Gold-catalyzed enantioselective ring-expanding cycloisomerization of cyclopropylidene bearing 1,5-enynes

Article abstract of DOI:10.1021/ol5007955

An enantioselective ring-expanding cycloisomerization of 1,5-enynes bearing a cyclopropylidene moiety has been developed. This methodology provides a new approach to bicyclo[4.2.0]octanes, a structural motif present in many biologically active natural products.

Full text of DOI:10.1021/ol5007955

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Enantioselective Ring-Expanding Cycloisomerization
of Cyclopropylidene Bearing 1,5-Enynes
Hongchao Zheng, Ryan J. Felix, and Michel R. Gagne*
́
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: An enantioselective ring-expanding cycloisomeriza-
tion of 1,5-enynes bearing a cyclopropylidene moiety has been
developed. This methodology provides a new approach to
bicyclo[4.2.0]octanes, a structural motif present in many
biologically active natural products.
atalysis as a tool for increasing molecular complexity is
C
crucial across the spectrum of chemical enterprises from
pharmaceuticals to commodity chemicals.1 Industry and
academia alike seek organic transformations that not only
produce important chemicals but do so efficiently and cost
effectively.2 In this regard, homogeneous gold catalysis is
particularly powerful for the construction of complex target
molecules.3 The bicyclo[4.2.0]octane is a structural motif that
occurs in a large number of natural products, e.g., Figure 1. Its
Figure 1. Natural products containing the bicyclo[4.2.0]octane core.
synthesis has therefore attracted much attention,4 including two
gold-catalyzed cycloisomerization approaches that generate a
key cyclopropylmethyl carbocation intermediate:5 one cyclo-
generated from 1,6-enynes (Toste)6 and a second from 1,7-
allene-enes (Echevarren).7 As part of a program aimed at
utilizing strain relief in alkylidenecyclopropanes to drive the
rearrangement of unsaturated hydrocarbons,8 we hypothesized
that easily synthesized 1,5-alkynylalkylidenecyclopropanes like
1 would efficiently yield the [4.2.0]-skeleton and further be
amenable to asymmetric catalysis (Figure 2C). We now report
a gold-catalyzed enantioselective ring-expanding cycloisomeri-
zation of 1,5-enynes 1 to chiral bicyclo[4.2.0]octadiene 2
(Figure 2C).
The high strain inherent in the cyclopropylidene moiety
(∼40 kcal/mol) underpins its utility as an important class of
synthetic intermediates in organic chemistry.9 The relief of its
strain can provide a potent thermodynamic driving force for
otherwise unfavorable reactions.8,10 Taking advantage of the
ring strain relief strategy, we recently reported the first gold-
catalyzed enantioselective Cope rearrangement of achiral,
acyclic 1,5-dienes (Figure 2A).8a The application of a similar
Figure 2. Gold-catalyzed (A) enantioselective Cope rearrangement of
achiral 1,5-dienes; (B) ring-expanding cycloisomerization of 1,5-
dienes; (C) proposed ring-expanding cycloisomerization of 1,5-enynes.
approach to cyclic 1,5-dienes led to an unexpected gold-
catalyzed ring-expanding cycloisomerization and access to fused
tricyclics containing the bicyclo[4.2.0]oct-1-ene core (Figure
2B).8b This result reasonably suggested that 1,5-enynes bearing
a cyclopropylidene unit, 1, could be coaxed to rearrange to
bicyclo[4.2.0] diene 2 under gold catalysis via a sequential 6-
endo-dig cyclization/ring expansion/net 1,2-hydrogen shift
sequence (Figure 2C). DFT calculations indicated that the 1
to 2 conversion was exothermic by ∼39 kcal/mol.11
To test the hypothesis outlined in Figure 2C, 1,5-enyne 1a
was treated with 10 mol % of Ph3PAuNTf2 in DCM. To our
delight, the desired 6,4-bicyclo diene 2a was obtained in 82%
yield within 2 h (entry 1, Table 1). The versatility of this
Received: March 17, 2014
Published: March 31, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Table 1. Gold-Catalyzed Ring-Expanding
Cycloisomerizations of 1,5-Enynes 1
Table 2. Survey of Catalysts for the Au-Catalyzed
a
Enantioselective Ring-Expanding Cycloisomerization of a
a
Model 1,5-Enyne 1a
b
entry
enyne
R1
Ph
R2
product
yield (%)
b
1
2
3
1a
1b
1c
1d
1e
1f
CH3
2a
2b
2c
2d
2e
2f
82
82
87
83
90
81
90
83
entry
ligand
X−
er
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3
H
cyclopropyl
1
(S)-xylyl-BINAP
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
NTf2
BF4
57:43
64:36
65:35
allyl
2
(R)-C3-TUNEPHOS
(R)-xylyl-MeO-BIPHEP
(R)-DIFLUORPHOS
(R)-xyl-SDP
c
4
vinyl
3
c
5
Ph
4
−
6
4-FC6H4
5
56:44
65:35
61:39
73:27
80:20
77:23
75:25
7
1g
1h
4-ClC6H4
2g
2h
6
(R)-DM-SEGPHOS
(R)-DTBM-SEGPHOS
(R,R)-Me-DuPHOS
(R,R)-i-Pr-DuPHOS (4)
(R)-SYNPHOS
8
4-CH3OC6H4
7
d
d
d
9
−
H
−
−
8
d
10
1i
Ph
Ph
2i
73
9
e
11
1j
2j
50
10
11
12
13
14
15
a
Reaction conditions: Ph3PAuNTf2 (0.01 mmol) was added to a
(R)-3,5-xylyl-PHANEPHOS
(R,R)-i-Pr-DuPHOS (4)
(R,R)-i-Pr-DuPHOS (4)
(R,R)-i-Pr-DuPHOS (4)
(R,R)-i-Pr-DuPHOS (4)
e
solution of 1,5-enyne 1 (0.1 mmol) in CH2Cl2 (1.0 mL). The solution
−
b
e
was stirred at rt for 2 h. Yields of isolated 2 purified by column
SbF6
PF6
−
c
d
chromatography on silica gel. 20 mol % catalyst loading was used. A
f
81:19
e
complex mixture was obtained. 2j is unstable and decomposes quite
f
OTf
−
rapidly at rt.
