Enantioselective Synthesis of 3,3′-Diaryl-SPINOLs: Rhodium-Catalyzed Asymmetric Arylation/BF3-Promoted Spirocyclization Sequence

Article abstract of DOI:10.1002/anie.201812266

The enantioselective synthesis of a series of C₂-symmetric 3,3′-diarylated 1,1′-spirobiindane-7,7′-diols (3,3′-diaryl-SPINOLs) was developed by sequential Rh-catalyzed twofold asymmetric conjugate arylation/BF₃-promoted diastereoselective spirocyclization (>20:1 d.r. and >99 % ee for all examples). Some phosphoramidite ligands were prepared from the 3,3′-Ph-SPINOL and applied to several catalytic asymmetric reactions, and the 3,3′-diarylated ligands showed higher enantioselectivities than the privileged nonsubstituted ligands.

Full text of DOI:10.1002/anie.201812266

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Accepted Article
Title: Enantioselective Synthesis of 3,3’-Diaryl-SPINOLS by Rh-
Catalyzed Asymmetric Arylation–BF3-Promoted Spirocyclization
Reactions
Authors: Long Yin, Junhao Xing, Yuhan Wang, Yue Shen, Tao Lu,
Tamio Hayashi, and Xiaowei Dou
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10.1002/anie.201812266
Angewandte Chemie International Edition
COMMUNICATION
Enantioselective Synthesis of 3,3'-Diaryl-SPINOLS by Rh-
Catalyzed Asymmetric Arylation–BF3-Promoted Spirocyclization
Reactions
Long Yin,# Junhao Xing,# Yuhan Wang, Yue Shen, Tao Lu,* Tamio Hayashi,* and Xiaowei Dou*
Abstract: Enantioselective synthesis of a series of C2-symmetric
3,3'-diarylated 1,1'-spirobiindane-7,7'-diols (3,3'-Diaryl-SPINOLS)
was developed via a sequential Rh-catalyzed two-fold asymmetric
conjugate arylation–BF3-promoted diastereoselective spirocyclization
process (>20:1 dr and >99% ee for all the examples). Some
phosphoramidite ligands were prepared from the 3,3'-Ph-SPINOL
and applied to several catalytic asymmetric reactions, where the
3,3'-diarylated ligands showed higher enantioselectivities than
the privileged non-substituted ones.
asymmetric hydrogenation, and those chiral ketones then
underwent TiCl4-promoted spirocyclization to give the
spirobiindanes, which upon treatment with BBr3 gave 2,2'-
cyclohexyl-fused SPINOL derivatives (Scheme 1c-1). It was also
demonstrated that the 2,2'-cyclohexyl-fused SPINOL-derived
ligands showed similar enantioselectivities as the privileged non-
substituted ones. Herein, we report a highly diastereo- and
enantioselective synthesis of 3,3'-diarylated SPINOL derivatives
(3,3'-Diaryl-SPINOLS), which was achieved via a sequential Rh-
catalyzed two-fold asymmetric conjugate arylation–BF3-
promoted diastereoselective spirocyclization process (Scheme
1c-2). The new method reported here tolerates phenolic
substrates to gives SPINOL derivatives directly. More
importantly, the 3,3'-diaryl substitutions were found to be
The privileged chiral structures are highly important in
asymmetric catalysis, as they constitute the backbone of a large
amount of useful chiral catalysts and ligands.[1] As an example,
1,1'-spirobiindane-7,7'-diol (SPINOL)[2] represents one of the
privileged axially chiral structures: since the venerable
pioneering work of Zhou and coworkers,[3] a variety of new
ligands, catalysts, and chiral reagents based on the SPINOL
structure have been developed,[4,5] and they proved to be highly
useful in broad types of asymmetric transformations.[6] Despite
the significance of SPINOLs, available methods to access
enantioenriched SPINOLs are rather limited. The classical
approach to enantioenriched SPINOLs relies on optical
resolution of racemic SPINOLs using resolving agents (Scheme
1a).[7,8] Asymmetric construction of the axially chiral SPINOLs
remained a formidable task for a long time, until recently, the
first catalytic asymmetric synthesis of SPINOL derivatives was
achieved by Tan and coworkers.[9] In Tan’s work, direct
asymmetric construction of the axially chiral center was realized
beneficial
phosphoramidite
for
development
ligands,
of
which
new
SPINOL-based
higher
showed
enantioselectivities than the non-substituted ones in several
different types of reactions.
a) Resolution of racemic SPINOL (Zhou et al.)
