Intermolecular Homopropargyl Alcohol Addition to Alkyne and a Sequential 1,6-Enyne Cycloisomerization with Triazole-Gold Catalyst

Article abstract of DOI:10.1021/jacs.6b00882

While gold-catalyzed homopropargyl alcohol cyclization is a known process, a triazole-gold catalyst prevented the intramolecular cyclization in the presence of terminal alkynes. As a result, an intermolecular addition to an alkyne was achieved. A sequential 1,6-enyne cycloisomerization gave the unusual 2,3-dihydrooxepine, which revealed another new reaction path. Diels-Alder reaction of oxepine followed by a 1,3-alkoxyl shift gave hydrobezofuran derivatives in high yields. Diasterioselective reaction of homopropargyl alcohol to final product enabled one-step formation of five stereogenic centers with excellent enantiomeric selectivity.

Full text of DOI:10.1021/jacs.6b00882

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Communication
Intermolecular Homopropargyl Alcohol Addition to Alkyne and a
Sequential 1,6-Enyne Cycloisomerization with Triazole-Gold Catalyst
Seyedmorteza Hosseyni, Lukasz Wojtas, Minyong Li, and Xiaodong Shi
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b00882 • Publication Date (Web): 09 Mar 2016
Downloaded from http://pubs.acs.org on March 10, 2016
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IntermolecularꢀHomopropargylꢀAlcoholꢀAdditionꢀtoꢀAlkyneꢀandꢀaꢀSe-
quentialꢀ1,6-EnyneꢀCycloisomerizationꢀwithꢀTriazole-GoldꢀCatalystꢀꢀ
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a
Seyedmorteza Hosseyni , Lukasz Wojtas , Minyong Li and Xiaodong Shi *
a
Department of Chemistry, University of South Florida, Tampa, FL 33620, USA
b
Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmacy, Shandong University,
Jinan, Shandong 250012, China
Supporting Information Placeholder
ABSTRACT: While gold-catalyzed homopropargyl alco-
hol cyclization is a known process, a triazole-gold catalyst
prevented the intramolecular cyclization in the presence of
terminal alkynes. As a result, an intermolecular addition to
an alkyne was achieved. A sequential 1,6-enyne cycloi-
somerization gave the unusual 2,3-dihydrooxepine, which
revealed another new reaction path. Diels-Alder reaction
of oxepine followed by a 1,3-alkoxyl shift gave hydrobezo-
furan derivatives in high yields. Diasterioselective reaction
of homopropargyl alcohol to final product enabled one-step
formation of five stereogenic centers with excellent enanti-
omeric selectivity.
lead to seven-membered diene intermediate of 1,6-enyne cycliza-
tion, which was never trapped before (Scheme 1C). Herein, we
report the first successful example of homopropargyl vinyl ether
cyclization in forming dihydrooxepine as unprecedented product.
The cycloaddition/isomerization of the dihydrooxepine (with the
presence of dienophile) gave highly functional tricyclic skeletons
with excellent stereoselectivity (Scheme 1C).
Scheme 1. Gold-catalyzed enyne cycloisomerizations
A) Gold catalyzed enyne cycloisomerization
+
Z
Z
Z
[
Au]
a
R
endo
R
R
a
Au
Au
b
Z
versatile approach in complex skeleton construction
R
+
Au
Z
Z
Z
b
[Au]
Gold-catalyzed reactions developed very fast during the last
exo
Au
Au
R
R
O
R
1
decade. The enyne cycloisomerization is a fundamentally im-
B) Systems that have been studied
portant process in chemistry research due to its ability to open
Au
R
2
Z
access to complex architectures through simple steps and its
R
Z
?
R
3
PivO
R
mechanisms that often reveal new chemistry insights. Homoge-
1
1,4-enyne
1,5-enyne
Z = C, O; ref 6
1,6-enyne
Z = C, O, N; ref 4
no example reported yet
neous gold(I) catalysts have been employed in promoting enyne
cycloisomerization with pioneering works reported by Echavar-
ref 5
C) This work: Homo propargyl alcohol addition followed by 1,6-enyne cycloisomerization
4
5
6
7
ren, Fürstner, Toste and others. Implementation of enyne cy-
R2
R2
5
% TA-Au
O
O
OH
+ R2
R1
cloisomerization for synthesizing complex building blocks and its
3
intermolecular
8
R1
mechanistic insight is advancing rapidly. In most of the gold-
R1
one pot,
up to 85%
Au
2
Au
catalyzed enyne cycloisomerization examples, formation of gold
6
5
9
[Au]
intramolecular
O
carbene intermediates was proposed. As shown in Scheme 1A,
R2
O
H
R2
O
depending on the endo or exo cyclization paths, various functional
cyclic skeletons can be synthesized.
