Three-component organocascade kinetic resolution of racemic nitroallylic acetates via sequential iminium/enamine asymmetric catalysis

Article abstract of DOI:10.1021/ol300783e

Nitroallylic acetates 1a-f have been kinetically resolved via an asymmetric three-component coupling that involves indoles, acrolein, and nitroolefin allylic acetates and is mediated by the chiral catalyst 2 (5 mol %). The reactions proceed via iminium/enamine cascade catalysis. Both recovered starting substrates and reaction products are typically obtained in high chemical yield and in good to excellent enantiopurity (79-95% ee for 1a-f and 83-99% ee for 3a-n). For the first time, a highly efficient three-component, organocascade kinetic resolution has been demonstrated.

Full text of DOI:10.1021/ol300783e

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2496–2499
Three-Component Organocascade Kinetic
Resolution of Racemic Nitroallylic
Acetates via Sequential Iminium/Enamine
Asymmetric Catalysis
Suparna Roy and Kwunmin Chen*
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 116, ROC
kchen@ntnu.edu.tw
Received March 27, 2012
ABSTRACT
Nitroallylic acetates 1aꢀf have been kinetically resolved via an asymmetric three-component coupling that involves indoles, acrolein, and
nitroolefin allylic acetates and is mediated by the chiral catalyst 2 (5 mol %). The reactions proceed via iminium/enamine cascade catalysis.
Both recovered starting substrates and reaction products are typically obtained in high chemical yield and in good to excellent enantiopurity
(79ꢀ95% ee for 1aꢀf and 83ꢀ99% ee for 3aꢀn). For the first time, a highly efficient three-component, organocascade kinetic resolution has been
demonstrated.
Kinetic resolution (KR) is now an established technique
for the preparation of optically pure enantiomers from
racemic mixtures.1 Apart from traditional enzyme-mediated
kinetic resolution, numerous metal-catalyzed processes
have also been devised for this purpose,2 and in recent
years, there has been substantial interest in the devel-
opment of organocatalytic asymmetric methods3 for
performing kinetic resolution, but so far success has
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J. Org. Chem. 2001, 2999. (b) Keith, J. M.; Larrow, J. F.; Jacobsen, E. N.
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4703.
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Biomol. Chem. 2010, 8, 2627. (c) Yu, J.; Chen, W.-J.; Gong, L.-Z. Org.
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ꢀ
r
10.1021/ol300783e
Published on Web 05/04/2012
2012 American Chemical Society

been attained in a few isolated cases,4 with numerous
challenges and synthetic opportunities still remaining.
Despite organocatalytic multicomponent cascade reac-
tions5 having been explored extensively in the litera-
ture, there exist only a handful of examples of this type
of process ever being used in KR.4e
Scheme 1. Three-Component Organocascade Kinetic Resolu-
tion
Recently, our research group reported a useful new
organocatalytic kinetic resolution of racemic nitroallylic
acetates that takes advantage of a novel conjugate addi-
tion-elimination SN20 process.6 Indole derivatives consti-
tute a ubiquitous class of biologically active substance, and
many such ring systems are found in important natural
products and pharmaceuticals.7 As such, there is substan-
tial synthetic interest in the preparation of these sub-
stances, most especially indoles that possess chiral side
chains or annulated chiral ring systems with side chains.8
The FriedelꢀCrafts alkylation of indole with R,β-unsatu-
rated carbonyls has been extensively explored for the
construction of “privileged” indole frameworks.9 We
now present an efficient strategy for the three-component
organocascade kinetic resolution involving indole, acro-
lein, and racemic nitroallylic acetates.
The reaction proceeds through a sequential Friedelꢀ
Crafts-type/conjugate addition-elimination (SN20) reac-
tion initiated by a chiral iminium/enamine catalytic path-
way. The resulting densely functionalized 3-alkylated
indole derivatives are typically obtained in enantiomeri-
cally enriched form in good to excellent ee (83ꢀ99%),
while the less reactive nitroallylic acetate enantiomers are
also often recovered with high optical purity (79ꢀ95% ee).
In this study we have once more chosen indole and
acrolein as reaction partners for a series of reactions medi-
ated by the diphenylprolinol trimethylsilyl ether5b,e,g,h,k,l,10
(2, 5 mol %), but on this occasion, we have also incorpo-
rated a third possible coupling component, namely, a
racemic ethyl 2-acetoxy-3-nitro-4-arylbut-3(E)-enoate.11
Itwas reasonedthattheinsitugenerated3-indoylaldehyde
would be a suitable intermediate for the kinetic resolution
of a nitroallylic acetate via enamine catalysis (Scheme 1).
Our first attempt at performing this reaction using
indole (0.3 mmol), acrolein (0.4 mmol), and the nitroallylic
acetate 1a (0.2 mmol) in toluene at ambient temperature
failed (Table 1, entry 1). However, a lowering of the
reaction temperature did prove beneficial and led to good
results. Indeed, when we carried out the aforementioned
reaction in CH2Cl2 at 0 °C, the highly 3-substituted indole
derivative 3a was isolated with excellent enantiomeric
enrichment (98%) (Table 1, entry 2). The unreacted ni-
troallylic acetate was also recovered in reasonably good
enantiomeric excess (81%) at 60% conversion. With this
encouraging result in hand, we directed our attention
toward optimizing the reaction conditions to maximize
enantioselectivity for both product and unreacted sub-
strate. As a result of solvent screening we quickly estab-
lished that toluene was the best solvent for effecting this
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Org. Lett., Vol. 14, No. 10, 2012
2497

