Catalyst-controlled switch in chemo- and diastereoselectivities: Annulations of morita-baylis-hillman carbonates from isatins

Article abstract of DOI:10.1002/anie.201510825

Regulating both the chemo- and diastereoselectivity, divergently, of a reaction is highly attractive but extremely challenging. Presented herein is a catalyst-controlled switch in the chemo- and diastereodivergent annulation reactions of Morita-Baylis-Hillman carbonates, derived from isatins and 2-alkylidene-1H-indene-1,3(2H)-diones, in exclusive α-regioselectivity. α-Isocupreine efficiently catalyzed [2+1] reactions to access cyclopropane derivatives, and the diastereodivergent [3+2] annulations were accomplished by employing either a chiral phosphine or a DMAP-type molecule. All reactions exhibited excellent chemoselectivities, and good to remarkable stereoselectivities were furnished, thus leading to a collection of compounds with skeletal and stereogenic diversity. Moreover, DFT computational calculations elucidated the catalyst-based switch in mechanism.

Full text of DOI:10.1002/anie.201510825

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201510825
German Edition: DOI: 10.1002/ange.201510825
Organocatalysis
Catalyst-Controlled Switch in Chemo- and Diastereoselectivities:
Annulations of Morita–Baylis–Hillman Carbonates from Isatins
Gu Zhan, Ming-Lin Shi, Qing He, Wei-Jia Lin, Qin Ouyang,* Wei Du, and Ying-Chun Chen*
Abstract: Regulating both the chemo- and diastereoselectivity,
divergently, of a reaction is highly attractive but extremely
challenging. Presented herein is a catalyst-controlled switch in
the chemo- and diastereodivergent annulation reactions of
Morita–Baylis–Hillman carbonates, derived from isatins and
Morita–Baylis–Hillman (MBH) adducts and their deriv-
atives are valuable building blocks in organic synthesis owing
[
5]
to their dense functionalities. In this respect, Lu and co-
workers first established interesting annulation pathways
between MBH derivatives and various electrophiles, thus
relying on the in situ formation of either zwitterionic allylic P
2
-alkylidene-1H-indene-1,3(2H)-diones, in exclusive a-regio-
[
6]
selectivity. a-Isocupreine efficiently catalyzed [2+1] reactions
to access cyclopropane derivatives, and the diastereodivergent
or N ylides. While MBH derivatives have widely served as
1,3-dipole synthons in asymmetric [3+2] reactions and other
types of annulation reactions, almost all examples exhibited
remote g-regioselectivity. In addition, there are few reports on
the realization of a switch in chemoselectivity from the same
[
3+2] annulations were accomplished by employing either
a chiral phosphine or a DMAP-type molecule. All reactions
exhibited excellent chemoselectivities, and good to remarkable
stereoselectivities were furnished, thus leading to a collection of
compounds with skeletal and stereogenic diversity. Moreover,
DFT computational calculations elucidated the catalyst-based
switch in mechanism.
[7]
set of substrates in this field. Moreover, a diastereodivergent
annulation reaction with MBH adducts has not yet been
accomplished. To address such deficiencies, herein we present
annulation reactions of MBH carbonates, derived from isatins
and 2-alkylidene-1H-indene-1,3(2H)-diones, with exclusive
a-regioselectivity, wherein a switch in the chemo- and
diastereoselectivities can be attained by employing different
chiral Lewis base catalysts.
T
he design and synthesis of structurally and stereochemically
diverse compound collections is important for the discovery
of probes and drug candidates, because the biological proper-
ties are intrinsically correlated to molecular structure. There-
fore, synthetic chemists have paid a great deal of attention to
the development of asymmetric reactions to construct libra-
The initial reaction of the MBH carbonate 1a and 2-
[
8]
benzylidene-1H-indene-1,3(2H)-dione (2a) proceeded effi-
ciently at room temperature in the presence of DABCO
(10 mol%; Table 1, entry 1). An unusual [2+1] cyclopropane
[1]
ries of chiral compounds having high molecular diversity.
