Generation of Donor/Donor Copper Carbenes through Copper-Catalyzed Diyne Cyclization: Enantioselective and Divergent Synthesis of Chiral Polycyclic Pyrroles

Article abstract of DOI:10.1021/jacs.9b09303

The generation of metal carbenes from readily available alkynes represents a significant advance in metal carbene chemistry. However, most of these transformations are based on the use of noble-metal catalysts and successful examples of such an asymmetric version are still very scarce. Here a copper-catalyzed enantioselective cascade cyclization of N-propargyl ynamides is reported, enabling the practical and atom-economical construction of diverse chiral polycyclic pyrroles in generally good to excellent yields with wide substrate scope and excellent enantioselectivities (up to 97:3 e.r.). Importantly, this protocol represents the first copper-catalyzed asymmetric diyne cyclization. Moreover, mechanistic studies revealed that the generation of donor/donor copper carbenes is presumably involved in this 1,5-diyne cyclization, which is distinctively different from the related gold catalysis, and thus it constitutes a novel way for the generation of donor/donor metal carbenes.

Full text of DOI:10.1021/jacs.9b09303

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Article
Generation of Donor/Donor Copper Carbenes through
Copper-Catalyzed Diyne Cyclization: Enantioselective
and Divergent Synthesis of Chiral Polycyclic Pyrroles
Feng-Lin Hong, Ze-Shu Wang, Dong-Dong Wei, Tong-Yi Zhai,
Guo-Cheng Deng, Xin Lu, Rai-Shung Liu, and Long-Wu Ye
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b09303 • Publication Date (Web): 26 Sep 2019
Downloaded from pubs.acs.org on September 26, 2019
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Generation of Donor/Donor Copper Carbenes through Copper-
Catalyzed Diyne Cyclization: Enantioselective and Divergent Synthesis of
Chiral Polycyclic Pyrroles
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Feng-Lin Hong,† Ze-Shu Wang,† Dong-Dong Wei,† Tong-Yi Zhai,† Guo-Cheng Deng,† Xin Lu,†
Rai-Shung Liu,‡ and Long-Wu Ye*,†,§
†State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province,
Key Laboratory for Theoretical and Computational Chemistry of Fujian Province, and College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen 361005, China
‡Department of Chemistry, National Tsing-Hua University, Hsinchu, Taiwan 30013, Republic of China
§State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Scienc-
es, Shanghai 200032, China
Supporting Information Placeholder
ABSTRACT: The generation of metal carbenes from readily available alkynes represents a significant advance in metal carbene
chemistry. However, most of these transformations are based on the use of noble-metal catalysts and successful examples of such an
asymmetric version are still very scarce. Here a copper-catalyzed enantioselective cascade cyclization of N-propargyl ynamides is
reported, enabling the practical and atom-economical construction of diverse chiral polycyclic pyrroles in generally good to excel-
lent yields with wide substrate scope and excellent enantioselectivities (up to 97:3 e.r.). Importantly, this protocol represents the
first copper-catalyzed asymmetric diyne cyclization. Moreover, mechanistic studies revealed that the generation of donor/donor
copper carbenes is presumably involved in this 1,5-diyne cyclization, which is distinctively different from the related gold catalysis,
and thus it constitutes a novel way for the generation of donor/donor metal carbenes.
metal catalysts and the asymmetric version, remain
challenging yet highly desirable.
INTRODUCTION
Catalytic transformations involving metal carbenes are ar-
guably the most important aspect of homogeneous transition
metal catalysis.1 Recently, catalytic generation of metal
Over the past decades, transition metal (M: Au, Pt, Ag, Rh,
Ru, Ir) catalyzed intramolecular cyclizations of 1,n-diynes (n
= 3, 4, 5, 6, 7, etc.) have proven to be a powerful method for
the rapid construction of various structurally complex cyclic
molecules due to their high bond-forming efficiency and atom
economy.9-14 Among those, catalytic 1,5-diyne cyclization,
primarily via metal vinylidene,11 carbene12 or vinyl cation in-
termediates,13 has attracted increasing attention in recent years.
Despite these remarkable achievements, these reactions have
so far been mostly limited to the noble-metal catalysts.
