Gold-catalyzed [4C+2C] cycloadditions of allenedienes, including an enantioselective version with new phosphoramidite-based catalysts: Mechanistic aspects of the divergence between [4C+3C] and [4C+2C] pathways

Article abstract of DOI:10.1021/ja905415r

Gold(I) complexes featuring electron acceptor ligands such as phosphites and phosphoramidites catalyze the [4C+2C] intramolecular cycloaddition of allenedienes. The reaction is chemo- and stereoselective, and provides trans-fused bicyclic cycloadducts in

Full text of DOI:10.1021/ja905415r

Published on Web 08/21/2009
Gold-Catalyzed [4C+2C] Cycloadditions of Allenedienes,
including an Enantioselective Version with New
Phosphoramidite-Based Catalysts: Mechanistic Aspects of the
Divergence between [4C+3C] and [4C+2C] Pathways
Isaac Alonso,† Beatriz Trillo,† Fernando Lo´pez,*,§ Sergi Montserrat,‡
Gregori Ujaque,*,‡ Luis Castedo,† Agust´ı Lledo´s,‡ and Jose L. Mascaren˜as*,†
Departamento de Qu´ımica Orga´nica, UniVersidade de Santiago de Compostela, 15782 Santiago
de Compostela, Spain, Departament de Qu´ımica, UniVersitat Auto´noma de Barcelona, 08193
Bellaterra, Barcelona, Spain, and Instituto de Qu´ımica Orga´nica General (CSIC), Juan de la
CierVa, 3, 28006, Madrid, Spain
Received April 10, 2009; E-mail: joseluis.mascarenas@usc.es
Abstract: Gold(I) complexes featuring electron acceptor ligands such as phosphites and phosphoramidites
catalyze the [4C+2C] intramolecular cycloaddition of allenedienes. The reaction is chemo- and stereose-
lective, and provides trans-fused bicyclic cycloadducts in good yields. Moreover, using novel chiral
phosphoramidite-based gold catalysts it is possible to perform the reaction with excellent enantioselectivity.
Experimental and theoretical data dismiss a cationic mechanism involving intermediate II and suggest that
the formation of the [4C+2C] cycloadducts might arise from a 1,2-alkyl migration (ring contraction) in a
cycloheptenyl Au-carbene intermediate (IV), itself arising from a [4C+3C] concerted cycloaddition of the
allenediene. Therefore, these [4C+2C] allenediene cycloadditions and the previously reported [4C+3C]
counterparts most likely share such cycloaddition step, differing in the final 1,2-migration step.
1. Introduction
catalyzed cycloadditions involving allenes instead of alkynes,
although certain allene-tethered 1,3-dienes have also been shown
to participate in Rh-catalyzed [4C+2C] cycloadditions to give
interesting 5,6- and 6,6-fused bicyclic systems.4 From a
mechanistic point of view, these type of reactions usually
proceed through a series of metallacyclic intermediates formed
through oxidative cyclization and carbometalation steps. A final
reductive elimination process affords the corresponding cy-
cloadducts and regenerates the metal catalyst.5
Cycloaddition reactions are among the most practical and
efficient methods to construct cyclic products from relatively
simple, acyclic starting materials.1 Needless to comment about
the enormous potential and historical relevance of the [4 + 2]
Diels-Alder cycloaddition, which is among the most powerful
synthetic tools for the assembly of six-membered cyclic
structures.2 Achieving mild and effective Diels-Alder cycload-
ditions requires that the two partners have complementary
electronic properties. This is usually accomplished by activating
the components with electron withdrawing or releasing substit-
uents (usually an electron deficient dienophile in combination
with an electron-rich diene). In some cases, however, it has been
shown that the [4C+2C] cycloaddition of nonactivated, ther-
mally unreactive substrates can be efficiently promoted at low
temperatures by employing appropriate transition metal catalysts.
Most of the reported examples deal with cycloadditions between
alkynes and 1,3-dienes, and are usually promoted by Rh, Ni or
Pd catalysts.3 Much less common are the transition metal
(3) For representative examples with 1,3-diene-ynes, see: (a) Wender,
P. A.; Jenkins, T. E. J. Am. Chem. Soc. 1989, 111, 6432–6434. (b)
Jolly, R. S.; Luedtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem.
Soc. 1990, 112, 4965–4966. (c) McKinstry, L.; Livinghouse, T.
Tetrahedron 1994, 50, 6145–6154. (d) Wender, P. A.; Smith, T. E. J.
Org. Chem. 1996, 61, 824–825. (e) Gilbertson, S. R.; Hoge, G. S.
Tetrahedron Lett. 1998, 39, 2075–2078. (f) Kumar, K.; Jolly, R. S.
Tetrahedron Lett. 1998, 3047–3048. (g) Motoda, D.; Kinoshita, H.;
Shinokubo, H.; Oshima, K. Angew. Chem., Int. Ed. 2004, 43, 1860–
1862. For intermolecular examples with 1,3-dienes and alkynes, see:
(h) Carbonaro, A.; Greco, A.; Dall’Asta, G. J. Org. Chem. 1968, 33,
3948–3950. (i) tom Dieck, H.; Diercks, R. Angew. Chem., Int. Ed.
Engl. 1983, 22, 778–779. (j) Paik, S.-J.; Son, S. U.; Chung, Y. K.
Org. Lett. 1999, 1, 2045–2047. (k) Hilt, G.; Hess, W.; Harms, K. Org.
Lett. 2006, 8, 3287–3290. For a related cycloaddition between
unactivated vinylallenes and alkynes, see: (l) Murakami, M.; Ubukata,
M.; Itami, K.; Ito, Y. Angew. Chem., Int. Ed. 1998, 37, 2248–2250.
For representative examples on Hetero-Diels-Alder reactions, respec-
tively, see: (m) Trost, B. M.; Brown, R. E.; Toste, F. D. J. Am. Chem.
Soc. 2000, 122, 5877–5878. (n) Koyama, I.; Kurahashi, T.; Matsubara,
S. J. Am. Chem. Soc. 2009, 131, 1350–1351.
† Universidade de Santiago de Compostela.
§ Instituto de Qu´ımica Orga´nica General.
‡ Universitat Auto`noma de Barcelona.
(1) Carruthers, W. Cycloaddition Reactions in Organic Synthesis; Per-
gamon: Oxford, 1990; pp 1-208.
(2) (a) Oppolzer, W. In ComprenhensiVe Organic Synthesis, Vol. 5; Trost,
B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon: Oxford, 1991;
pp 315-399. For reviews on applications of Diels-Alder reactions in
total synthesis, see: (b) Nicolaou, K. C.; Snyder, S. A.; Montagnon,
T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668–
1698. (c) Takao, K.; Munakata, R.; Tadano, K. Chem. ReV. 2005, 105,
4779–4807.
(4) (a) Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem. Soc. 1995,
117, 1843–1844. (b) Trost, B. M.; Fandrick, D. R.; Dinh, D. C. J. Am.
Chem. Soc. 2005, 127, 14186–14187. These type of [4C+2C]
cycloadditions were also observed as side-processes in Rh-catalyzed
dienyl Pauson-Khand reactions, see: (c) Wender, P. A.; Croatt, M. P.;
Deschamps, N. M. Angew. Chem., Int. Ed. 2006, 45, 2459–2462.
9
13020 J. AM. CHEM. SOC. 2009, 131, 13020–13030
10.1021/ja905415r CCC: $40.75  2009 American Chemical Society

Divergence between [4C+3C] and [4C+2C] Pathways
A R T I C L E S
On the other hand, the extraordinary growth of homogeneous
gold catalysis in recent years have resulted in new, entirely
different mechanistic scenarios for performing formal cycload-
dition reactions in unactivated, thermally unreactive substrates.6
In particular, carbophilic gold(I) complexes have been shown
to induce [4 + 2] annulations of several types of alkyne-
containing substrates.7 Common to these transformations are
the π-activation of the triple bond toward nucleophilic attack
and the participation of carbenoid gold intermediates.8,9
manner and with very high enantioselectivity. We also report
results of experimental and theoretical mechanistic studies which
do not support a reaction pathway involving stepwise cycliza-
tions through cationic intermediates but suggest an alternative
route comprising a [4C+3C] concerted cycloaddition and a
subsequent ring contraction in the resulting gold-carbene
intermediate. This mechanistic proposal is compatible with
experimental results and accounts for the observed [4C+3C]/
[4C+2C] dichotomy, however other alternatives cannot be fully
discarded.