Br
O
Br
steps
resolution
OH
OH
OH
OH
HO
HO
+
OMe
OMe
rac-SPINOL
(S)-SPINOL
(R)-SPINOL
b) Direct catalytic asymmetric construction of axially chiral center (Tan et al.)
R1
R1
R2
Ar
MeO OMe
R
cat. CPA
O
O
O
OH
OH
P
19 examples
OH
by
chiral
phosphoric
acid-catalyzed
intramolecular
R
R
up to 96% ee
Ar
R
OH
OH
spirocyclization of 1,5-diphenolic-3-ketal substrates (Scheme 1b).
We envisioned that a new strategy, i.e., construction of the
axially chiral center by diastereoselective spirocyclization of
centrally chiral reagents, may be developed as an alternative
approach to SPINOL derivatives. During the course of our study,
the Ding group reported a related strategy to prepare chiral
SPINOL derivatives.[10] Chiral cyclic ketones bearing ,'-
stereogenic centers were produced by iridium-catalyzed
R2
SPINOLs
CPA
c) New strategy: diastereoselective spirocyclization of centrally chiral ketones
1) Spirocyclization of chiral ketones bearing
R'
,
'-stereogenic centers (Ding et al.)
R'
R'
O
R'
1) [Ir]*, H2
BBr3
OMe
OMe
OH
OH
R
R
2) TiCl4
6 examples
up to >99% ee
OMe
R
OMe
R'
R'
L. Yin,# Dr. J. Xing,# Y. Wang, Y. Shen, Prof. Dr. T. Lu, Prof. Dr. X.
Dou
2) Spirocyclization of chiral ketones bearing , '-stereogenic centers (This work)
[*]
R'
Department of Chemistry and State Key Laboratory of Natural
Medicines, China Pharmaceutical University
Nanjing 211198, China
E-mail: dxw@cpu.edu.cn (Dou)
lut163@163.com (Lu)
Prof. Dr. T. Hayashi
Ar
O
1) [Rh]*, ArB(OH)2
OH
HO
OH
OH
2) BF3 OEt2
15 examples
R'
R'
Ar
all >20:1 dr, >99% ee
R'
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University, 21
Nanyang Link, Singapore 637371, Singapore
E-mail: hayashi@ntu.edu.sg
Scheme 1. Approaches to enantioenriched SPINOL derivatives.
[#]
These authors contributed equally to this work.
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10.1002/anie.201812266
Angewandte Chemie International Edition
COMMUNICATION
To realize the direct asymmetric synthesis of SPINOLs by
one showed higher catalytic reactivity (entry 4, 95% yield). A
screening of different solvents proved toluene to be the best
(entries 4 to 7). It was found that the non-basic reaction
conditions[14] worked well for the current reaction, and the yield
of 3a was improved to 99% (entry 8). The catalyst loading can
be reduced to 2 mol % Rh under non-basic conditions without
affecting the results (entry 9). The yield decreased when the
catalyst loading was further reduced to 1 mol % Rh, and
additional KOH was found to be beneficial for a higher yield
(entries 10 and 11). It is noteworthy that entry 10 gave 3a in
78% yield with unreacted 1a, and no mono phenylation product
was observed, indicating a higher reactivity of the mono
phenylation intermediate than 1a in the current reaction system.
diastereoselective spirocyclization,
a highly diastereo- and
enantioselective synthesis of centrally chiral phenolic ketones is
a necessary prerequisite. The rhodium-catalyzed asymmetric
conjugate arylation of ,-unsaturated ketones with arylboronic
acids has proved to be one of the most reliable methods to
generate ketones bearing -benzylic chiral centers.[11] We then
speculated that the target chiral ketones might be generated by
rhodium-catalyzed two-fold asymmetric conjugate arylation of
easily prepared ,'-bis(arylidene)ketones. We commenced our
investigation with the rhodium-catalyzed asymmetric conjugate
phenylation of (1E,4E)-1,5-bis(2-bromo-5-hydroxyphenyl)penta-
1,4-dien-3-one (1a), and the results are summarized in Table 1.
