Tethered Counterion-Directed Catalysis: Merging the Chiral Ion-Pairing and Bifunctional Ligand Strategies in Enantioselective Gold(I) Catalysis

Article abstract of DOI:10.1021/jacs.9b11154

Tethering a metal complex to its phosphate counterion via a phosphine ligand enables a new strategy in asymmetric counteranion-directed catalysis (ACDC). A straightforward, scalable synthetic route gives access to the gold(I) complex of a phosphine displaying a chiral phosphoric acid function. The complex generates a catalytically active species with an unprecedented intramolecular relationship between the cationic Au(I) center and the phosphate counterion. The benefits of tethering the two functions of the catalyst are demonstrated here in a tandem cycloisomerization/nucleophilic addition reaction, by attaining high enantioselectivity levels (up to 97% ee) at an unusually low 0.2 mol % catalyst loading. Remarkably, the method is also compatible with a silver-free protocol.

Full text of DOI:10.1021/jacs.9b11154

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Article
Tethered Counterion-Directed Catalysis: Merging the Chiral Ion-pairing
and Bifunctional Ligand Strategies in Enantioselective Gold(I) Catalysis
Zhenhao Zhang, Vitalii Smal, Pascal Retailleau, Arnaud
Voituriez, Gilles Frison, Angela Marinetti, and Xavier Guinchard
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b11154 • Publication Date (Web): 03 Feb 2020
Downloaded from pubs.acs.org on February 3, 2020
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Page 1 of 10
1
Journal of the American Chemical Society
Tethered Counterion-Directed Catalysis: Merging the Chiral
Ion-pairing and Bifunctional Ligand Strategies in
Enantioselective Gold(I) Catalysis
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Zhenhao Zhang,a,b Vitalii Smal,a Pascal Retailleau, a Arnaud Voituriez,a Gilles Frison,b Angela
Marinetti,*,a Xavier Guinchard*,a
a Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1 avenue de
la Terrasse, 91198 Gif-sur-Yvette, France.
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b LCM, CNRS, Ecole Polytechnique, Institut Polytechnique de Paris, 91128 Palaiseau, France.
Supporting Information Placeholder
ABSTRACT: Tethering a metal complex to its phosphate counterion via a phosphine ligand enables a new strategy in Asymmetric
Counteranion-Directed Catalysis (ACDC). A straightforward, scalable synthetic route gives access to the gold(I) complex of a chiral
phosphine displaying a phosphoric acid function. The complex generates a catalytically active species with an unprecedented intramolecular
relationship between the cationic Au(I) center and the phosphate counterion. The benefits of tethering the two functions of the catalyst is
demonstrated here in a tandem cycloisomerization/nucleophilic addition reaction, by attaining high enantioselectivity levels (up to 97% ee)
at a remarkable low 0.2 mol% catalyst loading. Remarkably the method is also compatible with a silver-free protocol.
reported. However in these cases, the chiral ligand does not
INTRODUCTION
dissociate from the metal all throughout the catalytic process.8
The challenge of enantioselective gold(I) catalysis clearly relates
to the linear geometry of the active complexes as well as, in many
instances, to the outer-sphere mechanisms of the
enantiodetermining step. Nevertheless, high enantioselectivity
Scheme 1. Proposed Enhanced Strategy for Asymmetric
Ion-pair Catalysis: Tethering a Chiral Phosphate Unit to
the Metal Complex.