We have recently reported that PtCl2 and N-heterocyclic
carbene-gold(I) complexes catalyze the intramolecular [4C(4π)+
3C(2π)] cycloadditions of allene-tethered 1,3-dienes.10 Experi-
mental and theoretical DFT studies agree with a mechanism
involving a π-activation of the allene moiety by the metal
catalyst to generate a metal-allyl cation intermediate, followed
by a concerted exo-like cycloaddition with the diene. A
subsequent 1,2-shift on the resulting cycloheptenyl metal-
carbene yields the final [4C+3C] adduct and regenerates the
catalyst. Overall, this method provides a straightforward and
atom economical entry to a variety of cycloheptene-containing
polycycles from readily available acyclic allenediene precursors.
Herein, we demonstrate that the same type of allenedienes, when
dialkylated at the distal position of the allene, undergo a mild
[4C+2C] intramolecular cycloaddition upon treatment with a
Au(I) complex featuring a phosphite ligand. The reaction is
chemo- and stereoselective, and provides synthetically relevant
trans-fused bicyclic cycloadducts (3) in good yields.11 Further-
more, we have prepared several novel chiral phosphoramidite-
based Au(I) complexes and demonstrate that some of them are
able to promote the reaction in a completely chemoselective
2. Results and Discussion
2.1. Au-Catalyzed [4C+2C] Cycloadditions of Allenedienes.
Scope and Limitations. This research aroused from the observa-
tion that the reaction of 1a in presence of catalyst A [(IPr)AuCl/
AgSbF6] (Table 1), in addition to providing the [4C+3C]
cycloadduct 2a, led to the [4C+2C] adduct 3a (3:1 ratio, Table
1, entry 1).10b,12 The [4C+2C] product must result from a Au-
catalyzed process, as the reaction does not proceed under thermal
conditions. The intriguing mechanistic reasons for the formation
of both adducts, together with the synthetic relevance of the
resulting trans-fused 5,6-bicycles, led us to further explore this
process and seek out other Au catalysts that could improve the
efficiency of the [4C+2C] cycloaddition. As can be deduced
from Table 1 (entries 1-4), lowering the donor ability of the
Table 1. Au-Catalyzed [4C+2C] vs [4C+3C] Cycloaddition of 1aa
(5) (a) Wender, P. A.; Love, J. A. In AdVances in Cycloaddition, Vol. 5.;
Harmata, M., Ed.; JAI Press: Greenwich, 1999; pp 1-45. (b) Lautens,
M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49–92. (c) Aubert, C.;
Buisine, O.; Malacria, M. Chem. ReV. 2002, 102, 813–834.
entry
[Au] (10 mol %)
2a:3a (ratio)b
yield (%)c
(6) For a recent review on Au-catalyzed cycloadditions, see: (a) Shen,
H. C. Tetrahedron 2008, 64, 7847–7870. For recent reviews on Au-
catalyzed reactions, see: (b) Li, Z.; Brouwer, C.; He, C. Chem. ReV.
2008, 108, 3239–3265. (c) Arcadi, A. Chem. ReV. 2008, 108, 3266–
3325. (d) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV. 2008,
108, 3351–3378. (e) Hashmi, A. S. K.; Rudolph, M. Chem. Soc. ReV.
2008, 37, 1766–1775. (f) Jimenez-Nun˜ez, E.; Echavarren, A. M. Chem.
ReV. 2008, 108, 3326–3350. (g) Patil, N. T.; Yamamoto, Y. Chem.
ReV. 2008, 108, 3395–3442. (h) Marion, N.; Nolan, S. P. Chem. Soc.
ReV. 2008, 37, 1776–1782.
1
2
3
4
A
C
3:1
1.4:1
1:1.9
1:2.5
1:10
1:7
66
78
71
78
55
75
72
Ph3PAuNTf2
Ph3PAuCl/AgSbF6
(PhO)3PAuCl/AgSbF6
5
6
B
B
7d
1:10
a [Au] (10 mol %) in CH2Cl2 (0.15 M) at rt for 3 h unless otherwise
noted. b Ratio determined by 1H NMR in the crude reaction mixtures.
c Isolated combined yields of 2a and 3a. d Carried out at 0 °C for 4 h.
(7) For different types of Au-catalyzed [4C+2C] cycloadditions and
annulations, see: (a) Nieto-Oberhuber, C.; Pe´rez-Gala´n, P.; Herrero-
Go´mez, E.; Lauterbach, T.; Rodr´ıguez, C.; Lo´pez, S.; Bour, C.;
Rosello´n, A.; Ca´rdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc.
2008, 130, 269–279. (b) Nieto-Oberhuber, C.; Lopez, S.; Echavarren,
A. M. J. Am. Chem. Soc. 2005, 127, 6178–6179. (c) Hashmi, A. S. K.;
Rudolph, M.; Weyrauch, J. P.; Wo¨lfle, M.; Frey, W.; Bats, J. W.
Angew. Chem., Int. Ed. 2005, 44, 2798–2801. (d) Fu¨rstner, A.; Stimson,
C. C. Angew. Chem., Int. Ed. 2007, 46, 8845–8849. (e) Zhang, G.;
Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc. 2008, 130, 1814–
1815. (f) Lemie`re, G.; Gandon, V.; Cariou, K.; Hours, A.; Fukuyama,
T.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc.
2009, 131, 2993–3006. (g) Barluenga, J.; Fernandez-Rodriguez, M. A.;
Garcia-Garcia, P.; Aguilar, E. J. Am. Chem. Soc. 2008, 130, 2764–
2765. (h) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto,
Y. J. Am. Chem. Soc. 2002, 124, 12650–12651.
ligand at gold enhances the proportion of the [4C+2C] adduct,
which becomes majoritary when PPh3 is used as ligand (entries
3 and 4). Comparison of entries 3 and 4 suggests that the nature
of the counterion also plays some role in the chemoselectivity
of the cycloaddition, presumably due to differences in coordi-
(8) (a) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395–403. (b) Furstner,
A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410–3449.
(9) For interesting discussions about the precise nature of some of these
gold carbene species and their possible consideration as gold-stabilized
carbocations, see: (a) Seidel, G.; Mynott, R.; Fu¨rstner, A. Angew.
Chem., Int. Ed. 2009, 48, 2510–2513. (b) Fu¨rstner, A.; Morency, L.
Angew. Chem., Int. Ed. 2008, 47, 5030–5033. For a highlight, see:
(c) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2008, 47, 6754–6756.
(10) (a) Trillo, B.; Lo´pez, F.; Gul´ıas, M.; Castedo, L.; Mascaren˜as, J. L.
Angew. Chem., Int. Ed. 2008, 47, 951–954. (b) Trillo, B.; Lo´pez, F.;
Montserrat, S.; Ujaque, G.; Castedo, L.; Lledo´s, A.; Mascaren˜as, J. L.
Chem.sEur. J. 2009, 15, 3336–3339.
(11) After initial submission of the first version of this manuscript, a paper
discussing ligand-dependent divergence between [4 + 3] and [4 + 2]
pathways was published by Toste et. al. See: Mauleo´n, P.; Zeldin,
R. M.; Gonza´lez, A. Z.; Toste, F. D. J. Am. Chem. Soc. 2009, 131,
6348–6349.
(12) The [4C+3C] cycloaddition of 1a can be achieved in good yields with
10 mol % of AuCl, AuCl3 or PtCl2. See also ref 10.
9
J. AM. CHEM. SOC. VOL. 131, NO. 36, 2009 13021

A R T I C L E S
Alonso et al.
Table 2. Gold-Catalyzed [4C+2C] Cycloadditions of Allenedienes 1a
a Conditions: (ArO)3AuCl (10 mol %) and AgSbF6 (10 mol %) in CH2Cl2 (0.15 M) at 0 °C for 1 h. b Ratio determined by 1H NMR in the crude
reaction mixtures. See ref 10 for data on the minor [4C+3C] adducts 2. c Isolated yields. d Five minutes at -15 °C. e Forty minutes at 0 °C. f Sixty
minutes at -40 °C g Thirty minutes at 0 °C, GC yield.
nating abilities. Gratifyingly, in presence of highly electrophilic
gold complexes featuring phosphite electron-acceptor ligands
(entries 5 and 6), the desired [4C+2C] cycloadduct was obtained
with high chemoselectivity and in a completely stereoselective
manner. In particular, the use of complex B [(ArO)3PAuCl/
AgSbF6],13 featuring a bulky phosphite ligand provided excellent
results in terms of yield and selectivity. The chemoselectivity
of the process could be further improved at 0 °C, without
significant deterioration of the rate or yield of the process (entry
7). Thus, either cycloaddition pathway ([4 + 2] or [4 + 3]) can
be suitably selected by just changing the Au catalyst, allowing
to obtain synthetically relevant 5,6- and 5,7-bicyclic systems
from the same allenediene substrates.
