Efficient access to bicyclo[4.3.0]nonanes: Copper-catalyzed asymmetric silylative cyclization of cyclohexadienone-tethered allenes

Article abstract of DOI:10.1002/anie.201508125

The creation of three consecutive chiral carbon centers in one step is achieved using Cu-catalyzed asymmetric silylative cyclization of cyclohexadienone-tethered allenes. Through regioselective β-silylation of the allene and subsequent enantioselective 1,4-addition to cyclohexadienone, this tandem reaction could afford cis-hydrobenzofuran, cis-hydroindole, and cis-hydroindene frameworks with excellent yields (80-98 %) and enantioselectivities (94-98 % ee) bearing vinylsilane and enone substructures. Meanwhile, this mild transformation is generally compatible with a wide range of functional groups, which allows further conversion of the bicyclic products to bridged and tricyclic ring structures. Three in one: Three consecutive chiral carbon centers are formed in one step by a copper-catalyzed asymmetric silylative cyclization of cyclohexadienone-tethered allenes. Thus cis-hydrobenzofuran, cis-hydroindole, and cis-hydroindene frameworks are prepared with exceptional yields (80-98 %) and enantioselectivities (94-98 % ee).

Full text of DOI:10.1002/anie.201508125

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201508125
German Edition: DOI: 10.1002/ange.201508125
Asymmetric Synthesis
Efficient Access to Bicyclo[4.3.0]nonanes: Copper-Catalyzed
Asymmetric Silylative Cyclization of Cyclohexadienone-Tethered
Allenes
Zhi-Tao He, Xiao-Qi Tang, Li-Bo Xie, Mian Cheng, Ping Tian,* and Guo-Qiang Lin
Abstract: The creation of three consecutive chiral carbon
centers in one step is achieved using Cu-catalyzed asymmetric
silylative cyclization of cyclohexadienone-tethered allenes.
Through regioselective b-silylation of the allene and subse-
quent enantioselective 1,4-addition to cyclohexadienone, this
tandem reaction could afford cis-hydrobenzofuran, cis-hydro-
indole, and cis-hydroindene frameworks with excellent yields
(80–98%) and enantioselectivities (94–98% ee) bearing vinyl-
silane and enone substructures. Meanwhile, this mild trans-
formation is generally compatible with a wide range of
functional groups, which allows further conversion of the
bicyclic products to bridged and tricyclic ring structures.
O
rganosilanes have broad and varied uses ranging from the
most frequently employed protecting groups, reducing agents
to valuable synthetic intermediates in organic chemistry.[1]
The efficient accesses to functionalized organosilanes are
continuously expanding to meet emerging needs. Recently,
silylboronate reagents introduced by Suginome and Ito[2] have
gained significant interest,[3–5] particularly in copper-catalyzed
[6]
À
C Si bond formation. Several research groups have con-
tributed greatly in the field of Cu-catalyzed silylative addition
[7]
[7c,8]
[9–10]
[11]
=
=
=
C C,
ꢀ
to C O, C N,
and C C bonds, and shaped
this arena as it stands today. However, the powerful cascade
approach forming multiple chemical bonds and stereocenters
was scarce to our knowledge.[12] Herein, we report the first
Cu-catalyzed asymmetric silylative cyclization of cyclohexa-
dienone-tethered allenes (1,6-enallenes).
Scheme 1. Strategic design for Cu-catalyzed asymmetric silylative cycli-
zation of cyclohexadienone-tethered allenes.
Allenes are like a chameleon in modern organic chemistry
and always fascinate chemists owing to their unique structural
and electronic properties.[13] It was reported that Cu–Si
species could react with allenes to form b-silylated allylcopper
intermediates.[14,15] Their three subsequent transformations
were reported using different electrophiles: MeOH for
hydrosilylation,[14a,b] aldehydes and ketones for 1,2-additio-
n,[14a,c] and CO2 for silacarboxylation.[15] Despite these advan-
ces, the challenging 1,4-addition of b-silylated allylcopper has
never been uncovered, because efficient 1,2-addtion remains
favored versus 1,4-addition in the addition of b-functionalized
allylcopper to a,b-unsaturated carbonyls (Scheme 1a).[16] To
address this issue, allene and a,b-unsaturated carbonyl are
integrated into a molecule, cyclohexadienone-tethered allene
1 (Scheme 1b). In this case, the 1,2- addition of b-silylated
allylcopper to ketone becomes rather difficult owing to its
inherent site restrictions. However, because the directing
group is not required during the selective b-silylation of
allene,[14,15] bicyclo[4.3.0]nonane frameworks 3, including cis-
hydrobenzofuran, cis-hydroindole, and cis-hydroindene could
be prepared, which overcomes the previous drawback that an
O-directing group is necessary.[18d]
Returning to the start of this cascade reaction, because the
direct conjugate silylation to cyclohexadienone is expected to
be suppressed by the neighboring steric hindrance, regiose-
lective b-silylation of the allene should preferentially occur
(Scheme 1b). In addition, Cu–Si addition places the Cu at the
less-hindered site of the allene, leading to the formation of b-
silylated allylcopper intermediate T2, rather than T1. Such
selective Cu–Si addition, together with the highly reactive
nature of cyclohexadienone, could potentially avoid the
competitive b-elimination pathway for the heteroatom-
linked 1,6-enallenes (X = O, N).[17] The subsequent intra-
[*] Z.-T. He, X.-Q. Tang, L.-B. Xie, M. Cheng, P. Tian, Prof. G.-Q. Lin
CAS Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: tianping@sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508125.