O
O
DA
O
1 + messy rxn
R
1,3-alkoxy
shift
R2
O
mixtures
R1
R1
7
1
Our interest in enyne cycoisomerization was initiated from
our recent success in synthesizing vinyl ethers through triazole
A
R
4
not observed new pathway
single isomer
We began our study with homopropargyl vinyl ether 1a. In
1
0
gold-catalyzed intermolecular alcohol addition to alkyne. As
shown in Scheme 1B, cycloisomerization of 1,6-enyne bearing
vinyl ether moiety has not been reported in the past. The attrac-
tive synthetic utility and mechanistic novelty ensured urgency and
significance of investigating cycloisomerization of this special
type of 1,6-enyne. Compared with other reported 1,6-enyne sub-
strates, the vinyl ether substrate 1 will give the oxonium interme-
diate instead of simple carbocation. Hence, thermodynamic sta-
bility of the oxonium cation 5 versus gold carbene 6 will play an
important role in this equilibrium. Thus, different reactivity is
expected. Hypothetically, protodeauration of intermediate 5 could
+
fact, reaction of 1a with typical [L-Au] catalysts gave rapid gold
decomposition associated with the formation of very complex
2
mixtures (Figure 1). Even, loading 20% XPhosAuNTf gave only
less than 50% conversion of 1a. During the last several years, our
group has been working on developing new transition metal cata-
1
1
lysts using 1,2,3-triazole as ligand. Those efforts led to the dis-
covery of triazole-gold (TA-Au) with significantly improved cata-
1
2
lyst stability. We charged enyne 1a with [XPhosAu(TA)]OTf,
which gave much slower catalyst decomposition (>80% TA-Au
remaining after 24h).
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Although TA-Au alone could not activate 1a, it offered a po-
2
(see detailed screening in SI) and Cu(OTf) gave the best result.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
tential solution to promote enyne cycloisomerization with bal-
anced catalyst reactivity-stability (developing more reactive TA-
Au). Additionally, synthesis of vinyl ethers are not straightfor-
ward since their synthesis needs almost stoichiometric amount of
Notably, product A was not observed in this new transformation.
Other typical catalysts, including Pt, Rh, Ag and HOTf, have also
been evaluated. The product 7a was not observed in all other
tested cases, which greatly highlighted the unique reactivity of
TA-Au catalyst for this cascade transformation.
2
Hg(OAc) in ethyl vinyl ether (as solvent), giving only 50% yield
13
Although, 7a was clearly observed according to the crude
NMR and MS, its purification using column chromatography and
concentration on roto-vap was problematic due to the gradual
decomposition. Theoretically, 7a as a highly reactive electron
rich diene, which makes it a good choice for Diels-Alder reac-
of product.
Figure 1. Challenges for vinyl ether reaction: gold decomposition
+
O
+
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
[
Au] cat
or
various
17
[
Au]
tion. Maleic anhydride was applied to the reaction mixture of 7a
products
[
Au]
Ph
Ph
[Au]
exo
Challenges: highly reactive oxonium intermediate and gold decomposition
(one-pot). As expected, the desired product 8 was observed in
excellent yields (Figure 2).
Ph
1
a
endo
Figure 2. Cascade, one-pot, three-component condensation
20% PPh
0% XPhosAuNTf
3
AuNTf
2
or
, 2 h
50% conversion
gold decomposition
O
messy reaction
1) XPhosAu(TA)OTf 5%,
Cu(OTf) 1%, Tol, rt, 24 h
Ph
2
2
R
3
2
O
O
OH
5
% [XPhosAu(TA)]OTf, 24 h
TA=benzotriazole
<5% 1a conversion
slow TA-Au decomposition
+
92% 1a recovered
2) Maleic anhydride, 45 oC, 24 h
O
Ph
8a: R = nBu, 72%
R
2
a
X-ray of 8b
8
b: R = Cy, 75%
single isomer isolated
With all these concerns, we proposed the intermolecular re-
action between homopropargyl alcohol and terminal alkyne to
Excellent stereoselectivity was achieved for this cascade re-
14
form vinyl ether 1 (1,6-enyne) in situ. This design, although is
challenging, will deliver an efficient method to synthesize oxygen
containing seven membered rings 7 (oxepane derivatives), which
can be further used as a building block in complex cyclic structure
synthesis. To evaluate this hypothesis, various gold catalysts
were applied to react with homopropargyl alkyne 2a and terminal
alkyne 3a. The results are summarized in Table 1.
