Fulvenes as effective dipolarophiles in copper(I)-catalyzed [6+3] cycloaddition of azomethine ylides: Asymmetric construction of piperidine derivatives

Article abstract of DOI:10.1002/anie.201208799

As easy as π: Fulvenes serve as 6π dipolarophiles in the title reaction in the presence of the chiral Cu^I/(S)-L complex. The present system provides a unique and straightforward access to enantioenriched, highly functionalized piperidine derivatives in good yields and excellent diastereoselectivities and enantioselectivities. Copyright

Full text of DOI:10.1002/anie.201208799

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DOI: 10.1002/anie.201208799
Asymmetric Catalysis
Fulvenes as Effective Dipolarophiles in Copper(I)-Catalyzed [6+3]
Cycloaddition of Azomethine Ylides: Asymmetric Construction of
Piperidine Derivatives**
Zhao-Lin He, Huai-Long Teng, and Chun-Jiang Wang*
Catalytic asymmetric [3+2] cycloaddition of azomethine
ylides is one of the best methods for constructing enantio-
enriched heterocyclic pyrrolidines,[1] and extensive studies
have been conducted on the use of various electron-deficient
alkenes as the 2p synthons over the past decade.[2] However,
although there are elegant and creative azomethine-ylide-
involved cycloaddition reactions toward the construction of
five-membered pyrrolidine architectures,[1,2] the direct cata-
lytic asymmetric approach to enantioenriched six-membered
Scheme 1. Catalytic asymmetric [3+2] cycloaddition reactions using
electron-deficient alkenes as 2p components (previous work) and
[6+3] cycloaddition using fulvenes as 6p components (this work).
EWG=electron-withdrawing group.
heterocyclic piperidines, which are prevalent scaffolds that
serve as the core structures of natural alkaloids and bioactive
molecules,[3] has met with little success,[4] and we believe this
represents a considerable challenge.
In 2003, Hong et al.[5] reported a [6+3] cycloaddition of
azomethine ylides with fulvenes[6], in which fulvenes served as
6p components, thus leading to the synthesis of racemic six-
membered piperidine derivatives. However, there is a lack of
catalytic asymmetric [6+3] cycloadditions which tolerate
variations in both the azomethine ylides and fulvenes.
Stimulated by the biological significance of piperidine deriv-
atives and the challenging synthetic difficulties associated
with enantio- and diastereoselectivity control, we questioned
whether fulvenes containing no electron-withdrawing groups
could be employed as efficient 6p dipolarophiles and provide
a straightforward and asymmetric approach to enantio-
enriched piperidines. Very recently, one example on the
asymmetric cycloaddition of unsymmetrical fulvenes and
azomethine ylides has been published concurrently with the
preparation of the present manuscript.[7] Herein, we report
the CuI/TF-BiphamPhos-catalyzed asymmetric synthesis of
highly substituted piperidines by the [6+3] cycloaddition of
azomethine ylides with various fulvenes (Scheme 1, right),
and subsequent transformations which allow facile access to
enantioenriched fused polycyclic piperidine derivatives with-
out loss in diastereoselectivity and enantioselectivity.
For our initial studies, the readily available fulvene 2a[8]
was chosen as the model 6p component. Initially we began
our investigations by examining the ability of CuI/TF-
BiphamPhos and AgI/TF-BiphamPhos[9] complexes to probe
the possibility of an asymmetric variant of this challenging
[6+3] cycloaddition reaction employing the N-(4-chloro-
benzylidene)glycine methyl ester 3a as the dipole precursor
(Table 1). To our delight, the reaction was completed in less
than 24 hours with AgOAc/(S)-TF-BiphamPhos (1a) as the
catalyst and Et3N as the base in dichloromethane at room
temperature, thus yielding the expected six-membered heter-
ocyclic piperidine 4a with excellent diastereoselectivity and
36% ee (Table 1, entry 1). Neither [3+2] nor regioisomeric
[6+3] cycloadducts were observed although the by-product[10]
formed by self-cycloaddition of 3a was isolated in 10% yield.