Moreover, no direct catalytic asymmetric intramolecular
cyclizations of 1,5-diynes have been reported to the best of our
knowledge.15,16 Therefore, it is highly desirable to develop a
non-noble metal catalyzed asymmetric cyclization of diynes,
which not only represents an attractive and efficient strategy to
build chiral cyclic molecules, but also may help to elucidate
carbenes from readily available alkynes represents
a
significant advance in metal carbene chemistry,2 and most
general methods for the generation of metal carbene
intermediates via this non-diazo approach include the
cycloisomerization of 1,6-enynes,3 1,2-acyloxy migration of
propargylic carboxylates,4 alkyne oxidation with pyridine N-
oxides or sulfoxides and alkyne amination based on azides,5
isoxazoles6 or sulfilimines7 (Scheme 1A). In addition, the
generation of donor/donor carbenes via transition metal-
catalyzed enynal/enynone cyclization has also been nicely
exploited by López, Zhu and others (Scheme 1B).8
Nevertheless, new ways for the generation of metal carbenes
from alkynes, especially those based on the use of non-noble
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the reaction mechanism. As a continuation of our work on
try 6). Of note, the reaction proved to be less efficient when it
developing ynamide chemistry for heterocycle synthesis,17,18
we herein report an efficient copper-catalyzed enantioselective
cascade cyclization of N-propargyl ynamides, which repre-
sents the first copper-catalyzed asymmetric diyne cyclization
(Scheme 1C). This method enables the practical and atom-
economical19 construction of diverse chiral polycyclic pyrroles
in generally good to excellent yields with wide substrate scope
and excellent enantioselectivities (up to 97:3 e.r.). Furthermore,
mechanistic studies revealed that the generation of do-
nor/donor copper carbene intermediates is presumably in-
volved in this 1,5-diyne cyclization, which is distinctively
different from the related gold catalysis, and thus it constitutes
a novel way for the generation of donor/donor metal carbenes.
was performed at lower temperatures (Table 1, entries 8 and 9).
Other Lewis acids, including Zn(OTf)2, Y(OTf)3 and
Yb(OTf)3, and Brønsted acids failed to catalyze this cascade
reaction.21 Interestingly, the use of racemic SEGPHOS as ad-
ditive could slightly improve the reaction yield (Table 1, entry
10).
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12
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Table 1. Optimization of Reaction Conditions for the Cas-
cade Cyclization of Ynamide 1aa
Scheme 1. Generation of Metal Carbenes from Alkynes
A) General methods for the generation of gold carbenes from alkynes
a)
X
b)
O
OCOR2
AuL+
AuL+
R
[Au]
[Au]
R1
O
R2
X
R1
R
H
c)
AuL+
R2
[Au]
R1
R1
R2
Nu-Lg
+
X = O, NR
X
B) General method for the generation of donor/donor metal carbenes from enynals/enynones
O
O
O
[M]
R2
R1
R2
R1
[M]
Ar
R
R3
R = aryl, vinyl
M = Au, Rh, Pd, Zn, etc.
O
ML+
donor/donor
metal carbenes
R3
C) Generation of donor/donor copper carbenes from diynes (this work)
PG
N
PG
PG
N
N
R3
[Cu]
R =
H
aReaction conditions: 1a (0.1 mmol), catalyst (0.01 mmol),
DCE (2 mL), rt-60 oC, 1-24 h, in vials. bMeasured by 1H NMR
using 2,6-dimethoxytoluene as the internal standard. c Racemic
SEGPHOS (0.012 mmol) was employed as additive.
R1
R
R2
[Cu]
R1
(R1 = aryl, vinyl)
R
R2
R2
R1
H
R3
up to 99% yield
[1,4]-H
shift
d.r. > 50/1
PG
N
PG
N
PG
R3
With the optimal reaction conditions in hand (Table 1, entry
6), the scope of this Cu-catalyzed cascade cyclization was then
investigated. As summarized in Table 2, an initial
investigation of N-protecting groups of the ynamides
demonstrated that the reaction proceeded efficiently with
various aryl sulfonyl groups to afford the desired tetracyclic
pyrroles 2a–2d in 73−86% yields while only 53% yield was
obtained in case of Ms-protected ynamide. In addition, a wide
array of aryl-substituted N-propargyl ynamides (R1 = Ar)
bearing both electron-donating and -withdrawing groups were
well tolerated in this reaction, leading to the desired pyrrole-
based cyclopropanaphthalenes 2f–2q in generally good to
excellent yields. The reaction was also extended to the
naphthyl- and heterocycle-substituted N-propargyl ynamides
to produce the corresponding 2r (96%), 2s (97%), and 2t
(77%), respectively. The method also occurred smoothly for
different aryl-substituted ynamides, and the desired products
2u–2w were formed in 60-85% yields. Moreover, ester-
substituted ynamide (R3 = CO2Et) and ynamide bearing a
terminal alkene moiety were suitable substrates for this tandem
cyclization, furnishing the expected products 2x and 2y in
56% and 50% yields, respectively. Interestingly, N-propargyl
ynamide with an n-propyl group on the N-propargyl also
N
R = H
R =
R1
biphosphine
BOX
ligand
R2
R2
R1
H
[Cu]
ligand
R1
R3
R2
donor/donor copper carbenes
R
up to 87% yield
97:3 e.r.
up to 99% yield
97:3 e.r.
