Phosphoric Acid-Catalyzed Asymmetric Synthesis of SPINOL Derivatives

Article abstract of DOI:10.1021/jacs.6b11435

Axially chiral 1,1′-spirobiindane-7,7′-diol (SPINOL) is the most fundamental and important privileged structure from which other chiral ligands containing a 1,1′-spirobiindane backbone are synthesized. Driven by the development of enantioselective syntheses of axially chiral SPINOL derivatives, we have successfully developed the first phosphoric acid-catalyzed asymmetric approach. This approach is highly convergent and functional group tolerant, efficiently providing SPINOLs in good yield with excellent enantioselectivity, thus delivering a practical and straightforward access to this privileged structure. It should be emphasized that the catalyst loading could be decreased to only 0.1 mol% for the preparative-scale synthesis. Furthermore, 4,4′-dimethyl-SPINOL-phosphoric acid was synthesized and applied to catalyze the model reaction for synthesis of enantioenriched SPINOL derivatives.

Full text of DOI:10.1021/jacs.6b11435

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Article
Phosphoric Acid-Catalyzed Asymmetric Synthesis of SPINOL Derivatives
Shaoyu Li, Ji-Wei Zhang, Xian-Lin Li, Dao-Juan Cheng, and Bin Tan
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11435 • Publication Date (Web): 02 Dec 2016
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Phosphoric Acid-Catalyzed Asymmetric Synthesis of SPINOL Deriva-
tives
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Shaoyu Li,† ‡ JiꢀWei Zhang,† XianꢀLin Li,† DaoꢀJuan Cheng† and Bin Tan†*
†
‡
Department of Chemistry, South University of Science and Technology of China, Shenzhen 518055, China and State Key
Laboratory and Institute of ElementoꢀOrganic Chemistry, Nankai University, Tianjin 300071, China.
ABSTRACT: Axially chiral 1,1’ꢀspirobiindaneꢀ7,7’ꢀdiol (SPINOL) is the most fundamental and important privileged structure to
synthesize other chiral ligands containing a 1,1’ꢀspirobiindane backbone. Driven by the development of enantioselective synthesis
of axially chiral SPINOL derivatives, we have successfully developed the phosphoric acidꢀcatalyzed asymmetric approach for the
first time. This approach is a highly convergent and functional group tolerant to efficiently provide SPINOLs in good yield with
excellent enantioselectivity, thus delivering a practical and straightforward access to this privileged structure. It should be emphaꢀ
sized that the catalyst loading could be decreased to only 0.1 mol% for the preparative scale synthesis. Furthermore, the 4,4’ꢀ
dimethyl SPINOLꢀphosphoric acid was synthesized and applied to catalyze the model reaction for synthesis of enantioenriched
SPINOL derivative.
and coꢀworkers firstly reported the successful outcome by
using a classic resolution strategy.6a In 2002, Zhou and coꢀ
INTRODUCTION
workers developed a more practical approach by employing
Axially chiral compounds are wide appearance in biologiꢀ
cally active compounds, materials, organocatalysts and ligꢀ
cinchonidinium chloride as a resolution reagent.6b Quite reꢀ
cently, a promising method for kinetic resolution of SPINOL
ands. Accordingly, much attention has been paid to asymmetꢀ
by Nꢀheterocyclic carbeneꢀcatalyzed enantioselective acylation
ric construction of axially chiral compounds and great proꢀ
gress has been achieved in recent years. Among the wellꢀ
was reported by Zhao and coꢀworkers,6c however, only one
substrate was utilized with moderate result (less than 50% ee;
known structures, axially chiral BINOL, BINAP and other
selectivity factor, s = 3.4). The large scale production of optiꢀ
biaryl derivatives have been extensively evaluated as versatile
cally pure SPINOL, however, still relies on conventional resoꢀ
chiral ligands/catalysts. Owing to the importance of these
lution, which requires the stoichiometric use of chiral reagents.
structural motifs, the catalytic asymmetric construction of
biaryl derivatives has been intensively investigated1 and could
Therefore, the development of a catalytic asymmetric synthetꢀ
ic approach to axially chiral SPINOL derivatives is very atꢀ
be accessed by stereoselective oxidative/crossꢀcoupling of two
aryl counterparts,2 asymmetric control of formation of an aroꢀ
tractive and highly desirable.