The cycloadduct 4a is formed exclusively and no [1,5] H-
shift[11] occurred, probably because most of the substituents
on the six-memebered piperidine ring are placed at thermo-
dynamically favored equatorial positions of the chairlike
conformation (see X-ray analysis of 4o below). 4a is
moderately stable, and can be kept at À108C for 2–3 weeks
without dimerization or oligomerization.[12] Studies showed
that using a copper(I) salt as the metal precursor gave better
results than a silver(I) salt in terms of the yield and
enantioselectivity (entry 2). Encouraged by these results,
Cu(CH3CN)4BF4 was selected as the model metal source for
additional ligand, solvent, and base screening. The ligand 1b,
bearing the bulkier and electron-donating xylyl group on the
phosphorus atom, had detrimental effects on the enantio-
selectivity (entry 3), while 1c, bearing 3,5-a bis(trifluorome-
thyl)phenyl group was totally inactive (entry 4). Further
ligand tuning revealed that 1d with two bromine atoms at the
[*] Z.-L. He,[+] H.-L. Teng,[+] Prof. Dr. C.-J. Wang
College of Chemistry and Molecular Sciences, Wuhan University
Wuhan, 430072 (China)
E-mail: cjwang@whu.edu.cn
Prof. Dr. C.-J. Wang
State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin, 300071 (China)
[+] These authors contributed equally to this work.
[**] This work is supported by the 973 Program (2011CB808600), NSFC
(21172176), NCET-10-0649, IRT1030, and the Fundamental
Research Funds for the Central Universities.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208799.
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Table 1: Optimization of catalytic asymmetric [6+3] cycloaddition of
imino ester 3a with fulvene 2a.[a]
Table 2: Substrate scope for catalytic asymmetric [6+3] cycloaddition of
various imino ester 3 with fulvene 2a.[a]
Entry
R
4
Yield [%][b,c]
ee [%][d]
1
2
3
4
5
6
7
8
p-ClC6H4 (3a)
Ph (3b)
4a
4b
4c
4d
4e
4 f
4g
4h
4i
77
80
87
69
87
72
75
81
78
72
73
68
94
90
93
94
99
90
99
96
92
86
95
91
m-ClC6H4 (3c)
p-BrC6H4 (3d)
p-CF3C6H4 (3e)
o-FC6H4 (3 f)
p-MeC6H4 (3g)
p-MeOC6H4 (3h)
2-naphthyl (3i)
2-thienyl (3j)
Cy (3k)
9
10
11
12
4j
4k
4l
Entry
L
[M]
Base
Solvent
T
[8C]
t
Yield
ee
iBu (3l)
[h] [%][b,c] [%][d]
[a] All reactions were carried out with 0.5 mmol of 2a and 0.25 mmol of 3
in 1.5 mL of CH2Cl2. [b] Yield of isolated product. [c] All the coupling
constants JaxÀax for H1-H7a in 4 are greater than 9.0 Hz. [d] Determined by
HPLC analysis.
1
2
3
4
5
6
7
8
1a AgOAc Et3N
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
24 70
24 74
24 73
24 trace
24 78
24 trace
24 trace
24 62
24 75
24 63
24 58
24 49
36
64
35
–
83
–
1a CuBF4
1b CuBF4
1c CuBF4
1d CuBF4
1e CuBF4
1 f CuBF4
1g CuBF4
1d CuBF4
1d CuBF4
1d CuBF4
1d CuBF4
1d CuBF4
1d CuBF4
1d CuBF4
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
on the aryl rings all work well and provide the corresponding
products in high yields (69–87%), excellent diastereoselec-
tivities (d.r. > 20:1), and enantioselectivities (90–99% ee;
Table 2, entries 1–9). The substitution pattern of the arene
had little effect on the selectivity of the cycloaddition
reaction, and the ortho-substituted imino ester 3 f underwent
this transformation, thus leading exclusively to the desired
piperidine with 90% ee (entry 6). Additionally, the hetero-
aryl-substituted imino ester 3j derived from 2-thenaldehyde
also works in this transformation leading to 72% yield and
86% ee (entry 10). Noticeably, the less reactive imino esters
3k and 3l from aliphatic aldehydes also proved to be viable
substrates in this process, thereby producing the correspond-
ing cycloadducts in good yields with 95 and 91% ee,
respectively (entries 11 and 12).
