Mechanistic insights in gold-stabilized nonclassical carbocations: Gold-catalyzed rearrangement of 3-cyclopropyl propargylic acetates

Article abstract of DOI:10.1021/ja909013j

The reaction of 3-cyclopropyl propargylic carboxylates with Au(I) and Au(III) catalysts affords selectively 5-(E)-alkylidenecyclopentenyl acetates via [3,3]-sigmatropic rearrangement of the carboxylic moiety followed by cyclopropyl ring opening and cyclization. DFT calculations have been performed, supporting a two-step no-intermediate mechanism along the cyclization coordinate. The stereoselective formation of the exocyclic alkenes is kinetically controlled in the first of these events. Although stereospecific in nature through a gold-stabilized nonclassical carbocation, the chirality transfer in these cyclopentannulations is not complete. Computational and experimental evidence is provided for a Au-promoted cyclopropyl ring opening/epimerization/ring closure in both cis- and trans-cyclopropyl settings, which competes with the cyclization event, thus eroding the stereochemical information transfer. When tertiary acetates were used, products of both 1,2- and 1,3-acyloxy migration processes could be isolated, supporting the competitive coexistence of these two pathways along the reaction profile, as suggested also by DFT calculations.

Full text of DOI:10.1021/ja909013j

Published on Web 03/12/2010
Mechanistic Insights in Gold-Stabilized Nonclassical
Carbocations: Gold-Catalyzed Rearrangement of
3-Cyclopropyl Propargylic Acetates
David Garayalde,† Enrique Go´mez-Bengoa,‡ Xiaogen Huang,† Andreas Goeke,§
and Cristina Nevado*,†
Organic Chemistry Institute, UniVersity of Zu¨rich, CH-8057, Zu¨rich, Switzerland, Dpto. de Qu´ımica
Orga´nica, UniVersidad del Pa´ıs Vasco, Apartado 1072, 20080 San Sebastia´n, Spain, and Shanghai
GiVaudan Ltd., Fragrances, 298 Li Shi Zhen Road, 201203, People’s Republic of China
Received October 22, 2009; E-mail: nevado@oci.uzh.ch
Abstract: The reaction of 3-cyclopropyl propargylic carboxylates with Au(I) and Au(III) catalysts affords
selectively 5-(E)-alkylidenecyclopentenyl acetates via [3,3]-sigmatropic rearrangement of the carboxylic
moiety followed by cyclopropyl ring opening and cyclization. DFT calculations have been performed,
supporting a two-step no-intermediate mechanism along the cyclization coordinate. The stereoselective
formation of the exocyclic alkenes is kinetically controlled in the first of these events. Although stereospecific
in nature through a gold-stabilized nonclassical carbocation, the chirality transfer in these cyclopentannu-
lations is not complete. Computational and experimental evidence is provided for a Au-promoted cyclopropyl
ring opening/epimerization/ring closure in both cis- and trans-cyclopropyl settings, which competes with
the cyclization event, thus eroding the stereochemical information transfer. When tertiary acetates were
used, products of both 1,2- and 1,3-acyloxy migration processes could be isolated, supporting the competitive
coexistence of these two pathways along the reaction profile, as suggested also by DFT calculations.
evolved for these transformations (Scheme 1).6 Gold in par-
ticular has proven to efficiently activate propargyl carboxylates
Introduction
From the seminal discovery of the Zn-mediated rearrangement
of propargyl acetates reported by Ohloff et al. in 1976, the
chemistry of propargyl esters has experienced an exponential
growth.1 Ten years later, a related Pd-catalyzed cyclization of
1-ethynyl-2-propenyl acetates to give 2-cyclopentenones was
reported by Rautenstrauch and co-workers.2 Although an in-
depth mechanistic study was lacking, the formation of a
Pd-carbene intermediate was already postulated. Work from
Ohe and Uemura with ruthenium3 and from Malacria with
platinum4 reopened the interest in this class of transformations
at the beginning of this decade. Later, Toste demonstrated that
intermediate achiral carbenes are an insufficient explanation for
the observed chirality transfer in a gold-promoted version of
the Rautenstrauch reaction.5 Now, after 30 years of research
mainly driven by the irruption of platinum and gold complexes
in modern catalysis, a more clear mechanistic picture has been
(I) toward 1,2-acyloxy migration and/or [3,3]-sigmatropic
acyloxy rearrangement at room temperature (red and blue paths,
respectively).7 These two competitive processes seem to be
mechanistically related: 1,2-migration proceeds via metal car-
bene (III), whereas [3,3]-sigmatropic rearrangement proceeds
via allenyl acetate (V) in a single process or stepwise by a
second acetate migration from III (Scheme 1).8 Allenyl acetates
V can be further activated in the presence of the metal catalyst
to give VI, triggering an extensive palette of transformations.
It is widely accepted that terminal or electron-poor alkynes react
via a 1,2-migration pathway,9,10 whereas internal alkynes prefer
the 1,3-migration pathway,11 and only a few exceptions to this
general pattern have been described.12
We have recently reported a new Au-catalyzed homo-
Rautenstrauch rearrangement of 1-cyclopropyl propargylic esters
(1, 2) to give five-, six-, and also seven-membered-ring vinyl
† University of Zu¨rich.
‡ Universidad del Pa´ıs Vasco.
§ Shanghai Givaudan Ltd.
(5) (a) Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
´
(1) Stickler, H.; Davis, J. B.; Ohloff, G. HelV. Chim. Acta 1976, 59, 1328–
5802–5803. (b) Nieto-Faza, O.; Lo´pez, C.; Alvarez, R.; de Lera, A. R.
1332.
J. Am. Chem. Soc. 2006, 128, 2434–2437.
(2) (a) Rautenstrauch, V. J. Org. Chem. 1984, 49, 950–952. (b) Rauten-
strauch, V.; Burger, U.; Wirthner, P. Chimia 1985, 39, 7.
(3) (a) Miki, K.; Ohe, K.; Uemura, S. Tetrahedron Lett. 2003, 44, 2019–
2022. (b) Miki, K.; Ohe, K.; Uemura, S. J. Org. Chem. 2003, 68,
8505–8513.
