Highly enantioselective nickel-catalyzed intramolecular reductive cyclization of alkynones

Article abstract of DOI:10.1002/anie.201410700

The first asymmetric nickel-catalyzed intramolecular reductive cyclization of alkynones is reported. A P-chiral monophosphine and triethylsilane were used as the ligand and the reducing reagent, respectively, to form a series of tertiary allylic alcohols bearing furan/pyran rings in excellent yields and enantioselectivities. This reaction has a broad substrate scope and enabled the efficient synthesis of dehydroxycubebin and chiral dibenzocyclooctadiene skeletons.

Full text of DOI:10.1002/anie.201410700

Angewandte
Chemie
DOI: 10.1002/anie.201410700
Asymmetric Cyclization
Highly Enantioselective Nickel-Catalyzed Intramolecular Reductive
Cyclization of Alkynones**
Wenzhen Fu, Ming Nie, Aizhen Wang, Ziping Cao, and Wenjun Tang*
Abstract: The first asymmetric nickel-catalyzed intramolecu-
lar reductive cyclization of alkynones is reported. A P-chiral
monophosphine and triethylsilane were used as the ligand and
the reducing reagent, respectively, to form a series of tertiary
allylic alcohols bearing furan/pyran rings in excellent yields
and enantioselectivities. This reaction has a broad substrate
scope and enabled the efficient synthesis of dehydroxycubebin
and chiral dibenzocyclooctadiene skeletons.
T
he transition-metal-catalyzed cyclization of alkynals/alky-
nones has become a powerful method for the efficient
construction of cyclic allylic alcohols in current organic
chemistry.[1] Recent developments based on the use of
transition-metal catalysts, such as Ni,[2] Rh,[3] Ir,[4] Ru,[5] or
Pd,[6] in combination with a variety of reducing/alkylating
agents have greatly expanded its scope. Among various
transition metals, the use of inexpensive Ni in reductive
cyclization,[7] as pioneered by the groups of Mori and
Sato,[2a–b,9c] Montgomery,[2c–f] and Jamison,[2g–j] is particularly
attractive, and with such catalysts, superior reactivities can be
achieved in the activation of a variety of functional groups.
However, whereas a number of enantioselective cyclizations
with chiral Rh,[3c–i] Ir,[4] and Pd[6c] catalysts have been reported
(Figure 1), asymmetric Ni-catalyzed cyclizations have hardly
been explored.[8] A few examples of asymmetric intermolec-
ular couplings with alkynes and aldehydes/ketones/imines
have been described,[8] but a highly enantioselective cycliza-
tion of alkynones[9] is yet to be developed. Herein, we report
a highly enantioselective Ni-catalyzed intramolecular reduc-
tive cyclization of alkynones with triethylsilane as the
reducing reagent by employing a chiral monophosphine
ligand. A broad range of chiral tertiary allylic alcohols
bearing furan/pyran rings were efficiently synthesized in
excellent yields and enantioselectivities. This method also
enabled the efficient asymmetric synthesis of lignan dehy-
droxycubebin[10] as well as the facile construction of chiral
dibenzocyclooctadiene skeletons.[11]
Figure 1. Nickel-catalyzed asymmetric reductive cyclization of alky-
nones.
Chiral tetrahydrofuran/tetrahydropyran moieties are
important substructures found in a broad range of natural
products.[12] Although the Ni-catalyzed reductive/alkylative
coupling has provided a facile method to obtain these
structures as racemic mixtures,[9,2d–f] to the best of our
knowledge, no efficient enantioselective reductive/alkylative
cyclization of alkynones has been reported. Because of the
small size of a nickel atom compared to those of most other
late transition metals, it is essential to develop efficient chiral
monophosphine ligands for enantioselective Ni catalysis.
