Axially chiral triazoloisoquinolin-3-ylidene ligands in gold(I)-catalyzed asymmetric intermolecular (4 + 2) cycloadditions of allenamides and dienes

Article abstract of DOI:10.1021/ja3065446

The first highly enantioselective intermolecular (4 + 2) cycloaddition between allenes and dienes is reported. The reaction provides good yields of optically active cyclohexenes featuring diverse substitution patterns and up to three stereocenters. Key to

Full text of DOI:10.1021/ja3065446

Communication
pubs.acs.org/JACS
Axially Chiral Triazoloisoquinolin-3-ylidene Ligands in
Gold(I)-Catalyzed Asymmetric Intermolecular (4 + 2)
Cycloadditions of Allenamides and Dienes
Javier Francos,† Francisca Grande-Carmona,§ Helio Faustino,† Javier Iglesias-Siguenza,∥ Elena Díez,∥
́
̈
Isaac Alonso,† Rosario Fernandez,*,∥ Jose M. Lassaletta,*,§ Fernando Lopez,*,‡ and Jose L. Mascarenas*,†
́
́
́
́
̃
†Centro Singular de Investigacion
Unidad Asociada al CSIC, Universidad de Santiago de Compostela, 15782, Santiago de Compostela, Spain
‡Instituto de Química Organ
ica General CSIC, Juan de la Cierva 3, 28006, Madrid, Spain
§Instituto de Investigaciones Químicas (CSIC-USe), Avda. Amer
ico Vespucio 49, 41092 Sevilla, Spain
∥Departamento de Química Organ
ica, Universidad de Sevilla, C/Prof. García Gonzalez, 1, 41012 Sevilla, Spain
́
en Química Biolox
́
ica e Materiais Moleculares (CIQUS) and Departamento de Química Organ
́
ica,
́
́
́
́
S
* Supporting Information
Table 1. Preliminary Screening of Chiral NHC−Gold
Catalyst
ABSTRACT: The first highly enantioselective intermolecu-
lar (4 + 2) cycloaddition between allenes and dienes is
reported. The reaction provides good yields of optically active
cyclohexenes featuring diverse substitution patterns and up to
three stereocenters. Key to the success of the process is the
use of newly designed axially chiral N-heterocyclic carbene−
gold catalysts.
a
b
atalytic asymmetric Diels−Alder (DA) cycloadditions are
Camong the most effective strategies to construct optically
active six-membered carbocycles.1 In recent decades there have
been many reports on enantioselective intermolecular versions
of these annulations, which are typically promoted by chiral
Lewis acids or by organocatalysts. In most of the cases, however,
these transformations are circumscribed to alkenyl dienophiles
equipped with carbonyl-activating groups (e.g., α,β-unsaturated
aldehydes, ketones, esters, amides).2,3 Enantioselective intermo-
lecular DA reactions involving other types of dienophiles are
much less frequent, and particularly, those between allenes and
dienes are virtually unexplored.4
We have recently reported a gold-catalyzed intermolecular
(4 + 2) cycloaddition between allenamides and dienes.5−7 The
transformation provides a simple, versatile, and stereoselective
entry to a variety of cyclohexenyl products incorporating an exo
enamide group and up to two new stereocenters. The reaction
is better carried out using AuCl as the catalyst but can also be
promoted by other gold(I) catalysts such as IPrAuCl/AgSbF6,
although in this case it is somewhat less selective with respect
to a competitive (2 + 2) annulation that provides cyclobutane
side adducts.5a,8
entry
[Au]
t (min)
3a, yield (%)
ee (%)
1
2
3
4
5
6
Au1
Au2
Au3
Au4
Au5
60
60
60
60
60
15
79
88
74
76
51
91
10
4
4
23
24
16
Au6
b
a
Isolated yield. Determined by HPLC on chiral stationary phases.
chiral NHC−gold(I) complex, Au8, in which the carbene gold
ligand is embedded in the cyclic backbone of an axially chiral
unit, is able to catalyze the (4 + 2) cycloaddition between
allenamides and a large number of dienes with total regio- and
stereoselectivity and excellent enantioselectivity.
