Enantioselective Folding of Enynes by Gold(I) Catalysts with a Remote C2-Chiral Element

Article abstract of DOI:10.1021/jacs.9b06326

Chiral gold(I) catalysts have been designed based on a modified JohnPhos ligand with a distal C₂-2,5-diarylpyrrolidine that creates a tight binding cavity. The C₂-chiral element is close to where the C-C bond formation takes place in cyclizations of 1,6-enynes. These chiral mononuclear catalysts have been applied for the enantioselective 5-exo-dig and 6-endo-dig cyclization of different 1,6-enynes as well as in the first enantioselective total synthesis of three members of the carexane family of natural products. Opposite enantioselectivities have been achieved in seemingly analogous reactions of 1,6-enynes, which result from different chiral folding of the substrates based on attractive aryl-aryl interactions.

Full text of DOI:10.1021/jacs.9b06326

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Communication
Enantioselective Folding of Enynes by Gold(I)
Catalysts with a Remote C2-Chiral Element
Giuseppe Zuccarello, Joan G. Mayans, Imma Escofet, Dagmar Scharnagel, Mariia S.
Kirillova, Alba H. Pérez-Jimeno, Pilar Calleja, Jordan R. Boothe, and Antonio M. Echavarren
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b06326 • Publication Date (Web): 10 Jul 2019
Downloaded from pubs.acs.org on July 10, 2019
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Enantioselective Folding of Enynes by Gold(I) Catalysts with a
Remote C2-Chiral Element
Giuseppe Zuccarello,†, ‡ Joan G. Mayans,†, ‡ Imma Escofet,†, ‡ Dagmar Scharnagel,† Mariia S. Kirillova,†
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Alba H. Pérez-Jimeno,†, ‡ Pilar Calleja,† Jordan R. Boothe† and Antonio M. Echavarren*,†,
‡
† Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Av. Països
Catalans 16, 43007 Tarragona (Spain).
‡ Departament de Química Orgànica i Analítica, Universitat Rovira i Virgili, C/ Marcel·lí Domingo s/n, 43007 Tarragona (Spain).
Supporting Information Placeholder
conceptual design based on mononuclear gold(I) complexes
with a new class of chiral JohnPhos-type ligands bearing a C2-
chiral trans-2,5-diaryl pyrrolidine at the para position of the
biphenyl backbone (Figure 1a). This type of C2-chiral
pyrrolidine motif has been incorporated in organocatalysts,9
chiral auxiliaries10 and chiral ligands.11 In our design, the rigid
biphenyl scaffold serves as a holder to connect the chiral
element and the phosphine, encompassing the gold(I) nucleus
in a chiral envelope-type cavity. The bulky substituents on the
phosphine prevent rotation around the Caryl-P bond and force
the P-Au-Cl axis to be parallel to the biphenyl axis, pointing
towards the chiral environment.
ABSTRACT: Chiral gold(I) catalysts have been designed based
on modified JohnPhos ligand with distal C2-2,5-
a
a
diarylpyrrolidine that creates a tight binding cavity. The C2-
chiral element is close to where the C-C bond formation takes
place in cyclizations of 1,6-enynes. These chiral mononuclear
catalysts have been applied for the enantioselective 5-exo-dig
and 6-endo-dig cyclization of different 1,6-enynes as well as in
the first enantioselective total synthesis of three members of
the carexane family of natural products. Opposite
enantioselectivities have been achieved in seemingly
analogous reactions of 1,6-enynes, which result from different
chiral folding of the substrates based on attractive aryl-aryl
interactions.
Gold(I) catalysts are highly selective for the activation of
alkynes under very mild conditions by the addition of a wide
variety of nucleophiles to intermediate (2-alkynes)gold(I)
complexes.1 However, in the context of asymmetric catalysis,
the linear coordination adopted by gold(I) complexes, which
places the substrate on the opposite side of the ancillary ligand
the outer-sphere nature of the nucleophilic attack, limits the
efficiency of the enantio-induction from chiral ligands (Figure
1a).2 The main solutions have been based on the use of axially
chiral digold complexes, monodentate phosphoramidite
ligands or the synergistic use of non-chiral gold(I) complexes
with chiral counter anions.1b,2a Recent progress relies on the
development of ligands bearing chiral sulfinamides,3 helically
chiral phosphine ligands,4 and the use of axially chiral
monodentate phosphine ligands with a remote cooperative
functionality.5 Other approaches such as the encapsulation of
gold(I) in capped cyclodextrin cavities6 and the use of well-
defined gold(III) complexes7 are recently emerging.