generation of donor/donor metal carbenes via diyne cyclization high enantioselectivity
copper catalysis divergent and atom-economical synthesis valuable heterocycles
RESULTS AND DISCUSSION
Based on our previous work on the gold-catalyzed cyclization
of N-propargyl ynamides,20 we chose alkenyl N-propargyl
ynamide 1a as the model substrate for the initial study, and
selected results are listed in Table 1.21 Somewhat surprisingly,
typical gold catalysts such as Ph3PAuNTf2 and IPrAuNTf2
were not effective in catalyzing this cascade cyclization (Table
1, entries 1 and 2) and, instead, we were delighted to find that
the desired tetracyclic pyrrole 2a was obtained in 67% yield
with excellent diastereoselectivity (d.r. > 50/1) in the presence
of 10 mol % of AgNTf2 (Table 1, entry 3). Gratifyingly, sub-
sequent screenings on the non-noble metal catalysts (Table 1,
entries 4–7) demonstrated that 2a could be formed in 87%
yield by employing Cu(CH3CN)4PF6 as catalyst (Table 1, en-
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underwent efficient cyclization to deliver the desired product
2z in 82% yield. Importantly, excellent diastereoselectivities
(d.r. > 50/1) were achieved in all cases.
development of
a
chiral copper complex-catalyzed
enantioselective version (Table 3). To our delight, the asym-
metric tandem reaction of 1a could proceed smoothly in the
presence of Cu(CH3CN)4PF6 (10 mol %), bisoxazoline (BOX)
ligands (12 mol %) and NaBArF4 (12 mol %). The screening of
a variety of BOX ligands L1–L9 (Table 3, entries 1–9) re-
vealed that diphenyl-substituted BOX ligands L5–L9 gave the
significantly improved enantioselectivities (Table 3, entries 5–
9), and e.r. of 88:12 was achieved by employing L6 as chiral
ligand (Table 3, entry 6). Lowering the reaction temperature
resulted in substantially increasing enantioselectivities (Table
3, entries 10 and 11), and a 99% yield with 96:4 e.r. was
furnished when running the reaction at 30 oC (Table 3, entry
11). It is notable that the use of chiral copper complex
significantly promotes the reaction at this temperature as the
racemic reaction proceeds in low efficiency at 30 oC (Table 1,
entry 9). Further solvent screening failed to improve the
enantioselectivity (Table 3, entries 12 and 13).
Table 2. Reaction Scope of the Cascade Cyclization of
Ynamides 1a
8
9
10
11
12
13
14
15
16
17
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20
21
22
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PG
Ph
Ts
Ts
N
N
N
R
R
H
H
H
Table 3. Optimization of Reaction Conditions for the
Asymmetric Cascade Cyclization of Ynamide 1aa
Ph
2a, PG = Ts, 86% (2 h)
2b, PG = SO2Ph, 73% (5 h) 2f, R = F, 71% (7 h)
Ph
Ph
2i, R = Me, 92% (1 h)
2j, R = OMe, 95% (1 h)
2k, R = OCF3, 51% (25 h)
2l, R = tBu, 88% (1 h)
2c, PG = MBS, 84% (2 h)
2d, PG = Bs, 80% (1 h)
2e, PG = Ms, 53% (18 h)
2g, R = Cl, 68% (13 h)
2h, R = Br, 60% (20 h)
Ts
N
Ts
N
Ts
N
R
R1 R2
R1 R2
H
H
H
O
O
O
O
Ph
Ph
Ph
Ph
Ph
2m, R = OMe, 99% (1 h)
2n, R = F, 62% (7 h)
2o, 74% (2 h)
2p, 90% (1 h)
N
N
N
N
R3
R3
Ph
Ph
Ts
N
Ts
N
Ts
N
L5, R1, R2 = Me
L6, R1, R2 = Bn
L7, R1, R2 = 2-Me-C6H4CH2
L8, R1, R2 = 4-Ph-C6H4CH2
L9, R1, R2 = 4-tBu-C6H4CH2
L1, R1, R2 = Me, R3 = Cy
L2, R1, R2 = Me, R3 = tBu
L3, R1 = Me, R2 = Bn, R3 = Cy
S
L4, R1 = Me, R2 = 4-Ph-C6H4CH2, R3 = Cy
H
H
H
Ph
Ph
Ph
yield (%)b
e.r.c
2r, 96% (2 h)
2s, 97% (1 h)
2q, 93% (1 h)
conditions
(+)-2a
entry
L
(+)-2a
Ts
N
Ts
Ts
1
2
L1
L2
L3
L4
L5
L6
L7
L8
L9
L6
L6
L6
L6
DCE, 50 oC, 30 h
DCE, 50 oC, 27 h
DCE, 50 oC, 35 h
DCE, 50 oC, 35 h
DCE, 50 oC, 20 h
DCE, 50 oC, 20 h
DCE, 50 oC, 33 h
DCE, 50 oC, 33 h
DCE, 50 oC, 33 h
DCE, 40 oC, 29 h
DCE, 30 oC, 60 h
DCM, 30 oC, 65 h
CHCl3, 30 oC, 65 h
70:30
66:34
78:22
81.5:18.5
85:15
88:12
85:15
87:13
86:14
93:7
85
90
90
95
90
99
99
99
99
99
99
95
95
N
N
R
S
3
Ph
Ph
MeO
4
H
H
H
Ph
Ph
Ph
5
2u, R = Me, 85% (1 h)
2v, R = Cl, 84% (1 h)
2t, 77% (36 h)
2w, 60% (4 h)
6
Ts
N
Ts
N
Ts
N
7
8
nC3H7
9
Ph
Ph
Ph
10
11
12
13
H
H
H
CO2Et
Ph
2z, 82% (1 h)
96:4
2x, 56% (3 h)
2y, 50% (2 h)
92:8
aReaction conditions: 1 (0.1 mmol), Cu(CH3CN)4PF6 (0.01 mmol),
DCE (2 mL), 60 oC, 1-36 h, in vials; isolated yields are reported.