Table 1. Optimization of Three-Component Organocascade
Kinetic Resolutiona
Table 2. Substrate Scopes of the Organocascade Kinetic
Resolutiona
time
(h)
conv
(%)b
3a yield
(%)b
3a ee
(%)c,d 1a ee (%)c
entry solvent
1e toluene
time
(h)
conv
(%)b
yield
yield
ee (%)d
3(%)c
1 (%)c
3/1
2
3
4
5
6
7
8
9
CH2Cl2
THF
7
60
13
51
46
58
<5
24
61
63
57
61
62
69
54
41
10
34
23
49
98
81
entry
R1
1
36
1
H
1a
1b
1c
1d
1e
1b
1d
1f
6.5
5.5
6.5
6
58
60
61
55
65
66
64
68
63
66
61
59
65
53
62
3a/47
3b/45
3c/30
3d/35
3e/38
3f/35
3g/43
3h/29
3i/35
3j/37
3k/34
3l/40
1a/36
1b/36
1c/31
1d/39
1e/31
1b/30
1d/30
1f/24
1a/30
1e/30
1b/36
1a/36
98/91
96/91
98/82
98/84
95/88
87/85
86/95
99/89
99/90
83/87
90/81
97/86
90/86
97/79
93/88f
CH3CO2Et 13
98
98
98
77
49
91
2
H
hexanes
toluene
EtOH
6
3
H
6.5
4
H
24
5
H
6.5
4
CH3CN
CHCl3
48
7
13
38
35
41
42
44
40
35
6
Br
Br
Br
Cl
Cl
Cl
Me
Me
98
99
98
98
98
98
98
83
91
91
86
91
92
77
7
6.5
5
10 Et2O
9
8
11f toluene
12g toluene
13h toluene
14i toluene
15j toluene
6
9
1a
1e
1b
1a
1e
6
6.5
10
11
12
13
14
15e
6
7
6
4.5
6
12
6
3m/32 1e/30
a Unless otherwise mentioned, all reactions were carried out with
indole (0.3 mmol), acrolein (0.4 mmol), and nitroallylic acetate 1a
(0.2 mmol) in the presence of organocatalysts 2 (5 mol %) in indicated
solvent (0.2 mL) at 0 °C. b Conversion and yield of 3a were determined by
1H NMR analysis of the crude reaction mixture using CH2Br2 as an
internal standard. c Ee was determined by chiral HPLC analysis.
d Dr (>99:1) of 3a was determined by 1H NMR analysis of crude
reaction mixture. e Reaction was performed at 25 °C. f PhCO2H (10
mol %). g 2-FPhCO2H (10 mol %). h AcOH (15 mol %) was used as
additive. i Catalyst 2 (10 mol %) was used with 0.5 M reaction concen-
tration. j Catalyst 2 (2.5 mol %) was used.
OMe 1a
1a
6.5
6.5
3n/33
3a/36
1a/44
1a/31
H
a All reactions were carried out with indole (0.3 mmol), acrolein
(0.4 mmol), and nitroallylic acetate 1a (0.2 mmol) in the presence of
orgaocatalysts 2 (5 mol %) in toluene (0.2 mL) at 0 °C. b Conversion was
determined by 1H NMR analysis of crude reaction mixture using
CH2Br2 as an internal standard. c Isolated yield. d Ee was determined
by chiral HPLC analysis. Diastereomeric ratios (>99:1) of products
3aꢀn were determined by 1H NMR analysis of crude reaction mixture.
e Reaction was performed with (R)-2 as a catalyst. f Opposite isomers.
reaction, both with respect to enantioselectivity and yield
of product (Table 1, entry 6). We also screened different
acid additives with a view to further improving our process
but found that their presence was not especially advanta-
geous; enantioselectivities remained the same or, in some
case, actually diminished (Table 1, entries 11ꢀ13). Finally,
we examined high and low catalyst loadings for our organo-
cascade reaction and noticed that the use of 5 mol % 2 was
optimal (Table 1, entries 14 and 15).
With finely tuned reaction conditions delineated, we
next tried to demonstrate the generality of our new multi-
component KR process (Table 2). Nitroallylic acetates
with different substitution patterns on the aryl group fell
well within the remit of our process. 5-Substituted indoles
also performed admirably. Extensive study further re-
vealed that the reaction was slightly faster for the 4-bromo
substituted nitroallylic acetate 1b, and that this substrate
also offered very good to moderate optically enriched
products and unreacted substrate with different indoles
(Table 2, entries 2, 6, and 11). Unsubstituted indoles also
consistently afforded products with high enantioselectivity
compared with their substituted analogues (Table 2, en-
tries 1ꢀ5), while 5-bromo- and 5-chloroindoles afforded
products with excellent enantioselectivity (99%) when
combined with 1f and 1a, respectively (Table 2, entries 8
and 9). The 4-methyl substituted nitroallylic acetate (1d)
only afforded the unreacted substrate with very high
enantioselectivity(95%), whenpairedwith5-bromoindole
(Table 2, entry 7). Indoles with electron-releasing groups
generally impart high enantioselectivities to the products
but also result in moderate enantioselectivities for the
unreacted acetates (Table 2, entries 12ꢀ14). We have also
carried out this KR process with (R)-diphenylprolinol
trimethylsilyl ether (ent-2), under the optimized reaction
conditions, and obtained product and unreacted acetate of
comparable enantioselectivity and opposite configuration
to those obtained with the (S)-catalyst (Table 2, entries
1 and 15).
2498
Org. Lett., Vol. 14, No. 10, 2012