1. Targeted catalytic reactions
could be achieved in recent years by means of either sterically
R
congested ligands, which create deep chiral pockets embedding the
O
R
distal active site, bifunctional phosphines or by dinuclear
complexes possibly shaped through aurophilic interactions.1
Alternatively, Toste2 introduced the chiral counterion strategy,
where notably BINOL-derived phosphates operate as chiral
inducers in reactions involving cationic gold intermediates. Despite
some uncertainties over the exact mechanisms and role of the
phosphate anions, this strategy has shown prominent potential and
has triggered significant advances in both gold3,4 and other
transition metal catalysis.5,6 In gold(I) catalysis, the first disclosed
intramolecular hydroalkoxylation, hydrocarboxylation and
hydroamination reactions remain so far the main application
domains of the counterion strategy, although the method should
apply, in theory, to a much wider range of reactions. Notably all
reactions involving tight ion pairs in the enantiodetermining step
are potentially suitable, including those going through
carbocationic intermediates with remote, neutral gold(I) units. This
scenario is suitably typified by the tandem heterocyclization-
[M]
O
O
R
Cat. [M]X
NuH
X
*
Nu
NuH
I
2. Proposed TCDC strategy
Au
L
Au
L
O
(-)O
O
(-)O
(+)
(+)
P
O
P
*
O
O
O
*
(b) Our TCDC approach
(a) Known approach
7
nucleophilic addition reactions in Scheme 1.1. In this case and
others, the stereochemical control from the chiral counterion
suffers however from the poorly defined and flexible spatial
arrangement of the phosphate-carbocation pair. We suggest that
this drawback might be overcame by tethering somehow the
phosphate counterion to the cationic Au complex (Scheme 1.2b). A
covalent tether connecting the phosphate unit to a gold ligand might
afford sufficient geometrical constraints and molecular
organization to the key intermediate to allow efficient
stereochemical control. This approach, when properly
implemented, might push the limits of the ‘ion-pairing strategy’ in
enantioselective gold catalysis and, more broadly, in
enantioselective transition metal catalysis. Previous transition
metal complexes embedding intramolecularly an anion have been
In this paper, we report on the specific design of a new bifunctional
ligand9 combining a mono-phosphine and a remote BINOL-
derived phosphate function. As a proof of concept, we show that
the corresponding Au(I) complex10 gives so far unattained levels of
enantioselectivity in the cycloisomerization/addition sequence
depicted in Scheme 1.1, at very low catalytic loading. Theoretical
studies enlighten and support mechanistic hypotheses on the role of
the phosphate counterion in these reactions.
RESULTS AND DISCUSSION
The targeted Au-precatalyst (S)-5 contains an (S)-BINOL-derived
phosphoric acid moiety, with an ortho-(diphenylphosphino)phenyl
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substituent at its 3-position.11,8a The key steps for the synthesis of
1
2
the LAuCl complex (S)-5, shown in Scheme 2, were inspired
Scheme 2. Synthesis of the Phosphoric Acid-tethered Phosphine Gold Chloride Complex 5
3
O
4
Ph2P
Ph2P
5
6
7
8
BPin
O
1) Pd(PPh3)4, K2CO3
Cl3SiH, Et3N
Ph2P
THF-H2O, 100 °C, 24 h
OMOM
OMOM
OH
OH
OH
OH
+
2) p-TsOH·H2O
THF/MeOH (1:1)
60 °C
Br
PhMe, 90 °C, 24 h
9
1
(S)-
2,
(S)- 74%
3
(S)- , 78%
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Ph2
P
ClAu
1. Me2SAuCl,
4,
DCM, rt, (S)- 89%
O
O
O
2. POCl3, pyridine
0 °C-rt, 24 h
then 1 M HCl, 88%
P
OH
BPin= 4,4,5,5-Tetramethyl-1,3,2-
dioxaborolane
MOM= methoxymethyl ether
5
(S)-
multi-gram scale
CD2Cl2.16 Interestingly, complex 6 do not show 31P-31P coupling in
by the respective work of Iwa and Sawamura,8a and Sasai12 who
reported on the synthesis of BINOL-based bifunctional phosphines
and studied their rhodium coordination or applications in
organocatalysis, respectively.
