Stereoselective Allylic Alkylation of 1-Pyrroline-5-carboxylic Esters via a Pd/Cu Dual Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b02902

The asymmetric allylation of 1-pyrroline-5-carboxylic esters has been accomplished through a synergistic Pd/Cu catalyst system under mild reaction conditions. The mechanistic studies suggested that (1) nucleophilic attack is the enantiodiscriminating step; (2) the cooperative action of two chiral reactive species, N-metalated azomethine ylides and ?€-allylpalladium, is most likely responsible for its high reactivity and excellent enantioselectivity (up to >99% ee); and (3) the steric hindrance and electronic factors of the allylic electrophiles and imino ester substrates are crucial for the formation of the linear products. A series of 3,4-2H-pyrrole derivatives bearing a quaternary stereogenic center were easily synthesized in high yields and with high to excellent regioselectivity and enantioselectivity.

Full text of DOI:10.1021/acs.orglett.8b02902

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoselective Allylic Alkylation of 1‑Pyrroline-5-carboxylic Esters
via a Pd/Cu Dual Catalysis
Penglin Liu,†,§ Xiaohong Huo,†,§ Bowen Li,† Rui He,† Jiacheng Zhang,† Tianhong Wang,† Fang Xie,*,†
and Wanbin Zhang*,†,‡
†Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, and ‡School
of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
S
* Supporting Information
ABSTRACT: The asymmetric allylation of 1-pyrroline-5-carboxylic esters has been accomplished through a synergistic Pd/Cu
catalyst system under mild reaction conditions. The mechanistic studies suggested that (1) nucleophilic attack is the
enantiodiscriminating step; (2) the cooperative action of two chiral reactive species, N-metalated azomethine ylides and π-
allylpalladium, is most likely responsible for its high reactivity and excellent enantioselectivity (up to >99% ee); and (3) the
steric hindrance and electronic factors of the allylic electrophiles and imino ester substrates are crucial for the formation of the
linear products. A series of 3,4-2H-pyrrole derivatives bearing a quaternary stereogenic center were easily synthesized in high
yields and with high to excellent regioselectivity and enantioselectivity.
ince the pioneering work of Tsuji and Trost, Pd-catalyzed
asymmetric allylic substitution has long been the focus of
catalysis. While organocatalysts can activate a range of
functional groups,7 metal catalysts possess a greater number
of activation modes.8 It is expected that this bimetallic catalysis
strategy would enable a much broader range of asymmetric
reactions. Indeed, enantioselective reactions with α-hydrox-
yketones compounds, amino acid derivatives, α-CF3 amides,
and azaaryl acetamides as nucleophiles have recently been
reported.9 It is believed that the combination of this bimetallic
catalysis strategy and the allylic chemistry will provide a great
opportunity for the enantioselective synthesis of natural
products and important bioactive compounds.
Recently, the enantioselective transformation of cyclic imino
esters has attracted much attention, as they serve as versatile
synthetic intermediates for the preparation of many natural
and biologically active compounds, for example, cis-5-phenyl-
proline, spirocyclic scaffolds, and pyrrolizidine (Scheme 1).10
Among various methodologies, the Pd-catalyzed asymmetric
allylic alkylation of readily available cyclic imino esters are
most promising in terms of operational simplicity, starting
material availability, and convenience of derivation. However,
this transformation has not been reported previously, mainly
due to (1) its low reactivity or need for harsh reaction
conditions, (2) the challenging stereocontrol of prochiral
nucleophiles, and (3) the regioselective formation of either the
branched or linear product. Herein, we implement a bimetallic
catalysis strategy for the enantioselective allylic alkylation of
cyclic imino esters and explore the specific performance of this
strategy in allylic substitution reactions from the viewpoint of
S
asymmetric catalysis research and has become an important
synthetic tool among chemists.1 This methodology not only
provides access to a number of enantiopure bioactive
molecules but also provides an opportunity for understanding
the mechanism of the stereocontrol of the enantioselective
catalysis.1,2 These are mainly due to the obvious advantages of
allylic chemistry, including: (1) the ease of derivatization of
target compounds containing an isolated double bond; (2) the
ability to produce enantiomerically pure products from either
achiral or chiral racemic substrates; and (3) the compatibility
with a large variety of nucleophiles and, thus, the
enantioselective catalytic formation of multiple types of
bonds. Accordingly, much effort has been devoted to this
area, and considerable progress has been achieved. However,
several issues still exist: (1) the scope of nucleophiles remains
limited;3 (2) problems associated with the stereocontrol of
prochiral nucleophiles owing to the long distance between the
stereogenic and catalytic centers; and (3) the regioselective
control of either the branched or linear products.4 Thus, the
development of catalytic strategies to address these issues are
highly desired.