(6) For general reviews, see: (a) Fu¨rstner, A.; Davies, P. W. Angew. Chem.,
Int. Ed. 2007, 46, 3410–3449. (b) Jime´nez-Nun˜ez, E.; Echavarren,
A. M. Chem. ReV. 2008, 108, 3326–3350. (c) Michelet, V.; Toullec,
P. Y.; Geneˆt, J.-P. Angew. Chem., Int. Ed. 2008, 47, 4268–4315.
(7) For a mini-review, see: (a) Marion, N.; Nolan, S. P. Angew. Chem.,
Int. Ed. 2007, 46, 2750–2752. (b) Marco-Contelles, J.; Soriano, E.
Chem. Eur. J. 2007, 13, 1350–1357.
(4) (a) Mainetti, E.; Mourie`s, V.; Fensterbank, L.; Malacria, M.; Marco-
Contelles, J. Angew. Chem., Int. Ed. 2002, 41, 2132–2135. (b) Harrak,
Y.; Blaszykowski, C.; Bernhard, M.; Cariou, K.; Mainetti, E.; Mourie`s,
V.; Dhimane, A.-L.; Fensterbank, L.; Malacria, M. J. Am. Chem. Soc.
2004, 126, 8656–8657.
(8) (a) Correa, A.; Marion, N.; Fensterbank, L.; Malacria, M.; Nolan, S. P.;
Cavallo, L. Angew. Chem., Int. Ed. 2008, 47, 718–721. (b) Marion,
N.; et al. Chem. Eur. J. 2009, 15, 3243–3260.
9
4720 J. AM. CHEM. SOC. 2010, 132, 4720–4730
10.1021/ja909013j  2010 American Chemical Society

Gold-Stabilized Nonclassical Carbocations
A R T I C L E S
Scheme 1. 1,2- vs 1,3-Carboxylate Migration
Scheme 2. Au-Catalyzed Homo-Rautenstrauch Rearrangement of
1-Cyclopropyl Propargylic Acetates
Scheme 3. Au-Catalyzed Acetate Migration + Fission to
R-Ylidene-ꢀ-diketones vs Cyclopentannulation
cyclohexadienyl (3) and cyclopentenyl acetates (4) could be
obtained when optically active starting materials were employed.
To get a further insight in the reactive species involved in
these transformations, we decided to explore the chemistry of
related 3-cyclopropyl propargylic carboxylates 5 (Scheme 3).
Such settings had already been studied by Zhang and co-
workers.14 In the presence of gold catalysts, Zhang’s group
developed an elegant method to obtain R-ylidene-ꢀ-diketones
as a result of the 1,3-migration of the acyl group onto the alkyne
moiety followed by acetate fission. The cyclopropyl ring
behaved in this case as a mere spectator in the reaction (5a to
6a; Scheme 3). On the basis of our previous experience, we
decided to explore whether the presence of a group able to
stabilize a developing positive electron density could induce
the cyclopropyl ring opening to give cyclopentannulation
products 7 instead.
acetates under mild conditions (Scheme 2).13 A key factor in
the successful development of this transformation is the presence
of a substituent at the cyclopropyl ring able to stabilize the
positive electron density developed during the concomitant ring-
opening process. The almost complete chirality transfer we
observed in these reactions suggested that gold-stabilized
nonclassical carbocations with a certain configurational stability
(VII, VIII) might be involved, since enantiomerically enriched
Herein, we report our in-depth investigation on the cyclization
of 3-cyclopropyl propargylic carboxylates and related species.
We also present a DFT computational study on the reaction
mechanism, which reveals the decisive intermediates determin-
ing the stereoselectivity of these transformations. This work also
sheds light on the role of the substituents at the propargylic
position in defining the reaction pathway, since products of both
1,2- and 1,3-acyloxy migration pathways have been found in
these processes.
(9) For selected references: (a) Mamame, V.; Gress, T.; Krause, H.;
Fu¨rstner, A. J. Am. Chem. Soc. 2004, 126, 8654–8655. (b) Johansson,
M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J. Am. Chem. Soc.
2005, 127, 18002–18003. (c) Gorin, D. J.; Dube´, P.; Toste, F. D. J. Am.
Chem. Soc. 2006, 128, 14480–14481. (d) Marion, N.; de Fre´mont, P.;
Lemie`re, G.; Stevens, E. D.; Fensterbank, L.; Malacria, M.; Nolan,
S. P. Chem. Commun. 2006, 2048–2050. (e) Buzas, A.; Gagosz, F.
Org. Lett. 2006, 8, 515–518. (f) Witham, C. A.; Mauleo´n, P.; Shapiro,
N. D.; Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 5838–
5839. (g) Amijs, C. H. M.; Lo´pez-Carrillo, V.; Echavarren, A. M.
Org. Lett. 2007, 9, 4021–4024.
(10) For applications of this methodology in synthesis, see: (a) Fehr, C.;
Galindo, J. Angew. Chem., Int. Ed. 2006, 45, 2901–2904. (b) Fu¨rstner,
A.; Hannen, P. Chem. Eur. J. 2006, 12, 3006–3019. (c) Fehr, C.;
Winter, B.; Magpantay, I. Chem. Eur. J. 2009, 15, 9773–9784.
(11) For selected references: (a) Zhang, L. J. Am. Chem. Soc. 2005, 127,
16804–16805. (b) Marion, N.; D´ıez-Gonza´lez, S.; de Fre´mont, P.;
Noble, A. R.; Nolan, S. P. Angew. Chem., Int. Ed. 2006, 45, 3647–
3650. (c) Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614–
12615. (d) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442–
1443.
Results and Discussion
Reaction Optimization. 3-((2-Methylpropenyl)cyclopropyl
propargyl)-1-phenylprop-2-ynyl acetate (5b) was used as a
benchmark substrate to find suitable reaction conditions. The
results of this optimization are summarized in Table 1. In the
presence of PtCl2 in toluene as solvent, no reaction was observed
at room temperature (Table 1, entry 1). On heating to 80 °C,
5b was completely consumed, affording a complex mixture of
products from which the R-ylidene-ꢀ-diketone 6b could be
isolated, albeit in low yield (Table 1, entry 2). This result reflects
the preference for the acetate fission pathway vs the cyclopropyl
ring opening with Pt salts. We then decided to turn our attention
toward gold catalysts in CH2Cl2 as a solvent. Treatment with
(12) For Au, see: (a) Huang, X.; de Haro, T.; Nevado, C. Chem. Eur. J.
