Enantioselective synthesis of cyclobutenes by intermolecular [2+2] cycloaddition with non-c2 symmetric digold catalysts

Article abstract of DOI:10.1021/jacs.7b07651

The enantioselective intermolecular gold-(I)-catalyzed [2+2] cycloaddition of terminal alkynes and alkenes has been achieved using non-C₂-chiral Josiphos digold(I) complexes as catalysts, by the formation of the monocationic complex. This new approach has been applied to the enantioselective total synthesis of rumphellaone A.

Full text of DOI:10.1021/jacs.7b07651

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Communication
Enantioselective Synthesis of Cyclobutenes by Intermolecular
[2+2] Cycloaddition with Non-C2 Symmetric Digold Catalysts
Cristina García-Morales, Beatrice Ranieri, Imma Escofet, Laura López-
Suárez, Carla Obradors, Andrey I. Konovalov, and Antonio M. Echavarren
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07651 • Publication Date (Web): 19 Sep 2017
Downloaded from http://pubs.acs.org on September 19, 2017
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Enantioselective Synthesis of Cyclobutenes by Intermolecular
[2+2] Cycloaddition with Non-C2 Symmetric Digold Catalysts
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Cristina García-Morales,† Beatrice Ranieri,† Imma Escofet,† Laura López-Suarez,† Carla Obra-
dors,† Andrey I. Konovalov,† 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
of functionalized cyclobutanes,7,8 present in a variety of natu-
ral products9 and pharmaceuticals.10
ABSTRACT: The enantioselective intermolecular gold(I)-
catalyzed [2+2] cycloaddition of terminal alkynes and alkenes
has been achieved using non C2-chiral Josiphos digold(I)
complexes as catalysts, by the formation of the monocationic
mides,11 thioacetylenes,12 or strained alkenes.9d,13 Herein, we
complex. This new approach has been applied to the enanti-
oselective total synthesis of rumphellaone A.
Enantioselective metal-catalyzed synthesis of cyclobutenes
by [2+2] cycloaddition has only been reported with yna-
report the first general enantioselective synthesis of cyclo-
butenes by intermolecular [2+2] cycloaddition using chiral
non-C2 symmetrical Josiphos digold(I) catalysts.14,15 To
demonstrate its potential, we have applied this method in a
concise asymmetric synthesis of the natural product
rumphellaone A.
Gold(I) complexes are the most powerful and selective cata-
lysts for the activation of alkynes in complex molecular set-
tings.1 Despite the success of gold(I) in homogeneous cataly-
sis, highly enantioselective reactions of alkynes are still rela-
tively scarce,2 particularly in the context of intermolecular
transformations.3 The linear geometry of gold(I) dicoordinat-
ed complexes poses a major limitation for the development
of asymmetric gold(I) catalysis since it locates the chiral
ligand very far away from the reaction center, where the
addition takes place through an outer-sphere mechanism
(Scheme 1). Atropoisomeric bidentate phosphines and phos-
phoramidites have been applied as ligands in asymmetric
gold(I)-catalyzed reactions,2 whereas the use of chiral coun-
terions has allowed the transfer of the chiral information via
tight ion pairs in allene cyclizations.4 The difficulty increases
when linear alkynes are used as substrates in intermolecular
reactions with alkenes. The problem of achieving stereocon-
trol in this process can be considered as a special case of the
more general class of similarly challenging enantioselective
electrophilic additions to alkenes,5 where the electrophile is
generated in situ by coordination of the alkyne to the chiral
gold(I) complex.
Table 1. Optimization of the Enantioselective Cycloadd-
tion of 1a with 2a to form 3a.a
yield
entry
complex
solvent
t (°C)
erc
(%)b
13
1
2
(S,RP)-A
(S,RP)-B
(CH2)2Cl2
(CH2)2Cl2
25
25
78:22
84:16
66
3
4
5
(R,SP)-C
(R,SP)-D
(R,SP)-E
(S,RP)-F
(S,RP)-B
(S,RP)-B
(CH2)2Cl2
(CH2)2Cl2
(CH2)2Cl2
(CH2)2Cl2
C6H5Cl
25
25
25
25
25
25
10
10
9
18:82
20:80
18:82
-
6
7
0d
76
78
84:16
86:14
8e
C6H5Cl
9f
10
11
(S,RP)-B
(S,RP)-B
(S,RP)-B
(S,RP)-B
C6H5Cl
(CH2)2Cl2
C6H5Cl
25
0
40
55
63
70
85:15
88:12
88:12
90:10
Scheme 1. General Scheme and Previous Work.