Figure 1. Traditional approach in asymmetric gold(I)
Due to the ambiguous mode of action of chiral catalysts,
to achieve high enantioselectivities in gold(I)-catalyzed
transformations often requires the screening of many chiral
ligands. Furthermore, the activation of alkynes, which are not
prochiral, presents a special difficulty in enantioselective
gold(I) catalysis. Thus, a system that allows for the accurate
study of the reaction pathway as well as the specific
enantioselective folding of enynes is highly desirable. To meet
this challenge, we took inspiration from the ability of polyene
cyclases to fold polyunsaturated molecules in an
catalysis and new catalyst design.
Here, we report the synthesis of new chiral catalysts A-G
(Figure 1b) and their application in the enantioselective
cyclization
of
1,6-enynes.
Remarkably,
opposite
enantioselectivities were observed in the cyclization of similar
substrates. One of these cyclizations has been applied in the
first enantioselective total synthesis of three members of the
carexane family of natural products. The model for stereo-
induction has been elucidated experimentally and
enantioselective fashion.8 Hence, we propose
a new
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computationally as arising from attractive aryl-aryl
interactions.
The new class of chiral ligands 4a-e (Scheme 1) was
was obtained with 81:19 er. The absolute configuration of 6o
was assigned as R by single crystal X-ray diffraction15 and those
of the rest of the cycloadducts were correlated with that of 6o
by circular dichroism.
Similarly, the 6-endo-dig cyclization16 reaction of N-
tethered 1,6-enynes 7a-e forms azabicyclo[4.1.0]hept-4-enes
8a-e in moderate to good yields and good enantioselectivities
(90:10 to 95:5 er), with the exception of mesyl-substituted 8d,
obtained with 74:26 er (Table. 2). Products 8f and 8g with
different substitution patterns were also obtained in good
yields and enantioselectivities. The absolute configuration of
these compounds was assigned by comparison with those
reported for 8b and 8e.17
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2
3
4
5
6
7
8
prepared modularly from enantiopure benzylic diols 2a-c and
biphenylamines 1a,b. Mesylation of diols 2a-c and reaction
with anilines 1a,b afforded 3a-d. Complexes A-E were
obtained by palladium-catalyzed coupling reaction of 3a-d
with dialkyl phosphines R2PH to give 4a-e, followed by
complexation with Me2SAuCl. Complex F was synthesized
from (R,R)-1,4-diphenylbutane-1,4-diol and complex G was
prepared by a similar route from 2'-bromo-(1,1'-biphenyl)-3-
amine. The structures of complexes C-G were confirmed by X-
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ray diffraction. Upon treatment of (R,R)-C with NaBArF ,
4
chloride-bridged digold complex (R,R)-C2-Cl was generated.12
Prolonged heating of this solution at 50 °C led to the formation
of a new species showing a singlet in the 31P NMR spectrum at
67.5 ppm, characteristic of arene-gold(I) complexes.13
Table 1. Enantioselective cyclization of 5a with catalysts
A-G and scope of formal [4+2] cycloaddition
Scheme 1. Synthetic sequence for the preparation of
complexes A-E
OH
X
Br
Br
Ar
N
NEt3, MsCl
CH2Cl2, - 20 ºC
Ar
OH
then, 1a or 1b,
- 20 ºC to 24 ºC
Ar
Ar
X
NH2
1a: X = H
1b: X = CF3 2b: Ar = C6F5
2c: Ar = 3,5-(CF3)2C6H3
2a: Ar = 3,5-Ph2C6H3
3a: X = H, Ar = 3,5-Ph2C6H3 (58%)
3b: X = H, Ar = C6F5 (36%)
3c: X = H, Ar = 3,5-(CF3)2C6H3 (39%)
3d: X = CF3, Ar = 3,5-(CF3)2C6H3 (35%)
R
Pd(OAc)2 (5 mol %)
dppf (6 mol %)
NaOtBu, R2PH
R
P
(R,R)-A
Ar
(R,R)-B
(R,R)-C
(R,R)-D
(R,R)-E
toluene, 120 ºC
Me2SAuCl
N
CH2Cl2, 24 ºC
Ar
X
(62-95%)
4a: R = Ad, X = H, Ar = 3,5-Ph2C6H3 (64%)
4b: R = Ad, X = H, Ar = C6F5 (45%)
4c: R = tBu, X = H, Ar = 3,5-(CF3)2C6H3 (96%)
4d: R = Ad, X = H, Ar = 3,5-(CF3)2C6H3 (94%)
4e: R = Ad, X = CF3, Ar = 3,5-(CF3)2C6H3 (88%)
a 58% of conversion. b 68% of conversion. c 82% conversion, 6% of a
side product. Yields determined by 1H NMR using 1,3,5-
tribromobenzene as internal standard.