2009, 15, 5904–5908. (b) Li, G.; Zhang, L. J. Am. Chem. Soc. 2008,
130, 3740–3741. For Pt, see: (c) Ji, K.-G.; Shu, X.-Z.; Chen, J.; Zhao,
S.-C.; Zheng, Z.-J.; Lu, L.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2008,
10, 3919–3922. (d) Cho, E. J.; Lee, D. AdV. Synth. Catal. 2008, 350,
2719–2723. For Ru, see: (e) Ohe, K.; Fujita, M.; Matsumoto, H.; Tai,
Y.; Miki, K. J. Am. Chem. Soc. 2006, 128, 9270–9271.
(13) (a) Zou, Y.; Garayalde, D.; Wang, Q.; Nevado, C.; Goeke, A. Angew.
Chem., Int. Ed. 2008, 47, 10110–10113. For a related study, see
also: (b) Mauleo´n, P.; Krinsky, J. L.; Toste, D. F. J. Am. Chem. Soc.
2009, 131, 4513–4520.
(14) Wang, S.; Zhang, L. J. Am. Chem. Soc. 2006, 128, 8414–8415.
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A R T I C L E S
Garayalde et al.
Table 1. Optimizing Reaction Conditions for the Cyclization of 3-Cyclopropyl Propargyl Acetate 5b
entry
catalyst (mol %)
conditions
time (h)
conversn (%)a
yield (%)b (ratio 6b:7b)
1
2
3
4
5
6
7
8
9
PtCl2 (5)
PtCl2 (5)
AuCl (2)
toluene, 25 °C
toluene, 80 °C
CH2Cl2, 25 °C
CH2Cl2, 25 °C
CH2Cl2, 25 °C
CH2Cl2, 50 °C
CH2Cl2, 25 °C
CH2Cl2, 25 °C
15
12
0
100
90
100
100
100
100
100
100
<10 (100:0)
complex mixture
75 (1:8)
0.5
0.25
0.25
1
0.1
0.1
0.1
[(Ph3P)Au(NTf2)] (3)
[(Ph3P)Au(SbF6)] (3)
85 (1:10)
c
LAuCl2 (5)
65 (1:>99)
85 (1:>99)e
90 (1:>99)f
75 (8b)f
{[(tBu)2(BPH)]P Au(SbF6)}d (5)
[(IPr)Au(NTf2)] (5)
[(IPr)Au(NTf2)] (5)
(i) CH2Cl2, 25 °C; (ii) K2CO3 (2 equiv), MeOH
a
Conversion calculated by H NMR. b Isolated yield after column chromatography. c L ) Pyridine-2-carboxylate. d BPH ) biphenyl. e Compound 7b
1
was obtained as a 2:1 (E:Z) mixture. f Compounds 7b and 8b were obtained as a 15:1 (E:Z) mixture.
Table 2. Au-Catalyzed Cyclization of 3-Cyclopropyl Propargyl Carboxylates
a Reaction conditions: (A) [(IPr)Au(NTf2)] (5 mol %), CH2Cl2, 25 °C, 30 min; (B) dichloro(pyridine-2-carboxylato)gold(III) (5 mol %), CH2Cl2, 50
°C, 30 min. b Only the major product is shown. c Isolated yield after column chromatography. d Determined by 1H NMR in the reaction mixture. e The
yields after methanolysis of the reaction mixtures to give the corresponding ketones can be found in the Supporting Information. f Decomposition was
observed.
gold(I) chloride delivered a complex mixture due to partial
decomposition of the starting material even at room temperature
(Table 1, entry 3). Cationic complexes generated by chloride
abstraction from [(Ph3P)Au(Cl)] such as [(Ph3P)Au(NTf2)] and
[(Ph3P)Au(SbF6)] provided, for the first time, cyclopentene
acetate 7b as the major product of the reaction (Table 1, entries
4 and 5). Surprisingly, dichloro(pyridine-2-carboxylato)gold(III),
the catalyst of choice in Zhang’s transformations,14 did not
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Gold-Stabilized Nonclassical Carbocations
A R T I C L E S
Scheme 4. Reaction of Tertiary Acetates with [(IPr)Au(NTf2)]
produce the expected R-ylidene-ꢀ-diketone 6b but only 7b in
moderate yield upon heating to 50 °C (Table 1, entry 6). The use
of a bulky phosphine ligand as in {[(tBu)2(BPH)]PAu(SbF6)}
afforded 7b in 85% yield as a 2:1 (E:Z) mixture of isomers
(Table 1, entry 7). Finally, [(IPr)Au(NTf2)] afforded the desired
alkylidene cyclopentenyl acetate 7b in almost quantitative yield
after 5 min of reaction (Table 1, entry 8). In situ methanolysis
of the product produced cyclopentenone 8b in 75% yield (Table
1, entry 9). Notably, in all the cases studied, 7b was obtained
as a variable E:Z mixture of isomers.15
The determining step for the E vs Z exocyclic alkene formation
seems to be thus under kinetic control.
Cyclization of Tertiary Acetates. We focused next on the
reaction of tertiary propargyl acetates, which have unraveled
interesting mechanistic features of these transformations. When
substrate 9a was treated with [(IPr)Au(NTf2)] (5 mol %) in
CH2Cl2 at room temperature, the expected product 10a was
obtained in 58% yield. A careful analysis of the reaction mixture
revealed the formation of 1,3-diketone 11a isolated in 27% yield
in its enolic form (Scheme 4). A similar behavior in the presence
of [(IPr)Au(NTf2)] as catalyst was observed for substrates 9b,c,
affording cyclopentenyl acetates 10b,c and diketones 11b,c in
1:2 and 2:1 ratios, respectively. In our View, formation of 11a-c
can be explained by a 1,2-acetoxy migration pathway followed
by cyclopropyl ring opening and cyclization terminating with
the fission of the acetate group. Formation of products from
both 1,2- and 1,3-acyloxy migration pathways from the same
substrate under a certain set of conditions is rare and deserves
further attention. Computational studies on these systems have
been performed, and the results will be discussed in a later
section.