–
25
67
80
84
73
82
89
94
9
10
11
12
13
14
15
PhMe
Et2O
MeCN
Cs2CO3 CH2Cl2
Cs2CO3 CH2Cl2
Cs2CO3 CH2Cl2
6
78
À20 12 72
À40 24 77
[a] All reactions were carried out with 0.5 mmol of 2a and 0.25 mmol of
3a in 1.5 mL of CH2Cl2. CuBF4 =Cu(CH3CN)4BF4. [b] Yield of isolated
product. [c] The coupling constant Jax-ax for H1-H7a in 4a is 10.4 Hz.
[d] The ee and >20:1 d.r. values were determined by HPLC analysis. The
minor diastereomer was not detected in the 1H NMR spectrum of the
crude reaction mixture. THF=tetrahydrofruran.
Next, we evaluated symmetrical fulvenes with different
ring sizes. As shown in Table 3, fulvenes bearing four-to
seven-membered rings did not influence the reaction out-
comes, thus delivering their respective spiropiperidines in
good yields with 91–94% ee (4m–p). A cyclic fulvene derived
from tetrahydro-4H-pyran-4-one was also a viable 6p dipo-
larophile, thereby furnishing the corresponding spirocycles
(4q–s) with excellent enantioselectivities. Additionally, good
yield and high diastereo- and enantioselectivity (4t) were
achieved for the symmetric acyclic fulvene 2g derived from
pentan-3-one. The relative and absolute configuration of the
spiropiperidine 4o, using CuI/(S)-1d, was unequivocally
determined as (1’S,3’R,7a’S) by X-ray crystallographic anal-
ysis.[13]
3,3’-position of TF-BIPHAM backbone was the most effec-
tive ligand (entry 5). Other commercially available ligands
are either ineffective or provide relatively poor enantiomeric
excess (entries 6–8). Dichloromethane was shown to be the
best solvent in terms of the yield and enantioselectivity
(entries 5 and 9–12). Examination of various organic and
inorganic bases disclosed that Cs2CO3 was the optimal base
and could accelerate the reaction without loss of diastereo-
selectivity and enantioselectivity (entry 13). The cycloaddi-
tion performed well at temperatures as low as À408C with
Cs2CO3 as the base, thus leading to full conversion with
excellent diastereoselectivity and 94% ee within 24 hours
(entry 15).
With the optimal reaction conditions established, the
scope of piperidine formation was demonstrated with various
imino esters. In general, the reaction proceeded well to afford
the desired products exclusively in good yields and excellent
diastereo- and enantioselectivity. As shown in Table 2,
aromatic imino esters bearing different electronic properties
Having succeeded in the stereoselective [6+3] cycloaddi-
tion reaction of imino esters with symmetrical fulvenes, we
investigated unsymmetrical fulvenes derived from aldehydes
which can generate an additional tertiary stereogenic center
on the piperidine ring along with the other three tertiary
stereogenic centers. The scope of the reaction of the unsym-
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Table 3: Substrate scope for catalytic asymmetric [6+3] cycloaddition of
imino ester 3 with symmetrical fulvenes 2.[a]
Table 4: Substrate scope for catalytic asymmetric [6+3] cycloaddition of
imino esters 3 with unsymmetrical fulvenes 5.[a]
[a] All reactions were carried out with 0.75 mmol of 5 and 0.5 mmol of 3.
[b] Yield of pure isolated 6, and the yield of pure isolated epi-6 has been
included in the Supporting Information. [c] The d.r. value was deter-
mined by 1H NMR analysis of the crude reaction mixture and additionally
confirmed by the yields of isolated 6 and epi-6. All the coupling constants
Jax-ax for H1-H7a in 6 and epi-6 are greater than 9.0 Hz; the coupling
constants Jax-ax for H3-H4 in 6 are greater than 9.0 Hz; the coupling
constants Jax-eq for H3-H4 in epi-6 are less than 5.0 Hz. [d] The ee value was
determined by HPLC analysis. [e] The number in bracket is the ee value of
the minor isomer epi-6.