action with only endo-product obtained. The structure was con-
firmed by X-ray crystallography (8b). To evaluate the reaction
scope, various homopropargyl alcohols, alkynes and dienophiles
were tested as shown in Table 2.
a,b
Table 2. Reaction scope for synthesis of Diels-Alder product
2
R
R1
EWG
EWG
R'
OH
EWG
standard
protocol
R
+
+
a,b
R
Table 1. Optimization of the reaction condition
R2
EWG
O
nBu
R'
O
Ph
nBu
R1
nBu
Ph
2
3
dienophile
8
O
O
O
O
O
single isomer isolated
OH 3a
[Au]
Ph
8a: R1 = nBu, 72%
8b: R1 = Cy, 75%
Ph
Tol. rt
Ph
Ph
Ph
R1 = Ph, complex reaction
O
O
8c: R1 = cyclopentyl, 69%
2
a
4a
4a'
7a
A
d: R1 = CH2-Cy, 66%
R1 = tBu, only cyclization of 2
8
O
8e: R1 = cyclopropane, nd
not observed
R1
formation of 9e (82%)
convn 4a+4a’ 7a
Entry
cat
Time
O
(
56
90
%)
(%)
46
40
16
11
60
(%)
0
33
37
84
32
R2
8
8
8
f: R2 = Tol, 79%
R2 = Et, nBu, TMS, SPh or
1
2
3
4
5
PPh
3
AuNTf
2
(5%)
(5%)
XPhosAu(TA)OTf (5%)
XPhosAu(TA)OTf (5%), Cu(OTf)
XPhosAuNTf (5%), Cu(OTf) (1%)
Other cat: 10% PtCl , 10% (COD) RhCl, 10%
Cu(OTf); 10% HOTf; 20% AgOTf etc
10 h
15 h
30 h
24 h
24 h
O
O
g: R2 = p-CF3-C6H4, 68%
XPhosAuNTf
2
All gave complex
reaction mixtures
h: R2 = m-Cl-C6H4, 67%
72
O
2
(1%)
100
100
up to
100
nBu
2
2
O
O
Ph
Ph
NC
NC
NC
NC
Ph
Ph
NC
NC
2
2
6
24 h
<20
<5
MeN
O
MeN
NC
NC
a
Conditions: 2a (1 mmol), 3a (3 mmol), gold cat. (5 mol %), copper (1 mol %),
O
O
b
1
O
O
O
solvent (10 mL). H-NMR yields using 1,3,5-trimethoxybenzene as internal stand-
ard.
Cy
nBu
8k, 80%
nBu
Cy
8
i, 63%c
8j, 64%
8l, 75%
Ph
O
Ph
Using PPh
3
AuNTf
2
catalyst, significant amount of intramo-
NC
NC
NC
NC
Ph
lecular cyclization product 4a and its derivative 4a’ was obtained,
O
O
NC
NC
NC
NC
along with rapid catalyst decomposition. Interestingly, with 5%
O
O
O
nBu
XPhosAuNTf
low yield. Notably, clear gold decomposition was observed over
long reaction time. Switching XPhosAuNTf to XPho-
2
, diene 7a was observed by crude NMR, though in
nBu
8
o, 77%
8m, 82%
X-ray
8n, 72%
O
O
CN Ph
2
Ph
NC
NC
NC
sAu(TA)OTf (TA-Au) not only helped preventing gold catalyst
decomposition, but also significantly reduced the formation of 4a.
As reported in our previous works, application of Lewis acid as
co-catalyst with TA-Au will help triazole dissociation of gold,
O
q, 82%
O
O
8
8
p, 68%
X-ray
1
5
giving more reactive catalyst while maintaining good stability.
Moreover, Lewis acid can reactivate the poisoned decomposed
a
General reaction conditions: a solution of 2 (1 mmol), 3 (3 mmol), gold cat. (5
mol%), copper (1 mol%) and toluene (10 mL) stirred at rt. The mixture passed
16
through a short silica pad and then dienophile (1.3 mmol) added and the mix-
2
catalyst. Using Cu(OTf) (1%) as co-catalyst, the desired inter-
o
b
c
ture heated on 45 C for 24 more hours. (See details on SI). Isolated yield.