31P NMR, indicating that the gold-oxygen interaction may be more
Scheme 3. Conversion of (S)-5 to cationic Au(I) species and 31
P
NMR Spectra of the Au(I) Complexes 5-7 inCDCl3
The synthetic approach starts with the synthesis of the BINOL-
substituted triarylphosphine oxide (S)-212-13 via the palladium
PPh2
Au
coupling
of
boronate
(S)-114
with
(2-
Ag2CO3 (3 equiv)
O
O
O
(eq. 1)
5
(S)-
P
bromophenyl)diphenylphosphine oxide, followed by MOM group
removal in acidic conditions. The phosphine oxide (S)-2 is obtained
in an overall 74% yield. Reduction with chlorosilane gives then the
trivalent phosphine (S)-3 that displays two sets of signals in both
O
PhMe/H2O (1:1)
rt, 18 h
6
(S)-
Au
NTf2
Ph2P
1
31P and H NMR spectra, as reported previously (31P NMR  = -
10.6 and -12.3 ppm). Complexation of (S)-3 to Au(I) was carried
out successfully using Me2SAuCl as the starting material. The final
setup of the cyclic phosphoric acid unit was done via a classical
procedure, by using P(O)Cl3 as the phosphorylating agent followed
by an acidic hydrolysis. It afforded the desired (phosphine)AuCl
complex (S)-5 as a crystalline solid in 88% isolated yield.15 The
whole sequence could be scaled-up to several grams without
notable difficulties (3.15 g of (S)-5 have been isolated, 3.7 mmol).
The molecular structure of (S)-5 has been ascertained by X-ray
crystallography (Scheme 2). The 31P NMR spectrum of acid (S)-5
in CDCl3 shows a 4:1 mixture of two species (31P NMR in CDCl3:
 = 27.6 and 2.9 ppm for the major isomer;  = 26.2 and 4.6 ppm
for the minor isomer, see Figure 1a), tentatively assigned as
equilibrating rotamers. When the 31P NMR of compound (S)-5 was
recorded in deuterated pyridine, very clean spectra were obtained
showing a single set of signals (31P NMR in d5-Pyridine:  = 29.2
and 6.7 ppm. In d6-DMSO at room temperature, compound (S)-5
also displays two sets of broad signals, which coalesce into a single
set at 110 °C ( = 26.8 ppm and 1.1 ppm).
AgNTf2 (1 equiv)
DCM, rt, 0.5 h
O
O
P
(eq. 2)
5
(S)-
O
OH
7a
(S)-
PAuNTf2
POOH
7a
(S)-
PAu
6
5
(S)-
POO
PAuCl
POOH
(S)-
Chloride abstraction from the gold complex (S)-5 has been carried
out then with the basic silver carbonate, so as to also deprotonate
concomitantly the phosphoric acid function (Scheme 3, eq. 1).
From this experiment, the putative Au(I) complex (S)-6 was
obtained. Its 31P NMR spectrum shows a broad signal at  = 21.8
ppm and a sharp one at 8.4 ppm. These data are in agreement with
the postulated formation of the phosphine-phosphate complex,
since both phosphorus signals are significantly shifted with respect
to (S)-5. Structurally related gold(I) phosphates from the literature
also display 31P NMR chemical shifts in the range 8-10 ppm, in
ionic than covalent.17 The molecular formula of (S)-6 has been
ascertained by mass spectrometry (ESI m/z calculated for
[M+HCOO]- = 849.0781; found: m/z = 849.0876). For comparison
purposes, complex (S)-5 was reacted also with AgNTf2, to give a
new complex (S)-7a. The 31P NMR of (S)-7a was diagnostic for a
Cl/NTf2 exchange (high-field shift of the phosphine signal from
27.7 to 22.9 ppm), while the signal of the phosphoric acid group
remained unchanged at 2.9 ppm. Overall, although we could not
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obtain so far crystals of (S)-6 suitable for X-ray diffraction studies,
- Another non-chelated analogue has been prepared purposely: the
1
2
3
4
5
6
7
8
both mass spectrometry and NMR data tend to support the
structural assignment, although they can’t discriminate so far
between monomeric species and more complex assemblies in
solution. Assemblies would have however little incidence on
catalytic processes, since coordination of the substrates will
generate then the same active species.
(Ph3P)Au(phosphate) (S)-13a which contain the same tethered
phosphine/phosphate of (S)-5 but displays an oxidized phosphorus
function. It gave a racemic product (entry 15).
Finally, from results in Table 1, it may be noted that Ag2CO3 does
not catalyzes, by itself, this reaction (entry 1) and the silver
phosphate (S)-13b displays low catalytic activity and low
enantioselectivity (entry 16). Therefore, silver catalysis should not
compete significantly with the gold promoted catalytic process in
entries 4-9.