a
Reaction conditions: L(AuCl)2 (0.005 mmol) was added to a
solution of AgX (0.01 mmol) in CH2Cl2 (1.0 mL) at rt. The solution
was stirred at rt for 15 min before addition of 1a (0.1 mmol). The
resulting mixture was stirred at rt for 4 h. Unless otherwise mentioned,
the reaction was complete and the GC yields of 2a fell within the 70−
catalytic system for ring-expanding cycloisomerization was
evaluated on a variety of 1,5-enynes. As shown in Table 1,
variable substitution on the cyclopropylidene were tolerated, as
cyclopropyl-, allyl-, vinyl-, and phenyl-substituted substrates all
reacted smoothly, yielding bicyclo[4.2.0] dienes 2b−e in
excellent yields (entries 2−5, Table 1). Aryl substitution at
R2 also proceeded efficiently, with electron-poor (entries 6−7)
and electron-rich substrates (entry 8) providing excellent yields
of the corresponding dienes. However, when the 1,5-enyne
bears a terminal cyclopropylidene, a complex mixture was
obtained (entry 9, Table 1). A variety of substituents on the
alkyne moiety were also tolerated (entries 10 and 11, Table 1).
The use of an aliphatic substituent in place of the aryl moiety at
R1 afforded the desired bicyclo[4.2.0] diene, 2i, but in a slightly
lowered yield (entries 10 vs 5, Table 1). A substrate bearing a
terminal alkynyl group also rearranged to the bicyclo[4.2.0]
diene (2j) successfully, although 2j was not stable and
decomposed at room temperature after isolation (entry 11,
Table 1). Unfortunately, 1,4-enynes were not suitable
substrates, as indicated by the failure of 3 to rearrange.12
Given the chirality of the generated bicyclo[4.2.0]octadienes
2 and the general need for de novo methods to access all-
carbon quaternary centers,13 we embarked on the development
of an enantioselective variant of this gold-catalyzed ring
expanding cycloisomerization. In the first round of exploration,
a number of chiral bis(gold) catalysts were evaluated for their
ability to enantioselectively catalyze the ring-expanding cyclo-
isomerization of 1a (entries 1−11, Table 2). The catalyst
derived from the activation of (R,R)-i-Pr-DuPHOS(AuCl)2 4
with AgNTf2 provided the highest enantioselectivity (entry 9,
Table 2). A subsequent screen of silver salts (entries 9 and 12−
15) confirmed that AgNTf2 was optimal in terms of yield and
enantioselectivity (entry 9, Table 2). Further experimentation
with the reaction in entry 9 revealed poor reproducibility, a
phenomenon that was traced to the high sensitivity of the yield
and enantioselectivity to the Au/Ag ratio, with the most robust
conditions coming from a 1:1 ratio of 4 to AgNTf2 (entry 1,
b
85% range. The er was determined by chiral stationary-phase GC,
and the absolute configuration of the major enantiomer was not
c
d
determined. No reaction. Enantioselectivity varied with the
equivalents of Ag(I) salts used. Most reproducible results came with
e
utilization of 5 mol % of AgNTf2. Catalyst decomposed during the
f
reaction. Significant acid-catalyzed side products were formed.
Table 3). Although this silver effect is not yet understood,
AgNTf2 alone slowly converts 1a to 2a.14
Further optimization of reaction parameters confirmed that
the use of catalyst 4 (5 mol %) and AgNTf2 (5 mol %) in
nitroalkane solvents provided the best reaction conditions
(entries 1−4, Table 3). This catalytic system was still effective
at 0 °C, affording the desired bicyclic diene 2a in a slightly
increased enantioselectivity, provided a longer reaction time
was used (entries 5 and 6, Table 3). Although better
enantioselectivity could be achieved at even lower reaction
temperatures, the yield was sacrificed significantly due to
undesired side reactions or incomplete reactions (entries 7 and
8, Table 3).
