Gold-catalyzed cycloisomerization and diels-alder reaction of 1,4,9-dienyne esters to 3 a,6-methanoisoindole esters with pro-inflammatory cytokine antagonist activity

Article abstract of DOI:10.1002/chem.201500795

A synthetic method to prepare 3a,6-methanoisoindole esters efficiently by gold(I)-catalyzed tandem 1,2-acyloxy migration/Nazarov cyclization followed by Diels-Alder reaction of 1,4,9-dienyne esters is described. We also report the ability of one example t

Full text of DOI:10.1002/chem.201500795

DOI: 10.1002/chem.201500795
Full Paper
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Homogeneous Catalysis |Hot Paper|
Gold-Catalyzed Cycloisomerization and Diels–Alder Reaction of
1,4,9-Dienyne Esters to 3a,6-Methanoisoindole Esters with Pro-
Inflammatory Cytokine Antagonist Activity
Dewi Susanti,[c] Li-Juan Liu,[d] Weidong Rao,[c] Sheng Lin,[e] Dik-Lung Ma,*[e] Chung-
Hang Leung,*[d] and Philip Wai Hong Chan*[a, b, c]
Abstract: A synthetic method to prepare 3a,6-methanoisoin-
dole esters efficiently by gold(I)-catalyzed tandem 1,2-acy-
loxy migration/Nazarov cyclization followed by Diels–Alder
reaction of 1,4,9-dienyne esters is described. We also report
the ability of one example to inhibit binding of tumor ne-
crosis factor-a (TNF-a) to the tumor necrosis factor recep-
tor 1 (TNFR1) site and TNF-a-induced nuclear factor k-light-
chain-enhancer of activated B cells (NF-kB) activation in cell
at a half-maximal inhibitory concentration (IC50) value of
6.6 mm. Along with this is a study showing the isoindolyl de-
rivative to exhibit low toxicity toward human hepatocellular
liver carcinoma (HepG2) cells and its possible mode of activi-
ty based on molecular modeling analysis.
sociation with the TNFR1 site.[3] However, a main drawback of
these protein agents is the need for intravenous administration
and the potential to cause serious side effects such as provok-
ing an autoimmune anti-antibody immune response and weak-
ening of the immune system to opportunistic infections.[4] As
a result, the development of alternative approaches such as
small molecule-based therapies has come under increasing
scrutiny in recent years for TNF-a inhibition. So far, this has led
to the discovery of a number of small molecule inhibitors, the
majority of which work by indirectly targeting TNF-a by down-
regulating the expression of the cytokine.[4,5] To our knowl-
edge, those that bind directly to TNF-a have, on the other
hand, remained limited to the compounds shown in Figure 1
Introduction
Through its binding to the TNFR1 site, the pro-inflammatory
cytokine TNF-a acts as a central biological mediator for critical
immune functions, including inflammation, infection and anti-
tumor responses in human cells.[1] The aberrant expression of
TNF-a has been implicated in an array of pathophysiologies
that include cancer, cardiovascular, autoimmune, metabolic dis-
orders and, in particular, chronic inflammatory diseases, such
as rheumatoid arthritis, psoriasis, refractory asthma and
Crohn’s disease.[2] Current clinically approved treatments make
use of the synthetic antibodies etanercept, infliximab and ada-
limumab, which bind directly to TNF-a and thus prevent its as-
[a] Prof. Dr. P. W. H. Chan
School of Chemistry, Monash University
Clayton, Victoria 3800 (Australia)
E-mail: phil.chan@monash.edu
[b] Prof. Dr. P. W. H. Chan
Department of Chemistry, University of Warwick
Coventry, CV4 7AL (UK)
E-mail: P.W.H.Chan@warwick.ac.uk
[c] D. Susanti, Dr. W. Rao, Prof. Dr. P. W. H. Chan
Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University
Singapore 637371 (Singapore)
[d] L.-J. Liu, Prof. Dr. C.-H. Leung
State Key Laboratory of Quality Research in Chinese Medicine
Institute of Chinese Medical Sciences
University of Macau, Macao (China)
E-mail: duncanleung@umac.mo
[e] S. Lin, Prof. Dr. D.-L. Ma
Department of Chemistry, Hong Kong Baptist University
Kowloon Tong, Hong Kong (China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500795.
Figure 1. Small molecule antagonists that directly target TNF-a-TNFR1 bind-
ing at the end of the template.[7–10]
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along with polysulfonated naphthylurea, suramin and its ana-
logues.[6–10] For this reason, the development of new classes of
small molecule antagonists of TNF-a that directly target the cy-
tokine and are non-toxic and thus suitable for therapeutic ap-
plications continues to be pursued.
of this concept with the development of an expedient and
chemoselective synthetic route to 3a,6-methanoisoindole
esters 8 as a single regio- and diastereomer from AuI-catalyzed
cycloisomerization/Diels–Alder reaction of 1,4,9-dienyne esters
5 (Scheme 1, Eq (2)).[22,23] In instances starting with a chiral
1,4,9-dienyne ester, the norbornane-fused pyrrolidine was addi-
tionally obtained as single enantiomer with four stereogenic
centers that illustrated the reaction to proceed with efficient
transfer of chirality from the enantioenriched substrate to the
product. A study that delineates one example to exhibit
potent antagonist activity toward TNF-a-TNFR1 binding and
TNF-a-induced NF-kB activation at an IC50 value of 6.6 mm is
also presented. Included in this investigation are our findings
demonstrating the low cytotoxicity of the isoindolyl derivative
toward HepG2 cells and its likely mode of interaction by em-
ploying molecular modeling calculations.