General Reactivity. Once the reaction conditions for the
selective cyclization of 3-cyclopropyl propargyl carboxylate 5b
had been established, we decided to explore the scope of this
transformation. First, we focused on substrates containing
secondary acetates, which proved to be unsuccessful in our
previously developed homo-Rautenstrauch rearrangement
reaction.13a The results have been summarized in Table 2. To
our delight, the 2-naphthyl derivative 5c afforded vinyl acetate
7c in 84% yield under the optimized reaction conditions (Table
2, entry 1). The presence of alkyl substituents at the propargylic
position was also examined. Thus, substrates 5d-f were
efficiently transformed into the corresponding cyclopentenyl
acetates (7d-f) (Table 2, entries 2-5). The cyclopropyl ring
cleavage can be also stabilized by a 1-phenylprop-1-en-2-yl
moiety as in 5g (Table 2, entries 6 and 7), and different
migrating groups such as benzoates (5h) were tolerated (Table
2, entries 8 and 9). In some cases, the dichloro(pyridine-2-
carboxylato)gold(III) catalyst seemed to give better results in
terms of yield and/or E:Z selectivity at the exocyclic olefin
compared to [(IPr)Au(NTf2)] (Table 2, entries 4, 6, 8, 10, 12,
14, 16 vs 5, 7, 9, 11, 13, 15, 17). Remarkably, except for 5j,
both catalysts delivered clean and complete conversions and
no R-ylidene-ꢀ-diketones (6) were observed. As was mentioned
above, E isomers were always obtained as major products of
these reactions.15 Attempts to transform Z into thermodynami-
cally favored E isomers in the presence of gold catalysts failed.16
After extensive experimentation, we found that treatment of
9a with [(PhO)3PAu(SbF6)] (5 mol %) allowed the clean
formation of cyclopentenyl acetate 10a in 81% yield (Table 3,
entry 1). Similarly, 10b-d were efficiently produced under the
same reaction conditions (Table 3, entries 2-4). The reaction
of cyclopentyl- and cyclohexyl-substituted derivatives 9e,f
proceeded cleanly at -20 °C to give products 10e,f in 85%
(16) Compound 7b was treated with catalytic amounts of IPrAuNTf2,
LAuCl2 (L ) pyridine-2-carboxylate), and [(Ph3P)Au(NTf2)], first at
room temperature and then at 50 °C without any remarkable change
in the isomeric ratio of the exocyclic alkene.
(15) The E configuration of the major isomer was assigned on the basis of
NOE studies.
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J. AM. CHEM. SOC. VOL. 132, NO. 13, 2010 4723

A R T I C L E S
Garayalde et al.
Table 3. Au-Catalyzed Cyclization of 3-Cyclopropyl Propargyl
Tertiary Carboxylates
Scheme 5. Evidence for the 1,2-Acyloxy Migration Pathway in the
Reaction of Tertiary Acetates with [(IPr)Au(NTf2)] as Catalyst
intermediates 14 and 15 operating in competition with the
predicted [3,3]-acyloxy rearrangement.
The results summarized in Schemes 4 and 5 and Table 3 can
be explained in light of the distinct nature of the reaction
intermediates depending on the ligand bound to the gold
center.18 [(PhO)3PAu(SbF6)] displays a more electrophilic
character compared to [(IPr)Au(NTf2)], due to the π-acceptor
phosphite ligand. The decrease in the gold-to-C π-donation
might enhance the carbocationic character of the reaction
intermediates, thus favoring the cyclopentannulation products
(10). In contrast, the IPr (1,3-bis(2,6-disiopropylphenyl)imida-
zol-2-ylidene) ligand is strongly σ-donating and only weakly
π-acidic, thus increasing the carbene-like reactivity favoring
intermediate 14 (also preferred by steric reasons) over the allene
intermediate and thus triggering the formation products such
as 11-13.
Cyclization of Propargyl Vinyl Ethers. In addition to car-
boxylic groups (acetates, benzoates, etc.), propargyl vinyl ethers
are also suitable motifs for rearrangement across the triple bond
upon metal activation.19 We expected to form two new C-C
bonds by coupling the [3,3]-sigmatropic rearrangement to the
cyclopropyl ring-opening reaction. Thus, substrate 16a was
treated with [(IPr)Au(NTf2)] (5 mol %), delivering the corre-
sponding cyclopent-1-enyl aldehyde 17a in 71% yield (Table
4, entry 1).15 To achieve higher yields, the Au-catalyzed
cyclization was coupled to an in situ reduction of the aldehyde
with NaBH4, as previoustly reported by Toste and co-workers
(Table 4, entry 2).19b A similar protocol was applied for
substrates 16b,c, which gave the corresponding alcohols 18b,c
in excellent yields (Table 4, entries 3 and 4). Interestingly,
electron-deficient vinyl ethers such as 16d,e were cleanly
transformed into the corresponding (Z)-methyl-2-(2-methyl-
enecyclopentylidene)-3-oxopropanoates 17d,e under the afore-
mentioned reaction conditions (Table 4, entries 5 and 6).15 It is
important to note that no heterocyclization on the allenyl
carbonyl intermediate to give 3-cyclopropyl-substituted furans
was observed, as previously reported by Kirsch and co-workers
for similar settings.20 In contrast to the mechanistic dichotomy
a Reactions run in CH2Cl2 as solvent with 5 mol % catalyst. b Isolated
yield after column chromatography. c Obtained as a 4:1 (E:Z) mixture of
isomers.
yield (Table 3, entries 5 and 6). Finally, compound 9g was
cyclized to give 10g as a 4:1 mixture of isomers (Table 3, entry
7).15
To further confirm the 1,2-acetoxy migration pathway operat-
ing in the reaction of tertiary acetates with [(IPr)Au(NTf2)] as
catalyst, the following experiments were designed (Scheme 5).