Once an optimal chemoselective protocol was established,
we analyzed the scope with respect to the allenediene. Gold
catalyst B turned to be also very effective with other allenedienes
disubstituted at the allene distal position (Table 2). Thus, the
[4C+2C] adducts 3b-f were obtained in good yields, with
complete trans selectivity and excellent chemoselectivity (Table
2, entries 1-6). Cycloadditions were typically carried out at 0
°C. However, it is worth to note that the cycloaddition of the
dimethyl-substituted allenediene derivatives 1c and 1d can be
carried out at -15 °C in just 5 min (entries 3 and 4), to give
the desired cycloadducts in excellent yields. On the other hand,
derivatives 1d-f provided exclusively the [4C+2C] adducts in
excellent yields (entries 4-6).
Elongation of the tethering chain was also tolerated (entry 7
and 8), providing for the assembly of trans-fused 6,6-bicyclic
systems in a completely stereoselective manner. Interestingly,
the [4 + 2] cycloaddition is particularly rapid with substrates
in which the diene is embedded in a furan ring, such as 1i (entry
8), which provides adduct 3i in 40% yield, at -40 °C.14 It is
also worth to note that the cycloadditions of allenedienes lacking
the geminal-diester moiety of the tether were equally effective,
as demonstrated by the cycloadditions of 1d, 1f and 1h, for
which the corresponding [4C+2C] adducts were obtained in
80-97% isolated yields. Confirmation of the structure and
relative stereochemical assignments was unambiguously ob-
tained by X-ray crystallographic analysis on [4C+2C] cycload-
ducts 3d, 3f, 3i, as well as on an immediate derivative of adduct
3g.14
The Au-catalyzed [4C+2C] cycloaddition requires that the
allene is disubstituted at the distal position, as it failed in the
cases of substrates 1j-k (entries 10 and 11). Nonsubstituted
allene 1j remains unchanged after treatment with catalyst B at
rt for several hours, whereas allenediene 1k, with just one
substituent at the distal position of the allene, generated a
complex mixture of products, being the [2C+2C] adduct 4k
the major and only identifiable component.15 Interestingly, the
rate of conversion of 1k into 4k is significantly lower than that
of the 1b into 3b, demonstrating that the degree of substitution
(13) Ar ) 2,4-di-tert-butylphenyl; For the pioneering use of this phosphite
gold complex, see: Lo´pez, S.; Herrero-Go´mez, E.; Pe´rez-Gala´n, P.;
Nieto-Oberhuber, C.; Echavarren, A. M. Angew 2006, 45, 6029–6032.
See also: (b) Gorin, D. J.; Watson, I. D. G.; Toste, F. D. J. Am. Chem.
Soc. 2008, 130, 3736.
(14) See the Supporting Information for more details.
(15) For related Au-catalyzed [2C+2C] cycloadditions of allene-tethered
alkenes (allenenes), see: (a) Luzung, M. R.; Mauleo´n, P.; Toste, F. D.
J. Am. Chem. Soc. 2007, 129, 12402–12403. See also: (b) Zhang, L.
J. Am. Chem. Soc. 2005, 127, 16804–16805.
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13022 J. AM. CHEM. SOC. VOL. 131, NO. 36, 2009

Divergence between [4C+3C] and [4C+2C] Pathways
A R T I C L E S
Table 3. Asymmetric Au(I)-Catalyzed [4C+2C] Cycloadditions and
Development of an Efficient Enantioselective Chiral Gold Catalysta
Figure 1. Bis(gold)-phosphine complexes employed in this study.
entry
[Au]
3a:2a (ratio)b
3a, ee (%)c
d
1
2
3
4
(R)-DTBM-Segphos(AuCl)2
(S)-BINAP(AuCl)2
D
(S)-E
1:1.7
1:1.2
3:1
8
1
-
2
in the allene moiety has a drastic influence in its reactivity
toward this gold(I) catalyst.16
d
2.2. Development of a Highly Enantioselective Variant
with New Phosphoramidite-Based Mononuclear Gold(I)
Catalysts. A New Paradigm for Asymmetric Gold Catalysis.
Despite the impressive increase of reports in recent years
documenting reactions catalyzed by homogeneous gold(I)
complexes,6 so far, only a handful of these transformations have
been rendered enantioselective.17 The preferred linear coordina-
tion geometry of gold(I), placing the attached ligand distant from
the reactive center, has been identified as the most important
obstacle to develop enantioselective processes with this metal.
This linear coordination mode also precludes asymmetric
strategies based on a bidentate coordination of chiral bisphos-
phines to the gold center, strategy particularly effective with
other transition metals, such as Pd, Ru, Rh or Ir.18 Consequently,
the development of enantioselective gold-catalyzed processes
represents a great challenge in current homogeneous catalysis.
The only example prior to 2005 was the Hayashi and Ito
enantioselective aldol reactions, in which a gold(I)-ferroce-
nylphosphine complex behaves as a traditional Lewis acid
catalyst, through carbonyl-group activation.19 More recently,
bis(gold)-phosphine complexes of the form [(AuX)2(P-P);
(P-P) ) chiral bisphosphine], such as DTBM-Segphos(AuCl)2
(Figure 1), have emerged as versatile chiral catalysts for the
development of certain enantioselective processes relying on
the activation of multiple-bonds toward addition of carbon- or
heteroatom-based nucleophiles.17,20 In particular, enantioselec-
tive cyclopropanation reactions and [2C+2C] cycloadditions of
6:1
5
6
7
8
(S,S)-F
3:1
4.5:1
3:1
4:1
7:1
4:1
8:1
14:1
8:1
8:1
4
20
4
(S,S,S)-G
(R,S,S)-G
(S,S)-H
(S,S,S)-I
(S,R,R)-I
(S,S,S)-I
(S,S,S)-I
(R,R,R)-J
(R,R,R)-K
(R,R,R)-K
22
52
14e
74
80
80e
84e
91e
9
10
11f,g
12h,i
13f, j
14k
15f, i
16:1
a [Au] (10 mol %) and AgSbF6 (10 mol %) in CH2Cl2 (0.15 M) for
1-3 h at room temperature unless otherwise noted. Conversions into
cycloadducts 3a and 2a > 99% (by 1H NMR in the crude mixtures)
b Determined by 1H NMR in the crude mixtures. c Enantiomeric excess
(ee) determined by HPLC (Chiralcel IA).14 d [Au] (5 mol %) and
AgSbF6 (10 mol %). e Major enantiomer is opposite to that obtained
with (S,S,S)-I catalyst, as deduced by chiral HPLC and optical rotation.
f Reaction carried out at -15 °C. g Pure 3a isolated in 78% yield after
column chromatography. h Reaction carried out at -30 °C. i 3a isolated
in 82% yield. j 3a isolated in 73% yield. k 3a isolated in 80% yield.
allenenes have been proven successful with these catalytic
systems.20e,15a On the basis of these precedents, the performance
of two of these catalysts, DTBM-Segphos(AuCl)2 and BINA-
P(AuCl)2 was initially tested for the model substrate 1a.
Unfortunately, these complexes containing moderately electron
donating bisphosphine ligands were poorly chemoselective,
providing mixtures of the [4C+3C] and [4C+2C] cycloadducts
2a and 3a (Table 3, entries 1 and 2). Moreover, the enantiose-
lectivity of the [4C+2C] cycloadduct was very low, suggesting
that the [4C+2C] process might involve a mechanism signifi-
cantly different than that of the [2C+2C] cycloadditions of
allenenes.15a On the basis of these results and considering the
apparent requirement of electron acceptor ligands at gold for
achieving selective [4C+2C] cycloadditions, we turned our
attention to chiral gold complexes containing such type of
ligands. In particular, the electronic resemblance between
arylphosphites and phosphoramidites suggested the possibility
of promoting these [4C+2C] cycloadditions with phosphora-
midite-gold complexes of the type [L*-AuCl; L* ) chiral
phosphoramidite], which could eventually introduce these highly
versatile and easily modulated chiral ligands into the realm of
asymmetric gold catalysis.21 Indeed, to the best of our knowl-
edge, these complexes have never been shown effective for any
type of gold catalyzed asymmetric reaction.22
(16) Reaction of 1b at-15 °C is almost completed in less than 10 min (>
95% conv.). At this temperature 1k requires 90 min to reach 50%
conversion.
(17) For a review highlighting the most recent enantioselective develop-
ments, see: (a) Widenhoefer, R. A. Chem.sEur. J. 2008, 14, 5382–
5391. See also: (b) Bongers, N.; Krause, N. Angew. Chem., Int. Ed.
2008, 47, 2178–2181.
