Organocatalytic asymmetric formal [3+2] cycloaddition reaction of isocyanoesters to nitroolefins leading to highly optically active dihydropyrroles

Article abstract of DOI:10.1002/anie.200800003

(Chemical Equation Presented) Closing the circle: The asymmetric [3+2] formal cycloaddition reaction of α-substituted isocyanoesters with nitroolefins is catalyzed by cinchona alkaloid derivatives to yield 2,3-dihydropyrroles with high diastereo- and enan

Full text of DOI:10.1002/anie.200800003

Communications
DOI: 10.1002/anie.200800003
Cycloaddition
Organocatalytic Asymmetric Formal [3+2] Cycloaddition Reaction of
Isocyanoesters to Nitroolefins Leading to Highly Optically Active
Dihydropyrroles**
Chang Guo, Meng-Xia Xue, Ming-Kui Zhu, and Liu-Zhu Gong*
Heterocyclic compounds containing a chiral pyrrolidine motif
commonly appear in natural alkaloids and pharmaceutically
active substances, and serve as building blocks commonly
used for total syntheses; therefore there has been great
demand for highly efficient asymmetric synthetic methods to
access these compounds.[1,2] Optically active 2,3-dihydropyr-
roles are important unsaturated heterocyclic compounds that
can not only be transformed into multisubstituted pyrroli-
dines for the synthesis of chiral building blocks, but can also
be applied to the total synthesis of natural products.[3] The
synthetic approaches to access enantioenriched pyrrolidines
include chiral-auxiliary-assisted asymmetric synthesis and a
number of transition-metal-catalyzed asymmetric dipolar
addition reactions.[2] However, organocatalytic approaches
to access chiral pyrrolidines are scarce[4] despite the growth in
asymmetric organocatalysis in modern organic synthesis.[5]
Moreover, the asymmetric catalytic synthesis of chiral 2,3-
dihydropyrroles remains elusive and the discovery of catalytic
asymmetric reactions that yield optically active 2,3-dihydro-
pyrroles is an important challenge. Over 30 years ago, cyclo-
addition reactions of metalated isocyanides to a,b-unsatu-
rated carbonyl and nitrile compounds were reported to
generate racemic 2,3-dihydropyrroles.[6] An enantioselective
version of this transformation may provide a method for
direct access to chiral dihydropyrroles and would therefore be
valuable in the synthesis of chiral building blocks and related
alkaloids.[2] In contrast to the long history of nonasymmetric
variants,[6] enantioselective, catalytic cycloaddition reactions
of isocyanoesters with electron-deficient olefins are not yet
available. Herein, we report the first catalytic asymmetric
cycloaddition reaction of isocyanoesters[7] to nitroolefins by
using alkaloid-derived bases to form highly functionalized
2,3-dihydropyrroles with excellent enantioselectivities (up to
> 99% ee).
Our mechanistic proposal for the formal cycloaddition
reaction catalyzed by a chiral base is shown in Scheme 1. The
Scheme 1. Proposed mechanism for the asymmetric cycloaddition
reactions of isocyanoesters to nitroolefins catalyzed by a chiral base.
chiral base could promote an asymmetric Michael addition of
isocyanoesters 1 to electron-deficient olefins, such as nitro-
olefins 2, by activating the acidic a-carbon atom of 1 to
generate intermediates I. Subsequent intramolecular cycliza-
tion reactions of intermediates I afforded precursor 1,2-
dihydropyrroles II, which may be converted into dihydropyr-
role 3 after protonation.[6]
Cinchona alkaloids and their derivatives have been
revealed as efficient organocatalysts for many asymmetric
reactions,[8] particularly for a variety of asymmetric C-
nucleophilic addition reactions in which the basic function-
alities of the alkaloid activates acidic a-carbon pronucleo-
philes (Figure 1).[9–12] Surprisingly, to the best of our knowl-
edge, isocyanoesters have not yet been used as nucleophiles in
these reactions, or in other organic base-catalyzed nucleo-
philic addition reactions. Despite this, we still believed that
cinchona alkaloids and their derivatives might be able to
activate isocynoesters by deprotonation in consideration of
the sufficient acidity of the a-hydrogen atom in isocyanoest-
ers 1 and in light of the earlier successes.[9–12] Thus, in the
presence of cinchona alkaloid derivatives the asymmetric
formal cycloaddition of isocyanoesters to nitroolefins may
proceed by the proposed mechanism (Scheme 1) and lead to
the formation of optically active 2,3-dihydropyrroles.
