Formal (4+1) Cycloaddition and Enantioselective Michael–Henry Cascade Reactions To Synthesize Spiro[4,5]decanes and Spirooxindole Polycycles

Article abstract of DOI:10.1002/anie.201701049

Spiro[4,5]decanes and polycyclic compounds bearing spiro[4,5]decane systems are important biofunctional molecules. Described are diastereoselective formal (4+1) cycloaddition reactions to afford oxindole-functionalized spiro[4,5]decanes and organocatalyti

Full text of DOI:10.1002/anie.201701049

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201701049
German Edition: DOI: 10.1002/ange.201701049
Spiro Compounds
Formal (4+1) Cycloaddition and Enantioselective Michael–Henry
Cascade Reactions To Synthesize Spiro[4,5]decanes and Spirooxindole
Polycycles
+
+
Ji-Rong Huang , Muhammad Sohail , Tohru Taniguchi, Kenji Monde, and Fujie Tanaka*
Abstract: Spiro[4,5]decanes and polycyclic compounds bear-
ing spiro[4,5]decane systems are important biofunctional
molecules. Described are diastereoselective formal (4 + 1)
cycloaddition reactions to afford oxindole-functionalized
spiro[4,5]decanes and organocatalytic enantioselective
Michael–Henry cascade reactions of the (4 + 1) cycloaddition
products to generate spirooxindole polycyclic derivatives
bearing the spiro[4,5]decane system. Spiro[4,5]decanes bear-
ing oxindoles containing three stereogenic centers and spi-
rooxindole polycycles having seven stereogenic centers, includ-
ing two all-carbon chiral quaternary centers and one tetrasub-
stituted chiral carbon center, were obtained with high diastereo-
and enantioselectivities.
Figure 1. Spiro[4,5]decanes and polycyclic compounds bearing spiro-
[4,5]decanes found in bioactive natural products.
S
piro[4,5]decanes and polycyclic compounds bearing spiro-
[
4,5]decane systems are found in bioactive natural products
[
1–4]
(
Figure 1).
Functionalized molecules with these cyclic
systems should be useful in drug discovery efforts. All-
carbon spiro five-membered ring systems, either isolated or in
the context of polycyclic systems, were previously synthesized
using, for example, cyclization reactions of linear carbon
[
2]
[3]
chains, Claisen rearrangement reactions, and [3+2] cyclo-
[
4]
addition reactions.
Synthesis of functionalized spiro-
Scheme 1. Strategies described in this work for the synthesis of spiro-
[4,5]decanes and polycyclic compounds bearing the spiro[4,5]decane
system by formal (4+1) cycloaddition and enantioselective Michael–
Henry cascade reactions.
[
[
4,5]decanes and polycyclic derivatives containing spiro-
4,5]decane ring systems has not been explored, except in
the synthesis of natural products and closely related mole-
cules.
[
2–4]
Because the oxindole moiety is present in many
biofunctional molecules, we sought to combine the spiro-
[
4,5]decane and its polycyclic ring systems with oxindole
2) subsequent Michael–Henry cascade transformations with
nitroalkenes to afford highly functionalized polycarbocyclic
[
5,6]
[8]
functionalities.
Herein, we report the development of
strategies to access highly functionalized spiro[4,5]decanes
and polycyclic compounds bearing the spiro[4,5]decane
systems with oxindole functionalities (Scheme 1). We report
compounds, bearing both the spiro[4,5]decane system and the
spirooxindole system, with high diastereo- and enantioselec-
tivities.
[
7]
1
) a new formal (4+1) cycloaddition system involving
In our formal (4+1) cycloaddition reactions, the enone
derivatives 1 were used as the C4 reactants. The enone
derivatives were synthesized by aldol reactions of enones with
reactions of enone derivatives with cyclic 1,3-diketones to
construct spiro[4,5]decanes bearing oxindole moieties, and
[9]
isatin derivatives. We hypothesized that 1 would act as
a formal double Michael acceptor when appropriate reaction
conditions were used (Scheme 1).