PG = protecting group, MBS = 4-methoxybenzenesulfonyl, Bs =
4-bromobenzenesulfonyl.
90.5:9.5
aReaction conditions: 1a (0.05 mmol), Cu(CH3CN)4PF6 (0.005
mmol), L (0.006 mmol), NaBArF (0.006 mmol), solvent (1 mL)
4
1
30-50 oC, 20-65 h, in Schlenk tubes. Measured by H NMR
b
using 2,6-dimethoxytoluene as the internal standard. cDeter-
After establishing a general and reliable method for this
copper-catalyzed diyne cyclization, we focused on the
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mined by HPLC analysis. NaBArF = sodium tetrakis[3,5-
bis(trifluoromethyl)phenyl] borate.
and Bs-protected ynamides 1, furnishing the corresponding
4
tetracyclic N-heterocycles (+)-2b (97%, e.r. of 94:6) and (+)-
2d (94%, e.r. of 90:10), respectively. In addition, various aryl-
substituted N-propargyl ynamides (R1 = Ar) were applicable
substrates to generate the desired products in 65-99% yields
with the e.r. of 90:10-97:3. The absolute configuration of (+)-
2f was confirmed by X-ray diffraction (Figure 1). Interestingly,
the naphthyl-substituted ynamide 1r and heterocycle-
substituted ynamide 1t were also suitable substrates for this
reaction to give the corresponding (+)-2r (99%) and (+)-2t
(85%) with good enantioselectivity, and L8 was employed as
chiral ligand in the former case. Then, other aryl-substituted
ynamides such as 1u and 1w were investigated, and the
desired products (+)-2u and (+)-2w were obtained with good
enantioselectivity. Finally, it was found that the different
alkenyl-substituted substrates 1x–1y also underwent smooth
cyclization to afford the expected products (+)-2x and (+)-2y
with the e.r. of 70:30. It should be specially mentioned that the
use of chiral copper complex significantly promotes the
reaction efficiency, and substantially improved yields were
obtained in almost all cases compared with the corresponding
racemic cases. Inspired by these, we were also delighted to
find that the cyclization of 3-iodophenyl and vinyl-substituted
ynamides, which were not successful substrates (<30% yield)
in racemic reactions, could proceed efficiently to deliver the
corresponding chiral products (+)-2aa (71%) and (+)-2ab
(85%), respectively. Our attempts to extend the reaction to
alkyl-substituted ynamide (R1 = alkyl) have been unsuccessful
as yet.21 Once again, excellent diastereoselectivities (d.r. >
50/1) were achieved in all cases.
Under the optimized reaction conditions (Table 3, entry 11),
the substrate scope of the Cu-catalyzed asymmetric synthesis
of tetracyclic pyrroles (+)-2 was then examined and the results
are shown in Table 4. Besides the Ts-protected model
substrate, the reaction also underwent efficiently with SO2Ph-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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27
28
29
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Scope of the Asymmetric Cascade Cyclization of
Ynamides 1a
Figure 1. Structure of compound (+)-2f in its crystal.
Inspired by the above copper-catalyzed asymmetric tandem
cyclization/cyclopropanation reaction, we then wondered
whether this asymmetric catalysis is applicable to our previous
protocol on the catalytic cascade cyclization of N-propargyl
ynamides.20b Particularly, this study may help to elucidate the
reaction mechanism. If such an asymmetric reaction can be
achieved, the proposed vinyl cation pathway is less likely as
the formed chiral carbon center is not bound to the chiral cop-
per species in this process. As outlined in Table 5, we were
delighted to find that the asymmetric cascade cyclization of N-
propargyl ynamide 3a afforded the desired tricyclic pyrrole (-
)-4a in excellent yields and promising enantioselectivities by
employing Cu/BOX ligands as chiral metal complexes (Table
aReaction conditions: 1 (0.1 mmol), Cu(CH3CN)4PF6 (0.01 mmol),
o
L6 (0.012 mmol), NaBArF (0.012 mmol), DCE (2 mL), 30 C,
4
60-132 h, in Schlenk tubes; yields are those for the isolated prod-
b
o
c
ucts; ers are determined by HPLC analysis. At 25 C. L8 was
d
used. Cu(CH3CN)4PF6 (20 mol %), L6 (24 mol %), NaBArF4 (24
mol %), at 40 oC.