NMR yield (due to the substrate decomposition during purification).
molecular condensation product 7a was observed in 84% NMR
yield. Other Lewis acid co-catalysts have also been evaluated
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1
For terminal alkyne 3, aliphatic R groups, such as nBu (lin-
terminal alkynes were used to evaluate the reaction scope. The
1
19
ear) and cyclohexyl (cyclic) alkynes work well, except tert-butyl-
acetylene and trimethylsilylacetylene. This is likely due to the
steric effect, which caused slow alcohol addition to terminal al-
kyne. Aromatic alkynes gave complex reaction mixtures, sug-
gesting the existence of alternative reaction path due to the for-
mation of benzylic carbocation intermediate. In contrast, the
homopropargyl alcohol bearing aromatic alkynes gave good re-
sults (8f–8h). Complex reaction mixtures were obtained with
result is shown in Table 3.
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a,b
Table 3. Reaction scope for synthesis of the tricyclic structures
O
a: R1 = nBu, 67%
O
9
O
O
9b: R1 = Cy, 73%
H
H
O
9c: R1 = cyclopentyl, 68%
O
9d: R1 = CH
-Cy, 60%
9e: R1 = cyclopropane, 82% nBu
pF
9f, 65%
2
R1
O
O
O
Ph
O
3
6 4
C-C H
O
O
O
H
O
O
O
O
2
aliphatic group at R positions. Potentially, 6-exo cyclization can
H
H
H
O
O
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
occur on those cases, which caused the undesired side reactions.
Other dienophiles were also tested. Both N-methylmaleimide and
tetra-cyanoethylene worked as efficient as maleic anhydride.
Mono-EWG activated alkene, including α,β-unsaturated ester and
nitroalkene, could not give good yield of the desired product un-
der optimal conditions due to their lower reactivity.
O
nBu
nBu
O
O
m-Cl-C
6
H
4
MeO-C
6
H
4
MeO-C H
Tol
6
4
9
g, 65%
9h, 63%
9i, 70%
9j, 77%
O
O
H
O
MeN
MeN
O
H
H
O
O
O
Excellent stereoselectivity was obtained in all cases with on-
ly endo product observed. Moreover, with substituted homo-
propargyl alcohol (R≠H), single isomer was isolated (8n–8q).
This result highlighted the great advantage of this new method in
constructing complicated multicyclic structures with high diaster-
oselectivity. One interesting observation was the reaction of cy-
clopropylacetylene, which under the standard conditions, Diels-
Alder product 8e was not observed. Instead, a tricyclic compound
9e was obtained as a single isomer with 82% isolated yield (Fig-
ure 3). But for the case of 8p, the Diels-Alder product formed.
O
nBu
O
O
O
Ph
Ph
Ph
9
k, 76%
9l, 61%
9m, 85%
X-ray of 9m
O
O
MeN
H
H
O
O
O
O
Ph
Ph
9o, 60%
9
n, 63%
X-ray
a
General reaction conditions: a solution of 2 (1 mmol), 3 (3 mmol), gold cat. (5
mol%), copper (1 mol%) and toluene (10 mL) stirred at rt. The mixture passed
through a short silica pad and then dienophile (1.3 mmol) added and the mix-
ture heated on 75 C for 24 more hours. (See details on SI). Isolated yield.
Figure 3. Rapid 1,3-Alkoxyl-shift to substituted hydro-
benzofuran
o
b
O
O
Ph
standard protocol
OH
O
+
+
O
As shown in Table 3, this 1,3-alkoxy rearangement works
for compounds 8 derivatives from either maleic anhydride or N-
methylmaleimide. Surprisingly, the tetracyano substituted prod-
ucts (8k-8m, 8o and 8q) demonstrated much higher stability to-
O
Ph
O
8
e
O
not observed
O
O-1,3-shift
1
O
O
ward alkoxyl shift even with cyclopropyl group at R position.
H
o
Even upon heating compound 8m at 100 C for 48 hours, no
X-ray of 9e
9e, 82%
single isomer
alkoxyl shift observed (>95% 8m recovered). Analyzing the crys-
tal structures of 8b and 8m revealed almost identical geometry of
the core [3. 2. 2] structure between the two compounds. Consid-
ering the significantly different reactivity between 8b and 8m, it is
likely that the electronic effect is very influential for this 1,3-O-
shift. Investigations on the mechanism are currently undergoing.
Excellent stereoselectivity was achieved with one dominat-
ing stereoisomer isolated in all cases. Additionally, using chiral
homo propargyl alcohol as the starting materials, the desired ben-
zofurans were obtained as a single isomer (9l–9p). The absolute
stereochemistry was again confirmed by X-ray crystallography
(9m and 9p). Based on these results, we developed protocol as
shown in Figure 4 to synthesize single enantiomer of 9m.