[
+]
[+]
[
*] Dr. J.-R. Huang, Dr. M. Sohail, Prof. Dr. F. Tanaka
Chemistry and Chemical Bioengineering Unit
Okinawa Institute of Science and Technology Graduate University
First, we searched for catalysts and reaction conditions for
the reaction of 1a with cyclohexane-1,3-dione (2a) to afford
spiro[4,5]decane derivative 3a or its diastereomers (such as
1919-1 Tancha, Onna, Okinawa 904-0495 (Japan)
E-mail: ftanaka@oist.jp
Dr. T. Taniguchi, Prof. Dr. K. Monde
4
a) in high yield with high diastereoselectivity (Table 1; see
also the Supporting Information). We found that the reaction
using CF SO H as catalyst at 608C efficiently gave 3a in high
Frontier Research Center for Advanced Material and Life Science
Faculty of Advanced Life Science, Hokkaido University
Kita 21 Nishi 11, Sapporo 001-0021 (Japan)
3
3
+
[
yield with high diastereoselectivity within 3 hours (97% and
] These authors contributed equally to this work.
9
3
8%, d.r. 16:1; Table 1, entries 9 and 12). In the formation of
a from 1a, an intermediate would likely be dienone 5a
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
http://dx.doi.org/10.1002/anie.201701049.
(Scheme 2). However, when 5a was used as the C4 reactant
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Table 1: Screening of catalysts and conditions in the formal (4+1)
cycloaddition reaction of 1a with 2a to give 3a/4a.
Table 2: Scope of the formal (4+1) cycloaddition: Variations of the
substitution at the oxindole amide nitrogen atom.
[
a]
[a]
[
b]
[c]
Entry
R
1
t [h] Product Yield [%]
d.r.
Entry
Catalyst
equiv to 1a)
T
[8C]
Solvent
t
[h]
Yield
[%]
d.r.
3a/4a
[
b]
[c]
(
1
2
3
4
5
6
7
8
9
1-naphthylmethyl
2-naphthylmethyl
1b
1c
1d
1e
1f
4
4
3b
3c
3d
3e
3f
82
95
80
83
63
75
75
44
75
56
12:1
12:1
17:1
18:1
14:1
6:1
1
2
3
4
5
6
7
8
9
p-TsOH (0.3)
45
45
45
45
25
60
80
60
60
60
60
60
DCE
DCE
DCE
DCE
DCE
DCE
DCE
TCE
TCE
TCE
TCE
TCE
40
67
68
7
68
3
88
20
49
74
76
87
87
89
97
89
96
4.6:1
2.0:1
2.6:1
9.0:1
8.3:1
9.0:1
7.2:1
14:1
16:1
7.7:1
10:1
16:1
CH3
3
4
3
C F CO H (0.3)
6
5
2
CH CH(CH )
3 2
CH CH=CH
Ph
acetyl
Boc in 1i; H in 3i 1i
H
CH Ph
C H PO H (0.3)
2
6
5
3
CF SO H (0.3)
2
2
3
3
1g
1h
3
24
5
3g
3h
3i
CF SO H (0.3)
3
3
5:1
CF SO H (0.3)
3
3
2.8:1
2.6:1
14:1
CF SO H (0.3)
3
3
2
3
3
3
3
3
1j
1k
3
3i
CF SO H (0.3)
3
3
[
d]
[d]
1
0
3
3a
CF SO H (0.45)
2
3
3
[
d]
e]
f]
1
1
1
0
CF SO H (0.45)
3
3
[a] Reaction conditions: 1 (0.20 mmol, 1.0 equiv), 2a (3.0 equiv), and
CF SO H (0.45 equiv) in TCE (1.0 mL). [b] Combined yield of the
diastereomers. [c] Determined by H NMR analysis before purification.
d] The OH group of 1 was Boc protected.
[
1
CF SO H (0.45)
3
3
3
3
[
[g]
2
CF SO H (0.45)
98
1
3
3
[
[a] Reaction conditions: 1a (0.05 mmol, 1.0 equiv) and 2a (3.0 equiv) in
the presence of catalyst in solvent (0.25 mL). [b] Combined yield of 3a
1
and 4a, determined by H NMR analysis using an internal standard
1
nitrogen atom was deprotected under the reaction conditions
Table 2, entry 8). The Boc protection at the hydroxy group of
did not affect the formation of 3 (Table 2, entry 10). The
(
CH Br or TCE). [c] Determined by H NMR analysis before purification.
2
2
(
1
[d] 2a (0.10 mmol). [e] Solvent (0.125 mL). [f] Solvent (0.5 mL). [g] Yield
of isolated product. DCE=1,2-dichloroethene, TCE=1,1,2,2-tetra-
chloroethane.
reaction of 1 without a substituent at the nitrogen atom also
gave product 3 (Table 2, entry 9). For the enone substitutions,
both alkyl-substituted and aryl-substituted enones 1 worked
to afford 3 (Table 3). The method was also applied to the
reactions with substituted cyclohexane-1,3-dione and with
cyclopentane-1,3-dione (3t and 3u, respectively).