One of the most important strategies in organic synthesis
for the efficient assembly of complex polycyclic systems is
transition metal-catalyzed cyclization of unsaturated hydrocar-
bons.[11–25] This has owed as much to the ease in which sub-
strates with various substitution patterns can be accessed as it
has been to the ability to provide a wide range of structures
from a single starting material by changing the catalyst and re-
action conditions. An illustrative example of this is the impres-
sive number of elegant methods to various synthetically useful
cyclic compounds from gold-catalyzed cycloisomerization of
1,n-enyne esters.[12–19] Of particular interest is a small handful of
work showing AuI-mediated 1,3- and 1,2-acyloxy migration of
the respective 1,3- and 1,4-enyne esters 5 followed by metallo-
Nazarov-type cyclization to give the corresponding carbenoid
(I) and cyclopentenium (II) intermediates of gold (Scheme 1,
Eq (1)).[18–21,25] Subsequent acyl elimination or cyclopropanation,
Results and Discussion
Our studies commenced by evaluating the gold-catalyzed cy-
cloisomerizations of 1,4,9-dienyne acetate 5a to establish the
reaction conditions (Table 1).[26] This initially revealed
treatment of the substrate with 5 mol% of AuI cata-
lyst A and 4 Š molecular sieves (MS) in toluene at
808C for 2 h gave 8a in 96% yield and as a single
regio- and diastereomer (Table 1, entry 1). The rela-
tive configuration and structure of the 3a,6-metha-
noisoindole adduct was determined by NMR spectro-
scopic measurements and X-ray crystallography.[27]
Reducing the reaction temperature from 808C to
room temperature gave a lower product yield of
82% (entry 2). Likewise, either lower or comparable
product yields of 76–99% were observed when the
reaction was repeated with AuI–phosphine com-
plexes B–E, NHC–gold(I) (NHC=N-heterocyclic car-
bene) complexes F–H, [(PPh3)Au(NTf2)], AuCl or AuCl3
in place of A as the catalyst (entries 3–8 and 10–12).
Our studies subsequently revealed reaction of 5a
mediated by 5 mol% of NHC–gold(I) complex H and
4 Š MS in toluene at 808C for 2 h provided the best
result, affording 8a in near quantitative yield
(entry 9). In addition, the use of the conditions described in en-
tries 11 and 12 by using AuCl or AuCl3 as the catalyst were
shown to be ineffective at mediating the reactions of other
substrates (vide infra). With NHC–gold(I) complex H as the cat-
alyst, further control reactions with THF, MeCN or 1,2-dichloro-
ethane in place of toluene as the solvent was found to furnish
lower product yields of 76–95% (entries 13–15). In contrast,
the analogous control experiment catalyzed by PtCl2 was the
only instance that gave a low product yield of 50% (entry 16).
Summarized in Table 2 are the results of the scope of the
present procedure that were assessed by examining the reac-
tions of a variety of 1,4,9-dienyne esters. Overall, these studies
revealed that with AuI complex H as the catalyst, the reaction
conditions proved to be general and a variety of 3a,6-metha-
noisoindole esters could be furnished in 40–99% yield from
the corresponding substrates 5b–x. Reactions of substrates
Scheme 1. AuI-catalyzed reactivities of 1,3- and 1,4-enyne esters.
for substrates bearing an alkene moiety at the R3-position, in
these putative adducts were then shown to afford the respec-
tive cyclopentenones 6 and cyclopropa[c]pentalenes 7. In the
case of the latter, the construction of the cyclopropane motif
also provided evidence for the involvement of the metallocar-
benoid species reputedly formed in the course of these reac-
tions. A tandem process that allows for the further functionali-
zation of the posited in situ generated cyclopentenyl gold-
complex II and access to a potentially wider scope of cycloiso-
merization products, by contrast, has not been examined.[19] In
this context, and as part of studies examining the utility of
gold catalysis in organic chemistry,[24] we queried whether
a suitably placed N-tethered C=C bond could trap such orga-
nogold intermediates. If so, it would be anticipated that the
formation of new bicyclic derivatives containing a fused N-het-
erocyclic motif might ensue. Herein, we report the realization
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Table 1. Optimization of the reaction conditions.[a]
Table 2. Cycloisomerization of 5b–x catalyzed by NHC–AuI complex H.[a]
Entry
Cat.
Solvent
t [h]
Yield [%][b]
1
A
A
B
C
D
E
F
G
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
THF
2
17
17
17
3
2
3
2
2
5
5
3
8
4
5
17
96
82
93
76
93
91
95
96
99 (99)[d]
95
97
93
95
91
76
50
2c
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
[(Ph3P)Au(NTf2)]
AuCl
AuCl3
H
H
H
[a] All reactions were performed at the 0.3 mmol scale with H/5 ratio=
1:20 and 4 Š MS (300 mg) in toluene at 808C for 1–17 h. Values in paren-
theses denote isolated product yields.
MeCN
(CH2Cl)2
PhMe
PtCl2
8x in 48 and 67% yield, respectively. Moreover, in all the
above transformations, the cycloisomerization process was
shown to occur in a highly selective manner with the bridged
N-heterocycle being obtained as a single diastereo- and regio-
isomer. Other than a number of unidentifiable decomposition
products, no other cycloadducts that could be formed from cy-
clopropanation or deacylation of the putative pentacyclic inter-
mediate were detected by 1H NMR spectroscopic analysis of
the crude mixtures.[17,18] In addition, the structure and relative
diastereochemistry of 8g, 8k, 8n and 8p were confirmed by
X-ray crystallographic analysis.[27] As shown in Scheme 2, this
[a] All reactions were performed at the 0.3 mmol scale with catalyst/5a
ratio=1:20 and 4 Š MS (300 mg) at 808C in given solvent and time.
