Stereoselective construction of spiro(butyrolactonepyrrolidines) by highly efficient copper(I)/TF-biphamphos-catalyzed asymmetric 1,3-dipolar cycloaddition

Article abstract of DOI:10.1002/chem.201103876

Pyrrole into one: The catalytic asymmetric 1,3-dipolar cycloaddition of cyclic aldimino esters has been accomplished for the first time, enabling facile access to spiro(butyrolactonepyrrolidines) containing one spiro quaternary center and three tertiary stereogenic centers (see scheme). The catalytic system performs well with a broad range of substrates, furnishing synthetically useful adducts in high yields, with excellent diastereo- and enantioselectivities under mild conditions. Copyright

Full text of DOI:10.1002/chem.201103876

DOI: 10.1002/chem.201103876
Stereoselective Construction of SpiroACTHNUTRGENUGN(butyrolactonepyrrolidines) by Highly
Efficient Copper(I)/TF-BiphamPhos-Catalyzed Asymmetric 1,3-Dipolar
Cycloaddition
Tang-Lin Liu,[a] Zhao-Lin He,[a] Hai-Yan Tao,[a] and Chun-Jiang Wang*[a, b]
Spirocyclic pyrrolidines with multiple contiguous stereo-
genic centers are core structural elements in a large number
of natural alkaloids and synthetic compounds exhibiting im-
portant biological activities.[1] Typical examples include
cephalotaxine,[2] stemmonamine,[3] and spirotryprostatins A
and B[4] (Figure 1).[5] Homoserine lactone derivatives have
The spirocyclic pyrrolidine skeleton has potential as a key
motif for the development of compounds leading to medici-
nal agents. For this reason, organic chemists have been in-
spired to pursue efficient methods for the synthesis of these
challenging compounds over the past few years.[8] Catalytic
asymmetric 1,3-dipolar cycloaddition of azomethine ylides
to activated alkenes[9] has been one of the most powerful
and most diversity-oriented synthetic (DOS)[10] methods
used for the construction of a range of structurally and ste-
reochemically rich pyrrolidines.[11] However, for the synthe-
sis of bioactive spirocyclic pyrrolidines, the direct catalytic
asymmetric approach has met with little success. Recently,
Gong et al. reported an elegant organocatalyzed asymmetric
1,3-dipolar cycloaddition reaction between N-Boc-2-oxoin-
dolin-3-ylidene derivatives and in situ formed azomethine
ylides, leading to the first asymmetric synthesis of spiro(ox-
indolepyrrolidine) derivatives.[12] Subsequently, the use of
chiral transition-metal complexes to catalyze asymmetric
1,3-dipolar cycloadditions for the construction of these spiro
structures was reported by Waldmann et al.[13] and our re-
search group.[14a] The common feature of these methods is
that one of the heterocyclic rings in the generated spirocy-
clic adducts is contributed by the cyclic dipolarophile.[12–14]
For spiro(butyrolactonepyrrolidines), only a few racemic ex-
amples have been reported to the best of our knowledge,[15]
and quite limited progress towards a direct catalytic asym-
metric approach to these spirocyclic compounds has been
made. Therefore, the development of a catalytic method for
the straightforward synthesis of enantioenriched spiro(bu-
tyrolactonepyrrolidines) is in high demand. Herein, we
report the first catalytic asymmetric synthesis of spiro(bu-
tyrolactonepyrrolidines) containing a unique spiro quaterna-
ry stereogenic center[16] by using a CuI/TF-BiphamPhos cata-
lyzed 1,3-dipolar cycloaddition, and by employing homoser-
ine lactone derived cyclic imino esters as the dipoles
(Scheme 1). A key feature of this method is that the lactone
Figure 1. Examples of biologically important molecules containing privi-
leged spiro pyrrolidines and homoserine lactones.
also attracted considerable attention due to their biological
activity profile.[6] Typical examples are the acyl homoserine
lactones (AHLs), which are important intercellular signaling
molecules in many Gram-negative bacteria and are responsi-
ble for bacterial quorum sensing (Figure 1).[7] Therefore,
combining the two classes of biologically active core struc-
ture through a unique spiro-quaternary stereogenic carbon
may introduce some unprecedented benefits to drug discov-
ery and is expected to find valuable applications in medici-
nal chemistry.
[a] T.-L. Liu, Z.-L. He, H.-Y. Tao, Prof. Dr. C.-J. Wang
College of Chemistry and Molecular Sciences
Wuhan University, 430072 (P.R. China)
Fax : (+86)27-68754067
E-mail: cjwang@whu.edu.cn
[b] Prof. Dr. C.-J. Wang
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Fenglin Road, Shanghai, 230032 (P.R. China)
E-mail: cjwang@whu.edu.cn
Scheme 1. Asymmetric synthesis of spiro(butyrolactonepyrrolidines) by
catalytic asymmetric 1,3-dipolar cycloaddition using homoserine lactone
derived cyclic imino esters as the dipoles.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103876.
