Enantioselective gold(I)-catalyzed vinylogous [3 + 2] cycloaddition between vinyldiazoacetates and enol ethers

Article abstract of DOI:10.1021/ja407179c

The reaction of vinyldiazoacetates with enol ethers catalyzed by the binuclear gold complex (R)-DTBMSegphos(AuCl)₂ activated by silver hexafluoroantimonate results in a highly enantioselective [3 + 2] cycloaddition. The [3 + 2] cycloaddition proceeds with dynamic kinetic resolution when the enol ether is a 4-substituted 1-(methoxymethylene)cyclohexane. The reaction is initiated by nucleophilic attack of the vinyl ethers at the vinylogous position of the gold vinylcarbene intermediate.

Full text of DOI:10.1021/ja407179c

Communication
pubs.acs.org/JACS
Enantioselective Gold(I)-Catalyzed Vinylogous [3 + 2] Cycloaddition
between Vinyldiazoacetates and Enol Ethers
John F. Briones and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
S
* Supporting Information
Scheme 1. Digold-Catalyzed [3 + 2] Cycloaddition between
Vinyl Ethers and Vinyldiazoacetates
ABSTRACT: The reaction of vinyldiazoacetates with enol
ethers catalyzed by the binuclear gold complex (R)-
DTBMSegphos(AuCl)2 activated by silver hexafluoroan-
timonate results in a highly enantioselective [3 + 2]
cycloaddition. The [3 + 2] cycloaddition proceeds with
dynamic kinetic resolution when the enol ether is a 4-
substituted 1-(methoxymethylene)cyclohexane. The reac-
tion is initiated by nucleophilic attack of the vinyl ethers at
the vinylogous position of the gold vinylcarbene
intermediate.
irhodium catalysts have played a pivotal role in the
Ddevelopment of the chemistry of metal carbenes derived
from diazo compounds.1 In contrast, the application of gold(I)
catalysts to the decomposition of diazo compounds is a
relatively unexplored area of research.2 Activity in this area has
increased in recent years, but the vast majority of the work still
involves achiral gold catalysts.3 Recently, we reported the
enantioselective cyclopropenation of internal alkynes with
aryldiazoacetates4 using digold(I)−BINAP complexes, such as
4 and 5.5 Inspired by the high level of enantioselectivity
exhibited in these cyclopropenation reactions, we have begun to
explore digold-catalyzed carbene reactions, with a particular
emphasis on developing new reactions that do not occur under
rhodium catalysis. The focus of our studies has been on the
reactions of metal-bound donor/acceptor carbenes because the
attenuated reactivity caused by the donor group makes these
carbenes highly versatile synthetic intermediates. In this paper
we describe the highly enantioselective Au(I)-catalyzed [3 + 2]
cycloaddition reaction between enol ethers 1 and vinyl-
diazoacetates 2 to generate cyclopentenecarboxylates 3
(Scheme 1).
we reported that the Rh2(S-DOSP)4-catalyzed reaction of cyclic
enol ether 6 with styryldiazoacetate 7 resulted in a combined
C−H insertion/Cope rearrangement (CHCR) affording the
vinylogous Mukaiyama aldol-type product 8 in a highly
diastereo- and enantioselective fashion (Scheme 2).8 In
Scheme 2. Effect of Catalyst on the Reaction between 6 and
7
From our studies on metal-bound donor/acceptor carbenes,
we have found that the silver and gold carbenes are more
reactive than the corresponding rhodium carbenes.6 They are
capable of cyclopropanating and cyclopropenating sterically
crowded alkenes and alkynes, which do not react under
rhodium catalysis. Furthermore, silver-catalyzed reactions of
vinylcarbenes display enhanced electrophilic character at the
vinylogous position of the vinylcarbenes.7 Therefore, we
decided to explore gold-catalyzed reactions of vinylcarbenes
with the expectation that the enhanced vinylogous reactivity
that is likely to occur3h would lead to new transformations that
had not been observed under rhodium-catalyzed conditions.
