Optically Active Helical Lanthanide Complexes: Storable Chiral Lewis Acidic Catalysts for Enantioselective Diels–Alder Reaction of Siloxydienes

Article abstract of DOI:10.1002/asia.201901705

Lanthanide triflates and a series of hexadentate chiral ligand complexes were synthesized. X-ray-quality crystals were obtained from mixtures of the lanthanide complexes, which were helical in shape. The complexes showed Lewis acidity and catalyzed the enantioselective Diels–Alder reaction of electron-rich siloxydienes. The complexes were stable enough to be stored at ambient temperature on a laboratory bench and retained their Lewis acidity even after a month.

Full text of DOI:10.1002/asia.201901705

CHEMISTRY
AN ASIAN JOURNAL
www.chemasianj.org
Accepted Article
Title: Optically Active Helical Lanthanide Complexes: Storable Chiral
Lewis Acidic Catalysts for Enantioselective Diels-Alder Reaction
of Siloxydienes
Authors: Shinji Harada, Saki Nakashima, Shihori Sekino, Wakana
Oishi, and Atsushi Nishida
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10.1002/asia.201901705
Chemistry - An Asian Journal
COMMUNICATION
Optically Active Helical Lanthanide Complexes: Storable Chiral
Lewis Acidic Catalysts for Enantioselective Diels-Alder Reaction
of Siloxydienes
Shinji Harada,*[a],[b] Saki Nakashima,[a] Shihori Sekino,[a] Wakana Oishi,[a] and Atsushi Nishida*[a],[b]
Abstract: Lanthanide triflates and a series of hexadentate chiral
ligands complexes were synthesized. X-ray-quality crystals were
obtained from mixtures of the lanthanide complexes, which were
helical in shape. The complexes showed Lewis acidity and catalyzed
the enantioselective Diels-Alder reaction of electron-rich siloxydienes.
The complexes were stable enough to be stored at ambient
temperature on a laboratory bench and retained their Lewis acidity
even after a month.
storable and each time had to be prepared in situ under rigorously
dried conditions prior to use.
LnX3, DBU
Binaphthyl diamine-
derived chiral ligand*
Chiral Catalyst
Solution
Unidentified Structure
Prepared for Each Batch
Tedious Procedure
*chiral ligands
F
O
O
O
Me
S
S
The Diels-Alder reaction, which gives a six-membered ring from a
diene and a dienophile, is one of the fundamental reactions in
organic synthesis.[1] Among frequently used dienes, siloxydiene is
a highly reactive substrate, and the siloxy group can be used after
the reaction as a versatile functional group.[2] However, a
challenge with the use of siloxydiene is its acid-lability. In general,
the Diels-Alder reaction is accelerated by acidic reagents.
Diastereo- and enantioselective variant could be also achieved by
acidic reagents. Thus, for the reaction using siloxydienes, the
applicable Lewis acidic catalyst is limited because acidic reagents
decompose the siloxydiene before promoting the desired reaction.
The product derived from siloxydiene is also unstable under acidic
conditions.
Our group has overcome this problem by using a lanthanide
catalyst (Scheme 1).[3],[4],[5] Lanthanides are reactive
electropositive metals, and their salts are often used as hard
Lewis acids.[6] They also accept large numbers of ligands with a
variety of coordination environments. By taking advantage of
these unique properties, we could control the Lewis acidity of the
metal center by adding proper ligands without saturating the
coordination site. In addition, their chemical and physical
properties are similar, but differ slightly according to the atomic
number.[7] Thus, we can tailor-make a suitable catalyst for a
specific substrate by screening the metal center. However, our
ternary lanthanide catalyst was not a crystalline complex, and the
structure is still unknown. Additionally, the catalyst was not
Me
Me
NH
N
H
H
N
N
H
H
N
Ph
Ph
N
H
H
N
N
H
H
N
F
F
NH
O
Me
F
Scheme 1. Our Previous Chiral Ternary Catalytic System for Enantioselective
Diels-Alder Reaction of Siloxydienes.
