Cu-catalyzed asymmetric borylative cyclization of cyclohexadienone- containing 1,6-enynes

Article abstract of DOI:10.1021/ja404593c

The first Cu-catalyzed asymmetric borylative cyclization of cyclohexadienone-containing 1,6-enynes is achieved through a tandem process: selective β-borylation of propargylic ether and subsequent conjugate addition to cyclohexadienone. The reaction proceeds with excellent regioselectivity and enantioselectivity to afford an optically pure cis-hydrobenzofuran framework bearing alkenylboronate and enone substructures. Furthermore, the resulting bicyclic products could be converted to bridged and tricyclic ring structures. This method extends the realm of Cu-catalyzed asymmetric tandem reactions using bis(pinacolato)diboron (B₂pin ₂).

Full text of DOI:10.1021/ja404593c

Communication
pubs.acs.org/JACS
Cu-Catalyzed Asymmetric Borylative Cyclization of
Cyclohexadienone-Containing 1,6-Enynes
Ping Liu, Yuki Fukui, Ping Tian,* Zhi-Tao He, Cai-Yun Sun, Nuo-Yi Wu, and Guo-Qiang Lin*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
Scheme 1. Strategic Design for Cu-Catalyzed Asymmetric
Borylative Cyclization of 1,6-Enynes
ABSTRACT: The first Cu-catalyzed asymmetric boryla-
tive cyclization of cyclohexadienone-containing 1,6-enynes
is achieved through a tandem process: selective β-
borylation of propargylic ether and subsequent conjugate
addition to cyclohexadienone. The reaction proceeds with
excellent regioselectivity and enantioselectivity to afford an
optically pure cis-hydrobenzofuran framework bearing
alkenylboronate and enone substructures. Furthermore,
the resulting bicyclic products could be converted to
bridged and tricyclic ring structures. This method extends
the realm of Cu-catalyzed asymmetric tandem reactions
using bis(pinacolato)diboron (B2pin2).
ransition-metal-catalyzed C−B bond formation1 always
Tfascinates organometallic chemists, due to its fundamental
scientific interest and great applications in organic synthesis.2
Because of the economic attractiveness and excellent functional
group tolerance, copper catalysis3 has recently attracted
renewed attention, particularly in the field of Cu-catalyzed
borylative addition to CO,4 CN,5 CC,6−8 and C
C9,13−16 bonds with B2pin2. In some cases, the copper
intermediate generated in this borylation process could
subsequently react with certain electrophiles. So far, Cu-
catalyzed asymmetric borylative tandem reactions are limited to
borylation/alkylation,10 conjugate borylation/aldol,11 and bor-
ylation/amination reactions.12 To the best of our knowledge,
no examples have been described in literature of asymmetric
borylative cyclization of 1,6-enyne using a copper catalyst.
Herein we communicated our finding in the Cu-catalyzed
asymmetric tandem reaction between 1,6-enyne and B2pin2,
which meanwhile provided an efficient approach to construct
an enantioenriched cis-hydrobenzofuran framework with
alkenylboronate and enone functionalities.
Scheme 1a shows several post-transformations of the
borylated alkenyl-copper intermediates with different electro-
philes: MeOH for the hydroboration,13−16 CO2 for the
boracarboxylation,17 and alkyl halides for the carboboration.18
Encouraged by these elegant reports, we envisioned that the
Cu-catalyzed tandem borylation/conjugate addition reaction of
cyclohexadienone-containing 1,6-enynes would possibly take
place (Scheme 1b). In order to obtain the cyclization product,
we need to minimize the conjugate borylation8 to the enone.