We then turned straight to catalytic tests by investigating the
tandem cycloisomerization/nucleophilic additions of 2-alkynyl-
enones typified in Table 1. As pointed out above, the rationale
behind this choice is that these reactions should involve
carbocation-phosphate pairs as the key intermediates and therefore
benefit from tethering gold to the chiral phosphate. The reaction,
initially reported by Larock7 by using AuCl3 as the catalyst, leads
to synthetically relevant, highly substituted furans. It applies to a
number of 2-alkynyl-enones (cyclohexenones, chromones, acyclic
enones) and tolerates a large set of nucleophilic partners: alcohols,
water, 1,3-dicarbonyls, indoles, allenamides, anilines and
carbamates. With imines,18 allenamides,19 3-styrylindoles20 and
nitrones21 as the nucleophiles, 3,4-fused bicyclic furans are
obtained. Beside Au(III) and Au(I) catalysts,22 also Pt(II),23
Pd(II),24 Ag(I),25 Cu(I), Cu(II),26 and In(III)27 salts proved to be
good catalysts. Despite the wide synthetic potential of these
reactions, enantioselective variants have been implemented
successfully for only a few substrate pairs. Beyond Toste’s initial
report on indole nucleophiles (Cu(TRIP)2 catalysts)26b and our
9
The absolute configuration of the final product 10aa has been
established, for the first time in this series, by X-ray
crystallography (see Supporting Information). The (S)-configured
catalyst 5 gives (R)-10aa as the major enantiomer.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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35
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40
41
42
43
44
45
46
47
48
49
50
51
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53
54
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57
58
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60
Overall, the comparative experiments in Table 1 clearly highlight
the positive effect of tethering the phosphine and phosphate
functions and therefore substantiate our catalyst design and
working hypothesis.
Table 1. Enantioselective Cyclization/Indole Addition
Reactions: Optimization with Precatalyst (S)-5a
Ph
O
Ph
O
[M]
+
Solvent
N
recent report with Ag+ catalysts,25 notable examples are the
*
H
28
reactions carried out with nitrones,9a,
3-styrylindoles20 and
8a
entry cat. (mol%)
9a
10aa
additive (mol%) solvent
NH
allenamides19 using either bis-gold complexes of diphosphines or
mono-gold complexes of sulfinamide-functionalized phosphines
and phosphoramidites.
yield
eec (%)
(%)b
1
-
Ag2CO3 (5)
Ag2CO3 (2.5)
Ag2CO3 (2.5)
Ag2CO3 (2.5)
Ag2CO3 (1)
Ag2CO3 (0.1)
Ag2CO3 (1)
PhMe
MeCN
THF
0
-
The gold complex (S)-5 was evaluated initially in the reaction of
2-(phenylethynyl)-2-cyclohexenone 8a with indole 9a.
Comparative experiments were also performed to support the
postulated involvement of the phosphate function in the
stereochemical control of this reaction. Selected experiments are
reported in Table 1. Initial experiments showed that in situ
activation of (S)-5 with Ag2CO3 in various solvents, enables a good
catalytic activity, with up to 88% ee for reactions performed in
toluene (Table 1, entries 2-4).29 Most rewardingly, the precatalyst
loading could be gradually decreased from 5 to 2, 0.2, 0.1 and 0.05
mol% leading to constantly good yields and enantioselectivities
(91-96% ee, entries 4-9). In the context of enantioselective Au(I)
catalysis, where a 3-5 mol% catalyst loading is usually employed,
a 0.05 mol% catalyst loading is extremely low. This excellent
catalytic activity (TON 1400) might suggest an exceptional
stability of the resting state of the catalyst towards decay, possibly
due to the tight intramolecular pairing between Au(I) and its
phosphate counterion. Alternatively, the high reactivity might be
assigned to the strained, non-linear coordination of gold in complex
6 (see calculated geometries hereafter), which would decrease the
deformation energy required for the coordination of the substrate.30
A few experiments have been carried out then, whose results
overall confirm the role of the phosphate tether.