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5, entries 1−4). Gratifyingly, further ligand screening revealed
Based on the optimized reaction conditions (Table 5, entry
that the chiral biphosphine ligands L10–L13 (Table 5, entries
5–8) gave the significantly improved enantioselectivities, and
e.r. of 91:9 was obtained in the presence of L11 and L12 as
chiral ligands (Table 5, entries 6 and 7). Subsequently, differ-
ent solvents were investigated (Table 5, entries 9–12), and
toluene was found to be the best solvent (Table 5, entry 9). A
significant temperature effect was observed (Table 5, entries
13 and 14), and lowering the reaction temperature to 20 °C
allowed for the isolation of (-)-4a with the e.r. of 97:3 (Table 5,
entry 14).
14), we also evaluated the scope of the asymmetric cascade
cyclization of ynamides 3 (Table 6). Besides the Ts-protected
substrate 3a, ynamides with different N-protected groups such
as SO2Ph-, MBS- and Bs-protected N-propargyl ynamides
were also tolerated, affording the corresponding tricyclic N-
heterocycles (-)-4b (70%, 95:5 e.r.), (-)-4c (80%, 96:4 e.r.), (-
)-4d (71%, 96.5:3.5 e.r.), respectively. The absolute configura-
tion of (-)-4d was unambiguously determined to be (R) by X-
ray diffraction (Figure 2). Then, various aryl-substituted yna-
mides (R1 = Ar) bearing both electron-donating and -
withdrawing groups were investigated to generate the desired
products (-)-4e–4h in 63-76% yields with the e.r. of 89:11-
91:9, and a longer reaction time was needed in the latter case.
The reaction was also extended to the heterocycle-substituted
ynamide 3i. In addition, a variety of aryl- and naphthyl-
substituted N-propargyl ynamides were also screened and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 5. Optimization of Reaction Conditions for the
Asymmetric Cascade Cyclization of Ynamide 3aa
Table 6. Scope of the Asymmetric Cascade Cyclization of
Ynamides 3a
yield (%)b
e.r.c
conditions
(-)-4a
entry
L
(-)-4a
56:44
55:45
54:46
70:30
90:10
91:9
L1
L2
DCE, 40 oC, 2 h
DCE, 40 oC, 2 h
DCE, 40 oC, 2 h
DCE, 40 oC, 9 h
DCE, 40 oC, 6 h
DCE, 40 oC, 6 h
DCE, 40 oC, 6 h
DCE, 40 oC, 6 h
toluene, 40 oC, 9 h
PhCl, 40 oC, 9 h
PhF, 40 oC, 9 h
86
88
89
86
83
90
87
85
84
85
90
73
83
84
1
2
L3
3
L6
4
5
L10
L11
L12
L13
L11
L11
L11
L11
L11
L11
6
91:9
7
85.5:14.5
94.5:5.5
93:7
8
9
10
11
12
13
14
93:7
PhCF3, 40 oC, 9 h
toluene, 30 oC, 15 h
toluene, 20 oC, 24 h
90:10
95.5:4.5
97:3
aReaction conditions: 3a (0.05 mmol), Cu(CH3CN)4PF6 (0.005
aReaction conditions: 3 (0.2 mmol), Cu(CH3CN)4PF6 (0.02 mmol),
L11 (0.024 mmol), NaBArF4 (0.024 mmol), toluene (3 mL), 20 oC,
18-72 h, in Schlenk tubes; yields are those for the isolated prod-
ucts; ers are determined by HPLC analysis. bAt 25 °C. cAt 30 °C.
dAt 0 °C. e(S)-SEGPHOS was employed as chiral ligand.
mmol), L (0.006 mmol), NaBArF (0.006 mmol), solvent (1 mL),
4
1
30-40 °C, 2-24 h, in Schlenk tubes. bMeasured by H NMR using
2,6-dimethoxytoluene as the internal standard. cDetermined by
HPLC analysis. PMP: 4-methoxyphenyl.
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and enantioselectivity under the standard conditions, led to the
formation of 2ac in almost quantitative yield. Then, protection
of 2ac with Me and Boc group afforded the desired 2ad in
82% yield and 2ae in 80% yield, respectively. In addition, the
N-Ts group in (-)-4a, prepared on a gram scale in 75% yield
with the e.r. of 96:4 in the presence of only 3 mol % of
Cu(CH3CN)4PF6 and 3.6 mol % of L11 and NaBArF , could be
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4
selectively reduced into the corresponding dihydropyrrole 4aa
in 94% yield and pyrrolidine 4ab bearing three contiguous
stereocenters with excellent diastereoselectivity (d.r. > 50/1) in
77% yield, respectively. Of note, this tricyclic pyrrolidine
motif can be found in a variety of bioactive molecules and
may be of medicinal interest.22 Importantly, the enantioselec-
tivity was well maintained in all these transformations.
