Construction of chiral 2-substituted octahydroindoles from cyclic ketones and nitroolefins bearing only one α-substituent

Article abstract of DOI:10.1002/adsc.201400851

A dual catalytic system has been developed following the screening of a series of chiral primary amine catalysts and chiral phosphoric acid catalysts for the Michael addition of cyclic ketones to nitroolefins bearing only one α-substituent. The resulting γ-nitro ketones, which contain a substituent on the carbon connected to the nitro group, were formed in excellent yields (>80%) with high levels of stereoselectivity (up to 94:6 dr and 98% ee) when the reaction was performed in benzene at 0 °C with 10 mol% of the optimal amine/phosphoric acid combination (1:1) as a catalyst. Subsequent reduction of the nitro group followed by intramolecular reductive amination could afford optically active cis-octahydroindole analogues bearing a non-functional substituent at their 2-position.

Full text of DOI:10.1002/adsc.201400851

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DOI: 10.1002/adsc.201400851
Construction of Chiral 2-Substituted Octahydroindoles from
Cyclic Ketones and Nitroolefins Bearing only One a-Substituent
Yong Han,+a Bo Zheng,+a and Yungui Penga,*
a
Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, Peopleꢀs Republic of China
Fax : (+86)-023-6825-3157; e-mail: pengyungui@hotmail.com or pyg@swu.edu.cn
+
These two authors contributed equally to this work.
Received: August 28, 2014; Revised: December 15, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400851.
Abstract: A dual catalytic system has been devel-
oped following the screening of a series of chiral
primary amine catalysts and chiral phosphoric acid
catalysts for the Michael addition of cyclic ketones
to nitroolefins bearing only one a-substituent. The
resulting g-nitro ketones, which contain a substituent
on the carbon connected to the nitro group, were
formed in excellent yields (>80%) with high levels
of stereoselectivity (up to 94:6 dr and 98% ee)
when the reaction was performed in benzene at
08C with 10 mol% of the optimal amine/phosphoric
acid combination (1:1) as a catalyst. Subsequent re-
duction of the nitro group followed by intramolecu-
lar reductive amination could afford optically active
cis-octahydroindole analogues bearing a non-func-
tional substituent at their 2-position.
considerable success has been achieved in the stereo-
selective construction of octahydroindole-2-carboxylic
acid and its derivatives.[2] In contrast, no general
methods currently exist for the construction of chiral
octahydroindole derivatives bearing non-functional
substituents at their 2-position.[4] Racemic 2-(3-dime-
thylcarbamoyloxyphenyl)-1-methyloctahydroindole,
which is an octahydroindole compound bearing
a non-functional substituent at its 2-position, exhibit-
ed strong inhibitory activity towards acetylcholines-
terase.[4a] It is well known that the biological activity
of these compounds is dependent on the configuration
of their stereocenters. It was envisaged that the devel-
opment of a general method for the synthesis of
chiral octahydroindoles bearing
a non-functional
group at their 2-position would provide a facile access
to a broad range of chiral analogues that could exhibit
potentially interesting biologically activities. Pansare
et al.[5] reported the stereoselective synthesis of 3-aryl-
Keywords: asymmetric Michael addition; chiral
phosphoric acids; chiral primary amines; counteran-
ion-directed catalyst; octahydroindoles
AHCTUNGTREGoNNUN ctahydroindoles from g-nitro ketones via the organo-
catalytic Michael reaction of cyclohexanone with b-
monosubstituted nitroolefins [Scheme 1, Eq. (1)]. We
were intrigued by this reaction, and wondered wheth-
er it would work with nitroolefins bearing only one a-
Octahydroindoles exist as the core structural unit in substituent. It was envisaged that the reaction of ni-
a wide range of biologically active natural products troolefins of this type with cyclohexanone would lead
and pharmaceutical agents.[1–4] For example, chiral 6- to the formation of g-nitro ketones bearing a substitu-
hydroxyoctahydroindole-2-carboxylic acid is an im- ent on the carbon directly attached to the nitro group.
portant component of aeruginosins,[1] and trans-octa- Furthermore, the reduction of the nitro group of
hydroindole-2-carboxylic acid is a key intermediate in these compounds followed by intramolecular reduc-
the synthesis of the cardiovascular drug trandolapril.[2] tive amination would therefore provide a general
Several other octahydroindole-containing compounds method for the construction of optically active octa-
have also been reported in the literature, including hydroindole analogues bearing a non-functional sub-
those isolated from plants belonging to the Amarylli- stituent at their 2-position [Scheme 1, Eq. (2)].
daceae family.[3] In light of their interesting biological Herein, we report our preliminary results towards the
activities, significant research efforts have been direct- realization of this synthetic methodology.