We report here a synthesis of new lanthanide complexes
(Scheme 2), which were prepared using a simple procedure and
were stable at ambient temperature. We elucidated the structure
unambiguously by X-ray crystallographic analysis. The Lewis
acidity of the metal center would be properly tuned by a
hexadentate ligand, and the catalytic and enantioselective Diels-
Alder reaction of siloxydiene was performed as an application of
the complex.
N
N
N
Ln
N
R
R
R
X3
R
N
N
N
N
N
N
N
N
*
*
LnX3
*
*
Crystallographically
Defined Structure
Storable
[a]
[b]
Prof. Dr. S. Harada, S. Nakashima, S. Sekino, W. Oishi, and Prof.
Dr. A. Nishida
Graduate School of Pharmaceutical Sciences
Chiba University
1-8-1 Inohana, Chuo-ku, Chiba, Japan.
E-mail: s.harada@faculty.chiba-u.jp, anishida@faculty.chiba-u.jp
Prof. Dr. S. Harada and Prof. Dr. A. Nishida
Molecular Chirality Research Center
Chiba University
Easy Preparation
Scheme 2. Preparation of Chiral Lanthanide Catalyst for Enantioselective Diels-
Alder Reaction of Siloxydienes.
We synthesized bis[imino-bipyridyl] (ImBpy) chiral ligand 1 from
(S,S)-cyclohexanediamine.[8],[9] When we mixed 1 and lanthanide
triflate, we obtained a crystalline compound (Scheme 3). This
complex is stable enough to store at ambient temperature on a
1-33 Yayoi-cho, Inage-ku, Chiba, Japan.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/asia.201901705
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COMMUNICATION
OTIPS
laboratory bench for at least one month. Figure 1 shows the X-ray
crystallographic analysis of gadolinium complex as an
example.[10] The chiral ligand 1 wound around the metal center
with a chiral coordination sphere to form a P-helix.[11] We focused
on the structure in which the metal center was multiply
coordinated by nitrogen functionalities. The genuine Lewis acidity
of the metal center would be decreased, and we envisioned that
the complex may act as a mild Lewis acidic catalyst. Incidentally,
Hasegawa reported the synthesis of racemic helical lanthanide
complexes from lanthanide nitrates and an ethylene-tethered
variant of ligand 1.[12]
OTIPS
catalyst
(10 mol%)
CO2Me
N
N
CO2Me
O
+
N
H
O
MeCN
0 ºC, 4 h
Mbs
Mbs
N
2
O
(1.5 equiv.)
O
O
O
4
3
Mbs:
4-MeO-C6H4-SO2-
Gd(OTf)3 / (S,S)-1
(prepared in situ)
37% yield, exo:endo = 6:1
86% ee (exo)
:
:
Crystal of
21% yield, exo:endo = 6:1
Gd(OTf)3 / (S,S)-1 84% ee (exo)
Scheme 4. Enantioselective Diels-Alder Reaction Using the New Binary
Lanthanide Complex as a Chiral Lewis Acidic Catalyst
OTf
N
N
N
Ln
N
N
N
N
N
N
N
N
N
Ln(OTf)3
We briefly surveyed rare-earth triflates to tailor-make the best-
suited catalytic composition for the Diels-Alder reaction of 2 and
3 (Table 1). While scandium catalyst gave the product with only
28% ee (entry 1), yttrium and other lanthanides showed high
enantioselectivity (entries 2-9). For lanthanides, the yields tended
to improve as the Lewis acidity of the elements increased.[7]
Regarding stereoselectivity, a smaller ionic radius was associated
with a higher ee of the product. Based on both the yield and
stereoselectivity, the ytterbium catalyst was considered to give
the best results.[13],[14]
MeCN
rt, 2 h
TfO
OTf
(S,S)-ImBpy 1
[Ln(1)(OTf)3]
Scheme 3. Synthesis of Chiral Lanthanide Complexes ([Ln(1)(OTf)3])
Table 1. Screening of Rare-Earth Triflates in the Asymmetric Diels-Alder
(A)
Reaction
rare earth triflate (10 mol%)
(S,S)-1 (10 mol%)
2
+
3
4
MeCN, 0 ºC, 4 h
Yield (%)
exo:endo[a]
(1.5 equiv.)