matic ring,3 atroposelective functionalization of biaryl comꢀ
pounds,4 and so on (Figure 1, left).5
R
R1
R2
R1
R2
biaryl coupling/
aryl formation/
X
Y
OH
OH
OH
OH
functionalization of
biaryl compounds
R'
axially chiral SPINOLs
biaryls
BINOLs
many approaches to chiral
BINOLs and biaryl compounds
no catalytic efficient approach for
asymmetric synthesis of SPINOLs
Figure 2. The useful ligands/organocatalysts with 1,1’ꢀ
spirobiindane backbone derived from SPINOL.
Figure 1. The existing approaches for catalytic asymmetric synꢀ
thesis of axially chiral biaryls and SPINOLs.
Since the pioneering reports of Akiyama and Terada, chiral
phosphoric acids (CPAs) have demonstrated great potential to
catalyze many reactions due to their capacity for synergistic
dual acid and base activation.8 More recently, List and coꢀ
workers have elegantly demonstrated the use of chiral conꢀ
fined phosphoric acid to synthesize an important spiroketal
moiety by spiroketalizations.9 Inspired by these successful
examples and the previous efforts for synthesis of racemic
SPINOL,6a,10 we envisioned that phosphoric acid could actiꢀ
In sharp contrast, the asymmetric synthesis of axially chiral
1,1’ꢀspirobiindaneꢀ7,7’ꢀdiol (SPINOL) remains largely unexꢀ
plored (Figure 1, right),6 although it is the most fundamental
and important privileged structure to synthesize other chiral
ligands containing a 1,1’ꢀspirobiindane backbone such as FuP,
SDP, SpiroPAP, SPIDAM, SIPHOX, SpiroBOX, SCp, SITCP
and CPA for asymmetric catalysis in recent years (Figure 2).7
In this regard, there have only been a few synthetic attempts
toward asymmetric synthesis of enantiopure SPINOL. Birman
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vate the carbonyl and hydroxyl group in a cooperative manner
via a bifunctional activation mode to give the final product
SPINOLs with good stereocontrol. As part of our ongoing
interest in asymmetric construction of axially chiral comꢀ
pounds11and phosphoric acid catalysis,12 we describe herein
the results of the investigation, leading to the first phosphoric
acidꢀcatalyzed enantioselective synthesis of axially chiral
SPINOLs to provide a practical and straightforward synthetic
route toward enantiopure SPINOL derivatives.
10
(R)ꢀC2
(R)ꢀC2
(R)ꢀC2
(R)ꢀC2
(S)ꢀC2
toluene
CHCl3
CHCl3
CHCl3
CHCl3
80
22
13
90
98
98
89
94
90
90
ꢀ90
1
2
3
4
5
6
7
8
11d
12d
13d,e
14d,e
60
120
120
120
a Unless otherwise stated, all reactions were carried out with 1a (0.1 mmol)
o
b
and CPA (5 mol%) in 1 mL of solvent at 80 C for three days under Ar.
Yield based on RPLC (for details, see supporting information). c Deterꢀ
mined by chiral HPLC analysis. d Reaction was run in 3 mL of CHCl3.
e
9
Reaction was run with 10 mol% of CPA for two days.
RESULTS AND DISCUSSION
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To validate the feasibility of our proposed transformation,
we initially investigated the reaction of 1,5ꢀbis(5ꢀhydroxyꢀ2ꢀ
methylphenyl)pentanꢀ3ꢀone 1a in the presence of 9ꢀanthrylꢀ
SPINOLꢀderived chiral phosphoric acid (R)-C1. Unfortunateꢀ
ly, no reaction was observed at room temperature. To our deꢀ
light, the reaction proceeded slowly to provide SPINOL derivꢀ
After an acceptable optimal reaction condition established,
we turned our attention to the substrate scope. As shown in
Table 2, the electronic properties of substituents on the aroꢀ
matic rings have a significant effect on the reactivity of the
transformation. Substrates bearing electronꢀdonating groups
(R = Me, nꢀBu, Ph, 4ꢀMeꢀPh) at the aryl ring proceeded effiꢀ
ciently to afford the corresponding products (S)-3a-3d in 90ꢀ
97% yield with 90ꢀ93% ee (Entries 1ꢀ4). To our disappointꢀ
ment, almost no desired SPINOL derivatives were detected
when substrates bearing electronꢀwithdrawing groups (R = F,
Cl, Br, I) at the aryl ring were used under optimized reaction
conditions. To our surprise, the expected products (S)-3g and
(S)-3h were achieved with good enantioselectivity by increasꢀ
ing catalyst loading to 20 mol% and extending the reaction
time to five days, albeit with very low yields (Table 2, entries
7 and 8), indicating that it is possible to expand the generality
of the substrate scope by further investigation of the reaction
parameters.
