Asymmetric gold-catalyzed hydroarylation/cyclization reactions

Article abstract of DOI:10.1002/chem.200802341

The asymmetric gold-catalyzed hydroarylation/cyclization reactions of 1,6-enynes under mild conditions was investigated. A mixture of L-(AuCl) ₂ (L=(R)-MeO-BIPHEP or (R)-4-MeO-3,5-(tBu)₂MeOBIPHEP) (3 mol %) and AgOTf (6 mol %) in dis

Full text of DOI:10.1002/chem.200802341

COMMUNICATION
DOI: 10.1002/chem.200802341
Asymmetric Gold-Catalyzed HydroACTHNUTRGENUGNarylation/Cyclization Reactions
Chung-Meng Chao, Maxime R. Vitale, Patrick Y. Toullec, Jean-Pierre GenÞt, and
Vꢀronique Michelet*[a]
Recent years have witnessed a substantial growth in the
ꢀ
ꢀ
number of gold-catalyzed reactions implying C C, C O or
ꢀ
C N bond-formation processes.[1] Despite the rapid develop-
ment of several synthetic applications, the enantioselective
aspects still require investigations.[2] Some reports described
the transfer of chirality from allenes and propargylic esters,
and the asymmetric hydroalkoxylation and hydroamination
of allenes.[2] Nevertheless examples are still scarce, most
probably due to the linear geometry of chiral gold(I) com-
plexes that explains a lack of steric interactions between the
chiral inducer and the activated function of the substrate.
Ito and Hayashiꢀs groups pioneered the field of asymmetric
gold catalysis by conceiving the addition of isocyanoacetates
to aldehydes in the presence of a cationic gold catalyst and
a chiral diphosphanyl ferrocene ligand.[3] Other groups have
recently challenged to discover new applications of linear
chiral gold complexes, but to the best of our knowledge,
only two of them implied alkyne activation.[4] In the course
of our research on metal-catalyzed cycloisomerization reac-
tions of enynes,[5] we and others have described novel rear-
rangements in the presence of external nucleophiles such as
alcohols, electron-rich aromatic rings, amines, carboxylic
acids and 1,3-dicarbonyl compounds (Scheme 1).[6]
Scheme 1. Metal-catalyzed cycloisomerization of 1,6-enynes in the pres-
ence of an external nucleophile.
were observed and only one example has been reported
with an ee higher than 90%. We envisaged to study these
challenging reactions and wish to present our preliminary
results leading to enantiomerically enriched functionalized
cyclic alkenes starting from 1,6-enynes.
Initial efforts have focused on the optimization of an effi-
cient system starting from enyne 1a as a model substrate
(Table 1). Based on our experience, we reasoned that the
addition of electron-rich aromatic rings would be successful
as the kinetics were fast and the steric hindrance of the nu-
cleophile would favor an enantioselective process. Accord-
ing to previously described procedures,[4a] we prepared
chiral AuI catalysts with MeOBIPHEP,[7] BINAP[8] and 4-
MeO-3,5-(tBu)2-MeOBIPHEP[7] ligands. The use of (R)-
MeOBIPHEP–(AuCl)2 associated with silver salt AgSbF6 in
diethyl ether[6n] led to the formation of the desired product
2a in excellent yield and 26% enantiomeric excess (Table 1,
entry 1). The influence of silver salts was investigated
(Table 1, entries 2–4), silver triflate and silver bis(trifluoro-
methanesulfonyl)imidate giving the best results. The use of
silver benzoate[9] was particularly striking as no conversion
was observed at room temperature for 240 h (Table 1,
entry 2). Lowering the temperature to 08C increased the re-
Despite the fact that these reactions seem mechanistically
related, they proved to be highly substrate and nucleophile
dependent. This explains the fact that no general asymmet-
ric version was described so far for these tandem atom-eco-
nomical processes. We described the first asymmetric Pt-cat-
alyzed alkoxycyclization reactions[6d] and Echavarrenꢀs
group published the first analogous gold-catalyzed pro-
ACHTUNGTRENNUNG
cess.[4a] In both cases, moderate to good enantioselectivities
[a] C.-M. Chao, Dr. M. R. Vitale, Dr. P. Y. Toullec, Prof. J.-P. GenÞt,
Dr. V. Michelet
Laboratoire de Synthꢁse Sꢂlective Organique et Produits Naturels
UMR 7573, Ecole Nationale Supꢂrieure de Chimie de Paris
rue P. et M. Curie, 75231 Paris cedex 05 (France)
Fax : (+33)144-071-062
E-mail: veronique-michelet@enscp.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802341.