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molecular 1,4-addition of T2 furnishes chiral cis-bicyclic
framework bearing three consecutive chiral carbon centers.[18]
Nevertheless, the remote control of reaction diastereo- and
enantioselectivity (1,8-asymmetric induction) remains quite
challenging during this addition process.
With these concerns in mind, a set of representative chiral
ligands were evaluated for the Cu-catalyzed asymmetric
silylative cyclization of 1,6-enallene 1a, and selected results
are summarized in Table 1.[19] When the previous superior
PhMe2Si-Bpin (2) loading gave no better results (Table 1,
entries 7,8). When the reaction was conducted in THF at
room temperature, excellent yield (93%), diastereo- and
enantioselectivity (14:1 d.r. and 97% ee) were all successfully
obtained (Table 1, entry 9). Lower temperature proved to be
inferior in terms of yield and ee value (Table 1, entry 10).
With the optimal reaction conditions identified, we
evaluated the scope of O-linked 1,6-enallenes 1 and the
results were summarized in Table 2. With the R substituent as
Table 1: Selected optimization studies.[a]
Table 2: O-Linked 1,6-enallene scope.[a]
Entry
Subs. 1
t [h]
d.r.[b]
14:1
Prod. 3 Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
11
11
11
16
15
15
16
15
12
16
15
14
14
15
15
14
15
15
3a
3b
3c
3d
3e
3 f
3g
3h
3i
93
94
94
93
92
95
92
98
97
92
90
96
90
93
96
91
91
92
97
95
96
96
98
95
95
97
97
94
94
96
96
96
96
95
96
95
16:1
>20:1[e]
>20:1[e]
12:1
>20:1[e]
12:1
>20:1[e]
>20:1[e]
12:1
Entry
L
Solvent
t [h]
Conv.
[%][b]
d.r.[b]
Yield
[%][c]
ee
9
[%][d]
10
11
12
13
14
15
16
17
18
3j
3k
3l
>20:1[e]
>20:1[e]
17:1
1
2
3
4
5
6
L1
L8
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
THF
15
13
11
12
11
11
11
11
11
11
60
20
99
70
75
70
90
90
100
70
2.6:1
4.3:1
1.9:1
3.5:1
11:1
10:1
12:1
9:1
40
16
64
55
67
60
79
55
93
64
À29
69
À72
À80
À91
93
92
90
97
96
L13
L16
L18
L19
L19
L19
L19
L19
3m
3n
3o
3p
3q
3r
13:1
>20:1[e]
10:1
7[e]
8[f]
9[e]
10[e,g]
13:1
12:1
14:1
16:1
[a] Reactions were performed under a N2 atmosphere. [b] Determined by
the ratio of isolated yield of product 3 and its minor diastereomer.
[c] Yield of isolated product 3. [d] Determined by HPLC analysis. [e] The
minor diastereomer was not observed.
THF
[a] Reactions were performed under a N2 atmosphere. [b] Determined by
1H NMR (400 MHz) analysis of unpurified product mixtures. [c] Yield of
isolated product 3a. [d] Determined by HPLC analysis. [e] 2 (1.2 equiv)
was used. [f] 2 (1.3 equiv) was used. [g] At 08C.
alkyl, vinyl, allyl, benzyl, and phenyl group, the reactions
proceeded smoothly with excellent yields (92–98%) and
enantioselectivities (95–97% ee, Table 2, entries 1–9). With
a heteroatom (N, O, S, Br, or I) as part of R in substrates 1, the
reaction yields and ee values still remained excellent, respec-
tively (Table 2, entries 10–18). Note that the bromo- and iodo-
alkyl groups in substrates 1q and 1r were comfortably
tolerated in this transformation (Table 2, entries 17 and 18).
