovered in 40% yield with 99% ee.
Then, the optically active 6 was subjected to Baeyer–Villiger
oxidation with m-CPBA17 to give (+)-8 in 44% yield without
loss of optical purity.
In conclusion, we have developed an oxidative kinetic
resolution of cis-fused 3,4-cyclopenta- and 3,4-cyclohexa-
1-tetralones rac-4 catalyzed by guanidine–bisurea bifunc-
tional organocatalyst 1a in the presence of cumene hydrop-
eroxide as an oxidant. The kinetic resolution proceeded ef-
ficiently with various tricyclic tetralones rac-4, and the cor-
responding hydroxylated 5 and recovered 4 were obtained
in good to high enantioselectivity, with s values of up to 42.
In addition, the kinetic resolution reaction was efficiently
applied to an asymmetric synthesis of (+)-8, the core struc-
ture of kainoid derivative MFPA (9), from rac-6.
O
O
O
1a (5 mol%)
CHP (0.75 equiv)
K2CO3 (1.0 equiv)
CO2t-Bu
CO2t-Bu
CO2t-Bu
OH
H
H
+
H
toluene (0.025 M)
0 °C, 72 h
H
H
H
N
N
N
Ts
Ts
Ts
rac-6
7
6
57%, 69% ee
40%, 99% ee
s = 27
a. TFA, toluene
b. TfOH, m-CPBA
CH2Cl2
CO2Me
CO2H
MeO
HO
c. K2CO3, MeOH
CO2H
N
N
44% (3 steps)
H
Ts
MFPA (9)
(+)-8, 99% ee
Scheme 4 Synthesis of (+)-8, the core structure of kainoid derivative MFAP (9)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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Acknowledgment
(9) Duthaler, R. O.; Ginsburg, D. Helv. Chim. Acta 1986, 69, 1559.
(10) Oh, S. H.; Tamura, K.; Sato, T. Tetrahedron 1992, 48, 9687.
(11) Ramana, M. M. V.; Potnis, P. V. Synthesis 1996, 1090.
(12) Odagi, M.; Furukori, K.; Watanabe, T.; Nagasawa, K. Chem. Eur. J.
2013, 19, 16740.
(13) Odagi, M.; Furukori, K.; Yamamoto, Y.; Sato, M.; Iida, K.;
Yamanaka, M.; Nagasawa, K. J. Am. Chem. Soc. 2015, 137, 1909.
(14) In the case of rac-4d, TS-4d-I is unfavorable compared to TS-4d-
II (Scheme 5) due to steric repulsion between the cyclopentane
moiety and methoxy group on the aromatic ring. On the other
hand, TS-4d-II also exhibits steric repulsion between CHP and
the carbon atom at C3 in rac-4d.
This work was supported in part by a Grant-in-Aid for Scientific Re-
search on Innovative Areas ‘Advanced Molecular Transformations by
Organocatalysts’ (no. 23105013) and ‘Middle Molecular Strategy’ (no.
JP16H01134), from The Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan, and a grant from the Uehara Memorial
Foundation. MO is grateful for a Grant-in-Aid for Scientific Research
for Young Scientists (B) (no. 16K17897) from the Japan Society for the
Promotion of Science (JSPS).
Supporting Information
Me Me
Me Me
Supporting information for this article is available online at
O
Ph
http://dx.doi.org/10.1055/s-0036-1588151.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
O
Ph
steric
repulsion
HO
O-
OH
H
H
O-
CO2t-Bu
References and Notes
3
CO2t-Bu
MeO
H
H
MeO
(1) Neumeyer, J. L.; Bidlack, J. M.; Zong, R.; Bakthavachalam, V.;
Gao, P.; Cohen, D. J.; Negus, S. S.; Mello, N. K. J. Med. Chem. 2000,
43, 114.
steric repulsion
low reactivity
TS-4d-II
TS-4d-I
(2) Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.; Bergquist, P. R.
J. Nat. Prod. 2000, 63, 79.
Scheme 5
(3) Singh, A. J.; Dattelbaum, J. D.; Field, J. J.; Smart, Z.; Woolly, E. F.;
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(6) Nicolaou, K. C.; Gray, D.; Tae, J. Angew. Chem. Int. Ed. 2001, 40,
3679.
(15) We have reported DFT calculation studies of the transition
states of oxidative kinetic resolution.13 Based upon the calcula-
tions, we proposed transition state models of oxidation for rac-
4i and rac-4j in Scheme 3 (TS-cis-I–IV and TS-trans-I–IV).
(16) (a) Hashimoto, K.; Horikawa, M.; Shirahama, H. Tetrahedron
Lett. 1990, 31, 7047. (b) Hashimoto, K.; Shirahama, H. Tetrahe-
dron Lett. 1991, 32, 2625.
(17) (a) Demir, A. S.; Aybey, A. Tetrahedron 2008, 64, 11256.
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(7) Uenoyama, Y.; Tsukida, M.; Doi, T.; Ryu, I.; Studer, A. Org. Lett.
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(8) Sato, T.; Tamura, K. Tetrahedron Lett. 1984, 25, 1821.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E