Reaction of 9b in the presence of 1 equiv of p-anisaldehyde
gave a mixture of 10b and 11b in 85% yield together with
dihydropyran 12 in 9% yield. The latter can be explained by a
[4C + 2C] cycloaddition reaction between the 1,4-dipole 15
(generated in situ along the 1,2-migration path) and p-anisal-
dehyde as dipolarophile.17 On the other hand, when 9c was
treated with [(IPr)Au(NTf2)] in MeOH as a cosolvent, compound
13 was isolated in 28% yield. Formation of both 12 and 13 is
a clear indication of a 1,2-acyloxy migration manifold via
(18) (a) Benitez, D.; Shapiro, N. D.; Tkatchouk, E.; Wang, Y.; Goddard,
W. A.; Toste, F. D. Nature 2009, 1, 482–486. (b) Gorin, D. J.; Sherry,
B. D.; Toste, F. D. Chem. ReV. 2008, 108, 3351–3378.
(17) (a) Zhang, G.; Huang, X.; Li, G.; Zhang, L. J. Am. Chem. Soc. 2008,
130, 1814–1815. (b) Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2008,
130, 12598–12599.
(19) (a) Sherry, B. D.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 15978–
15979. (b) Benjamin, D. S.; Maus, L.; Laforteza, B. N.; Toste, F. D.
J. Am. Chem. Soc. 2006, 128, 8132–8133.
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Gold-Stabilized Nonclassical Carbocations
A R T I C L E S
Table 4. Au-Catalyzed Cyclization of 3-Cyclopropyl Propargyl Enol Ethers
a Reaction conditions (A) [(IPr)Au(NTf2)] (5 mol %), CH2Cl2, 25 °C, 30 min; (B) (i) [(IPr)Au(NTf2)] (5 mol %), CH2Cl2, 25 °C, 30 min, (ii) NaBH4
(5 equiv), MeOH. b Only the major product is shown. c Isolated yield after column chromatography. d Determined by 1H NMR in the reaction mixture.
e Reaction time 90 min.
manifold observed in the migration of tertiary acetates with
[(IPr)Au(NTf2)], the rearrangement of tertiary vinyl ethers under
similar reaction conditions delivered only the products derived
from a propargyl-Claisen rearrangement. Substrates 16f,g with
a 2-methyl-2-propen-1-yl substituent at the cyclopropyl ring
delivered upon NaBH4 reduction the expected alcohols 18f,g
together with 18f′,g′ (Table 4, entries 7 and 8).21 The reaction
of 16h afforded aldehyde 17h in modest yield (Table 4, entry
9), whereas the reductive workup in MeOH allowed us to isolate
alcohol 18h in 70% yield and a small amount of 19. The latter
is presumably formed by trapping the carbocationic intermediate
formed during [3,3]-rearrangement in the first step of the
reaction with MeOH, which is used as solvent in the subsequent
step (Table 4, entry 10).19b
in Scheme 1) upon Au-catalyzed [3,3]-sigmatropic rearrange-
ment. To further confirm this hypothesis, we decided to explore
the reactivity of “non-activated” cyclopropyl allenes in the
presence of gold complexes. We were pleased to observe that
substrate 20a reacted in the presence of 5 mol % of [(IPr)
Au(NTf2)] to afford the 2-(ethylidene)cyclopent-3-enyl species
21a in excellent yield following the previously proposed
sequence: gold activation of the allene-cyclopropyl ring-
opening-cyclization (Scheme 6). Tri- and tetrasubstituted
allenes were well tolerated, as shown by the reactions of 20b,c
to give cyclopentenes 21b,c in 67 and 92% yields, respectively.
When a 1-methyleth-2-enyl substituent is placed at the terminal
position of the allene (20d), the reaction in the presence of
[(IPr)Au(NTf2)] afforded a complex reaction mixture. In the
presence of dichloro(pyridine-2-carboxylato)gold(III), a clean
6-π-electron cyclization takes place to give bicyclic compound
22 in almost quantitative yield, as previously reported by other
groups.22
Cyclization of Non-activated Allenes. The cyclization of
propargylic esters and enol ethers presented above presumably
proceed by the formation of an oxo-allene intermediate (see V
(20) (a) Suhre, M. H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925–
3927. (b) Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151–2153.
(21) Longer reaction times and the Au catalyst seem to be crucial for this
somewhat unexpected isomerization,which is currently the focus of
further mechanistic studies.
Mechanistic Discussion. A simplified vision of the cyclization
of 3-cyclopropyl propargylic acetate 5 presumably involves
allenyl intermediate IX, which undergoes ring expansion to form
the 1,5-dipole X, where the carbocation is stabilized by aromatic
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through TSXIa-XIIa (∆Hq ) 6.5 kcal/mol) and TSXIIa-XIIIa (∆H+
) 2.8 kcal/mol) to give gold coordinated allene XIIIa in a
reversible and slightly endothermic process (∆H ) 0.4 kcal/
mol) (Scheme 8).24 XIIIa shows a clear “allene” character, with
gold coordinated to the more external double bond and the four
allenyl substituents disposed perpendicularly resembling the
gold-coordinated minimized structures of simple allenes 20a-d
(Scheme 6). XIIIa is in equilibrium with the more cationic-
type derivative XIVa through TSXIIIa-XIVa (∆Hq ) 3.4 kcal/mol)
thermodynamically more stable (∆H ) -4.0 kcal/mol), where
the internal double bond is now activated, leaving the gold
almost exclusively coordinated to the central carbon atom of
the allene.25 From XIIIa, the formation of the E-configured vinyl
gold derivative XIVd can also be envisioned, although, for the
sake of clarity, only XIIIa will be considered here (a complete
version of Scheme 8 summarizing all possible isomers can be
found in the Supporting Information).26 The stereochemical
information of the acetate at the propargylic position is lost by
the low barrier transition state TSXIVa-XIVb (∆Hq ) 3.1 kcal/
mol), which converts XIVa into its enantiomer XIVb in a
slightly exothermic transformation (∆H ) -0.7 kcal/mol). On
the other hand, XIVb could also arise from XIb in a manner
analogous to that described above. Such an epimerization event
is well precedented experimentally27 and was recently studied
by the groups of Malacria25 and Toste.13b,19
Scheme 6. Cyclization of 3-Cyclopropyl Allenes
Cyclization Step. The next step along the reaction coordinate
involves cyclopropyl ring opening and C-C bond formation
to give the cyclopentannulation products. The parallel reactions
of the four isomers XIVa-d were computed, although for the
sake of clarity, only the structures of intermediates derived from
XIVa are explicitly shown (Scheme 9, left). The relative
energies for the other isomers (XIVb, epimer at the carbon
bearing the acetate; XIVc,d, (E)-vinyl gold isomers) have been
summarized in the right-hand side of Scheme 9. Thus, from
XIVa two adjacent transition states, one higher in energy
(TSXIVa(1); ∆Hq ) 19.9 kcal/mol) and a second one being lower
in the reaction profile (TSXIVa(2); ∆Hq ) 10.9 kcal/mol) were
found to deliver cyclopentene acetate XVa without an interven-
ing intermediate.28 Interestingly, TSXIVa(1) can be described as
a gold-stabilized nonclassical carbocation related to those
proposed in Scheme 2.13a,29 On the other hand, TSXIVa(2)
constitutes a “bifurcation point” in the reaction profile, which
can evolve either to cyclopentenyl XVa or toward the six-
membered ring XVIa, although formation of XVa is thermo-
dynamically much more favorable (HXVa ) -36.7 kcal/mol vs
HXVIa ) -17.1 kcal/mol). The product of a ꢀ-hydride elimina-
tion in XVIa would yield cyclohexadiene XVIIa, which was
never detected experimentally.