O
Ph
The relative configuration of each stereogenic center of 9e
was confirmed by X-ray crystallography. Based on the structure,
9
e was evolved from 8e through an unusual (unprecedented)
alkoxyl 1,3-rearrangement. Notably, no cyclopropane ring open-
ing products were observed, suggesting the concerted mechanism
over stepwise carbocation pathway approach. There are few ex-
amples reported in literature for concerted 1,3-O-suprafacial rear-
18
rangements, unlike hydrogen or alkyl 1,3-shift. It is possible
that the shape of cyclopropyl group forced the structure of 8e to
adopt a conformation that allowed the orbital rearrangement at
o
1
relatively mild condition (45 C). Whereas, compound 8a (R =
nBu) needed elevated temperature in order for oxygen shift to
take place. Conducting this reaction in a one-pot fashion (directly
Figure 4. Diasterioselective reaction of non-racemic homopro-
pargyl alcohol with alkyne.
OH
O
O
O
o
from 1a and performing second step at 75 C, the desired substi-
(R)
1) XphosAu(TA)OTf 5%
Cu(OTf)2 1%. Tol. rt. 24 h
H
7
8%
Ph
O
(
R)
tuted hydrobenzofuran 9a was obtained in 67% isolated yield
9
9% ee
+
2) Maleic Anhydride
75 oC, 20 h
O
(
combining three steps). This result is exciting since it not only
Ph
m, 81% yield, 99% ee
revealed an interesting 1,3-O sigmatropic rearrangement, but also
provided a new strategy to prepare complex hydrobezofuran de-
rivatives from simple starting materials with excellent overall
yield and stereoselectivity. Various homopropargyl alcohols and
9
The enantiomeric enriched homopropargyl alcohol can be
readily prepared from alkyne addition to chiral epoxide. Charging
the non-racemic homopropargyl alcohol with terminal alkyne
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under the standard protocol, the chiral hydrobenzofuran 9m was
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
observed in 81% isolated yields with more than 99% ee. Overall,
five stereogenic centers were successfully set up through two
simple steps. Application of this strategy toward some challeng-
ing natural product synthesis are currently undergoing in our
group.
Int. Ed. 2008, 47, 4268–4315. (d) Trost, B. M.; Gutierrez, A. C.; Ferreira, E.
M. J. Am. Chem. Soc. 2010, 132, 9206–9218.
(
4) (a) Méndez, M.; Paz Muñoz, M.; Nevado, C.; Cárdenas, D. J.; Echavarren, A.
M. J. Am. Chem. Soc. 2001, 123, 10511–10520. (b) Nieto-Oberhuber, C.;
López, S.; Muñoz, M. P.; Cárdenas, D. J.; Buñuel, E.; Nevado, C.; Echavarren,
A. M. Angew. Chem. Int. Ed. 2005, 44, 6146-6148. (c) Nieto-Oberhuber, C.;
López, S.; Echavarren, A. M. J. Am. Chem. Soc. 2005, 127, 6178-6179.
In conclusion, we report herein the first intermolecular
homopropargyl alcohol addition to alkyne followed by intramo-
lecular enyne cycloisomerization. Using triazole-gold catalyst,
we effectively prevented both the homopropargyl alcohol intra-
molecular cyclization and gold decomposition caused by the vinyl
ether intermediate. The success in trapping diene 7 through Diels-
Alder cycloaddition and observation of unusual 1,3-O-shift high-
lighted the advantages of this new strategy for the preparation of
complex organic molecules with high efficiency and excellent
stereoselectivity.
(5) Mamane, V.; Gress, T.; Krause, H.; Fürstner, A. J. Am. Chem. Soc. 2004, 126,
654–8655.
8
(
6) (a) Luzung, M. R.; Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126,
10858-10859. (b) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem.
Soc. 2005, 127, 5802-5803.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
7) (a) Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962–6963. (b)
Wang, S.; Zhang, L. J. Am. Chem. Soc. 2006, 128, 14274–14275 (c) Lin, M-
Y.; Das, A.; Liu, R-S. J. Am. Chem. Soc. 2006, 128, 9340–9341. (d) Ma, S.;
Yu, S.; Gu, Z. Angew. Chem. Int. Ed. 2006, 45, 200–203.
