Gold(I)/Xiang-Phos-Catalyzed Asymmetric Intramolecular Cyclopropanation of Indenes and Trisubstituted Alkenes

Article abstract of DOI:10.1021/acs.orglett.8b02999

The first intramolecular enantioselective cyclopropanation of indenes and trisubstituted alkenes was accomplished by using new chiral phosphine X5 derived gold(I) complexes. This reaction is a straightforward, efficient method for constructing [5-3-6] fused-ring compounds with two vicinal all-carbon quaternary stereogenic centers, a core structure shared by numerous pharmacological products, and bioactive compounds. The salient features of this transformation include high enantioselectivity (up to >98% ee), excellent yield (>97%), and nice functional group tolerance.

Full text of DOI:10.1021/acs.orglett.8b02999

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Gold(I)/Xiang-Phos-Catalyzed Asymmetric Intramolecular
Cyclopropanation of Indenes and Trisubstituted Alkenes
Pei-Chao Zhang,† Yidong Wang,† Zhan-Ming Zhang,† and Junliang Zhang*,†,‡
†Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University,
3663 North Zhongshan Road, Shanghai 200062, P. R. China
‡Department of Chemistry, Fudan University, 2005 Songhu Road, Shanghai 2000438, P. R. China
S
* Supporting Information
ABSTRACT: The first intramolecular enantioselective cyclopropanation of indenes and trisubstituted alkenes was
accomplished by using new chiral phosphine X5 derived gold(I) complexes. This reaction is a straightforward, efficient
method for constructing [5−3−6] fused-ring compounds with two vicinal all-carbon quaternary stereogenic centers, a core
structure shared by numerous pharmacological products, and bioactive compounds. The salient features of this transformation
include high enantioselectivity (up to >98% ee), excellent yield (>97%), and nice functional group tolerance.
Scheme 1. Asymmetric Intramolecular Cyclopropanation of
Olefins for Constructing [5−3−6] Fused-Ring Systems
used-ring molecules containing vicinal all-carbon quater-
Fnary stereocenters are particularly important, and they
exhibit a variety of biological and pharmacological activities,
due to their unique structural features and tendency to tightly
bind to target molecules.1 However, the construction of such a
structural motif, especially bearing multiple vicinal all-carbon
quaternary stereocenters, remains a significant challenge in a
single-step operation. Transition-metal-catalyzed intramolecu-
lar asymmetric cyclopropanation (ACP) of olefins is one of the
most powerful and straightforward synthetic tools for
constructing fused-ring systems from simple linear substrates.2
Cyclopropanation represents a typical cycloisomerization of
1,6-enyne, which provides an efficient approach to ring-fused
compounds. Recently, Toste3a reported the gold(I)-catalyzed
stereoselective olefin cyclopropanation. Zhu and Zhou3b
reported the first copper- or iron-catalyzed intramolecular
ACP of indole for constructing a [5−3−6] fused-ring system
(Scheme 1b). Indole-to-indene core change led to the the large
difference in the reactivity and stability (Scheme 1a).4
However, the method for building polycyclic systems with
indene skeletons remains unexplored so far.
The fused [5−3−6] ring system bearing one or two vicinal
all-carbon quaternary stereocenters is a subunit frequently
found in pharmaceuticals and agrochemicals.5 Intramolecular
cyclopropanation of the 1,6-enynes is one of the most efficient
approaches to construct bicyclo[4.1.0]heptene derivatives.6,7
Despite much progress that has been made, the development
of a highly enantioselective version still poses a considerable
challenge, and only a few examples have been reported so far.8
We herein report the first gold-catalyzed ACP of indenes using
alkynes as gold(I) carbene precursors, which provides a reliable
strategy for the efficient construction of a valuable [5−3−6]
Received: September 19, 2018
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.8b02999
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Letter
a
fused-ring system with indene skeletons featuring three
continuous stereocenters including two vicinal all-carbon
quaternary stereocenters in a highly stereoselective manner
(Scheme 1c).