To understand the mechanism of this diyne cyclization, sev-
eral control experiments were conducted. First, it was found
that when ynamide 3s was subjected to this copper-catalyzed
cascade reaction, the corresponding alkene-pyrrole 5a was
isolated in 27% yield (eq 1).21 Interestingly, the reaction of
methyl-blocked diyne 3t with styrene under the current copper
catalysis could lead to the formation of the corresponding
pyrrole-based cyclopropane 5b in 80% yield (eq 2). In addi-
tion, the reactions were also conducted in the presence of 5
equiv of CD3OD by employing Cu(I) and Au(I) catalysts, re-
spectively, and substantially different deuterium incorporation
(<1% vs 30%) was observed (eq 3). These results further con-
firm that copper carbenes are presumably involved as key in-
termediates in such a cascade cyclization, which has been
strongly supported by the realization of the above asymmetric
process. Thus, the copper-catalyzed diyne cyclization is dis-
tinctively different from the related gold catalysis, where the
Figure 2. Structure of compound (-)-4d in its crystal.
transformed into the desired pyrrole-fused indenes (-)-4j–4r
in generally good to excellent yields with the e.r. of 92:8-96:4.
Our attempts to extend the reaction to alkyl- or alkenyl-
substituted ynamide only led to the formation of the corre-
sponding products in low yields (<30%).21 Finally, it was
found that the reaction occurred smoothly by employing (S)-
SEGPHOS as chiral ligand, delivering the desired (+)-4a in
76% yield and e.r. of 5:95 with the opposite enantioselectivity.
Scheme 2. Gram-Scale Reaction and Synthetic Transfor-
mations
Ts
H
N
Ts
N
N
standard
KOH (5 equiv)
conditions
Ph
Ph
Ph
MeOH/THF
50 oC, 5 h
Ph
Ph
H
H
Ph
(+)-2a (1.16 g, 95%, 95:5 e.r.)
1a (2.5 mmol, 1.22 g)
2ac, 99%, 95:5 e.r.
Boc
N
Me
N
Ts
Ts
N
Cu(CH3CN)4PF6 (10 mol %)
N
NaH (2 equiv)
MeI (2 equiv)
4-DMAP (0.1 equiv)
Boc2O (1.5 equiv)
L11 (12 mol %)
Ph
(1)
2ac
NaBArF4 (12 mol %)
DCE, 60 oC, 24 h
Ph
Ph
Ph
DCM, rt, 1 h
DMF, rt, 1 h
H
H
Ph
3s
5a, 27%
2ad, 82%, 95:5 e.r.
2ae, 80%, 95:5 e.r.
Ts
N
Ts
N
Ts
N
styrene (10 equiv)
Cu(CH3CN)4PF6 (10 mol %)
Ts
N
Cu(CH3CN)4PF6 (3 mol %)
L11 (3.6 mol %)
(2)
PMP
DCE, 40 oC, 4 h
NaBArF4 (3.6 mol %)
toluene, 20 oC, 28 h
PMP
PMP
PMP
Ph
3a (2.5 mmol, 1.04 g)
(-)-4a (0.78 g, 75%, 96:4 e.r.)
3t
5b, 80%, d.r. > 20/1
Ts
Ts
N
Ts
N
H
PtO2 (10 mol %)
2 (2 M Pa)
NaBH3CN
(3 equiv)
N
Ts
N
H
catalyst
(-)-4a
(3)
TFA, rt, 0.5 h
AcOH, 30 oC, 72 h
Ph
H
CD3OD (5 equiv)
DCE, 60 oC, 2 h
PMP
D
Ph
PMP
Ph
4ab, 77%
95:5 e.r., > 50/1 d.r.
4aa, 94%, 96:4 e.r.