(R,R)-C
(R,R)-C2-Cl
We studied the performance of the new catalysts on the
formal [4+2] reaction previously reported by our group.14 1,6-
Enyne 5a was converted into cycloadduct 6a with complexes
A-G and AgNTf2 (Table 1). The best enantioselectivities were
obtained with complexes D and E, which led to 6a with 90:10
er to 92:8 er, although the reaction with catalyst D was cleaner.
Complex (R,R)-G afforded 6a in good yield, but with moderate
er. Interestingly, although the absolute configuration of A-E
and G at the pyrrolidine is identical, catalyst (R,R)-G favors
the formation of the opposite enantiomer ent-6a.
Table 2. Synthesis of azabicyclo[4.1.0]hept-4-enes 8a-g
Upon further reaction optimization with (R,R)-D using
AgPF6 instead of AgNTf2, compound 6a was isolated in 64% of
yield and 93:7 er (Table 1). Fused tricyclic compounds 6a-q
were obtained from the corresponding 1,6-enynes 5a-q.
Substrates with methyl- or MOM-protected alcohols at the
enyne tether gave consistent good results (90:10 to 96:4 er),
whereas the diacetate 6d was obtained with lower
enantioselectivity (79:21 er). The cyclizations leading to 6p
and 6q, which were obtained as single diastereomers, required
long reaction times (7 days and 14 days, respectively) and 6q
To study the generality of our system we tested the
cyclization of 1,6-enynes 9a-d and 9i-l in the presence of water
and other nucleophiles to give 2,3-disubstituted 1,2-
dihydronaphthalenes 10a-l by gold(I)-catalyzed 6-endo-dig
cyclization, followed by nucleophilic addition (Table 3).18 The
reaction optimization was performed for the formation of 10k,
for which we tested ca. 80 chiral ligands from different
families. Among them, only the JosiPhos family of ligands led
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to significant enantioselectivities (up to 80:20 er).19
reagent gave 14 (83%, two steps). Desilylation of 14 afforded
carexane I in 97% yield. Carexane P was prepared from 14 by
selective deprotection of one methyl ether and desilylation
(36% yield, two steps).22 Carexane O was prepared from 11a by
demethylation23 in low yield (18-39%) or more efficiently from
10l (68% yield and 98:2 er, >99:1 er after recrystallization), by
hydroboration-oxidation to give 11b (62% yield) and
subsequent hydrogenolysis of the benzyl ethers (98% yield).
Thus, the concise total synthesis of carexanes I (8 steps), P (9
steps), and O (6 steps) has been achieved in 15%, 6% and 17%
overall yield respectively, including the three steps required
for the preparation of 9k-l.
1
2
3
4
5
6
7
8
Gratifyingly, complex (R,R)-D gave 10k in 60% yield and
excellent 99:1 er. Dihydronaphthalenes 10a-g and 10i-l were
obtained in presence of water, alcohols, or acetic acid in 41-
75% yield and 90:10 to 99:1 er. Remarkably, fluoride transfer
was also achieved in the cyclization of 9a with HF·pyridine to
give 10h (40%, 96:4 er).
Table 3. Synthesis of 1,2-dihydronaphtalenes 10a-l
9
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The simple design of our chiral mononuclear catalysts
allows for the systematic investigation of their mode of action.
The absolute configuration in 6, 8 and 10 results from the
different geometrical arrangement of 1,6-enynes 5, 7, and 9
inside the active chiral catalysts. The chiral folding favors
reaction of the (2-alkyne)gold(I) complex with either the Re
or the Si-prochiral face of the alkenes in the stereo-
determining formation of the key cyclopropyl gold(I)
intermediates (Scheme 3a). Remarkably, two different folding
modes occur for this type of related substrates: 1,6-enynes 5
and 7 are disposed in a way that the alkene reacts with the (2-
alkyne)gold(I) complex through the Si face, whereas 1,6-
enynes 9 react at the alkene Re face. This suggests that, despite
their similarity, 1,6-enynes 5 and 9 adopt distinct geometrical
arrangements inside the chiral cavity.
Scheme 2. Asymmetric total synthesis of carexanes I,
O, and P
10k,10l
We hypothesized that the aryl at C1 of the alkyne, which is
a common element in enynes 5 and 7, is the main responsible
for the recognition by the chiral catalysts, whereas in the case
of 9 the aryl tethering the alkynyl and the allyl chains directs
the stereocontrol of the cyclization (Scheme 3a). To probe this
assumption, we performed the cyclization of dienyne 15 in
which the aryl at the alkyne is replaced by a smaller vinyl
group, expected to have a weaker interaction with the catalyst.