In other words, the b-silylated allylcopper selectively under-
went 1,4-addition rather than nucleophilic substitution in
both cases,[20] which corroborated the high reactivity of
cyclohexadienone.
phosphoramidite ligand L1 was tested,[18d] the desired silyla-
tive cyclization product 3a was obtained without the forma-
tion of b-elimination product, albeit in poor diastereo- and
enantioselectivity (Table 1, entry 1). The bisphosphine ligand
L8 was recently reported to effectively promote the asym-
metric 1,2-addition of b-borylated allylcopper complexes.[16]
In our case, the ee value was dramatically increased to 69%
despite with low yield and d.r. value (Table 1, entry 2).
Several bisphosphine ligands L13, L16, L18, and L19 were
subjected to this reaction afterwards. To our delight, all the
yields, d.r. and ee values of 3a were greatly improved,
especially for (S)-P-Phos (L19) (Table 1, entry 6). Increasing
In line with our expectation, as for the N-linked 1,6-
enallenes, the corresponding cis-hydroindole products, 3s, 3t,
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Table 3: N- and C-Linked 1,6-enallene scope.[a]
[a] Reactions were performed under a N2 atmosphere. [b] Determined by
the ratio of isolated yield of product 3 and its minor diastereomer.
[c] Yield of isolated product 3. [d] Determined by HPLC analysis. [e] The
Scheme 2. Selected examples of subsequent transformations, see text
for details. Crystal structure: O red, N dark blue, Si light blue.
1
minor diastereomer was not observed. [f] Determined by H NMR
(400 MHz) analysis of unpurified product mixture.
a tandem process: selective b-silylation of the allene and
subsequent enantioselective 1,4-addition to cyclohexadie-
none. This reaction proceeded smoothly to afford cis-hydro-
benzofuran, cis-hydroindole, and cis-hydroindene frame-
works bearing three consecutive chiral carbon centers with
excellent yields and enantioselectivities. The cyclization
products could be subjected to several transformations for
elaborating synthetic utility. Further studies on the applica-
tions of cyclohexadienone-tethered allenes are underway.
and 3u, were constructed with exceptionally excellent yields
(91–94%) and enantioselectivities (94–96% ee; Table 3). For
the C-linked 1,6-enallenes, the reactions still proceeded
equally well to give optically pure cis-hydroindene products,
3v, 3w, and 3x, (80–95% yield, 97–98% ee, Table 3). As
revealed in Tables 2 and 3, the mild reaction conditions are
compatible with a wide range of functional groups, providing
a versatile platform for further synthetic manipulations.
The absolute configuration of the cyclization product 3a
was assigned as (3S,3aR,7aR).[21] The vinylsilane, enone
functionalities and diverse substituents in the cyclization
products can serve as synthetically valuable handles for
further transformations. Through the successive hydrogena-
tion, Fleming–Tamao oxidation and PCC oxidation of 3a, the
diketone product 4a could be readily prepared (Scheme 2).
Upon treatment of 3r with tBuLi, the resulting alkyllithium
underwent an intramolecular Michael addition to give the
tricyclic product 4r. When the C-linked product 3x was
treated with LiHMDS, an intramolecular alkylation pro-
ceeded uneventfully to deliver the bridged ring product 4x
(Scheme 2). Dealcoholization of 3x took place under acidic
conditions and the simultaneous aromatization afforded the
phenol product 5x (Scheme 2). As for N-linked product 3s,
the Boc group was easily removed and the resulting amine
could react with 4-bromophenyl isocyanate, to give a tricyclic
product 4s, whose absolute configuration was established by
X-ray crystallography (Scheme 2) and vibrational circular
dichroism (VCD) analysis.[21,22] No loss of enantiomeric ratios
was observed in all above transformations.
Acknowledgements
Financial support was provided by the 973 Program
(2015CB856600), NSFC (21372243, 21232009, 21572251,
21572253), SMSTC (13JC1406900), and Collaborative Inno-
vation Center of Chemical Science and Engineering (Tianjin).
We thank Xiaoge Li (SIOC) for VCD analysis, Dr. Xiaodi
Yang (Fudan University) for X-ray crystallographic analysis,
and Dr. Hanqing Dong (Arvinas Inc.) for helpful discussions.
Keywords: allenes · asymmetric synthesis · copper · cyclization ·
silylation
How to cite: Angew. Chem. Int. Ed. 2015, 54, 14815–14818
Angew. Chem. 2015, 127, 15028–15031
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Received: August 30, 2015
Published online: October 16, 2015
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