Scheme 7. Simplified Mechanism for the Cyclopentannulation
Reaction of 3-Cyclopropyl Propargyl Acetates
or vinylic groups. From X, a cyclization to form alkylidene
cyclopentenyl acetates 7 can be proposed (Scheme 7).
To gain a deeper insight into the reaction intermediates
defining the stereochemistry of the exocyclic double bond, the
different behavior of secondary vs tertiary carboxylates, and a
potential chirality transfer in this process, we performed DFT
calculations on the model gold(I) complex XI.23
(24) Alternatively, a double 1,2-migration of the acetoxy moiety could also
explain the formation of allenyl intermediate XIII. For an in-depth
study on this possibility, see ref 8.
(25) Gandon, V.; Lemie`re, G.; Hours, A.; Fensterbank, L.; Malacria, M.
Angew. Chem., Int. Ed. 2008, 47, 7534–7538.
Allenyl Acetate Formation. The Au(I) complex of (S)-4-
((1R,2S)-2-vinylcyclopropyl)but-3-yn-2-yl acetate XIa reacts
(26) Further details can be found in the Supporting Information.
(27) Schlossarczyk, H.; Sieber, W.; Hesse, M.; Hansen, H.-J.; Schmid, H.
HelV. Chim. Acta 1973, 56, 875–944.
(22) (a) Lemie`re, G.; Gandon, V.; Cariou, K.; Fukuyama, T.; Dhimane,
A.-L.; Fensterbank, L.; Malacria, M. Org. Lett. 2007, 9, 2207–2209.
(b) 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. (c) Funami, H.; Kusama, H.; Iwasawa, N.
Angew. Chem., Int. Ed. 2007, 46, 909–911. (d) Lee, J. H.; Toste, F. D.
Angew. Chem., Int. Ed. 2007, 46, 912–914.
(28) TSXIVa(1) and TSXIVa(2) form a two-step no-intermediate system. For
related examples, see: Singleton, D. A.; Hang, C.; Szymanski, M. J.;
Meyer, M. P.; Leach, A. G.; Kuwata, K. T.; Chen, J. S.; Greer, A.;
Foote, C. S.; Houk, K. N. J. Am. Chem. Soc. 2003, 125, 1319–1328.
(29) (a) Olah, G.; Reddy, V. P.; Prakash, G. K. S. Chem. ReV. 1992, 92,
69–95. (b) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001,
123, 11863–11869. (c) Fu¨rstner, A.; Davies, P. W.; Gress, T. J. Am.
Chem. Soc. 2005, 127, 8244–8245. (d) Fu¨rstner, A.; Morency, L.
Angew. Chem., Int. Ed. 2008, 47, 5030–5033.
(23) Calculations performed with Gaussian 03 (full reference in the
Supporting Information).
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A R T I C L E S
Scheme 8. Reaction Coordinate Diagram for the [3,3]-Acetoxy Migration of XIa to Cationic Intermediate XIVa,ba
a Calculations were carried out at the B3LYP/6-31G(d) (C, H, O) and LANL2DZ (Au) levels (+ZPE corrected energies are given in kcal/mol). Au )
(IPr)Au.
Scheme 9. Reaction Coordinate Diagram for the Cyclopentannulation of XIVaa
a Calculations were carried out at the B3LYP/6-31G(d) (C, H, O) and LANL2DZ (Au) levels (+ZPE corrected energies are given in kcal/mol; values in
brackets are those considering solvent effects (CH2Cl2)). Au ) (IPr)Au.
Solvent effects (CH2Cl2) were considered in these calculations
(energy values in brackets in Scheme 9). As expected, the
energies of all TS(1) species are lower than those in the gas
phase, since the stabilization of the carbocation retards the
cyclopropyl ring opening and promotes the formation of the
cycle. More importantly though, the energies of all TS(1) species
are still higher than those of TS(2), so that the first step remains
the rate-limiting step.
Since the stereochemistry observed in the exocyclic olefin
of cyclopentene acetates 7 seems to be under kinetic control,16
transition states TSXIVa-d(1), higher in energy than TSXIVa-d(2),
were closely examined. In TSXIVa(1) and TSXIVc(1), we observe
that the configuration at C6 of the cyclopropyl ring forces an
“endo” reaction, where the Au-C bond is always oriented
toward the cyclopropyl ring, whereas TSXIVb(1) and TSXIVd(1),
higher in energy, present an “exo” approach, where the cy-
clization takes place from the opposite side of the cyclopropyl
ring (Scheme 9). TSXIVa-d(1) shows an early carbocation being
formed at C6 with the cyclopropyl unit almost intact. The δ+
developing in the incipient carbocation interacts with the
electron-rich vinyl gold forming a pseudo-six-membered ring
cycle in a boat conformation (Figure 1).