(18) (a) Caprio, V.; Williams, J. M. J. Catalysis in Asymmetric Synthesis;
John Wiley and Sons: Chichester, 2009. (b) Christmann, M.; Bra¨se,
S. Asymmetric Synthesis: The Essentials; Wiley-VCH: Weinheim,
2007. (c) Jacobsen, E. N.; Pflatz, A.; Yamamoto, H. ComprehensiVe
Asymmetric Catalysis I-III; Springer-Verlag: Berlin, Germany, 1999.
(d) Bo¨rner, A. Phosphorus Ligands in Asymmetric Catalysis: Synthesis
and Applications; Wiley-VCH: Wenheim, 2008.
(19) (a) Sawamura, M.; Ito, Y. In Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; VCH Publishers: New York, 1993; p 367. (b) Ito, Y.;
Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405–6406.
(c) Hayashi, T.; Sawamura, M.; Ito, Y. Tetrahedron 1992, 48, 1999–
2012.
(20) For the first application of bis(gold)complexes in enantioselective
catalysis, see: (a) Paz Mun˜oz, M.; Adrio, J.; Carretero, J. C.;
Echavarren, A. M. Organometallics 2005, 24, 1293–1300. For other
representative examples, see: (b) Gonza´lez-Arellano, C.; Corma, A.;
Iglesias, M.; Sanchez, F. Chem. Commun. 2005, 3451–3453. (c) Zhang,
Z.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2007, 46, 283–285.
(d) Tarselli, M. A.; Chianese, A. R.; Lee, S. L.; Gagne´, M. R. Angew.
Chem., Int. Ed. 2007, 46, 6670–6673. (e) Johansson, M. J.; Gorin,
D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002–
18003. (f) Watson, I. D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc.
2009, 131, 2056–2057. (g) See also ref 15a.
The feasibility of performing the [4C+2C] cycloaddition with
a phosphoramidite-based Au catalyst was initially tested with
(21) For representative reviews on the use of phosphoramidite ligands in
other transition metal catalyzed asymmetric processes, see: Cu:(a)
Feringa, B. L Acc. Chem. Res. 2000, 33, 346–353. Rh and Ir: (b)
Minnaard, A. J.; Feringa, B. L.; Lefort, L.; De Vries, J. G. Acc. Chem.
Res. 2007, 40, 1267–1277.
9
J. AM. CHEM. SOC. VOL. 131, NO. 36, 2009 13023

A R T I C L E S
Alonso et al.
Figure 2. New chiral phosphoramidite-based gold(I) complexes.
the achiral complex D (Figure 2), in combination with AgSbF6.23
Gratifyingly, treatment of 1a with D/AgSbF6 (10 mol %) in
CH2Cl2 at room temperature provided, after 1 h, full conversion
to cycloadducts 3a and 2a, which were isolated in a good 3:1
ratio (Table 3, entry 3). Use of phosphoramidite complexes (S)-E
or (S,S)-F, incorporating chiral groups either at the diol or amine
unit, did not allow to obtain significant enantioselectivities
(entries 4 and 5), but importantly, the chemoselectivity and rate
of the process were not affected. Notably, a modest enantiose-
lectivity could be obtained with complex (S,S,S)-G, which
incorporates both elements of chirality, the bis(1-phenylethy-
l)amine moiety and the chiral binaphthol skeleton (entry 6).
Analysis of results of entries 6 and 7 clearly shows that complex
(S,S,S)-G corresponds to the match situation (20% ee), whereas
its diastereoisomer (R,S,S)-G is a mismatched catalyst, as it
provided 3a with only 4% ee and also with lower chemoselec-
tivity. At this point, we reasoned that introduction of bulky
substituents at the 3 and 3′ position of the biphenol or binaphthol
units of (S,S)-F or (S,S,S)-G could positively influence the
enantioselectivity of the process, since it could reduce the
flexibility around the Au center, while bringing closer the chiral
information to the new carbon stereocenters. Indeed, reaction
with (S,S)-H, which incorporates two phenyl substituents at the
3 and 3′ positions of the biphenyl unit (entry 8), provided 3a in
a somewhat higher ee than its unsubstituted analog (S,S)-F
(increment of 18% ee). More importantly, gold-complex (S,S,S)-
I, which incorporates the phenyl substituents at the 3 and 3′
positions of the binaphthyl moiety, afforded the [4C+2C]
cycloadduct 3a with good chemoselectivity and 52% ee (32%
higher than that obtained with (S,S,S)-G, entries 6 and 9).24 In
analogy to the results with complexes of type G (entries 6 and
7), the diastereoisomeric gold complex (S,R,R)-I corresponded
to a mismatched situation, providing the cycloadduct 3a with
significantly lower selectivity than (S,S,S)-I (entry 10). More-
over, the major enantiomer obtained with (S,R,R)-I turned out
to be the opposite to that obtained with (S,S,S)-I, indicating that
the chirality of the bis(phenylethyl)amine dictates the absolute
stereochemistry of the [4C+2C] cycloadduct. Gratifyingly,
further optimization of the chemo- and enantioselectivity of the
process could be achieved with complex (S,S,S)-I, just by
lowering the temperature of the reaction (entries 11-12). Thus,
the cycloaddition of 1a could be efficiently performed at -15
°C and even at -30 °C, providing the [4C+2C] cycloadduct
3a in 82% yield and with 80% ee. These results clearly validate
the strategy and suggested that further improvement on the
enantioselectivity might be feasible by fine-tuning of substituents
at 3 and 3′ positions. Thus, novel bulky phosphoramite ligands
with 1-naphthyl and 9-anthracenyl substituents were synthesized
and transformed into their corresponding chiral gold complexes,
(R,R,R)-J and (R,R,R)-K (Figure 2). As expected, the major
enantiomer obtained with these complexes turned out to be
opposite to that obtained from (S,S,S)-I. Naphthyl-derived
complex (R,R,R)-J provided, at -15 °C, the cycloadduct 3a
with 80% ee (entry 13), a value somewhat superior to that
achieved at that temperature with the enantiomeric homologue
(S,S,S)-I (entry 11). However, the 9-anthracenyl-derived analog
(R,R,R)-K was much more effective, providing excellent yields
of 3a and enantioselectivities ranging from 84% at room
temperature, to 91% at -15 °C (entries 14 and 15). Not less
remarkable, the chemoselectivity of the process was also very
high in favor of the [4C+2C] adduct 3a.
With these results in hand, the performance of complexes
(S,S,S)-I and (R,R,R)-K was next evaluated on other allene-
dienes. As can be deduced from Table 4, the cationic gold
complex generated from (R,R,R)-K and AgSbF6 turned out to
be an excellent catalyst for these [4C+2C] cycloadditions
providing, in every case, higher enantioselectivities than those
obtained with its homologue (S,S,S)-I/AgSbF6. Indeed, catalyst
(R,R,R)-K/AgSbF6 afforded the corresponding cycloadducts with
high to very high enantioselectivities (entries 5-8), whereas
yields, chemo- and stereoselectivities are fully comparable to
those previously obtained with racemic catalyst B. Thus,
cycloadditions of allenedienes 1d, 1f and 1h were completely
chemoselective at -15 °C, whereas 1a provided a high
chemoselectivity. On the other hand, the enantioselectivities
(24) The introduction of substituents at the 3 and 3′ positions of the
binaphthol or biphenol skeletons of phosphoramidites has been proven
successful in other transition metal catalyzed asymmetric processes
which make use of these ligands. For representative examples, see:
(a) Giacomina, F.; Meetsma, A.; Panella, L.; Lefort, L.; de Vries,
A. H. M.; de Vries, J. G. Angew. Chem., Int. Ed. 2007, 46, 1497–
1500. (b) Hua, Z.; Vassar, V. C.; Choi, H.; Ojima, I. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5411–5416. Phosphoramidite ligand precursor
of complex (S,R,R)-I has been proven successful in Pd-catalyzed
enantioselective hydrogenolysis of arene tricarbonyl chromium(0)
complexes, see: (c) Ku¨ndig, E. P.; Chaudhuri, P. D.; House, D.;
Bernardinelli, G. Angew. Chem., Int. Ed. 2006, 45, 1092–1095. For
beneficial effects of 3,3′-diaryl substitution on BINOL-phosphoric
acids, employed as chiral Bronsted acid catalysts in several asymmetric
processes, see: (d) Terada, M. Chem. Commun. 2008, 4097–4112, and
references therein.
(22) A chiral phosphoramidite gold catalyst has been described in ref 20a
and evaluated in alkoxycyclization reactions of 1,6-enynes, but
provided racemic products (less than 2% ee).