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COMMUNICATION
Table 1. Optimization of the catalytic asymmetric 1,3-dipolar cyclo-
addition of homoserine lactone derived aldimino ester 1a with dimethyl
maleate 2a.[a]
ring in the generated spirocycles is provided by the dipole,
rather than by the dipolarophile. Inspired by the seminal
work of Grigg et al. on the 1,3-dipolar cycloaddition of ho-
moserine lactone derived aldimino esters with electron-defi-
cient olefins in the presence of a substoichiometric amount
of silver salts,[15] our initial studies began with the reaction
of the cyclic aldimino ester 1a, which was readily synthe-
sized from homoserine lactone hydrochloride and benzalde-
hyde, with dimethyl maleate (2). We used the reaction of 1a
as a model reaction to probe the possibility of employing
a catalytic amount of metal complex in this transformation.
To our delight, 5 mol% of the AgOAc/PPh3 complex exhib-
ited high catalytic efficiency, and the model reaction was fin-
ished in less than 3 h in dichloromethane at room tempera-
ture. The expected spiro(butyrolactonepyrrolidine) 3a was
produced in high yield (93%) with excellent diastereoselec-
tivity (diastereomeric ratio (d.r.)>98:2; Scheme 2).
Entry Ligand [M]
Solvent
T
Time Yield[b] ee[c]
[oC]
[min] [%]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
L1
L1
L2
L2
L3
L3
L4
L4
L5
L5
L5
L5
L5
L5
L5
AgOAc
[Cu(MeCN)4]
AgOAc
[Cu(MeCN)4]
AgOAc
[Cu(MeCN)4]
AgOAc
[Cu(MeCN)4]
AgOAc
CH2Cl2 RT 1440 60
5
3
58
65
0
G
ACHTUNGTRENNUNG
E
ACHTUNGTRENNUNG
N
T
0
CH2Cl2 RT
CH2Cl2 RT
15 78
10 80
10 90
10 80
60 90
40 80
40
63
25
88
73
72
67
97
97
G
ACHTNUGERTN[NUGN BF4] CH2Cl2 RT
[Cu
[Cu
[Cu
[Cu
[Cu
[Cu
G
ACHTNUGERTN[NUGN BF4] CH2Cl2 RT
R
N
RT
RT
E
ACHTUNGTRENNUNG
N
ACHTUNGTREN[UNNG BF4] EtOAc RT 120 85
R
[BF4] CH2Cl2
[BF4] CH2Cl2 À20
0
20 89
40 88
A
A
[a] All reactions were carried out by using 1a (0.26 mmol) and
2
(0.20 mmol) in solvent (2 mL). [b] Isolated yield. [c] The ee and >98:2
diastereomeric ratio were determined by HPLC analysis. The minor dia-
stereomer was not detected by crude HNMR analysis.
Scheme 2. AgI/PPh3-catalyzed 1,3-dipolar cycloaddition of homoserine
lactone derived cyclic imino ester 1a with dimethyl maleate 2.
1
Encouraged by this promising result, different metal salts
and commercially available chiral ligands (Figure 2) were
subsequently examined to establish optimal reaction condi-
tions and representative results are summarized in Table 1.
Combined with Monophos (L1), both AgOAc and
showed better asymmetric induction than monophosphine li-
gands. With AgOAc or [CuACHTNUTGRENNUG(MeCN)4]ACHTUNTGREN[NUGN BF4] as the catalyst
precursor, BINAP (L2) gave the desired adduct with 58 and
65% ee, respectively (Table 1, entries 3 and 4). To our sur-
prise, the bulkier and electron-donating biphenyl ligand (R)-
DTBM-segphos (L3) was not suitable for this transforma-
tion; only the racemic spiroadduct was achieved, accompa-
nied by a remarkable decrease in catalytic activity (Table 1,
entries 5 and 6). The chiral ligands TF-BiphamPhos (L4,
L5),[18] developed in this laboratory, were next screened to
identify a more efficient catalyst system. In general, TF-Bi-
phamPhos ligands exhibited the best results in terms of the
reaction rate and asymmetric induction, and copper salts
gave better enantioselectivity than silver salts (Table 1, en-
[CuACHTUNGTRENNUNG(CH3CN)4]ACHTUNGTRENNUNG[BF4] salts successfully promoted this model
cycloaddition reaction; however, spiroadduct 3a was formed
with a very low enantioselectivity (Table 1, entries 1 and 2)
even though Monophos has exhibited excellent asymmetric
induction in several AgI-catalyzed asymmetric 1,3-dipolar
cycloadditions of azomethine ylides.[17] Bisphosphine ligands
tries 7–10). By using a [CuACTHNUTRGENNUG(CH3CN)4]AHCTUGNTERN[NUGN BF4]/L4 complex as
the catalyst, the adduct 3a was achieved with good yield, ex-
cellent diastereoselectivity, and moderate enantioselectivity
(63%; Table 1, entry 8). TF-BiphamPhos L5 with two bro-
mine atoms at the 3,3’ positions of the TF-Bipham back-
bone was shown to be the most promising ligand when com-
plexed with [CuACTHNUTRGENN(UG CH3CN)4]CAHTUNGTERN[NUGN BF4], and provided 3a as the
only product in 85% yield and 88% ee (Table 1, entry 10).