ed towards the development of efficient methods for
As part of our ongoing work towards the develop-
the synthesis of octahydroindoles.[2–4] Most notably, ment of new methods for the organocatalytic asym-
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lefins bearing only one a-substituent.[6a] This catalyst
was also evaluated in the current study in regard to
its ability to mediate the model reaction between 1a
and 2a. Unfortunately, however, no product was ob-
served in this reaction (Table 1, entry 1). Several
other catalysts, which have performed well in the
asymmetric Michael addition of cyclic ketones to b-
substituted nitroolefins,[7a–e] were also investigated in
this model reaction. Disappointingly, however, all of
these catalysts gave poor results, even in the presence
of a non-chiral Brønsted acid co-catalyst (Table 1, en-
tries 2–7). Although good yields and enantioselectivi-
ties were achieved when the reaction was performed
in the presence of catalysts 5a and 7a, the diastereose-
lectivities observed in these reactions were poor
Scheme 1. Alkylation reactions of cyclohexanone with a-
and b-substituted nitroolefins.
metric Michael addition of carbonyl compounds to ni- (Table 1, entries 2 and 7). Based on these poor results,
troolefins,[6] we developed catalyst 4, which allowed we turned our attention to the use of a catalytic
for the asymmetric reaction of aldehydes with nitroo- system combining a chiral primary amine[8] with an
Table 1. Optimization of the catalyst.[a]
Entry
Cat A
Cat B
Solvent
Time [days]
Yield [%][b]
dr[c]
ee [%][c]
1[d]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4
BA[e]
BA
BA
BA
BA
BA
BA
8b
8b
8b
8b
8b
8b
8b
8b
8a
8c
8d
8e
8f
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
1
3
7
7
5
5
3
0
–
–
5a
5b
5c
6a
6b
7a
7a
7a
7b
7c
7d
7e
7f
7g
7e
7e
7e
7e
7e
7e
7e
7e
7e
7e
84
31
38
42
46
67
65
83
65
83
92
88
75
88
60
67
71
86
82
27
81
42
69
80
67:33
52:48
58:42
64:35
68:32
65:35
75:25
88:12
90:10
91:9
89:11
93:7
90:10
89:11
94:6
94:6
94:6
92:8
86:14
55:45
82:18
51:49
94:6
87
72
55
75
81
83
88
91
66
92
96
96
80
98
94
97
96
92
94
96
78
87
91
38
2.5
2.5
2.5
2.5
2.5
2.5
4
2.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
3.5
2.5
8g
8h
8i
8j
PhH
PhH
PhH
PhH
ent-8b
94:6
[a]
Reactions of 1a (2 mmol, 10 equiv.) and 2a (0.2 mmol, 1 equiv.) proceeded in the given solvent at the catalyst loading of
10 mol% Cat A/Cat B (1:1) at 08C.
Isolated yield.
Determined by chiral HPLC analysis.
Reaction at room temperature.
BA =benzoic acid.
[b]
[c]
[d]
[e]
2
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Construction of Chiral 2-Substituted Octahydroindoles
Based on this result, 7e was selected as the opti-
mum chiral primary amine catalyst for the transfor-
mation and several other chiral Brønsted acids (8a,
8c–j) were selected as potential partner catalysts for
the combined binary catalyst system (Table 1, en-
tries 16–24). Good diastereoselectivities (86:14–94:6
dr) and enantioselectivities (92–97% ee) were ob-
tained when there were no substituents (i.e., 8a) or
only moderately sized substituents (i.e., 8b–f) at the
3,3’-positions of the chiral binaphthol phosphoric acid
core (Table 1, entries 16–20). Interestingly, the use of
8c as an acid co-catalyst led to a slight increase in the
enantioselectivity and diastereoselectivity compared
with 8b (i.e., 94:6 dr and 97% ee vs. 93:7 dr and 96%
ee), although the yield of 3a was only 67% yield after
3.5 days, and therefore much lower than that obtained
using 8b (88% yield after 2.5 days). The introduction
of larger substituents at the 3,3’-positions (i.e., 8g–i)
led to a decrease in the diastereo- or enantioselectivi-
ty (Table 1, entries 21–23). This tendency, however,
À
was inconsistent, in that the introduction of Si(Ph)3
groups at the 3,3’-positions (8j) led to good diastereo-
selectivity and enantioselectivity (Table 1, entry 24).
