Ag(I)-Catalyzed Kinetic Resolution of Cyclopentene-1,3-diones

Article abstract of DOI:10.1021/acs.orglett.8b01254

An efficient kinetic resolution of readily available racemic cyclopentene-1,3-diones has been developed via a Ag(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This methodology shows good functional-group tolerance, delivering an array of synthetically valuable cyclopentene-1,3-diones with excellent stereoselectivity and generally high resolution efficiency (s = 48-226) accompanied by the biologically important fused pyrrolidine derivatives. Notably, this strategy allows facile access to the key intermediates for the synthesis of (+)-madindolines A and B.

Full text of DOI:10.1021/acs.orglett.8b01254

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ag(I)-Catalyzed Kinetic Resolution of Cyclopentene-1,3-diones
Hua-Chao Liu,† Liang Wei,† Rong Huang,† Hai-Yan Tao,† Hengjiang Cong,†
and Chun-Jiang Wang*,†,‡
†College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 230021, China
S
* Supporting Information
ABSTRACT: An efficient kinetic resolution of readily available racemic
cyclopentene-1,3-diones has been developed via a Ag(I)-catalyzed
asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This method-
ology shows good functional-group tolerance, delivering an array of
synthetically valuable cyclopentene-1,3-diones with excellent stereo-
selectivity and generally high resolution efficiency (s = 48−226)
accompanied by the biologically important fused pyrrolidine derivatives.
Notably, this strategy allows facile access to the key intermediates for the
synthesis of (+)-madindolines A and B.
Scheme 1. Strategies for the Synthesis of Chiral
Cyclopentene/ane-1,3-dione Framework
he optically active cyclopentene/ane-1,3-dione frame-
Twork, particularly when it is decorated with all-carbon
quaternary stereogenic centers, constitutes a privileged building
block and a core structure frequently found in a broad range of
biologically relevant natural products and pharmaceutical
ingredients (Figure 1).1,2 Due to the unique and promising
physiological activity presented by these versatile molecules,
convenient synthetic methods capable of accessing such
frameworks pose an ever-growing demand, and considerable
efforts3 have been devoted to the asymmetric construction of
various cyclopentene/ane-1,3-diones bearing the challenging
all-carbon quaternary stereogenic centers.4
Among various accesses to such valuable scaffolds,
asymmetric desymmetrization5 of prochiral cyclopentene-1,3-
diones has emerged as a powerful tool for the construction of
enantioenriched cyclopentene/ane-1,3-dione frameworks
(Scheme 1a). Despite the elegant preparation of such
frameworks, there is still some inherent drawback in those
methodologies in view of preparing the starting material
cyclopentene-1,3-diones via an oxidative−dehydration step.6
Although some synthetic improvement has been made by
Kreiser and co-workers, more than 2 equiv of Cu(II) salts was
still required to promote the oxidation of cyclopentane-1,3-
dione into cyclopentene-1,3-dione. The racemic cyclopentene-
1,3-dione could be easily achieved in one-pot directly from
cyclopentane-1,3-dione via aldol condensation followed by a
spontaneous elimination/isomerization (AEI) process (Scheme
1b, left side; see the Supporting Information for more details),
Figure 1. Examples of biologycally important natural products
containing cyclopentene/ane-1,3-dione moieties.