[b] 1H NMR yield with CH2Br2 as the internal standard. [c] Reaction carried
out at room temperature. [d] Value in parentheses denotes isolated prod-
uct yield.
containing a Bz (5b) instead of an Ac migrating group or a cy-
cloalkyl (5c,d) or benzyl (5e,f) moiety in place of the methyl
substituent at the acetate carbon center were found to pro-
ceed to give 8b–f in 85–99% yield. The presence of various
substitution patterns on the allylic amine side chain of the ter-
tiary acetate (5g–v) was found to have no influence on the
course of the reaction. Under standard conditions, these ex-
periments gave the corresponding nitrogen-containing tricyclic
products 8g–v in 40–99% yield. Pleasingly, this included start-
ing acetates containing a benzyl ether (5j,l), OTBS (5k,m), 2-
furanyl (5s) or 2-thiophenyl (5t) moiety, showing that such
functional groups were well tolerated under the reaction con-
ditions. Added to this is the construction of one example con-
taining a tetrafused ring motif (8o) from the corresponding
substrate bearing a pendant cyclohexenyl ring (5o). Likewise,
reactions of secondary carboxylic esters (5w,x) were found to
give the corresponding 3a,6-methanoisoindole esters 8w and
Scheme 2. Cycloisomerization of ent-5v catalyzed by NHC–AuI complex H.
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was further exemplified by repeating the AuI-catalyzed rear-
rangement of enantioenriched ent-5v prepared from the corre-
sponding 1,6-enyne (ent-S1v) with an ee value of 96%.[26] Sub-
sequent K2CO3-mediated deacylation of the resulting tricyclic
adduct ent-8v, obtained in 77% yield, in methanol provided
ent-9v in 93% yield and with an ee value of 96%. The
(1S,3aS,5S,6S,7aS) absolute stereochemistry of the chiral isoin-
dolyl compound was ascertained by X-ray single-structure
crystallography.[27]
Scheme 4. Control experiment with 5a.
a reaction temperature of 808C for 4 h then gave the expected
isoindole product 8a in 80% yield.
A plausible mechanism for the present AuI-catalyzed 3a,6-
methanoisoindole ester forming reaction is outlined in
Scheme 3. Using 5a as a representative example, the first step
Prompted by the presence of the indolyl motif in the TNF-
a inhibitors 2,[9] 3[10] and SPD304[7] shown in Figure 1, we next
queried whether the isoindolyl adducts prepared in this work
would exhibit this type of bioactivity. With this in mind, a TNF-
a enzyme-linked immunosorbent assay (ELISA) was performed
with compounds 8a–x at a concentration of 100 mm (Figure 2
Scheme 3. Proposed mechanism for AuI-catalyzed rearrangement of 1,4,9-di-
enyne esters represented by 5a.
Figure 2. Compound inhibition of TNFR1 binding to immobilized TNF-
a (ELISA). Microtiter plates coated with TNF-a were incubated with TNFR1
together with compounds 8a–x or SPD304 at the indicated concentration.
TNFR1 binding was detected using anti-TNFR1 antibody and horseradish
peroxidase-conjugated secondary antibody. Error bars represent the stan-
dard deviations of the results from three independent experiments.
could involve activation of the alkyne moiety of the carboxylic
ester in the substrate by the AuI catalyst. The AuI-coordinated
complex IIIa might then become prone to syn-1,2-acyloxy mi-
gration to produce the putative vinyl gold adduct Va via 1,3-
dioxin-1-ium intermediate IVa (Scheme 3, path a).[28] Subse-
quent metallo-Nazarov-type cyclization of this newly formed
organogold species followed by deauration of the ensuing cy-
clopentenium intermediate IIa that was put forward in
Scheme 1, Eq. (2), would give the cyclopentadiene VIa. Alterna-
tively, the carbocyclic 1,3-diene intermediate might be generat-
ed directly from metallo-Nazarov-type cyclization of IVa upon
its formation followed by deauration of IIa (Scheme 3,
path b).[15i] Diels–Alder reaction of the cyclopentadiene inter-
mediate generated by one of these two possible mechanistic
pathways might consequently deliver the product 8a. For the
reaction involving enantioenriched ent-5v, the observed ste-
reochemistry at the newly formed chiral centers in the product
could be due to the stereogenic benzyl position in the sub-
strate directing the Diels–Alder reaction to occur at the steri-
cally less hindered opposite face of the alkene bond to the aryl
group. The proposed involvement of the cyclopentadiene in-
termediate VIa would also be in good agreement with our
findings for the control experiment shown in Scheme 4. Treat-
ment of 5a with 5 mol% of AuI complex H and 4 Š MS in tolu-
ene at room temperature for 30 min provided the cyclopenta-
diene adduct 10a (VIa in Scheme 3) as the only product in
74% yield. Further subjecting the cycloadduct in toluene to
and Figure S1 in the Supporting Information). This test re-
vealed the isoindolyl derivative 8i to be the most effective at
inhibiting TNF-a-TNFR1 binding. At the same concentration,
the positive control experiment with SPD304, the most potent
small molecule TNF-a inhibitor reported to date, was shown to
be about three times less active. This was further supported by
dose-response ELISA experiments aimed at determining the
IC50 values of these compounds against TNF-a-TNFR1 interac-
tion (Figure 3). Under our test conditions, isoindole 8i was
shown to exhibit concentration-dependent inhibition of TNF-
a-TNFR1 binding, with an approximate IC50 value of 2.6 mm.
This compared favorably to an IC50 ꢀ23 mm found for SPD304
and the reported literature value of about 22 mm for the
indole-tethered chromone.[7]
The ability of 8i to attenuate NF-kB transcriptional activity
through inhibition of TNF-a signaling in a HepG2 cell line was
also investigated. TNF-a was pre-incubated with different con-
centrations of the isoindolyl adduct or SPD304 prior to its addi-
tion to HepG2 cells stably transfected with the NF-kB-luciferase
(NF-kB-Luc) reporter gene (Figure 4). By monitoring the reduc-
tion in the luciferase activity of the cell lysates, this test re-
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Figure 5. Dose-dependent effect of inhibition on cell viability in HepG2 cells
exhibited by 8i. HepG2 cells were treated with the cycloadduct 8i at the in-
dicated concentrations for 72 h. Cell viability was determined by measuring
the color intensity at 570 mm. IC50 = >100 mm. Error bars represent the stan-
Figure 3. Dose-dependent compound inhibition of TNFR1 binding to immo-
bilized TNF-a (ELISA). Microtiter plates coated with TNF-a were incubated
with TNFR1 together with compound 8i or SPD304 at the indicated concen-
trations. TNFR1 binding was detected using anti-TNFR1 antibody and horse-
radish peroxidase-conjugated secondary antibody. Approximate IC50 values:
8i: 2.6 mm, SPD304: 23 mm. Error bars represent the standard deviations of
&
dard deviations of the results from three independent experiments. : 8i.