Recently, synergistic catalysis has attracted increasing
attention due to its advantages over traditional catalytic
methodologies for reactivity and selectivity.5 By introducing
a second organocatalyst to this process, a series of uncommon
nucleophiles (e.g., simple aldehydes and ketones) could be
successfully applied in the asymmetric allylic alkylation under
mild conditions through the combined use of palladium/
enamine.6 Meanwhile, a second metal catalyst is introduced to
this process for the realization of synergistic bimetallic
Received: September 11, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02902
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Bimetallic Catalysis Strategy for the Asymmetric
Allylic Alkylation of 1-Pyrroline-5-carboxylic Esters
Scheme 3. Substituent Effects on Regioselectivity
a
Reaction conditions: see Table 1, entry 4. Isolated yield of the linear
b
products. 24 h.
a
a
Table 2. Substrate Scope of the Allylic Acetates
Table 1. Optimization of Reaction Conditions
b
T
(°C)
yield
(%)
ee of
c
dr of
ee of 4
c
d
entry
1
1
l/b
3a
4
(%)
1a
1a
1a
1a
1b
1c
rt
rt
rt
50
50
50
67
6
0
93
93
94
1:1.8
1:4.3
94
6
1.7:1
1.3:1
98/95
3/44
e
2
3
f
4
5
6
1:1.4
1:1.4
1:1.3
93
94
93
2.2:1
2.2:1
2.2:1
96/93
96/93
97/94
a
Reaction conditions: 2a (0.25 mmol), 1 (1.4 equiv), Pd/L (5 mol
%), Cu/L (5 mol %), K2CO3 (1.0 equiv), THF (1.5 mL), 16 h.
b
Isolated yield of the mixture of the linear and branched products.
c
The ee values were determined by HPLC using chiral columns, and
the absolute configuration was determined by comparison of the sign
d
of the optical rotation with that in the reported data.10a Determined
e
1
by H NMR integration of the crude reaction mixtures. Without Cu
f
catalyst. Without Pd catalyst.
Scheme 2. Proposed Mechanism for the Asymmetric Allylic
Alkylation of 1a−c
a
b
Reaction conditions: see Table 1, entry 4. Isolated yield of the
c
d
e
f
linear products. See Table 1, footnote c. For 1b. For 1c. 24 h.
were mainly formed via the attack of the carbon nucleophiles
at the phenyl substituted position (l/b = 1:1.8) and the
enantioselectivity of the linear and branched products are both
satisfactory (94% ee and 98%/95% ee, respectively).
Subsequently, control experiments were conducted to probe
the cooperative interplay of the bimetallic catalyst system. Only
a trace amount of the substituted product was obtained in the
reactivity, regioselectivity, and stereocontrol of the prochiral
nucleophiles (Scheme 1).
Initially, cinnamyl acetate 1a was selected as an electrophilic
precursor for the asymmetric allylation of the cyclic imino ester
2a in the presence of K2CO3 using a [Pd/L + Cu/L] catalyst
combination (Table 1). We found that the branched products
B
DOI: 10.1021/acs.orglett.8b02902
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Organic Letters
Letter
a
The linear E substrate 1a usually forms a syn-configured allyl
complex that may produce the linear E and/or the branched
product. The linear Z substrate 1c will initially form an anti-
configured allyl complex, which may react directly with the
nucleophile to generate the Z linear and/or the branched
product. As for the branched allylic substrate 1b, these are
expected to give a mixture of the syn and anti-configured allyl
intermediates (Scheme 2).4a Accordingly, reactions with two
linear (E and Z) and the branched allylic precursors were
conducted under the optimal reaction conditions. Similar
results, including the l/b ratio, yield, and enantioselectivity of
both the linear and branched products were obtained (Table 1,
entries 4−6). It can be concluded that the rate of nucleophilic
attack is slower than that of anti-syn equilibration, which may
be suggested by the result that the reaction of the linear Z
substrate gave only the linear E product without any the linear
Z product (Table 1, entry 6). Oxidative addition of the three
different isomers 1a−c is expected to give the same
monosubstituted π-allyl complex. High stereoselectivity of
the linear products suggested that π−σ−π equilibration is fast
compared to nucleophilic substitution and the chiral catalysts
may allow preferential attack of the nucleophile to one of the
two rapidly equilibrating π-allyl intermediates (Table 1, entries
4−6). That is to say that the nucleophilic attack is the
enantiodiscriminating step.13
Table 3. Substrate Scope of Cyclic Imino Esters
We then attempted to regulate and control the regiose-
lectivity of this reaction by (1) changing the steric environ-
ment or electronic factors, such as charge separation on the
two allylic termini of the allylic electrophiles, and (2) changing
the steric environment of the cyclo imino ester nucleophiles
(Scheme 3). To test the feasibility of our hypothesis,
nonconjugated alkyl group allylic precursors were first
screened. To our delight, the ratio of l/b could be reversed
using the crotyl esters (5:1 vs 1:1.4). Furthermore, the l/b ratio
increased rapidly when the steric hindrance of the substituent
group was increased. These results indicate that the
regioselectivity is sensitive to the steric environment and
electronic factors of the two allylic termini. Indeed, the linear
products were also smoothly obtained when the methyl ester
was replaced with a butyl ester (9:1 vs 1:1.4).
a
b
Reaction conditions: see Table 1, entry 4. Isolated yield of the
c
linear products. See Table 1, footnote c.
