Morita-Baylis-Hillman adducts as effective dipolarophiles in Copper(i)-catalyzed 1,3-dipolar cycloaddition with azomethine ylides: Asymmetric construction of pyrrolidine derivatives containing quaternary stereogenic center

Article abstract of DOI:10.1039/c1cc11138h

The first catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with easily accessible Morita-Baylis-Hillman adducts as the dipolarophiles has been developed successfully and provides the highly substituted pyrrolidines bearing a unique quat

Full text of DOI:10.1039/c1cc11138h

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COMMUNICATION
Morita–Baylis–Hillman adducts as effective dipolarophiles in
Copper(I)-catalyzed 1,3-dipolar cycloaddition with azomethine ylides:
asymmetric construction of pyrrolidine derivatives containing quaternary
stereogenic centerw
Huai-Long Teng,a He Huang,a Hai-Yan Taoa and Chun-Jiang Wang*ab
Received 25th February 2011, Accepted 21st March 2011
DOI: 10.1039/c1cc11138h
The first catalytic asymmetric 1,3-dipolar cycloaddition of
azomethine ylides with easily accessible Morita–Baylis–Hillman
adducts as the dipolarophiles has been developed successfully
and provides the highly substituted pyrrolidines bearing a unique
quaternary and two tertiary stereogenic centers in excellent
diastereoselectivity and up to 97% ee.
far.5 An enantioselective version of this transformation may
not only diversify the existing asymmetric 1,3-dipolar cycloaddi-
tion but also be valuable in the synthesis of a new kind of highly
substituted pyrrolidine derivatives containing a unique quaternary
stereogenic center6 at the 4-position and two tertiary stereogenic
center at the 2,5-positions of the five-membered ring (Scheme 2).
In a continuation of our interest in the field of asymmetric
construction of bioactive pyrrolidine derivatives,7 we herein
report the first catalytic asymmetric version of 1,3-dipolar
cycloaddition of azomethine ylides to easily accessible Morita–
Baylis–Hillman adducts with excellent diastereoselectivity and
high enantioselectivity.
The Morita–Baylis–Hillman reaction is one of the most
important and atom economical carbon–carbon bond-forming
reactions, straightforwardly affording densely functionalized
molecules, and has received considerable attention recently1
(Scheme 1). Multifunctionalized Morita–Baylis–Hillman
adducts have been employed successfully as valuable starting
materials for the synthesis of heterocycles and many biologically
active molecules.2
At the outset of this study, we chose the Morita–Baylis–
Hillman adduct 2-hydroxymethyl methyl acrylate 2a and
N-(4-chlorobenzylidene)-glycine methyl ester 3a as the model
substrates in the presence of chiral TF-BiphamPhos and
metal salts to establish the optimal reaction condition. The
results are summarized in Table 1. The reaction was finished
smoothly with AgOAc/(S)-TF-BiphamPhos (1a) as the catalyst
and Et3N as base in dichloromethane at room temperature,
the desired cycloadduct 4aa, bearing a unique quaternary
stereogenic center, was isolated as a single diastereomer in
92% yield (regioselectivity >98 : 2) with albeit low enantio-
selectivity (Table 1, entry 1), which demonstrated that Morita–
Baylis–Hillman adducts could be applied in the catalytic 1,3-
dipolar cycloaddition reaction as dipolarophiles for the
construction of highly substituted pyrrolidine derivatives. To
our delight, significant enhancement of the enantioselectivity
(62% ee) was achieved with maintained diastereoselectivity for
this 1,3-dipolar cycloaddition reaction by switching the metal
precursor from AgOAc into Cu(CH3CN)4BF4 (Table 1, entry 2).
Replacing the methyl ester in the Morita–Baylis–Hillman
adduct (2a) with a bulky tert-butyl ester (2b) led to further
improvement of the enantioselectivity (Table 1, entry 3).
Encouraged by these promising results, Cu(CH3CN)4BF4
The highly substituted pyrrolidines derivatives containing
multiple stereogenic centers are observed widely in pharma-
ceuticals, natural alkaloids, organocatalysts and also useful
building blocks in synthetic chemistry.3 During the last decade,
catalytic asymmetric 1,3-dipolar cycloaddition of azomethine
ylides with electron-deficient alkenes has emerged as one of the
efficient approaches for the asymmetric construction of pyrro-
lidine derivatives.4 Although various electron-deficient alkenes
have been applied as dipolarophiles for this transformation,
most of them are limited to maleates, fumarates, maleimides,
acrylates, nitroalkenes and vinyl phenyl sulfones.4 However,
Morita–Baylis–Hillman adducts bearing allylic hydroxyl and
electron-deficient alkene units has not yet been exploited as
dipolarophiles in the asymmetric 1,3-dipolar cycloaddition of
azomethine ylides. To the best of our knowledge, only
limited racemic examples have been reported involving
Morita–Baylis–Hillman adducts as the dipolarophiles so
a College of Chemistry and Molecular Sciences, Wuhan University,
Wuhan 430072, China. E-mail: cjwang@whu.edu.cn;
Fax: 86-27-68754067
b State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, 354 Fenglin Road, Shanghai 200032,
China