2
(S)-5 (5)
76
29
69
88
75
68
73
70
85
76
85
90
60
70
12
12
86
88
91
96
94
93
91
29
62
15
12
2425
0
3
(S)-5 (5)
4
(S)-5 (5)
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
5
(S)-5 (2)
6
(S)-5 (0.2)
(S)-5 (0.2)
(S)-5 (0.1)
(S)-5 (0.05)
(S)-7a (0.2)
(S)-7b (0.2)
7
d
8
Ag2CO3
d
9
Ag2CO3
10
11
12
13
14
15
16
-
-
-
-
-
-
-
(S)-11a (0.2)
(S)-11b (0.2)
(R)-12 (10)
(S)-13a (0.2)
(S)-13b (0.2)
10
AuX
Ph2P
AuX
Ph2(O)P
Ph2P
Ar
O
O
O
O
O
- Catalysts (S)-7a,b, generated from (S)-5 with the non-basic silver
salts AgNTf2 and AgSbF6, gave significantly lower enantiomeric
excesses (entries 10, 11).
- Catalysts (S)-11a,b which display the same molecular scaffold as
(S)-5 but a methyl phosphate function, instead of the phosphoric
acid function, give very low enantiomeric excesses.31
- The (Ph3P)Au(TRIP) complex (R)-12, that may be viewed as a
non-chelated structural analogue of 6, gives a much lower
enantiomeric excess (24% ee,25 entry 14).
O
O
O
O
O
P
P
P
P
O
OMe
OM
Au
PPh3
OH
O
O
Ar
11a
, X= NTf2
11b
, X= SbF6
Ar = 2,4,6-(i-Pr)3C6H2
12
13a
13b
Au
PPh3
, M= Ag
(S)-
(S)-
(S)-
(S)-
, M=
5
(S)- , X= Cl
7a
(R)-
(S)- , X= NTf2
7b
(S)- , X= SbF6
a Reactions were run with a 1:1 ratio of 8a and 9a, at rt for 18 h. Reactions
in entries 1-5 were performed at a 0.1 mmol scale (0.1 M). In entries 6-10
(0.55 mmol scale), the concentration of the catalyst was 0.4 mM. b Isolated
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yields. c Determined by chiral HPLC. d At low catalytic loading, the silver
carbonate was used in excess, with no impact on the enantioselectivity level.
R1
O
R1
+
1
3
O
5
6
R2
5
(S)- (0.2 mol%)
2
3
2
The high catalytic performance of (S)-5 in the reaction above,
encouraged us then to investigate the substrate scope by
considering the substituted indoles 9b-g (Scheme 4). Substituents
such as methoxy-, bromine, and methyl groups were tolerated on
the C5 and C6 positions of indole delivering 10ab-ad in high
enantiomeric excesses. Interestingly, the C2-substituted 2-
methylindole gave 10ae in high ee and higher yield than the Cu(II)
based method.26b
R2
1
Ag2CO3
(0.1 mol%)
PhMe, rt,
16 h
N
*
H
4
n
n
9a-g
10
8a-g
5
NH
6
7
8
R1
Ph
O
O
R2
9
In a second series of experiments, the 2-alkynyl-cyclohexenones
8b-e, displaying various R1 groups, were reacted with indole 9a
(R2=H). For R1 = p-anisyl, p-tolyl, and m-anisyl, the corresponding
bicyclic furanes 10ba, 10ca and 10da were obtained in high yields
and enantioselectivities. Finally, an alkyl substituted substrate 8e
(R1 = C5H11) was reacted with indole and led to the expected furane
10ea with 87% ee. Most notably, the reaction between N-Me-indole
9f and 8a delivered the addition product 10af in high yield (92%)
*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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31
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
*
NH
10ba
NH
10aa
n= 1
n= 1
2
1
R = H,
, 75%, 96% ee
10ab
R = 4-MeOC6H4,
, 87%, 91% ee
2
1
R = 5-OMe,
, 81%, 97% ee
, 77%, 97% ee
10ca
R = 4-MeC6H4,
, 95%, 95% ee
2
1
10ac
R = 5-Br,
10da
R = 3-MeOC6H4,
, 77%, 84% ee
2
R1= C5H11
,
, 46%, 87% ee
10ad
R = 6-Me,
, 44%, 96% ee
10ea
2
10ae
R = 2-Me,
, 49%, 82% ee
and enantiomeric excess (94% ee).