For a linear substrate, (2E)-2-nonen-7-ynal, the conjugate
borylation was found to be unfortunately preferred to the
borylation of the CC bond.8g However, such conjugate
borylation was not observed for 4,4-dimethyl-2-cyclohexenone
due to the steric hindrance from the quaternary carbon.8c In
our case with prochiral cyclohexadienone-containing 1,6-enynes
119 as the substrates for the Cu-catalyzed asymmetric borylative
cyclization,20 the conjugate borylation could be suppressed by
the neighboring substituents. More importantly, the regiose-
lective β-borylation of an alkyne could be achieved through the
O-coordination of a propargyl ether unit (T1).15 The resulting
borylated alkenyl-copper T2 could immediately undergo
enantioselective conjugate addition to a cyclohexadienone
moiety in a syn fashion to generate the chiral product 3.
With this mind-set, we began to examine the borylation of
the model substrate 1a with Ph3P as the ligand. To our delight,
the desired racemic product 3a was obtained, albeit in a modest
yield of 49% (Table 1, entry 1). Chiral monophosphine ligand
Received: May 7, 2013
© XXXX American Chemical Society
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Journal of the American Chemical Society
Communication
a
a
Table 1. Initial Evaluation of Various Ligands
Table 2. Substrate Scope
b
c
entry
substrate
product
yield (%)
Ee (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
70
70
65
60
58
63
65
64
51
60
55
72
49
55
47
63
65
61
94
99
95
99
99
99
92
97
92
95
94
99
88
92
87
70
90
82
b
c
d
entry
L
conv. (%)
yield (%)
Ee (%)
1
2
3
4
5
6
7
Ph3P
L1
L2
L3
L4
L5
L6
L6
L6
75
84
55
40
43
65
76
73
67
49
47
15
12
7
−
−2
56
1g
1h
1i
3g
3h
3i
−21
−65
−10
94
33
70
58
51
d
10
1j
3j
11
1k
1l
3k
3l
e
8
f
90
e
12
9
87
e
13
1m
1n
1o
1p
1q
1r
3m
3n
3o
3p
3q
3r
a
b
Reactions were performed under a N2 atmosphere. Conversion was
determined by the isolated recovered 1a. Yield of isolated product 3a.
Determined by HPLC analysis using a chiral stationary phase. B2pin2
(2, 1.2 equiv) was used. B2pin2 (2, 1.3 equiv) was used.
14
c
e
15
d
e
16
17
18
f
(R)-MOP (L1) was subsequently subjected to this reaction.
Unfortunately, almost no enantioselectivity was observed
(Table 1, entry 2). Next, a set of representative chiral
bisphosphine ligands (L2−L4) and phosphine-oxazoline ligand
(L5) were investigated, still affording low yields and low to
moderate enantioselectivities (Table 1, entries 3−6). Phosphor-
amidites proved to be versatile ligands for Cu-catalyzed
conjugate addition reactions.21 In our case, the application of
ligand (S,R,R)-L6 dramatically improved both the reaction yield
(up to 70%) and the enantioselectivity (up to 94% ee, Table 1,
entry 7). However, increasing B2pin2 (2) loading led to
different levels of erosion in both yields and enantioselectivities
(Table 1, entries 8−9), which might be caused by further
conjugate borylation of the excessive B2pin2 to 3a (Supporting
Information).
a
b
Reactions were performed under a N2 atmosphere. Yield of isolated
c
product. Determined by HPLC analysis using a chiral stationary
phase. B2pin2 (2, 1.2 equiv) was used. B2pin2 (2, 1.3 equiv) was
used.
d
e
the terminal alkyne substrate 1p (R1 = H), the reaction still
worked well (Table 2, entry 16). With the substituent at the β-
or α-position of the dienone, the reactions readily provided
cyclization products possessing two quaternary stereocenters
(3q) or three contiguous stereocenters (3r) in high yields and
ee values, respectively (Table 2, entries 17 and 18).
To better understand the regioselectivity of Cu-catalyzed
borylation which was proposed to be controlled through the
coordination with the oxygen atom in the propargylic ether
unit, substrates 1s and 1t with an additional O-coordinating
center were prepared and applied to this reaction (Scheme 2).
