CuH-Catalyzed Asymmetric Intramolecular Reductive Coupling of Allenes to Enones

Article abstract of DOI:10.1021/acs.orglett.7b03608

The CuH-catalyzed asymmetric intramolecular reductive coupling of allenes to enones is successfully realized, providing cis-hydrobenzofurans with promising yields and excellent enantioselectivities. Such brilliant enantioselectivities are partially contributed by CuH-catalyzed favorable kinetic resolution of the cyclization products. This protocol tolerates a broad range of functional groups, allowing for further construction of tricyclic and bridged-ring structures. Moreover, the meta-chiral functionalization of 4-substituted phenol and asymmetric dearomatization modification of phenol-contained bioactive molecules are also described.

Full text of DOI:10.1021/acs.orglett.7b03608

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
CuH-Catalyzed Asymmetric Intramolecular Reductive Coupling of
Allenes to Enones
Yun-Xuan Tan,†,∥ Xiao-Qi Tang,†,‡,∥ Ping Liu,† De-Shen Kong,†,§ Ya-Li Chen,*,‡ Ping Tian,*,†,§
and Guo-Qiang Lin*,†,§
†Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, University of Chinese Academy
of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
‡Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, China
§Institute of Innovative Chinese Medicine (ICM), Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai
201203, China
S
* Supporting Information
ABSTRACT: The CuH-catalyzed asymmetric intramolecular
reductive coupling of allenes to enones is successfully realized,
providing cis-hydrobenzofurans with promising yields and
excellent enantioselectivities. Such brilliant enantioselectivities
are partially contributed by CuH-catalyzed favorable kinetic
resolution of the cyclization products. This protocol tolerates a
broad range of functional groups, allowing for further
construction of tricyclic and bridged-ring structures. Moreover,
the meta-chiral functionalization of 4-substituted phenol and asymmetric dearomatization modification of phenol-contained
bioactive molecules are also described.
ver the past two decades, asymmetric copper hydride
(CuH) chemistry has blossomed and become an
(enone-tethered allenes), enabled by in situ generated chiral
ligand-bound CuH catalysts to furnish the optically pure
cyclization products.
O
attractive alternative to related C−C bond formations. It
delivers hydride asymmetrically at newly created sp3 centers
with absolute stereocontrol, while early studies tended to focus
on simple 1,2- and 1,4-reduction.1 Very recently, a significant
breakthrough has been achieved, demonstrating that the
transient nucleophilic alkylcopper species can be in situ
generated via unactivated alkenes insertion to CuH and
intercepted with a range of electrophiles (Scheme 1, eq
1).2−6 Currently, the asymmetric reductive coupling strategy
has been extended to hydroallylation of alkynes.7 However, as
for allenes, major efforts were devoted to the racemic reductive
coupling reaction in the primary literature, and an asymmetric
version is still unavailable to the best of our knowledge.8
Herein, we report the first asymmetric intramolecular reductive
coupling of allenes to enones through a CuH-based strategy.
The insertion of terminal allenes to CuH produces the
nucleophilic α-substituted allylcopper complexes. A handful of
their racemic post-transformations using different electrophiles,
allyl halides for allylic substitution,8c CO2, and imines, for allylic
addition has been reported (Scheme 1, eq 2).8a,b Among them,
there are only two asymmetric entries, and promising levels of
enantioselectivities (ee ≤85%) have been described.8b
Compared to the simple and β-substituted allylcopper
nucleophiles,9 the absolute stereocontrol in the asymmetric
conversion of α-substituted (β-nonsubstituted) allylcopper
intermediates becomes more challenging.9c We hypothesized
that such a challenge could be addressed through the
intramolecular reductive coupling of allenes to enones
As for enone-tethered allenes,10 the neighboring steric
repulsion impedes the direct 1,4-reduction of CuH to enone;
thus, the regioselective insertion of terminal allene to CuH
consequently occurs in the first and places the Cu at the less
hindered site of the allene to form α-substituted allylcopper
intermediate T (Scheme 1, eq 3). One major concern for the
following cyclization process is the potential β-oxygen
elimination pathway.11 In our control experiment, the CuH-
catalyzed hydrogenation of α-benzyloxymethyl allene only
afforded semireduction product, suggesting that a β-oxygen
elimination process would not take place easily.12 Subsequently,
the α-substituted allylcopper undergoes preferential intra-
molecular α-addition rather than γ-addition to enone,
simultaneously generating three consecutive stereogenic centers
in cis-hydrobenzofuran products. However, the remote stereo-
control (1,8-asymmetric induction) of such addition process in
a diastereo- and enantioselective manner remains quite
challenging. Thus, successful implementation of this strategy
requires a powerful catalyst capable of efficient hydrocupration
of the allene and, more importantly, the effective enantiotopic
facial discrimination of the enone moiety.