Table 1. Rhodium-catalyzed asymmetric addition of PhB(OH)2 (2a) to (1E,4E)-
1,5-bis(2-bromo-5-hydroxyphenyl)penta-1,4-dien-3-one (1a).[a]
With enantioenriched 3a (>20:1 dr, >99% ee) in hand, we set
out to explore the spirocyclization of 3a. After extensive studies
of the reaction conditions, boron trifluoride diethyl etherate was
found to promote the spirocyclization efficiently, and SPINOL
derivative 4a was generated in a high yield with excellent
diastereocontrol (Scheme 2, 95% yield, >20:1 dr, >99% ee). The
structure of 4a was unambiguously confirmed by single-crystal
X-ray diffraction analysis.[15]
Entry
L
Solvent
Yield (%)[b]
dr[c]
--
ee (%)[d]
--
1
2
(R)-binap
toluene/H2O (10:1)
<5
92
90
95
94
94
95
99
99
78
95
(R,R)-Ph-bod toluene/H2O (10:1)
2.5:1
>20:1
>20:1
>20:1
16:1
87
3
L1
L2
L2
L2
L2
L2
L2
L2
L2
toluene/H2O (10:1)
toluene/H2O (10:1)
dioxane/H2O (10:1)
THF/H2O (10:1)
>99
>99
99
4
Scheme 2. Spirocyclization of 3a to 3,3'-Ph-SPINOL derivative 4a.
5
6
99
7
DCE/H2O (10:1)
19:1
>99
>99
>99
>99
>99
Next, with the non-basic conditions for asymmetric conjugate
arylation, and with boron trifluoride diethyl etherate for
spirocyclization, the scope of the 3,3'-Diaryl-SPINOLS synthesis
was investigated (Scheme 3).[16] Arylboronic acids bearing
variable substitutions at different positions were found to be
suitable in the current method, and >20:1 dr and >99% ee were
observed in all the investigated cases. For instance, in addition
to the simple phenylboronic acid (4a), arylboronic acids bearing
electron-donating groups at the meta- or para-positions worked
well (4b – 4d). The structure of the products was further
confirmed by single-crystal X-ray diffraction analysis of 4c.[15]
Electron-withdrawing group substituted arylboronic acid was
also tolerated, albeit the yield was lower (4e, 67% yield).
Halogen-substituted arylboronic acids worked equally well (4f –
4i). 3,5-Disubstituted arylboronic acid and 2-naphthylboronic
acid were verified, and the corresponding SPINOL derivatives
were obtained in moderate yields (4j and 4k). It should be
pointed out that the relatively lower yields of 4e, 4i, 4j and 4k
were mainly due to the low conversion at the spirocyclization
step. At last, ,'-bis(arylidene)ketones bearing different
substitutions were tested, and those substrates bearing -OMe, -
Cl, and -F substitutions were well-tolerated (4l – 4o). Iodide
substitution can be easily installed to the ortho-position of the
8[e]
9[e,g]
10[e,h]
11[h]
toluene/H2O (2:1)[f]
toluene/H2O (2:1)[f]
toluene/H2O (2:1)[f]
toluene/H2O (2:1)[f]
>20:1
>20:1
>20:1
>20:1
[a] Reaction conditions: 1a (0.10 mmol), 2a (0.30 mmol), and Rh catalyst (4
mol % Rh), KOH (20 mol %) in solvent (1.1 mL) at 60 °C for 12 h. [b] Isolated
yield of 3a and meso-3a. [c] The ratio of 3a:meso-3a, determined by HPLC
and 1H NMR analysis. [d] The ee value of 3a, determined by HPLC analysis on
a chiral stationary phase column. [e] no KOH. [f] toluene/H2O (1.0 mL/0.5 mL)
was used as the solvent. [g] 2 mol % Rh was used. [h] 1 mol % Rh was used.
At first, (R)-binap ligated rhodium catalyst was tested,
however, only negligible amount of the desired two-fold
conjugate phenylation product 3a was detected (Table 1, entry
1). In contrast to the ineffective chiral bisphosphine ligand, chiral
diene ligands were found to be superior. (R,R)-Ph-bod[12] ligated
rhodium catalyst gave a promising result: the desired ,'-
phenolic ketone 3a was obtained in a high yield with a good
enantioselectivity, albeit with a poor diastereoselectivity (entry 2).
Other chiral diene ligated catalysts were then investigated, and
to our delight, chiral dienes L1 and L2 (both are derived from
(R)--phellandrene)[13] ligated catalysts gave excellent dr and ee
values (entries 3 and 4, >20:1 dr, >99% ee), and the less bulky
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10.1002/anie.201812266
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COMMUNICATION
phenolic OH group, producing a useful intermediate for further
cross-couplings (4p).