A similar level of
enantioselectivity was then obtained from N-benzyl indole 9g
(10ag, 92%). These two results are crucial to enlighten the
mechanism of the stereochemical control. They indeed indicate that
the NH function of indole is not essential and rule out the
involvement of H-bonds between phosphate and indole in the
stereodetermining step. They also demonstrate that our method
enables the previously unsuccessful use of N-substituted indoles in
these cataytic reaction.25 Cyclopentenone 8f and cycloheptanone
8g were then used in the reaction leading to the corresponding
bicyclic furanes 10fa and 10ga in 21% ee and 94% ee, respectively.
These unprecedented reactions show that the enantioselective
cyclization/nucleophilic addition sequence apply successfully, not
only to six-membered but also to seven-membered enones.
Ph
Ph
O
Ph
O
O
*
N
R2
N
H
N
H
n= 1
2
n= 0
n= 2
10ga
c
, 41%, 94% ee
10af
R = Me,
, 92%, 94% ee 10fa
, 55%, 21% ee
2
10ag
R = Bn,
, 83%, 92% ee
Isolated yields. b Enantiomeric excesses were determined by
a
chiral HPLC. c Reaction performed with 2 mol% of the precatalyst
Scheme 4. Scope of the Enantioselective Addition of Indoles
9 to Enones 8.
5.
In another series of experiments, 3-substituted indoles were
considered (Scheme 5). 3-Methylindole could be reacted: addition
through its C2-position afforded compound 14ah in high yield and
enantioselectivity (93% ee). Extension of the process to 1,3-
dimethylindole gave 14ai in high 95% ee but moderate yield, that
could however be increased to 91% using 2 mol% of the catalyst.
When increasing the steric hindrance at the C3 position we
observed, interestingly, that the reaction leads to mixtures of two
products resulting from C2 and N-alkylations, respectively. While
methyl-3-indolylacetate 9j led to an essentially 50/50 mixture of
14aj and 15aj in excellent ee’s, the 3-isopropylindole 9k afforded
mainly the N-alkylated product 15ak in 94% ee. This unusual
behavior offers the possibility to engage the three potentially
nucleophilic positions of indoles in highly enantioselective
cycloisomerization/addition of indoles processes.
Scheme 5. Enantioselective Additions of C3-substituted
Indoles to Enone 8a.
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Ph
O
Ph
O
1
2
3
4
5
6
7
8
O
Ph
+
5
(S)- (0.2 mol%)
Ph
Ph
N
HXR2
8a
O
O
Ag2CO3 (0.1 mol%)
PhMe, rt, 16 h
5
(S)- (0.2 mol%)
*
XR2
R3
+
R2
Ag2CO3
(0.1 mol%)
PhMe, rt,
16 h
and/or
16
8a
*
N
*
1
14
15
R2
N
R3
Ph
Ph
O
Ph
R2
O
O
9h-k
9
O
Ph
Ph
Ts
N
10
11
12
13
14
15
16
17
18
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Ph
OBn
N
H
N
O
O
H
H
16a
16b
16c
, 89%
65% ee
H
, 88%
94% ee
, 80%
88% ee
Me
*
N
*
N
Ph
Ph
Ph
Ph
Me
Me
O
O
O
O
14ah
, 83%, 93% ee
Ph
14ai
, 40%, 95% ee
91%, 95% ee (2 mol% of (S)- )
Ph
O
OH
5
O
Ph
Ph
16eb-16ec,
68%
16d
90% ee
16ea
79% ee
, 93%
, 32%
O
O
O
Ph
H
*
N
*
*
O
N
N
Obtained from
O
O
i-Pr
CO2Me
, 46%, 95% ee
CO2Me
O
O
14aj
, 53%, 92% ee 15aj
15ak
, 59%, 94% ee
16f
, 77%
89% ee
The N-additions observed here encouraged us to move then to
totally different series of nucleophiles as reaction partners. We
were pleased to find that unprecedented enantioselectivity levels
can be attained with hetero-nucleophiles such as benzylcarbamate
(94% ee), tosylamide (87% ee) and phenol (90% ee) (Scheme 6).