Table 1. Screening Reaction Conditions
Indene-derived 1,6-enyne 1aa was easily prepared by the
Mitsunobu reaction from the corresponding (1H-inden-3-
yl)methanol and propargylamine. A series of commercially
available chiral ligands such as (S)-BINAP, (R)-MOP, (R)-
DM-SEGPhos, BIPHEP, binol-derived phosphoramidite, and
our recently developed chiral Ming-Phos,9a,b,c,e PC-Phos,9f,g
and Xiang-Phos9d (Figure 1) were investigated for the gold-
b
entry
ligand
additive
solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
toluene
CF3Ph
4-F-CF3Ph
4-F-CF3Ph
4-F-CF3Ph
4-F-CF3Ph
4-F-CF3Ph
yield [%] ee [%]
1
2
3
4
5
6
7
(S,Rs)-X1
(S,Rs)-X2
(S,Rs)-X3
(R,Rs)-X4
(R,Rs)-X5
(R,Rs)-X6
(R,Rs)-X5
(R,Rs)-X5
(R,Rs)-X5
(R,Rs)-X5
(R,Rs)-X5
(R,Rs)-X5
(R,Rs)-X5
(R,Rs)-X5
(R,Rs)-X5
(R,Rs)-X5
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgNTf2
AgOTf
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
NaBArF
>90
>90
>90
>90
>90
>90
>90
(82)
>90
>90
>90
>90
>90
>90
(99)
>90
−35
−13
11
63
67
−45
46
37
66
77
80
81
82
83
91
88
c
8
d
9
10
11
12
13
14
e
f
g
cd
,
15
16
i
a
Unless otherwise noted, all reactions were carried out with 0.1 mmol
of 1a and 5 mol % of catalyst ([Au]/Xiang-Phos) in 2.0 mL of solvent
Figure 1. Screening chiral ligands.
b
c
at rt for 0.5−12 h. Determined by HPLC analysis. Isolated yield.
d
e
catalyzed intramolecular ACP of 1aa (for more details, see
Supporting Information (SI), Scheme S1). The new (R,Rs)-
X4−X6 were prepared from the corresponding (Rs)-3 with the
corresponding aryl lithium instead of the previous alkyl
magnesium (Scheme 2). The structure and absolute
NaBArF: sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate.
0
f
g
h
°C. −10 °C. −15 °C. 10 mol % of NaBArF, 6.0 mL of solvent at
−15 °C. 10 mol % of NaBArF, 6.0 mL of solvent at −20 °C.
i
electron-withdrawing groups on the para- and meta-positions
of the phenyl ring (R2) were compatible, and the desired
products 2aa−2ar were isolated in 98−99% yields with 90−
96% ee’s. Gratifyingly, the 1-naphthyl, 2-naphthyl, and 2-
thienyl derived 1as−1au also worked well, delivering the
desired products 2as−2av in 98−99% yields with 89−94%
ee’s. Moreover, benzoindene and the 4,7-dimethyl-substituted
indene-derived substrates 1av−1ax could also work well,
furnishing the desired product 2av−2ax with 99% yield with
93−98% ee’s. When the R2 is an ortho-substituted phenyl
group 1ay or methyl group 1az, the desired products 2ay in
98% yield, 67% ee, and 2az were isolated in 98% yield but with
only 62% ee, indicating further ligand modification is
necessary. For the substrate with terminal alkyne 1ba (R2 =
H), the reaction is messy.
Inspired by the above success, we next turned our attention
to examine the scope and limitation of the reaction by
extending the indene moiety of 1,6-enynes to other alkenes
(Scheme 4). Gratifyingly, a substrate bearing acyclic
trisubstituted olefin 4 was also highly reactive, allowing for
an ACP reaction under the standard reaction conditions to
give the desired bicyclic product 4a in 99% yield with 97% ee.
1,6-Enynes 5−9 with 5−8 cycloalkene moieties also worked
smoothly, delivering the corresponding 5a−9a in excellent
yields with 85−90% ee’s. It is noteworthy that the yne-diene 7
was also comptible to selectively produced the desired tricyclic
product 7a in 99% yield, with 89% ee. O-tethered 1,6-enyne 10
also worked well under the standard reaction conditions, to
give the desired bicyclic product 10a in 98% yield but with
only 24% ee, indicating the tether moiety affects the
enantioselectivity significantly. Boc was used, which is another
easily removable protecting group, and the desired bicyclic
product 11a was obtained in 98% yield with 96% ee.