Considering both the yield and enantioselectivity of
the process, it was concluded that 8b was the most
Scheme 2. Amide-based bifunctional organocatalysts and
dual-catalyst for asymmetric reactions.
asymmetric
counteranion-directed
catalyst suitable co-catalyst acid. When the reaction was cata-
(Scheme 2), because systems of this type have been lyzed by 7e/ent-8b, only 38% ee was obtained with
shown to exhibit high levels of stereocontrol.[9] The 80% yield and 94:6 dr, this result indicated that the
combined use of 7a and 8b as catalysts in this reaction chirality of 7e and ent-8b was a mismatch (Table 1,
afforded the desired product 3a with high levels of entry 25). With the optimum combined catalytic
enantioselectivity and diastereoselectivity compared system 7e/8b in hand, we proceeded to systematically
with the combined use of 7a and BA (Table 1, en- investigate several other factors to determine their
tries 7 and 8). The stereoselectivities were further in- effect on the outcome of the reaction (see the Sup-
creased to 91% ee and 88:12 dr when the reaction porting Information), including the solvent, ratio of
was conducted in benzene compared with isopropyl 7e to 8b, catalyst loading, reaction temperature and
alcohol, and the yield also increased from 65 to 83% ratio of 1a to 2a. The results of these experiments re-
(Table 1, entries 8 and 9). Based on the results ob- vealed that the best results were achieved when the
tained using the chiral Brønsted acid[10] 8b as a co-cat- reaction of 1a and 2a (1a/2a=10:1) was conducted in
alyst, we proceeded to screen a series of chiral pri- benzene in the presence of 10 mol% of the combined
mary amines (7b–g) (Table 1, entries 10–15). When catalyst 7e/8b (1:1) at 08C.
the MeO substituent (7a) at the 6-position of the
With the optimal reaction conditions in hand, we
quinoline ring was replaced with an i-PrO group (7b), proceeded to evaluate the scope of the reaction using
the diastereoselectivity of the reaction increased other nitroolefins bearing only one a-substituent. Ni-
slightly from 88:12 to 90:10 dr, but the enantioselec- troolefins bearing a variety of different electron-do-
tivity decreased dramatically and from 91 to 66% ee nating and electron-withdrawing substituents on their
(Table 1, entries 9 and 10). The introduction of an i-Pr phenyl ring behaved as suitable substrates for the
group (7c) at the 2-position of the quinoline ring led asymmetric Michael addition with cyclohexanone.
to a slight increase in the diastereoselectivity and High enantioselectivities (94 to >99% ee) were
enantioselectivity of the reaction (Table 1, entries 9 achieved in all cases with good diastereoselectivities
and 11). Based on this result, several other substitu- (84:16–94:6 dr) and yields (67–93%) (Table 2, en-
ents, including n-Bu (7d), t-Bu (7e), Ph (7f) and Bn tries 1–8). The position of the substituent appeared to
(7g), were selectively installed at the 2-position of the have a significant influence on the yield (73–85%)
quinoline, and the resulting materials were screened and diastereoselectivity (88:12–94:6 dr) of the trans-
as catalyst for the reaction of 1 with 2 (Table 1, en- formation, although the effect of the substituent on
tries 12–15). The use of 7e as a catalyst gave the best the enantioselectivity was only minor (94 to >99%
results when it was used in combination with 8b ee) (Table 2, entries 4–6). Furanyl- and 2-naphthyl-
(Table 1, entry 13).
substituted nitroolefins also gave good results (74%
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Table 2. Scope of the dual-catalyst system for the conjugate addition of ketones to a-nitroolefins.[a]
Entry
R1
R2
Product
Yield [%][b]
dr[c]
ee [%][c]
1
2
3
4
5
6
7
8
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
88
70
93
73
85
80
67
86
74
79
45
94
73
47
42
70
95
82
75
93:7
87:13
92:8
92:8
88:12
94:6
87:13
84:16
93:7
92:8
91:9
72:7:16:5
67:6:25:2
65:35
>99:1
81:19
92:8
94
>99
95
96
98
98
98
99
>99
>99
98
>99
36.5
84 (74)
>99
97
2-CH3C6H4
4-CH3OC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
2-FC6H4
2-furanyl
2-naphthyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9
CH2
CH2
10
11
12
13
14[d]
15[d]
16
17
18[d]
19[d]
CMe2
CHMe
CHEt
(CH2)0
(CH2)2
NCOOEt
NBoc
O
>99
81 (55)
96 (44)
70:30
73:27
S
3s
[a]
Reactions of 1 (2 mmol, 10 equiv.) and 2 (0.2 mmol, 1 equiv.) proceeded in benzene at the catalyst loading of 10 mol%
7e/8b (1:1) at 08C.
Isolated yield.
Determined by chiral HPLC analysis.
20 mol% 7e/8b was used.
