Gold-Catalyzed 1,2-Acyloxy Migration/Coupling Cascade of Propargyl Diazoacetates: Synthesis of Isomycin Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b00392

An efficient gold(I)-catalyzed carbocyclization reaction for the synthesis of isomycin derivatives from propargyl diazoacetates has been developed. The suggested cyclization pathway delineated the first example of a vinyl gold carbenoid species generated in situ from gold(I)-catalyzed 1,2-acyloxy migration and intercepted by a cross-coupling reaction with the remaining tethered diazo functionality. The use of protic additives was essential to regulating the reaction outcome by fine-tuning the catalytic preference of the gold(I) complex.

Full text of DOI:10.1021/acs.orglett.9b00392

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold-Catalyzed 1,2-Acyloxy Migration/Coupling Cascade of
Propargyl Diazoacetates: Synthesis of Isomycin Derivatives
Ming Bao,†,§,∥ Xin Wang,†,∥ Lihua Qiu,§ Wenhao Hu,† Philip Wai Hong Chan,*,‡,¶
and Xinfang Xu*,†,§
†School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
‡School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
¶Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom
§College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, China
S
* Supporting Information
ABSTRACT: An efficient gold(I)-catalyzed carbocyclization reaction for
the synthesis of isomycin derivatives from propargyl diazoacetates has been
developed. The suggested cyclization pathway delineated the first example
of a vinyl gold carbenoid species generated in situ from gold(I)-catalyzed
1,2-acyloxy migration and intercepted by a cross-coupling reaction with
the remaining tethered diazo functionality. The use of protic additives was
essential to regulating the reaction outcome by fine-tuning the catalytic
preference of the gold(I) complex.
omogeneous gold-catalyzed alkyne transformations have
emerged as some of the most powerful tools for the
rapid assembly of complex molecules from readily available
materials.1−3 A particularly attractive strategy among the
advances made in the field is the [2,3]-sigmatropic rearrange-
ment of propargyl esters (Scheme 1a).2 This is followed by
decomposition of an azide or a diazo group in substrates
H
containing both moieties and access to a potentially wider
scope of carbocyclic and heterocyclic products, by contrast, has
remained unexplored. One possible reason for this could be
due to the propensity in such substrates to undergo
preferential decomposition of an azide or a diazo group over
alkyne activation.14,15 Added to this is a recent study by us
showing the gold(I)-catalyzed reaction of propargyl diazo-
acetates favoring the in situ formation of the putative
organogold intermediate B (Scheme 1b).16 This was followed
by a ylide formation, cyclization, and cycloisomerization
cascade to give a wide variety of 2-furyl-substituted aryl ketone
derivatives.
Scheme 1. Catalytic Alkyne Carbocyclizations
Recently, a number of studies have highlighted carbene/
alkyne metathesis (CAM) cascade reactions of alkynyl-tethered
diazo compounds to be an efficient and straightforward
strategy for the construction of polycyclic frameworks.17−19
Inspired by these works and as a continuation of our interest in
CAM cascade reactions,19 we were intrigued by the potential
reaction chemistry of propargyl diazoacetates 1 initiated by a
gold(I)-catalyzed 1,2-acyloxy migration (Scheme 1c). We
envisaged this might be facilitated by exploiting an appropriate
gold(I) complex that operated as more of a π- than σ-bond
acceptor in nature, thus favoring alkyne motif activation over
direct dinitrogen extrusion.20 Herein, we report our recent
results along this direction involving gold(I)-catalyzed 1,2-
acyloxy migration of propargyl diazoacetates with retention of