In the two transition states of lower energy, TSXIVa(1) and
TSXIVc(1), the substituents at C1 and C6 are eclipsed. This
unfavorable eclipsing interaction is enhanced in TSXIVc(1), where
methyl and vinyl groups are in pseudoaxial positions (Figure
1, right upper row). Therefore, for each couple, the transition
states displaying the Au and Me in a “syn” disposition have an
activation energy lower than those with both groups in a “trans”
disposition (TSXIVa(1) < TSXIVc(1) and TSXIVb(1) < TSXIVd(1)).
These observations led us to conclude that the lower energy
reaction path goes from XIVa via TSXIVa(1) and TSXIVa(2),
yielding (E)-cyclopentenyl acetate XVa as a major product under
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d(C2-C6) ) 1.953 Å). In contrast with the steric interactions
analyzed for TSXIVa(1) vs TSXIVc(1), the stronger steric conges-
tion occurs between vinyl and methyl groups in TSXIVa(2),
disfavoring it compared to TSXIVc(2) (Figure 1, lower row).
Nevertheless, since these are the lower energy transition states
in the reaction coordinate, they have no influence in the structure
of the final products. Solvent effects also influence the key C-C
distances (C1-C2, C1-C6, C2-C6, Au-C2), which are slightly
shorter in the gas phase (Figure 1).
1,2- vs 1,3-Acyloxy Migration. The results obtained with
tertiary acetates and [(IPr)Au(NTf2)] (Schemes 4 and 5), where
products presumably arising from both 1,2- and 1,3-acyloxy
migration paths could be isolated, prompted us to study this
mechanistic dichotomy more in depth. Previous work in this
area has shown how minimal changes in the structure of starting
materials, catalysts, etc. can play a key role in the preference
for one of these two reaction manifolds.8 Our computational
models were the IPrAu complexes of (S)-4-((1R,2S)-2-p-me-
thoxyphenylcyclopropyl)but-3-yn-2-yl acetate (XVIII) and 2-
methyl-4-((1R,2S)-2-p-methoxyphenylcyclopropyl)but-3-yn-2-
yl acetate (XVIII′), respectively (Scheme 10).
For the secondary acetate XVIII (route in black), the reaction
coordinate following a 1,2-acetoxy migration (left path) has in
TSXIX-XX the higher energy barrier (∆Hq ) 9.6 kcal/mol),
whereas the 1,3-migration (right path) proceeds smoothly by
the previously described intermediates, with lower activation
energy for the determining step TSXXIV-XXV (∆Hq ) 7.6 kcal/
mol), which could explain why no products derived from a 1,2-
acetoxy migration were found in the reaction of secondary
acetates.
In sharp contrast, for the tertiary acetate XVIII′ (route in red)
the steric hindrance caused by the presence of two methyl groups
at the propargylic position raises the activation energy along
the 1,3-migration pathway (right path) to almost 10.5 kcal/mol
for TSXXIV-XXV. This barrier is now comparable to the energy
needed in the 1,2-migration path via TSXXI-XXII (11.6 kcal/mol).
Since the system can be considered under Curtin-Hammet
conditions (from XVIII′ to XXI′-XXIV′), the product com-
position will depend on the difference in energies between the
respective transition states (∆∆Hq ) 1.1 kcal/mol) thus becom-
ing competitive. It is important to mention that, as shown in
Scheme 5, products arising from the cyclopropyl ring opening
of XVIII′ have been isolated in the reaction, which has never
been the case for the secondary acetate derivatives XVIII.
Figure 1. (Upper row) Structures of transition states TSXIVa(1) and
TSXIVc(1), highlighting the interaction between the cyclopropyl ring and
the vinyl gold moiety and the eclipsed interaction between substituents C1
and C6 and relevant distances (values in brackets are those considering
solvent effects). (Lower row) Structures of transition states TSXIVa(2) and
TSXIVc(2) highlighting the steric interaction between methyl at C1 and vinyl
at C6 and relevant distances (values in brackets are those considering solvent
effects). Au ) (IPr)Au.
kinetic control, although the E product (XVa) is also thermo-
dynamically more stable than XVc.16
The stabilizing effect of the vinylic (or aromatic) substituent
by delocalization of the δ+ generated upon cyclopropyl ring
opening can be easily rationalized by looking at the key C-C
distances in the transition states. In fact, the C6-C7 and the
C7dC8 distances measured in XIa and XIVa are 1.48, 1.47 Å
and 1.33, 1.34 Å, respectively. In contrast, in TSXIVa(1), the
distances reflect the more allylic character of the vinyl moiety
with values of 1.42 and 1.36 Å. Furthermore, the NBO analysis
of TSXIVa(1) shows a strong interaction (63.8 kcal/mol) between
the π orbital of the double bond and the empty developing
orbital on C6, which is not present either in XIa or in XIVa.
This strong interaction is also reflected in the analysis of the
partial charges, which shows an increasing positive charge (+0.2
e) in the vinyl moiety of TSXIVa(1) vs the value measured in
XIa (+0.06 e).
Chirality Transfer. The interesting issue of a possible chirality
transfer in these systems was addressed both experimentally and
computationally. The optically active substrates 23 and 24 were
prepared from (1R,3R)-(-)-trans-chrysanthemum acid (99% ee)
(Scheme 11).26 In sharp contrast with our previous results
obtained with 1-cyclopropyl propargyl acetates,13a the cyclo-
isomerization of 23 (dr ) 1:1, 99% de) under standard
conditions with different catalytic systems afforded, after
methanolysis, cyclopentanone 25 in 61% ee in the best case
using pyridine-2-carboxylate gold(III) catalyst. A similar be-
havior was observed for tertiary acetate 24, which upon
treatment with [(PhO)3PAu(SbF6)] (5 mol %) and methanolysis
afforded 26 in only 50% ee.30
In the second transition states (TSXIVa(2), TSXIVc(2)) a
complete rupture of the cyclopropyl ring can be observed, with
the fully developed carbocation in close interaction with the
metal-vinyl bond (TSXIVa(2), d(C2-C6) ) 2.0 Å and TSXIVc(2),
These results prompted us to re-examine our mechanistic
proposal for these cycloisomerizations. According to the
calculations presented in Scheme 9, the reaction is stereospecific,
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A R T I C L E S
a
Scheme 10. Reaction Coordinate Diagrams for the 1,2- vs 1,3-Acyloxy Migration of Secondary vs Tertiary Propargyl Acetates
a Calculations were carried out at the B3LYP/6-31G(d) (C, H, O) and LANL2DZ (Au) levels (+ZPE corrected energies are given in kcal/mol). Au )
(IPr)Au.