We initially focused on C2-symmetric dihydroimidazole NHC−
gold complexes Au1−Au5, incorporating the 1,2-diphenyl-
ethylene backbone.11,12 These complexes promoted the (4 + 2)
cycloaddition between 1a and 2a to afford the desired cycloadduct
3a in moderate to good yields and complete stereoselectivity;13
however, the enantioselectivity was consistently poor (Table 1).
We were then curious to know the performance of chiral
triazolylidene−gold complexes. Triazole-based NHCs have been
successfully used in asymmetric oganocatalysis;14 however, their
organometallic complexes and, in particular, the gold counterparts,
are essentially unexplored.15 Interestingly, Au(I) complex Au6,
prepared from Bode's triazolylidene ligand,16 promoted the
On the above basis, we were challenged to explore the
viability of achieving this type of allene−diene cycloadditions in
an enantioselective manner, using chiral NHC−gold catalysts.
Curiously, despite the wide use of racemic NHC-gold catalysts,9
applications of their chiral counterparts are very scarce;10 only
recently have ee values above 90% been reported for a couple of
reactions, both promoted by chiral acyclic diaminocarbene gold
complexes.10g,h Herein, we demonstrate that a newly designed
Received: July 5, 2012
Published: August 14, 2012
© 2012 American Chemical Society
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Figure 1. Design of new chiral NHC ligands.
cycloaddition in just 15 min at −50 °C, providing 3a in an
excellent 91% yield, albeit with low ee.
In view of the good catalytic activity of Au6, we explored other
triazole-based NHC ligands that could generate a more effective
chiral environment within proximity of the gold center. Relying on
our recent work on imidazo[1,5-a]pyridin-3-ylidene (A)17 and
[1,2,4]triazolo[4,3-a]pyridin-3-ylidene (B)18 NHC architectures,
we envisioned that gold complexes of type C (Figure 1) could be
particularly well poised for this task. The rigid bicyclic structure of
these NHC units should fix the relative orientation of the
C(carbene)−Au bond while forcing the C(5)-aryl substituent in
close proximity to this reacting center, and therefore might favor
an efficient transfer of axial chirality. Moreover, the asymmetric
induction might be further tuned by modulating the steric
demands of R, and particularly R′.19
Figure 2. X-ray structure of (Ra)-Au8. H-atoms are omitted for clarity.
Additionally, the structure suggests that there might be
substantial differences in the accessibility of either prochiral
face of the allyl−cation gold intermediate that is presumably
formed by activation of the allenamide.5a,b
Gratifyingly, complex Au7/AgSbF6 catalyzed the cyclo-
addition of 1a and 2a, providing the expected cycloadduct 3a
in good yield and a promising 63% ee (Table 2, entry 1).
Importantly, the cyclohexyl-substituted derivative Au8 provided
a similar yield but an excellent 90% ee (entry 2). This ee value
could be improved by using AgNTf2 as a silver salt (entry 3)25
and further increased up to >99% by lowering the temperature
(entry 4). As can be seen in entries 5 and 6, the reaction
tolerates different types of substituents at the aryl group of the
diene, thereby 3b and 3c could be isolated with 94% and 96%
ee, respectively.26 The presence of substituents at the internal
position of the diene is well tolerated (entry 7), and 1,4-
disubstituted dienes such as 2e and 2f also participate in the
process providing a direct and diastereoselective access to 1,4-
cis disubstituted cyclohexenes (3e and 3f) with excellent ee’s
(entries 8 and 9).27 Dienes lacking aryl substituents such as
(E)-penta-1,3-diene (2g) or (E)-3-methylpenta-1,3-diene (2h)
are also suitable substrates, providing the corresponding
adducts with ee’s varying from 91 to 94% (entries 10 and
11). Whereas furan was too reactive and gave a mixture of
products, challenging 1,4-dialkyl-substituted dienes such as 2i
and 2j provided satisfactory results under the standard
conditions (entries 12 and 13), producing the expected adducts
with complete chemo-,28 regio-, and diastereoselectivity, and
ee’s close to 90%.29 Excellent enantioselection was obtained in
the cycloaddition of oxazolidinone-diene 2k, which provides a
N-substituted chiral cyclohexene (entry 14). Other allenamides,
such as 1b (entry 15) or, more importantly, terminally
substituted derivatives such as 1c, do also provide excellent
results. For instance, cycloaddition of 2d with allenamide 1c
provided a 6:1 mixture of diastereoisomeric cycloadducts 3dc
and 3dc′ with a 75% combined yield and 96% ee (entry 16).