Scheme 4. Gram-Scale Experiments with 1a
The allylic electrophile scope was explored using the cyclic
imino tert-butyl ester 2b as a representative substrate (Table
2). At first, two linear (E and Z) and the branched allyl
precursors were subjected to the reaction conditions, providing
almost identical results (entries 1−3). A series of allylic
substrates substituted with arenes bearing electron-withdraw-
ing and electron-donating substituents all furnished the
corresponding products with high reactivities and satisfactory
regioselectivities and enantioselectivities (5b−p). To our
delight, simple allyl acetate, crotyl acetate, and trans-2-hexenyl
acetate proved to be good substrates, affording the
corresponding products in high yields and enantioselectivities
(5q,r). Furthermore, 1,3-diphenyl-substituted substrate 1s is
also compatible with the reaction conditions, providing the
product 5s in 81% yield, 7:1 dr, and 98% ee.
The scope of the cyclic imino esters was next investigated
(Table 3). Various aryl substituted cyclic imino esters bearing
electron-deficient or electron-rich groups were all tolerated in
this reaction (6a−i), giving the desired products in good yields
and with excellent stereoselectivities. Reactions involving
naphthyl-, furyl-, 2-methoxypyridinyl-, and alkyl-substituted
cyclic imino esters also proceeded well to deliver the desired
absence of the Cu catalyst and the ee decreased rapidly from
94% to 6% (entry 2). The results indicate that the chiral
copper complex is indispensable to the reactivity and
enantioselectivity. Additionally, none of the target product
was obtained in the absence of the Pd catalyst (entry 3). These
results suggest that the combined use of two chiral metal
catalysts seems to be important for the reactivity and
stereochemical control of this reaction. To improve the
regioselectivity, the effects of other parameters, including
temperature, base, and ligands were carefully screened.11 Only
negligible effects of these factors on the regioselectivity were
found.
Pd-catalyzed allylic substitution reactions with monosub-
stituted allylic electrophiles typically give linear products in
which the nucleophile adds to the least hindered terminus and
the regioselective formation of a branched product is
particularly difficult.1 In contrast, the formation of the
branched product is usually found in Ir-catalyzed allylic
substitution reactions.9g,12 Interestingly, the branched products
are mainly produced in our present Pd/Cu catalyst system. To
obtain the linear products, it is necessary to gain insight into
the mechanism of this dual catalysis (Scheme 2).
C
DOI: 10.1021/acs.orglett.8b02902
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Organic Letters
Letter
2687. (n) Grange, R. L.; Clizbe, E. A.; Evans, P. A. Synthesis 2016, 48,
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products in good to high yields and with high enantioselectiv-
ities (6j−n).
To confirm the scalability of the present methodology, we
performed a larger scale synthesis of 4a using the standard
reaction conditions, and comparable results were obtained with
higher regioselectivity (Scheme 4).
In summary, we have developed a synergistic Pd/Cu catalyst
system for the asymmetric allylation of 1-pyrroline-5-carboxylic
esters. A series of 3,4-2H-pyrrole derivatives bearing a
quaternary stereogenic center were easily synthesized in high
yields and with high to excellent enantioselectivity and
regioselectivity under mild conditions. Mechanistic studies
revealed that the cooperative action of the two chiral metal
complexes is most likely responsible for its high reactivity and
excellent enantioselectivity; the steric hindrance and electronic
factors of the electrophiles and the nucleophiles are crucial for
the formation of the linear products. Further applications of
this bimetallic catalysis strategy for use in other asymmetric
transformations are ongoing in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02902.
Experimental procedures, full spectroscopic data for all
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1
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AUTHOR INFORMATION
Corresponding Authors
■
́
Wang, H. Chem. Commun. 2014, 50, 4272. (d) Afewerki, S.; Cordova,
*E-mail: xiefang@sjtu.edu.cn.
*E-mail: wanbin@sjtu.edu.cn.
ORCID
A. Chem. Rev. 2016, 116, 13512. For selected examples, see:
́
(e) Ibrahem, I.; Cordova, A. Angew. Chem., Int. Ed. 2006, 45, 1952.
(f) Mukherjee, S.; List, B. J. Am. Chem. Soc. 2007, 129, 11336.
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Wanbin Zhang: 0000-0002-4788-4195
Author Contributions
§P.L. and X.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSFC (Nos. 21472123, 21620102003,
21572129, and 21831005), the SHMEC (No.
201701070002E00030), and the STCSM (No.
18ZR1431700) for financial support.
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E
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