w Electronic supplementary information (ESI) available: Experimental
section. CCDC 813952. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc11138h
Scheme 1 Morita-Baylis-Hilman reaction. (EWG = Electron-with-
drawing group).
c
5494 Chem. Commun., 2011, 47, 5494–5496
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enantioselectivity while ether was totally ineffective for this
transformation (Table 1, entries 7–10). Reducing the temperature
to ꢀ20 1C in DCM led to full conversion with exclusive
diastereoselectivity and 94% ee within 24 h (Table 1, entry 11),
but further lowering the temperature could not improve the
enantioselectivity. Thus, the optimized reaction conditions
were established as 3 mol% of Cu(CH3CN)4BF4/1e and
15 mol% Et3N in DCM at ꢀ20 1C.
Scheme
2 Catalytic asymmetric 1,3-dipolar cycloaddition using
MBH adducts as dipolarophiles for the construction of pyrrolidines
containing a unique quaternary and two tertiary stereogenic centers.
Next, the scope and generality of this novel 1,3-dipolar
cycloaddition of MBH adduct 2-hydroxymethyl tert-butyl
acrylate 2b with a series of representative imino esters 3
derived from glycinate were investigated under the optimized
experimental conditions, and the results were summarized in
Table 2. In general, excellent diastereoselectivities were observed
in all the tested reactions. Imino esters bearing electron-
deficient (Table 2, entries 1–6), electron-neutral (Table 2,
entries 7 and 11), and electron-rich substituents (Table 2,
entries 8–10) on the aryl rings all worked well, providing the
corresponding products in good yields (68–90%), good to
excellent enantioselectivities (86–97% ee). The electronic property
of the substituent on the aryl ring has some effect on this
transformation: electron deficient aromatic aldehyde derivatives
exhibited a little higher reactivity compared with electron rich
one although the enantioselectivity was kept at the similar
level. On the contrary, the substitution pattern of the arene
had little effect on the selectivity of the reaction. It is noteworthy
that comparable results were still achieved for the sterically
hindered ortho-chloro-substituted imino ester 3b and ortho-
methoxy-substituted imino ester 3i in terms of diastereo-
selectivity and enantioselectivity (Table 2, entry 2). Additionally,
the heteroaryl substituted imino ester 3l derived from 3-pyridyl-
aldehyde also worked in this transformation leading to 41%
yield and 72% ee (Table 2, entry 11).8
Table 1 Screening studies of the asymmetric 1,3-dipoar cycaloadditon
of azomethine ylide 3a with Morita–Baylis–Hillman adduct 2aa
Entry L [M]
R
T/1C Solvent 4
Yieldb (%) Eec (%)
1
2
3
4
5
6
7
8
1a AgOAc Me (2a) rt
1a CuBF4 Me (2a) rt
1a CuBF4 t-Bu (2b) rt
1b CuBF4 t-Bu (2b) rt
1c CuBF4 t-Bu (2b) rt
1d CuBF4 t-Bu (2b) rt
1e CuBF4 t-Bu (2b) rt
1e CuBF4 t-Bu (2b) rt
1e CuBF4 t-Bu (2b) rt
1e CuBF4 t-Bu (2b) rt
DCM 4aa 92
28
62
75
75
85
8
90
86
86
—
94
DCM 4aa 88
DCM 4ba 86
DCM 4ba 83
DCM 4ba 68
DCM 4ba 91
DCM 4ba 86
To determine the absolute configuration of cycloadduct 4ba,
the dibenzoylated 5 was synthesized via highly efficient and
simple benzoylation protocol9 (Fig. 1). A X-ray analysis of the
THF
PhMe 4ba 91
Et2O 4ba trace
4ba 80
9
10
11
1e CuBF4 t-Bu (2b) ꢀ20 DCM 4ba 82
Table 2 Substrate scope of Cu(I)/(S)-1e-catalyzed asymmetric 1,3-dipolar
cycloaddition of various azomethine ylides 3 with Morita–Baylis–Hillman
Adduct 2ba
a
All reactions were carried out with 0.23 mmol of 2 and 0.40 mmol
b
of 3a in 2 mL solvent. CuBF4 = Cu(CH3CN)4BF4. Isolated yield.
c
Ee was determined by chiral HPLC analysis, and >98 : 2 dr was
determined by HPLC analysis. Minor diastereomer was not detected
1
on the crude H NMR.
was selected as the metal precursor for further ligand
and solvent screening. Similar asymmetric inductions were
observed when the phenyl group on the phosphorus atom of
TF-BiphamPhos (1a) was replaced by a Xylyl group (1b)
(Table 1, entry 4), better enantiocontrol was exhibited by
chiral ligand TF-BiphamPhos (1c) bearing a 3,5-bis(trifluoro-
methyl)-phenyl group on the phosphorus atom (Table 1, entry 5).
However, much poorer enantioselectivity was obtained with
ligand 1d bearing a bulky cyclohexyl group on the P atom
(Table 1, entry 6). Further ligand tuning revealed that TF-
BiphamPhos (1e) with two bromine atoms at the 3,30-position
of TF-BIPHAM backbone was the most effective chiral ligand
and provided 4ba exclusively in 86% yield and 90% ee
(Table 1, entry 7). The solvent effect was also studied, CH2Cl2
was revealed to be the best solvent in terms of the yield and
Entry R (2)
4
Time (day) Yield (%)b Ee (%)c
1
2
3
p-Cl-Ph (3a)
o-Cl-Ph (3b)
p-F-Ph (3c)
4ba
4bb
4bc
4bd
4be
4bf
4bg
4bh
4bi
1
1
1
1
1
1
2
3
3
3
2
2
88
85
72
80
88
65
90
70
68
72
72
41
94
92
95
90
97
92
97
95
86
86
91
72
4
5
6
7
p-Br-Ph (3d)
p-CF3-Ph (3e)
p-CN-Ph (3f)
Ph (3g)
8
9
10
11
12d
p-MeO-Ph (3h)
o-MeO-Ph (3i)
m-MeO-Ph (3j)
4bj
2-Naphthyl (3k) 4bk
4bl
3-Pyridyl (3l)
a
b
See Table 1. See Table 1. See Table 1. Reaction was carried out
c
d
at 0 1C.
c
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Chem. Commun., 2011, 47, 5494–5496 5495