[
9]
On one hand, a number of examples have been presented to
access structurally varied products in a chemo- or regiodiver-
gent manner by employing different chiral catalysts or by
product (3a) was cleanly obtained after 5 hours. The
reaction exhibited exclusive diastereoselectivity, and the
expected [3+2] annulation product was not observed. Ph P
3
[
2]
tuning the catalytic conditions. On the other hand, an array
of elegant strategies to diversify the diastereochemical out-
showed lower catalytic activity, but it delivered the a-
regioselective [3+2] product 4a in a moderate yield with
[3]
[8]
comes have also been reported. An extremely challenging
but ideal aspect of asymmetric catalysis is the ability to
construct libraries of molecules, with both skeletal and
stereogenic divergence, from identical starting materials
under readily tunable catalytic conditions. As Trost pointed
out: engineering a catalyst that completely overrides inherent
regio- or chemoselectivity to give exclusively the desired
high diastereoselectivity, along with a few unidentified
minor by-products (entry 2). Better catalysis was observed
with Ph PMe, but results similar to those obtained with Ph P
2
3
were obtained (entry 3). Interestingly, DMAP furnished the
[3+2] product 5a, thus demonstrating a switch in diastereo-
selectivity, in a good yield, and a minor unconjugated product
(6a) was isolated with a moderate diastereoselectivity
(entry 4). The yield of 6a could be improved by simply
extending the reaction time (entry 5), and almost complete
conversion of 5a into 6a was observed by running the reaction
at 508C for 24 hours (entry 6). In contrast, the DMAP-
catalyzed reaction proceeded smoothly at 08C, and 5a was
produced in a high yield within 5 hours (entry 7).
[
4]
product requires creativity and insight. The concurrently
achieving stereodivergence would further increase the diffi-
culty.
[
*] G. Zhan, M.-L. Shi, Q. He, W.-J. Lin, Dr. W. Du, Prof. Dr. Y.-C. Chen
Key Laboratory of Drug Targeting and Drug Delivery System of the
Ministry of Education, West China School of Pharmacy, and State Key
Laboratory of Biotherapy, West China Hospital, Sichuan University
Chengdu, 610041 (China)
Consequently, we investigated potential asymmetric ver-
sions under the catalysis of various chiral Lewis base catalysts.
[10]
At first, a-isocupreine (C1 or a-IC; 10 mol%) was highly
E-mail: ycchen@scu.edu.cn
efficient for the reaction of 1a and 2a in toluene at ambient
temperature, thus giving the desired [2+1] product 3a in an
excellent yield with high enantiomeric purity (Table 2,
entry 1). The reaction proceeded well with 5 mol% of C1,
though a longer reaction time was required (entry 2).
Subsequently, different types of substrates were explored
Dr. Q. Ouyang, Prof. Dr. Y.-C. Chen
College of Pharmacy, Third Military Medical University
Chongqing, 400038 (China)
E-mail: ouyangq@tmmu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510825.
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[
a]
[a]
Table 1: Screening studies for annulation of 1a and 2a.
Table 2: Substrate scope and limitations of [2+1] annulations.
1
[b]
[c]
[
b]
[c]
Entry
1
R
R
t [h]
Yield [%]
ee [%]
Entry
1
Cat
T [8C]
t [h]
Yield [%]
d.r. [%]
[
d]
H
H
5-Cl
5-Br
7-F
Ph
Ph
Ph
Ph
Ph
Ph
Ph
9 (9) 3a, 96 (95) >99 (>À99)
DABCO
Ph3P
RT
50
RT
RT
RT
50
0
5
8
8
12
24
24
5
3a, 82
4a, 65
4a, 68
>19:1
>19:1
>19:1
[e]
[d]
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
22
9
9
10
12
9
3a, 95
3b, 95
3c, 94
3d, 94
3e, 88
3 f, 97
3g, 98
3h, 95
99
99
98
97
98
98
>99
97
2
3
4
5
6
7
[d]
Ph PMe
2
DMAP
DMAP
DMAP
DMAP
5a, 70; 6a, 21
5a, 45; 6a, 42
5a, <5; 6a, 85
5a, 93; 6a, <5
>19:1; 4.8:1
>19:1; 4.8:1
–; 4.5:1
5-NO2
5-Me
>19:1; –
5-MeO Ph
5,7-Me2 Ph
9
9
[
1
a] Unless otherwise noted, reactions were performed with 0.11 mmol of
a, 0.1 mmol of 2a, 10 mol% of catalyst in 1.0 mL of toluene. [b] Yield of
isolated product. [c] Determined by H NMR analysis. [d] With 20 mol%
of catalyst. Boc=tert-butoxycarbonyl, DABCO=1,4-diaza-bicyclo-
2.2.2]octane, DMAP=4-dimethylaminopyridine.