Noteworthy, even the simple addition of water takes place with
high stereocontrol, leading to the alcohol 16ea in 79% ee. The
reaction also affords ethers 16eb and 16ec (homochiral 16eb 50%
yield, meso 16ec 18% yield). Finally, the use of cyclohexanedione
as nucleophile afforded 16f in 77% yield and 89% ee, resulting
from O-addition of the nucleophile to the carbocation, as
previously observed by Larock.7b Overall these experiments
demonstrate the high stereocontrol induced by the newly designed
(S)-5/Ag2CO3 catalytic system in reactions involving a variety of
nucleophiles from substituted indoles to simple nitrogen and
oxygen nucleophiles.
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51
52
53
54
55
56
57
58
59
60
Finally, during these studies, we disclosed rewardingly that
activation of precatalyst (S)-5 by a silver salt may not be
systematically required (Table 2). The reaction of ketones 8a and
8g with representative nucleophiles could be performed in the
presence of (S)-5 only and the corresponding products were
obtained in moderate to good yields and very high enantiomeric
excesses. The gold chloride (S)-5 gives a slightly lower reaction
rate, with respect to the Ag2CO3 activated catalyst. Thus, we
believe that the precatalyst reacts in situ with the weakly basic
nucleophiles of the reaction mixture, resulting in the spontaneous,
reversible formation of the active gold phosphate catalyst by HCl
abstraction. The precatalyst 5 may thus be considered as a reservoir
of stable Au(I) complex gradually delivering the active catalyst.
This rare property of (S)-5 may be extremely important in the
general context of Au(I) catalysis, where the effects of silver salts
are far from being benign.4b, 32
Scheme 6. Enantioselective Tandem Cyclisation - Addition
of Heteronucleophiles Promoted by (S)-5/Ag2CO3
Table 2. Use of Non-activated (S)-5 in the Enantioselective
Cyclization/Addition Reactions:
Ph
O
O
Ph
+
5
(S)- (0.2 mol%)
Nucleophile
PhMe, rt, 16 h
*
Nu
n
n
No silver salt
8a,g
10 16
or
entry
1
8
nucleophile
product
yield (%)a
ee (%)b
92
8a
9a
10aa
80
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2
3
4
5
8a
8a
8g
8a
9b
10ab
10ac
10ga
16b
73
94
75
95
88
and strained geometry (P-Au-O bond angle = 155.5° for 6b vs
159.9° for 6a; Au-P = 2.290 Å for 6b vs 2.088 Å for 6a).
1
2
3
4
9c
30
55
41
9a
Figure 1. DFT Calculated Structures of Catalyst (S)-6 and its
Non-tethered Analogue 17. Relative Gibbs Free Energy in
kJ.mol-1.
TsNH2
a Isolated yields. b. Determined by chiral HPLC.
5
6
7
8
9
The search for alternative silver-free gold catalysts is a long-lasting
quest.33 Most approaches rely on protic acid activation of LAuMe
complexes,34 Brønsted acid activation of LAu(OH),35 activation of
37
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LAuCl with silylium36 or Cu(OTf)2 and addition of a Brønsted
acid/Lewis acid to (PPh3)Au(Pht).32c As far as we know, a
spontaneous dissociation of an IPrAuCl Au(I) complex has been
claimed only in the gold-catalyzed hydration of alkynes.38
The mechanistic pathway currently postulated for these reactions
is illustrated in Scheme 7, with enone 8 and indole 9 as the
substrates. Activation of the alkyne unit by Au(I) (Int. I) triggers
the cycloisomerization of enone 8 into the cationic intermediate II
featuring a phosphate counterion. The nucleophilic addition of
indole to II, leads then to intermediate III. From III, the proto-
deauration step proceeds through formal H-transfer, that might be
mediated actually by the phosphate itself, or by trace amounts of
other bases (e.g. HO-). According to the postulated mechanism
below, high enantioselectivity levels should result from a tight ion
pairing in intermediate II which will bring the chiral phosphate unit
closer to the prochiral carbon in the enantiodetermining step. It can
be assumed that the geometrical constraints enforced by tethering
gold(I) to phosphate, create a more organized spatial arrangement
in II and enable the excellent stereocontrol.