3g
4g
H
H
H
NBn
yield
catalyst
product
NH
NH
MeO
Cu(CH3CN)4PF6 (10 mol %)/NaBArF4 (12 mol %)/L11 (12 mol %)
4g (<1% D)
4g (30% D)
53%
55%
H
OMe
MeO
H
H
Cy-JohnPhosAuNTf2 (5 mol %)
R
Cl
R = Me or Cl
antiobesity agents
>99% D
5-HT2C receptor agonist
antihypertensive agent
Ts
N
D
D
Ts
standard
conditions
D
N
>99% D
(4)
Ph
D
toluene, 30 oC, 36 h
Further synthetic transformations of the as-synthesized pyr-
role-based cyclopropanaphthalenes and -indenes were then
explored (Scheme 2). First, facile deprotection of (+)-2a,
which could be synthesized on a gram scale in excellent yield
Ph
Ph
[D2]-3g (>99% D)
[D2]-4g, 69%
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vinyl cation intermediate is presumably involved.20b Moreo-
good to excellent yields with wide substrate scope and
excellent enantioselectivities (up to 97:3 e.r.). To our best
knowledge, this protocol represents the first copper-catalyzed
asymmetric diyne cyclization. Moreover, mechanistic studies
revealed that this copper-catalyzed 1,5-diyne cyclization
presumably proceeds through donor/donor copper carbene
intermediates, which is distinctively different from the related
gold catalysis. Thus, the generation of donor/donor metal
carbenes directly from diyne cyclization is achieved, which
constitutes a novel way for the generation of metal carbenes
via non-diazo approach. The development of non-noble metal-
catalyzed asymmetric cascade cyclization of ynamides for
heterocycle synthesis and mechanistic investigations are the
subjects of ongoing research in our laboratory.
ver, we also performed deuterium labeling studies and found
that two deuteriums on the methylene group of substrate are
totally transferred to two deuteriums on the pyrrole α-positions,
thus indicating that this process is most likely to involve an
intramolecular hydride shift (eq 4). Finally, the relevant kinet-
ic isotopic effect (KIE) studies were also performed, and no
significant primary kinetic isotope effects were observed,21
which indicated that the cleavage of aromatic C−H bond
should not be involved in the rate-limiting step.
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On the basis of the above experimental results and previous
protocols on ynamide chemistry,18 a plausible mechanism for
the synthesis of tetracyclic pyrrole 2a and tricyclic pyrrole 4g
is illustrated in Scheme 3 (path a). Initially, electron-rich
ynamide moiety attacks the [Cu]-activated another C−C triple
of 1a to afford the vinyl copper intermediate A23,24 or its reso-
nance form B.10a Subsequent [1,4]-H shift25,26 generates the
donor/donor copper carbene intermediate C. Of note, C-H
insertion followed by electrocyclic ring opening via the for-
mation of Dewar pyrrole may also be possible for this pro-
cess.25b,27 Finally, intermediate C undergoes intramolecular
cyclopropanation to deliver the desired product 2a in the case
of R = styryl. Alternatively, [1,4]-H shift may occur first and
then form the copper carbene C. In the case of R = H, the
formed donor/donor copper carbene intermediate would be
trapped by the aryl group via C−H insertion, furnishing the
corresponding tricyclic pyrrole 4g. In particular, the use of
chiral copper complexes would lead to the chiral tricyclic pyr-
roles. Instead, the vinyl cation intermediate E, which is gener-
ated from the phenyl acetylene group attack of [Cu]-activated
ynamide (path b), is presumably involved in the related gold
catalysis.20b
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: .
Experimental procedures, characterizations and analytical
data of products, NMR and HPLC spectra (PDF)
Crystallographic structure of (+)-2f (CIF)
Crystallographic structure of (-)-4d (CIF)
AUTHOR INFORMATION
Corresponding Authors
*E-mail: longwuye@xmu.edu.cn
Notes
The authors declare no competing financial interest.
Scheme 3. Plausible Reaction Mechanism
ACKNOWLEDGMENT
We are grateful for financial support from the National Natural
Science Foundation of China (21622204, 21772161 and
91545105), the Natural Science Foundation of Fujian Province
of China (2019J02001), the President Research Funds from
Xiamen University (20720180036), NFFTBS (No. J1310024),
PCSIRT, and Science & Technology Cooperation Program of
Xiamen (3502Z20183015). We also thank Mr. Zanbin Wei
from Xiamen University for assistance with X-ray crystallo-
graphic analysis.
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chiral azahelicenes, see: Nakamura, K.; Furumi, S.; Takeuchi, M.;
Shibuya, T.; Tanaka, K. Enantioselective Synthesis and Enhanced
Circularly Polarized Luminescence of S-Shaped Double Azahelicenes.
J. Am. Chem. Soc. 2014, 136, 5555−5558.
(16) Previous asymmetric reactions of diynes mostly focus on the
enantioselective [2+2+2] cycloadditions for the synthesis of axially
chiral compounds, see: (a) Shintani, R.; Takagi, C.; Ito, T.; Naito, M.;
Nozaki, K. Rhodium-Catalyzed Asymmetric Synthesis of Silicon-
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7444−7448. (d) Rao, W.; Susanti, D.; Ayers, B. J.; Chan, P. W. H.