With an optimized set of reaction conditions in hand, the
1,5-enynes 1a−i listed in Table 1 were investigated (Scheme 1).
All substrates readily rearranged to the desired bicyclo dienes 2
in high yields within 4 h. Although the substituent on the
cyclopropylidene moiety had only a small impact on the yield
of 2, it played an important role in the enantioselectivity of the
rearrangement. As a result, the alkyl- (2a,b), allyl- (2c), and
electron-rich aryl-substituted bicyclic dienes (2h) were
obtained with good enantioselectivities; vinyl- (2d), phenyl-
(2e), and electron-poor aryl-substituted bicyclic dienes (2f,g)
gave only moderate enantioselectivities (Scheme 1).
From a mechanistic point of view,15 the present Au(I)-
catalyzed ring-expanding cycloisomerization can be rationalized
as depicted in Scheme 2. π-Acid activation of the alkyne in 1a
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Organic Letters
Letter
Table 3. Solvent and Temperature Optimization for the Au-
Catalyzed Enantioselective Ring-Expanding
Cycloisomerization of 1a
Scheme 2. Proposed Mechanism and Supporting Control
Experiment for the Conversion of 1a to 2a
a
b
entry
solvent
temp (°C)
time (h)
er
1
2
3
4
5
6
7
8
CH2Cl2
1,2-DCE
CH3NO2
EtNO2
rt
rt
2
70.5:29.5
79:21
2
rt
2
83:17
rt
2
81.5:18.5
85:15
CH3NO2
EtNO2
0
2.5
2.5
6
0
84:16
c
EtNO2
−20
−50
86.5:13.5
d
c
also suggests an explanation for the poor behavior of the
unsubstituted enyne in entry 9 (Table 1), which would
cyclogenerate a secondary cation in the initiating 6-endo-dig
cyclization. These data point to the viability (and trapability) of
allylic carbocation 7 as a reactive intermediate during the gold-
catalyzed ring-expanding cycloisomerization of 1,5-enynes.
It is also intriguing to consider which elementary step in
Scheme 2 is stereochemistry determining. Provided that no
steps are reversible (a questionable hypothesis), good
enantioselectivities suggests that the chiral catalyst may be
controlling which enantiotopic cyclopropane C−C bond
migrates to the adjacent carbenium ion (i.e., 5 to 7).18 This
ring expansion sets the all-carbon quaternary center and the
stereochemistry of the product.
EtNO2
−
91.5:8.5
a
Reaction conditions: 4 (0.005 mmol) was added to a solution of
AgNTf2 (0.005 mmol) in the indicated solvent (1.0 mL) at rt. The
solution was stirred at rt for 15 min and then cooled to the indicated
temperature. 1a (0.1 mmol) was added to the above solution and the
reaction stirred at the indicated temperature for the specified time.
Unless otherwise mentioned, the reaction was complete and the GC
yields of 2a fell within the 70−85% range. er values determined by
chiral stationary-phase GC, and the absolute configuration of the
major enantiomer was not determined. Significant side products
formed. Reaction incomplete after 24 h.
b
c
d
Scheme 1. Gold-Catalyzed Enantioselective Ring-Expanding
Cycloisomerizations of the 1,5-Enynes 1
In summary, we have developed a gold-catalyzed enantiose-
lective ring-expanding cycloisomerization of 1,5-enynes, leading
to enantioenriched bicyclo[4.2.0]octadienes in high yields and
with moderate-to-good enantioselectivities. Although room
remains for improvement in enantioselectivity, the present
asymmetric gold catalysis represents an efficient approach to
6,4-bicyclo structures bearing a quaternary all-carbon stereo-
center, a structural motif found in many biologically active
natural products. Studies to apply this methodology to the total
synthesis of biologically important molecules are underway.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data, and spectra are
included. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mgagne@unc.edu.
Notes
The authors declare no competing financial interest.
by gold triggers a 6-endo-dig16 cyclization that generates
cyclopropylcarbinyl cation (5), which ring expands to the
more stable allylic carbocation 7 and terminates by a net 1,2-
hydrogen shift to form 2a.6 Consistent with this proposal, the
addition of CH3OH as an external nucleophile generates
bicyclo ether 6 as a single diastereomer in 90% yield. Since 6 is
not formed from a Au-catalyzed electrophilic addition of
CH3OH to 2a, it most likely results from a trapping of 7.17
Compound 6 is similar in structure and stereochemistry to the
russujaponol D family of natural products.7 This mechanism
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health, General Medicine
(GM-60578), for generous support. We thank Dr. Mee-Kyung
Chung (UNC Chapel Hill) for help with HRMS analyses.
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Letter
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