Gratifyingly, the diastereoselectivity of this reaction could be
increased by performing the reaction with catalyst Au7/AgSbF6
at −50 °C, which provided exclusively 3dc, still with a good yield
and an excellent 93% ee (entry 17). Finally, the excellent
performance and wide scope of this catalyst was again
demonstrated in the cycloaddition of 2f to 1c, which
provided the cyclohexenyl adduct 3fc, including three new
stereogenic centers with complete regio- and diastereoselec-
tivity as well as an excellent 91% ee (entry 18).30
To test the efficacy of these ligands we prepared the
complexes Au7 (R′ = Me) and Au8 (R′ = Cy), according to the
reaction sequence indicated in Scheme 1. The process involves
a selective Suzuki coupling between 1,3-dichloroisoquinoline 4
and boronic acids 5a,b (→6a,b),20 followed by Buchwald−
Hartwig amination with BocNHNHBoc (→7a,b).21 After
deprotection, formylation, and cyclization (→8a,b), the
racemic mixtures were resolved by chiral HPLC.22 Ensuing
alkylation with 1-adamantyl bromide [→9a,b(Br)] and anion
exchange23 gave the triazolium salts 9a(Cl) and 9b(Cl), and finally,
metalation with Ag2O (→10a,b) followed by transmetalation with
AuCl·Me2S gave the desired gold complexes Au7 and Au8.
The X-ray structure of complex (Ra)-Au8 (Figure 2) allowed
the assignment of the absolute configuration and the
quantification of the steric demand of the ligand, measured as
the percentage of buried volume (%Vbur) around the gold center.
Using the SambVca software,24 we calculated a %Vbur value of
46.2, among the highest described for monodentate NHCs.19b
a
Scheme 1. Synthesis of Au7 and Au8
a
Reagents and conditions: (a) Pd(PPh3)4, CsF, DME, reflux, 15 h;
In summary, we described the first examples of a highly enantio-
selective intermolecular (4 + 2) cycloaddition between allenes and
dienes, which also represents the first asymmetric intermolecular
(4 + 2) cycloaddition promoted by a chiral carbophilic metal
(b) BocNHNHBoc, Pd2(dba)3, dppf, CsCO3, toluene; (c) HCl 4 M
dioxane; (d) HCOOH, reflux; (e) (i) POCl3, toluene, reflux, (ii)
HPLC chiral resolution; (f) 1-BrAd, AcOH, reflux; (g) Dowex 22
(Cl−); (h) Ag2O, CHCl3, MS 4 Å; (i) AuCl·Me2S, toluene.
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Communication
a
Table 2. Catalyst Identification and Scope of the Enantioselective (4 + 2) DA Cycloaddition of Allenamides and Dienes
a
Conditions: Diene (3 equiv) and allenamide (1 equiv) were added to a cooled solution of (Ra)-Au8 and AgX in CH2Cl2 (0.1 M) unless otherwise
b
noted. Conv. > 99%. N* = (2-oxo)oxazolidin-3-yl, N** = (2-oxo)pyrrolidin-1-yl. The absolute configuration of (S)-3c was determined by X-ray
c
diffraction analysis; see the Supporting Information. The absolute configuration of all other products 3 was assigned by analogy. Isolated yields.
d
e
f
g
Determined by HPLC on chiral stationary phases. Unoptimized yield. Carried out with 4 equiv of diene. Carried out with (Sa)-Au8, instead of
h
i
j
k
(Ra)-Au8. Carried out with allenamide 1b. Carried out with allenamide 1c. Ratio of (2S,6R)-3dc:(2S,6S)-3dc′ (crude 1H NMR). Same ee values
l
(97%) were observed for both diastereoisomers, (2S,6R)-3dc and (2S,6S)-3dc′. Ratio of (2R,6S)-3dc:(2R,6R)-3dc′ (crude1H NMR).