Early work by Jamison and co-workers[8b] showed that
encouraging enantioselectivity could be achieved with a
P-chiral ferrocenyl monophosphine for the asymmetric
reductive coupling of 1,3-enynes and ketones. We envisioned
that the P-chiral biaryl monophosphine ligands developed in
our group[13] could be applicable for enantioselective Ni
catalysis.
We thus chose 1a as a substrate to study the Ni-catalyzed
intramolecular cyclization of alkynones with triethylsilane as
the reducing reagent. As shown in Table 1, no reaction was
observed without the addition of phosphine ligands with
[Ni(cod)2] as the catalyst precursor (entry 1). The bisphos-
phine ligand BINAP also provided no cyclization product
(entry 2). In contrast, the monophosphine ligand triphenyl-
phosphine afforded the product in moderate yield (54%,
entry 3). Interestingly, using the biaryl monophosphine ligand
SPhos led to an excellent yield (98%, entry 4). The high
reactivity achieved with SPhos prompted us to explore the
performance of the P-chiral biaryl monophosphine ligand (S)-
BI-DIME, which was developed in our laboratory.[14] Excit-
ingly, BI-DIME provided the desired product in excellent
yield and enantioselectivity (97%, 97% ee; entry 5). Further
screening of the reaction conditions showed the importance
of the Ni0 precursor for the high reactivity, as no product was
[*] W. Fu, M. Nie, A. Wang, Z. Cao, Prof. Dr. W. Tang
State Key Laboratory of Bio-organic and Natural Products Chemis-
try, Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Ling Ling Rd, Shanghai 200032 (China)
E-mail: tangwenjun@sioc.ac.cn
[**] We are grateful to the NSFC (21432007, 21272254), STCSM
(13J1410900), the “Thousand Plan” Youth program, and Mettler
Toledo for a ReactIR Instrument.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410700.
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Table 1: Nickel-catalyzed reductive cyclization of alkynone 1a.
Table 2: Asymmetric nickel-catalyzed reductive cyclization.[a]
Entry[a] Precursor
Ligand
Solvent Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
–
dioxane
dioxane
dioxane
dioxane
NR
NR
54
98
97
NR
93
NR
18
NR
46.2
–
–
–
–
97
–
96
–
96
–
95
99
–
(S)-BINAP
PPh3
SPhos
(S)-BI-DIME dioxane
[Ni(dme)Br2] (S)-BI-DIME dioxane
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
[Ni(cod)2]
(S)-BI-DIME THF
(S)-BI-DIME MeOH
(S)-BI-DIME EtOAc
(S)-BI-DIME CH2Cl2
(S)-BI-DIME toluene
(S)-AntPhos dioxane
9
10
11
12
13
14[d]
98
NR
36
(S)-L3
(S)-AntPhos dioxane
dioxane
99
[a] Reaction conditions unless otherwise specified: 1a (0.2 mmol), Ni
precursor (5 mol%), ligand (5 mol%), and triethylsilane (2 equiv) in the
specified solvent (2 mL) at room temperature under nitrogen atmos-
phere for 20 h. The absolute configuration of 3a was assigned by analogy
to the absolute structure of 3e, which was determined by X-ray
crystallography.[15] [b] Yields of isolated products. [c] The enantioselec-
tivities were determined by HPLC analysis on a chiral stationary phase
(Chiralcel OD-H). [d] [Ni(cod)2] (2 mol%), (S)-AntPhos (2 mol%).
BINAP=2,2’-bis(diphenylphosphino)-1,1’-binaphthene, cod=1,5-cyclo-
octadiene, dme=dimethoxyethane, NR=no reaction.
[a] Conditions unless otherwise specified: Substrate (0.2 mmol),
[Ni(cod)2] (5 mol%), (S)-AntPhos (5 mol%), triethylsilane (2 equiv),
dioxane (2 mL), nitrogen atmosphere, room temperature, 20 h. Yields of
isolated products are given. [b] (S)-BI-DIME (10 mol%). [c] (S)-BI-DIME
(5 mol%). [d] 48 h.
obtained when [NiII(dme)Br2] was employed (entry 6). The
solvent also played an important role for the reactivity
(entries 7–11), and dioxane was found to be most suitable.