(8) For reports on gold catalyze enyne reactions see: (a) Dorel, D.; Echavarren,
A. M. J. Org. Chem. 2015, 80, 7321–7332. (b) Wegener, M.; Kirsch. S. F.
Org. Lett. 2015, 17, 1465–1468. (c) Robertson, B. D.; Brooner, R. E. M.;
Widenhoefer, R. A. Chem. Eur. J. 2015, 21, 5714–5717.(d) Jaimes, M. C. B.;
Rominger, F.; Pereira, M. M.; Carrilho, R. M. B. Chem. Commun. 2014, 50,
4
9
937-4940. (e) Obradors, K.; Echavarren, A. M. Acc. Chem. Res. 2014, 47,
02–912. (f) Fürstner, A. Acc. Chem. Res. 2014, 47, 925–938. (g) Zheng, H.;
ASSOCIATED CONTENT
Felix, R. J.; Gagné, M. R. Org. Lett. 2014, 16, 2272–2275. (h) Brooner, R. E.
M.; Robertson, B. D.; Widenhoefer, R. A. Organometallics 2014, 33, 6466–
Supporting Information. Experimental procedures, characteri-
zation data, and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
6
473. (i) Carreras, J.; Livendahl, M.; McGonigal, P. R.; Echavarren, A. M.
Angew. Chem. Int. Ed. 2014, 53, 4896-4899. (j) Gaydou, M.; Miller, R.E.;
Delpont, N.; Ceccon, J.; Echavarren, A.M. Angew. Chem. Int. Ed. 2013, 52,
6
396-6399. (k) Reeds, J. P.; Whitwood, A. C.; Healy, M. P.; Fairlamb, I. J. S.
AUTHOR INFORMATION
Organometallics 2013, 32, 3108–3120. (l) Ziping, C.; F.Gagosz, F. Angew.
Chem. Int. Ed. 2013, 52, 9014−9018. (m) Ariafard, A.; Asadollah, E.;
Ostadebrahim, M.; Rajabi, N. A.; Yates, B. F. J. Am. Chem. Soc. 2012, 134,
Corresponding Authors
1
6882–16890. (n) Hashmi, A. S. K.; Weibo Yang, W.; Rominger, F. Chem.
*
Email: xmshi@usf.edu
Eur. J. 2012, 18, 6576-6580. (o) Hashmi, A. S. K.; Yang, W.; Rominger, F.
Angew. Chem. Int. Ed. 2011, 50, 5762 –5765. (p) Gorin, D. J.; Watson, I. D.
G.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 3736-3737. (q) Jiménez-Núñez,
E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326–3350. (r) Buzas, A. K.; Is-
trate, F. M.; Gagosz, F. Angew. Chem. Int. Ed. 2007, 46, 1141–1144. (s) Fer-
rer, C.; Raducan, M.; Nevado, C.; Claverie, C. K.; Echavarren, A. M. Tetrahe-
dron 2007, 63, 6306-6316. (t) López, S.; Herrero-Gómez, E.; Pérez-Galán, P.;
Nieto-Oberhuber, C.; Echavarren, A. M. Angew. Chem. Int. Ed. 2006, 45,
ACKNOWLEDGMENT
We thank the NSF (CHE-1362057) and NSFC (21228204) for
financial support. We are thankful to Sri Krishna Nimmagadda
and Professor Jon Antilla in helping us performing chiral HPLCs.
6
029-6032. (u) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Org. Lett. 2001, 3,
3769–3771. (v) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc.
000, 122, 11553–11554. (w) for intermolecular gold-catalyzed enyne-type fu-
REFERENCE
2
ran-yne cyclizations, see: Zeiler, A.; Ziegler, M. J.; Rudolph, M.; Rominger,
F.; Hashmi, A. S. K. Adv. Synth. Catal. 2015, 357, 1507-1514.
(9) Hashmi, A. S. k.; Rudolph, M.; Siehl, H-U.; Tanaka, M.; Bats, J. W.; Frey, W.
(
1) For recent advancements in gold catalysis see: (a) Jin, H.; Huang, L.; Xie, J.;
Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem. Int. Ed. 2016, 55,
794–797. (b) Dorel, R.; Echavarren, A. M. Chem. Rev. 2015, 115, 9028-9072.
Chem. Eur. J. 2008, 14, 3703-3708.
(
10) (a) Hosseyni, S.; Ding, S.; Su, Y.; Akhmedov, N. H.; Shi, X. Chem. Commun.
2
6
1
2
016, 52, 296-299. (b) Hosseyni, S.; Su, Y.; Shi, X. Org. Lett. 2015, 17, 6010–
013. (c) Veenboer, R. M. P.; Dupuy, S.; Nolan, S. P. ACS Catal. 2015, 5,
330−1334. (d) Ketcham, J. M.; Biannica, B.; Aponick, A. Chem. Commun.
