Highly efficient construction of spirocyclic chromanone-pyrrolidines via Cu(i)/TF-BiphamPhos-catalyzed asymmetric 1,3-dipolar cycloaddition

Article abstract of DOI:10.1039/c1cc13554f

A facile synthesis of highly functional spiro-[4-chromanone-3,3′- pyrrolidine] bearing one unique spiro quarternary and three tertiary stereogenic centers is developed in excellent stereoselectivity for the first time. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc13554f

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COMMUNICATION
Highly efficient construction of spirocyclic chromanone–pyrrolidines via
Cu(I)/TF–BiphamPhos-catalyzed asymmetric 1,3-dipolar cycloadditionw
Tang-Lin Liu,a Zhao-Lin Hea and Chun-Jiang Wang*ab
Received 15th June 2011, Accepted 15th July 2011
DOI: 10.1039/c1cc13554f
A facile synthesis of highly functional spiro-[4-chromanone-3,30-
pyrrolidine] bearing one unique spiro quarternary and three
tertiary stereogenic centers is developed in excellent stereo-
selectivity for the first time.
of the two key units via a spiro carbon, may introduce some
unprecedented benefits and is expected to find valuable appli-
cations in medicinal chemistry. In sharp contrast to the well-
documented approaches to access either 4-chromanones6 or
pyrrolidine-containing compounds,5 an effective and atom-
economic construction of the spiro-[4-chromanone-3,30-pyrroli-
dine] structural skeletons still remains elusive. In consideration
of the simultaneous creation of one unique spiro quarternary7
and several contiguous stereogenic centers in the spiro-
[4-chromanone-3,30-pyrrolidine] motif, it is a great challenge
to control both high enantioselectivity and diastereoselectivity
in its stereo-controlled synthesis (Scheme 1). To the best of our
knowledge, there has been no report on the catalytic asymmetric
synthesis of the spiro-[4-chromanone-3,30-pyrrolidine] moiety
so far.8 Recently, we reported that the Ag(I)/TF–BiphamPhos
complex exhibited good stereoselectivities in asymmetric
synthesis of spiro[oxindole-3,30-pyrrolidine] derivatives via
catalytic asymmetric 1,3-dipolar cycloaddition.9 Encouraged
by those achievements, we envisioned that easily available
3-alkylidene-4-chromanones could be employed as dipolarophiles
in the asymmetric 1,3-dipolar cycloaddition for the facile access
to enantioenriched spiro-[4-chromanone-3,30-pyrrolidine] deriva-
tives (Scheme 1). Herein, we reported the first asymmetric
construction of spiro-[4-chromanone-3,30-pyrrolidine] derivatives
containing unique spiro quarternary stereogenic centers via
Cu(I)/TF–BiphamPhos-catalyzed 1,3-dipolar cycloaddition10
of azomethine ylides with 3-alkylidene-4-chromanones.
Highly functionalized 4-chromanones are commonly present
in many bioactive natural products and have attracted much
attention due to their significant pharmaceutical properties.1
4-Chromanones are also versatile intermediates for the synthesis
of many natural products such as brazillin, hematoxylin,
ripariochromene, clausenin and calanolide A.2 The spirocyclic
4-chromanones play a significant role in the structure–activity
relationship of several antibacterial, antifungal and antitumor
agents as exemplified by the naturally occurring compound
morellin I1 shown in Fig. 1. The significant biological activity
of these natural products has also encouraged the develop-
ment of biologically promising 4-chromanone heterocycles.
For example, acetyl-CoA carboxylase (ACC) inhibitor II3
and its derivatives demonstrate the potential to favorably
affect the multitude of risk factors associated with metabolic
syndrome, obesity and type-2 diabetes. The privileged spiro-
cyclic 4-chromanone skeletons have high potential as core
elements for the development of related compounds leading
to medicinal agents.3,4 Five-membered nitrogen heterocycles,
especially the highly substituted pyrrolidines, are observed
widely in pharmaceuticals and natural alkaloids.5 Therefore, the
spiro-[4-chromanone-3,30-pyrrolidine] motif, the combination
Initially, our studies began with the reaction of N-(4-chloro-
benzylidene)-glycine methyl ester 1a with (E)-3-benzylidene-
chroman-4-one 2a in the presence of a catalytic amount of
AgOAc/(ꢀ)-TF-BinphamPhos (L1) (3 mol%) and Et3N
(15 mol%). Gratifyingly, the reaction was finished in 3 h with
the catalytic amount of catalyst at room temperature in
dichloromethane affording the desired adduct spirocyclic
Fig. 1 Representatives of bioactive spiro chromanones.