Ligand-Controlled Product Selectivity in Gold-Catalyzed Double
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Soc. 2015, 137, 6350−6355. (e) Tokimizu, Y.; Oishi, S.; Fujii, N.;
Ohno, H. Gold-Catalyzed Cascade Cyclization of 2-Alkynyl-N-
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Hirao, H.; Chan, P. W. H. Gold-Catalyzed Cycloisomerization of 1,6-
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(11) For selected examples on the Au-catalyzed cyclization of 1,5-
diynes via gold vinylidenes, see: (a) Ye, L.; Wang, Y.; Aue, D. H.;
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Wieteck, M.; Rudolph, M.; Rominger, F. Simple Gold-Catalyzed
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Molecules. Angew. Chem., Int. Ed. 2015, 54, 10903−10907. (f)
Tokimizu, Y.; Wieteck, M.; Rudolph, M.; Oishi, S.; Fujii, N.; Hashmi,
A. S. K.; Ohno, H. Dual Gold Catalysis: A Novel Synthesis of
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(g) Zhao, Q.; Rayo, D. F. L.; Campeau, D.; Daenen, M.; Gagosz, F.
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Ynamide Derivatives Bearing Terminal Alkyne Chains: Scope and
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(h) Zamani, F.; Babaahmadi, R.; Yates, B. F.; Gardiner, M. G.;
Ariafard, A.; Pyne, S. G.; Hyland, C. J. T. Dual Gold-Catalyzed
Cycloaromatization of Unconjugated (E)-Enediynes. Angew. Chem.,
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(12) For selected examples on the Au-catalyzed cyclization of 1,5-
diynes via gold carbenes, see: (a) Hansmann, M. M.; Rudolph, M.;
Rominger, F.; Hashmi, A. S. K. Mechanistic Switch in Dual Gold
Catalysis of Diynes: C(sp3)–H Activation through Bifurcation—
Vinylidene versus Carbene Pathways. Angew. Chem., Int. Ed. 2013,
52, 2593−2598. (b) Wang, Y.; Yepremyan, A.; Ghorai, S.; Todd, R.;
Aue, D. H.; Zhang, L. Gold-Catalyzed Cyclizations of cis-Enediynes:
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(13) For selected examples on the Au-catalyzed cyclization of 1,5-
diynes via vinyl cations, see: (a) Wurm, T.; Bucher, J.; Duckworth, S.
B.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. On the Gold-
Catalyzed Generation of Vinyl Cations from 1,5-Diynes. Angew.
Chem., Int. Ed. 2017, 56, 3364−3368. (b) Wurm, T.; Bucher, J.;
Rudolph, M.; Rominger, F.; Hashmi, A. S. K. On the Gold-Catalyzed
Generation of Phenyl Cations from 1,5-Diynes. Adv. Synth. Catal.
2017, 359, 1637−1642. For the relevant intermolecular diyne
cyclization see: (c) Claus, V.; Schukin, M.; Harrer, S.; Rudolph, M.;
Rominger, F.; Asiri, A. M.; Xie, J.; Hashmi, A. S. K. Gold-Catalyzed
Dimerization of Diarylalkynes: Direct Access to Azulenes. Angew.
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(17) For recent reviews on ynamide reactivity, see: (a) Zhou, B.;
Tan, T.-D.; Zhu, X.-Q.; Shang, M.; Ye, L.-W. Reversal of
Regioselectivity in Ynamide Chemistry. ACS Catal. 2019, 9,
6393−6406. (b) Evano, G.; Theunissen, C.; Lecomte, M. Ynamides:
Powerful and Versatile Reagents for Chemical Synthesis.
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Ynamides in Ring Forming Transformations. Acc. Chem. Res. 2014,
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Group for the New Millennium. Chem. Rev. 2010, 110, 5064−5106.
(e) Evano, G.; Coste, A.; Jouvin, K. Ynamides: Versatile Tools in
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(18) For selected examples by our group, see: (a) Xu, Y.; Sun, Q.;
Tan, T.-D.; Yang, M.-Y.; Yuan, P.; Wu, S.-Q.; Lu, X.; Hong, X.; Ye,
L.-W.
Organocatalytic
Enantioselective
Conia-Ene-Type
Carbocyclization of Ynamide-Cyclohexanones: Regiodivergent
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(19) Trost, B. M. The Atom Economy–A Search for Synthetic
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(21) For details, see the Supporting Information.
(22) For selected examples, see: (a) Yang, H.; Liu, D.; Yu, Q.; Xia,
S.; Yu, D.; Zhang, M.; Sun, B.; Zhang, F.-L. DBU-Promoted
Intramolecular Crossed Aldol Reaction: A Facile Access to Indane-
Fused Pyrrolidine. Eur. J. Org. Chem. 2019, 852−856. (b) Huck, B.
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Crumrine, C.; Stricker-Krongrad, A.; Harrington, J.; Brunden, K. R.;
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(23) Diyne cyclization involving the ynamide moiety attack of
another alkynyl group is very scarce, see a recent example: Claus, V.;
Molinari, L.; Bellmann, S.; Thusek, J.; Rudolph, M.; Rominger, F.;
Hashmi, A. S. K. Gold-Catalyzed Cyclisation by 1,4-Dioxidation.
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(24) The vinyl cation of intermediate A may exist as its resonance
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