1
1
1
1
1
1
1
1
1
1
2
H
H
H
H
H
H
H
H
H
H
H
2-ClC H
4-ClC H
3-BrC H
4-MeC H
9 (9) 3i, 92 (90) >99 (>À99)
6
4
4
1
9
9
9
12
11
12
12
12
3j, 97
3k, 97
3l, 96
3m, 93
3n, 89
3o, 91
3p, 92
3q, 90
3r, 87
3s, 82
94
99
97
6
6
4
[
6
4
4-MeOC H
96
6
4
1-naphthyl
2-naphthyl
2-furyl
2-thienyl
N-Me-2-indolyl 12
>99
>99
99
>99
>99
>99
under the catalysis of C1. As summarized in Table 2, the scope
was substantial, and high yields and stereoselectivities were
generally obtained for substrates having various substitutions
[
f]
(
entries 3–21). Nevertheless, the acceptors (2) with branched
[f]
2-styryl
12
alkyl groups failed to give the cyclopropane products,
probably because of the crowded structures. In contrast,
optically pure 3a and 3i, having the opposite configuration,
[
f]
2
1
H
12
3t, 83
98
[a] Unless noted otherwise, reactions were performed with MBH
carbonate (1; 0.11 mmol), acceptor (2; 0.1 mmol), the catalyst C1
10 mol%) in toluene (1.0 mL) at RT. Data within parentheses were
obtained with the catalyst C2. [b] Yield of isolated product. [c] Deter-
mined by HPLC analysis using a chiral stationary phase; d.r.>19:1
determined by H NMR analysis. [d] The absolute configuration of 3a
was determined by X-ray analysis. The other products were assigned by
analogy. [e] With 5 mol% of C1. [f] At 508C.
[
10]
were obtained by using b-isocupreidine
(C2 or b-ICD;
(
entries 1 and 10; data within parentheses, respectively).
We next screened an array of chiral phosphines and
reaction parameters to promote the asymmetric [3+2]
1
[
12]
annulations.
The bifunctional catalyst C3, developed by
[11]
[
13]
the group of Lu, was optimal at a 10 mol% loading in 4-tert-
butyltoluene. The desired [3+2] product 4a was obtained
after 24 hours at ambient temperature in an excellent yield
and with a high ee value (Table 3, entry 1). As summarized, an
array of MBH carbonates, derived from isatins and 2-
alkylidene-1H-indene-1,3(2H)-diones, having a variety of
aryl substitutions were well tolerated, thus giving the corre-
sponding products in excellent yields and with good to high
enantioselectivities (entries 2–13). At higher temperature,
even alkyl-substituted electrophiles could be smoothly uti-
lized (entries 14 and 15).
using either C4 or C5 (entries 2–14). Excellent results were
generally obtained, thus demonstrating the wide compatibil-
ity of both catalysts. C5 was superior to C4 in most cases, and
was further verified for two acceptors having either an N-Me-
2-indolyl or alkenyl group (entries 15 and 16).
As outlined in Scheme 1, the activated alkenes 7 and 9,
derived from cyclohexane-1,3-dione and Meldrumꢀs acid,
respectively, also exhibited high reactivity with 1a in the
presence of C5, thus producing the corresponding bis(spiro-
cycle)s 8 and 10 in high yields and with excellent stereose-
lectivities. In addition, after the asymmetric [3+2] annula-
tion of 1a and 2c in DCE at 08C, C5 successfully promoted
deconjugation to give 6j by simply heating in THF at 508C.
The product 6j was obtained in high yield, as well as enantio-
and diastereoselectivity, thus further demonstrating the
power of the current catalytic system to construct molecules
with structural and stereochemical diversity.