Indeed, cycloadduct 16 was obtained with poor
enantioselectivity (Scheme. 3b). On the other hand, the
1. H3B·THF
THF, 50 ºC, 24 h
2. NaOH, H2O2
THF, 25 ºC, 2 h
OH
HO
Ph
OH
H2, Pd/C, MeOH/EtOAc 1:1
24 ºC, 24 h
RO
Ph
OH
(from 11b)
OH
Carexane O: 98%, > 99:1 er
OH
OR
11a: R = Me, 67%
11b: R = Bn, 62%
TIPSOTf, 2,6-lutidine
CH2Cl2, 0 ºC, 1.5 h
(from 11a)
hydroxycyclization of 17, an analogue of 9a with
a
OTIPS
Ph
cyclohexenyl ring instead of the phenyl at C1, gave
dihydronaphthalene 18 with essentially the same
enantioselectivity observed in the cyclization of 9a to form
10a.
12
MeO
OH
OH
OMe
13
MeO
Ph
Burgess reagent
THF, 24 ºC, 1 h
TBAF
Scheme 3. Stereo directing moieties in 1,6-enynes 5, 7a
and 9 and control experiments with 15 and 17
OMe
THF, 24 ºC, 1 h
OTIPS
Ph
Carexane I: 97%, > 99:1 er
MeO
OH
MeO
Ph
1. NaSEt
dodecanethiol
DMF, 130 ºC, 2 h
OMe
14: 83%,
(two steps)
OH
2. TBAF, THF
60 ºC, 3 h
Carexane P: 36%,
two steps, > 99:1 er
We applied the preparation of 1,2-dihydronaphthalenes to
the first enantioselective total synthesis of three members of
the carexane family of natural products, which were isolated
from
the
leaves
of
Carex
distachya.20
Chiral
dihydronaphthalene 10k (60% yield and 99:1 er, >99:1 er after
recrystallization) was converted into diol 11a in 67% yield by
hydroboration–oxidation (Scheme 2). Reaction of 11a with
ferrocenoyl chloride gave crystalline ester 12 (73% yield),
which allowed establishing its S absolute configuration by X-
ray diffraction.21 After selective protection of the benzylic
alcohol with TIPSOTf to form 13, dehydration with Burgess
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MeO
OMe
a
OMe
b
MeO
CF3
H
CF3
CF3
F3C
CF3
F3C
tBu
tBu
tBu
tBu
tBu
tBu
Au P
tBu
tBu
Re
Re
H
P
Si
P
Au
Au
Au
P
Si
H
F3C
H
F3C
N
MeO
N
N
OMe
OMe
N
CF3
CF3
CF3
OMe
CF3
F3C
CF3
CF3
F3C
orientation A (G = 2.7)
G‡ = 7.0
orientation B (G = 0)
G‡ = 4.5
orientation A (G = 0)
G‡ = 4.2
orientation B (G = 4.4)
G‡ = 6.7
C-C bond
formation
3.32 Å
- interaction
3.62 Å
-
interaction
C-C bond
formation
3.47 Å
-
interaction
3.53 Å
--interaction
3.01 Å
Aryl-OMe
interaction
3.40 Å
--interaction
TS for the reaction of 5b at the Si face of alkene with catalyst C (orientation B)
TS for the reaction of 9k at the Re face of alkene with catalyst C (orientation A)
Figure 2. Two most relevant binding orientations (A and B) of enynes 5b and 9k coordinated to catalyst C and lowest energy
transitions states (CYLview representations and NCI plots). Hydrogen atoms are omitted for clarity with the exception of the
stereocenters. Strong attractive interactions are blue (C-C bond formation), weak attractive interactions are green (non-covalent
interactions), and strong repulsive interactions are red. Color code: P: orange, Au: yellow, F: cyan, O: red, C: grey, and H: white.
Energy values in Kcal/mol relative to the most stable orientation.