o
ative (S)-3a in 17% yield with 41% ee after stirring at 80 C
in a sealed vial for three days (Table 1, entry 1). This result
encouraged us to further evaluate different chiral phosphoric
acids for the transformation. As shown in Table 1, the electron
properties and the steric bulk of substituents at the catalysts as
well as the axially chiral backbone have very strong influences
on the reactivity and enantioselectivity (Table 1, entries 2ꢀ8).
Catalyst (R)-C2 displayed the best result in terms of the chemꢀ
ical yield (60%) and stereocontrol (92% ee) (Table 1, entry 2).
Upon optimizing the reaction conditions through variations of
the solvent, temperature, catalyst loading, and concentration
(Table 1, entries 9ꢀ13 and Table S1 in Supporting
Information), we identified the following protocol as optimal:
reaction of 1a (0.1 mmol) in the presence of catalyst (R)-C2
(10 mol%) in CHCl3 (3 mL) at 120 oC for two days, the axially
chiral (S)ꢀ3a was obtained in 98% isolated yield with 90% ee
(Table 1, entry 13). The opposite enantiomer of (R)-3a could
be obtained with similar result by using (S)-C2 as chiral cataꢀ
lyst (Table 1, entry 14).
Table 2. The Substrate Scope with Respect to Ketones.a
Table 1. Optimization of the Reaction Conditionsa
entry substrate 1
t (d) yield
(%)b
ee
3
(%)c
1
1a, R = Me
1b, R = nBu
1c, R = Ph
(S)ꢀ3a
(S)ꢀ3b
(S)ꢀ3c
2
2
2
2
3
3
5
5
97
90
91
92
93
ꢀ
2
95
3
90
4
1d, R = 4ꢀMeꢀPh (S)ꢀ3d
92
5d
6d
7d
8d
1e, R = F
1f, R = Cl
1g, R = Br
1h, R = I
(S)ꢀ3e
(S)ꢀ3f
(S)ꢀ3g
(S)ꢀ3h
trace
trace
19
ꢀ
93
93
entry
solvent
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCE
T (oC)
80
yield (%)b ee (%)c
CPA
20
a
Unless otherwise stated, all reactions were carried out with 1a-1h (0.1
1
2
3
4
5
6
7
8
9
(R)ꢀC1
(R)ꢀC2
(R)ꢀC3
(S)ꢀC4
(S)ꢀC5
(S)ꢀC6
(R)ꢀC7
(R)ꢀC8
(R)ꢀC2
17
41
92
40
ꢀ11
0
o
mmol) and (R)ꢀC2 (10 mol%) in 3 mL of CHCl3 at 120 C for two days
under Ar. b Isolated yields. c Determined by chiral HPLC analysis. d 20
mol% catalyst (R)ꢀC2 was used.
80
60
80
23
80
40
Considering the aboveꢀmentioned results, we thought that
the improvement of the reactivity of ketones might be the key
point to promote the outcome of this transformation. Thus, we
turned our attention to investigating the reaction with a more
reactive substrate (ketal 2a, R1 = R2 = Me) (For details of opꢀ
timization, see supporting information Table S2). Gratifyingly,
the reaction proceeded very well by use of 1 mol% of catalyst
80
43
80
NR
trace
48
ꢀ
80
ꢀ36
ꢀ34
83
80
80
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(S)ꢀC2 and the desired product (R)-3a was obtained in 90%
yield with 94% ee in two days at 60 C (Table 3, the first exꢀ
over 90% with good chemical yields after further modification
of the reaction condition (Entries 8 and 9). Having identified
the optimized conditions, we proceeded to investigate the subꢀ
strates bearing other aromatic groups. Several substituted ketꢀ
als (Ph, 4ꢀMeꢀPh, 3ꢀFꢀPh and 4ꢀFꢀPh) were successfully apꢀ
plied in the reaction (Table 5). The corresponding 6,6’ꢀdiaryl
SPINOL derivatives 3pꢀ3s were isolated with moderate chemꢀ
ical yields (58ꢀ62%) and good enantioselectivities (83ꢀ95%
ee).