&
&
the results from three independent experiments. : 8i, : SPD304.
signed a score reflecting the quality of the complex. In the
lowest-energy binding pose, the N-heterocycle was observed
to be located at the hydrophobic binding pocket at the pro-
tein–protein interface of the TNF-a dimer (Figure 6a). The cy-
cloadduct closely contacts the residues of the b-strand
(Leu120-Gly121-Gly122) of TNF-a subunit A, with its relatively
more polar acetate and tosylate functional groups orientated
away from the binding pocket and exposed to the aqueous
environment. Furthermore, the isoindole appeared to be situ-
ated slightly further from TNF-a subunit B compared to
SPD304, which is predicted to lie an approximately equal dis-
tance from both subunits (Figure 6b). The lack of salt bridges
or hydrogen-bonding networks in our models of 8i and
SPD304 with TNF-a suggest that the interaction between the
small molecules and TNF-a is primarily hydrophobic and
shape-driven, consistent with previous findings. As can be
seen in the superposition of 8i and SPD304 with the TNF-
a dimer shown in Figure 6c, both molecules are large enough
to simultaneously contact both subunits of the TNF-a. This
presumably prevents the binding of the third subunit to form
the biologically active trimer complex, thus accounting for the
observed anti-TNF-a activity of the isoindolyl derivative.
Figure 4. Dose-dependent compound inhibition of cellular TNF-a-induced
NF-kB activity. HepG2 cells stably transfected with the NF-kB-Luc reporter
gene were stimulated with TNF-a pre-incubated with the indicated concen-
trations of 8i or SPD304. Cell lysates were analyzed for firefly luciferase activ-
ity to determine the extent of NF-kB inhibition. Approximate IC50 values: 8i:
6.6 mm, SPD304: 25 mm. Error bars represent the standard deviations of the
&
&
results from three independent experiments. : 8i, : SPD304.
vealed the isoindolyl derivative inhibited TNF-a-induced NF-kB
activation in a dose-dependent manner, with an IC50 value of
about 6.6 mm. This indicated 8i was slightly more active than
SPD304, which gave an IC50 of approximately 25 mm in a side-
by-side assay. More importantly, using the 3-(4,5-dimethylthia-
zol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, the
bridged N-heterocycle was shown to exhibit only moderate in-
hibition of HepG2 cells, as witnessed by an IC50 value of more
than 100 mm (Figure 5). This suggested 8i is relatively non-cy-
totoxic toward this in vitro cell line and, thus, has potential for
further development as an anti-inflammatory drug candidate.
To gain an insight into the mechanism of action of 8i as an
antagonist toward TNF-a-TNFR1 binding, we employed molec-
ular modeling to analyze the interaction between the small
molecule and TNF-a (Figure 6). The initial model of TNF-a was
built from the X-ray crystal structure of its dimer with SPD304
(PDB code: 2AZ5)[7] with the binding interaction being evaluat-
ed using the Molsoft ICM method (ICM-Pro 3.6-1d molecular
docking software).[29] The geometry of the isoindolyl derivative
was optimized using DFT calculations and the small molecule
was docked to a grid representation of the receptor and as-
Conclusion
In summary, we have developed a synthetic strategy to con-
struct 3a,6-methanoisoindole esters that relies on gold(I)-cata-
lyzed cycloisomerization of 1,4,9-dienyne esters. The transfor-
mation was shown to tolerate a diverse set of carboxylic ester
substrates to efficiently furnish stereochemically well-defined
norbornane-fused pyrrolidines. The efficacy of the substituted
N-heterocycles at inhibiting TNF-a was demonstrated by using
a TNF-a-TNFR1 binding ELISA and a cell-based luciferase re-
porter assay. Notably, one example was shown to possess su-
perior potency at inhibiting TNF-a compared to the positive
control compound SPD304 in the in vitro assays. The isoindolyl
derivative was also found to be relatively non-cytotoxic in
a HepG2 cell line study while molecular docking analysis sug-
gested that it bound to the protein–protein interface of the
TNF-a dimer primarily via hydrophobic interactions. Taken to-
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Experimental Section
General method
NHC–gold(I) complex H (15 mmol, 13 mg) was added to a solution
of 1,4,9-dienyne ester 5 (0.3 mmol) and 4 Š MS (300 mg) in toluene
(3 mL) under an argon atmosphere. The resulting solution was
heated 808C and the reaction was monitored by thin layer chroma-
tography. Upon completion, the reaction mixture was cooled to
room temperature, filtered through a pad of Celite, washed with
EtOAc (10 mL) and the solvent was removed under reduced pres-
sure. Purification by flash column chromatography on silica gel (n-
hexane/EtOAc=9:1 as eluent) gave the product 8.
Acknowledgements
This work is supported by Start-Up Grants from the School of
Chemistry, Monash University and Department of Chemistry,
University of Warwick, and a Tier 2 Grant (MOE2013-T2-1-060)
from the Ministry of Education of Singapore (to P.W.H.C.),
a State Key Laboratory of Synthetic Chemistry, Science and
Technology Development Fund (103/2012A3, to C.H.L.), and
a Health and Medical Research Fund (HMRF/13121482, to
D.L.M.). We thank Dr. Y. Li (Nanyang Technological University)
for providing the X-ray crystallographic data reported in this
work.