As for 1s, due to the directing capacity O1 > O2 (less hindrance
for −OBn), α-borylation of an alkyne took place, thus leading
to noncyclized product 3s, which was very unstable and directly
oxidized to ketone 4s in the air. In contrast, because of the
directing capacity O2 > O3 (more hindrance for −OTrt) in 1t,
β-borylation of the alkyne occurred, resulting in the desired
cyclization product 3t. For the N-linked substrates (1u, 1v, and
1w), no desired cyclization products were observed under the
standard reaction conditions, which may be attributed to the
weak directing ability of N-functional groups.
With the optimal reaction conditions identified, various
substrates were investigated and the results are summarized in
Table 2. With the R2 substituent as the alkyl, allyl, benzyl, vinyl,
and phenyl group, the reactions proceeded smoothly with
moderate to high yields (58%−70%) and excellent enantiose-
lectivities (92−99% ee, Table 2, entries 1−8). With a
heteroatom (O and Br) as part of R2 in substrates 1, the
reaction yields and ee values remained high (Table 2, entries 9−
13). It is worth mentioning that the alkyl bromide group in
substrate 1l was well tolerated in this reaction (Table 2, entry
12); i.e., the borylated alkenyl-copper intermediate selectively
underwent conjugate addition rather than nucleophilic
substitution.
To determine the absolute configurations of the cis-
hydrobenzofuran products in Table 2, the boronate 3a was
converted, through Suzuki−Miyaura coupling with 4-bromo-
Bigger R1 substituents (Et and n-Bu) resulted in slightly
lower enantioselectivities (Table 2, entries 14 and 15). As for
B
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Journal of the American Chemical Society
Communication
acrylate through double Michael additions. As for 3l, the
corresponding iodide product 4l was easily obtained. Upon
treatment of 4l with LiHMDS, an intramolecular alkylation
reaction occurred to deliver the bridged ring product 5l. During
treatment of 4l with t-BuLi, the resulting alkyl lithium
underwent an intramolecular Michael reaction to give the
tricyclic product 6l. All the above transformations proceeded
smoothly with no loss of the enantiomeric excesses.
Scheme 2. Directing Capacity of Propargylic Oxygen Atom
towards β-Borylation of Alkyne
In summary, the first Cu-catalyzed asymmetric borylative
cyclization reaction between cyclohexadienone-containing 1,6-
enynes and B2pin2 has been established through a tandem
process: selective β-borylation of the propargylic ether and
subsequent enantioselective conjugate addition to cyclohex-
adienone.22 This reaction is conducted under mild and
convenient conditions, affording enantioenriched cis-hydro-
benzofuran with moderate yields and high to excellent
enantioselectivities. The functional groups of alkenylboronate
and enone in the cyclization products could be subjected to
various transformations for elaborating the synthetic utility. The
present results extend the realm of the Cu-catalyzed
asymmetric tandem reaction using B2pin2. Further studies on
the applications of cyclohexadienone-containing 1,6-enynes are
in progress in our laboratories and will be reported in due
course.
ASSOCIATED CONTENT
■
phenyl iodide, to a known compound (S,S)-4a which was fully
confirmed by X-ray crystallography (Scheme 3).19e The
alkenylboronate and enone functionalities in the cyclization
products could be further modified to other useful structures. A
facile oxidation of alkenylboronate 3a produced the methyl-
ketone 5a in 94% yield. The bridged cyclic product 6a could be
acquired from a formal [4 + 2] reaction between 3a and methyl
S
* Supporting Information
Experimental procedures, structural proofs, and spectral data
for all new compounds are provided. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
tianping@sioc.ac.cn; lingq@sioc.ac.cn
Scheme 3. Several Transformations of the Cyclization
Products
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was generously provided by the
973 Program (2010CB833302), National Natural Science
Foundation of China (NSFC 21232009, 21102161), and
Chinese Academy of Sciences (CAS). We thank Dr. Hanqing
Dong for helpful discussions.
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