Further modification of the chiral ligand showed that chiral
AntPhos[14] provided the product with almost perfect enan-
tioselectivity (99% ee) and yield (98%, entry 12). It is
important to note that the yields of the nickel-catalyzed
process compare favorably with those reported for Rh[3i] or
Pd[6c] catalysis. The use of ligand L3[13c] with an isopropyl
substituent led to no conversion (entry 13). This could be due
to the increased steric bulk of L3 rendering substrate
coordination to the nickel catalyst difficult. The cyclization
required 5 mol% of the Ni catalyst for completion, as only
36% yield was achieved when 2 mol% of the Ni/AntPhos
catalyst system were employed (entry 14).
We then studied the generality of this asymmetric Ni-
catalyzed reductive cyclization of alkynones. As shown in
Table 2, a wide range of cyclic tertiary allylic alcohols bearing
furan or pyran rings were efficiently synthesized and isolated
in excellent yields (86–98%) and enantioselectivities (91–
99% ee). For a series of aromatic alkyne substrates, high
yields and ee values were observed regardless of the
substitution pattern and the electronic properties of the aryl
ring (3b–f). Aliphatic alkynes were also suitable substrates
(3g–h). Aromatic ketones (3i–n) with various substituents
and electronic properties were also compatible with the
reaction conditions. A 1-naphthyl-substituted ketone was
successfully cyclized to provide compound 3o in 97% ee and
95% yield. Various aliphatic ketones were also efficiently
converted into chiral 2-alkyl furanols (3p–r) in excellent
yields and enantioselectivities. An isopropyl ketone with an
aliphatic alkyne chain was also smoothly transformed into
chiral tertiary alcohol 3s in 97% yield and 96% ee,
demonstrating the high tolerance of this method towards
various substituents and functional groups. Aside from the
tetrahydrofuran products, a chiral tetrahydropyran product
(3t) was also formed in 94% ee and excellent yield (97%).
The high enantioselectivities and yields prompted us to
study the mechanism of this catalytic reaction and develop
a stereochemical model. Reductive cyclization of 1a with
2
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peared after the addition of a stoichiometric amount of
AntPhos, indicating that the cycloaddition of 1a with a nickel
species bearing an AntPhos ligand has occurred. Based on
these results and a kinetic study by Montgomery and co-
workers[16] and computational studies by the groups of
Houk,[17] Jamison,[17a] and Montgomery[17c,d] on Ni-catalyzed
intermolecular or intramolecular ynal reductive cyclizations,
we propose the catalytic cycle depicted in Figure 4. Cyclo-
Figure 2. Linear relationship between the ee values of the ligand
AntPhos and product 3a.
a scalemic composition of AntPhos revealed the linear
relationship between the ee values of the ligand and of 3a
(Figure 2), indicating that the reaction is catalyzed by a nickel
complex bearing a single AntPhos ligand. To understand
whether the cycloaddition of 1a with the Ni complex takes
place prior to the action of HSiEt3, a stoichiometric amount of
[Ni(cod)2]was mixed with 1a in dioxane at room temperature,
and the process was monitored by ReactIR (Figure 3). An
absorption peak at 1704 cmÀ1 appeared and persisted after the
addition of 1a, indicating the presence of a carbonyl group
while the cycloaddition did not proceed without the phos-
phorus ligand. However, the absorption peak slowly disap-
Figure 4. Proposed mechanism and stereochemical model for the
asymmetric reductive cyclization of alkynones. L*=(S)-AntPhos.
