Highly diastereo- and enantioselective Cu-catalyzed [3 + 3] cycloaddition of propargyl esters with cyclic enamines toward chiral bicyclo[n.3.1] frameworks

Article abstract of DOI:10.1021/ja303129s

A new Cu-catalyzed asymmetric [3 + 3] cycloaddition of propargyl esters with cyclic enamines is reported. With a combination of Cu(OAc) ₂·H₂O and a chiral tridentate ferrocenyl-P,N,N ligand as the catalyst, perfect endo selectivities (endo/exo > 98/2) and excellent enantioselectivities (up to 98% ee) for endo cycloadducts were achieved under mild conditions. This method provides a simple and efficient approach for the synthesis of optically active bicyclo[n.3.1] frameworks.

Full text of DOI:10.1021/ja303129s

Communication
pubs.acs.org/JACS
Highly Diastereo- and Enantioselective Cu-Catalyzed [3 + 3]
Cycloaddition of Propargyl Esters with Cyclic Enamines toward Chiral
Bicyclo[n.3.1] Frameworks
Cheng Zhang,†,‡ Xin-Hu Hu,† Ya-Hui Wang,† Zhuo Zheng,† Jie Xu,† and Xiang-Ping Hu*,†
†Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
‡Graduate University of the Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
propargyl alcohol derivatives as C3 synthons have recently been
ABSTRACT: A new Cu-catalyzed asymmetric [3 + 3]
cycloaddition of propargyl esters with cyclic enamines is
reported. With a combination of Cu(OAc)2·H2O and a
chiral tridentate ferrocenyl-P,N,N ligand as the catalyst,
perfect endo selectivities (endo/exo > 98/2) and excellent
enantioselectivities (up to 98% ee) for endo cycloadducts
were achieved under mild conditions. This method
provides a simple and efficient approach for the synthesis
of optically active bicyclo[n.3.1] frameworks.
reported, and the Ru-catalyzed cycloadditions of propargyl
alcohols with 2-naphthols reported by Uemura and Nishibaya-
shi have demonstrated that propargyl alcohols can be used as
dielectrophilic C3 synthons via Ru−allenylidene intermediates
(Scheme 2). In this work, we report the first example of highly
Scheme 2. Propargyl Alcohol Derivatives as C3 Synthons for
Cycloaddition via Metal−Allenylidene Intermediates
icyclo[n.3.1]alkane frameworks are quite common in
B
nature as a constituent of many natural and biologically
active products and their metabolites.1 Cycloaddition of
appropriate C3 synthons with cyclic ketones via α,α′-annulation
or with their enamine derivatives via β,β′-annulation would
offer straightforward access to such frameworks. Since cyclic
ketones or enamines provide two nucleophilic C atoms, C3
synthons possessing two electrophilic centers are required.
With this strategy, many approaches have been developed,
including asymmetric versions.2 However, only a few catalytic
asymmetric methods have been achieved to date.3 The
development of catalytic enantioselective access to stereo-
chemically defined bicyclo[n.3.1] molecules remains challeng-
ing.
diastereo- and enantioeslective Cu-catalyzed [3 + 3] cyclo-
addition of cyclic enamines with propargyl esters as C3
synthons employing a chiral ferrocenyl-P,N,N ligand, leading
to optically active bicyclo[n.3.1] skeletons.
Recently, catalytic transformations featuring metal−allenyli-
dene intermediates generated from propargyl alcohols or their
derivatives have attracted a great deal of attention.4 Theoretical
and experimental studies have indicated that the Cα and Cγ
atoms of the metal−allenylidene complexes are the electrophilic
centers.5 We therefore envisioned that a cycloaddition of cyclic
enamines with propargyl esters as C3 synthons would be
possible if the metal−allenylidene could be catalytically
generated in the presence of a suitable metal catalyst (Scheme
1). In fact, some Au-6 and Ru-catalyzed7 cycloadditions using
We started our investigation by screening different metal
catalysts for the cycloaddition of 1-phenyl-2-propynyl acetate
(1a) with N,N-diethyl-1-cyclohexen-1-amine (2a), and some
representative results are summarized in Table 1. Whereas most
of the tested metal catalysts were inefficient in the attempted
catalytic cycloaddition, Cu(OAc)2·H2O was found to be a
probable catalyst [see the Supporting Information (SI)]. The
use of Cu(OAc)2·H2O afforded the propargyl alkylation
product 4,8 accompanied by the formation of the expected
1
cycloadduct 3a to a small extent as detected by H NMR
analysis (entry 1). This result prompted us to modify
Cu(OAc)2·H2O with a chiral ligand in an attempt to improve
the cyclization outcome and achieve enantioinduction in 3a.