We computed the reaction coordinate for the cyclizations
of enynes 5b and 9k using DFT calculations (BP86-D3/6-
31G(d) (C, H, P, O, F, N) and SDD (Au), PCM = CH2Cl2) with
complex C, which is similar to the best catalyst D (Figure 2a-
b). In all cases, we found four minima resulting from two
binding orientations A and B of the substrate coordinated to
gold(I) through the alkyne and the reaction of the two
enantiotopic faces of the alkene.24 In the cyclization of 5b
(Figure 2a) with catalyst C, our computational work predicted
preferential reaction through the Si face of the alkene, whereas
for 9k (Figure 2b) reaction through the Re face was favored, in
agreement with the experimental results. In both cases, the
lowest energy transitions states were achieved from the most
stable orientations (B for 5b and A for 9k). As revealed by the
NCI plots, attractive interactions between the aromatic
moieties of the substrates and the aromatic substituents of the
pyrrolidine of catalyst C, play the major role in the chiral
folding of the substrate and in the stabilization of the
corresponding transitions states. Additional stabilization is
provided by interactions between the substrates and the
biphenyl scaffold of the ligand. In the case of substrate 5b,
attractive aryl-OMe interactions are also stereo-controlling
elements that favor reaction through the Si face of the alkene
in orientation B (Figure 2a). This model is consistent with the
lower enantioselectivity obtained with diacetate 5d, in which
a weaker stabilizing interaction probably occurs between the
more electronegative OAc groups and the aryl substituent of
the pyrrolidine. Hence, substrate recognition by the chiral
catalysts induces one specific binding orientation via non-
covalent interactions and leads to the distinct enantioselective
folding in the enantioselective cyclization.25
A Hammett study of the reactions of substrates 5b, 5e-i (er
vs. + ) and 9a-d (er vs. +m) with catalyst D, showed negative
slopes confirming the preferred binding of the most electron-
p
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rich substrates by the catalyst bearing strongly electron-
withdrawing CF3-substituted aryl groups (Scheme 4).
ACKNOWLEDGMENT
1
2
3
4
5
6
7
8
We thank MINECO/FEDER, UE (CTQ2016-75960-P), the
AGAUR (2014 SGR 818), CERCA Program / Generalitat de
Catalunya for financial support. D.S. acknowledges the receipt
Scheme 4. Hammett study of formal [4+2] cyclization of 5
and hydroxycyclization of 9
OMe
OMe
of
a
postdoctoral fellowship from the Deutsche
(R,R)-D (4 mol %)
AgPF6 (4 mol %)
R
Forschungsgemeinschaft. J.R.B. acknowledges the Rackham
Global Engagement Fund for financial assistance for his
summer stay at ICIQ. We also thank the ICIQ X-ray diffraction
unit for the crystallographic data and Dr. M. Besora (URV
University) for support with the NCI plots and VMD software.
MeO
MeO
R
ClCH2CH2Cl
H
24 ºC, 12 h-17 h
5b: R = H, 5e: R = OMe,
5f: R = NO2, 5g: R = tBu,
5h: R = Cl, 5i: R = CF3
6b, 6e-i
+

= - 0.26 (er vs.  )
p
9
10
11
12
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Ph
(R,R)-D (1 mol %)
AgSbF6 (1 mol %)
R
Ph
R
H2O
5 equiv
REFERENCES
PhCF3
24 ºC, 12 h-18 h
OH
10a-d
(1) (a) Fürstner, A. Gold and platinum catalysis–a convenient
tool for generating molecular complexity. Chem. Soc. Rev. 2009,
38, 3208–3221. (b) Shapiro, N. D.; Toste, F. D. A Reactivity-Driven
Approach to the Discovery and Development of Gold-Catalyzed
Organic Reactions. Synlett, 2010, 675–691. (c) Obradors, C.;
Echavarren, A. M. Gold-Catalyzed Rearrangements and Beyond.
Acc. Chem. Res. 2014, 47, 902–912. (d) Fensterbank, L.; Malacria,
M. Molecular Complexity from Polyunsaturated Substrates: The
Gold Catalysis Approach. Acc. Chem. Res. 2014, 47, 953–965. (e)
Dorel, R.; Echavarren, A. M. Gold(I)-Catalyzed Activation of
Alkynes for the Construction of Molecular Complexity. Chem.
Rev. 2015, 115, 9028–9072. (f) Pflästerer, D.; Hashmi, A. S. K. Gold
catalysis in total synthesis – recent achievements. Chem. Soc. Rev.
2016, 45, 1331–1367. (g) Boyle, J. W.; Zhao, Y.; Chan, P. W. H.
Product Divergence in Coinage-Metal-Catalyzed Reactions of -
Rich Compounds. Synthesis, 2018, 50, 1402-1416. (h) Day, D.P.;
Chan, P.W. H. Gold-Catalyzed Cycloisomerizations of 1,n-Diyne
Carbonates and Esters. Adv. Synth. Catal. 2016, 358, 1368-1384.