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, Shanghai, China 230032
w Electronic supplementary information (ESI) available: Experimental
section. CCDC 828929. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc13554f
Scheme 1 Construction of enantioenriched spiro-[4-chromanone-
3,30-pyrrolidine] derivatives via catalytic asymmetric 1,3-dipolar
cycloaddition using 3-alkylidene-4-chromanones as the dipolarophiles.
c
9600 Chem. Commun., 2011, 47, 9600–9602
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Table 1 Screening studies of the catalytic asymmetric 1,3-dipolar
cycloaddition of imino ester 1a with (E)-3-benzylidenechroman-4-one
Table 2 Substrates scope of Cu(I)-catalyzed 1,3-dipolar cycloa-
ddition of various imino esters 1 with (E)-3-benzylidenechroman-4-
one 2aa
2aa
Entry
R1 (1)
3
Yieldb (%)
Eec (%)
1
p-Cl–Ph (1a)
o-Cl–Ph (1b)
m-Cl–Ph (1c)
Ph (1d)
p-MeO–Ph (1e)
p-Me–Ph (1f)
o-Me–Ph (1g)
m-Me–Ph (1h)
1-Naphthyl (1i)
2-Naphthyl (1j)
2-Furyl (1k)
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
85
81
87
85
90
86
95
94
93
83
86
91
89
89
92
94
89
89
89
90
86
90
2
3d
4
5
6
7
8d
9
Entry
L
[M]
Solvent T/1C Time/h Yieldb (%) Eec (%)
10
11
3ja
3ka
1
2
3
4
5
6
7
8
L1 AgOAc DCM
L1 CuBF4 DCM
L2 CuBF4 DCM
L3 CuBF4 DCM
L4 CuBF4 DCM
L5 CuBF4 DCM
L5 CuBF4 THF
L5 CuBF4 EtOAc rt
L5 CuBF4 MeCN rt
L5 CuBF4 PhMe
L5 CuBF4 DCM
rt
rt
rt
rt
rt
rt
rt
3
3
3
8
6
3
3
5
5
5
5
85
78
45
30
85
88
86
77
82
86
85
23
35
40
34
15
89
80
82
—
86
91
a
b
c
d
See Table 1. See Table 1. See Table 1. Carried out at ꢁ45 1C,
24 h.
With the optimal reaction conditions in hand, the scope of
spiro-[4-chromanone-3,30-pyrrolidine] derivatives formation
was demonstrated with various imino esters derived from
glycine esters. As shown in Table 2, a wide array of imino
esters derived from aromatic aldehydes reacted smoothly with
3-benzylidene chroman-4-one 2a to afford the corresponding
spiro-[4-chromanone-pyrrolidine] adducts exclusively in high
yields and good enantioselectivities (Table 2, entries 1–8). It
appears that the position and the electronic property of the
substituents on the aromatic rings have very limited effect on
the enantioselectivities. It is noteworthy that comparable results
were still achieved for the sterically hindered ortho-chloro and
ortho-methyl imino esters 1b and 1g in terms of diastereo/
enantioselectivity and reactivity (Table 2, entries 2 and 7).
Imino esters from a- or b-naphthylaldehyde also worked well
in this transformation producing the spirocyclic 3ia and 3ja
with 90% and 86% ee, respectively (Table 2, entries 9 and 10).
Remarkably, heteroaromatic imino ester 1k was also tolerated
in this reaction, and the desired spirocyclic 3ka could be obtained
in 86% yield and 90% ee (Table 2, entry 11). However, no
cycloaddition was observed when alkyl substituted imino ester
was tested under the same reaction conditions.
9
10
11
rt
ꢁ20
a
All reactions were carried out with 0.40 mmol of 1a and 0.20 mmol
b
of 2a in 2 mL solvent. CuBF4 = Cu(CH3CN)4BF4. Isolated yield.
c
Ee and 498 : 2 dr were determined by HPLC analysis.
4-chromanone–pyrrolidine 3aa in 91% yield with excellent
diastereoselectivity (dr 498 : 2). Encouraged by this promising
reactivity and diastereoselectivity of 3-benzylidene-chroman-
4-one in the racemic version, we then conducted the asym-
metric reaction to evaluate the enantioselective inductivity of
various chiral TF–BiphamPhos ligands developed in our group
recently, and the results are summarized in Table 1. Although
almost the same catalytic activity and diastereoselectivity
were achieved when using AgOAc/TF-BinphamPhos (L1)
and Cu(CH3CN)4BF4/TF-BinphamPhos (L1) as the catalyst,
the latter exhibited better asymmetric induction capacity
(Table 1, entries 1–2), which was different from our former
studies on the asymmetric synthesis of spiro-[oxindole-
3,30-pyrrolidine]9 employing N-unprotected 2-oxoindolin-
3-ylidenes as the dipolarophiles. Then, Cu(CH3CN)4BF4 was
selected as the metal source for further ligand survey (Table 1,
entries 2–6). Among the tested chiral TF–Biphamphos ligands,
L5 bearing two bromine at the 3,30-position of the backbone
was revealed as the most promising one, and provided spiro-
cyclic 3aa as the sole product in 88% yield and 89% ee (Table 1,
entry 6). The solvent effect was also studied, CH2Cl2 was revealed
to be the best solvent in terms of the yield and enantio-
selectivity while CH3CN was not suitable for this reaction
(Table 1, entries 6–10). Reducing the reaction temperature
from rt to ꢁ20 1C led to completion of reaction with an
excellent enantioselectivity of 91% ee (Table 1, entry 11).