The solvent effects were also investigated, and CH2Cl2 was
revealed to be the best solvent for the reaction (Table 1, en-
tries 10–13). Reducing the reaction temperature from RT to
08C resulted in full conversion with 97% ee (Table 1,
entry 14). Lowering the temperature further did not im-
prove the enantioselectivity, and had a detrimental effect on
the reaction rate (Table 1, entry 15).
Figure 2. Screened chiral ligands.
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C.-J. Wang et al.
Table 2. Substrate scope of the CuI-catalyzed asymmetric 1,3-dipolar cy-
that the reaction took place smoothly and led to the desired
adduct 3n in good yield, albeit with only 63% ee. Fortunate-
ly, the enantioenriched compound was easily obtained by
simple recrystallization of the crude product (Table 2,
entry 14).
cloaddition of various cyclic aldimino esters 1 with dimethyl maleate 2.[a]
To determine the relative and absolute configuration of
spiro adduct 3b, the derived compound 4 was synthesized
by
a highly efficient and simple amidation protocol
Entry
R
3
Yield[b]
[%]
ee[c]
[%]
(Scheme 3). An X-ray analysis of the crystal of 4 revealed
a (2S,3R,4S,5R) configuration for the spiro quaternary
center and the three adjacent tertiary stereogenic centers,
and therefore also for the corresponding moiety in 3b
(Figure 3).[19] The absolute configuration of all other prod-
ucts was assigned by analogy.
1
2
3
4
5
6
7
8
9
10
11
12
13
14[d]
Ph (1a)
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
89
84
86
83
89
90
89
86
93
90
90
94
83
80
97
96
98
97
99
99
98
99
99
96
99
99
p-ClPh (1b)
o-ClPh (1c)
m-ClPh (1d)
p-BrPh (1e)
p-MePh (1 f)
o-MePh (1g)
m-MePh (1h)
p-MeOPh (1i)
1-naphthyl (1j)
2-naphthyl (1k)
2-furyl (1l)
2-thienyl (1m)
Cy (1n)
96
63 (96)[e]
Scheme 3. Amidation of the spiro adduct 3b.
[a] All reactions were carried out by using
2
(0.26 mmol) and
1 (0.20 mmol) in CH2Cl2 (2 mL). [b] Isolated yield. [c] The ee and >99:1
diastereomeric ratio were determined by HPLC analysis. The minor dia-
stereomer was not detected by crude 1H NMR analysis. [d] 10 mol% of
Ag2O/L5 was employed as the metal source. [e] The ee value in paren-
theses was achieved after simple recrystallization.
Having established an optimal reaction protocol, we next
explored the scope and the generality of the method. As
shown in Table 2, a wide range of aromatic-aldehyde-de-
rived cyclic imino esters were examined, and it was observed
that with electron-neutral (Table 2, entries 1, 10, and 11),
electron-deficient (Table 2, entries 2–5), or electron-rich
groups (Table 2, entries 6–9) on the phenyl ring, the desired
spiro(butyrolactonepyrrolidines) (3a–3k) were obtained in
satisfactory yields (83–93%) and excellent selectivities (96–
99% ee, >98:2 d.r.). It is worth noting that comparable re-
sults were achieved for the sterically hindered ortho-chloro-
and ortho-methyl-substituted imino esters 1c and 1g in
terms of stereoselectivity and reactivity, demonstrating that
the substitution pattern of the arene had little effect on the
selectivity of the reaction (Table 2, entries 3 and 7). Cyclic
imino esters derived from 1- and 2-naphthylaldehyde also
worked well in this annulation reaction, providing the spiro
adducts 3j and 3k with 96% and 99% ee respectively
(Table 2, entries 10 and 11). Remarkably, heteroaromatic al-
dehyde-derived cyclic imines 1l and 1m were also tolerated
in this reaction, and the desired spiro(butyrolactonepyrroli-
dines) were obtained with excellent enantioselectivity
(Table 2, entries 12 and 13). No cycloaddition reaction oc-
curred when the less reactive imino ester 1n, derived from
aliphatic cyclohexanecarbaldehyde, was tested under the op-
timal reaction conditions. Considering Ag2O exhibited sig-
nificant activity for the 1,3-dipolar cycloaddition of some ali-
phatic aldehyde-derived imino esters,[15] we changed the
Figure 3. ORTEP representation of the cocrystal of (2S,3R,4S,5R)-4 and
acetone (1:1) with thermal ellipsoids at 30% probability level.