o
1
2
3
4
5
6
7
8
ample). Remarkably, the scope of this catalytic system turned
out to be very broad. Various ketals (2a-2i) with different subꢀ
stitution properties including electronꢀdonating groups (R1 =
R2 = Me, nꢀBu, Ph, 4ꢀMeꢀPh, OMe) and electronꢀwithdrawing
groups (R1 = R2 = F, Cl, Br, I) at the aryl ring performed
smoothly with high enantioselectivities and good to excellent
chemical yields (90ꢀ96% ee, 62ꢀ95% yield). We have also
investigated nonꢀsymmetrical substrates (2j-2o) and found
them to be suitable substrates for delivering products 3j-3o in
good results. Thus, the current results demonstrated that this
method is an efficient and straightforward process to access
enantiomerically pure SPINOL derivatives.
9
Table 4. Screening of the Reaction Conditions for Aryl
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Substituted Ketal 2p.a
Me
Me
Me
Ph
OH
MeO OMe
CPA (10 mol%)
OH
Table 3. The Substrate Scope with Respect to Ketals.a,b,c
CHCl3
Ph
Ph
Ph
OH
Ar
OH
2p
(S)-3p
Me
Ar
Ar
(R)-C1: Ar = 9-anthryl
O
O
O
O
O
O
(R)-C2: Ar = 3,5-(CF3)2C6H3
(R)-C3: Ar = 9-phenanthryl
O
O
P
P
P
OH
OH
OH
O
(S)-C4: Ar = 4-Cl-C6H4
(S)-C5: Ar = 1-pyrenyl
Ar
Ar
Ar
(R)-C9
C10
(R)-
Ar = 9-phenanthryl
Ar = 9-phenanthryl
entry
1
T (oC)
yield (%)b
55
ee (%)c
80
CPA
(R)ꢀC1
(R)ꢀC2
(R)ꢀC3
(S)ꢀC4
(S)ꢀC5
(R)ꢀC9
(R)ꢀC10
(R)ꢀC3
(R)ꢀC3
(R)ꢀC3
(R)ꢀC3
(R)ꢀC3
100
100
100
100
100
100
100
100
100
120
80
2
53
45
3
60
88
4
50
ꢀ67
ꢀ84
ꢀ72
ꢀ
5
55
6
52
7
trace
61
8d
9e
10d
11d
12d, f
90
60
91
61
88
20
92
100
13
90
a
Unless otherwise stated, all reactions were carried out with 2p (0.1
mmol) and CPA (10 mol%) in 3 mL of solvent at 100 oC for five days
under Ar. b Isolated yield based on 2p. Determined by chiral HPLC analꢀ
c
ysis. d 5 mL of CHCl3 was used. e 7 mL of CHCl3 was used. f 1 mol% of
(R)ꢀC3 was used.
a
Unless otherwise stated, all reactions were carried out with 2a-2o (0.1
Table 5. The Substrate Scope in Terms of Synthesis of 6,6’-
Diaryl-SPINOLs.a
mmol) and (S)ꢀC2 (1 mol%) in 3 mL of CHCl3 at 60 oC under Ar. b Isolatꢀ
ed yields. Determined by chiral HPLC analysis. d The reaction was run at
c
70 oC and 5 mol% (S)ꢀC2 was used.