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(2011CB808600), SRFDP (20090141110042), and the
Fundamental Research Funds for the Central Universities.
Notes and references
z Crystal data for (2R,4R,5R)-5: C32H32ClNO7, Mr
= 578.04,
T = 293 K, Orthorhombic, space group P21212, a = 19.401(3),
b = 24.000(6), c = 6.6143(9) A, V = 3079.8(7) A3, Z = 4, 6359
reflections measured, 4817 unique (Rint = 0.0412) which were used in
all calculations. The final wR2 = 0.0844 (all data). Flack w = 0.03(8).
CCDC 813952 (5).
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Fig. 1 X-ray structure of compound 5.
crystal of 510 revealed R configuration for the quaternary
stereogenic center at the 4-position and R,R configuration
for the two tertiary stereogenic centers at the 2 and 5-position
of the pyrrolidine ring therefore also for the corresponding
moieties in 4ba (Fig. 1, Flack w = 0.03(8)).z
Noticeably, the racemic Morita–Baylis–Hillman adduct
(ꢁ)-2c derived from tert-butyl acrylate and benzaldehyde
could also be applied as dipolarophile in this 1,3-dipolar
cycloaddition reaction with the azomethine ylide 3a giving
rise to the desired cycloadducts bearing one quaternary and
three tertiary stereogenic centers as two diastereomers in 94%
yield with 1 : 1 diastereoselectivity and excellent enantio-
selectivities (95% ee and 85% ee). Fortunately, the two
diastereomers could be easily separated by column chromato-
graphy (Scheme 3).
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In summary, we have successfully developed the first cata-
lytic asymmetric 1,3-dipolar cycloaddition of azomethine
ylides with easily accessible Morita–Baylis–Hillman adducts
as the dipolarophiles. This catalytic system performs well over
a broad scope of substrates and provides the highly substituted
pyrrolidine derivatives bearing a unique quaternary and two
to three tertiary stereogenic centers in excellent diastereo-
selectivity and up to 97% ee. The ready availability of the
starting materials and the great importance of the enantiopure
products make the current methodology particularly interesting
in synthetic chemistry. Further investigations of the scope and
limitation of this methodology are ongoing.
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Murugan,
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Lett.,
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This work was supported by National Natural Science
Foundation of China (20702039, 20972117), 973
8 No cycloaddition was observed when alkyl substituted imino ester
was tested under the same reaction conditions.
9 (a) W. Zhang, Y. M. Lu, C. H. T. Chen, D. P. Curran and S. Geib,
Eur. J. Org. Chem., 2006, 2055; (b) C. Na
M. M. Rodrıguez, J. M. Sansano, A. D. Co
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´
jera, M. D. G. Retamosa,
´
´
zar and F. P. Cossıo,
´
Scheme 3 Catalytic asymmetric 1,3-dipolar cycloaddition of Morita-
Baylis-Hilman adduct (ꢁ)-2c and imino ester 3a.
10 H. D. Flack and G. Bernardinelli, Acta. Cryst., 1999, A55, 908.
c
5496 Chem. Commun., 2011, 47, 5494–5496
This journal is The Royal Society of Chemistry 2011