(2) (a) Wang, Y.; Lackner, A. D.; Toste, F. D. Development of
Catalysts and Ligands for Enantioselective Gold Catalysis. Acc.
Chem. Res. 2014, 47, 889–901. (b) Zi, W.; Toste, F. D. Recent
advances in enantioselective gold catalysis. Chem. Soc. Rev. 2016,
45, 4567–4589. (c) Li, Y.; Li, W.; Zhang, J. Gold-Catalyzed
Enantioselective Annulations. Chem. Eur. J. 2017, 23, 467–512.
(3) (a) Wang, Y.; Zhang, P.; Di, X.; Dai, Q.; Zhang, Z.-M.; Zhang,
J. Gold-Catalyzed Asymmetric Intramolecular Cyclization of N-
Allenamides for the Synthesis of Chiral Tetrahydrocarbolines.
Angew. Chem. Int. Ed. 2017, 56, 15905–15909. (b) Wang, Y.; Zhang,
Z-M.; Liu, F.; He, Y.; Zhang, J. Ming-Phos/Gold(I)-Catalyzed
Diastereo- and Enantioselective Synthesis of Indolyl-Substituted
Cyclopenta[c]furans. Org. Lett. 2018, 20, 6403-6406. (c) Zhang, P-
C.; Wang, Y.; Zhang, Z-M.; Zhang, J. Gold(I)/Xiang-Phos-
Catalyzed Asymmetric Intramolecular Cyclopropanation of
Indenes and Trisubstituted Alkenes. Org. Lett. 2018, 20, 7049-
7052.
(4) (a) Yavari, K.; Aillard, P.; Zhang, Y., Nuter, F.; Retailleau, P.;
Voituriez, A.; Marinetti, A. Helicenes with Embedded Phosphole
Units in Enantioselective Gold Catalysis. Angew. Chem. Int. Ed.
2014, 53, 861–865. (b) Aillard, P.; Dova, D.; Magné, V.; Retailleau,
P.; Cauteruccio, S.; Licandro, E.; Voituriez, A.; Marinetti A. The
synthesis of substituted phosphathiahelicenes via regioselective
bromination of a preformed helical scaffold: a new approach to
modular ligands for enantioselective gold-catalysis. Chem.
Commun 2016, 52, 10984–10987.
(5) (a) Wang, Z.; Nicolini, C.; Hervieu, C.; Wong, Y.-F.; Zanoni,
G.; Zhang, L. Remote Cooperative Group Strategy Enables Ligands
for Accelerative Asymmetric Gold Catalysis. J. Am. Chem. Soc.
2017, 139, 16064–16067. (b) Cheng, X.; Wang, Z.; Quintanilla, C.
D.; Zhang, L. Chiral Bifunctional Phosphine Ligand Enabling
Gold-Catalyzed Asymmetric Isomerization of Alkynes to Allene
and Asymmetric Synthesis of 2,5-Dihydrofuran. J. Am. Chem. Soc.
2019, 141, 3787-3791.
9a: R = H, 9b: R = CF3
9c: R = Cl, 9d: R = OMe
+

= - 0.62 (er vs. 
)
m
In summary, we have designed a new class of chiral gold(I)
catalysts with monodentate pyrrolidinyl-biphenyl phosphine
ligands that promotes the enantioselective cyclization of
different types of 1,6-enynes. Non-covalent attractive -
interactions with the chiral cavity of the catalysts induced by
the distal C2-chiral pyrrolidine have been shown to be key to
achieve high enantioselectivities in cycloisomerization,
hydroxycyclization, and other related gold(I)-catalyzed
addition reactions, even in cases in which the alkyne is
substituted by two aryl groups. The hydroxycyclization
reaction has been applied for the first enantioselective total
synthesis of three members of the carexane family of natural
products. This work sets the basis for the design of similar
modular catalysts to expand the scope of asymmetric gold(I)-
catalyzed transformations and to mimic the action of polyene
cyclases.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Crystallographic data for (R,R)-C (CIF)
Crystallographic data for (R,R)-D (CIF)
Crystallographic data for (R,R)-E (CIF)
Crystallographic data for (S,S)-F (CIF)
Crystallographic data for (R,R)-G (CIF)
Crystallographic data for (R,R)-C2-Cl (CIF)
Crystallographic data for 60 (CIF)
Crystallographic data for 10k (CIF)
Crystallographic data for 12 (CIF)
Crystallographic data for Carexanene I (CIF)
Crystallographic data for Carexanene P (CIF)
Crystallographic data for Carexanene O (CIF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: aechavarre@iciq.es
ORCID
Giuseppe Zuccarello: 0000-0001-6644-9300
Antonio M. Echavarren: 0000-0001-6808-3007
Mariia S. Kirillova: 0000-0003-1628-4186
Notes
The authors declare no competing financial interest.