Received: April 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01254
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a
Table 1. Reaction Optimization
Table 2. Scope of Imine Ester 2 for Kinetic Resolution of
rac-1a
a
b
yield (ee) (%)
c
entry
R
3
3a
(R)-1a
S
1
2
3
4
p-ClC6H4
p-BrC6H4
m-ClC6H4
m-BrC6H4
o-FC6H4
3a
3b
3c
3d
3e
3f
49 (94)
50 (94)
49 (92)
48 (92)
48 (92)
46 (94)
48 (91)
47 (94)
47 (94)
47 (92)
49 (92)
54 (90)
51 (93)
42 (98)
42 (97)
46 (97)
47 (98)
50 (92)
45 (94)
40 (90)
41 (94)
44 (93)
48 (95)
43 (98)
41 (99)
44 (97)
149
136
101
110
79
b
yield (ee) (%)
d
5
ratio of
temp
c
6
Ph
115
65
entry
[M]
L
1a/2a
(°C)
3a
(R)-1a
S
e
7
e
o-MeC6H4
m-MeC6H4
p-MeC6H4
m-MeOC6H4
p-MeOC6H4
2-thienyl
3g
3h
3i
1
2
Cu(I)
Ag(I)
Ag(I)
Ag(I)
Ag(I)
Ag(I)
Ag(I)
Ag(I)
Ag(I)
Ag(I)
L1
L1
L2
L2
L2
L2
L2
L2
L2
L2
2:1
2:1
2:1
2:1
5:3
5:4
1:1
5:4
1:1
5:4
rt
rt
32 (53)
42 (82)
45 (90)
46 (92)
46 (88)
48 (87)
50 (83)
48 (91)
49 (86)
49 (94)
48 (29)
51 (41)
52 (48)
51 (71)
49 (88)
45 (95)
42 (99)
44 (94)
40 (99)
42 (98)
4
8
115
110
89
15
31
9
3
rt
e
10
3j
4
0
51
d
11
3k
3l
110
99
5
0
45
12
13
6
0
53
2-naphthyl
3m
116
7
0
56
a
Unless otherwise noted, all reactions were carried out with AgOAc/
(S)-L2 (5 mol %), 0.40 mmol of rac-1a, and 0.32 mmol of 2 in 2.5 mL
of CH2Cl2. Isolated yield based on rac-1a, >20:1 dr was determined
by crude H NMR, and the ee values of 3 and recovered 1a were
8
−20
−20
−30
75
9
69
b
10
149
1
a
c
All reactions were carried out with rac-1a (0.40 mmol) and Et3N (15
mol %) in 2.5 mL of CH2Cl2. [Cu(I)] = Cu(MeCN)4BF4. [Ag(I)] =
determined by chiral-phase HPLC and GC analysis, respectively. S =
ln[(1 − conv)(1 − ee1)]/ln[(1 − conv)(1 + ee1)], conv = ee1/(ee1 +
ee3). 0.60 mmol of imine esters 2 was used. 0.48 mmol of imine
esters 2 was used.
b
d
e
AgOAc. Isolated yield based on rac-1a, 20:1 dr was determined by
crude 1H NMR, and the ee values of 3a and recovered 1a were
c
determined by HPLC and GC analysis, respectively. S = ln[(1 −
conv)(1−- ee1)]/ln[(1 − conv)(1 + ee1)], conv = ee1/(ee1 + ee3).
room temperature. To our delight, both the cycloadduct 3a
with exclusive regioselectivity (controlled by steric effect not
electronic effect, see Supporting Information for more details)
and exclusive diastereoselectivity (>20:1 dr) and the unreacted
1a were obtained after 12 h, albeit with a lower level of
enantiomeric purity (53% ee for 3a; 29% ee for the recovered
1a) (s = 4, Table 1, entry 1). Subsequently, switching the metal
source to AgOAc promoted this process in both reactivity and
enantioselectivity (s = 15, entry 2). AgOAc/(S)-L2 markedly
provided 3a with 90% ee and the recovered 1a with 48% ee in
higher yield (s = 31, entry 3). Encouraged by the promising
results, further attempts to identify the optimal reaction
parameters were focused on screening of the ratio of rac-1a
to 2a and reaction temperature (entries 4−9). Treating rac-1a
with different amounts of 2a revealed that the use of 0.8 equiv
of 2a was the best choice (entry 8). Reducing the temperature
to −30 °C exhibited the best outcome, affording 3a in 49%
yield with 94% ee and the recovered 1a in 42% yield with 98%
ee, respectively (s = 149, entry 10). The absolute configuration
of 3a was determined as (1R,3R,3aR,5S,6aS) by X-ray analysis,
and that of the recovered 1a was assigned as (R), which was
deduced from the stereochemical outcome.