Gratifyingly, the addition of (S)-BINAP (L1) significantly
facilitated cycloaddition over competitive propargyl substitution
Scheme 1. General Reaction Scheme for [3 + 3]
Cycloaddition of Propargyl Esters with Cyclic Enamines
Received: April 1, 2012
Published: May 30, 2012
© 2012 American Chemical Society
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Communication
Table 1. Optimization of [3 + 3] Cycloaddition of Propargyl
Acetate 1a with Cyclic Enamines 2a−d
Table 2. Enantioselective Cu-Catalyzed [3 + 3]
a
a
Cycloaddition: Propargyl Acetate Scope
yield
ee of endo-3
b
c
d
entry
R
1
3
(%)
endo/exo
(%)
1
2
3
4
5
6
7
8
9
C6H5
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
86
85
88
86
86
88
80
84
87
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
95
97
98
96
97
97
97
94
92
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-FC6H4
c
yield of 3a
endo-3a (% ee
d
b
entry
[M]
2
L*
(%)
):exo-3a:4
1
2
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OTf)2
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
−
trace
58
62
82
86
87
25
82
52
49
−
7:0:93
4-BrC6H4
4-CF3C6H4
4-MeC6H4
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
61 (60):12:27
78 (42):6:16
97 (90):3:0
>98 (95):<2:0
97 (94):3:0
34 (93):1:65
97 (96):3:0
49 (80):29:22
48 (82):16:36
6:0:94
1g
1h
1i
3g
3h
3i
3
4
4-
5
MeOC6H4
6
10
11
2-naphthyl
2-furyl
3-pyridyl
n-Pr
1j
3j
86
86
71
68
58
74
>98/2
>98/2
>98/2
>98/2
>98/2
−
97
95
89
91
97
67
7
CuCl
1k
1l
3k
3l
8
CuOAc
e
12
9
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
13
14
1m
1n
1o
3m
3n
3o
10
11
Me
f
15
H
a
Conditions: 1a (0.3 mmol, 1.0 equiv), 2a−d (0.36 mmol, 1.2 equiv),
[M] (0.015 mmol, 5 mol %), L* (0.0165 mmol, 5.5 mol %), i-Pr2NEt
(0.36 mmol, 1.2 equiv), 2 mL of MeOH, rt, 12 h. Isolated yields.
The %ee was determined by chiral HPLC analysis. The endo-3a:exo-
a
Conditions: 1 (0.3 mmol, 1.0 equiv), 2a (0.36 mmol, 1.2 equiv),
Cu(OAc)2·H2O (0.015 mmol, 5 mol %), (Rc,Sp)-6 (0.0165 mmol, 5.5
mol %), i-Pr2NEt (0.36 mmol, 1.2 equiv), 2 mL of MeOH, rt, 12 h.
Isolated yields. Determined by H NMR analysis. Determined by
chiral HPLC analysis. A catalyst loading of 10 mol % was used.
Instead of propargyl acetate 1o, the corresponding ethyl carbonate
b
c
d
b
c
d
1
1
3b:4 ratios were determined by H NMR analysis.
e
f
was used, and (R)-5 was used as the catalyst ligand.
observed, with an endo/exo ratio as high as >98/2. It appeared
that the position of the substituent on the phenyl ring had little
effect on this process. Thus, the three substrates with a Cl
group at the different positions of the phenyl ring gave similar
results (entries 2−4). However, the electronic properties of the
substituent at the para position showed some influence on the
enantioselectivity, with substrates having an electron-with-
drawing group tending to give higher enantioselectivities than
those having an electron-donating group (entries 5−9). Thus, a
p-methoxy substituent led to slightly decreased enantioselec-
tivity (92% ee) (entry 9). 2-Naphthyl-substituted substrate 1j
was also a suitable reaction partner, giving endo cycloadduct 3j
with 97% ee (entry 10). O-Heteroaromatic substrate 1k turned
out to serve well as the substrate for this process, providing
endo cycloadduct 3k with 95% ee (entry 11). However, 3-
pyridyl substrate 1l was less efficient in this reaction, as a 71%
yield with 89% ee was achieved under a catalyst loading of 10
mol % (entry 12). It is noteworthy that the propargyl acetates
1m and 1n with a nonaromatic substituent were also suitable
substrates, providing the corresponding endo cycloadducts 3m
and 3n with good enantioselectivities (entries 13 and 14).