the diazo functionality. This is followed by the cross-coupling
reaction of the gold carbenoid motif with the diazo tether in
further functionalization by a remaining pendant moiety of the
ensuing vinyl gold carbenoid species A.4−13 In recent years,
such subsequent functional group transformations have
included intramolecular cyclization/cycloisomerization,4−6
C−H bond insertion,7 conjugate addition,8 cyclopropanation,9
and [3 + n]-cycloadditions (n = 2−4)10−12 among others.13
A
cascade process that is initiated by selective 1,2-acyloxy
migration of a propargyl ester unit rather than the
Received: January 30, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00392
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the ensuing organogold species C and the delivery of isomycin
derivatives in high yields for a wide variety of substrates under
mild reaction conditions. It provides a facile and chemo-
selective route to a core structural motif that is found in many
bioactive molecules with anti-inflammatory, antibacterial, and
anticancer activities.21 It also demonstrates the ability to
control the chemoselective outcome of such reactions in gold
catalysis through the introduction of protic additive(s) that can
fine-tune the catalytic preference of the metal complex.22
We began our studies by examining the metal-catalyzed
cyclizations of propargyl diazoacetate 1a, readily prepared by
esterification of phenylacetic acid with phenylpropiolic alcohol
followed by a diazo-transfer reaction, to establish the optimum
conditions (Table 1).16 Initial studies with PPh3AuNTf2 as the
obtained on switching the counteranion of the gold(I) catalyst
from NTf2 to SbF6 (entry 7).23 The analogous JohnPhos-
Au(CH3CN)SbF6- and IPrAuNTf2-catalyzed cyclizations were
found to influence the outcome of the reaction, giving none of
2a and 4a in 65% and 90% yield (entries 8 and 9). In the case
of the control reaction mediated by AgSbF6, a mixture of all
three adducts 2a, 3a, and 4a in yields of 18%, <5%, and 70%
were found (entry 10). The O−H bond insertion product 4a
was furnished as the only adduct in yields of 62−78% in
control experiments with Rh2(OAc)4, ZnCl2, or Cu(OTf)2 in
place of PPh3AuNTf2 as the catalyst (entries 11−13). On the
other hand, repeating the cyclizations with ethanol or
isopropanol instead of methanol was found to afford the
isomycin adduct in comparable yields of 78% and 83%,
respectively (entries 14 and 15).
−
−
a
Table 1. Optimization of the Reaction Conditions
With the optimal reaction conditions in hand, the generality
of the present procedure was investigated for a series of
propargyl diazoacetates (Scheme 2). Overall, the reaction
conditions were found to be broad, producing a variety of
a
Scheme 2. Substrate Scope
b
yield (%)
entry
1
2
catalyst
PPh3AuNTf2
PPh3AuNTf2
additive
2a/3a/4a
−
12/57/−
−/−/−
c
4 Å MS
3
4
5
6
7
8
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuNTf2
PPh3AuCl + AgSbF6
JohnPhosAu(CH3CN)
SbF6
H2O
MeOH
MeOH + 4 Å MS
MeOH + H2O
MeOH + H2O
MeOH + H2O
11/83/<5
43/18/15
−/−/86
84/<5/<5
79/9/<5
−/23/65
9
IPrAuNTf2
AgSbF6
Rh2(OAc)4
ZnCl2
Cu(OTf)2
PPh3AuNTf2
PPh3AuNTf2
MeOH + H2O
MeOH + H2O
MeOH + H2O
MeOH + H2O
MeOH + H2O
EtOH + H2O
iPrOH + H2O
−/<5/90
18/<5/70
−/−/74
−/−/62
−/−/78
78/10/−
83/8/−
10
11
12
13
14
15
d
a
Reaction conditions: to a solution of catalyst (2.0 mol %), and
additive (10.0 equiv of ROH, 5.0 equiv of H2O, 100 mg of 4 Å MS) in
DCE (1.0 mL), was added 1a (55.2 mg, 0.2 mmol) in DCE (1.0 mL)
via a syringe pump in 1 h under an argon atmosphere at 30 °C, and
b
the reaction was run for 8 h under these conditions. Isolated yield.
c
The dimerization product of 1a was isolated in 88% yield as a 2:1
d
mixture of Z/E isomers. Product 4a was obtained in 78% yield at 60
°C.