instability (Scheme 12).26 First, XXIV can undergo a cyclo-
propyl ring opening via TSXXIV-XXVI to give the high-energy
intermediate XXVI. The process is endothermic due to the
intrinsically unstable nature of such a purely carbocationic inter-
mediate, even if the calculation takes into account solvent effects
(∆H ) 8.2 kcal/mol). Upon C-C rotation via TSXXVI-cis-XXIV, the
minor isomer cis-XXIV is formed. The activation barriers to
transform XXIV into cis-XXIV are comparable to those
obtained for the cyclopentannulation process and summarized
in Scheme 10. Therefore, we have to assume that even if the
cycloisomerization is an intrinsically stereospecific process, a
competitive epimerization at the cyclopropyl moiety can erode
the chirality transfer of these transformations. To understand
the loss of chirality by such a mechanism, XXIV should be in
equilibrium with cyclopropyl propargyl acetate XVIII (or
analogously, XIVa with XIa), which seems to be the case
according to the energy barriers summarized in Schemes 8 and
10. A final requirement involves the transformation of cis-XXIV
into the final cyclopentenyl acetate ent-XXV, which seems to
be possible according to the ∆Hq values obtained for such
process, comparable to those obtained for the trans product
(∆Hq(TSXXIV-XXV) ) 8.1 vs ∆Hq(TScis-XXIV-entXXV) ) 4.0 kcal/
mol, considering solvent effects in both cases).
Scheme 11. Chirality Transfer of Compounds 23 and 24
since the ring opening of the cyclopropyl via gold-stabilized
carbocations TSXIVa(1) and TSXIVa(2) takes place with retention
of the configuration, which in principle should be translated in
Acetate Fission vs Cyclopropyl Ring Opening. Finally, from
intermediates of type XIVa, we decided to study the competitive
acetate fission process to give R-ylidene-ꢀ-diketones XXVIIa,
as previously described by Zhang and co-workers.14 The
activation energy for the attack of a metal-vinyl bond into the
acetate TSXIVa-XXVIIa is approximately 25-26 kcal/mol, inde-
pendent of the substituent at the cyclopropyl ring (Scheme 13,
1
the final products. A careful H NMR analysis of the reaction
of trans-5k in the presence of [(IPr)Au(NTf2)] or pyridine-2-
carboxylate gold(III) showed that, in addition to the expected
scrambling at the propargylic position as predicted in Scheme
8,31 a partial epimerization at the cyclopropyl occurred prior to
the cyclization event.26 A computational study revealed a
reaction pathway that could account for such configurational
(31) In ref 13b Toste et al. have shown that scrambling in the cis-1-
cyclopropyl propargyl acetates at both propargylic and cyclopropyl
positions takes place before the cyclization is complete. However, no
such phenomenon was detected for the trans-cyclopropyl derivatives
they studied nor could the responsible intermediates for the second of
these processes be fully characterized computationally.
(30) The absolute configuration shown here for the cyclopentenone products
was proposed on the basis of our previous results on the cyclization
of 1-cyclopropyl propargyl acetates.13a
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Scheme 12. Reaction Coordinate Diagrams for the Cyclopropyl Epimerization of XXIVa
a Calculations were carried out at the B3LYP/6-31G(d) (C, H, O) and LANL2DZ (Au) levels (+ZPE corrected energies are given in kcal/mol; calculations
considering solvent effects (CH2Cl2)). Au ) (IPr)Au.
Scheme 13. Reaction Coordinate Diagrams for the Cyclopentannulation vs the Acetate Fission Reactiona
a Calculations were carried out at the B3LYP/6-31G(d) (C, H, O) and LANL2DZ (Au) levels (+ZPE corrected energies are given in kcal/mol). Au )
(IPr)Au.
right). However, the activation barrier for the ring opening of
the methyl-substituted cyclopropyl rises to more than 27.6 kcal/
mol (vs 19.9 kcal/mol for the vinyl-substituted one), thus
highlighting the importance of the cyclopropyl substituent in
the reaction mechanism (Scheme 13, left).
process competes with a gold-triggered cyclopropyl opening/
closure prior to the cyclization event. Surprisingly, such
cyclopropyl scrambling has been found for both cis and trans
settings, thus highlighting the configurational promiscuity of
these motifs. The rearrangement of tertiary acetates has been
highly illuminative of the competitive nature of the 1,2- and
1,3-acyloxy migration pathways, opening the venue for new
transformations orchestrated in that regard, which is currently
being pursued and will be reported in due course.
Conclusion
We present here a complete study on the reactivity of
3-cyclopropyl propargylic acetates and enol ethers with Au(I)
and Au(III) catalysts. The intelligence gathered in the develop-
ment of the gold-catalyzed homo-Rautenstrauch rearrangement
previously reported by our group aided the selection of
substituents at the cyclopropyl ring able to tune the reactivity
of these settings in favor of a cyclopentannulation vs an acetate
fission process to give R-ylidene-ꢀ-diketones. Supported by DFT
calculations, this study sheds light on the key gold-stabilized
“nonclassical carbocationic” intermediates involved in the
stereocontrolled synthesis of 5-(E)-alkylidene cyclopentenyl
acetates and reveals the intrinsic stereospecific nature of these
transformations. Further experimental and computational evi-
dence is disclosed to explain the lack of a complete chirality
transfer in optically active settings: the cyclopentannulation
Acknowledgment. We thank the Organic Chemistry Institute
of the University of Zu¨rich, Givaudan, and the Swiss National
Science Foundation for financial support and the SGI/IZO-SGIker
UPV/EHU and Matterhorn (UZH) for allocation of computational
resources.
Supporting Information Available: Text, figures, and tables
giving experimental and computational details and NMR spectra.
This material is available free of charge via the Internet at http://
pubs.acs.org.
JA909013J
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