Asymmetric organocatalytic michael/henry domino reactions through hydrogen-bond activation: Kinetic access to indane scaffolds bearing cis-vicinal substituents

Article abstract of DOI:10.1002/chem.201302131

Catalyst directs towards cis! A bifunctional hydrogen-bond-catalyzed Michael/Henry domino reaction allows preferential asymmetric access to the kinetic cis-nitroindanol products with excellent enantioselectivity through a postulated matched transition state (see scheme; H-Bo = hydrogen bond activation). This high yielding protocol opens up a new strategy to access highly useful enantio-enriched cis-aminoindanol-containing ligands and catalysts.

Full text of DOI:10.1002/chem.201302131

DOI: 10.1002/chem.201302131
Asymmetric Organocatalytic Michael/Henry Domino Reactions through
Hydrogen-Bond Activation: Kinetic Access to Indane Scaffolds Bearing cis-
Vicinal Substituents
Charles C. J. Loh, Iuliana Atodiresei, and Dieter Enders*[a]
Dedicated to Professor Wolfgang Steglich on the occasion of his 80th birthday
The indane scaffold containing cis-vicinal substituents is
an important chiral motif, which has found significant appli-
cations in both bioactive compounds as well as a versatile
building block in catalysts for asymmetric synthesis.[1] The
first widespread usage of such a building block was first
demonstrated by Merck researchers in the development of
the HIV protease inhibitor Crixivan (1), which still remains
one of the leading drugs for AIDS treatment.[2] In addition,
many different chiral catalysts incorporate similar cis-indane
backbones to reach high asymmetric inductions. This in-
cludes transition-metal catalysts bearing bis(oxazoline) li-
gands such as 2,[3] and asymmetric organocatalysts such as
the Rovis N-heterocyclic carbene precatalyst 3,[4] Ricciꢀs
While the widespread importance of enantio-enriched cis-
vicinal indane motifs is undisputed, it is interesting to note
that the efficient enantioselective access of such structures is
relatively limited. The most commonly utilized method is to
employ the asymmetric Mn–(salen)-catalyzed Jacobsen ep-
oxidation on indenes (84–88% ee), followed by epoxide
opening to provide the trans-aminoindanols. The trans sub-
strates are then converted to the enantiopure cis-aminoinda-
nols after a benzamide crystallization under acidic or Ritter
conditions.[8] Alternatively, lengthy enzyme catalysis or the
resolution of racemic mixtures are required in order to
access this building block.[9] In view of the upsurge of orga-
nocatalytic domino reactions in recent years,[10] we postulat-
ed that it might be possible to diastereo- and enantioselec-
tively access novel cis-vicinal substituted indanes directly
chiral thiourea 4,[5] as well as Seidelꢀs thioamide
5
(Figure 1).[6] Furthermore, oxazaborolidines such as 6 are
also an important class of reducing agents for enantioselec-
tive reduction reactions.[7]
through
a metal free organocatalytic domino reaction
(Scheme 1).
Scheme 1. Retrosynthetic analysis of the organocatalytic cis-nitro indanol
domino synthesis.
Figure 1. Examples of drugs, ligands and catalysts bearing a chiral indane
scaffold with cis-vicinal substituents.
The synthetic challenge of a direct diastereoselective
access to cis-substituted indanes lies in the thermodynamic
unfavorable conformation of two vicinal cis substituents.
This was very recently demonstrated by Sun et al. in a race-
mic organo-base catalyzed aza-Michael/aldol domino reac-
tion,[11a] and Csꢁkꢂ et al. in a LDA mediated Michael/Mi-
chael domino reaction to yield the thermodynamically fa-
vored racemic all trans indane framework.[11b] In order to
impede thermodynamics to yield the kinetic vicinal cis-vici-
nal product 8, we reasoned that an effective syn binding
[a] C. C. J. Loh, Dr. I. Atodiresei, Prof. Dr. D. Enders
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Fax : (+49)241-809-2127
E-mail: enders@rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302131.
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COMMUNICATION
Table 1. Optimization of the reaction conditions.[a,b]
mode by a bi-functional hydrogen-bonding catalyst on both
the nucleophile and electrophile in the matched transition
state 9 is essential (Scheme 1).[11c,d] Moreover, we also pre-
dicted retrosynthetically (Scheme 1) that a simple functional
group interconversion from an amino group in 7 to a nitro
group in 8 would help to access the cis-aminoindanol prod-
uct 7, which can be incorporated as a chiral backbone for
various purposes.