Scheme 2. Concise Synthetic Approach to (R,Rs)-X4−6 and
Gold Complexes
configuration of the gold complex X5−AuCl were established
by single-crystal X-ray diffraction analysis. To our delight, this
gold complex treated with AgSbF6 could deliver 2aa as a single
diastereomer in high yield with 67% ee (Table 1, entry 5).
Subsequently, the effect of the counterion was investigated
(Table 1, entries 6−9). With the use of sodium tetrakis[3,5-
−
bis(trifluoromethyl) phenyl]borate (BArF ) as additive, the
desired product 2aa was obtained in 99% yield with 66% ee at
room temperature for 2 h. The solvent screening showed that
the benzene solvent was favorable to the reaction, and 4-F-
PhCF3 proved to be the best solvent (Table 1, entries 10−12
and SI). Finally, running the reaction at lower temperature
(−15 °C) with the use of 10 mol % of NaBArF led to a
significant improvement in enantioselectivity, thus affording
(−)-2aa in 99% isolated yield with 91% ee. The structure and
absolute configuration of (S,R,R)-2aa were determined by
single-crystal X-ray diffraction analysis.
With the optimal reaction conditions in hand, we next
examined the scope of the reaction by variation of the 1,6-
enyne 1 (Scheme 3). First, the R2 substituent effect at the
alkyne moiety was studied. Not only electron-donating but also
B
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afford 1.1 g of 2aa in 99% yield with 89% ee under the optimal
conditions (Scheme 5). The selective oxidative cleavage of the
Scheme 3. Gold(I)-Catalyzed Intramolecular ACP of
Indene-Derived 1,6-Enyne 1
Scheme 5. Synthetic Transformations of 2aa
double bond of 2aa with ozone led to the highly functionalized
cyclopropane 12 in 91% yield with 89% ee. It is interesting to
find that the selective epoxidation of the double bond of 2aa
with m-CPBA delivered the unstable N-tosylamide 13, which
would quickly convert into 12 in 95% yield with 89% ee.
Moreover, the allylation of 2aa by treatment with allyltrime-
thylsilane in the presence of trifluoroacetic acid delivered the
allylation product 14 in 96% yield with 92% ee and 9:1 dr.
In summary, we have demonstrated for the first time
intramolecular ACP of 1,6-enynes under the catalysis of X5/
gold complexes. Chiral [5−3−6] fused-ring compounds with
two vicinal all-carbon quaternary stereogenic centers were
prepared in high yields (98−99%) with excellent enantiose-
lectivities (up to >98% ee) under mild reaction conditions.
This method provides an efficient, reliable, and atom-economic
strategy for the excellent diastereo- and enantioselectivity
construction of valuable highly chiral [5−3−6] fused-ring
compounds featuring two vicinal all-carbon quaternary stereo-
genic centers. Moreover, the broad substrate scope, easy scale-
up, and the easily made ligand in the large scale make this
reaction quite practical and highly attractive. Further studies
including synthetic application of this efficient transformation
and the employment of the chiral catalyst to other reactions are
currently in progress.
Scheme 4. Gold(I)-Catalyzed Intramolecular ACP of 1,6-
Enynes 4−11
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02999.
Experimental procedures, 1H and 13C NMR spectra, and
HPLC data for all new products (PDF)
Accession Codes
CCDC 1859820−1859821 and 1868217 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
To display the synthetic utility of the present methodologies,
the reaction of 1aa proceeded smoothly on a gram scale to
*E-mail: junliangzhang@fudan.edu.cn.
C
DOI: 10.1021/acs.orglett.8b02999
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Organic Letters
ORCID
Letter
(7) For representative examples, see: (a) Blum, J.; Beer-Kraft, H.;
Badrieh, Y. J. Org. Chem. 1995, 60, 5567−5569. (b) Fu
̈
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Junliang Zhang: 0000-0002-4636-2846
Notes
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The authors declare no competing financial interest.
̈
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ACKNOWLEDGMENTS
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We gratefully acknowledge the funding support of the NSFC
(21425205, 21672067), the 973 Program (2015CB856600),
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