[*] C. Guo, Prof. L.-Z. Gong
Hefei National Laboratory for Physical Sciences at the Microscale
Joint Laboratory of Green Synthetic Chemistry and
Department of Chemistry
University of Science and Technology of China
Hefei, 230026 (China)
Fax: (+86)551-360-6266
E-mail: gonglz@ustc.edu.cn
M.-X. Xue, M.-K. Zhu, Prof. L.-Z. Gong
Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences (CAS)
Chengdu, 610041 (China)
M.-X. Xue, M.-K. Zhu
Graduate School of CAS
Beijing (China)
[**] We are grateful for financial support from the NSFC (20732006 and
20325211) and the Chinese Academy of Sciences.
We first examined a cycloaddition reaction of methyl a-
phenylisocyano acetate (1a) to nitroalkene 2a in CH2Cl2 at
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cinchona alkaloids bearing a C6’-hydroxy group can serve as a
bifunctional organocatalyst,[12] and they showed much higher
stereoselectivity than their parent molecules (Table 1,
entries 7–13). Of the 6’-hydroxy cinchona alkaloids screened,
Q-4c was the best catalyst and afforded 3a in 68% yield, 19:1
d.r., and 97% ee (Table 1, entry 12). Slightly higher enantio-
and diastereoselectivities were observed for the reaction
carried out in chloroform, but the product was isolated in a
lower yield (Table 1, entry 14). Very low conversion occurred
when the reaction was conducted in toluene, albeit with a high
ee value (Table 1, entry 15). Increasing the reaction temper-
ature enhanced the reaction rate, but it was deleterious to the
diastereo-and enantioselectivities (Table 1, entry 16).
The cycloadditions of methyl a-phenylisocyano acetate
(1a) with a variety of nitroolefins were investigated under the
optimized reaction conditions (Table 2); the nitroolefins
included those bearing electron-withdrawing and electron-
donating substituents on the aryl ring and aliphatic nitro-
alkenes. High enantioselectivities ranging from 91% to more
than 99% ee and synthetically useful diastereoselectivities
were observed for all the nitrostyrenes tested; the selectivities
depend on the steric and electronic features of the substitu-
ents (Table 2, entries 1–9). Electron-deficient aryl substitu-
ents facilitate the cycloaddition with excellent stereoselectiv-
ity (Table 2, entries 1–5 and 8–9). Electron-rich aryl nitro-
olefins also underwent smooth cycloaddition reactions with
Figure 1. Organocatalysts used in this study.
room temperature in the presence of 20 mol% of naturally
available quinidine. However, the reaction gave the desired
product in only 48% yield with poor diastereo-and enantio-
selectivity after three days (Table 1, entry 1). No significant
enhancement in the yield was achieved when the reaction was
carried out at 358C (Table 1, entry 2). Although quinine
provided a high overall yield, low diastereo-and enantiose-
lectivities were obtained for the major diastereomer of 3a
(Table 1, entry 3). Neither (DHQD)2AQN, (DHQD)2PYR,
nor (DHQD)2PHAL served as an efficient and highly