addition of alkynone 1a with the Ni0 species I provides NiII
metallacycle II. This is followed by coordination and s-bond
metathesis of triethylsilane to generate NiII hydride species
III. Reductive elimination of III provides 2a and regenerates
the Ni0 catalyst. The stereoselectivity is apparently deter-
mined at the cycloaddition stage. Conformational analysis of
metallacycle II with AntPhos as the ligand indicates that in
conformer IIB, the steric interactions between the phenyl
group on the metallacycle ring and the anthracenyl moiety of
AntPhos are greater than in conformer IIA. The more
favorable conformer IIA led to the formation of the cycliza-
tion product with the S configuration, which is in accordance
with the absolute configuration of product 3e, which was
determined by X-ray crystallography.[15]
The highly enantioselective transformation allowed us to
synthesize chiral tetrahydrofuran lignans, such as dehydroxy-
cubebin,[10] in a very efficient fashion. Thus, by employing 4 as
the starting material and Ni/(R)-BI-DIME (10 mol%) as the
catalyst, the chiral cyclization product 5 was formed in 82%
yield and 97% ee. Hydrogenation of the double bond in 5
over Pd/C took place stereospecifically at the opposite side to
the OTES group, forming compound 6 quantitatively. TBAF
treatment followed by Barton–McCombie deoxygenation
provided (+)-dehydroxycubebin (7a) and cis-dehydroxycu-
bebin (7b) in a 2:1 ratio; their spectra were fully identical to
previously reported data (Scheme 1).[10d–f]
Chiral dibenzocyclooctadiene lignans are members of an
important class of natural products with various interesting
Figure 3. Stoichiometric reaction of [Ni(cod)2], 1a, and AntPhos moni-
tored by React-IR.
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tion is catalyzed by a Ni catalyst with a single chiral
monophosphine ligand. A simple stereochemical model has
been proposed to rationalize the stereochemical outcome.
Further applications of this asymmetric cyclization in the
synthesis of various lignan natural products are currently
being studied, and progress will be reported in due course.
Received: November 3, 2014
Revised: December 10, 2014
Published online: && &&, &&&&
Keywords: alkynones · asymmetric catalysis · cyclization ·
.
nickel · P ligands
Scheme 1. Synthesis of (+)-dehydroxycubebin (7a). AIBN=azobisiso-
butyronitrile, TBAF=tetrabutylammonium fluoride, TES=triethylsilyl.
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desirable. With Ni/(R)-BI-DIME as the catalyst, alkynone 8
was successfully converted into cyclization product 9 in
96% ee and 80% yield. Hydrogenation of 9 provided com-
pound 10 exclusively. Stereospecific biaryl coupling mediated
by Fe(ClO4)3 formed dibenzocyclooctadiene 11 as a single
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ments (Scheme 2).[18]
In conclusion, the first highly enantioselective Ni-cata-
lyzed reductive cyclization of alkynones was realized by
employing a P-chiral monophosphine ligand, namely either
AntPhos or BI-DIME. A broad range of chiral tertiary allylic
alcohols with various alkyl/aryl substituents bearing furan/
pyran rings were efficiently synthesized and isolated with
excellent ee values and yields. This method further allowed
the efficient synthesis of the lignan dehydroxycubebin as well
as the facile construction of chiral dibenzocyclooctadiene
skeletons. Mechanistic studies demonstrated that the cycliza-
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Scheme 2. Construction of the chiral dibenzocyclooctadiene skeleton.
M.S.=molecular sieves, PCC=pyridine chlorochromate.
4
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[18] See the Supporting Information for details.
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Cyclization
W. Fu, M. Nie, A. Wang, Z. Cao,
W. Tang*
&&& — &&&
Highly Enantioselective Nickel-Catalyzed
Intramolecular Reductive Cyclization of
Alkynones
A P-chiral monophosphine is used as the
ligand in the first asymmetric nickel-
catalyzed intramolecular reductive cycli-
zation of alkynones. This transformation
enabled the formation of a series of
tertiary allylic alcohols bearing furan/
pyran rings in excellent yields and enan-
tioselectivities and the efficient synthesis
of dehydroxycubebin and the chiral
dibenzocyclooctadiene skeleton.
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!