[b]
[c]
[d]
and 79% yields, 93:7 dr and 92:8 dr, >99% ee) transformation and achieved moderate diastereoselec-
(Table 2, entries 9 and 10). The optimized conditions tivities (70:30 dr and 73:27 dr), good yields (82% and
were also applied to several substituted cyclohexa- 75%) and enantioselectivities (81% ee and 96% ee)
nones. 4,4-Dimethylcyclohexanone gave good stereo- (Table 2, entries 18 and 19).
selectivities (91:9 dr and 98% ee), but a low yield of
The relative configuration of the major diastereo-
45% (Table 2, entry 11). 4-Monosubstituted cyclohex- mer of 3g was confirmed by X-ray analysis
anones reacted smoothly to obtain the additions prod- (Figure 1).[11] To account for the observed outcome,
ucts in good yields (73 and 94%), with moderate dia- a transition state model is proposed as shown in
stereoselectivities (72:7:16:5 and 67:6:25:2 dr) and ex- Scheme 3. The enamine, the activated form of cyclo-
cellent enantioselectivities (36.5% and >99% ee) for hexanone by interaction with primary amine, under-
the major products (Table 2, entries 12 and 13). Cy- went nucleophilic attack from its Si face with the ni-
clopentanone and cycloheptanone afforded moderate toolefin, which was simultaneously activated via hy-
yields (47% and 42%) even at the catalyst loading of drogen bond between the ammonium and nitro
20 mol% 7e/8b, cyclopentanone led to moderate dia- groups. Then, enantioselective protonation of the re-
stereoselectivity (65:35 dr) and good enantioselectivi- sulting carbanion from the Re face gave the product.
ty (84% ee), while cycloheptanone resulted in excel-
To realize our designed purpose and demonstrate
lent stereoselectivities (>99:1 dr and >99% ee) the potential use of the resulting Michael addition
(Table 2, entries 14 and 15). N-Protected piperidin-4- products in organic synthesis, we treated 3g with Zn
ones also reacted smoothly to give good yields (70 in a mixture of THF/H2O to give intermediate 9,
and 95%) and diastereoselectivities (81:19 and 92:8 which was reduced with NaCNBH3 in EtOH to afford
dr) with high enantioselectivities (97 and >99% ee) diastereoisomers cis-10a and trans-10b in a 7.6:1 ratio.
(Table 2, entries 16 and 17). Tetrahydropyran-4-one Subsequent treatment of the major isomer 10a with
and tetrahydrothiopyran-4-one are amenable to this indium (In) in a mixture of EtOH/H2O gave the cis-
4
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Construction of Chiral 2-Substituted Octahydroindoles
Scheme 4. Synthesis of chiral 2-substituted octahydro-1H-
indole 12.
chael addition of a series of cyclic ketones to nitroole-
fins bearing only one a-substituent. The resulting Mi-
chael addition products could be transformed into
chiral octahydroindoles bearing a non-functional sub-
stituent at their 2-position. Thus, an effective and un-
precedented protocol has been successfully developed
for the construction of octahydroindoles, which could
possess potentially interesting biological activities.
Figure 1. X-ray crystallographic structures of enantiopure 3g
and 12.
Experimental Section
General Procedure
Catalyst 7e (0.02 mmol, 10 mol%) and 8b (0.02 mmol,
10 mol%) were dissolved in anhydrous benzene (1.0 mL),
and the resulting mixture was treated with a cyclic ketones
(2 mmol, 10 equiv.) at 258C under an atmosphere of argon.
After being stirred for 5 min, the reaction mixture was
cooled to 08C and treated with a-nitroolefin (0.2 mmol,
1 equiv.). The reaction mixture was then warmed to ambient
temperature and purified directly by flash chromatography
over silica gel eluting with a 20:1 (v/v) mixture of petroleum
ether/ethyl acetate to give the corresponding product 3. For
further details of the synthesis and characterization, see the
Supporting Information.
Scheme 3. Proposed transition-state model
octahydroindole 11 bearing a 2-(O-bromobenzyl) sub-
stituent. Protection of the amine group of 11 with
TsCl afforded 12 (Scheme 4), which gave a single
crystal suitable for X-ray analysis (Figure 1).
In conclusion, we have developed a binary catalytic
system involving the combination of a quinine-based
chiral primary amine with a 3,3’-diphenyl BINOL-de-
Acknowledgements
We are grateful to the National Science Foundation of China
(21172180) and Specialized Research Fund for the Doctoral
rived phosphoric acid to realize the asymmetric Mi- Program of Higher Education (20110182110006).
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Construction of Chiral 2-Substituted Octahydroindoles
Chem. Rev. 2007, 107, 5713–5743; d) T. Akiyama,
Chem. Rev. 2007, 107, 5744–5758; e) T. Akiyama, J.
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[11] CCDC 885434 (3g) and CCDC 1038178 (12) contain
the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The
Cambridge
Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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8 Construction of Chiral 2-Substituted Octahydroindoles from
Cyclic Ketones and Nitroolefins Bearing only One a-
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Adv. Synth. Catal. 2015, 357, 1 – 8
Yong Han, Bo Zheng, Yungui Peng*
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