With the optimized conditions established, we first
investigated the generality of the current protocol with respect
to imino esters, and the results were revealed in Table 2.
Various tested imino esters 2a−k bearing electronically
divergent phenyl rings were all well tolerated, giving rise to
the corresponding products with excellent enantioselectivity
(91−94% ee for 3a−k; 90−98% ee for the recovered 1a) and
high selectivity factors ranging from 65 to 149 (Table 2, entries
1−11). It was worth noting that para- and meta-substituted
we wondered whether a kinetic resolution strategy7,8 could be
employed to differentiate the two enantiomers of cyclo-
pentenedione via functionalization of the double bond
embedded in the backbone and therefore provided a valuable
alternative method for the preparation of enantioenriched
cyclopentenediones without the above-mentioned oxidation
step (Scheme 1b, right side). Along with our research interest
in asymmetric 1,3-dipolar cycloaddition of azomethine ylide for
the preparation of various bioactive N-heterocycles,9−11 we
envisioned that kinetic resolution of racemic cyclopentene-
diones as the potential dipolarophiles can afford both the
recovered cyclopentene-1,3-diones and the bicyclic pyrroli-
dines, the latter of which also constitute the core structure of
numerous bioactive natural products and pharmaceuticals.12
However, the challenging features of this hypothetical approach
that differentiates it from the substantial majority of 1,3-dipolar
cycloadditions descried previously include (1) the lower
reactivity of the trisubstituted alkenes caused by the steric
congestion and (2) the subtle facial difference of CC bond
caused by the remote all-carbon stereogenic center. Herein, we
communicate our preliminary results on the highly efficient
kinetic resolution of racemic cyclopentene-1,3-diones via Ag(I)-
catalyzed 1,3-dipolar cycloaddition. Remarkably, the current
methodology could provide the key intermediates for the
synthesis of natural product (+)-madindolines A and B.2a
We commenced our investigation by identifying a suitable
catalyst system for the kinetic resolution of racemic cyclo-
pentene-1,3-dione 1a with imino ester 2a as the reaction
partner. The initial study was conducted in the presence of a 5
mol % loading of Cu(I)/(S)-TF-BiphamPhos (L1) complex at
B
DOI: 10.1021/acs.orglett.8b01254
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Letter
Figure 2. Kinetic resolution of rac-1. Unless otherwise noted, all reactions were carried out with AgOAc/(S)-L2 (5 mol %), 0.40 mmol of rac-1, and
0.32 mmol of 2a in 2.5 mL of CH2Cl2. Isolated yield was obtained on the basis of rac-1, >20:1 dr was determined by crude 1H NMR, and ee values of
3 and recovered 1 were determined by chiral-phase HPLC and GC analysis, respectively. S = ln[(1 − conv)(1 − ee1)]/ln[(1 − conv)(1 + ee1)], conv
= ee1/(ee1 + ee3). Gram-scale reaction was conducted in entry 1 (see the SI for more details). Inorganic base Cs2CO3 was used in entry 13.
a
Scheme 2
a
Reaction conditions: (i) (HCHO)n (2.0 equiv), TsOH (0.5 equiv), CH3CO2H, 80 °C; (ii) AgOAc/(S)-L2 (5 mol %), CH2Cl2, Et3N (15 mol %),
−30 °C; (iii) nBuNO2 (2.0 equiv), nBu4N+Br− (0.2 equiv), KOH, THF, rt, 1 h; (iv) AgOAc/(R)-L2 (5 mol %), CH2Cl2, Et3N (15 mol %), −30 °C.
imino esters had a negligible effect on the enantioselectivity,
and s-factor while ortho-substituted imino esters (entries 5 and
7) allowed a slightly decrease of ee values, which presumably
resulted from the steric repulsion. Notably, imino esters 2l and
2m bearing a heteroaryl and fused 2-naphthyl ring also acted as
suitable partners with satisfied selectivity factors (entries 12 and
13). Alkyl-substituted imino ester was not tolerated in this
reaction, probably due to the lower reactivity.