Keywords: alkynes
·
cycloisomerization
·
cytokine
antagonists · gold · homogeneous catalysis
[1] H. Wajant, K. Pfizenmaier, P. Scheurich, Cell Death Differ. 2003, 10, 45.
[2] a) E. Esposito, S. Cuzzocrea, Curr. Med. Chem. 2009, 16, 3152; b) B. B. Ag-
garwal, Nat. Rev. Immunol. 2003, 3, 745.
[3] K. Chatzantoni, A. Mouzaki, Curr. Top. Med. Chem. 2006, 6, 1707.
[4] M. A. Palladino, F. R. Bahjat, E. A. Theodorakis, L. L. Moldawer, Nat. Rev.
Drug Discovery 2003, 2, 736.
[5] a) C.-H. Leung, S. P. Grill, W. Lam, W. Gao, H.-D. Sun, Y.-C. Cheng, Mol.
Pharmacol. 2006, 70, 1946; b) S. Haraguchi, N. K. Day, W. Kamchaisatian,
M. Beigier-Pompadre, S. Stenger, N. Tangsinmankong, J. W. Sleasman,
S. V. Pizzo, G. J. Cianciolo, AIDS Res. Ther. 2006, 3, 8; c) M. R. Lee, C.
Dominguez, Curr. Med. Chem. 2005, 12, 2979; d) H. Rasmussen, P. P.
McCann, Pharmacol. Ther. 1997, 75, 69; e) J. R. Burke, M. A. Pattoli, K. R.
Gregor, P. J. Brassil, J. F. Macmaster, K. W. McIntyre, X. Yang, V. S. Iotzova,
W. Clarke, J. Strnad, Y. Qiu, F. C. Zusi, J. Biol. Chem. 2003, 278, 1450.
[6] a) R. Alzani, A. Corti, L. Grazioli, E. Cozzi, P. Ghezzi, F. Marcucci, J. Biol.
Chem. 1993, 268, 12526; b) F. Mancini, C. M. Toro, M. Mabilia, M. Gian-
nangeli, M. Pinza, C. Milanese, Biochem. Pharmacol. 1999, 58, 851.
[7] M. M. He, A. S. Smith, J. D. Oslob, W. M. Flanagan, A. C. Braisted, A.
Whitty, M. T. Cancilla, J. Wang, A. A. Lugovskoy, J. C. Yoburn, A. D. Fung,
G. Farrington, J. K. Eldredge, E. S. Day, L. A. Cruz, T. G. Cachero, S. K.
Miller, J. E. Friedman, I. C. Choong, B. C. Cunningham, Science 2005, 310,
1022.
Figure 6. As generated by virtual ligand docking, low-energy binding pose
of: a) compound 8i to the TNF-a dimer; b) SPD304 to the TNF-a dimer; and
c) superposition of 8i (white) and SPD304 (blue) bound to the TNF-a dimer.
In each figure, the small molecules are shown in ball-and-stick form and the
TNF-a dimer is shown in ribbon form.
[8] C.-H. Leung, H.-J. Zhong, H. Yang, Z. Cheng, D. S.-H. Chan, V. P.-Y. Ma, R.
Abagyan, C.-Y. Wong, D.-L. Ma, Angew. Chem. Int. Ed. 2012, 51, 9010;
Angew. Chem. 2012, 124, 9144.
[9] D. S.-H. Chan, H.-M. Lee, F. Yang, C.-M. Che, C. C. L. Wong, R. Abagyan,
C.-H. Leung, D.-L. Ma, Angew. Chem. Int. Ed. 2010, 49, 2860; Angew.
Chem. 2010, 122, 2922.
[10] K. S. Kumar, P. M. Kumar, K. A. Kumar, M. Sreenivasulu, A. A. Jafar, D.
Rambabu, G. R. Krishna, C. M. Reddy, R. Kapavarapu, K. Shivakumar, K. K.
Priya, K. V. L. Parsa, M. Pal, Chem. Commun. 2011, 47, 5010.
[11] For selected reviews, see: a) B. Alcaider, P. Almendros, C. Aragoncillo,
Chem. Soc. Rev. 2014, 43, 3106; b) A. S. K. Hashmi, Acc. Chem. Res. 2014,
47, 864; c) M. Presset, Y. Coquerel, J. Rodriguez, Chem. Rev. 2013, 113,
525; d) A. V. Gulevich, A. S. Dudnik, N. Chernyak, V. Gevorgyan, Chem.
gether, these results demonstrate the potential of this new
class nitrogen-containing heterocyclic compounds as promis-
ing lead structures for the development of more potent TNF-
a inhibitors.
Chem. Eur. J. 2015, 21, 9111 – 9118
www.chemeurj.org
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Rev. 2013, 113, 3084; e) Y. Yamamoto, Chem. Rev. 2012, 112, 4736; f) D.-
H. Zhang, Z. Zhang, M. Shi, Chem. Commun. 2012, 48, 10271; g) C.
Aubert, L. Fensterbank, P. Garcia, M. Malacria, A. Simonneau, Chem. Rev.
2011, 111, 1954; h) N. Chatani, S. I. Lee, Chem. Commun. 2009, 371; i) V.
Michelet, P. Y. Toullec, J. P. GenÞt, Angew. Chem. Int. Ed. 2008, 47, 4268;
Angew. Chem. 2008, 120, 4338; j) I. Nakamura, Y. Yamamoto, Chem. Rev.
2004, 104, 2127.
[17] For selected examples of gold-catalyzed cycloisomerization of 1,n-
enyne esters through an initial 1,3-acyloxy migration step, see: a) W.
Yang, Y. Yu, T. Zhang, M. M. Hansmann, D. Pflästerer, A. S. K. Hashmi,
Adv. Synth. Catal. 2013, 355, 2037; b) W. Rao Sally, M. J. Koh, P. W. H.