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(6) Zhang, P.; Tugny, C.; Suárez, J. M.; Guitet, M.; Derat, E.;
(16) Nieto-Oberhuber, C.; Muñoz, M. P.; López, S.; Jiménez-
Núñez, E.; Nevado, C.; Herrero-Gómez, E.; Raducan, M.;
Echavarren, A. M. Gold(I)-Catalyzed Cyclizations of 1,6-Enynes:
Alkoxycyclizations and Exo/Endo Skeletal Rearrangements.
Chem. Eur. J. 2006, 12, 1677–1693.
Vanthuyne, N.; Zhang, Y.; Bistri, O.; Mouriès-Mansuy, V.;
Ménand, M.; Roland, S.; Fensterbank, L.; Sollogoub, M. Artificial
Chiral Metallo-pockets Including a Single Metal Serving as
Structural Probe and Catalytic Center. Chem 2017, 3, 174-191.
(7) Bohan, P. T.; Toste, F. D. Well-Defined Chiral Gold(III)
Complex Catalyzed Direct Enantioconvergent Kinetic Resolution
of 1,5-Enynes. J. Am. Chem. Soc. 2017, 139, 11016-11019.
1
2
3
4
5
6
(17) Teller, H.; Corbet, M.; Mantilli, L.; Gopakumar, G.;
Goddard, R.; Thiel, W.; Fürstner, A. One-Point Binding Ligands
for Asymmetric Gold Catalysis: Phosphoramidites with
a
7
8
9
(8) Christianson, D. W. Structural Biology and Chemistry of the
Terpenoid Cyclases. Chem. Rev. 2006, 106, 3412–3442.
(9) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.;
Jørgensen, K. A. Direct Organocatalytic Asymmetric α-
Chlorination of Aldehydes. J. Am. Chem. Soc. 2004, 126, 4790–
4791.
TADDOL-Related but Acyclic Backbone. J. Am. Chem. Soc. 2012,
134, 15331–15342.
(18) Sanjuán, A. M.; Martínez, A.; García-García, P.; Fernández-
Rodríguez, M. A.; Sanz, R. Gold(I)-catalyzed 6-endo
hydroxycyclization of 7-substituted-1,6-enynes. Beilstein J. Org.
Chem. 2013, 9, 2242–2249.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10) Liu, Z.; Qu, H.; Gu, X.; Min. B. J.; Nyberg, J.; Hruby, V. J.
(19) García-Morales, C.; Ranieri, B.; Escofet, I.; López-Suarez, L.;
Obradors, C.; Konovalov, A. I.; Echavarren, A. M. Enantioselective
Synthesis of Cyclobutenes by Intramolecular [2+2] Cycloaddition
with Non-C2 Symmetric Digold Catalysts. J. Am. Chem. Soc. 2017,
139, 13628–13631.
(20) (a) D’Abrosca, B.; Fiorentino, A.; Golino, A.; Monaco, P.;
Oriano, P.; Pacifico, S. Carexanes: prenyl stilbenoid derivatives
from Carex distachya. Tetrahedron Lett. 2005, 46, 5269–5272. (b)
Fiorentino, A.; D’Abrosca, B.; Izzo, A.; Pacifico, S.; Monaco, P.
Structural elucidation and bioactivity of novel secondary
metabolites from Carex distachya. Tetrahedron 2006, 62, 3259–
3265. (c) Fiorentino, A.; D’Abrosca, B.; Pacifico, S.; Natale, A;
Monaco, P. Structures of bioactive carexanes from the roots of
Carex distachya Desf. Phytochemistry 2006, 67, 971–977. (d)
Fiorentino, A.; D’Abrosca, B.; Pacifico, S.; Iacovino, R.; Izzo, A.;
Uzzo, P.; Russo, A.; Di Blasio, B.; Monaco, P. Carexanes from
Enantioselective
Synthesis
of
anti-β-Substituted
γ,δ-
Unsatureated Amino Acids: A Highly Selective Asymmetric Thio-
Claisen Rearrangement. Org. Lett. 2008, 10, 4105–4108.
(11) (a) Denmark, S. E.; Chang, W-T. T.; Houk, K. N.; Liu, P.