catalyst in 1,2-dichloroethane (DCE) revealed that the
chemoselective outcome of the reaction was dominated by
the used additives (entries 1−6). The reaction gave a mixture
of the isomycin 2a and 2-furyl-substituted phenyl ketone 3a in
respective yields of 12% and 57% in the absence of an additive
(entry 1). The introduction of 4 Å molecular sieves (MS) to
the reaction conditions was found to lead to the dimerization
product of the substrate being isolated as a 2:1 mixture of Z/E
isomers in 88% yield (entry 2). In contrast, reactions with
either water or methanol or the latter with 4 Å MS were shown
to give a mixture of both O-heterocycles or the propargyl ester
4a (entries 3−5). Our investigations subsequently discovered
the combination of water and methanol in a 2:1 ratio gave the
best result, promoting the desired cyclization to give 2a in 84%
yield (entry 6).22 A comparable product yield of 79% was
a
Reaction conditions: to a solution of PPh3AuNTf2 (3.0 mg, 2.0 mol
%), MeOH (10.0 equiv), and H2O (5.0 equiv) in DCE (1.0 mL) was
added 1 (0.2 mmol) in DCE (1.0 mL) via a syringe pump in 1 h
under an argon atmosphere at 30 °C, and the reaction was running for
8 h under these conditions. Values in parentheses denote isolated
b
product yields. Isolated yield on a 4.0 mmol scale for 12 h.
B
DOI: 10.1021/acs.orglett.9b00392
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Organic Letters
Letter
substituted isomycins in >70% yield from the corresponding
substrates 1b−x. Reactions of starting diazoacetates containing
an electron-donating or electron-withdrawing aryl group at the
a-carbon center to the diazo group were observed to proceed
well to afford the corresponding adducts 2b−h in 70%−80%
yield. Likewise, starting materials in which the distal alkynyl
carbon center contained an electron-withdrawing aryl, p-tolyl,
or m-tolyl moiety were found to be well tolerated, giving the
corresponding products 2i−n in 78%−82% yield. This was
further exemplified by the reaction of 1k (4.0 mmol, 1.54 g) at
the gram scale, which furnished 2k in 72% yield (1.03 g).
Substrates with a pendant o-tolyl, o-bromophenyl, o-styrenyl, o-
azidophenyl, or o-anisyl group at this position were also shown
to have minimal influence on the outcome of the reaction. In
these experiments, the corresponding isomycin derivatives 2o−
s were obtained in 74%−89% yield. Similarly, the 1-naphthyl,
1-thienyl, and alkyl substituted diazo compounds also
underwent the reaction smoothly, delivering the corresponding
five-membered ring compounds 2t−2w in 77%−82% yields.
Added to this is one example containing a methyl group at the
propargyl carbon center (1x), which gave the (Z)-alkene
adduct 2x as a single isomer in 88% yield and its structural
confirmation by X-ray crystallography (CCDC 1879936). The
reactions of substrates containing an acceptor/acceptor or
acceptor type diazo functionality or a TMS-tethered alkyne
group were found to be the only exception (see Figures S10−
S12 in the SI for details). In these latter experiments, either the
starting material was recovered or a complex mixture of
unidentifiable decomposition products was obtained.
gold(I)-mediated standard reaction conditions, which gave
the hydroarylation product 7 in 81% yield (eq 2). In our hands,
treating the propargyl acetate 8 to the gold(I)-mediated
standard reaction conditions was also found to lead to a
mixture of unidentifiable decomposition products (eq 3).