Chan, J. Org. Chem. 2013, 78, 3183; c) A. S. K. Hashmi, W. Yang, Y. Yu,
M. M. Hansmann, M. Rudolph, F. Rominger, Angew. Chem. Int. Ed. 2013,
52, 1329; Angew. Chem. 2013, 125, 1368; d) S. Cai, Z. Liu, W. Zhang, X.
Zhao, D. Z. Wang, Angew. Chem. Int. Ed. 2011, 50, 11133; Angew. Chem.
2011, 123, 11329; e) W. Rao, D. Susanti, P. W. H. Chan, J. Am. Chem. Soc.
2011, 133, 15248; f) D. Garayalde, E. Gómez-Bengoa, X. Huang, A.
Goeke, C. Nevado, J. Am. Chem. Soc. 2010, 132, 4720; g) P. Mauleón, J. L.
Krinsky, F. D. Toste, J. Am. Chem. Soc. 2009, 131, 4513; h) G. Lemi›re, V.
Gandon, K. Cariou, A. Hours, T. Fukuyama, A.-L. Dhimane, L. Fenster-
bank, M. Malacria, J. Am. Chem. Soc. 2009, 131, 2993; i) G. Lemi›re, V.
Gandon, K. Cariou, T. Fukuyama, A.-L. Dhimane, L. Fensterbank, M. Mal-
acria, Org. Lett. 2007, 9, 2207; j) A. Buzas, F. Gagosz, J. Am. Chem. Soc.
2006, 128, 12614; k) A. Buzas, F. Istrate, F. Gagosz, Org. Lett. 2006, 8,
1957; l) L. Zhang, S. Wang, J. Am. Chem. Soc. 2006, 128, 1442; m) L.
Zhang, J. Am. Chem. Soc. 2005, 127, 16804.
[18] For gold-catalyzed cycloisomerization of 1,3-enyne esters to form cyclo-
pentenones, see refs. [17h], [17i], [17l] and: F.-Q. Shi, X. Li, Y. Xia, L.
Zhang, Z.-X. Yu, J. Am. Chem. Soc. 2007, 129, 15503.
[19] For the only other known example of gold-catalyzed cycloisomerization
of 1,4-enyne esters to give cyclopentenones, see: ref. [16i].
[20] For general reviews on Nazarov cyclizations, see: a) M. A. Tius, Chem.
Soc. Rev. 2014, 43, 2979; b) T. N. Grant, C. J. Rieder, F. G. West, Chem.
Commun. 2009, 5676; c) W. Nakanishi, F. G. West, Curr. Opin. Drug Dis-
covery Devel. 2009, 12, 732; d) A. J. Frontier, C. Collison, Tetrahedron
2005, 61, 7577; e) H. Pellissier, Tetrahedron 2005, 61, 6479.
[21] For selected examples of gold-catalyzed Nazarov cyclizations, see:
refs. [18], [19] and: a) M. Hoffmann, J.-M. Weibel, P. de FrØmont, P. Pale,
A. Blanc, Org. Lett. 2014, 16, 908; b) R. B. Dateer, K. Pati, R.-S. Liu, Chem.
Commun. 2012, 48, 7200; c) A. S. K. Hashmi, S. Pankajakshan, M. Ru-
dolph, E. Enns, T. Bander, F. Rominger, W. Frey, Adv. Synth. Catal. 2009,
351, 2855; d) G. Y. Lin, C. W. Li, S. H. Hung, R.-S. Liu, Org. Lett. 2008, 10,
5059; e) C. C. Lin, T. M. Teng, C. C. Tsai, H. Y. Liao, R. S. Liu, J. Am. Chem.
Soc. 2008, 130, 16417; f) T. Jin, Y. Yamamoto, Org. Lett. 2008, 10, 3137;
g) A. S. K. Hashmi, M. Bührle, R. SalathØ, J. W. Bats, Adv. Synth. Catal.
2008, 350, 2059; h) C.-C. Lin, T.-M. Teng, A. Odedra, R.-S. Liu, J. Am.
Chem. Soc. 2007, 129, 3798; i) J. H. Lee, F. D. Toste, Angew. Chem. Int. Ed.
2007, 46, 912; Angew. Chem. 2007, 119, 930; j) H. Funami, H. Kusama, N.
Iwasawa, Angew. Chem. Int. Ed. 2007, 46, 909; Angew. Chem. 2007, 119,
927.
[22] For general reviews on Diels–Alder reactions, see: a) R. A. A. Foster,
M. C. Willis, Chem. Soc. Rev. 2013, 42, 63; b) S. Kotha, M. Meshram, A.
Tiwari, Chem. Soc. Rev. 2009, 38, 2065; c) S. Reymond, J. Cossy, Chem.
Rev. 2008, 108, 5359; d) P. Wessig, G. Müller, Chem. Rev. 2008, 108, 2051;
e) K. Takao, R. Munakata, K. Tadano, Chem. Rev. 2005, 105, 4779; f) The
Diels–Alder Reaction: Selected Practical Methods (Eds. F. Fringuelli, A. Ta-
ticchi), Wiley, Hoboken, 2002; g) Cycloaddition Reactions in Organic Syn-
thesis (Eds. S. Kobayashi, K. A. Jørgensen), Wiley-VCH, Weinheim, 2002;
h) K. C. Nicolaou, S. A. Snyder, T. Montagnon, G. Vassilikogiannakis,
Angew. Chem. Int. Ed. 2002, 41, 1668; Angew. Chem. 2002, 114, 1742;
i) E. J. Corey, Angew. Chem. Int. Ed. 2002, 41, 1650; Angew. Chem. 2002,
114, 1724; Angew. Chem. Angew. Chem 2002, 114, 1724.