F
F
O F
S
Entry
Ln(OTf)3
% ee (exo)
O
N
TfO
O
N
N
1
2
3
4
5
6
7
8
9
Sc(OTf)3
Y(OTf)3
69
65
42
29
37
60
60
79
77
14:1
4:1
4:1
4:1
6:1
9:1
4:1
5:1
16:1
28
77
71
76
86
83
78
78
89
N
NTfO
N
N
Gd
(B)
Gd
N
N
O
O
O
N
S
O
La(OTf)3
Nd(OTf)3
Gd(OTf)3
Ho(OTf)3
Er(OTf)3
Tm(OTf)3
Yb(OTf)3
OTf
O
F
S
O
F
F
F
F
F
top view
side view
Figure 1. Crystallographic Characterization of the Chiral Gadolinium Complex
[Gd(1)(OTf)3]. ORTEP Drawings (A) and ChemDraw Drawings (B). Hydrogen
atoms and disordered atoms have been omitted for clarity. Ellipsoids are drawn
at the 50% probability level.
To verify the catalytic ability of this new lanthanide complex, we
considered the Diels-Alder reaction of pyrrolidine-incorporated
siloxydiene 2[4e] and dienophile 3. The solution of the complex was
first used as a catalyst, and the product 4 with a silyl enol ether
was obtained in 37% yield with 86% ee (Scheme 4). When the
isolated single crystal was used as a catalyst, it still showed a
similar high stereoselectivity. These results indicated that this new
lanthanide complex acted as a chiral Lewis acidic catalyst, and
we speculated that a helical lanthanide complex [Ln(1)](3-
n)+•n(OTf)– would be the active catalyst.
[a] calculated by 1H NMR of diastereomixture.
We proposed the reaction mechanism shown in Scheme 5 based
on the X-ray crystallographic analysis of the catalyst. The
dienophile 3 would coordinate to the lanthanide catalyst in a
bidentate manner by the ligand exchange with triflates to form a
corresponding complex 5, while a complex 6 had a steric
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COMMUNICATION
Scheme 6. Enantioselective Diels-Alder Reaction of Danishefsky Diene (8) and
Maleimide 9.
repulsion and would be unstable. Next, the diene 2 would
approach the complex from the front-left side, because the
opposite side (back-right) of the dienophile was blocked by the
bipyridyl unit of the chiral ligand. Finally, the product 4 with the
actual stereochemistry was obtained via transition state 7.
The catalytic activity of the lanthanide complex was maintained
even after isolation of the complex as a powdery reagent. We
prepared the reagent by simply removing volatiles (Scheme 7 (a)),
and the resulting powdery solid was placed in a vial and sealed
with argon. After storage for 30 days, it was used as a catalyst for
the Diels-Alder reaction of 8 and 9 (Scheme 7 (b)), and product
10 was obtained in 94% yield with comparable stereoselectivity.
F
F
2
OTf
2
OTf
F
F
O F
S
O F
S
O
N
O
N
O
N
O
N
N
N
Ln
Ln
(S,S)-1 Yb(OTf)3
N
N CO2Me
O
H
H
O
O
O
(a)
H
O
N
N
O
rt, 2 h
MeO2C
[complex 5]
[complex 6]
MeCN evaporation &
OTIPS
dried in vacuo
[Yb(1)(OTf)3]solid
N
[Yb(1)(OTf)3]solid
(10 mol%)
*
2
Mbs
(b)
8
+
9
10
F
MeCN, 0 ºC, 30 min
92% yield, 96% ee
endo only
2
OTf
(1.5 equiv.)
F
*stored for 30 days
O F
S
O
OTIPS
Scheme 7. Chiral Ytterbium Powdery Complex as a Storable Catalyst
O
N
N
N
CO2Me
Ln
N
H
O
Mbs
OTIPS
The enantiomeric excess of the Diels-Alder adduct 10 could be
enriched by recrystallization (Scheme 8).[17] A methoxy carbonyl
moiety was successfully removed by mixing with NH-silica gel.
Through these operations, the silyl enol ether was intact, and
compound 11 could be used as a versatile building block.
N
N CO2Me
O
O
O
O
N
Mbs
N
4
O
[complex 7]
Scheme 5. Proposed Reaction Mechanism
OTBS
OTBS
NH-silica gel
(8.9 w/w equiv.)