stereoselective organocatalyst (Table 1, entries 4–6). Notably,
Table 2: Cycloadditions of methyl a-phenylisocyano acetate (1a) with
various nitroolefins.[a]
Table 1: Catalyst screening and optimization of reaction conditions.[a]
Entry
3
R
t
[h]
Yield
[%][b]
d.r.[c]
ee
[%][d]
1
2
3
4
3b 4-BrC6H4 (2b)
3c 4-ClC6H4 (2c)
3d 4-FC6H4 (2d)
3e 4-CNC6H4
(2e)
3 f 4-CF3C6H4
(2 f)
3g 4-MeC6H4
(2g)
30(29) 74(52) >20:1(>20:1)
29(30) 75(65) 8:1(>20:1)
14:1
96(96)
91(98)
96
28
29
61
82
Entry Catalyst
Solvent T [8C] Yield [%][b] d.r.[c]
ee [%][d]
10:1
10:1
8:1
95
1
2
3
QD
QD
Q
CH2Cl2 25
CH2Cl2 35
CH2Cl2 25
48
40
70
33
44
30
40
41
51
42
46
68
50
31
9
2:1 21(22)[e]
4:1 27(37)
3:1 25(80)[e]
5:1 0(0)[f]
2:1 4(43)
4:1 4(14)[f]
4:1 87(33)
11:1 96
10:1 94
10:1 98
19:1 96
19:1 97
5
6
29
29
68
59
98
96
4
5
6
(DHQD)2AQN CH2Cl2 25
(DHQD)2PYR CH2Cl2 25
(DHQD)2PHAL CH2Cl2 35
7
3h
106
60
4:1
91
97
7
8
9
10
11
12
13
14
15
16
QD-4a
QD-4b
QD-4c
Q-4a
Q-4b
Q-4c
Q-4d
Q-4c
Q-4c
CH2Cl2 35
CH2Cl2 35
CH2Cl2 35
CH2Cl2 35
CH2Cl2 35
CH2Cl2 35
CH2Cl2 35
CHCl3 35
PhCH3 35
CHCl3 50
8
9
3i 3-ClC6H4 (2i)
3j 3-NO2C6H4
(2j)
3k a-C4H3S (2k)
3l a-C10H7 (2l)
3m b-C10H7 (2m)
3n 3,5-Br2C6H3
(2n)
24
56
69
61
11:1
7:1
>99
10
11
12
13
29
63
8:1
98
97(96)
95
22(28) 86(79)
8:1(>20:1)
48
47
66
66
5:1
7:1
>20:1 96
>20:1 99
>20:1 98
3:1 94
98
14
15
3o Cy (2o)
3p Et (2p)
125
134
52
51
8:1
10:1
93
97
Q-4c
66
[a] The reaction of 1a (0.45 mmol), 2a (0.3 mmol), and a catalyst in
solvent (1.0 mL) was stirred for 24 h unless indicated otherwise.
[b] Yields of isolated products. [c] Determined by 1H NMR spectroscopy
of the crude product. [d] Determined by HPLC analysis and ee values are
shown in parentheses for the minor diastereomer. [e] Run for 3 days.
[f] Run for 4 days.
[a] Conditions: 1a (0.45 mmol), 2 (0.3 mmol), and Q-4c (0.06 mmol) in
CH2Cl2 (1.0 mL). The results in parentheses were obtained with 20 mol%
QD-4c for opposite enantiomers. Cy=cyclohexyl. [b] Yields of isolated
products. [c] Determined by 1H NMR spectroscopy of crude product.
[d] Determined by HPLC analysis.
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91–96% ee (Table 2, entries 6 and 7), although a prolonged
reaction was needed in the case of 2h (Table 2, entry 7).
Generally high enantioselectivities were attained with nitro-
olefins bearing a heterocyclic, naphthyl, or a disubstituted
phenyl group (Table 2, entries 10–13, 95–98% ee). Alkyl
substituted nitroalkenes also furnished 3o and 3p with high
diastereo-and enantioselectivities, respectively (Table 2,
entries 14 and 15). Notably, QD-4c afforded opposite enan-
tiomers of the products with high ee values (Table 2, entries 1,
2, and 11).
Investigations into the scope of a-substituted isocyanoest-
ers was carried out by using 2b and 2l as the reaction partners
under the optimized conditions (Table 3). A cyclization of
benzyl a-phenylisocyano acetate (1b) with 2l occurred in
Scheme 2. Stereoselective reduction of the dihydropyrrole and X-ray
crystallographic structure of 5.TFA=trifluoroacetic acid.