The other challenge posed in this domino reaction is the
presence of two acceptor groups, a nitroolefin and an alde-
hyde in substrate 10, which might result in competing side
reactions.[12] Hence, it is crucial to select a nucleophile (ab-
breviated as Nu, Scheme 1) that selectively attacks the nitro-
olefin and precludes the aldehyde in the first nucleophilic
step. While common carbonyl nucleophiles such as alde-
hyde-derived enolates poses chemoselectivity problems due
to a competing aldol reaction, we decided to utilize the Frie-
del–Crafts type Michael addition of indoles to regioselec-
tively trigger this cascade reaction.[6,13] To the best of our un-
derstanding, the currently reported literature examples to
access indanols via domino reactions can only be performed
resulting in racemic mixtures.[11]
Therefore, we would like to report a kinetically controlled
asymmetric organocatalytic Michael addition/intramolecular
Henry domino reaction, which allows a facile access to
enantio-enriched cis-nitroindanol products 12a–m (see
Table 2) that can be easily converted to their useful cis-ami-
noindanol derivatives, such as 7.[14]
We first conducted a series of experiments to determine
the optimal hydrogen-bonding catalyst for the domino reac-
tion (Table 1). We realized that of all catalysts screened,
only hydrogen-bonding catalysts 4, 5 and 13 containing the
cis-aminoindanol moiety gave the desired kinetic cis-cascade
product 12a (Table 1, entries 1, 2, 5). The best result was ob-
tained using Seidelꢀs thioamide catalyst 5 (entry 5) produc-
ing almost quantitative yield (98%),[6a] a very good ee
(87%) and very good d.r (9:1). It is noteworthy to point out
that bifunctional catalysts containing basic moieties, such as
the catalyst 14 and squareamide 15, did not yield the desired
product 12a due to product decomposition and a complex
mixture was obtained.
With the best catalyst obtained, we proceeded to screen
various solvents for the domino reaction (Table 1, entries 5–
10). The best solvent tested was CHCl3 (entry 5). Finally, we
lowered the temperature to 08C (entry 11) and adjusted the
catalyst loading, where the optimal condition was obtained
at 10 mol% loading of catalyst 5 (Table 1, entry 13) yielding
excellent ee (93%) and d.r (10:1) and almost quantitative
yield (96%).
Subsequently, we proceeded to determine the scope of
this useful organocatalytic domino reaction (Table 2).
The cascade reaction turned out to be generally very ver-
satile and a wide spectrum of indoles 11a–j ranging from
electron-withdrawing group to electron donating group con-
taining indoles were found to be extremely well tolerated in
this methodology. Moreover, various derivatives of o-benzal-
dehyde nitroolefins containing electron-withdrawing (Cl,
Entry Cat.
t
x
Solvent
T
Yield
d.r[d] ee
[%][e]
[h] [mol%]
[8C] [%][c]
1
2
3
4
5
6
4
24 20
136 10
16 20
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
1,2-diCl ben- 23
zene
1,3-diCl ben- 23
zene
2,4-diCl ben- 23
zene
1,2,4-triCl
toluene
toluene
CHCl3
23
23
23
23
23
99
34
–
–
98
57
9:1 68
9:1 34
13
14
15
5
–
–
–
–
7
10
14 15
15 15
9:1 87
8:1 72
5
7
8
9
5
5
5
15 15
16 15
16 15
85
85
83
6:1 85
4:1 86
6:1 82
23
10
5
5
5
5
15 15
21 15
15
23
0
0
80
99
99
96
5:1 81
5:1 95
9:1 90
10:1 93
11
12[f]
13[f]
5
CHCl3
CHCl3
17 10
0
[a] Reactions were conducted on a 0.2 mmol scale of o-benzaldehyde ni-
troolefin 10a (1 equiv) and indole 11a (1.2 equiv). [b] The relative and
absolute configuration of 12a was determined by X-ray crystallography.
[c] Yield of isolated 12a after flash column chromatography. [d] Deter-
1
mined by H NMR. [e] Determined by HPLC analysis on a chiral station-
ary phase. [f] These reactions were conducted on a 0.5 mmol scale of o-
benzaldehyde nitroolefin 10a.
10c) to electron-donating (OMe, 10b) substituents were
also tolerated to give predominantly the cis kinetic products
12a–m.
In addition, the majority of the yields in the substrate
scope were excellent (>90%) with two examples (12e and
12m) achieving almost quantitative yields in the domino re-
action, hence substantiating the effectiveness and the effi-
ciency of this methodology. All examples tested also pro-
duced excellent enantioselectivity with a very high selectivi-
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D. Enders et al.
Table 2. Scope of the kinetically-controlled Michael/Henry domino reac-
tion.[a,b]
diastereomer and hence a diastereomeric reversal giving a
6:1 d.r in favor of the thermodynamic all trans product 1-
epi-12a without any further epimerization at C2 and C3.