With these considerations in mind, a set of privileged
nonracemic ligands in asymmetric CuH chemistry were
Received: November 21, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03608
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Strategic Design
Table 1. Selected Optimization Studies
b
c
d
temp
(°C)
time
(h)
conv
yield
ee
entry
L
X
(%)
(%)
(%)
1
L1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
2.0
2.2
0
0
12
12
12
12
12
12
24
48
48
48
48
97
90
78
30
51
81
60
31
55
67
65
51
43
39
7
2
L8
3
L9
0
85
−5
−35
52
4
L16
L21
L29
L21
L21
L21
L21
L21
0
100
88
5
0
6
0
75
−50
60
7
−20
−40
−40
−40
−40
84
8
81
57
9
98
68
10
11
100
100
86
95
evaluated for this catalytic asymmetric intramolecular reductive
coupling using enone-tethered allene 1a, and selected results
are summarized in Table 1.12 The use of (R)-Binap L1 as ligand
afforded the desired product 3a in good yield but with poor
enantioselectivity (Table 1, entry 1), and further reduction of
3a by the CuH catalyst was also observed to generate two side
products, ketone 4a and alcohol 5a. Next, several bisphosphine
ligands L8,3,5 L9, L16, L21,3a and L294,6 were subjected to this
reaction, and only (R,R)-iPr-DuPhos L21 gave a promising
yield and ee value (Table 1, entry 5 vs entries 2−4). Lowering
the reaction temperature resulted in slight improvement of
enantioselectivity (Table 1, entries 7 and 8), but increasing
DEMS loading led to great enhancement of enantioselectivities
(Table 1, entries 9−11). In particular, excellent enantioselec-
tivity was achieved when 2.2 equiv of DEMS was used (Table 1,
entry 11). The moderate yield was mainly caused by further
reduction of 3a, which is considered as a favorable kinetic
resolution process.
With the optimal conditions identified, we next evaluated the
scope of enone-tethered allenes 1. With the R1 substituent as an
alkyl, cycloalkyl, vinyl, allyl, benzyl, or phenyl group, the
reactions proceeded smoothly with moderate yields and high to
perfect enantioselectivities (Scheme 2, 3a−j, ee up to 99%).
The absolute configuration of the cyclization product 3j was
unambiguously established as (3R,3aS,7aS) by X-ray crystallog-
raphy. With a heteroatom O, N, Br, and I as part of the R1
substituent in substrates 1, the ee values remained at excellent
levels (Scheme 2, 3k−r, ee = 97−99%). It was particularly
noted that the highly reactive bromo- and iodoalkyl groups
were comfortably tolerated without any observation of
nucleophilic substitution product (Scheme 2, 3q and 3r).13
For α-methylenone-tethered allene 1s, the corresponding
cyclization product 3s was obtained in much higher yield
(95%) and with high enantioselectivity.
a
b
Reactions were performed under an Ar atmosphere. Determined by
c
1H NMR analysis of unpurified mixtures. Yield of isolated product 3a.
d
Determined by HPLC analysis. DEMS = diethoxymethylsilane.
excessive DEMS, racemic cyclization product 3a was subjected
to these reaction conditions. In line with our expectations, the
remaining 3a was recovered with good enantioselectivity (ee =
82%, Scheme 3). This study clearly demonstrated that the
further reduction was a favorable kinetic resolution process, and
this can be used to explain excellent enantioselectivity could be
achieved by using excessive DEMS (Table 1, entry 11).
As revealed in Scheme 2, this mild protocol tolerates a wide
range of functional groups, providing a flexible platform for
further conversion. When 3r was treated with t-BuLi, the
resulting alkyllithium underwent an intramolecular Michael
addition to deliver the tricyclic product 6r (Scheme 4). In
addition, an intramolecular alkylation occurred equally well to
give the bridged-ring structure 7r upon treatment of 3r with
LiHMDS.
Under acidic conditions, the rearomatization of 3a afforded
the optically enriched meta-substituted phenol 8a (Scheme 4).
On the other hand, 1a was easily prepared from oxidative
dearomatization of p-cresol.10 Thus, such a stepwise dearoma-
tization, asymmetric cyclization, and rearomatization process
presents a novel strategy for meta-chiral functionalization of 4-
substituted phenols.14
The phenol structure widely exists in numerous bioactive
molecules. As for salidroside tetraacetate 9, the phenol moiety
was similarly dearomatized to afford the enone-tethered allene
substructure (Scheme 5).12 Through CuH-catalyzed asymmet-
To confirm that the further reduction of cyclization products
was a favorable kinetic resolution process, i.e., the minor
enantiomer of the cyclization product was consumed faster by
B
DOI: 10.1021/acs.orglett.7b03608
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Scope of Enone-Tethered Allenes
Scheme 5. Asymmetric Dearomatization Modifications of
Bioactive Molecules
This combination of dearomatization and asymmetric cycliza-
tion provided an alternative to catalytic asymmetric dearoma-
tization strategy.15 Using the same procedure as above, the
asymmetric dearomatization modification of estrone 13 also
proceeded uneventfully to afford optically pure and pharma-
ceutically potential cis-hydrobenzofuran 15 (Scheme 5), whose
absolute configuration was confirmed by X-ray crystallography.