With the method for the synthesis of racemic 3 in hand,
the construction of polycyclic systems from 3 was studied. For
this aim, catalysts and reaction conditions were screened for
the transformation of racemic 3a with nitrostyrene to afford
the spirooxindole polycyclic product 6a (Table 4). When 3a
was treated with bases (e.g., DABCO or DBU), isomerization
of 3a into its diastereomer 4a occurred and little 6a was
observed (Table 4, entries 1 and 2). When either quinine or
quinidine was used as the catalyst under appropriate reaction
conditions, the reaction of racemic 3a with nitrostyrene
resulted in the formation of the enantiomerically enriched
polycyclic product 6a (Table 4, entries 3, 4, 6–8). The
formation of the diastereomers of 6a was not detected
under either the quinine or quinidine catalysis conditions,
although 6a has seven stereogenic centers. Of these seven
stereogenic centers, two are all-carbon quaternary centers
and one is tetrasubstituted carbon center. Formation of
enantiomerically enriched forms of 6a from racemic 3a using
either quinine or quinidine as the catalyst occurred through
a kinetic resolution mechanism. The best conditions for the
synthesis of 6a in high enantioselectivity from racemic 3a
among those tested were the use of quinine as the catalyst
with 4 ꢀ molecular sieves (Table 4, entry 8). The enantiopur-
ity of 6a decreased as the yield of 6a increased and as the
reaction time was prolonged (see below and the Supporting
Information). Isolation of 6a from the reaction mixture within
5 to 10 hours or up to 30% yield of 6a resulted in obtaining 6a
Scheme 2. Reaction of 5a and 2a in CHCl CHCl (TCE) at 608C under
the same reaction conditions as those used in Table 1, entry 12, except
that 5a was used instead of 1a.
2
2
under the same reaction conditions used for the reaction of 1a
with 2a (conditions from Table 1, entry 12), a long reaction
time (72 h) was required to form 3a/4a in high yield, and the
diastereoselectivity was low (Scheme 2). Reaction of 5a with
2
a under basic conditions did not give either 3a or 4a in good
yields under our tested conditions. Thus, to generate 3a in
high yield with high diastereoselectivity, the use of 1a as the
C4 reactant with the CF SO H catalysis was the best among
3
3
the reaction conditions tested (Table 1, entry 12). The product
a has three stereogenic carbon centers and thus it is possible
to form four diastereomers, however, only two diastereomers,
3
[
10]
3
a and 4a, were obtained.
Next, the scope of the formal (4+1) cycloaddition reaction
to synthesize spiro[4,5]decane derivatives 3 was examined
using the optimum CF SO H catalysis conditions identified in
3
3
the synthesis of 3a. Various spiro[4,5]decane derivatives 3
were obtained as shown in Tables 2 and 3.
In the N substitutions of 1, substituents including alkyl,
allyl, aryl, acetyl, and Boc substitutions were accepted to give
products 3 (Table 2, entries 1–8). The Boc group at the
2
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Table 3: Scope of the formal (4+1) cycloaddition: Products obtained
from various 1 and cyclic 1,3-diketone derivatives under the CF SO H
catalysis.
Table 4: Screening of catalysts and conditions in the Michael–Henry
cascade reaction of (Æ)-3a with nitrostyrene to afford 6a.
[
a]
3
3
[
a]
[
b]
Entry
Catalyst
equiv to 3a)
Solvent
CH Cl
t [h]
6a/3a/4a
e.r.
6a
[
c]
(
1
2
3
4
5
DABCO (0.1)
DBU (0.1)
72
72
96
96
96
24
24
10
4:22:74
12:52:36
39:47:14
59:11:30
50:16:34
18:73:9
4:94:2
–
–
2
2
2
CH Cl
2
quinine (0.2)
quinidine (0.2)
quinidine (0.2)
quinine (0.2)
quinine (0.05)
quinine (0.05)
toluene
toluene
CH Cl
83:17
23:77
48:52
85:15
88:12
96:4
2
2
[
[
[
d]
6
7
8
toluene
toluene
benzene
d]
d,e]
31:69:<1
[
(
a] Reactions conditions: (Æ)-3a (0.022 mmol, 1.0 equiv), nitrostyrene
3.0 equiv), and catalyst in solvent (1.0 mL) at room temperature (258C).