The relative configuration of the minor diastereomer 1-epi-
12a is determined by both 1,3-cis NOESY contacts and
comparing the a and b hydroxyl effects on the 13C NMR
shifts (see Supporting Information).[16,17]
12
R1
R2
t [h]
d.r.[c]
ee [%][d]
Yield [%][e]
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
H
H
H
H
Cl
MeO
MeO
17
16
43.5
72
17.5
17
10:1
9:1
7:1
93 (88)
91 (90)
92 (92)
90 (81)
90 (91)
97 (95)
91 (87)
91 (89)
90 (89)
95 (93)
91 (99)
94 (89)
93 (86)
96
94
61
64
>99
95
91
98
90
74
90
94
>99
5-MeO
5-Cl
5-Br
5-Me
7-Me
5-F
6-Me
6-Cl
–
9:1
10:1
11:1
9:1
11:1
11:1
9:1
17:1
11:1
11:1
73
18
Scheme 2. Thermodynamic base-catalyzed cis/trans epimerization.
63.5
18
16.5
19.5
18
j
k
l
7-Me
H
5-Me
We propose that the domino reaction undergoes a first
chemoselective and enantioselective hydrogen-bonding cata-
lyzed Friedel–Crafts type Michael addition through transi-
tion state 13 (Scheme 3). After the installation of the first
stereocenter, the bifunctional catalyst 5 then forms hydrogen
bonds to both the nitro and the aldehyde moiety through a
cis matched transition state 14, in preparation for the Henry
cyclization step. A final Henry reaction yields the desired
cis kinetic product 12a, which can be epimerized to the
trans thermodyamic product 1-epi-12a by TMG.
m
[a] Reactions were conducted on a 0.5 mmol scale of o-benzaldehyde ni-
troolefin 10a–c (1 equiv) and indole 11a–j (1.2 equiv). [b] Relative and
absolute configuration of the major diastereomer was determined by
analogy to the X-ray crystal structure of derivative 12a. [c] Determined
by 1H NMR. [d] Determined by HPLC analysis on a chiral stationary
phase, values in parentheses indicate the ee of the minor diastereomer 1-
epi-12a–m. [e] Yields isolated after flash column chromatography.
Figure 2. X-ray crystal structure of the major diastereomer 12a.
ty for the desired cis nitro-indanol diastereomer. The abso-
lute and relative configuration of the major diastereomer
was unambiguously determined by X-ray crystallography of
derivative 12a (Figure 2).[15]
Scheme 3. Proposed mechanism for the domino Michael/Henry reaction.
To better understand the reaction mechanism, we then
proceeded to determine the relative configuration of the
minor diastereomer. To achieve this, the major diastereomer
12a was subjected to a tetramethylguanidine (TMG) cata-
lyzed retro-Henry/Henry epimerization reaction (Scheme 2).
Interestingly, we observed that the epimerization proceeded
quantitatively and resulted in an enrichment of the minor
To demonstrate that the derivatized kinetic cascade prod-
uct is of synthetic value as a chiral building block, 12a was
first enantio-enriched via a single recrystallization in CH2Cl2
to yield 12a in excellent diastereo- and enantiomeric purity
(99% ee, >20:1 d.r). 12a was then further reduced to its
corresponding cis-aminoindanol, and subsequently attached
to form a quinolinyl thioamide precatalyst 16 (Scheme 4).
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Asymmetric Organocatalytic Michael/Henry Domino Reactions
COMMUNICATION
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In conclusion, we demonstrated that hydrogen-bonding
catalysis can be utilized effectively in an asymmetric organo-
catalytic domino reaction to afford predominantly the cis-ni-
troindanol product by bifunctional kinetic control. The
direct asymmetric domino access of the synthetically useful
cis kinetic product was challenging since all known cases re-
ported gave racemic mixtures, most probably due to chemo-
selectivity or problems in effecting good kinetic control. In
addition, we demonstrated the possibility of attaching the
chiral cascade scaffold on a catalyst precursor 16 and this
opens up further avenues in utilizing this protocol to access
chiral catalysts, ligands or for biological purposes. Further
investigations on the utility of the cascade product as a
building block in various chiral catalysts and ligands are cur-
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Experimental Section
A solution of 10a (0.5 mmol, 1 equiv) in CHCl3 (3 mL) was added to a
solution of catalyst 5 (0.05 mmol, 0.1 equiv) and 200 mg activated pow-
dered 3 ꢄ MS in CHCl3 (3 mL). This reaction mixture was cooled to
08C. The indole 11a (0.60 mmol, 1.2 equiv) was then transferred into the
cooled reaction mixture. The reaction was monitored by TLC until com-
pletion of the domino reaction to form 12a, which was directly loaded on
a flash column for purification.
Keywords: asymmetric synthesis · domino reaction · indole ·
Michael addition · organocatalysis
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[15] CCDC-933132 contains 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.
[16] Only 1,3-cis NOESY relationships are useful in determining relative
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[17] For 1-epi-12a, the absolute configuration of the stereocenter formed
in the first Michael addition step is assigned in analogy to the crystal
structure of 12a.
Received: June 4, 2013
Published online: July 2, 2013
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