important building blocks for the synthesis of biologically
active substances.[14] The presence of a nitro group also allows
these compounds to be transformed into synthetically useful
molecules.[15]
Table 3: Cycloadditions of a-substituted isocyanoesters (1) with various
The 2,3-dihydropyrroles (3) contain multiple functional-
ities and can therefore be transformed into structurally
diverse heterocycles by Michael addition reactions with
organometallics. For example, 2,3-dihydropyrrole 3b was
first protected with a tert-butoxycarbonyl (Boc) group by
exposure to di-tert-butyl dicarbonate (Boc2O) and 4-dimeth-
ylaminopyridine (DMAP), and then treated with phenyl-
ethynyl lithium (generated in situ from phenylacetylene and
n-butyllithium) to undergo a conjugate addition to yield
pyrrolidine 7 containing four stereogenic centers, including a
quaternary stereogenic carbon center, with high stereochem-
ical outcome (Scheme 3). The carbon–carbon double bond
nitroolefins.[a]
Entry
3
R1 R2
2
t [h] Yield [%][b] d.r.[c]
ee [%][d]
1
2
3
4
5
6
3q Bn Ph
3r Et Ph
3r Et Ph
3s Me PhCH2
3t Me 4-MeOC6H4 2b 88
3u Me 4-AcOC6H4 2b 24
2l 44
2l 44
2l 31
2l 92
73
85
78
64
60
99
20:1 97
8:1 92
>20:1 91[e]
5:1 90
>20:1 97
6:1 90
[a] Conditions: 1 (0.45 mmol), 2 (0.3 mmol), and Q-4c (0.06 mmol) in
CH2Cl2 (1.0 mL). [b] Yields of isolated products. [c] Determined by
1H NMR spectroscopy of crude product. [d] Determined by HPLC
analysis. [e] The opposite enantiomer was obtained with 20 mol% QD-
4c.
Scheme 3. The preparation of pyrrolidines by Michael addition of
phenylethynyl lithium to Boc-protected dihydropyrrole 6.
73% yield with a 20:1 d.r. and 97% ee (Table 3, entry 1). A
comparably lower stereoselectivity was obtained in the case
of ethyl a-phenylisocyano esters (Table 3, entry 2). Once
again, QD-4c provided the opposite enantiomer with com-
parable ee values (Table 3, entries 2 and 3). Notably, methyl
a-benzylisocyano acetate underwent reaction to furnish 3s in
64% yield with 5:1 d.r. and 90% ee (Table 3, entry 4).
Moreover, isocyanoesters substituted with an electron-rich
phenyl group at the a carbon successfully reacted with 2b to
give high stereochemical outcomes (Table 3, entries 5 and 6).
However, the a-unsubstituted alkylisocyano acetate failed to
undergo the cycloaddition, indicating that the substituent is
crucial for the reaction to succeed.[13]
The relative and absolute configurations of 3b were
assigned by X-ray crystallographic analysis of optically pure
compound 5, which was prepared from 3b by reduction with
triethylsilane in trifluoroacetic acid and subsequent recrystal-
lization from a solvent mixture of isopropanol and hexane
(Scheme 2). The structure confirmed the (2R,3R) assignment
of the newly formed stereogenic centers in 3b. Notably,
compound 5 and its structural analogues could be obtained by
similar reductions of 3 to give a,a-disubstituted amino esters,
and nitro group make pyrrolidine 7 structurally flexible and
thus allow it to be converted into other chiral heterocyclic
building blocks. The transformation shown in Scheme 3,
together with the diastereoselective reduction shown in
Scheme 2, enhances the importance of the current asymmet-
ric cycloaddition in organic synthesis.
In conclusion, we have disclosed the first asymmetric
catalytic cycloaddition reaction of a-substituted isocyanoest-
ers with nitroolefins by cinchona alkaloid derivatives to yield
2,3-dihydropyrroles with high diastereo- and enantioselectiv-
ities (up to > 20:1 d.r., > 99% ee). This reaction provides a
convenient method to access multiply substituted dihydro-
pyrroles and related heterocyclic compounds in high optical
purity. The applications of this asymmetric cycloaddition in
the synthesis of structurally diverse pyrrolidines was demon-
strated by performing a diastereoselective reduction and a
Michael addition with phenylethynyl lithium. As isocyanoest-
ers frequently serve as reactants in many organic reac-
tions,[7b,16] this work might facilitate the creation of other new
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enantioselectivity · isocyanoesters · pyrroles
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