0
R3
12g
C6H5Cl
−20
R2
a
b
c
R1
H
H
2a/1a = 2:1 (1a = 0.1 mmol). Isolated yield. er determined by
UPC2. d Oligomerization of 2a. e NaBAr4 (5 mol %). f NaBAr4 (10
F
F
H
L
Au
X
mol %). g Slow addition of 2a.
tBu
tBu
P
Au NCMe
iPr
iPr
Ph
iPr
(3 mol %)
CH2Cl2, 23 ºC, 12 h
X- = SbF6- (80%)6a, BAr4F- (95%)6b
+
Ph
Ph
Ph
1a
2a
3a
The gold(I)-catalyzed reaction of terminal alkynes 1 with
alkenes 2 leads to cyclobutenes 3 by a [2+2] cycloaddition
(Scheme 1),6 which are valuable synthons for the preparation
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were determined for 3f, 3u, 3v, 3ad, and 3ae. The absolute configura-
tion of 3f and 3v was also determined by X-ray diffraction.
We screened ca. 90 chiral ligands for the synthesis of cyclo-
butene 3a using high-throughput methods. Although the
vast majority of chiral ligands led to 3a with low enantiose-
lectivities, the breakthrough was achieved using the Josiphos
ligands family (Table 1).16 Cyclobutene 3a was isolated in low
yields with precatalysts (S,RP)-A, (R,SP)-C, (R,SP)-D and
(R,SP)-E (Table 1, entries 1 and 3-5), whereas complex (S,RP)-B
led to 3a in 66% yield and 84:16 er (Table 1, entry 2). Complex
(S,RP)-F led to extensive oligomerization of the alkene 2a
(Table 1, entry 6). Further optimization with complex (S,RP)-
B showed that chlorinated solvents were superior both in
terms of enantioselectivity and conversion.16 As we have
found before,6b,c BAr4F- was the best counterion.16 Using chlo-
robenzene as solvent, 2.5 mol% of NaBArF4 as chloride scav-
enger and performing the reaction at 0 °C led to 3a in 63%
yield and 88:12 er (Table 1, entry 11). By lowering the tempera-
ture to -20 °C, the enantioselectivity reached 90:10 er (Table
1, entry 12). When the reaction was carried out using 2.5 mol
% of the silver(I) salt Ag{Al[O(CF3)3]4} to assure the for-
mation of a monocationic species, cyclobutene 3a was ob-
tained in 65% and 84:16 er. However, no reaction was ob-
served by abstracting both chlorides from (S,RP)-B with 5
mol % of silver(I) salt.16 Similarly, monogold complex (S,RP)-
G bearing the same ligand as (S,RP)-B, but with only the
metal center coordinated to the trialkylphosphine, led to
traces of racemic 3a.16
1
2
3
4
5
6
7
8
The gold(I)-catalyzed cycloaddition of terminal alkynes 1a-i
with 1,1-disubstituted alkenes led to cyclobutenes 3a-ab in
moderate to excellent yields and enantioselectivities up to
94:6 er with catalyst (S,RP)-B (Table 2). This is significant, as
only a few examples of asymmetric electrophilic additions to
1,1-disusbstituted alkenes have been achieved before.5f The
reaction proceeded satisfactorily with aryl alkynes bearing
electron rich substituents in para and meta position. 3-
Ethynylthiophene also led to the corresponding cyclobutenes
3i, 3t, 3v, and 3aa. Good enantioselectivities were obtained
with α-alkyl styrenes. However, 1,1-diakyl substituted alkenes
or simple styrene resulted in a significant loss of enantiose-
lectivity, as shown in the case of 3ab and 3ac. The absolute
configuration of cyclobutenes 3f and 3v was determined to be
R by X-ray diffraction. Biscyclobutenes 3ad-ah were also
obtained with high enantioselectivities from dialkynes or
dialkenes as reaction counterparts by twofold cycloaddition.
The corresponding meso derivatives were obtained as minor
products in these reactions (20-30% yields).
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The cycloaddition of trisubstituted alkenes with terminal
alkynes was carried out with catalyst (R,SP)-F to give 1,3,3,4-
tetrasubstituted cyclobutenes 3ai-ap with moderate to excel-
lent regioselectivities (Scheme 2).17 The enantioselectivities
were on the same range to those obtained with 1,1-
disusbtituted alkenes using catalyst (S,RP)-B.