Chem. Eur. J. 2009, 15, 1319 – 1323
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1319

Table 2. Asymmetric AuI-catalyzed cycloisomerization of 1,6-enynes.
action time but moderately influenced the enantiomeric ex-
cesses (Table 1, entries 5–8). The use of BINAP induced an
important decrease of the observed ee (Table 1, entries 6–7),
whereas a hindered and electron-rich ligand 4-MeO-3,5-
(tBu)2-MeOBIPHEP recently used in asymmetric styrene
cyclopropanation and allene hydroamination reactions al-
lowed a consistent leap as the desired arylated product 2a
was isolated in 80% enantiomeric excess (Table 1, entries 8–
9). The best result was obtained in the presence of 3 mol%
Entry
1
Nucleophile Ar-H
2
Yield[a]
[%]
ee[b] [%]
(configuration)
of 4-MeO-3,5-(tBu)2-MeOBIPHEPACHTNUGTRNEUNG(AuCl)2, 6 mol% of
AgOTf in diethyl ether at room temperature (Table 1,
entry 9). We also investigated the influence of the Ag/Au
ratio and observed a decrease of the ee when employing one
equivalent of silver salts compared to digold complex
(Table 1, entry 10). It should be noted that, although compe-
tition between Au and Brønsted acids has been reported in
the literature,[10] no conversion has been observed from the
reaction of enyne 1a and 1-methylindole in the presence of
10 mol% triflic acid.[11]
1
2
3
4
5
6
7
8
9
1a 1,3,5-trimethoxybenzene
1a pyrrole
1b 1-Me-indole
1b 1-Me-2-Ph-indole
1c 1-Me-indole
1c 1-Me-2-Ph-indole
1c 1,3,5-trimethoxybenzene
1d 1,3-dimethoxybenzene
1d 1,3,5-trimethoxybenzene
1d 1,3,5-trimethoxy-2-bromo-
benzene
2b 92
2c 86
2d 94
2e 99
2 f 99
2g 99
2h 99
2i 86
2j 99
2k 85
72 (ꢀ)
80 (ꢀ)
95 (+)
95 (ꢀ)
81 (+)
82 (ꢀ)
82 (ꢀ)
98 (ꢀ)
98 (ꢀ)
94 (ꢀ)
10
11
1e 1-Me-indole
2l 37
88 (ꢀ)
Table 1. L–(AuCl)2-catalyzed Friedel–Crafts/cyclization reaction of
enyne 1a.
[a] Isolated yield. [b] See Supporting Information.
To evaluate the influence of steric crowding of the tether-
ing moiety on enantioselectivity,[12] enynes 1b and 1c were
engaged in control cycloisomerization reactions in the pres-
ence of 1-methylindole and 1-methyl-2-phenylindole.
Indeed, a beneficial substrate effect was apparent in the
case of 1b (Table 2, entry 3) as the observed enantiomeric
excess (95%) was more than ten points higher than in the
case of 1a (Table 1, entry 9). Increasing the nucleophile hin-
drance had no detrimental effect on enantioselectivity
(Table 2, entry 4). Replacement of iPr with a benzyl ester
group did not lead to better results (Table 2, entries 5–7), as
the enantioselectivity observed for enyne 1c turned out to
be equivalent to the one of 1a. In the case of the sulfone-
substituted enyne 1d, the enantioselectivities were excellent
as the arylated cyclic derivatives were obtained in 98 and
94% ee (Table 2, entries 8–10). Itꢀs noteworthy that the
presence of a bromine atom on the aromatic nucleophile
partner was tolerated (Table 2, entry 10). The addition of 1-
Me-indole on a trisubstituted double bond afforded the cor-
responding cyclic alkene 2l in a good ee (Table 2, entry 11).
The unprecedented reactivity of the challenging substrate
1 f was then investigated in the presence of 4-MeO-3,5-
(tBu)2-MeOBIPHEP–(AuCl)2 catalyst (Scheme 2). We were
pleased to observe an enantiodiscrimination in the presence
of the chiral gold catalyst: the functionalized heterocycles
were indeed isolated in good yields and 53–59% ee. Notably,
these results may open new opportunities for the synthesis
of antitumor lignans derivatives.[13]
Entry Cond[a] [Ag]
T/ [8C], t [h] Yield[b] [%] ee[c] [%]
(configuration)
1
2
3
4
5
6
7
8
A
A
A
A
A
B
B
C
C
C
AgSbF6 RT, 0.3
AgOBz RT, 240
AgOTf RT, 20
AgNTf2 RT, 0.3
AgOTf 0, 24
AgOTf 0, 36
AgNTf2 0, 24
AgOTf 0, 2
96
0
26 (+)
–
96
91
71
46
99
91
99
95
36 (+)
45 (+)
54 (+)
12 (+)
20 (+)
80 (+)
83 (+)
74 (+)
9
10
AgOTf RT, 48
AgOTf 0, 1
[a] A=(R)-MeOBIPHEP
MeO-3,5-(tBu)2MeOBIPHEP
by HPLC analysis OD-H, hexane/iPrOH 98:2, 1 mLminꢀ1
G
ACHTUNGTERN(NGNU AuCl)2, C=(R)-4-
AHCTUNGTRENNUNG
.
We then decided to screen nucleophiles and react them
with various 1,6-enynes in the presence of the optimized cat-
alytic system (Table 2). A single diastereomer of 2 was
formed in all 1,6-enyne/nucleophile combinations tested.[6]
Addition of 1,3,5-trimethoxybenzene and pyrrole on enyne
1a was achieved in 72 and 80% ee, respectively (Table 2, en-
tries 1–2).
The intramolecular version of this reaction was particular-
ly interesting and challenging considering the occurrence of
tricyclic skeletons in natural products.[14] The enantioselec-
tive hydroarylation/cyclization reaction was found to be suc-
cessful (Scheme 3). Cycloisomerization of enynes 1g–h[6n,q]
1320
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Gold Catalysis
COMMUNICATION
Scheme 2. Asymmetric AuI-catalyzed cycloisomerization of oxygen-teth-
ered 1,6-enynes.
Scheme 4. Mechanism rationale.
the existence of an equilibrium between forms A and B/B’.
The intervention of C would theoretically lead to a diaste-
reomeric mixture of syn/anti derivatives if bond rotation of
the carbocationic intermediates is faster compared to the
addition of the carbon nucleophile, which has never been
observed in our hand.
Scheme 3. Asymmetric intramolecular AuI-catalyzed cycloisomerization
of 1,6-enynes.
afforded the tricyclic structures 2p and 2q in 93 and 92%
ee. It is remarkable to note that no reaction occurred in the
presence of chiral platinum complexes.[6t]
Our experience in this field and recent results concerning
asymmetric gold-catalyzed addition of oxygen nucleophiles
prompted us to assume that the addition of the nucleophile
is concerted with the cyclization.[6u] In the case of more nu-
cleophilic electron-rich aromatic rings, the “carbocation-
like” contribution of the intermediate is less pronounced
than in the case of oxygen nucleophile, which explains the
higher ee values. In this scenario, the intervention of a con-
formationally favored intermediate D, as proposed by Fꢄrst-
ner,[6r] would better account for the experimental results. It
is indeed observed that the ee values increase with the size
of the enyne tether Z (see Table 2 and Scheme 2, compare
In all 1,6-enyne/nucleophile combinations tested, and in
accordance with previous contributions under racemic con-
ditions, a single diastereoisomer of 2 was formed. The anti
diastereoselectivity of the reaction had been unambiguously
established by X-ray analysis of hetero- and carbocyclic de-
rivatives. The mechanism of such transformation has been
widely argued and is still under debate (Scheme 4). Based
on a combined theoretical and experimental study, the nu-
cleophilic attack/cycloisomerization reaction has been pro-
posed to operate via a transient unstable cyclopropylcarbene
B by the group of Echavarren.[5,6,15] More recently, Fꢄrstner
and Morency proposed an alternative rationale relying on
the mesomeric “nonclassical” carbocation C.[6r,16] The pres-
ent results of the asymmetric reactions show a variation of
enantioselectivity observed for a given enyne substrate in
the presence of different carbon nucleophiles. In this regard,
intermediates B and C do not adequately account for the
formation of cyclic alkene E. Indeed, considering the anti
nucleophilic attack on the cyclopropylcarbene intermediate
B as a stereospecific event, the external carbon nucleophile
does not take part in the cyclopropylcarbene formation
which represents the enantiodetermining step of the trans-
formation. Considering the variation of enantioselectivity
observed for a given enyne substrate and different carbon
nucleophiles (Table 2), the major contribution of intermedi-
ate B, and of its diastereomeric counterpart B’, is bound to
Z=O, CACHTGNUERTNNN(UG CO2Me)2, CACHNUTRTEGNGN(UN CO2iPr)2 and CACHTNGURTEN(NUGN SO2Ph)2). Consider-
ing a “chair-like” h2-complex D, the addition of the nucleo-
phile would occur in complete analogy with the Stork–
Eschenmoser hypothesis,[17] introduced to account for the se-
lectivity of polyene cyclization reactions.
We therefore extended the methodology developed for
chiral gold complexes and discovered that the combination
of atropisomeric electron-rich and hindered chiral ligand 4-
MeO-3,5-(tBu)2-MeOBIPHEP associated to AuI and silver
salts promotes the enantioselective hydroarylation/cycliza-
tion reaction of 1,6-enynes under mild conditions. Some
enantiomerically enriched functionalized carbo- and hetero-
cycles were isolated in good to excellent yields and with ee
values up to 98%. Further studies will be focused on appli-
cation of this methodology to the synthesis of natural and
biologically active compounds.
Chem. Eur. J. 2009, 15, 1319 – 1323
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1321

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C. Ferrer, A. M. Echavarren, J. Org. Chem. 2008, 73, 7721; t) P. Y.
Toullec, C.-M. Chao, Q. Chen, S. Gladiali, J.-P. Genet, V. Michelet,
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Toullec, J.-P. Genet, V. Michelet, J. Organomet. Chem. 2008, DOI:
10.1016/j.jorganchem.2008.08.008.
Experimental Section
Typical experimental procedure: A mixture of L–(AuCl)2 (L=(R)-MeO-
BIPHEP or (R)-4-MeO-3,5-(tBu)2MeOBIPHEP) (3 mol%) and AgOTf
(6 mol%) in distilled Et2O (10ꢀ2 m) was stirred under argon atmosphere
at room temperature for 30 min. The aromatic nucleophile (3 equiv) was
then added and the mixture was stirred for 5 min. Enyne (1 equiv) was fi-
nally added and the mixture was stirred until completion of the reaction.
The mixture was then filtered through a short pad of silica to eliminate
the catalyst (EtOAc) and the solvents were evaporated under reduced
pressure. The crude product was purified by silica gel flash chromatogra-
phy (petroleum ether/ethyl acetate 90:10 ! 70:30) if necessary.
Acknowledgements
This work was supported by the Centre National de la Recherche Scienti-
fique (CNRS) and the Ministꢁre de l’Education et de la Recherche.
C.M.C. is grateful to the Ministꢁre de l’Education et de la Recherche for
financial supports. The authors thank Dr. M. Scalone (Hoffmann-La
Roche) for generous gift of MeOBIPHEP and 4-MeO-3,5-(tBu)2-MeO-
BIPHEP ligands.
Keywords: asymmetric catalysis · cyclization · electron-rich
arenes · gold · tandem reaction
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ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Gold Catalysis
COMMUNICATION
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Received: September 25, 2008
Published online: January 2, 2009
Chem. Eur. J. 2009, 15, 1319 – 1323
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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