Taken together, these findings led us to surmise that
delocalization of the diazo group’s electron density into the
electron-withdrawing carbonyl motif in the substrate plays a
key role in promoting the propensity of the latter to undergo
the initial 1,2-acyloxy migration step. The observed effect of
MeOH and water in deactivating the Au(I) complex toward
decomposition of this functional group was also supported by
the following control reactions (see Figures S1−S5 in the SI
for details).24 We found subjecting methyl 2-diazo-2-phenyl-
acetate to 2 mol % of PPh3AuNTf2 in CDCl3 at 0 °C was
found to result in complete decomposition in 10 min, but this
required more than 4 h when the reaction was repeated in the
presence of MeOH and water (Figures S1 and S2). Likewise,
the control experiments with methyl 2-diazo-2-(4-(phenyl-
ethynyl)phenyl)acetate was observed to undergo complete
decomposition within 10 min (Figure S3). While no reaction
occurred in the presence of methanol and water, complete
decomposition of the diazo compound was only found on
increasing the reaction temperature to 30 °C after 7 h (Figures
S4 and S5). Additionally, the initial premise that product
formation did not occur via a gold carbenoid species through
diazo group decomposition was further supported by our
findings for the reaction of 1y containing a strongly electron-
donating trimethoxyphenyl group (Scheme 3, eq 4). Under the
standard conditions, the isomycin product 2y contaminated
with tricyclic adduct 9 was obtained in respective yields of 28%
and 61%. This would be consistent with the hypothesis that
such electronically biased substrates might favor the formation
of the gold carbenoid species I. Subsequent CAM reaction of
this intermediate would then deliver the second gold carbenoid
species II, which can terminate by an electrophilic aromatic
substitution to afford the indenyl-fused γ-lactone.17,25 It might
be anticipated that it would not be possible to form the
isomycin 2y consequently from generation of either the
proposed gold carbenoid intermediate species I or II.
To gain insight into the reaction mechanism, a series of
control experiments were next carried out (Scheme 3). In a
first set of control experiments, subjecting the propargyl ester 5
to the gold(I)-mediated standard reaction conditions was
found to lead to no reaction (Scheme 3, eq 1). This was in
contrast to the analogous reaction of propargyl ester 6
containing an electron-rich 1,1′-biaryl motif under the
Scheme 3. Control Experiments with 1y, 5, 6, and 8
On the basis of the above results and previous reports,2,17
a
tentative mechanism for the present Au(I)-catalyzed carbocyc-
lization is presented in Scheme 4. This might initially involve
Scheme 4. Proposed Reaction Mechanism
C
DOI: 10.1021/acs.orglett.9b00392
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Organic Letters
Letter
the partial deactivation of the gold(I) complex through its
interactions with the alcoholic additive (Figures S7 and S8 in
SI for the NMR spectral comparison). As a consequence, this
might sufficiently reduce the propensity of the metal catalyst to
preferentially mediate decomposition of the diazo moiety in
the substrate. This would then allow the selective activation of
the alkyne moiety in 1 to give the organogold complex III.
Subsequent 1,2-acyloxy migration would give the key vinyl
gold carbenoid species V via IV (Scheme 4, path a). A second
possibility, which cannot be ruled out, could be the generation
of the gold carbenoid species V following path b via the
organogold intermediates VI and VII in sequence.26 It might
be anticipated that an intramolecular cross-coupling reaction
between the tethered diazo group and gold carbenoid motif in
V would then deliver the product 2.27
In summary, we have disclosed a novel gold(I)-catalyzed
1,2-acyloxy migration/cross-coupling cascade reaction of
propargyl diazoacetates, which provides a straightforward
method for the synthesis of isomycin derivatives in excellent
yields. The salient features of this reaction include readily
available starting materials, mild conditions, and a broad
substrate scope. The mechanistic studies indicate that the
synergic effect of an alcoholic additive is essential in this
unprecedented cascade carbocyclization transformation, which
acts as a regulator of the gold(I) catalyst to preferentially
activate the alkyne motif over that of the diazo moiety in the
substrate.
Technology Major Project “Key New Drug Creation and
Manufacturing Program” from China (2018ZX09711002-006,
W.H.H.), and a Discovery Project Grant (DP160101682,
P.W.H.C.) from the Australian Research Council is acknowl-
edged.
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Accession Codes
CCDC 1879936 contains the supplementary crystallographic
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AUTHOR INFORMATION
Corresponding Authors
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*E-mail: phil.chan@monash.edu.
*E-mail: xinfangxu@suda.edu.cn.
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Wenhao Hu: 0000-0002-1461-3671
Philip Wai Hong Chan: 0000-0002-8786-6143
Xinfang Xu: 0000-0002-8706-5151
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Support for this research from the National Natural Science
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