Table 2. Synthesis of Cyclobutenes 3a-ah using 1,1-
Disubstituted Alkenes.a
Scheme 2. Synthesis of Cyclobutenes 3ai-ap from Trisub-
stituted Alkenes.a
a 1a-i (0.3 mmol scale). er determined by UPC2. b Regioisomeric ratio.
c 1f (o. 1 mmol scale). d 0 °C. e 25 °C.
Scheme 3. Synthesis of Rumphellaone A
To demonstrate the utility of the asymmetric cyclobutene
synthesis, we developed a second-generation synthesis of
rumphellaone A (4) (Scheme 3), following our first diastere-
oselective total synthesis, which was achieved in 12 steps by a
gold(I)-catalyzed [2+2] macrocyclization of a 1,10-enyne.18
The key intermolecular [2+2] cycloaddition of 1a with trisub-
stituted alkene 2o in the presence of catalyst (R,SP)-F fur-
a 1a-i (0.3 mmol scale). Isolated yields average of two runs. er deter-
mined by UPC2. b 1c (0.1 mmol scale). c 25 °C. X-ray crystal structures
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Journal of the American Chemical Society
nished cyclobutene 3aq in 70% yield and 91:1 er. Cyclobutene
alkyne)]+ to the alkene leading to (R)-3a when complex
(S,RP)-B is used as the precatalyst (Figure 3b).16 The calculat-
1
2
3
4
5
6
7
8
3aq was then converted into intermediate 7 following our
previously described conditions,18 which allowed completing
a formal synthesis of rumphellaone A (4) in 9 steps. This
synthesis also allows establishing the S-configuration for
cyclobutene 3aq. Those of 3ai-ap were assigned as S by anal-
ogy.
ed energy difference between the lowest transition states
that lead to (S)- and (R)-3a ΔG‡ = 0.7-1.1 kcal·mol-1 (de-
S-R
pending on the method) is in good agreement with experi-
mentally derived value of ΔG‡ ≈ 1 kcal·mol-1. Apart from
S-R
the combination of stabilizing π-stacking and unfavorable
steric effects between the approaching alkene and the naph-
thyl rings of the ligand, we identified a strong C-H – AuCl
repulsion between the (naphthyl)2P-AuCl and the methine
hydrogen atom in the α-position to the Cp-ring of the ferro-
cenyl moiety, which rises the energy of the TSS transition
state vs. TSR. Calculations of the corresponding transition
states without the second AuCl on (naphthyl)2P resulted in
the complete loss of stereoselectivity, in agreement with the
experimental data using complex (S,RP)-G.16
In the range of applied concentrations, the [2+2] cycloaddi-
tion reaction exhibited first order kinetic dependence on
each reactant.19 The reaction also showed a first order de-
pendence on the catalyst concentration when complex
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(R,SP)-B and NaBArF were mixed in a 1:1 ratio. A Hammett
4
plot for a series of para-substituted α-methyl styrenes 2a-g,p
showed linear correlations with σ+ constants for two different
sets within the series, one for R = Me, iPr, tBu and cyclopro-
pyl (ρ = +7.05, R2 = 0.99) and the other one for R = F, H, Cl,
and Br (ρ = -2.32, R2 = 0.97) (Figure 2).
Figure 3. (a) X-Ray Crystal Structure of (S,RP)-B and (b)
Lowest Energy Transition State for the Reaction of 1a
and 2a with (S,RP)-B.a
Figure 2. Hammett Plot for the Reaction of 1a and 2a-g, p
with (S,RP)-B.
(b)
(a)
0.3
tBu
iPr
F
0.1
-0.1
-0.3
-0.5
-0.7
-0.9
H
Me
Cl
DZ = 7.05
R² = 0.99
Br
DZ = -2.32
R² = 0.97
a Calculated at PCM(PhCl)-BP86-D3, SDD(Au, Fe), 6-31G(d) (C, H, P,
Cl) level of theory using G09 package.16
Cyclop
-0.5
-0.3
-0.1
0.1
0.3
In summary, we have developed a broad scope enantioselec-
tive synthesis of cyclobutenes by intermolecular [2+2] cy-
cloaddition of alkynes with alkenes using Josiphos digold(I)
catalysts. This reaction allowed us to streamline the enanti-
oselective synthesis of rumphellaone A, which was achieved
in only 9 steps. Our studies indicate that only one of the
gold(I) centers is directly involved in the activation of the
alkyne, although the second one is required to induce the
enantioselectivity. Our work also reveals that both ligand
exchange and electrophilic addition can be turnover-limiting
steps in this catalytic cycloaddition. Further chiral ligand
development based on the proposed stereochemical model is
underway.