(23) Phosphoramidite gold complexes were prepared following procedures
similar to those described in: (a) Alder, M. J.; Flower, K. R.; Pritchard,
R. G. J. Organomet. Chem. 2001, 629, 153–159. (b) See also ref 20a.
9
13024 J. AM. CHEM. SOC. VOL. 131, NO. 36, 2009

Divergence between [4C+3C] and [4C+2C] Pathways
A R T I C L E S
Table 4. Enantioselective Au(I)-Catalyzed Allenediene [4C+2C]
Cycloadditions with (S,S,S)-I and (R,R,R)-Ka
3:2b
yieldc
3
ee, %d e
,
entry
1
L*-AuCl
temp. (°C)
1
2
3
4
5
6
7
1a (S,S,S)-I
1d (S,S,S)-I
-30
-15
-15
-15
-15
-15
-15
-15
-15
-15
14:1 82% 3a
1:0 84% 3d
1:0 70% 3f
1:0 55% 3h
16:1 82% 3a
1:0 93% 3d
1:0 88% 3f
1:0 90% 3h
1:0 87% 3a
1:0 92% 3d
80
76
86
52
91
92
97
91
92
92
(-)
(-)
(-)
(-)
(+)
(+)
(+)
(+)
(+)
(+)
1f
(S,S,S)-I
1h (S,S,S)-I
1a (R,R,R)-K
1d (R,R,R)-K
1f
(R,R,R)-K
Figure 3. X-ray crystallographic structure of (3aR,7aS)-3d, obtained as
major enantiomer in the cycloaddition of 1d with (S,S,S)-I/AgSbF6 (Table
4, entry 2). Flack parameter ) 0.00(8).
8
1h (R,R,R)-K
1a (R,R,R)-K
1d (R,R,R)-K
9f
10f
enantiomeric excess of the major [4C+2C] cycloadduct 3a was
virtually identical ((1-2%) to that of the minor [4C+3C]
products 2a regardless of the phosphoramidite gold catalyst
(Table 5, entries 1-11) and temperature (entries 7-9) employed.
Moreover, entirely different gold-complexes, such as DTBM-
Segphos(AuCl)2 also provided the same ee values for both
[4C+3C] and [4C+2C] adducts (entry 12). These results highly
suggest that both cycloadditions share the same enantiodeter-
mining step, with the resulting common intermediate evolving
to either the six or the seven-membered carbocycle.
The aforementioned result could be a priori compatible with
an hypothetical stepwise mechanism involving a common
carbocationic intermediate such as II (Scheme 1). Indeed, vinyl
metal species related to II have been previously postulated as
intermediates in gold and platinum catalyzed [2 + 2] and [3 +
2] cycloadditions of allenenes.15,29 After the initial enantio- and
diastereoselective cyclization to give II, an intramolecular attack
from the R, or ꢀ carbon of the vinyl-gold species to the less
substituted position of the generated allyl cation (6-endo Vs
7-endo cyclization of II), would respectively lead to the
formation of the [4C+2C] or [4C+3C] cycloadduct. Alterna-
tively, a cis-trans isomerization of II, followed by a 4-exo
cyclization on its cis-fused isomer (cis-II) would account for
the formation of a [2C+2C] adduct.15a
a L*-AuCl [(S,S,S)-I or (R,R,R)-K] (10 mol %) and AgSbF6 (10 mol
%) in CH2Cl2 (0.15 M) for 1-3 h, unless otherwise noted. b Determined
by 1H NMR in the crude mixtures. c Isolated yields of pure 3.
d Enantiomeric excess (ee) determined by HPLC (Chiralcel IA).14
e Optical rotation sign under parentheses.14 f Reaction carried out with 2
mol % of (R,R,R)-K and AgSbF6.
varied from 91% (entries 5 and 8) to a maximum value of 97%,
observed for the cycloaddition of allenediene 1f (entry 7).25
Particularly relevant are the results with allenediene 1h, cy-
cloaddition which provides an enantioselective entry to relevant
trans-fused 6,6-bicyclic systems. Treatment of this allenediene
with catalyst (S,S,S)-I/AgSbF6 (10 mol %) afforded the corre-
sponding adduct (3h) in a moderate 52% ee, whereas (R,R,R)-
K/ AgSbF6 provided 3h in 90% yield and 91% ee (entries 4
and 8). No less significant, the catalyst loading could be
significantly reduced without affecting the selectivity of the
reaction. Thus, with only 2 mol % of catalyst, the cycloaddition
of 1a or 1d provided, after 3 h at -15 °C, the desired
cycloadducts in excellent yields and 92% ee (entry 9 and 10).
To the best of our knowledge, the above cycloadditions represent
the first examples of an efficient asymmetric process catalyzed
by a mononuclear phosphorus-based carbophilic Au complex.
Furthermore, this methodology constitutes one of the very few
transition metal catalyzed enantioselective [4C+2C] cycload-
ditions of nonactivated substrates and the first of this type
leading to 6,6-trans-fused bicyclic systems.26,27
(27) Only very recently, chiral phosphoramidites have been shown effective
in other transition metal catalyzed asymmetric cycloadditions with Rh,
Pd or Co catalysts. For representative cases with Pd, see: (a) Shintani,
R.; Park, S.; Shirozu, F.; Murakami, M.; Hayashi, T. J. Am. Chem.
Soc. 2008, 130, 16174–16175. (b) Shintani, R.; Park, S.; Duan, W. L.;
Hayashi, T. Angew. Chem., Int. Ed. 2007, 46, 5901–5903. (c) Shintani,
R.; Murakami, M.; Hayashi, T. J. Am. Chem. Soc. 2007, 129, 12356–
12357. (d) Trost, B. M.; McDougall, P. J.; Hartmann, O.; Wathen,
P. T. J. Am. Chem. Soc. 2008, 130, 14960–14961. (e) Trost, B. M.;
Cramer, N.; Silverman, S. M. J. Am. Chem. Soc. 2007, 129, 12398–
12399. (f) Trost, B. M.; Stambuli, J. P.; Silverman, S. M.; Schworer,
U. J. Am. Chem. Soc. 2006, 128, 13328–13329, For Rh, see. (g) Yu,
R. T.; Lee, E. E.; Malik, G.; Rovis, T. Angew. Chem. Int. Chem. 2009,
48, 2379–2382, and references therein. For Co, see: (h) Toselli, N.;
Martin, D.; Achard, M.; Tenaglia, A.; Burgi, T.; Buono, G. AdV. Synth.
Catal. 2008, 350, 280–286.
Finally, the absolute configuration of cycloadduct 3d, pre-
pared with (S,S,S)-I/AgSbF6 (entry 2, 76% ee), was unambigu-
ously determined to be (3aR,7aS) by X-ray crystallographic
analysis, after recrystallization from a mixture of Et2O/hexanes
(Figure 3).28
2.3. Mechanistic Experimental Studies. Key mechanistic
information can be deduced from the observation that the
(25) Decreasing the reaction temperature to-30 °C did not bring any
significant improvement on the enantioselectivity of cycloadditions
with substrates 1d, 1f, or 1h, neither with catalyst (S,S,S)-I or (R,R,R)-
K.
(26) Previously reported examples deal with alkyne-tethered 1,3-dienes.
For instance, see: (a) Shintani, R.; Sannohe, Y.; Tsuji, T.; Hayashi,
T. Angew. Chem., Int. Ed. 2007, 46, 7277–7280. (b) Aikawa, K.;
Akutagawa, S.; Mikami, K. J. Am. Chem. Soc. 2006, 128, 12648–
12649, and references therein. (c) Gilbertson, S. T.; Hoge, G. S.;
Genov, D. G. J. Org. Chem. 1998, 63, 10077–10080, and references
therein.
(28) Comparison of optical rotations and chiral HPLC analysis allow to
propose the same absolute configuration for the remaining [4C+2C]
adducts obtained with (S,S,S)-I. Catalyst (R,R,R)-K provided, in every
case, opposite absolute configuration than (S,S,S)-I.
(29) For a Pt-catalyzed [3C+2C] cycloaddition of allenenes: (a) Zhang,
G.; Catalano, V. J.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 11358–
11359. (b) For two examples on Au-catalyzed [3C+2C] cycloadditions,
see also ref 11.
9
J. AM. CHEM. SOC. VOL. 131, NO. 36, 2009 13025

A R T I C L E S
Alonso et al.
Scheme 2. Gold-Catalyzed Cycloaddition Reactions of cis-1d
Table 5. Comparison of the enantioselectivities of 2a and 3a,
isolated from the reaction of 1a using different Au catalysts.a
temp.