Notes
complex. The reaction provides a versatile and practical approach
to a variety of optically active cyclohexene products which are not
easily accessible using other methodologies.31 Success in the
asymmetric induction relies on the development of a novel class of
designed ligands featuring a triazole unit embedded in a rigid
axially chiral cyclic frame. These ligands might find utility in other
metal-catalyzed asymmetric processes; in particular, the excellent
results obtained with catalyst Au8 augurs well for further
applications in other gold-catalyzed transformations.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Spanish MINECO (SAF2010-
20822-C02, CTQ2010-15297, CTQ2010-14974, and Consolider
Ingenio 2010 CSD2007-00006), the ERDF funds, the Xunta de
Galicia (INCITE09209084PR, GRC2010/12), and the Junta de
Andalucía (2008/FQM-3833 and 2009/FQM-4537, predoctoral
fellowship to F.G.-C). H.F. acknowledges the Fundaca̧ o para a
̃
̂
Ciencia e Tecnologia (FCT, Portugal) and POPH/FSE for a
ASSOCIATED CONTENT
■
Ph.D. grant (Grant SFRH/BD/60214/2009). Johnson-Matthey
PLC is acknowledged for a gift of metal complexes.
S
* Supporting Information
Experimental procedures, characterization and X-Ray data, and
HPLC traces. This material is available free of charge via the
Internet at http://pubs.acs.org.
REFERENCES
■
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AUTHOR INFORMATION
■
Corresponding Author
joseluis.mascarenas@usc.es; fernando.lopez@iqog.csic.es;
ffernan@us.es; jmlassa@iiq.csic.es
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(22) The racemic mixtures 8a,b were resolved by preparative HPLC
(Chiracel IA). See the Supporting Information for further details.
(23) The exchange to Cl prevents Cl/Br mixtures after trans-
metalation of the NHC-AgBr intermediate with AuCl·SMe2.
(24) (a) Poater, A.; Cosenza, B.; Correa, A.; Giudice, S.; Ragone, F.;
Scarano, V.; Cavallo, L. Eur. J. Inorg. Chem. 2009, 1759. (b) http://
www.molnac.unisa.it/OMtools.php. The calculated value (H-atoms
omitted) was obtained using the standard parameters: radius of sphere
= 3.5 Å; distance from sphere = 2.1 Å; mesh step = 0.05.
(25) Equivalent results to those of entries 2 and 3 were obtained
when the cationic catalyst was previously filtered through celite. For a
pertinent discussion on the “silver effect”, see: Wang, D.; Cai, R.;
Sharma, S.; Jirak, J.; Thummanapelli, S. K.; Akhmedov, N. G.; Zhang,
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and references therein.
(26) A highly electron-withdrawing p-NO2 substituent at the aryl
group of the diene still provided the reaction product with 92% ee,
although in just 11% yield. See the Supporting Information for details.
(27) The reaction of (1Z,3E)-2f with 1a did not provide any (4 + 2)
adduct, suggesting that it might proceed via concerted rather stepwise
pathways. Further mechanistic studies are ongoing.
(28) In contrast to the reaction of 2i and 1a catalyzed by
IPrAuSbF6,5a we did not observe (2 + 2) adducts when using Au8/
AgNTf2.
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(29) Cycloaddition experiments of 1a with dienes 2i, 2a, and 2h
using gold catalysts featuring chiral phosphoramidites or bisphos-
phines led to low ee’s and/or yields. See the Supporting Information
for details.
(30) This reaction fails with AuCl or IPrAuCl/AgSbF6,5a which
further highlights the potential and efficiency of Au8.
(31) The exoenamide group can be readily elaborated. For instance,
treatment of (S)-3d with HCl and subsequent reduction (NaBH4)
yields the expected alcohol in good yield.5a
(11) For other types of transition-metal catalysts incorporating these
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4455 and references therein. (g) See also ref 10i.
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