In summary, the first CuH-catalyzed asymmetric intra-
molecular reductive coupling of allenes to enones has been
established through regioselective insertion of allenes to CuH
and subsequent enantioselective addition to enones. This
tandem reaction proceeded smoothly to furnish cis-hydro-
benzofurans with promising yields and excellent enantioselec-
tivities (ee up to 99%). Such brilliant enantioselectivities proved
to be partially caused by further favorable kinetic resolution of
the cyclization products, i.e., the in situ reduction of enone
functionality. The cyclization products could be converted to
tricyclic and bridged-ring structures. Additionally, meta-chiral
functionalization of 4-substituted phenols and asymmetric
dearomatization modification of phenol-contained bioactive
molecules were presented. Our next challenge is to develop the
intermolecular asymmetric version.
a
b
Reactions were performed under an Ar atmosphere. Yield of isolated
c
d
product 3. Determined by HPLC analysis. 1.0 mmol of 1e was used.
Boc = tert-butoxycarbonyl, TBS = tert-butyldimethylsilyl, and Ac =
acetyl.
Scheme 3. CuH-Catalyzed Kinetic Resolution of ( )-3a
Scheme 4. Synthetic Transformations
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.7b03608.
Experimental procedures, spectra for all new compounds,
and X-ray crystallographic data for compounds 3j and 15
(PDF)
Accession Codes
CCDC 1572373−1572374 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ric cyclization, the optically pure cis-hydrobenzofuran derivative
12 was achieved with excellent diastereoselectivity (dr = 97:3).
C
DOI: 10.1021/acs.orglett.7b03608
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) For CuH-catalyzed asymmetric reductive coupling of alkenes to
carboxylic anhydrides and unsaturated carboxylic acids, see: (a) Bandar,
J. S.; Ascic, E.; Buchwald, S. L. J. Am. Chem. Soc. 2016, 138, 5821−
5824. (b) Zhou, Y.; Bandar, J. S.; Buchwald, S. L. J. Am. Chem. Soc.
2017, 139, 8126−8129.
ing 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 Authors
■
(7) For CuH-catalyzed asymmetric reductive coupling of alkynes,
see: (a) Xu, G.; Zhao, H.; Fu, B.; Cang, A.; Zhang, G.; Zhang, Q.;
Xiong, T.; Zhang, Q. Angew. Chem., Int. Ed. 2017, 56, 13130−13134.
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(b) Fujihara, T.; Xu, T.; Semba, K.; Terao, J.; Tsuji, Y. Angew.
Chem., Int. Ed. 2011, 50, 523−527. (c) Uehling, M. R.; Rucker, R. P.;
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(12) For more details, see the Supporting Information.
(13) In some cases of CuH-catalyzed cross-coupling reactions, the
alkyl and alkenyl copper intermediates underwent nucleophilic
substitution with the alkyl triflates and alkyl bromides. See refs 5a
and 7d.
(14) For selected meta-functionalization of phenols, see: (a) Dai, H.
X.; Li, G.; Zhang, X. G.; Stepan, A. F.; Yu, J. Q. J. Am. Chem. Soc. 2013,
135, 7567−7571. (b) Wang, P.; Farmer, M. E.; Huo, X.; Jain, P.; Shen,
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Angew. Chem., Int. Ed. 2012, 51, 12662−12686. (b) You, S. L.
Asymmetric Dearomatization Reactions; Wiley-VCH: Weinheim, 2016.
*Email: ylchen@staff.shu.edu.cn.
*Email: tianping@sioc.ac.cn, tianping@shutcm.edu.cn.
*Email: lingq@sioc.ac.cn.
ORCID
Ping Tian: 0000-0002-5612-0664
Author Contributions
∥Y.-X.T. and X.-Q.T. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was generously provided by the 973 Program
(2015CB856600), NSFC (21372243, 21232009, 21572251,
21572253), the Strategic Priority Research Program of the
Chinese Academy of Sciences (XDB 20020100), and the
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin). We thank Dr. Hanqing Dong (Arvinas,
Inc.) for helpful discussions.
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DOI: 10.1021/acs.orglett.7b03608
Org. Lett. XXXX, XXX, XXX−XXX