(°C)
entry
L*AuCl
3a:2ab
3a, erc
2a, erc
of the acyclic hydroalkoxylated products 5d and its regioisomer
6d (ratio 5d:6d ) 85:15, entry 3), while no traces of trapping
products derive from II could be detected. Similar results were
obtained from allenediene 1a.31
1
2
3
4
5
6
7
8
9
(S)-E
(S,S)-F
23
23
6:1
3:1
51:49 50.5:49.5
52:48
60:40
52:48
61:39
57:43
76:24
87:13
90:10
90:10
95.5:4.5
54:46
52:48
59:41
53:47
61:39
56:44
76:24
87:13
90:10
91:9
(S,S,S)-G
(R,S,S)-G
(S,S)-H
(S,R,R)-I
(S,S,S)-I
(S,S,S)-I
(S,S,S)-I
23 4.5:1
23
23
23
23
-15
-30 14:1
-15
-15 16:1
23 1:1.7
According to the hypothesis of Scheme 1, it might be
expected that an isomer of 1 bearing an internal cis alkene (cis-
1) would lead to similar results to those obtained from the trans
isomer 1. However, treatment of cis-1d with catalyst B afforded,
after 8 h at rt, a 3.5: 1 mixture of the [2C+2C] and [4C+2C]
adducts 4d and 3d, in 46% yield (Scheme 2). The acute
differences in the outcomes of cycloadditions of 1d (trans) and
cis-1d seem to ruled out the possibility that [4C+2C] and
[4C+3C] cycloadditions of 1d (trans), promoted by catalyst
B, occur via a cationic cascade involving the intermediate
formation of II.32 Moreover, cis-1d remained unchanged after
several hours of treatment with PtCl2 (110 °C) or catalyst A
(rt), a result that sharply contrasts with that obtained from trans-
1d, which provides the [4C+3C] cycloaddition using PtCl2 (10
mol %), and a mixture of [4C+3C] and [4C+2C] adducts upon
reaction with catalyst A [(IPr)AuCl/AgSbF6, 10 mol %).14 This
lack of reactivity of the cis precursor with these two catalysts
further suggests that they do not promote the cationic cascade
depicted in Scheme 1, and that the [4C+2C] adducts might be
formed through an alternative mechanism.
3:1
4:1
4:1
7:1
8:1
10 (R,R,R)-J
11 (R,R,R)-K
8:1
96:4
54:46
12d (R)-DTBM-Segphos (AuCl)2
a Conditions: 1a (1 equiv), L*-AuCl (10 mol %) and AgSbF6 (10 mol
%) in CH2Cl2 (0.15 M) for 1-3 h unless otherwise noted. Conversions
>99%. b Determined by 1H NMR in the crude mixtures. c er
)
enantiomeric ratio (HPLC).14 d (R)-DTBM-Segphos (AuCl)2 (5 mol %)
and AgSbF6 (10 mol %) was used.
Scheme 1. Hypothetical Stepwise Mechanism Involving
Carbocationic Intermediate II
2.4. DFT Studies. Several hypothetical reaction pathways for
the formation of the [4C+2C] adducts were evaluated by means
of DFT calculations on the model dimethylallenediene 1b′
(Scheme 3), using [(MeO)3PAu]+ as catalyst system. The
validity of [(MeO)3PAu]+ as model catalyst for the theoretical
study of the [4C+2C] process was confirmed by experimentally
running the cycloaddition reaction of 1a in the presence of
(EtO)3PAuCl/AgSbF6, instead of the phosphite or phosphora-
midite complexes previously shown. The reaction took place
with comparable rates and provided a mixture of 3a and 2a in
a 5:1 ratio and a 95% combined yield. Analogously, the
cycloaddition of 1c with this catalyst provided a 10 to 1 mixture
of 3c and 2c in 82% combined yield.
Table 6. Gold-Catalyzed Cycloadditions of 1c in the Presence of
MeOHa
entry
solvent
MeOH
3d:5d:6db
1
2
3
CH2Cl2
MeNO2
MeOH
3 equiv
3 equiv
solvent
100:0:0
85:15:0
0:85:15
The cationic stepwise pathway represented in Scheme 1,
involving the formation of cationic species II, was initially
analyzed. However, in spite of an intensive exploration of the
potential energy surface, not such or related species could be
located.33 This exploration also revealed that the initial activation
of the allene by the phosphite gold catalyst triggers a concerted
[4C+3C] cycloaddition with the diene, process which occurs
a Conditions: 1d (1 equiv, 0.15 M), B (10 mol %) and AgSbF6 (10
mol %) for 1-3 h. Conversions >99%. Ratios determined by H NMR
in the crude mixtures.
b
1
To corroborate or discard this hypothesis, we carried out
several experiments in the presence of different amounts of
MeOH, aiming at intercepting the allyl cation present in species
II. However, reactions of allenediene 1d in CH2Cl2, in presence
of complex B and 3 equiv of MeOH as trapping agent, provided
only the [4C+2C] cycloadduct 3d (Table 6, entry 1). Using a
more polar solvent such as MeNO2, the reaction provided a 8.5:
1.5 mixture of the [4C+2C] adducts 3d and the acyclic
compound 5d (entry 2). This new product (5d) is the result of
a hydroalkoxylation reaction of the allene, a type of process
that has recently been shown to be efficiently promoted by
related gold(I) catalysts.30 Increasing the amount of MeOH did
not afford any relevant product that could validate the cationic
annulation pathway depicted in Scheme 1. Indeed, when MeOH
was employed as solvent, the reaction led to the sole formation
(30) (a) Zhang, Z.; Widenhoefer, R. A. Org. Lett. 2008, 10, 2079–2081.
For intramolecular versions, see: (b) Zhang, Z.; Liu, C.; Kinder, R. E.;
Han, X.; Qian, H.; Widenhoefer, R. A. J. Am. Chem. Soc. 2006, 128,
9066–9073, and references therein.
(31) Reaction of allenediene 1a with catalyst B (10 mol %), in the presence
of 3 equiv of MeOH, provided the same ratio of [4C+3C] and
[4C+2C] products as obtained in the absence of MeOH (2a:3a ratio
) 1:10).
(32) In consonance with this proposal, Toste et. al. reported that a related
allenediene selectively mono deuterated at the terminal position of
the diene provided a stereoselective [4C+2C] cycloaddition, making
very unlikely a cationic pathway involving species such as II (see ref
11).
9
13026 J. AM. CHEM. SOC. VOL. 131, NO. 36, 2009

Divergence between [4C+3C] and [4C+2C] Pathways
A R T I C L E S
Scheme 3. Mechanistic Proposal for a [4C+2C] Process Resulting from an Initial [4C+3C] Cycloaddition and a Subsequent Ring
Contraction (Blue Arrow)
with an extremely low energy barrier. This fact together with
the experimental information indicating that both [4C+2C] and
[4C+3C] cycloadditions are stereospecific processes sharing a
common stereo and enantio-determining step, led as to consider
a mechanistic scenario in which the [4C+2C] cycloadduct could
be eventually generated after an initial concerted [4C+3C]
cycloaddition of the allenediene leading to Au-carbene IV
(Scheme 3). Indeed, the DFT calculations revealed that the
[4C+2C] adduct 3b′ might result from an internal 1,2-alkyl
migration (ring contraction) on the cycloheptenyl carbene
intermediate IV, itself arising from the concerted [4C+3C]
cycloaddition of III (Scheme 3).
types of adducts in the cycloaddition of allenedienes 1b and 1c
catalyzed by complex B (Table 2, entries 1-3) or (EtO)3PAuCl/
AgSbF6. Furthermore, it is in total agreement with the asym-
metric results with phosphoramidite gold catalysts, since both
[4C+3C] and [4C+2C] pathways are sharing the same stereo-
andenantio-determiningstep,aconcertedexo-like[4C(4π)+3C(2π)]
cycloaddition between the diene and the Au-allyl cation (from
III to IV). The chemoselective differentiation takes place in a
posterior step (from IV to V/VI).34 Finally, it is also consistent
with the requirement of a trans-diene to achieve an efficient
[4C+2C] cycloaddition, since it is mandatory for the initial
[4C+3C] concerted cycloaddition leading to IV.35
The reaction mechanism for the Au-catalyzed [4C+3C]
cycloaddition of allenedienes leading to products of type 2
through the intermediacy of cycloheptenyl carbene IV was
recently described employing AuCl, AuCl3 and [(NHC)Au]+
as model gold catalysts.10b A DFT analysis of the mechanism
using [(MeO)3PAu]+ as catalyst gives similar reaction pathways
to those previously found for the former Au catalysts. The set
of steps describing the mechanism involves initial catalyst
coordination to the allene (I), generation of the metal-allyl
intermediate (III), and [4C+3C] concerted cycloaddition pro-
viding the cycloheptene structure (IV). At this point, this
intermediate might evolve by means of an standard 1,2-H-shift
giving rise to the final [4C+3C] cycloaddition product 2b′.