H
H
We then tried the Diels-Alder reaction using a combination of
more common substrates: Danishefsky diene (8) and maleimide
9 (Scheme 6 (a)).[15] The desired hydroisoindole 10 with a silyl
enol ether was obtained in 97% yield with 94% ee. Our previous
ternary catalyst[3a] gave 10 in only 85% yield with 65% ee.[16] Thus
the enantio-inductive potential of Yb(1)(OTf)3 catalyst for this
reaction was superior to that of our previous ternary catalyst. In
addition, we confirmed that a gram-scale reaction with 1 mol% of
the catalyst also gave comparable results (Scheme 6 (b), 92%
yield, 89% ee).
O
O
MeO
MeO
H
H
CH2Cl2
rt, 24 h
N
NH
O
O
CO2Me
10
94% ee
11
quant.
recrystallized from
CH2Cl2/Hexane
>99% ee
Scheme 8. Enantio-enrichment of 10, and Its Transformation in the Presence
of Silyl Enol Ether.
In conclusion, we synthesized novel lanthanide complexes having
a chiral helical shape. Their chiral helicity served as a powerful
structural motif in the induction of enantioselectivity, and they
exhibited catalytic activity for the enantioselective Diels-Alder
reaction of electron-rich siloxydienes. We also successfully
isolated the chiral catalyst as a storable reagent. Studies on the
optical properties of these complexes are now ongoing.
OTBS
OTBS
Yb(OTf)3 (10 mol%)
(S,S)-1 (10 mol%)
H
(a)
+
O
O
MeO
MeO
H
MeCN
0 ºC, 10 min
N
N
Danishefsky
diene (8)
O
CO2Me
O
CO2Me
10
9
(2.0 equiv.)
97% yield, 94% ee
(endo only)
Yb(OTf)3 (1 mol%)
(S,S)-1 (1 mol%)
Acknowledgements
(b)
8
+
9
10
MeCN, 0 ºC, 3 h
92% yield, 89% ee
(1.5 equiv.)
We thank Prof. M. Hasegawa (Aoyama Gakuin University) for her
fruitful discussions regarding lanthanide complexes. We thank
Prof. T. Yoneda (Hokkaido University) for his help with X-ray
(1.0 gram-scale)
(endo only)
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Schaffner, Dalton Trans 2009, 8165-8167; c) E. C. Constable, G. Zhang,
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crystallographic analyses. We are grateful to Mr. Sakamoto, Mr.
Emori, and Mr. Ikeda (Chiba University) for their support with the
preliminary survey. This work was supported by the Japan Society
for the Promotion of Science (JSPS) KAKENHI [Grant Numbers
16K08154 & 19K06991 (SH), and 17H03969 (AN)], and the Tokyo
Biochemical Research Foundation [Grant Number 16-B1-5 (SH)].
We acknowledge the Institute for Global Prominent Research,
Chiba University, for providing financial support.
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[10] CCDC 1961513 contains the supplementary crystallographic data.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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[13] We constructed an ImBpy library. For the results using those ligands in
combination with other lanthanide salts, see Supporting Information.
[14] We succeeded in the X-ray crystallographic analyses of chiral complexes
synthesized from other lanthanide salts and ImBpy derivatives which had
similar helical structures. CCDC 1961514, 1961516, and 1961517
contain the supplementary crystallographic data. These data can be
obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. See also Supporting
Information.
Conflict of Interest
A patent application on storable chiral lanthanide catalyst has
been filed, where S.H., S.N., and A.N. are listed as inventors.
Keywords: asymmetric synthesis • lanthanides • Diels-Alder
reaction • Lewis acid • helical structure
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Entry for the Table of Contents
COMMUNICATION
New chiral lanthanide complexes were
synthesized and applied to the
enantioselective Diels-Alder reaction
of siloxydienes. The complex was
stable enough to be stored at room
temperature.
Shinji Harada,* Saki Nakashima, Shihori
Sekino, Wakana Oishi, Atsushi Nishida*
Page No. – Page No.
Optically Active Helical Lanthanide
Complexes: Storable Chiral Lewis
Acidic Catalysts for Enantioselective
Diels-Alder Reaction of Siloxydienes
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