Development of Chiral Bis-hydrazone Ligands for the
Enantioselective
Cross-Coupling
Reactions
of
Aryldimethylsilanolates. J. Org. Chem. 2015, 80, 313–366. (b) NHC-
gold(I) complexes bearing a 2,5-diphenylpyrrolidine close to the
metal center have been prepared, although their applications in
catalysis have not been described: Espina, M.; Rivilla, I.; Conde,
A.; Díaz-Requejo, M. M.; Pérez, P. J.; Álvarez, E.; Fernández, R.;
Lassaletta, J. M. Chiral, Sterically Demanding N-Heterocyclic
Carbenes Fused into a Heterobiaryl Skeleton: Design, Synthesis,
and Structural Analysis. Organometallics 2015, 34, 1328–1338.
(12) Homs, A.; Escofet, I.; Echavarren, A. M. On the Silver Effect
and the Formation of Chloride-Bridged Digold Complexes. Org.
Lett. 2013, 15, 5782–5785.
(13) (a) Herrero-Gómez, E.; Nieto-Oberhuber, C.; López, S.;
Benet-Buchholz, J.; Echavarren, A. M. Cationic η1/η2-Gold(I)
Complexes of Simple Arenes. Angew. Chem. Int. Ed. 2006, 45,
5455–5459. (b) Pérez-Galán, P.; Delpont, N.; Herrero-Gómez, E.;
Maseras, F.; Echavarren, A. M. Metal–Arene Interactions in
Dialkylbiarylphosphane Complexes of Copper, Silver, and Gold.
Chem. Eur. J. 2010, 16, 5324–5332.
(14) (a) Nieto-Oberhuber, C.; López, S.; Echavarren, A. M.
Intramolecular [4+2] Cycloadditions of 1,3-Enynes or Arylalkynes
with Alkenes with Highly Reactive Cationic Phosphine Au(I)
Complexes. J. Am. Chem. Soc. 2005, 127, 6178–6179. (b) Nieto-
Oberhuber, C.; Pérez-Galán, P.; Herrero-Gómez, E.; Lauterbach,
T.; Rodrígez, C.; López, S.; Bour, C., Rosellón, A.; Cárdenas, D. J.;
Echavarren, A. M. Gold(I)-Catalyzed Intramolecular [4+2]
Cycloadditions of Arylalkynes or 1,3-Enynes with Alkenes: Scope
and Mechanism. J. Am. Chem. Soc. 2008, 130, 269–279.
(15) Escudero-Adán, E. C.; Benet-Buchholz, J.; Ballester, P. The
use of Mo Kα radiation in the assignment of the absolute
configuration of light-atom molecules; the importance of high-
resolution data. Acta Cryst. B 2014, 70, 660–668.
Carex distachya
Desf.:
revised
stereochemistry
and
characterization of four novel polyhydroxylated prenylstilbenes.
Tetrahedron 2008, 64, 7782–7786.
(21) Holstein, P. M.; Holstein, J. J.; Escudero-Adán, E. C.;
Baudoin, O.; Echavarren, A. M. Ferrocene derivatives of liquid
chiral molecules allow assignment of absolute configuration by X-
ray crystallography. Tetrahedron: Asymmetry 2017, 28, 1321–1329.
(22) Burgess, E. M.; Penton Jr., H. R.; Taylor, E. A. Thermal
Reactions of Alkyl N-Carbomethoxysulfamate Esters. J. Org.
Chem. 1973, 38, 26–31.
(23) Dodge, J. A.; Stocksdale, M. G.; Fahey, K. J.; Jones C. D.
Regioselectivity in the Alkaline Thiolate Deprotection of Aryl
Methyl Ethers. J. Org. Chem. 1995, 60, 739–741.
(24) See Supplementary Information.
(25) (a) Neel, A. J.; Hilton, M. J.; Sigman, M. S.; Toste, F. D.
Exploiting non–covalent  interactions for catalyst design.
Nature 2017, 543, 637–646. (b) Toste, F. D.; Sigman, M. S.; Miller,
S. J. Pursuit of Noncovalent Interactions for Strategic Site-
Selective Catalysis. Acc. Chem. Res. 2017, 50, 609-615.
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Novel Catalyst design for
Substrate Encapsulation in
Ar
Chiral Pocket
Ar
R
S
+
NuH
R
H
Nu
CF3
R1
F3
C
Ad
Ad
R2
R
P
Au
E
E
E
R
R
E
N
R
H
R1
R1
8
9
F3
C
S
Ar
Ar
RN
CF3
RN
S
R1
R1
Structurally Related 1,6-enynes
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3 Different Cyclizations
One Catalyst, up to 99:1 er
Distinct Chiral Folding
7
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