However, DFT calculations also confirm the viability of a
different scenario in which the same intermediate (IV) can
evolve by means of an internal 1,2-alkyl migration (ring
contraction), giving rise to the [4C+2C] cycloaddition product
3b′ (Scheme 3, Figure 4). Such mechanistic divergence from
intermediate IV is in full agreement with the formation of both
The overall energy profiles for the mechanism, including the
divergence from intermediate IV, are shown in Figure 4. The
two initial steps are common for both pathways. They start with
the initial coordination of the allene to the metal center, I
(selected as energy reference). This species evolves to the
formation of a Au-allyl cation intermediate, III, through an
energy barrier of 4.2 kcal/mol (ts1). The energy of III is 0.2
kcal/mol compared to I. This precursor easily gives rise to a
7-membered ring intermediate IV through a concerted cycload-
dition (ts2) with a small relative energy barrier of 2.5 kcal/
mol. The structure of this transition step is depicted in Figure
5. Interestingly, the formation of the two σ-bonds in this step
is much more asynchronous than with any of the other gold
catalyst previously investigated in [4C+3C] allenediene
cycloadditions.10b Cycloheptene-gold species IV is the most
stable intermediate within the reaction profile with a relative
energy of -12.1 kcal/mol. IV can evolve in two ways: by a
1,2-hydrogen shift to V (ts3) or by a 1,2-alkyl migration (ring
contraction, ts3′) to VI. Each of the products is obtained with
Figure 4. DFT profile for the cycloaddition of a model substrate 1b′ with [(MeO)3PAu]+.
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A R T I C L E S
Alonso et al.
Figure 5. DFT calculated structures for concerted cycloaddition (ts2), the 1,2-H shift (ts3) and ring contraction (ts3′) transition states, leading to the
corresponding [4C+3C] and [4C+2C] cycloadducts V and VI.
Table 7. Calculated Energy Barriers for Competitive Migration
the new formed C-C double bond coordinated to the Au metal
Steps with Subtrate 1b′ (kcal/mol)
center. The energy barriers for these two competitive pathways
are 10.3 and 8.7 kcal/mol, respectively.36 These data are
1,2-H migration barrier 1,2-alkyl migration barrier
(Ets3 - EIV)
entry
catalyst
∆E
(Ets3′ - EIV)
reasonably consistent with the experimental results which
indicate that the energy barrier associated to each of the routes
must not be too different since both products are observed,
although the formation of the [4C+2C] adduct is slightly
favored. The transition states corresponding to the 1,2-H shift
(ts3) and 1,2-ring contraction (ts3′), respectively leading to the
[4C+3C] and [4C+2C] cycloadducts V and VI, are depicted
in Figure 5.
We also analyzed these pathways with other Au complexes
such as [(PH3)Au]+, as a model for Ph3PAuCl/AgSbF6, [(NH-
C)Au]+, as a model for catalyst A,10b and AuCl. As can be
deduced from the energetic data of Table 7 the difference in
energy barriers between the 1,2-H migration and the 1,2-ring
contraction is not high, confirming that both pathways are
competitive. It can be observed that the more electron acceptor
is the ligand at gold the more favored is the internal 1,2-alkyl
migration that leads to the [4C+2C] adduct, a result in
1
2
3
4
[(MeO)3PAu]+
[(PH3)Au]+
AuCl
10.3
8.1
14.6
8.7
8.7
8.5
17.7
10.8
-1.6
0.4
3.1
[(NHC)Au]+
2.1
agreement with experimental observations. Thus, the highest
energy barrier difference (Ets3′ - Ets3) in favor of the [4C+2C]
adduct is found for [(MeO)3PAu]+ catalyst. [H3PAu]+ afforded
similar barriers for both processes (0.4 kcal/mol difference),
whereas the highest difference in favor of the [4C+3C]
cycloadduct corresponds to AuCl and [(NHC)Au)]+, catalysts
that have been successful used for this type of cycloadditions.10b
The calculations with AuCl gave rise to a energy barrier
difference (Ets3 - Ets3′) slightly superior to 3 kcal/mol (entry
3), whereas for the cationic catalyst [(NHC)Au]+ the difference
is of 2.1 kcal/mol, again favoring the formation of the [4C+3C]
adduct (entry 4). The higher reactivity experimentally observed
with [(NHC)Au]+, as compared to AuCl, is reflected in the lower
energy barrier associated to the transformation of IV into V
(8.7 vs 14.6 kcal/mol, entries 3 and 4), a step that has been
postulated as rate determining for the [4C+3C] cycloadditions.
The precise reasons why an electron acceptor ligand at gold
might favor the 1,2-ring contraction, whereas an electron
donating one preferentially promotes the 1,2-H shift, are not
easy to identify. Steric reasons depending on the ligand structure
might not be critical, since different gold catalysts with more
or less sterically demanding acceptor ligands provided similar
results (i.e., (EtO)3PAuCl/AgSbF6 vs catalyst B). It is plausible,
however, that the electronic factors such as the interaction
between the new double bond being generated at ts3 or ts3′
(33) A cationic structure keeping frozen the C-C distance of the new
formed C-C bond (forming the 5-membered ring) resembling the
structure of II was optimized. Nonetheless, when performing a full
geometry optimization starting from this forced structure, it always
evolved to initial reactants breaking the C-C bond, therefore
suggesting that this is not a stable species.
(34) An alternative 1,2-methyl shift on intermediate IV might also be
proposed and would lead to a [4C+3C] cycloadduct of type 2b′′ (see
equation below). However, this cycloadduct was never observed in
the cycloaddition of 1b. This type of 1,2-alkyl migration was only
observed when the allene has a cyclic substituent at the distal position,
such as in 1a. Apparently, the release of strain associated with the
1,2-alkyl shift allows to overcome the preference of a 1,2-H shift.
For reviews on migratory aptitudes of different substituents on metal
carbenes, see: (a) Crone, B.; Kirsch, S. F. Chem.sEur. J. 2008, 14,
3514–3522. (b) Nickon, A. Acc. Chem. Res. 1993, 26, 84–89. (c) Liu,
M. T. H. Acc. Chem. Res. 1994, 27, 287-294]
(36) The 1,2-H shift leading to V is actually a two step process: the first
one with a 8.6 kcal/mol activation barrier corresponds to an axial-to-
ecuatorial conformational change on the seven-membered ring to obtain
the appropriate parallel disposition of the orbitals implicated in the
subsequent 1,2-H shift; this intermediate, IV′, lies 8.1 kcal/mol over
IV. The second step is the 1,2-H shift properly speaking with an
activation barrier of 2.2 kcal/mol. The energy barrier for the
transformation of IV′ to IV is so small (0.5 kcal/mol), that in practice,
the evolution from intermediate IV to the product V can be considered
taking place in a single step. Thus, for clarity reasons, we depicted
this process in Figure 4 as a single step with the overall barrier of
10.3 kcal mol. For a complete description of this process, see the
Supporting Information.
(35) The minor formation of the [4C+2C] adduct 3d from cis-1d (vide
supra), might be explained by a partial Z/E-isomerization (see ref 15a).
Alternatively, cationic stepwise mechanisms operating from cis-1d
cannot be fully discarded. For instance, see: Gassman, P. G.; Singleton,
D. A. J. Org. Chem. 1984, 106, 6085–6086.
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Divergence between [4C+3C] and [4C+2C] Pathways
A R T I C L E S
is the ligand the more favored is the formation of the [4C+2C]
product. However, other mechanisms cannot yet be fully
discarded.
3. Conclusions and Outlook
In summary, we report a new Au-catalyzed [4C+2C] cy-
cloaddition of allenedienes, along with a highly asymmetric
variant promoted by novel phosphoramidite-gold catalysts.
Indeed, these reactions represent the first processes in which a
gold complex derived from a phosphoramidite or any other type
of monodentate ligand acts as an efficient carbophilic chiral
catalyst. We have also reported mechanistic studies suggesting
that the divergence between [4C+2C] and [4C+3C] paths might
arise from relative 1,2-migration tendencies in a common
cycloheptentyl Au-carbene intermediate. Current efforts are
focused to further mechanistic studies, synthetic applications
and the use of these new phosphoramidite complexes to other
Au-catalyzed transformations.