However, using the most simple propargyl acetate, 1o (R = H),
as the substrate for this cycloaddition was less successful. With a
combination of Cu(OAc)2·H2O and (R)-5 as the catalyst, the
ethyl carbonate corresponding to 1o (i.e., the ethyl carbonate of
prop-2-yn-1-ol) smoothly gave cycloadduct 3o in 74% yield
with 67% ee (entry 15).
with a 3a/4 selectivity of 73/27 (entry 2). Subsequent ligand
screening identified chiral P,N,N-tridentate ligands developed
within our group as promising ligands (entries 3−5). Among
them, the ferrocenyl ligand (Rc,Sp)-6 (L4) showed the best
performance, affording the cycloadduct 3a as the only product
in good yield (86%) with excellent endo selectivity (endo/exo
> 98/2) and high enantioselectivity (95% ee) for endo-3a (entry
5). Investigation of Cu salts modified with (Rc,Sp)-6 showed
that except for CuCl,9 all of the Cu salts, including Cu(OTf)2
and CuOAc, displayed excellent performance, exclusively
providing the cycloadduct 3a in good yields with high
diastereo- and enantioselectivities (entries 5, 6, and 8).10 In
addition, we investigated the influence of the amino group of
the cyclic enamine substrate on the selectivity between
cycloaddition and competitive propargyl alkylation. The results
disclosed that the presence of cyclic amino groups dramatically
decreases the selectivity for cycloaddition. Thus, the use of
morpholine-derived enamine 2d greatly suppressed the cyclo-
addition, predominantly forming the alkylation product 4
(entry 11).
Under the optimized conditions (see Table 1, entry 5), the
scope of the cycloaddition with respect to the propargyl acetate
substrate was investigated (Table 2). We were pleased to find
that the reaction worked efficiently for all of the phenyl-
substituted substrates tested, which gave the desired endo
adducts in good yields with excellent enantioselectivities (92−
98% ee). In all cases, the cycloadduct was the only product
The cyclic enamine scope was also surveyed (Table 3). The
reaction demonstrated a broad generality with respect to the
cyclic enamine. In all cases, the cycloadducts were obtained as
the only product, with endo selectivities of >98/2. Enamine 2e
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Communication
cycloaddition with five-membered substrate 8 resulted in
efficient formation of endo cycloadduct 10 as the only product
in 50% yield with 98% ee. For 9, however, a higher reaction
temperature (40 °C) and a longer reaction time (60 h) were
required in order to obtain a reasonable conversion.
Table 3. Enantioselective Cu-Catalyzed [3 + 3]
Cycloaddition: Cyclic Enamine Scope
a
The absolute configuration of endo-3a was determined by X-
ray analysis of compound 12, which was obtained by
derivatization of endo-3a with (S)-1-amino-2-(methoxymethyl)-
pyrrolidine (SAMP) (Scheme 4).11
Scheme 4. Derivatization of endo-3a for Determination of
the Absolute Configuration
We propose the plausible mechanism shown in Scheme 5. In
the first step, the Cu complex probably forms a π complex with
Scheme 5. Proposed Mechanism for [3 + 3] Cycloaddition
of Propargyl Acetate with Cyclic Enamine
a
Conditions: 1 (0.3 mmol, 1.0 equiv), 2a (0.36 mmol, 1.2 equiv),
Cu(OAc)2·H2O (0.015 mmol, 5 mol %), (Rc,Sp)-6 (0.0165 mmol, 5.5
mol %), i-Pr2NEt (0.36 mmol, 1.2 equiv), 2 mL of MeOH, rt, 12 h. All
yields are isolated yields, and ee values were determined by chiral
HPLC analysis. The endo/exo and trans/cis ratios were determined by
b
c
1H NMR analysis. Isolated yield of a cis/trans mixture. The reaction
was performed at 40 °C.
derived from 4-oxacyclohexanone worked as efficiently as its
cyclohexenyl analogue 2a. The presence of a para group on the
cyclohexenamine had some effect on the reactivity and
enantioselectivity, and a bulky tert-butyl group led to
diminished enantioselectivity (81% ee). When a 4,4-disub-
stituted cyclohexenamine was probed as the substrate, an
elevated reaction temperature (40 °C) was necessary for
complete conversion.
In contrast to 2a, its five- and seven-membered analogues 8
and 9 proved to be more difficult substrates for this process
(Scheme 3). Under the optimized conditions, the reactions of
propargyl acetate 1a with 8 and 9 proceeded very sluggishly.