Scheme 7. Postulated Mechanistic Pathway
R1
O
O
R1
R2
*
P-Au-O-P
8
N
10
H
R1
H
O
R1
[Au]
Examination of the metrical parameters of 6a around the metal
center reveals a significantly bent phosphine-gold-phosphate unit
(P-Au-O bond angle = 159.9°), due to the geometrical constraints
enforced by the molecular backbone of the ligand. For comparison,
the geometry of the non-tethered (triphenylphosphine)gold(I)
BINOL-phosphate complex 17 has been calculated as well (Figure
1). In 17, the linearity at gold is almost restored (P-Au-O bond
angle = 172.9°), in line with the previously reported X-ray structure
(172.7°).16 The deviation from linearity observed in 6 has only
limited effect on the bond lengths: the Au-P (2.279 Å) and Au-O
(2.088 Å) bond distances are similar to those observed
experimentally for a (triphenylphosphine)gold-phosphate (2.20 and
2.058 Å respectively)16 and its computational model 17 (2.280 and
2.106 Å respectively). The bent geometry of the complex might
have effects on the energy profile throughout the catalytic cycle.
O
Au-P
P-O
R2
*
I
R1
N
H
III
O-P
R1
O
Au-P
O
R2
Au-P
O-P
N
H
9
II
To gain better insight into the structure of the potential catalyst (S)-
6 and the postulated reaction intermediates II and III, we have
carried out computational studies at the DFT level (see the SI for
computational details). The lowest energy structure for monomeric
catalyst (S)-6 is displayed in Figure 1 (6a). It shows that
coordination of the phosphate to gold involves preferentially the
pro-S oxygen atom, which gives a S-configured phosphorus.
Coordination of the other PO unit would lead to 6b which is 42
kJ.mol-1 higher in energy compared to 6a, due to its more distorted
The key carbocationic intermediate IIa features an electrostatic
pairing between the carbocation and the tethered phosphate group
leading to the preferred conformation shown in Figure 2. The
stereochemistry control should result then from two combined
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effects: the preferred conformation of the zwitterionic intermediate
other transition metals. The scope of these catalysts is being
1
2
3
4
5
6
7
8
IIa and the preferred addition of the nucleophilic indole that is
likely to take place from the face opposite to the phosphate group.
Importantly, the resulting configuration of stereogenic center in
IIIa converges with that of the final product 10a established by X-
Ray crystallography (R-configuration). Overall, our preliminary
calculations (See Supporting Information) highlight (a) the non-
linear geometry of the P-Au-O moiety in catalyst 6 that might be
responsible for its increased reactivity; (b) an easy
cycloisomerization process triggered by gold(I) (G≠ = 36.6
kJ.mol-1,; (c) the strong preference of the carbocationic
intermediate II for ion-pairing with the phosphate anion; (d) an
exoergonic nucleophilic addition step taking place from the less
hindered face, opposite to the phosphate group.
investigated in our group.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website. Details of the experimental procedures, NMR
spectra, HPLC data and computational data (pdf).
CIF files (.cif)
9
AUTHOR INFORMATION
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Corresponding Authors
angela.marinetti@cnrs.fr
xavier.guinchard@cnrs.fr
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Figure 2. Optimized Geometry of Intermediate IIa and
Postulated Direction of the Nucleophilic Addition (for clarity, a
wireframe representation of some aryl groups is used).
We thank the China Scholarship Council for PhD funding to Z. Z.
and the CHARMMMAT Labex (ANR-11-LABX0039) for the
funding of V.S.
Indole 9a
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