013, 49, 4157-4159.
(
(
c) Lu, Z.; Han, J.; Hammond, G. B.; Xu, B. Org. Lett. 2015, 17, 4534–4537.
d) Zi, W.; Wu, H.; Hongjian, L.; Toste, F. D. Angew. Chem. Int. Ed. 2015, 54,
8529-8532. (e) Rettenmeier, E.; Hansmann, M. M.; Ahrens, A.; Rübenacker,
K.; Sahib, T.; Massholder, J.; Meier, C.; Rudolph, M.; Rominger, F.; Hashmi,
A. S. K. Chem. Eur. J. 2015, 21, 14401-14409. (f) Harris, R. J.; Widenhoefer,
R. A. Angew. Chem. Int. Ed. 2015, 54, 6867–6869. (g) Adcock, H. V.;
Chatzopoulou, E.; Davies, P. W. Angew. Chem. Int. Ed. 2015, 54,15525–
(11) (a) Cai, R.; Yan, W.; Bologna, M. G.; de Silva, K.; Ma, Z.; Finkle, H. O.;
Petersen, J. F.; Li, M.; Shi, X. Org. Chem. Front. 2015, 2, 141-144. (b) Yan,
W.; Ye, X.; Akhmedov, N. G.; Petersen, J. F.; Shi, X. Org. Lett. 2012, 14,
2358–2361. (c) Duan, H.; Sengupta, S. S.; Petersen, J. F.; Shi, X. Organome-
tallics 2009, 28, 2352–2355. (d) Hashmi, A. S. K.; Lothsch´tz, C. Chem-
CatChem. 2010, 2, 133-134.
(12) (a) Motika, S. E.; Wang, Q.; Ye, X.; Shi, X. Org. Lett. 2015, 17, 290-293. (b)
Duan, H.; Sengupta, S.; Petersen, J. L.; Akhmedov, N.; Shi, X. J. Am. Chem.
Soc. 2009, 131, 12100-12102.
1
5529. (h) Speck, K.; Karaghiosoff, K.; Magauer, T. Org. Lett. 2015, 17,
1982–1985. (i) Ferrand, L.; Das Neves, N.; Malacria, M.; Mouriès-Mansuy,
V.; Ollivier, C.; Fensterbank, L. Journal of Organometallic Chemistry 2015,
7
95, 53-57. (j) Rao, W.; Susanti, D.; Ayers, B. J.; Chan, P. W. H. J. Am.
Chem. Soc. 2015, 137, 19, 6350-6355. (k) Maity, A.; Sulicz, A.N.; Deligonul,
N.; Zeller, M.; Hunter, A.D.; Gray, T.G. Chemical Science 2015, 6, 981-986.
(
13) McMurry, J. E.; Andrus, A.; Ksander, G. M.; Musser, J. H.; Johnson, M. A. J.
Am. Chem. Soc. 1979, 101, 1330-1334.
(
4
l) Okumura, M.; Fujitani, T.; Huang, J.; Ishida, T. ACS Catal. 2015, 5, 4699–
707. (m) Zhu, Y.; Yu, B.; Chem. Eur. J. 2015, 21, 8771–8780. (n) Zhdanko,
(
14) a) D. V. Vidhani, M. E. Krafft, I. V. Alabugin, Org. Lett., 2013, 15, 4462-
A.; Maier, M. E. ACS Catal. 2015, 5, 5994–6004. (o) Veenboer, R. M. P.;
Dupuy, S.; Nolan, S. P. ACS Catal. 2015, 5, 1330–1334. (p) Goodwin, J, A.;
Ballesteros, C. F.; Aponick, A. Org. Lett. 2015, 17, 5574–5577. (q) Belger, K.;
Krause, N. Org. Biomol. Chem. 2015, 13, 8556-8560. (r) Henrion, G.; Chavas,
T. E. J.; Goff, X. L.; Gagosz, F. Angew. Chem. Int. Ed. 2013, 52, 6277−6282.
4
465. b) S. G. Nelson, K. Wang, J. Am. Chem. Soc., 2006, 128, 4232-4233. c)
Kuroda, C.; Shimizu, S.; Satoh, J. Y. Chem. Commun. 2013, 49, 2272—2283.
d) Shade, R. E.; Hyde, A. M.; Olsen, J-C.; Merlic, C. A. J. Am. Chem. Soc.
2
010, 132, 1202–1203. e) Xie, Y.; Hu, J.; Xie, P.; Qian, B.; Huang, H. J. Am.