Interestingly, the bicyclic chiral phosphine C4, developed
[14]
by the group of Kwon, exhibited different diastereoselec-
tivity compared with other chiral phosphines. The [3+2]
product 5a was obtained in a high yield and with remarkable
stereoselectivity at 108C by using 1,2-dichloroethane (DCE)
and running the reaction for 36 hours (Table 4, entry 1).
Importantly, a newly designed and more stable chiral DMAP-
[16]
[12,15]
type compound,
C5, showed better catalytic activity, even
at 08C, thus affording the same chiral product with out-
standing results after 24 hours (entry 1, data within paren-
theses). Therefore, we explored a number of substrates by
To rationalize the catalyst-controlled switch in annula-
tions, density-functional theory (DFT) calculations were
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Table 3: Substrate scope and limitations of [3+2] annulations to access
Table 4: Substrate scope and limitations of [3+2] annulations to access
5.
[
a]
[a]
4.
1
[b]
[c]
Entry
R
R
t [h]
Yield [%]
ee [%]
1
[b]
[c]
1
2
3
4
5
6
7
8
9
H
Ph
Ph
Ph
Ph
Ph
Ph
2-ClC H
4-ClC H
3-BrC H
6 4
4-MeC H
6 4
24
28
28
28
24
24
20
20
24
24
10
30
25
12
12
4a, 93
4b, 92
4c, 92
4d, 90
4 f, 95
4g, 93
4i, 91
4j, 96
4k, 95
4l, 92
4m, 80
4n, 86
4o, 89
4u, 83
4v, 80
87
85
86
85
85
86
89
87
79
88
94
92
81
85
82
Entry
R
R
t [h]
Yield [%]
ee [%]
5-Cl
5-Br
7-F
5-Me
5-MeO
H
H
H
H
H
1
2
3
4
5
6
7
8
9
H
Ph
Ph
Ph
Ph
Ph
Ph
36 (24) 5a, 95 (98)
48 (28) 5b, 92 (95)
48 (28) 5c, 90 (93)
48 (28) 5d, 89 (96)
99 (99)
96 (>99)
96 (>99)
96 (>99)
94
97 (93)
97 (95)
97 (96)
89 (96)
97 (>99)
5-Cl
5-Br
7-F
5-NO2
5-Me
[d]
48
5e, 94
6
4
32 (24) 5 f, 95 (97)
32 (24) 5g, 94 (95)
28 (24) 5j, 90 (94)
32 (24) 5k, 89 (92)
32 (24) 5l, 92 (98)
6
4
5-MeO Ph
H
H
H
H
H
H
H
H
4-ClC H
6 4
3-BrC H
4
4-MeC H
6 4
4-MeOC H
2-naphthyl
2-furyl
2-thienyl
1
1
1
1
1
1
0
[
e]
6
1
2
3
4-MeOC H
6
4
1
1
1
1
1
0
1
2
3
4
H
H
H
H
1-naphthyl
2-naphthyl
cPentyl
36 (28) 5m, 93 (96) 97 (>99)
6
4
36 (28) 5o, 88 (94)
36 5p, 89
36 (24) 5q, 83 (93)
94 (91)
[
e]
4
[d]
90
[
e]
5
cHexyl
89 (>99)
– (74)
[
a] Unless noted otherwise, reactions were performed with MBH
carbonate (1; 0.11 mmol) and acceptor (2; 0.1 mmol), the catalyst C3
10 mol%) in toluene (1.0 mL) at RT. [b] Yield of isolated product.
c] Determined by HPLC analysis using a chiral stationary phase;
d.r.>19:1 determined by H NMR analysis. [d] The absolute configu-
ration of 4g was determined by X-ray analysis. The other products were
assigned by analogy. [e] At 508C. TBDPS=tert-butyldiphenylsilyl.
15
N-Me-2-indolyl 24 (36) 5r, – (93)
1
6
H
24 (36) 5t, – (95)
– (70)
(
[
[a] Unless noted otherwise, reactions were performed with MBH
carbonate (1; 0.11 mmol), acceptor (2; 0.1 mmol), the catalyst C4
(10 mol%) in DCE (1.0 mL) at 108C. Data within parentheses were
obtained with the catalyst C5 at 08C. [b] Yield of isolated product.