[12] For selected reviews on gold catalysis, see ref. [11b] and: a) C. M. Friend,
A. S. K. Hashmi, Acc. Chem. Res. 2014, 47, 729; b) C. Obradors, A. M.
Echavarren, Chem. Commun. 2014, 50, 16; c) Modern Gold Catalyzed Syn-
thesis (Eds. A. S. K. Hashmi, F. D. Toste), Wiley-VCH, Weinheim, 2012;
d) M. Rudolph, A. S. K. Hashmi, Chem. Soc. Rev. 2012, 41, 2448; e) C. D.
Pina, E. Falletta, M. Rossi, Chem. Soc. Rev. 2012, 41, 350; f) A. Corma, A.
Leyva-PØrez, M. J. Sabater, Chem. Rev. 2011, 111, 1657; g) N. Krause, C.
Winter, Chem. Rev. 2011, 111, 1994; h) D. J. Gorin, B. D. Sherry, F. D.
Toste, Chem. Rev. 2008, 108, 3351; i) A. S. K. Hashmi, M. Rudolph, Chem.
Soc. Rev. 2008, 37, 1766; j) A. Fürstner, P. W. Davies, Angew. Chem. Int.
Ed. 2007, 46, 3410; Angew. Chem. 2007, 119, 3478; k) A. S. K. Hashmi,
Chem. Rev. 2007, 107, 3180; l) E. JimØnez-NfflÇez, A. M. Echavarren,
Chem. Commun. 2007, 333; m) A. S. K. Hashmi, G. J. Hutchings, Angew.
Chem. Int. Ed. 2006, 45, 7896; Angew. Chem. 2006, 118, 8064.
[13] For reviews on gold-catalyzed cycloisomerizations of propargylic esters,
see: a) R. K. Shiroodi, V. Gevorgyan, Chem. Soc. Rev. 2013, 42, 4991;
b) X.-Z. Shu, D. Shu, C. M. Schienebeck, W. Tang, Chem. Soc. Rev. 2012,
41, 7698; c) S. Wang, G. Zhang, L. Zhang, Synlett 2010, 692; d) N.
Marion, S. P. Nolan, Angew. Chem. Int. Ed. 2007, 46, 2750; Angew. Chem.
2007, 119, 2806; e) J. Marco-Contelles, E. Soriano, Chem. Eur. J. 2007, 13,
1350.
[14] For selected reviews on gold-catalyzed cycloisomerization of 1,n-
enynes, see: a) L. Fensterbank, M. Malacria, Acc. Chem. Res. 2014, 47,
953; b) C. Obradors, A. M. Echavarren, Acc. Chem. Res. 2014, 47, 902;
c) D. Garayalde, C. Nevado, ACS Catal. 2012, 2, 1462; d) A. S. K. Hashmi,
Angew. Chem. Int. Ed. 2010, 49, 5232; Angew. Chem. 2010, 122, 5360;
e) E. Soriano, J. Marco-Contelles, Acc. Chem. Res. 2009, 42, 1026; f) A.
Fürstner, Chem. Soc. Rev. 2009, 38, 3208; g) E. JimØnez-NfflÇez, A. M.
Echavarren, Chem. Rev. 2008, 108, 3326; h) L. Zhang, J. Sun, S. A.
Kozmin, Adv. Synth. Catal. 2006, 348, 2271; i) S. Ma, S. Yu, Z. Gu, Angew.
Chem. Int. Ed. 2006, 45, 200; Angew. Chem. 2006, 118, 206.
[15] For selected examples of gold-catalyzed cycloisomerization of 1,n-
enynes, see: a) N. Marien, B. Brigou, B. Pinter, F. De Proft, G. Verniest,
Org. Lett. 2015, 17, 270; b) C. V. S. Kumar, C. V. Ramana, Org. Lett. 2014,
16, 4766; c) D. B. Huple, R.-S. Liu, Chem. Commun. 2012, 48, 10975; d) K.
Wittstein, K. Kumar, H. Waldmann, Angew. Chem. Int. Ed. 2011, 50, 9076;
Angew. Chem. 2011, 123, 9242; e) M. Schelwies, A. L. Dempwolff, F. Ro-
minger, G. Helmchen, Angew. Chem. Int. Ed. 2007, 46, 5598; Angew.
Chem. 2007, 119, 5694; f) A. K. Buzas, F. M. Istrate, F. Gagosz, Angew.
Chem. Int. Ed. 2007, 46, 1141; Angew. Chem. 2007, 119, 1159; g) P. Y.
Toullec, E. Genin, L. Leseurre, J.-P. GenÞt, V. Michelet, Angew. Chem. Int.
Ed. 2006, 45, 7427; Angew. Chem. 2006, 118, 7587; h) A. S. K. Hashmi,
M. C. Blanco, E. Kurpejovic, W. Frey, J. W. Bats, Adv. Synth. Catal. 2006,
348, 709; i) A. S. K. Hashmi, M. Rudolph, J. P. Weyrauch, M. Wçlfle, W.
Frey, J. W. Bats, Angew. Chem. Int. Ed. 2005, 44, 2798; Angew. Chem.
2005, 117, 2858; j) A. S. K. Hashmi, T. M. Frost, J. W. Bats, J. Am. Chem.
Soc. 2000, 122, 11553.
[16] For selected examples of gold-catalyzed cycloisomerization of 1,n-
enyne esters through an initial 1,2-acyloxy migration step, see: a) W.
Rao Sally, S. N. Berry, P. W. H. Chan, Chem. Eur. J. 2014, 20, 13174; b) M.
Uemura, D. G. Watson, M. Katsukawa, F. D. Toste, J. Am. Chem. Soc.
2009, 131, 3464; c) I. D. G. Watson, S. Ritter, F. D. Toste, J. Am. Chem. Soc.