σ+
The abrupt difference in the ρ values is indicative of a change
in the catalytic turnover-limiting step. The observation of a
highly positive ρ value for 2e-g,p in an alkene electrophilic
addition is seemingly puzzling, although it can be explained
considering that in these cases the turnover limiting step is
the ligand exchange between [LAu(η2-alkene)]+ and the
alkyne to form [LAu(η2-alkyne)]+ and free alkene, which
experiences a decrease in positive charge. Indeed, we have
shown that the associative ligand exchange is the slowest
step in the [2+2] cycloaddition reaction with mononuclear
gold(I) complexes.6b For substrates 2a-d the formation of
[LAu(η2-alkene)]+ is less favored,20 and therefore the ob-
served negative ρ value is a result of the build-up of positive
charge at the most substituted carbon of the alkene in a
turn-over limiting Markovnikov-type addition of electro-
philic [LAu(η2-alkyne)]+ complex.6c
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website.
Additional details, experimental procedures and characteriza-
tion data for compounds (PDF).
Crystallographic data (CIF)
Aurophilic interactions have been shown to be important in
other ferrocenyl diphosphino gold(I) complexes.21 However,
in the solid state of (S,RP)-B (Figure 3a) and related complex-
es,22 the two gold(I) centers are anti-oriented with respect to
each other and no aurophilic interactions were observed.
DFT calculations provide a model to explain the asymmetric
induction in the key electrophilic addition of [LAu(η2-
AUTHOR INFORMATION
Corresponding Author
* E mail for A.M.E. aechavarren@iciq.es
ORCID
Antonio M. Echavarren: 0000-0001-6808-3007
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Journal of the American Chemical Society
Page 4 of 6
Cristina García-Morales: 0000-0002-3566-2608
1
2
3
4
Laura López-Suárez: 0000-0002-8750-2294
Carla Obradors: 0000-0002-2339-9398
Notes
No competing financial interests have been declared.
ACKNOWLEDGMENTS
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(14) A single example of gold(I)-catalyzed asymmetric intermolecular
[2+2] cycloaddition has been reported in low enantioselectivity
(65:35 er) using an axially chiral imidazoisoquinolin-2-ylidene
ligand: Grande-Carmona, F.; Iglesias-Sigüenza, J.; Álvarez, E.; Dí-
ez, E.; Fernández, R.; Lassaletta, J. M. Organometallics 2015, 34,
5073–5080.
(15) Using (R)-DM-SEGPHOS(AuCl)2 as a chiral catalyst, lactones
were obtained with modest to moderate enantioselectivities
(60:40-82:18 er) in the intermolecular reaction of t-butyl propio-
late with alkenes: Yeom, H.-S.; Koo, J.; Park, H.-S.; Wang, Y.;
Liang, Y.; Yu, Z.-X.; Shin, S. J. Am. Chem. Soc. 2012, 134, 208–211.
(16) See Supporting Information for additional details.
(17) Cyclobutenes 3ai (78%, 3:1, 67:33 er), 3ak (78%, 2:1, 64:36 er) and
3an (91%, 1.5:1, 69:31 er) were obtained with (S,RP)-B (2.5 mol%),
NaBArF4 (2.5 mol%) in chlorobenzene (0.5 M) at 25 °C.
5
We thank MINECO/FEDER, UE (CTQ2016-75960-P and FPI
Fellowship to C.G.M.), MINECO-Severo Ochoa Excellence
Acreditation 2014-2018, SEV-2013-0319), MECD (FPU Fel-
lowship to C. O,), the European Research Council (Advanced
Grant No. 321066), the AGAUR (2014 SGR 818), the Marie
Curie program (Postdoctoral Fellowship 658256-MSCA-IF-EF-
ST to B.R.) CERCA Program / Generalitat de Catalunya for
financial support. We also thank the ICIQ X-ray diffraction
unit, the Chromatography, Thermal Analysis and Electrochem-
istry unit and CELLEX-ICIQ HTE laboratory.
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