4. Experimental Section
Figure 6. Cycloaddition of model substrate 1j′: energy profile involving
the 1,2-alkyl migration (ts3′)and 1,2-H migration (ts3).
Computational Details. Calculations were performed with the
Gaussian03 program package37 at density functional theory (DFT)
level by means of the hybrid B3LYP functional.38 For geometry
optimization, the main group elements (C, Cl, O, N, P, H) were
described using the 6-31G(d) basis set (labeled as basis set I). The
Au metal center was described by the LANL2DZ effective core
potential39 and its associated basis set for the outermost electrons.
An extra series of f-polarization functions were also added for Au
atom (Au: exp. ) 1.050).40 Moreover, additional single point
calculations using the 6-311++G(d,p) basis set for all the main
group elements were also performed (basis set II), including solvent
effects by means of the CPCM method (CH2Cl2; ꢀ ) 8.93) (see
Supporting Information).
The geometries of the reactants, intermediates, transition states,
and products were fully optimized without any symmetry restriction.
Frequency calculations were performed on all optimized structures
(at the optimization level) to characterize the stationary points as
minima (non imaginary frequencies) or transition states (one
imaginary frequency).
General Procedure for the [4C+2C] Cycloaddition of Al-
lenedienes 1 (Exemplified for 1a). A solution of compound 1a
(100 mg, 0.291 mmol) in CH2Cl2 (0.8 mL) was added to a
suspension of (ArO)3PAuCl (25.6 mg, 0.029 mmol) and AgSbF6
(10.0 mg, 0.029 mmol) in CH2Cl2 (1.2 mL) in a dried Schlenk tube
under argon, at 0 °C. The mixture was stirred at that temperature
for 3 h and filtered through a short pad of florisil eluting with Et2O.
The filtrate was concentrated and purified by flash chromatography
(10-15% Et2O/hexanes) to afford 72 mg of a 1:10 mixture of
cycloadducts 2a and 3a (72%, 2a:3a ) 1:10).
(3aR*,7aS*)-4-Cyclopentylidene-2-tosyl-2,3,3a,4,5,7a-hexahy-
dro-1H-isoindole (3a). 1H NMR (500 MHz, CDCl3): δ (ppm) 7.73
(d, J ) 8.3 Hz, 2H), 7.31 (d, J ) 8.0 Hz, 2H), 5.71 (s, 2H), 3.87
(dd, J ) 9.4 and 5.8 Hz, 1H), 3.63 (dd, J ) 9.1 and 7.1 Hz, 1H),
3.37 (t, J ) 10.1 Hz, 1H), 2.86 (dd, J ) 10.9 and 9.2 Hz, 1H),
2.70 (d, J ) 21.2 Hz, 1H), 2.66 (d, J ) 21.9 Hz, 1H,), 2.42 (s,
with the highly electrophilic gold atom could play a key role.
Indeed, the exocyclic double bond which is being generated in
the ring contraction process (ts3′) might easily optimize its
orientation in such a way that donation from the occupied
π-orbitals to the electrophilic gold metal center is maximized,
and therefore ts3 could be favored when an electron acceptor
ligand is placed at gold (i.e., phosphites or phosphoramidites).
Conversely, the endocyclic double bond formed at ts3, could
have more conformational restrictions to fully optimize such
interaction and, accordingly, a transition state ts3, leading to
V, might not be particularly favored with such highly electro-
philic gold complexes.
Albeit [4C+3C] cycloaddition products have been observed
for [(NHC)Au]+-catalyzed reactions of substrates in which the
allene is monosubstituted at the C-terminus position,10b we never
observed [4C+2C] adducts from these substrates using
[(RO)3PAu]+. Therefore, we carried out DFT calculations to
quantify the eventual dependence of the ring contraction step
on the presence of substituents at the allene C-terminus. The
proposed mechanisms for the formation of [4C+2C] and
[4C+3C] adducts were theoretically evaluated with
[(MeO)3PAu]+ for the model substrate 1j′, which includes
hydrogen atoms instead of methyl groups at the distal position
of the allene (Figure 6). The mechanisms for the formation of
the two different products are qualitatively similar to those
previously commented and share the two initial steps. Once the
7-membered ring intermediate IV is formed, the relative energy
barrier for the 1,2-H-shift (formation of [4C+3C] product) is
11.7 kcal/mol. For the case of the 1,2-alkyl migration (formation
of [4C+2C] product), however, the relative energy barrier is
23.8 kcal/mol (Figure 6). According to these values, the
formation of [4C+2C] cycloadduct seems to be strongly
dependent on the presence of a quaternary center at the adjacent
position of the Au-carbene center (see the Supporting Informa-
tion for more details).
(37) Frisch, M. J. et al. Gaussian 03, ReVision C.02; Gaussian, Inc.:
Wallingford CT, 2004. (See Supporting Information, ref 21.)
(38) (a) Lee, C.; Parr, R. G.; Yang, W. Phys. ReV. 1988, 37, B785. (b)
Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (c) Stephens, P. J.;
Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994,
98, 11623–11627.
(39) (a) Hay, P. J.; Wadt, W. R. J. Phys. Chem. 1985, 82, 299. (b) Wadt,
W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284–298.
(40) Ho¨llwarth, A.; Bo¨hme, M.; Dapprich, S.; Ehlers, A. W.; Gobbi, A.;
Jonas, V.; Ko¨hler, K. F.; Stegman, R.; Veldkamp, A.; Frenking, G.
Chem. Phys. Lett. 1993, 208, 237–240.
In summary, the calculations have provided interesting
information into the plausible mechanistic bases of the [4C+3C]
and [4C+2C] divergence. The nature of the ligand guides the
formation of the final product: the more electron withdrawing
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A R T I C L E S
Alonso et al.
3H), 2.30-2.14 (m, 4H), 1.76-1.50 (m, 4H); 13C NMR (125.8
MHz, CDCl3): δ (ppm) 143.2 (C), 136.1 (C), 134.7 (C), 129.7 (CH),
128.8 (CH), 127.2 (CH), 125.3 (CH), 122.2 (C), 51.3 (CH2), 50.8
(CH2), 47.1 (CH), 42.8 (CH), 32.0 (CH2), 31.6 (CH2), 30.9 (CH2),
27.4 (CH2), 25.8 (CH2), 21.5 (CH3). LRMS (m/z, I): 343 ([M+],
9), 188 (97), 154 (29), 91 (100). HRMS calculated for C20H25NO2S
316.16060, found 316.16061. Further confirmation of the structure
of 3a was obtained by X-ray crystallography. The remaining
cycloadducts of Table 2 were prepared using this procedure and
their spectroscopic data can be found in the Supporting Information.
cycloadduct 3a (87% yield). HPLC analysis on Chiralcel IA (0.5
mL/min, hexane: i-PrOH ) 99: 1) showed a 92% enantiomeric
excess (retention times: 55.1 min, major enantiomer; 61.7 min,
minor enantiomer).
Acknowledgment. This research was supported by the Spanish
MICINN [SAF2007-61015, CTQ2008-06866-CO2-02, Consolider-
Ingenio 2010 (CSD2007-00006)], Xunta de Galicia (GRC2006/
132 and PGIDIT06PXIB209126PR), CSIC and Comunidad de
Madrid (CCG08-CSIC/PPQ3548). B.T. and S.M. thank the Spanish
MICINN for each FPU fellowship. I.A. thanks the Xunta de Galicia
for a fellowship. We thank Johnson-Matthey for a gift of metals
and Takasago for a gift of (R)-DTBM-Segphos.
General Procedure for the [4C+2C] Cycloaddition of Al-
lenedienes 1 with Phosphoramidite-Based Gold Catalysts (Ex-
emplified for 1a with (R,R,R)-K). A solution of compound 1a
(100 mg, 0.291 mmol) in CH2Cl2 (0.8 mL) was added to a
suspension of [(R,R,R)]-K (6.55 mg, 5.82 µmol, 2 mol %) and
AgSbF6 (2.0 mg, 5.82 µmol, 2 mol %) in CH2Cl2 (1.2 mL) in a
dried Schlenk tube, under argon, at -15 °C. The mixture was stirred
at that temperature for 3 h (the progress of the reaction was easily
monitored by tlc) and filtered through a short pad of florisil eluting
with Et2O. The filtrate was concentrated and purified by flash
chromatography (10-15% Et2O/hexanes) to afford 87 mg of
Supporting Information Available: Full experimental proce-
dures, spectroscopy data, crystallographic information files and
energies and Cartesian coordinates of optimized geometries. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JA905415R
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13030 J. AM. CHEM. SOC. VOL. 131, NO. 36, 2009