A breakthrough in this project was made when we studied
the reaction of gold vinylcarbenes with enol ethers. Recently,
contrast, when we conducted the (R)-DTBMSegphos(AuCl)2
((R)-5)-catalyzed reaction of 6 with 7 an entirely different
product was formed. The formal [3 + 2] cycloadduct 9 was
obtained in 81% yield with neither C−H insertion nor
cyclopropanation products observed (Scheme 2). Furthermore,
9 was formed as a single diastereomer and with a high level of
enantioselectivity (88% ee).9
Received: July 13, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja407179c | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
The scope and generality of this unusual [3 + 2]
cycloaddition was then examined with various trisubstituted
enol ethers. Various cyclic and acyclic enol ethers were
synthesized via a known procedure8 and subjected to the
standard reaction conditions (Table 1). The reaction worked
Scheme 3. Au(I)-Catalyzed Reaction of E/Z Mixture of 11
and 7
Table 1. Au(I)-Catalyzed Vinylogous [3 + 2] Reaction of
Enol Ethers and Various Vinyl Diazoacetates
suggests that the gold catalyst does not distinguish between the
E/Z isomers of 11, but the facial selectivity during the [3 + 2]
cycloaddition event of both isomers of 11 is still high.
One of the most intriguing substrates for the Au-catalyzed
reaction of vinylcarbenes is the 4-substituted 1-
(methoxymethylene)cyclohexane (14). In the case of the
Rh2(S-DOSP)4-catalyzed reaction of the vinyldiazoacetate 7
(0.6 equiv) with 14, we reported that the CHCR reaction
demonstrated exceptional kinetic resolution, generating 15 as a
single diastereomer with 99% ee (Scheme 4).8 The
Scheme 4. Reaction of Enol Ether 14 and 7 under Rh(II) and
Au(I) Catalysis
a
Standard reaction conditions: 2 (0.6 mmol, 1.2 equiv) in degassed
enantioenriched enol ether (S)-14 was recovered in 40%
yield and 98% ee. When the reaction was conducted using the
gold catalyst (S)-4 a very interesting result was obtained. The
[3 + 2] cycloadduct 16 was obtained in 78% yield and 94% ee,
but the recovered 14 was racemic. The absolute configuration
dichloromethane (8 mL) was added to a 2 mL dichloromethane
solution of 1 (0.5 mmol, 1.0 equiv), AgSbF6 (0.015 mmol), and (R)-5
b
c
(0.015 mmol) at 23 °C. The dr is >30:1 in all cases. Isolated yield of
d
e
10. Determined by chiral HPLC. (S)-4 was used as catalyst.
well with both cyclic and acyclic substrates, providing the
desired cyclopentene derivatives 10a−d in good yields (68−
81%) and excellent enantioselectivity (88−92%). Again, it is
noteworthy that the reaction is chemoselective toward the
formation of the cyclopentene products. The reaction can also
be expanded to different aryl and alkyl vinyldiazoacetates using
enol ether 6 as the representative substrate (entries 5−11). The
cyclopentene derivatives 10e−k were obtained in good yields
(70−90%) and excellent enantioselectivity (91−95% ee).
The study was then extended to the trisubstituted enol ether
11, in which the two alkyl substituents were different (Scheme
3). The reaction was conducted on a stereoisomeric mixture of
E and Z enol ethers (ca. 1:1 ratio). The reaction provided a 1:1
mixture of diastereomers 12 and 13, in good overall yield and
both diastereomers were generated with high levels of
asymmetric induction. The relative configuration of each
diastereomer was determined by NOE analyses. This result
of 16 was determined by X-ray crystallographic analysis.10
A
minor product, aldehyde 17, was also formed in the reaction
and was isolated in 6% yield and 31% ee. The relative
configuration of 17 was not determined. The formation of 16 in
good yield and enantioselectivity with the starting material 14
recovered as a racemate suggests that 14 is isomerizing under
the reaction conditions. Evidence to support this hypothesis
was obtained by exposing (S)-14 (98% ee) to the catalyst
mixture for 12 h at room temperature. Under these conditions,
(S)-14 partially racemized to material of 43% ee.