Next, we turned our attention to explore the scope of
cyclopentene-1,3-diones. As shown in Figure 2, the substrates
1b−f bearing different functional groups at the stereocenter,
such as electronically divergent arene rings, 2-naphthyl ring,
and allyl substituent, all reacted well, providing the correspond-
ing adducts and the recovered starting materials on par with the
excellent results observed in the model reaction (Figure 2,
entries 2−6). Remarkably, the highly efficient kinetic resolution
C
DOI: 10.1021/acs.orglett.8b01254
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could be still realized in spite of the subtle difference between
the two substituents (Me and Et) at the quaternary carbon of
1g (s = 98, entry 7). The substrates 1h and 1i having a phenyl
group and spiro moiety on the quaternary carbon center also
gave excellent enantioselectivities and high resolution efficiency
(entries 8 and 9). This methodology was also successfully
extended to silyloxy-, acetoxy-, and benzyloxy-substituted
diones 1j−l, and the desired products were obtained with
excellent s factors ranging from 75 to 121 (entries 10−12).
Notably, the substituent on the CC bond of cyclopentene-
1,3-dione was not limited to the methyl group. The substrates
1n, 1q, and 1r containing ethyl, n-butyl, and isoamyl groups
proved to be viable partners, giving the corresponding products
with high selectivity factors (entries 14, 17, and 18), which
indicates that the size of alkyl chain has a negligible effect on
this reaction. The benzyl group could also be well tolerated
with Cs2CO3 as the base, furnishing a 47% yield of 3y with 90%
ee accompanied by a 41% yield of 1m with 96% ee (entry 13).
No reaction occurred when cyclopentenedione bearing a
phenyl group on the CC bond was used, probably due to
the steric hindrance. The reaction employing 1o and 1p with
hydroxyethyl- and TBS-protected hydroxyethyl groups also
proceeded smoothly with slightly reduced s factors of 52 and
48, respectively (entries 15 and 16). Furthermore, a gram-scale
reaction with rac-1a could be conducted to deliver the adduct
3a and (R)-1a with comparable yield and maintained
stereoselectivity (entry 1).
To demonstrate the synthetic utility of this methodology,
with readily available rac-1l as the dipolarophile, 46% yield of
(R)-1l or (S)-1l could be obtained in optically pure form,
respectively, with (S)-L2 or (R)-L2 as the chiral ligand under
the optimized conditions (Scheme 2). Then, treatment of the
resolved (R)-1l and (S)-1l with nitrobutane under basic
conditions with TBAB as PTC catalyst efficiently produced
(S)-5 and (R)-5 in excellent yields with maintained
enantioselectivity, which are the key intermediates of antibiotic
natural product (+)-madindolines A and B.3h
In conclusion, we have successfully developed a highly
efficient kinetic resolution of racemic cyclopentene-1,3-diones
with in situ generated azomethine ylide enabled by a chiral
Ag(I)/TF-BiphamPhos complex. This novel methodology
works well with a broad substrate scope, affording an array of
synthetically important cyclopentene-1,3-diones accompanied
by the fused pyrrolidine derivatives with high functionalities.
Further efforts on the mechanism and applications of this
methodology are currently ongoing in our laboratory.
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cjwang@whu.edu.cn.
ORCID
Hengjiang Cong: 0000-0002-9225-0095
Chun-Jiang Wang: 0000-0003-3629-6889
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSFC (21372180, 21525207) and
the Large-scale Instrument and Equipment Sharing Founding
of Wuhan University. The Program of Introducing Talents of
Discipline to Universities of China (111 Program) is also
appreciated.
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