When 1a was replaced with the corresponding ethyl carbonate
7 and the reaction was performed in EtOH at 0 °C, the
the propargyl acetate (A). Deprotonation of A with a base
would then give Cu−acetylide complex B, which would explain
why a propargyl acetate bearing an internal alkyne moiety such
as 1,3-diphenyl-2-propynyl acetate did not react at all (see the
SI). Loss of an acetyl group from B would form Cu−
allenylidene complex C.12 Recent studies of Cu-catalyzed
propargyl substitution have supported the formation of a Cu−
allenylidene complex as a key intermediate.13 Nucleophilic
attack of the enamine Cβ at the Cγ atom of C would give the
corresponding Cu−acetylide complex D, which should be the
key step for the stereoselection. The H atom could then shift to
Cβ of the Cu−acetylide complex to give Cu−vinylidene
complex E. Intramolecular nucleophilic attack of the enamine
Cβ at the Cα atom of E would afford alkenyl complex F. Further
investigations to elucidate the reaction mechanism are
underway and will be reported in due course. In addition,
Scheme 3. Cycloaddition of Propargyl Carbonate 7 with
Five- and Seven-Membered Cyclic Enamines
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Journal of the American Chemical Society
Communication
(5) (a) Pilette, D.; Ouzzine, K.; Le Bozec, H.; Dixneuf, P. H.;
Rickard, C. E. F.; Roper, W. R. Organometallics 1992, 11, 809.
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2126.
unambiguous structural characterization of a CuCl−(Rc,Sp)-6
complex by X-ray analysis has been achieved.14
In summary, we have developed the first example of Cu-
catalyzed asymmetric [3 + 3] cycloaddition of propargyl esters
with cyclic enamines. A combination of Cu(OAc)2·H2O and a
chiral tridentate ferrocenyl-P,N,N ligand has been identified as
an efficient catalyst that afforded excellent endo selectivity
(endo/exo > 98/2) and normally excellent enantioselectivity
for a wide range of substrates. The mild conditions, broad
substrate scope, good yield, and high diastereo- and
enantioselectivity make the present process highly useful in
the synthesis of optically active bicyclo[n.3.1] frameworks.
Efforts to expand the scope of this cycloaddition and to
determine the reaction mechanism are underway.
(8) For reviews of catalytic propargyl substitution, see: (a) Detz, R.
J.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2009, 6263.
(b) Miyake, Y.; Uemura, S.; Nishibayashi, Y. ChemCatChem 2009, 1,
342. (c) Ding, C.-H.; Hou, X.-L. Chem. Rev. 2011, 111, 1914.
(d) Nishibayashi, Y. Synthesis 2012, 489.
(9) Fang and Hou recently reported that no reaction was observed in
the propargyl substitution of 2a with 1a by a CuCl/(R)-Cl-
MeOBIPHEP catalyst and that a low yield of the substitution product
4 was achieved by replacing 1a with the corresponding benzoate. See:
Fang, P.; Hou, X.-L. Org. Lett. 2009, 11, 4612.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental procedures; characterization data, H NMR and
13C NMR spectra, and HPLC data for ee analysis for endo-3a−
t, exo-3a, 4, and 10−12; and X-ray data (CIF) for 12 and the
CuCl/(Rc,Sp)-6 complex. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
(10) (a) Yazaki, R.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc.
2010, 132, 10275. (b) Rauniyar, V.; Wang, Z. J.; Burks, H. E.; Toste, F.
D. J. Am. Chem. Soc. 2011, 133, 8486.
■
Corresponding Author
xiangping@dicp.ac.cn
(11) For details of the X-ray analysis of 12, see the SI.
(12) For recent examples of Cu-catalyzed asymmetric propargyl
substitution, see: (a) Detz, R. J.; Delville, M. M. E.; Hiemstra, H.; van
Maarseveen, J. H. Angew. Chem., Int. Ed. 2008, 47, 3777. (b) Hattori,
G.; Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int. Ed.
2008, 47, 3781. (c) Hattori, G.; Yoshido, A.; Miyake, Y.; Nishibayashi,
Y. J. Org. Chem. 2009, 74, 7603. (d) Hattori, G.; Miyake, Y.;
Nishibayashi, Y. ChemCatChem 2010, 2, 155. (e) Detz, R. J.; Abiri, Z.;
le Griel, R.; Hiemstra, H.; van Maarseveen, J. H. Chem.Eur. J. 2011,
17, 5921. (f) Yoshida, A.; Hattori, G.; Miyake, Y.; Nishibayashi, Y. Org.
Lett. 2011, 13, 2460.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this research from the Dalian Institute of Chemical
Physics (CAS) is gratefully acknowledged.
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