10 was generated in a higher ee value, without affecting the high
yield and excellent branched/linear selectivity (Scheme 4d).
SIPHOS-iPr was identified as the best SIPHOS-type ligand in
the copper-catalyzed asymmetric conjugate addition of
diethylzinc to chalcone 11,[20] and its 3,3'-diphenylated congener
L5 showed a higher enantioselectivity (74% ee vs. 71% ee).
Moreover, L4 further improved the enantioselectivity to 93% ee,
which is much higher than the ee value obtained (70% ee) with
the corresponding SIPHOS-PE (Scheme 4e).
Scheme 3. Scope of the 3,3'-Diaryl-SPINOLS synthesis.
Underscoring the utility of our protocol, a gram-scale
synthesis of 4a was conducted. As shown in Scheme 4a, with 1
mol % Rh catalyst loading, 4a was produced in a high yield with
excellent diastereo- and enantiocontrol (1.07 g, 95% yield, >20:1
dr, >99% ee). From the X-ray structure of 4a, it can be clearly
seen that the phenyl substitutions are located on the same side
as the OH groups. We envisioned this special spatial
arrangement should have great influence on the selectivities of
the SPINOL-based ligands/catalysts. At this stage, we prepared
several 3,3'-Ph-SPINOL-based phosphoramidite ligands[17]
(Scheme 4b) and examined their performance in metal-
catalyzed asymmetric transformations. As shown in Scheme 4,
phosphoramidite ligands L3, L4, and L5 were used for direct
comparison with their non-substituted congeners, and they were
found to give higher enantioselectivities in several different types
of reactions. At first, the cationic rhodium-catalyzed asymmetric
hydrogenation of aminocinnamic acid derivative 6 was tested,
and gratifyingly, using L3 as the chiral ligand, a higher
enantioselectivity was achieved than the privileged SIPHOS-
Me[18] and Ding’s 2,2'-cyclohexyl-fused L6[10] (Scheme 4c, 99.8%
ee vs. 97% ee and 96% ee). When L4 was applied to the
rhodium-catalyzed asymmetric acylation reaction between
salicylaldehyde 8 and homoallylic sulfide 9,[19] the chiral ketone
Scheme 4. Gram-scale synthesis, phosphoramidite ligand preparation and
applications.
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10.1002/anie.201812266
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COMMUNICATION
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In summary, we have developed the enantioselective
synthesis of a series of 3,3'-Diaryl-SPINOLS, and the present
method features readily available reagents, easy operation, and
excellent diastereo- and enantiocontrol. More importantly, the
3,3'-Diaryl-SPINOLS-based phosphoramidite ligands showed
higher enantioselectivities than the privileged SPINOL-based
ones in several different types of reactions, indicating great
potentials of the newly developed 3,3'-Diaryl-SPINOLS in
ligand/catalyst development. Further studies on understanding
the origin of higher enantioselectivities of 3,3'-Diaryl-SPINOLS-
based phosphoramidite ligands, as well as development of other
3,3'-Diaryl-SPINOLS-based ligands/catalysts are currently
ongoing in our laboratory.
Acknowledgements
We thank the financial support from the National Natural
Science Foundation of China (21602253), the Natural Science
Foundation of Jiangsu Province (BK20160749), and the “Double
First-Class” University project (CPU2018GY35, CPU2018GF02).
T.H. thanks the Ministry of Education (MOE) of Singapore
(MOE2017-T2-1-064) for financial support.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric synthesis • rhodium • conjugate addition
• spirocyclization • SPINOL
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Entry for the Table of Contents
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L. Yin, J. Xing, Y. Wang, Y. Shen, T.
Lu,* T. Hayashi,* X. Dou*
Page No. – Page No.
Enantioselective Synthesis of 3,3'-
Diaryl-SPINOLS by Rh-Catalyzed
Asymmetric Arylation–BF3-Promoted
Spirocyclization Reactions
Enantioselective synthesis of a series of 3,3'-diarylated 1,1'-spirobiindane-7,7'-diols
(3,3'-Diaryl-SPINOLS) was developed via a sequential Rh-catalyzed two-fold
asymmetric conjugate arylation–BF3-promoted diastereoselective spirocyclization
process. Some phosphoramidite ligands were prepared from the 3,3'-Ph-SPINOL
and applied to several catalytic asymmetric reactions, where the 3,3'-diarylated
ligands showed higher enantioselectivities than the privileged non-substituted ones.
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