Next, alkylidene chroman-4-ones were investigated under
the optimized experimental conditions to test the dipolarophiles
scope of this asymmetric 1,3-dipolar cycloaddition reaction,
and representative results are summarized in Table 3. For
dipolarophile partners, various arylidene chroman-4-ones
bearing electron-rich and electron-deficient groups on the
phenyl rings with different substitution patterns proved to be
viable substrates for this reaction, providing excellent diastereo-
selectivities and high enantioselectivities (Table 3, entries 1–5,
9 and 10). Hetero-aromatic arylidene chroman-4-one 2f derived
from 2-furylaldehyde also worked well for this reaction,
delivering the desired spirocyclic compound 3af with 89%
yield and 91% ee (Table 3, entry 6). Remarkably, alkylidene
c
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Table 3 Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of
imino esters 1a with various (E)-3-alkylidenechroman-4-ones 2a
spirocyclic [4-chromanone-3,30-pyrrolidine], a valuable structural
motif for drug discovery. Further investigations of the scope
and synthetic application of this methodology are ongoing,
and the results will be reported in due course.
This work is supported by the NSFC (20972117), the
Program for New Century Excellent Talents in university
(NCET-10-0649), the Program for Changjiang Scholars and
Innovative Research Team in University of the Ministry of
Education (IRT1030), 973 program (2011CB808600), SRFDP
(20090141110042), and the Fundamental Research Funds for
the Central Universities.
Entry
2
R2
R3
X
3
Yieldb (%) Eec (%)
1
2
3
4
5
6
7
8
2a Ph
H
H
H
H
H
H
H
H
Me
Cl
H
O
O
O
O
O
O
O
O
O
O
S
3aa 85
3ab 88
3ac 95
3ad 87
3ae 88
3af 89
3ag 75
3ah 88
3ai 95
3aj 87
3ak 93
91
92
94
92
91
91d
94
93
93
93
95
2b p-MeO–Ph
2c p-Cl–Ph
2d o-Cl–Ph
2e m-Cl–Ph
2f 2-furyl
2g CH3CH2CH2
2h Ph–CHQCH–
2i Ph
Notes and references
z For (20R,3R,40R,50R)-3aa: C26H22ClNO4, Mr = 447.90, T = 293 K,
orthorhombic, space group P212121, a = 9.960(9), b = 12.124(11), c =
18.738(16) A, V = 2263(3) A3, Z = 4, 4436 reflections measured, 2920
unique (Rint = 0.0503) which were used in all calculations. The final
wR2 = 0.1037 (all data), Flack w = ꢁ0.10(10). CCDC 828929 (3aa).
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10
11
2j Ph
2k Ph
a
b
c
d
See Table 1. See Table 1. See Table 1. 95 : 5 dr was determined
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were also tolerated in this transformation affording the corres-
ponding adducts with 94 and 93% ee, respectively (Table 3,
entries 7 and 8). Additionally, 3-benzylidene-thiochroman-
4-one 2k containing sulfur-tether also proved to be excellent
dipolarophile in this transformation producing the expected
spirocyclic 4-thiochromanone-3,30-pyrrolidine 3ak with excellent
diastereoselectivity and enantioselectivity (Table 3, entry 11).
The relative and absolute configuration of 3aa achieved by
Cu(CH3CN)4BF4/(S)-L5 was unequivocally determined as
(20R,3R,40R,50R) by X-ray diffraction analysis (see Fig. 2).z
Those of other adducts were tentatively proposed on the basis
of these results.
R. J. Vickers, A. Padwa and W. Pearson, Wiley
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In conclusion, we have developed a direct and facile access
to various enantioenriched spirocyclic [4-chromanone-3,30-
pyrrolidine] derivatives featuring one unique quarternary
stereogenic center and three tertiary stereogenic centers via
Cu(I)/TF–BiphamPhos-catalyzed asymmetric 1,3-dipolar cyclo-
addition reaction for the first time. This catalytic system
exhibited high reactivity, excellent diastereoselectivity, good
enantioselectivity and broad substrate scope under mild condi-
tions. This methodology presented herein could open up new
prospects for stereoselectively constructing highly functional
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Fig. 2 X-Ray structure of (20R,3R,40R,50R)-3aa.
9602 Chem. Commun., 2011, 47, 9600–9602
c
This journal is The Royal Society of Chemistry 2011