To further expand the synthetic utility of this transforma-
tion for the construction of spiro(butyrolactonepyrrolidines)
containing a unique quaternary stereogenic center, other di-
polarophiles were also examined under the optimized reac-
tion conditions. As shown in Figure 4, tert-butyl acrylate and
(E)-4-phenylbut-3-en-2-one proved to be excellent dipolaro-
Figure 4. The results of the 1,3-dipolar cycloaddition of cyclic aldimino
metal precursor from Cu
A
ester 1a with other dipolarophiles catalyzed by CuI/L5.
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Stereoselective Construction of Spiro(butyrolactonepyrrolidines)
COMMUNICATION
philes, affording the desired spiroadducts 3o and 3p with
high yields and excellent diastereo- and enantioselectivity.
Moreover, dimethyl fumarate was also investigated; al-
though the diastereoselectivity (85:15) was lower than that
of dimethyl maleate (>98:2), the expected spirocyclic
adduct 3q was still obtained in satisfactory yield and
95% ee (major diastereomer).
Based on the relative and absolute configuration of
(2S,3R,4S,5R)-3a, the high stereoselectivity observed in the
CuI/(S)-TF-BiphamPhos-catalyzed 1,3-dipolar cycloaddition
of cyclic aldimino esters with dimethyl maleate can be ra-
tionalized by using the proposed tetracoordinated complex
shown in Figure 5. The in situ-formed azomethine ylide is
Experimental Section
General Procedure: Under an argon atmosphere, (S)-TF-BiphamPhos
L5 (5.8 mg, 0.0072 mmol) and [CuACTHNUTRGENNUG(CH3CN)4]ACHTUGNTREN[NUGN BF4] (2.0 mg, 0.006 mmol)
were dissolved in dichloromethane (2 mL) and stirred at room tempera-
ture for approximately 1 h. The cyclic aldimino ester (0.26 mmol), Et3N
(0.03 mmol) and dimethyl maleate (0.2 mmol) were then added sequen-
tially. Once the starting material had been fully consumed (monitored by
TLC), the mixture was filtered through Celite and the filtrate was con-
centrated to dryness. The crude product was analyzed by 1H NMR spec-
troscopy to determine the diastereoselectivity, and the residue was puri-
fied by column chromatography to give the corresponding cycloadduct as
a white solid. This was then directly analyzed by chiral HPLC to deter-
mine the enantiomeric excess.
Acknowledgements
This work is supported by the NSFC (20972117, 21172176), the Program
for New Century Excellent Talents in university (NCET-10–0649), the
Program for Changjiang Scholars and Innovative Research Team in Uni-
versity of the Ministry of Education (IRT1030), the 973 program
(2011CB808600), the SRFDP (20090141110042), the Fundamental Re-
search Funds for the Central Universities, Large-scale Instrument and
Equipment Sharing Foundation of Wuhan University, and an academic
award for excellent PhD candidates funded by the Ministry of Education
of China (5052011203011, T.-L. Liu). We thank Prof. Hua Li at Wuhan
University for solving the crystal structure.
Figure 5. Proposed transition states leading to (2S,3R,4S,5R)-3a.
Keywords: asymmetric
catalysis
·
cycloaddition
·
diastereoselectivity · enantioselectivity · spiro compounds
coordinated to the metallic center and is oriented in this
specific way because of the steric repulsion between the
phenyl group in the ylide and the phenyl ring on the phos-
phorus atom of the chiral ligand. The high steric congestion
imposed by the P-phenyl group effectively blocks the ap-
proach of the dipolarophile, dimethyl maleate, from the Re
(C=N) face of the azomethine ylide. Instead, the
(2S,3R,4S,5R)-spiro(butyrolactonepyrrolidine) 3a is formed
by a Si face attack, which is compatible with the experimen-
tal results. The carbonyl group of dimethyl maleate could
coordinate with the CuI center, stabilizing the negatively
charged oxygen atom in the proposed transition states.
However, this does not rule out the possible hydrogen-bond-
ing interaction between the carbonyl group of the dipolaro-
phile and the NH2 group of the chiral (S)-TF-BiphamPhos
ligand, which might also facilitate stabilization of the pro-
posed transition states.[20]
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Received: December 10, 2012
Published online: June 4, 2012
8046
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