[a] All reaction were carried out with 0.5 mmol of 2 and 0.25 mmol of 3 in
1.5 mL of CH2Cl2. [b] Yield of isolated product. [c] All the coupling
constants Jax-ax for H1’-H7a’ in 4 are greater than 9.0 Hz. [d] Determined by
HPLC analysis.
metrical fulvenes 5 with imino esters is summarized in
Table 4. Indeed, all tested unsymmetrical fulvenes have
proven to be excellent substrates in this cycloaddition
reaction, thus giving rise to the desired cycloadducts as two
diastereomers in good yields with good diastereoselectivities
and excellent enantioselectivities (6a–e). In general, much
higher reactivity was exhibited by unsymmetrical fulvenes
compared with symmetrical ones probably because of the
reduced steric hindrance. Noticeably, the 3,4-trans-substituted
piperidine 6 was formed as the major isomer according to the
bulky disubstituted double bond, thus affording 7 while the
bulky trisubstituted double bond adjacent to the quaternary
carbon center remains untouched (Scheme 2a). Both double
bonds in 6c could be reduced efficiently because of the
absence of an adjacent bulky quaternary center, thus deliver-
ing 8 with acceptable diastereoselectivity (Scheme 2b). Con-
jugated double bonds in the cycloadducts render those
piperidine derivatives suitable dienes for a Diels–Alder
reaction. Compounds 4a, 6c, and 6d can be readily converted
into the corresponding fused piperidines 10, 11c, and 11d,
bearing seven to eight stereogenic centers, by a facile catalyst-
free Diels–Alder reaction in highly diastereoselective manner
(Scheme 2c,d). An X-ray analysis of a single crystal of 11d[13]
showed an R configuration for the stereogenic center at the 4-
position of the piperidine ring, and thus also corresponding to
the moiety in 6d (Figure 1).
4
Hax3-Hax coupling constant (> 10.0 Hz) in the corresponding
1H NMR spectra, and was additionally confirmed by X-ray
analysis of the derived 11d[13] (see below). The minor isomer
epi-6 was determined to have a 3,4-cis-configuration based on
a less than 5.0 Hz coupling constant between H3 and H4, and
assigned as a Jax-eq value for Hax3-Heq4. Additionally, the
consistently excellent diastereo- and enantioselectivity (6e)
obtained for the cycloaddition of the fulvene 5e derived from
aliphatic aldehyde is noteworthy as such a reaction partner
was shown to be relatively challenging substrate in previous
studies.[5,7]
A plausible transition-state model is proposed as a well-
defined tetrahedral catalyst/azomethine ylide complex, in
which the in situ formed azomethine ylide is coordinated to
the copper center of the active species bearing (S)-TF-
BiphamPhos because of the unfavorable steric repulsion
between the phenyl group in the ylide and the phenyl ring on
The optically active piperidines can be readily converted
into synthetically useful compounds. The direct hydrogena-
tion of 4a in the presence of Pd/C specifically reduced the less
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Figure 2. Proposed transition state leading to (1S,3R,4R,7aS)-6.
forwardly constructing structurally and stereochemically rich
piperidines, a valuable structural motif for drug discovery.
Efforts are currently underway to elucidate the mechanistic
details, and the scope and limitations of this reaction, the
results of which will be reported in due course.
Received: November 2, 2012
Revised: December 24, 2012
Published online: January 30, 2013
Keywords: asymmetric catalysis · azomethine ylides · copper ·
.
cycloaddition · heterocycles
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In summary, we have described a novel asymmetric [6+3]
cycloaddition of imino esters with various readily available
fulvenes catalyzed by CuI/TF-Biphamphos under mild reac-
tion conditions with good yields, excellent diastereoselecti-
viyies, high enantioselectivities, and broad substrate scope.
Notably, this methodology and subsequent transformations
presented herein could open up new prospects for straight-
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can be kept for 4–7 days at À108C without dimerization or
oligomerization.
[13] CCDC 897072 (4p) and 899358 (11d) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[5] B.-C. Hong, A. K. Gupta, M.-F. Wu, J.-H. Liao, G.-H. Lee, Org.
Lett. 2003, 5, 1689.
[6] For review on fulvenes, see: a) J. H. Day, Chem. Rev. 1953, 53,
167; b) E. D. Bergmann, Chem. Rev. 1968, 68, 41.
[14] M. Wang, C.-J. Wang, Z. Lin, Organometallics 2012, 31, 7870.
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Angew. Chem. Int. Ed. 2013, 52, 2934 –2938