The observation that the enol ether 14 isomerizes under the
reaction conditions indicates that a dynamic kinetic resolution
may be feasible. In order to explore this possibility, we
conducted a series of reactions in which the enol ether substrate
was the limiting reagent (Table 2). Under these conditions, the
spirocyclic products 19a−c were produced as single diaster-
eomers in greater than 50% isolated yield (62−70%) and with
B
dx.doi.org/10.1021/ja407179c | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Dynamic Kinetic Resolution in the Au(I)-Catalyzed
Vinylogous [3 + 2] Reaction
Scheme 6. Dynamic Kinetic Resolution Model
a
b
c
d
entry
R
product
dr
yield (%)
ee (%)
1
2
3
Me
Ph
19a
19b
19c
>30:1
>30:1
>30:1
65
62
70
93
93
97
tBu
a
Standard reaction conditions: 7 (0.6 mmol, 1.2 equiv) in degassed
ether 18.11 Only the isomer 18a is matched for reaction at the
re face of the carbene 20 leading to the enantioselective
formation of 19. Even though a number of examples of kinetic
resolutions using carbene intermediates are known,12−14 as far
as we are aware, this is the first carbene example of dynamic
kinetic resolution.
We have developed the highly enantioselective Au(I)-
catalyzed vinylogous [3 + 2] cycloaddition of enol ethers and
vinyldiazoacetates. This reaction accesses highly functionalized
cyclopentene derivatives possessing three stereocenters con-
structed in a single step. Moreover, dynamic kinetic resolution
was achieved when cyclic enol ethers bearing axial substituents
were used as substrates for the reaction. This report constitutes
the first example of dynamic kinetic resolution in metal
carbenoid chemistry. This work illustrates the synthetic
potential of the growing field of asymmetric gold-catalyzed
carbene transformations.
dichloromethane (8 mL) was added to a 2 mL dichloromethane
solution of enol ether 18 (0.5 mmol, 1.0 equiv), AgSbF6 (0.015
b
c
mmol), and (R)-5 (0.015 mmol) at 23 °C. Isolated yield of 19. The
d
dr was determined from the crude reaction mixture. Determined by
chiral HPLC.
excellent enantioselectivity (93−97% ee). The absolute
configuration of spirocyclic product 19c was also confirmed
by X-ray crystallographic analysis.10 Formation of the aldehyde
product (analogous to 17) was minimal in all cases.
These studies demonstrate that the gold-catalyzed reactions
of vinyldiazoacetates with trisubstituted vinyl ethers are very
different from the corresponding rhodium-catalyzed reactions.
Considering the similarity between silver- and gold-catalyzed
reactions, it would be reasonable to assume that the initial
attack of the gold carbene 20 is occurring at the vinylogous
position of the carbene (Scheme 5). In the case of the silver-
Scheme 5. Proposed Mechanism of Au(I)-Catalyzed [3 + 2]
Cycloaddition
ASSOCIATED CONTENT
* Supporting Information
Synthetic details and spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
hmdavie@emory.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support of this work by the National Science Foundation
(CHE- 1213246) is gratefully acknowledged. We thank John
Bacsa for the X-ray crystallographic structural determination.
We also thank David Primer for his assistance with some of the
reactions during the course of this work.
catalyzed O−H insertion of vinylcarbenes, the experimental and
computational studies suggest that the vinylogous reaction
proceeds through the s-cis isomer of the silver vinylcarbenes.7
Vinylogous attack of the vinyl ether 1 on the s-cis configuration
of the vinylcarbene 20 would generate a zwitterionic
intermediate 21. Alternatively, the reaction could behave like
a highly asynchronous [4 + 2] cycloaddition generating a
metallocyclohexene 22. The zwitterionic intermediate has the
correct geometry to cyclize to the metallocyclohexane or close
directly to the cyclopentene 23. Reductive elimination of the
metallocyclohexene 22 would be an alternative way of
generating 23. If the reaction does involve zwitterionic
intermediates, the high diastereo- and enantioselectivity suggest
that the cyclization event is very fast, as otherwise scrambling of
the stereocontrol would occur.
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