Chem. Soc. 2013, 135, 18327–18330.
(
s) Kim, C.; Kang, S.; Rhee, Y. H. J. Org. Chem. 2014, 79, 11119-11123. (t)
(
15) Xi, Y.; Wang, Q.; Su, Y.; Li, M.; Shi, X. Chem. Commun. 2014, 50, 2158-
D. Weber, M. R. Gagné, Chem. Sci. 2013, 4, 335-338. (u) Krause, N.; Winter,
C. Chem. Rev. 2011, 111, 1994–2009.
2
160.
(16) (a) Kumar, M.; Hammond, G. B.; Xu, B. Org. Lett. 2014, 16, 3452–3455. (b)
Han, J.; Shimizu, N.; Lu, Z.; Amii, H.; Hammond, G. B.; Xu, B. Org. Lett.
(
2) (a) Li, X.; Song, W.; Tang, W. J. Am. Chem. Soc. 2013, 135, 16797–16800.
(
b) Yeom, H-S.; Koo, J.; Park, H-S.; Wang, Y.; Liang, Y.; Yu, Z-X.; Shin, S.
2
014, 16, 3500–3503. (c) Wang, X.; Yao, Z.; Dong, S.; Wei, F.; Wang, H.;
J. Am. Chem. Soc. 2012, 134, 208–211. (c) Aubert, C.; Fensterbank, L.; Gar-
cia, P.; Malacria, M.; Simonneau. A. Chem. Rev. 2011, 111, 1954–1993. (d)
Hansen, E. C.; Daesung Lee, D. J. Am. Chem. Soc. 2004, 126, 15074–15080.
(e) Trost, B. M. Acc. Chem. Res. 1990, 23, 34–42.
Xu, Z. Org. Lett. 2013, 15, 2234-2237. (d) Guérinot, A.; Fang, W.; Sircoglou,
M.; Bour, C.; Bezzenine-Lafollée, S.; Gandon, V. Angew. Chem., Int. Ed.
2
013, 52, 5848–5852.
(
17) (a) Yan, J.; Tay, G. L.; Neo, C.; Lee, B. R.; Chan, P. W. H. Org. Lett. 2015,
17, 4176–4179. (b) Borrero, N. V.; DeRatt, L. G.; Barbosa, L. F.; Abboud, K.
A.; Aponick, A. Org. Lett. 2015, 17, 1754–1757. (c) González, A. Z.; Toste,
D. F. Org. Lett. 2010, 12, 200–203.
(
3) (a)ꢀHansmann, M. M.; Melen, R. L.; Rudolph, M.; Rominger, F.; Wadepohl,
H.; Stephan, D. W.; Hashmi, A. S. K. J. Am. Chem. Soc. 2015, 137, 15469–
15477. (b) Gregg, T. M.; Keister, J. B.; Diver, S. T. J. Am. Chem. Soc. 2013,
1
35, 16777–16780. (c) Michelet, V.; Toullec, P. Y.; Genêt, J-P. Angew. Chem.
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5
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5
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5
6
(18) (a) Bolte, B.; Gagosz, F. J. Am. Chem. Soc. 2011, 133, 7696–7699. (b) Fulioon,
B.; EI-Nabi, H. A. A.; Keflenz. G.; Wentrup, C. Tetrahedron Lett. 1996, 36,
547-6550.
(19) The resulting core structure is the key skeleton for mintlactone and nepa-
lensolide A. a) Hexum, J. K.; Tello-Aburto, R.; Struntz, N. B.; Harned, A. M.;
Harki, D. A. ACS Med. Chem. Lett. 2012, 3, 459–464. b) Huang, H-L.; Liu, R-
S. J. Org. Chem. 2003, 68, 805-810. c) Strobykina, T. Y.; Belenok, M. G.;
Semenova, M. N.; Semenov, V. V.; Babaev, V. M.; Rizvanov, I. K.; Mironov,
V. F.; Kataev, V. E. J. Nat. Prod. 2015, 78, 1300−1308. d) Zhu, L.; Luo, J.;
Hong, R. Org. Lett. 2014, 16, 2162−2165. e) Daniewski, W. M.; Kubak, E.;
Jurczak, J. J. Org. Chem. 1985, 50, 3963-3965. f) Abad, A.; Agullb, C.; Arnb,
M.; Cuiiat, A. C.; Zaragozd, R. J. J. Org. Chem. 1989, 54, 5123-5125. g) Gao,
P.; Xu, P-F.; Zhai, H. J. Org. Chem. 2009, 74, 2592–2593.
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