2009, 131, 2056; d) Y. Zou, D. Garayalde, Q. Wang, C. Nevado, A. Goeke,
Angew. Chem. Int. Ed. 2008, 47, 10110; Angew. Chem. 2008, 120, 10264;
e) F.-D. Boyer, X. Le Goff, I. Hanna, J. Org. Chem. 2008, 73, 5163; f) G. Li,
G. Zhang, L. Zhang, J. Am. Chem. Soc. 2008, 130, 3740; g) X. Moreau, J.-
P. Goddard, M. Bernard, G. Lemi›re, J. M. López-Romero, E. Mainetti, N.
Marion, V. Mouri›s, S. Thorimbert, L. Fensterbank, M. Malacria, Adv.
Synth. Catal. 2008, 350, 43; h) N. Marion, P. de FrØmont, G. Lemi›re, E. D.
Stevens, L. Fensterbank, M. Malacria, S. P. Nolan, Chem. Commun. 2006,
2048; i) X. D. Shi, D. J. Gorin, F. D. Toste, J. Am. Chem. Soc. 2005, 127,
5802; j) V. Mamane, T. Gress, H. Krause, A. Fürstner, J. Am. Chem. Soc.
2004, 126, 8654; k) K. Miki, K. Ohe, S. Uemura, J. Org. Chem. 2003, 68,
8505; l) K. Miki, K. Ohe, S. Uemura, Tetrahedron Lett. 2003, 44, 2019.
[23] For selected examples on gold-initiated transformations involving
a Diels–Alder reaction step, see: a) L. Zhou, M. Zhang, W. Li, J. Zhang,
Angew. Chem. Int. Ed. 2014, 53, 6542; Angew. Chem. 2014, 126, 6660;
b) X. Wu, S.-S. Chen, Y. Hu, L.-Z. Gong, Org. Lett. 2014, 16, 3820; c) B. Liu,
K.-N. Li, S.-W. Luo, J.-Z. Huang, H. Pang, L.-Z. Gong, J. Am. Chem. Soc.
2013, 135, 3323; d) A. M. Sanjuµn, P. García-García, M. A. Fernµndez-Ro-
dríguez, R. Sanz, Adv. Synth. Catal. 2013, 355, 1955; e) Z.-Y. Han, D.-F.
Chen, Y.-Y. Wang, R. Guo, P.-S. Wang, C. Wang, L.-Z. Gong, J. Am. Chem.
Soc. 2012, 134, 6532; f) X.-R. Song, X.-F. Xia, Q.-B. Song, F. Yang, Y.-X. Li,
X.-Y. Liu, Y.-M. Liang, Org. Lett. 2012, 14, 3344; g) T.-M. Teng, R.-S. Liu, J.
Am. Chem. Soc. 2010, 132, 9298; h) J. Barluenga, J. Calleja, A. Mendoza,
F. Rodríguez, F. J. FaÇanµs, Chem. Eur. J. 2010, 16, 7110; i) H. Kusama, Y.
Karibe, Y. Onizawa, N. Iwasawa, Angew. Chem. Int. Ed. 2010, 49, 4269;
Angew. Chem. 2010, 122, 4365; j) J. Barluenga, M. . Fernµndez-Rodrí-
guez, P. García-García, E. Aguilar, J. Am. Chem. Soc. 2008, 130, 2764;
k) N. Asao, K. Sato, Org. Lett. 2006, 8, 5361.
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[24] For selected examples, see refs. [16a], [17b], [17e] and: a) W. Rao, M. J.
Koh, D. Li, H. Hirao, P. W. H. Chan, J. Am. Chem. Soc. 2013, 135, 7926;
b) W. Rao, M. J. Koh, P. Kothandaraman, P. W. H. Chan, J. Am. Chem. Soc.
2012, 134, 10811; c) P. Kothandaraman, W. Rao, S. J. Foo, P. W. H. Chan,
Angew. Chem. Int. Ed. 2010, 49, 4619; Angew. Chem. 2010, 122, 4723.
[25] For the seminal work in the field showing 1,2-acyloxy migration/metal-
lo-Nazarov-type cyclization of 1,4-enyne acetates to cyclopentenones
by using palladium catalysis, see: V. Rautenstrauch, J. Org. Chem. 1984,
49, 950.
[26] For the synthesis of starting materials 5 and ent-5v, see the Supporting
Information for details; for the synthesis of gold complexes A–H, see:
a) F. BarabØ, P. Levesque, I. Korobkov, L. Barriault, Org. Lett. 2011, 13,
5580; b) V. López-Carrillo, A. M. Echavarren, J. Am. Chem. Soc. 2010, 132,
9292; c) C. H. M. Amijs, V. López-Carrillo, M. Raducan, P. PØrez-Galµn, C.
Ferrer, A. M. Echavarren, J. Org. Chem. 2008, 73, 7721; d) L. Ricard, F.
Gagosz, Organometallics 2007, 26, 4704; e) E. Herrero-Gómez, C. Nieto-
Oberhuber, S. López, J. Benet-Buchholz, A. M. Echavarren, Angew. Chem.
Int. Ed. 2006, 45, 5455; Angew. Chem. 2006, 118, 5581; f) A. S. K. Hashmi,
´
J. P. Weyrauch, M. Rudolph, E. Kurpejovic, Angew. Chem. Int. Ed. 2004,
43, 6545; Angew. Chem. 2004, 116, 6707.
[27] CCDC 973692(8a), 973691(8g), 1013492(8k), 973690(8n), 973689(8p)
and 1013494(ent-9v) contain the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[28] For computational studies on the AuI-catalyzed 1,2-acyloxy migration/
metallo-Nazarov-type cyclization of 1,4-enyne esters by path a, see:
O. N. J. Faza, C. S. López, R. lvarez, A. R. de Lera, J. Am. Chem. Soc.
2006, 128, 2434.
[29] M. Totrov, R. Abagyan, Proteins 1997, 29, 215.
Received: February 26, 2015
Published online on May 15, 2015
Chem. Eur. J. 2015, 21, 9111 – 9118
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim