Enantioselective IrI-catalyzed carbocyclization of 1,6-enynes by the chiral counterion strategy

Article abstract of DOI:10.1002/chem.201102723

Enantioenriched bicyclo[4.1.0]hept-2-enes were synthesized by Ir ^I-catalyzed carbocyclization of 1,6-enynes. No chiral ligands were used, CO and PPh₃ were the only ligands bound to iridium. Instead, the stereochemical information was

Full text of DOI:10.1002/chem.201102723

FULL PAPER
DOI: 10.1002/chem.201102723
Enantioselective IrI-Catalyzed Carbocyclization of 1,6-Enynes by the Chiral
Counterion Strategy
Marion Barbazanges,[a] Mylꢀne Augꢁ,[a] Jamal Moussa,[a] Hani Amouri,*[a]
Corinne Aubert,*[a] Christophe Desmarets,[a] Louis Fensterbank,*[a] Vincent Gandon,*[b]
Max Malacria,[a] and Cyril Ollivier[a]
Abstract: Enantioenriched bicyclo-
[4.1.0]hept-2-enes were synthesized by
when this catalytic mixture was used.
31P NMR and IR spectroscopy suggest
cationic moiety. The chiral phosphate
À
G
anion (O P*) controls the enantiose-
IrI-catalyzed carbocyclization of 1,6-
enynes. No chiral ligands were used,
CO and PPh3 were the only ligands
bound to iridium. Instead, the stereo-
chemical information was localized on
the counterion of the catalyst, generat-
ed in situ by reaction of Vaskaꢀs com-
that
[Ir(CO)ACTHUNGTRENNNUG
formation
of
the
trans-
lectivity through formation of a loose
ion pair with the metal center and es-
(PPh3)2]+ moiety occurs by
À
À
chlorine abstraction. Moreover, density
functional theory calculations support a
6-endo-dig cyclization promoted by this
tablishes a C H···O P* hydrogen bond
with the substrate. This is a rare exam-
ple of asymmetric counterion-directed
transition-metal catalysis and repre-
sents the first application of such a
Keywords: chirality
·
enynes
·
À
plex (trans-[IrCl(CO)
N
strategy to a C C bond-forming reac-
tion.
homogeneous catalysis · ion pairs ·
iridium
chiral silver phosphate. Enantiomeric
excesses up to 93% were obtained
Introduction
interaction with Au+ or Y, the use of a chiral anion, as in
+
[L Au ···Y]
[A*À], can bring this information closer to the
À
Asymmetric counterion-directed transition-metal catalysis is
an emergent strategy in organic synthesis.[1] Whether the
chiral anion acts as an organocatalyst[2] (for example, by as-
sisting proton transfers) or remains a spectator but gener-
ates an asymmetric environment,[3] this new approach has
proven to be a powerful tool. Interest in this concept has
been notably illustrated by Toste et al. in the field of gold-
catalyzed allene cyclizations.[3b,e] Because gold forms linear
substrate and give rise to highly enantioselective processes.[5]
Chiral silver phosphates or phosphoric acids were used for
this purpose, which led to gold phosphates of type A after
halide abstraction or methane elimination (Scheme 1a).[3b,
d,e,h]
Such species catalyze enantioselective intramolecular
hydroamination or hydroalkoxylation of allenes (Sche-
me 1b).[3b,e] To the best of our knowledge, the chiral anion
strategy has been limited to heterocyclizations. We decided
to explore the vast area of carbocyclizations, starting from
the typical cycloisomerization of 1,6-enynes.[6]
+
À
À
cationic intermediates of type [L* Au ···Y][A ], in which
L* is an L-type chiral ligand, Y is the substrate, and [AÀ] is
the counterion, the stereochemical information at L* is
remote from Y.[4] Provided the anion can establish a binding
A large array of products can be obtained from 1,6-enyne
substrates, which include chiral members of the bicyclo-
AHCTUNGTREG[NNNU 4.1.0]hept-2-ene family (Scheme 2). The success of this
transformation, which can be performed by using various
metal salts of platinum,[7] gold,[8] rhodium,[9] or iridium,[10] is
often critically dependent on the presence of a nitrogen or
an oxygen atom in the tether. Asymmetric versions have
been reported with chiral platinum–monophosphine,[7k–l]
[a] Dr. M. Barbazanges, M. Augꢁ, Dr. J. Moussa, Dr. H. Amouri,
Dr. C. Aubert, Dr. C. Desmarets, Prof. Dr. L. Fensterbank,
Prof. Dr. M. Malacria, Dr. C. Ollivier
UPMC Paris 06
IPCM (UMR CNRS 7201)
4 Place Jussieu
75252 Paris cedex 05 (France)
Fax : (+33)144273078
E-mail: louis.fensterbank@upmc.fr
corinne.aubert@upmc.fr
hani.amouri@upmc.fr
[b] Prof. Dr. V. Gandon
Universitꢁ Paris-Sud
ICMMO, UMR CNRS 8182
91405 Orsay (France)
E-mail: vincent.gandon@u-psud.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102723.
Scheme 1. Chiral-phosphate-directed gold-catalyzed allene cyclization.
Chem. Eur. J. 2011, 17, 13789 – 13794
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13789

Table 1. Computed dissociation energies [kcalmolÀ1].
X
DE
DH
DG
I
II
III
113.08
73.90
48.05
111.62
97.79
[a]
[a]
Scheme 2. Cycloisomerization of nitrogen- and oxygen-tethered 1,6-
enynes.
–
–
[a]
[a]
–
–
[a] The frequency calculation could not be carried out due to the size of
the system.
gold–bisphosphine,[8e,g] gold–phosphoramidite,[8f] iridium–
bisACHTUNGTRENNUNG
phosphine (under a CO atmosphere),[10] rhodium–tetra-
fluorobenzobarrelene,[9b] and rhodium–diene–phosphine
complexes.[9d]
Results and Discussion
Whereas the Ph3PAuCl/AgACTHUNTRGNEU[GN SbF6] catalytic mixture promotes
the cycloisomerization of nitrogen-bridged enynes,[8a,c] our
initial attempts to carry out enantioselective carbocycliza-
tions by using the chiral silver phosphate (S)-2[3b] were un-
successful (Scheme 3). No reaction occurred, even after pro-
longed heating.
Thus, we turned our attention to iridium and rhodium cat-
alysts, initially the relatively cheap Vaskaꢀs complex.[15] To
the best of our knowledge, this compound has only been
used once as precatalyst, in racemic experiments for enyne
cycloisomerization by Shibata and co-workers.[10] Reaction
of substrate 1a with Vaskaꢀs complex (10 mol%) and silver
salt (S)-2 (12 mol%) in toluene (c=0.134m) at 908C led to
the expected bicyclic product 3a in 80% yield and 81% ee
(see Table 2, entry 1 and Table S1 in the Supporting Infor-
Table 2. Optimization of the reaction conditions.
Scheme 3. Attempted chiral-phosphate-directed gold-catalyzed carbocyc-
lization of 1a.
Entry
[M]
[IrCl(CO)
[IrCl(CO)(PPh3)2]
[IrBr(CO)(dppe)]
[RhCl(CO)(PPh3)2]
Yield [%][a]
ee [%][b]
We hypothesized that, in contrast to the successful hetero-
cyclization process, the impossible formation of a strong O/
1
2
3
4
G
G
80
81
80
43
48
E
R
74[c]
10[d]
69[d]
À
N H···O hydrogen bond between the phosphate and a ZH
N
group might go against the dissociation of species A
(Scheme 1).[11,12] We reasoned that this step would be easier
with a square planar active species, such as B, because of
steric hindrance between the ligands cis to the bulky phos-
phate.
N
[a] Isolated yield. [b] HPLC, AS-H column. [c] c=0.250m. [d] [M]
(20 mol%), (S)-2 (24 mol%).
Our hypothesis was corrobo-
mation for a full screening of conditions).[16] At a higher
concentration (c=0.250m), although the same enantioselec-
tivity was detected, the yield was lower (Table 2, entry 2).
Vaskaꢀs complex was found to be more efficient in terms of
yield and enantioselectivity than either [IrBr(CO)
(Table 2, entry 3; dppe=1,2-bis(diphenylphosphino)ethane)
or [RhCl(CO)(PPh3)2] (Table 2, entry 4).
The scope and limitations of the reaction were investigat-
ed next (Table 3). In addition to the p-toluenesulfonyl (p-
Ts) derivative 1a, several protecting groups at the nitrogen
rated by DFT calculations[13]
carried out on species of type
B, which arise from Vaskaꢀs-
type
[IrX(CO)
complexes,
(PPh3)2]
trans-
(X=phos-
(dppe)][17]
ACHTUNGTRENNUNG
N
phate I, II, or III). Estimated
gas-phase dissociation energies
(DE) actually decreased with
the steric demand (Table 1).[14]
ACHTUNGTRENNUNG
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Chem. Eur. J. 2011, 17, 13789 – 13794

IrI-Catalyzed Carbocyclization
FULL PAPER
Table 3. Scope and limitations of the reaction.
found to be opposite to that observed for the nitro-
gen-bridged products.[19] Lastly, the carbon-tethered
enyne 1n transformed into a complex mixture of
products from which 3n could not be detected.
Overall, in terms of stereoselectivity, the use of a
chiral counterion provided products 3 with better ee
values than reaction in the presence of chiral di-
phosphine ligands.[10] Additionally, because the
starting iridium complex already bears a p-acceptor
CO ligand, the use of a CO atmosphere could be
avoided. To gain insight into the structure of the
active species, the following control experiment was
carried out (Figure 1): Vaskaꢀs complex was mixed
with (S)-2 in [D8]toluene and the yellow suspension
was stirred at room temperature. Although virtually
no change in the chemical shift of the PPh3 signal in
the 31P NMR spectra was observed at 928C, the
peak of the phosphate was significantly shifted up-
Entry Enyne
Z
R1
R2
R3
R4
Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1 f
1g
1h
1i
o-TsN
MesN[c]
p-NsN[d]
o-NsN
BocN[e]
p-TsN
p-TsN
p-TsN
p-TsN
p-TsN
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
PMP
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
74
77
79
73
38[f]
76
79
61
47
87
93
82
72
80
86
89
86
43
17
n.d.[i]
88[j]
–
Ph
PMP[g]
4-ClPh
Me
H
9[h]
10
11
12
13
1j
1k
1l
1m
1n
H
Ph
H
Ph
Me Me 16
H
Ph
H
H
H
H
16
73
0
O
C
(CO2Et)2 Me
field: trans-[IrCl(CO)ACHTUNGRTNEUNG(PPh3)2]: d=25.6 ppm (PPh3);
[a] Isolated yields. [b] HPLC, AS-H or AD-H column. [c] Mes=(2,4,6-Me3)C6H2SO2.
(S)-2: d=14.8 ppm (silver phosphate); 4: d=25.5
À
[d] Ns=O2N C6H4SO2. [e] Boc=tert-butoxycarbonyl. [f] 59% brsm. [g] PMP=4-
(PPh3) and 3.4 ppm (iridium phosphate).[20] More-
MeOC6H4. [h] 1108C for 40 h. [i] None detected. [j] Opposite absolute configuration.
atom were tested (Table 3, en-
tries 1–4). Whereas the o-Ts
and mesityl (Mes) groups sig-
nificantly improved the stereo-
selectivity (Table 3, entries 1
and 2), o-nosyl (o-Ns) provoked
a decrease in the enantioselec-
tivity to 72% ee (Table 3,
entry 4). On the other hand, p-
Ns substrate 1d (Table 3,
entry 3) gave similar results to
1a. N-tert-butoxycarbonyl (N-
Figure 1. IR and 31P NMR spectroscopic monitoring (242 MHz, 928C).
Boc) enyne 1 f led cleanly to
the desired vinylcyclopropane
3 f with a satisfying 80% ee,
albeit in moderate yield due to a low conversion [38%,
59% based on recovered starting material (brsm)]. Within
the family of p-TsN-bridged enynes, we noticed that the in-
troduction of either an electron-donating or electron-with-
drawing substituent at the para position of the phenyl group
located at the internal double-bond carbon atom resulted in
an increase of the ee value (Table 3, entries 6 and 7).
The presence of a para-methyl group, as in 1i (Table 3,
entry 8), rather than an aryl group did not alter the ee, but
decreased the yield by 15–18% due to the formation of
other unidentified products. In the absence of any substitu-
tion at R2, as in 1j and 1k (Table 3, entries 9 and 10), both
the yields and ee values dramatically decreased.[18] The re-
placement of the p-TsN framework of 1a with an oxygen
atom (1l) seriously impeded the reaction (Table 3, entry 11).
Nevertheless, the oxygen-bridged enyne 1m, which displays
no substitution at R2 and a phenyl group at R3, transformed
efficiently into the desired product with 88% ee (Table 3,
entry 12). The absolute configuration of product 3m was
over, the IR spectra remained similar. After completion of
the reaction (15 h), the white precipitate of AgCl was fil-
tered off and the solution transferred to an NMR tube that
contained a solution of enyne 1a in [D8]toluene. The tube
was sealed and heated to 928C. No change in the 31P NMR
spectra could be detected during the course of the reac-
tion;[21] likewise, the IR spectra after the reaction was simi-
lar to that recorded before the reaction (n˜CO =1966 cmÀ1). In
particular, no loss of CO or PPh3 could be observed. These
results suggest that chloride metathesis takes place and that
the trans geometry of Vaskaꢀs complex is conserved (the two
phosphine groups remain magnetically equivalent).
All attempts to isolate suitable crystals for an X-ray study
of the iridium–chiral phosphate adduct have so far been un-
successful. Moreover, because of the narrow range of the
chemical shifts, even when a 600 MHz spectrometer was
used, it was not possible to identify any reaction intermedi-
ate.[22] Thus, density functional theory (DFT) calculations
were carried out to shed light on some mechanistic issues.
Chem. Eur. J. 2011, 17, 13789 – 13794
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13791

H. Amouri, C. Aubert, Louis Fensterbank, V. Gandon et al.
atom of the tolyl group (Figure 3). The distances are typical
An initial set of results was rapidly generated for PH3 and a
model enyne with an NH tether and no substituent
(Figure 2, Y=R=R’=H). Both the 5-exo-dig and 6-endo-
À
for strong C H···O hydrogen bonds that involve phosphates
À
À
(although N H···O and O H···O hydrogen bonds remain
Figure 3. Optimized 6-endo and 5-exo transition states.
3
the strongest type).[11] It is noteworthy that NC
(sp ) H···O
À
hydrogen bonds may participate in the control of the stereo-
selectivity in some organocatalyzed reactions.[26] Again, tran-
sition state TSCE was found to be the lowest lying, although
close to TSCD (DDG° =0.81 kcalmolÀ1).
Thus, these calculations support a 6-endo-dig cyclization
pathway and corroborate our hypothesis that the chiral
phosphate controls the enantioselectivity through the forma-
tion of a loose ion pair with the metal center.[27]
Figure 2. Calculated energy profile (DG, kcalmolÀ1) for the cyclization of
Conclusion
enynes mediated by [Ir(CO)ACHTNUGRTNEUNG
(PH3)2]+ (values in bold correspond to Y=
R=R’=H).
The first asymmetric chiral-anion-directed transition-metal-
catalyzed carbocyclizations have been achieved. Although
the chiral counterion strategy proved to be successful in the
field of gold-catalyzed heterocyclizations, the choice of iridi-
um as catalyst was adequate in the case of nitrogen- and
oxygen-bridged 1,6-enynes.[29] Of particular interest, the
combination of Vaskaꢀs complex with a chiral silver phos-
phate provided better enantioselectivities than the classical
approach, which involves an Ir+/chiral diphosphine mixture.
Our results suggest the formation of a loose ion pair, in
which the organometallic fragment and the chiral phosphate
are separated by the substrate. The Ir+ moiety coordinates
dig cyclization pathways were modeled.[23,24] From C, in
which the alkyne moiety of the enyne coordinates iridium,
the direct cyclization pathways were found to proceed to
give D and E with very close free energies of activation
(DG°) of 11.71 and 11.54 kcalmolÀ1, respectively. The endo
pathway is appreciably more exergonic than the exo path-
way. The final product F is obtained by a 1,2-hydride shift to
the carbenic center of E. A p-Ts group at nitrogen, a phenyl
group at the internal alkene carbon atom, and a methyl
group at the alkyne terminus (as in 1a) were then intro-
duced in the computations (Y=p-Ts, R=Me, R’=Ph). The
transition states were reoptimized. The 6-endo transition
state (TSCE) was again the lowest lying, followed by the 5-
exo analogue (TSCD) at DDG° =0.83 kcalmolÀ1.
À
the triple bond and the phosphate can establish strong C
3
À
H···O hydrogen bonds, even with less acidic C
U
donors.[28] Extension of this concept to other types of cyclo-
AHCTUNGTREGUNiNN somerizations is underway in our laboratory.
À
The model phosphate HPO4 was next considered and the
two transition states TSCD and TSCE were reoptimized.
Trying to bring the phosphate close to the iridium center re-
sulted in its systematic repulsion from the coordination
sphere. Other 5- and 6-coordinate geometries were attempt-
ed, yet it was not possible to keep all of the ligands togeth-
er.
The best option we could find was to put the phosphate in
such a way that it could establish hydrogen bonds with the
CH2 a to the nitrogen atom[25] and with one ortho-hydrogen
Experimental Section
Typical experimental procedure when the enyne is a solid: In a glovebox,
[IrCl(CO)(PPh3)2] (7.8 mg, 0.010 mmol, 0.10 equiv), (10.3 mg,
G
2
0.012 mmol, 0.12 equiv), and enyne 1 (0.1 mmol, 1 equiv) were added to
a vial equipped with a magnetic stirring bar. The vial was sealed, taken
out of the glovebox, and freshly distilled toluene (0.75 mL, c=0.134m)
was added through the cap. The vial was immersed in a preheated oil
bath at 908C. After 23 h, the reactor was cooled to RT and the vial was
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Chem. Eur. J. 2011, 17, 13789 – 13794

IrI-Catalyzed Carbocyclization
FULL PAPER
opened. The reaction mixture was filtered through a short pad of silica
(Et2O), then concentrated under reduced pressure. Subsequent purifica-
tion by flash chromatography on silica gel afforded cyclized product 3.
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[IrCl(CO)ACHTUNGTRENNUNG(PPh3)2] (7.8 mg, 0.010 mmol, 0.10 equiv) and 2 (10.3 mg,
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0.012 mmol, 0.12 equiv) were added to a vial equipped with a magnetic
stirring bar. The vial was sealed, then taken out of the glovebox. A solu-
tion of enyne 1 (0.1 mmol, 1 equiv) in freshly distilled toluene (0.75 mL,
c=0.134m) was added through the cap and the vial was immersed in a
preheated oil bath (908C). After 23 h, the reactor was cooled to RT and
the vial was opened. The reaction mixture was filtered through a short
pad of silica (Et2O) and the volatile substances were removed in vacuo.
Subsequent purification by flash chromatography on silica gel afforded
cyclized product 3.
Acknowledgements
This work was supported by CNRS and ANR BLAN 09-BLAN0108. L.F.
and M.M. are members of IUF. We used the computing facilities of
CRIHAN, project 2006–013. We thank E. Caytan and F. Goascoz for
NMR spectroscopic studies, E. Kolodziej for HPLC analysis of vinyl-
ACHTUNGTRENNUNGcyclopropane 3 f and E. Benedetti for providing us with enyne 1i.
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À
À
À
gen bonds, and strong C H···O hydrogen bonds, see: a) T. Dorn, A.-
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[12] Despite the so-called “weakly coordinating” nature of the phos-
À
phate, the Au O bond is expected to be strong. Crystal structure
analysis of [(o-Tol)P]3AuOTf showed a short Au···O contact of
2.110(3) Š, indicative of a strong covalent bonding: M. Preisenberg-
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[13] All geometries of intermediates and transition states were optimized
fully without symmetry constraints by using the Gaussian 09 pro-
gram. The iridium atom was described by a double-z basis set
(LANL2DZ), and the 6–31GACTHUNRGTNE(NUG d,p) basis set was used for the other
elements. See the Supporting Information for details.
[14] DH and DG values could not be computed because of the size of
À
the system. However, DE is close to DH with H2PO4 (Table 1, X=
I).
[15] Approximately 95 E per gram.
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[16] Lowering the load of iridium to 5 mol% resulted in a much longer
reaction time of 71 h. The best ee value (75%) was obtained at c=
0.268m (77% yield).
[17] B. J. Fisher, R. Eisenberg, Inorg. Chem. 1984, 23, 3216.
[18] The dimethyl group in 1k presumably renders the double bond
more nucleophilic, which would alter the reactivity of the system.
For examples of diverted cycloisomerization reactivity with a prenyl
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Chem. Eur. J. 2011, 17, 13789 – 13794
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13793

H. Amouri, C. Aubert, Louis Fensterbank, V. Gandon et al.
3
À
unit, see: Y. Harrak, A. Simonneau, M. Malacria, V. Gandon, L.
Fensterbank, Chem. Commun. 2010, 46, 865 and references therein.
[19] See ref. [8e] and P. J. Stephens, D. M. McCann, E. Butkus, S. Stron-
[25] For representative examples of such XC
G
in crystallographic structures, see: a) S. Sarkhel, G. R. Desiraju, Pro-
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Acc. Chem. Res. 1996, 29, 441; and references therein.
ˇ
cius, J. R. Cheeseman, M. J. Frisch, J. Org. Chem. 2004, 69, 1948.
[20] Modest shifts in n˜CO and d31P have been reported for trans-[Ir-
[26] See: a) S. Bahmanyar, K. N. Houk, J. Am. Chem. Soc. 2001, 123,
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[27] However, we note that such anions may also act as X-type chiral li-
gands for enantioselective transition-metal catalysis, see ref. [3j].
[28] Asymmetric organocatalyzed reactions that involve hydrogen bonds
ACHTUNGTRENNUNG(OCF3SO2)(CO)ACHTUNGTRENNUNG(PPh3)2] relative to trans-[IrCl(CO)ACHTNGUTRENN(NGU PPh3)2], see:
a) D. J. Liston, Y. J. Lee, W. R. Scheidt, C. A. Reed, J. Am. Chem.
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[21] In this NMR spectroscopic monitoring, the anion metathesis was
complete before introduction of the enyne, in contrast with the pro-
tocol used for the results in Tables 2 and 3. Nevertheless, 3a was ob-
tained as in Table 2, entry 8, which suggests that the presence of the
enyne from the beginning of the reaction is inconsequential to the
ee.
can be carried out at elevated temperatures, see: M. Meciarovà, S.
Toma, R. Sebesta, Tetrahedron: Asymmetry 2009, 20, 2403 and the
ˇ
references therein.
[29] Note added in proof: During the course of the reviewing process,
the following articles, dealing with asymmetric, chiral-anion-direct-
ed, transition-metal catalysis, were published: a) G. Jiang, B. List,
Chem. Commun. 2011, 47, 10022; b) G. Jiang, R. Halder, Y. Fang, B.
List, Angew. Chem. 2011, 123, 9926; Angew. Chem. Int. Ed. 2011, 50,
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Kobayashi, Angew. Chem. 2011, 123, DOI:10.1002/ange.201105182;
Angew. Chem Int. Ed. 2011, 50, DOI: 10.1002/anie.201105182.
[22] The absence of detection of any intermediate could also be due to
transient character on the NMR spectroscopic timescale.
[23] For related calculations in the gold and platinum series, see ref. [8a]
and a) E. Soriano, P. Ballesteros, J. Marco-Contelles, J. Org. Chem.
2004, 69, 8018; b) N. Cabello, E. Jimꢁnez-NfflÇez, E. BuÇuel, D. J.
Cµrdenas, A. M. Echavarren, Eur. J. Org. Chem. 2007, 4217.
[24] The direct 1,2-hydrogen shift originally proposed by Shibata (see
ref. [10]) was also modeled but proved to be energetically disfavored
compared with these two (see the Supporting Information).
Received: August 31, 2011
Published online: November 3, 2011
13794
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 13789 – 13794