1
[
[
b] Determined by H NMR analysis. [c] Determined by HPLC analysis.
d] 4 ꢀ molecular sieves (50 mg) were added. [e] Nitrostyrene
(0.20 mmol, 9.0 equiv) and solvent (0.25 mL) were used.
demonstrated that enantioselective synthesis of 3a was
possible in the reactions of 1a and of 5a with 2a in the
presence of homochiral catalysts, although further develop-
ment is required (see the Supporting Information).
Further, the highly enantiomerically enriched form of 3a
obtained by kinetic resolution was transformed into the
highly enantiomerically enriched form of 6a in high yield
[
(
a] Reaction conditions: 1 (0.20 mmol, 1.0 equiv), 1,3-diketone derivative
3.0 equiv), and CF SO H (0.45 equiv) in TCE (1.0 mL) at 608C. The d.r.
3
3
1
values were determined by H NMR analyses before purification.
b] Ratio of yields of the isolated products.
[
(Scheme 3). This 6a was the opposite enantiomer to the one
with high enantioselectivity (because of the kinetic resolution,
the maximum yield is 50%).
obtained by the quinine catalysis from racemic 3a (Scheme 3
versus Table 5).
Using the quinine catalysis conditions with 4 ꢀ molecular
sieves, various polycyclic compounds 6 were obtained from
racemic 3 as single diastereomers in highly enantiomerically
enriched forms (Table 5). With crystallization, the enantio-
purities of 6 were further improved (> 99% ee).
In summary, we have developed formal (4+1) cyclo-
addition reactions to synthesize the spiro[4,5]decane deriva-
tives bearing oxindole moieties, and have also developed
diastereo- and enantioselective Michael–Henry cascade reac-
tions of the (4+1) cycloaddition products to afford spiroox-
indole polycyclic derivatives bearing the spiro[4,5]decane
system with seven stereogenic centers. The Michael–Henry
cascade reaction step occurred with kinetic resolution.
Through the kinetic resolution, the spiro[4,5]decanes bearing
The relative stereochemistry of 6a was determined by
[
11]
X-ray crystal structural analysis of the racemic crystals. The
absolute configuration of 6 f obtained by the quinine catalysis
was determined by VCD analysis (see the Supporting
Information) to be as shown in Table 5. The absolute
configuration of the major enantiomer of 6j obtained by the
quinine catalysis was also determined by X-ray crystal
[11]
structural analysis to be as shown in Table 5.
By tuning the reaction time, highly enantiomerically
enriched forms of 3 were also obtained (i.e., unreacted
enantiomers of 3 were recovered; Table 6). The absolute
stereochemistries of 3a that reacted with nitrostyrene under
the quinine catalysis and of the remaining enantiomer of 3a
were deduced from the configuration of 6a and 6 f. We also
Scheme 3. Transformation of an enantiomer of 3a into 6a.
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Table 5: Scope of the formation of the spirooxindole polycycles 6.
Products obtained from (Æ)-3 with nitrostyrenes under the quinine
Table 6: Kinetic resolution of (Æ)-3 to afford 3 with high enantiopurity
through the reaction that forms 6 under the quinine catalysis.
[
a]
[
a]
catalysis.
[
(
a] Reaction conditions: (Æ)-3 (0.023 mmol, 1.0 equiv), nitrostyrene
9.0 equiv), quinine (0.05 equiv), and 4 ꢀ molecular sieves (40 mg) in
benzene (0.25 mL) at room temperature (258C).
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric catalysis · cycloaddition ·
Michael addition · organocatalysis · spiro compounds
[
(
a] Reaction conditions: (Æ)-3 (0.045 mmol, 1.0 equiv), nitrostyrene
[
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supported by the Okinawa Institute of Science and Technol-
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Angewandte
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Chem. 2007, 119, 5010; b) S. Varga, G. Jakab, L. Drahos, T.
Manuscript received: January 30, 2017
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Spiro Compounds
J.-R. Huang, M. Sohail, T. Taniguchi,
K. Monde, F. Tanaka*
&&&& — &&&&
Formal (4+1) Cycloaddition and
Enantioselective Michael–Henry Cascade
Reactions To Synthesize
Spiro[4,5]decanes and Spirooxindole
Polycycles
Spiro strategies: Strategies to construct
oxindole-functionalized spiro[4,5]decanes
and polycyclic derivatives were devel-
oped. Through formal (4+1) cycloaddi-
tion and catalytic asymmetric Michael–
Henry cascade reactions, products con-
taining seven chiral centers, including
two all-carbon quaternary centers and
one tetrasubstituted carbon center, were
obtained with high diastereo- and enan-
tioselectivities in two steps.
6
www.angewandte.org
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!