enantiomeric purity (up to 95%) for the unreacted sub-
strates. The absolute configuration of the product 3h was
determined as (4S,5R) by single crystal X-ray data ana-
lysis,12 while the unreacted substrates (R)-1aꢀf had their
configurations determined by comparison with our pre-
vious report.6b
Scheme 2. Synthesis of Tetrahydrocyclopenta[b]indole Deriva-
tive 5
In conclusion, an interesting multicomponent organo-
cascade kinetic resolution using indole, acrolein, and
racemic nitroallylic acetates has been demonstrated. Low
catalyst loading (5 mol %) of the organocatalystwas found
to be enough for smooth progression of the KR process in
a short time frame (4ꢀ7 h). The enantio-enriched, 3-alky-
lated indoles were obtained with high-to-excellent stereo-
selectivity, while the less reactive starting substrates could
also be recovered with high optical purity. The reaction
proceeds via a FriedelꢀCrafts/SN20 additionꢀelimination
process following sequential iminium/enamine catalysis.
This is the first example of a three-component coupling
reaction being used to carry out an asymmetric kinetic
resolution, and it has provided new insights and conceptual
paradigms for novel organocascade kinetic resolution.
Further studies are underway.
We further examined the reproducibility of our KR
process on gram scale and found that it performs similarly
with regard to chemical yields and enantioselectivity
(Scheme 2). The utility of the product 3awas demonstrated
by an intramolecular electrophilic cyclization reaction,
using the quinine-based thiourea catalyst 4, to obtain
tetrahydrocyclopenta[b]indole derivative 5 with excellent
enantiocontrol (>99% ee).
It is worth mentioning that the KR process of various
nitroallylic acetates 1aꢀf via our three-component reac-
tion with indoles and acrolein has provided good to
excellent (up to >99%) enantioselectivity for various
products, alongside superb chemical yields and very high
Acknowledgment. We thank the National Science
Council of the Republic of China (NSC 99-2113-M-003-
002-MY3 and NSC 99-2119-M-003-001-MY2) and Na-
tional Taiwan Normal University (99-D and 100-D-06) for
financial support of this work. Our gratitude extends to the
Academic Paper Editing Clinic at NTNU.
Supporting Information Available. Experimental pro-
cedures, characterization data for new compounds, and
X-ray crystallographic data in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
(12) The trans geometry of the double bond in 3a was well-under-
stood by the 1H NMR analysis showing single proton signal as doublet
at δ 6.96 with J = 2.0 Hz, due to the allylic coupling, see ref 6. Detailed
X-ray crystallographic data for compound 3h (CCDC 869206) is avail-
able from the CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K.
(www.ccdc.cam.ac. uk/data_request/cif).
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
2499