1
[
11]
[
c] Determined by HPLC analysis using a chiral stationary phase;
1
d.r.>19:1 by H NMR analysis. [d] The absolute configuration of 5p was
determined by X-ray analysis. The other products were assigned by
[11]
analogy. DCE=1,2-dichloroethane, Ts =4-toluenesulfonyl.
(Figure 1). In the reaction catalyzed by DABCO, the newly
formed carbanion could attack the a-position through an SN2
process via TS2-A to produce 3a. In contrast, a sequential
Michael addition could occur via TS2-B, thus generating 4a.
À1
The energy barrier of TS2-B is 19.7 kcalmol higher than
that of TS2-A, thus indicating that the [3+2] process is
unfavorable. The calculation is consistent with the exper-
imental results in entry 1 of Table 1. Since the reaction
catalyzed by DMAP also involved an N-ylide intermediate,
the annulation selectivity was compared. Interestingly, the
À1
energy of TS2-C, which could lead to 5a, is 4.2 kcalmol
lower than that of TS2-D which leads to 3a, thus suggesting
that the [3+2] pathway was favorable for the DMAP-
catalyzed annulation reaction. Moreover, as shown in TS2-
Scheme 1. Additional substrates to explore products having structural
diversity.
1
2
3
4
B, the distances between H and H , and H and H are 1.91 Š
1
and 1.98 Š, respectively, whereas the distance between C and
1
performed. The geometries of the intermediates and tran-
sition states (TSs) were optimized using the B3LYP functional
together with the standard 6-31G(d) basis set, and the
energies were calculated at the 6-31 ++ G(d,p) level of
N is 1.65 Š, which is much longer than that of normal CÀN
bond (1.53 Š in TS2-C). Therefore, the steric hindrance from
DABCO in the [3+2] pathway is the main contribution to the
[17]
switch in selectivity to the [2+1] reaction. In contrast, we
[
12]
theory (toluene as solvent). We focused on the ring-closure
step after the initial Michael addition of the ylide intermedi-
ate of 1a to 2a, a step which determines the final product
also studied the switch in diastereoselectivity observed with
DMAP and PPh . As illustrated, TS2-E is the more feasible
3
À1
TS leading to 4a, and its energy is 9.2 kcalmol higher than
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Keywords: annulations · density-functional calculations ·
diastereoselectivity · heterocycles · organocatalysis
How to cite: Angew. Chem. Int. Ed. 2016, 55, 2147–2151
Angew. Chem. 2016, 128, 2187–2191
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3
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À1
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[
[
In conclusion, we have investigated the asymmetric
annulation reactions of Morita–Baylis–Hillman carbonates,
derived from isatins and 2-alkylidene-1H-indene-1,3(2H)-
diones, catalyzed by various chiral Lewis bases, thus leading
to a switch in chemo- and diastereoselectivity. While [2+1]
reactions catalyzed by chiral tertiary amines, derived from
cinchona alkaloids, produced densely substituted cyclopro-
panes, diastereodivergent [3+2] annulations to generate
bis(spirocycl)ic oxindoles were successfully realized by
employing either a chiral phosphine or a DMAP-type
catalyst. All reactions exhibited exclusive a-regioselectivity
and excellent chemoselectivity, and good to outstanding
stereoselectivity, thus furnishing a collection of complex
compounds having structural and stereogenic diversity. More-
over, DFT calculations elucidated the catalyst-based switch in
the annulation mechanism, and should thus be helpful for
developing other asymmetric annulation reactions with MBH
derivatives. Additional results will be reported in due course.
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6g) contain the supplementary crystallographic data for this
(
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
[
[
12] For more details, see the Supporting Information.
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We are grateful for financial support from the NSFC
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21125206, 21572135, and 21321061).
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2150
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 2147 –2151

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Communications
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[
16] An activated alkene from Meldrumꢀs acid also gave the [2+1]
product when catalyst C1 was used, but the reaction failed with
C3. See the Supporting Information.
17] The nucleophilic and Lewis-basic difference between DABCO
and DMAP might also affect the annulation patterns. See: M.
Received: November 23, 2015
Revised: December 8, 2015
Published online: January 6, 2016
Angew. Chem. Int. Ed. 2016, 55, 2147 –2151
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2151