Nickel-Catalyzed Desymmetrizing Cyclization of 1,6-Dienes to Construct Quaternary Stereocenters

Article abstract of DOI:10.1021/acs.orglett.1c00796

A highly enantioselective and diastereoselective nickel-catalyzed desymmetrizing cyclization of 1,6-dienes was developed by using chiral spiro phosphoramidite ligands. The reaction provides a new atom- and step-economical approach to chiral spiro lactones and analogues bearing a quaternary stereocenter.

Full text of DOI:10.1021/acs.orglett.1c00796

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Letter
Nickel-Catalyzed Desymmetrizing Cyclization of 1,6-Dienes to
Construct Quaternary Stereocenters
Tian-Yuan Zhao, Ke Li, Liang-Liang Yang, Shou-Fei Zhu, and Qi-Lin Zhou*
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ABSTRACT: A highly enantioselective and diastereoselective
nickel-catalyzed desymmetrizing cyclization of 1,6-dienes was
developed by using chiral spiro phosphoramidite ligands. The
reaction provides a new atom- and step-economical approach to
chiral spiro lactones and analogues bearing a quaternary stereo-
center.
Scheme 1. Transition-Metal-Catalyzed 1,6-Diene
Cyclizations
uaternary stereocenters widely exist in the structures of
Q natural products and pharmaceuticals. For instance, of
the top 120 chiral small-molecule pharmaceuticals by retail
sales in the United States in 2018, 13% contain a quaternary
stereocenter.1 In organic synthesis, most of the quaternary
stereocenter units originate from the natural product
precursors. Chemists have been trying to develop efficient
methods to construct quaternary stereocenters and have made
remarkable progress.2 At present, there are mainly two
strategies for constructing quaternary stereocenters: One is
the addition of a carbon nucleophile to a carbon−carbon
double bond or to a tricarbon-substituted cation, and the other
is the desymmetrization of the prebuilt quaternary center.3
Desymmetrization is a unique way to construct quaternary
stereocenters, in which the quaternary center is already present
in the molecule, and the reaction occurs enantioselectively on
one of the side chains. Thus, the nuisance steric hindrance in
the formation of a quaternary stereocenter can be avoided. In
the past decades, desymmetrization attracted extensive
attention for enantioselective preparation of the chiral
compounds containing a quaternary stereocenter.4 For
example, in the Hajos−Parrish−Eder−Sauer−Wiechert reac-
tion, the desymmetrizing cyclization of prebuilt α,α-disub-
stituted 1,3-diketone produced chiral polycyclic molecules,4a,b
which have been widely applied in the total synthesis of natural
products. Desymmetric ring-opening and ring-expanding
reactions of small-ring systems containing quaternary centers
are also useful reactions in organic synthesis.4c
a quaternary center. Herein, we report a desymmetrizing
cyclization of 1,6-dienes to synthesize chiral spiro lactones and
analogues in high enantioselecitvity (Scheme 1c).
We began by exploring the desymmetrizing cyclization of
1,6-diene 1a. The reactions were performed in CH2Cl2 at 20
°C with a nickel catalyst prepared in situ from 2.5 mol % of
[Ni(allyl)Br]2, 5 mol % of monodentate phosphine ligand, and
6 mol % of sodium tetrakis(3,5-bis(trifluoromethyl)phenyl)-
borane (NaBArF). First, various chiral spiro monodentate
phosphorus ligands8 developed in our laboratory were
evaluated (see the Supporting Information for details).
Phosphonite ligand L1 and phosphoramidite ligands L2 and
Transition-metal-catalyzed asymmetric cyclization of 1,6-
dienes provided an efficient method for the preparation of
chiral cyclopentenes (Scheme 1a).5 However, the desymme-
trizing cyclization of 1,6-dienes to construct a quaternary
stereocenter has only one example by using a rhodium catalyst
(Scheme 1b).6 In the previous work, we developed a nickel-
catalyzed enantioselective cyclization of N- or O-tethered 1,6-
dienes to form six-membered chiral heterocycles.7 Encouraged
by this success, we envisioned whether this reaction can be
applied to desymmetrizing cyclization of 1,6-dienes containing
Received: March 7, 2021
Published: May 7, 2021
https://doi.org/10.1021/acs.orglett.1c00796
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3814−3817
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Letter
L3 provided low yield and poor enantioselectivity (Table 1,
entries 1−3). The substitution at the 6,6′-position of the
Scheme 2. Nickel-Catalyzed Desymmetric Cyclization of
1,6-Dienes
a
Table 1. Nickel-Catalyzed Desymmetrizing Cyclization of
a
1,6-Diene 1a: Optimization of Reaction Conditions
entry
L
T/°C
solvent
yield (%)
dr
ee
1
2
3
4
5
6
7
8
9
10
11
12
13
14
(S)-L1
(R)-L2
(R)-L3
(S)-L4
(S)-L5
(R)-L6
(S)-L7
(R)-L8
(S)-L9
(S)-L7
(R)-L8
(S)-L7
(S)-L7
(S)-L7
20
20
20
20
20
20
20
20
20
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
36
56
76
80
82
82
90
87
70
90
85
57
N.R.
N.R.
>20:1
>20:1
10:1
20
6
20
19
30
63
82
85
79
96
96
94


10:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1

0
0
0
0
hexane

a
Reaction conditions: [Ni(allyl)Br]2 (0.0025 mmol), ligand (0.005
mmol), NaBArF (0.006 mmol), 1a (0.10 mmol), 48 h. Isolated yield.
1
The dr values were determined by H NMR. The ee values were
determined by HPLC on a chiral stationary phase.
phosphoramidite ligands (L4−L9) has a significant influence
on the enantioselectivity of the reaction (entries 4−9). Ligands
L7, L8, and L9, which have bulky groups at the 6,6′-position,
exhibited high yield, high enantioselectivity, and excellent
diastereoselectivity (entries 7−9). Moreover, the enantiose-
lectivity of the reaction can be improved by lowering the
reaction temperature. At 0 °C, with L7 and L8 as ligands, the
enantioselectivity of the reaction reached 96% ee (entries 10
and 11). Solvent effect was studied by using ligand L7. In
addition to CH2Cl2, toluene can also be used, but the
conversion and yield are lower (entry 12). However, the
reaction does not occur in THF or hexane.
a
Reaction conditions: [Ni(allyl)Br]2 (0.0025 mmol), (R)-L7 (0.005
mmol), NaBArF (0.006 mmol), 1 (0.10 mmol), in 1.5 mL of CH2Cl2,
1
at 0 °C, 48 h. Isolated yield. The dr values were determined by H
b
NMR. The ee values were determined by HPLC. Ar1 = 4-NO2C6H4.
c
d
e
Ar2 = 4-(CO2Me)C6H4. 1 mmol of 1o was used. 5 % mol
[Ni(allyl)Br]2 was used. Ligand (R)-L8 was used. The use of (R)-L7
provides 2p in 84% yield, 10:1 dr, and 84% ee. The absolute
f
Under the optimal reaction conditions (Table 1, entry 10),
various isochromanone-derived 1,6-dienes 1 were studied. The
1,6-dienes bearing either an electron-rich or an electron-
deficient group on the arene ring performed well to afford the
corresponding spiro lactone products in good yield (81−95%)
with high enantioselectivity (86−96% ee) and excellent
diastereoselectivity (dr >20:1) (Scheme 2, 2b−2o). A variety
of functional groups, such as halogen (2c, 2f, 2h, 2i), methoxy
(2d, 2g), nitro (2k), ester (2l), and piperonyl (2o), were
tolerated under the reaction conditions. The absolute
configuration of the product 2n was determined by single-
crystal X-ray diffraction analysis. We then investigated the
desymmetrizing cyclization of 1,6-dienes containing diol. For
these noncyclic substrates, L8 was the most efficient ligand,
affording cyclized products (2p−2s) in good yield (80−92%)
configuration was determined by reducing 2n with LiAlH4 and
comparing the HPLC chart of the product with that of 2s. Use ligand
(S)-L9, at 20 °C, 30 h.
g
with high enantioselectivity (82−89% ee) and satisfactory
diastereoselectivity (dr = 10:1). The desymmetrizing cycliza-
tion of the diene having an ester group (1t) by using ligand L9
afforded the cyclization product 2t in high yield (96%) with
good enantioselectivity (76% ee and 97% ee) and moderate
diastereoselectivity (dr = 3:1). We also studied the
desymmetrizing cyclization of benzofuranone-derived and
lactam-derived 1,6-dienes 1u and 1v. The cyclization of 1u
produced the desired product 2u in high yield (95%) with low
enantioselectivity (47% ee and 17% ee) and moderate
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Letter
diastereoselectivity (dr = 4:1). However, 1v could not afford
the cyclized product.
bearing a quaternary stereocenter. These chiral spiro lactones
and analogues also afford potential candidates for drug
screening.
To gain mechanistic insight into the desymmetrizing
cyclization reaction, deuterium-labeling experiments were
performed with deuterated diene substrates 1a-d1 and 1a-d2
ASSOCIATED CONTENT
■
1
sı
(Scheme 3). H NMR spectroscopy analysis of the products
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00796.
Scheme 3. Deuterium-Labeling Experiments
Experimental procedures and spectral data (PDF)
Accession Codes
CCDC 2041656 contains the supplementary 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Qi-Lin Zhou − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-
0002-4700-3765; Email: qlzhou@nankai.edu.cn
indicated that the deuterium atom at the terminal position of
diene 1a-d1 was not transferred (Scheme 3a), and the
deuterium atom at the 2-position of diene 1a-d2 was
transferred to the 1′-position of the cyclized product 2a-d2
(Scheme 3b).
Authors
Tian-Yuan Zhao − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Ke Li − State Key Laboratory and Institute of Elemento-
Organic Chemistry, College of Chemistry, Nankai University,
Tianjin 300071, China
Based on the previous studies7 and the above experimental
results, we proposed a mechanism for the nickel-catalyzed
desymmetrizing cyclization of 1,6-dienes (Scheme 4). In the
Scheme 4. Proposed Mechanism
Liang-Liang Yang − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China
Shou-Fei Zhu − State Key Laboratory and Institute of
Elemento-Organic Chemistry, College of Chemistry, Nankai
University, Tianjin 300071, China; orcid.org/0000-
0002-6055-3139
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00796
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 21790330, 21532003, 91956000) and the “111” project
(B06005) of the Ministry of Education of China for financial
support.
presence of the phosphine ligand and NaBArF, allyl nickel
bromide dimer A dissociates to allyl nickel B. The migratory
insertion of the CC bond of the diene into the nickel−
carbon bond of B generates alkyl nickel intermediate C. Then,
a β-H elimination of intermediate C forms Ni−H species D.9
The migratory insertion of the CC bond of the diene 1a into
the Ni−H bond of D generates the alkyl nickel intermediate E.
Next, cyclization of E forms alkyl nickel intermediate F.
Finally, β-H elimination of the intermediate F gives product 2a
and regenerates the active Ni−H species D.
DEDICATION
■
Dedicated to the 100th Anniversary of Chemistry at Nankai
University.
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