Encouraged by these results, we therefore expanded the
generality of the reaction with regard to the ketals bearing
aromatic groups at the ortho position. When phenyl substituted
ketal 2p was investigated, the reaction proceeded very slowly
under the optimized conditions and only trace amount of
product could be formed after several days. To our delight, the
expected SPINOL derivative (3p) was produced with 53%
o
yield when the reaction was conducted at 100 C, albeit with
moderate enantioselectivity (45% ee). Encouraged by this
result, we further screened the reaction condition by evaluatꢀ
ing different chiral phosphoric acids for the transformation
(Table 4, entries 1ꢀ7). The catalyst (R)ꢀC3 was proved to be
optimal (Entry 3). The enantioselectivity could be improved to
a
Unless otherwise stated, all reactions were carried out with 2p-2s (0.1
o
mmol) and (R)ꢀC3 (10 mol%) in 5 mL of CHCl3 at 100 C for five days
under Ar.
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To further demonstrate the practicality of such process, we
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1
2
3
4
5
6
7
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carried out a gramꢀscale synthesis of product (R)ꢀ3a and (S)ꢀ
3g under the optimal reaction conditions. As displayed in
Scheme 1a, there were almost no change in chemical yields
and stereoselectivities. It is noteworthy that the catalyst
loading can be decreased to 0.1 mol% for synthesis of (R)ꢀ3a
without any influence on the outcome, albeit with a higher
temperature and longer reaction time. It should be worth highꢀ
lighting that the debromination of (R) or (S)ꢀ3g can be easily
realized to synthesize the (R) or (S)ꢀSPINOL in the presence
of Pd/C catalyst without any effect on enantioselectivities
(Scheme 1b).6a To our delight, the ee value could be improved
to >99% after once recrystallization.
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Scheme 1. Preparative Synthesis and Debromination.
To gain further insight into the reaction mechanism, we
conducted control experiments to rationalize the current reacꢀ
tion process and its stereochemistry. Fortunately, when ketal
2g was tested under the similar reaction conditions by using 1
mol% of catalyst (S)ꢀC2 for just four days, the key intermediꢀ
ate 4 was formed in 37% yield and accompanied with forꢀ
mation of the desired product in 25% yield with 96% ee
(Scheme 3a). Furthermore, treating the intermediate 4 with 5
mol% of (S)ꢀC2 at 70 oC for five days, the final product (R)ꢀ3g
was formed in almost quantitative yield with the same enantiꢀ
oselectivity (Scheme 3a). On the basis of the above observaꢀ
tions and previous reports,14a,b the reaction may initially form
an intermediate B in situ generated from A and further go
through an active oꢀQM intermediate14 C to deliver the
SPINOL derivative. The excellent stereocontrol was attributed
to the simultaneous interaction between the bifunctional phosꢀ
phoric acid and intermediate C via hydrogen bonding (Scheme
3b). At the present stage, the ion pair interactions10,15 between
the substrate and the catalyst cannot be ruled out from the
reaction process with respect to the excellent enantioselection
observed in the reaction. Therefore, further investigations are
necessary to unambiguously elucidate the mechanism.
After the practical approach to synthesize the SPINOL deꢀ
rivatives established, we are interested in exploring the appliꢀ
cation of 4,4’ꢀdisubstituted SPINOLs in asymmetric catalysis.
Inspired by the pioneering works of Zhou13a and Wan13b that
4,4’ꢀdisubstituted SPINOLs and their derived compounds
could be utilized as efficient chiral ligands for addition reacꢀ
tion and hydrogenation, we envisioned that 4,4’ꢀdisubstituted
SPINOLꢀderived phosphoric acids might be acted as organoꢀ
catalysts to catalyze the model reaction. According to Wang’s
elegant synthetic procedure for synthesis of SPINOLꢀ
phosphoric acid,7h we have synthesized the 4,4’ꢀdimethyl
SPINOLꢀphosphoric acid (R)ꢀC3a by using modified reaction
procedures (Scheme 2a, for synthetic details, see Supplemenꢀ
tary information). To really investigate the potential applicaꢀ
tion of the resultant new chiral phosphoric acid in the field of
asymmetric catalysis, we chose the synthesis of (S)ꢀ3a and (S)ꢀ
3g from ketal 2a and 2g respectively as model reactions. Gratꢀ
ifyingly, the reactions proceeded smoothly and the correꢀ
sponding products were obtained in good results (Scheme 2b),
demonstrating that the newly developed phosphoric acid has
the potential application in asymmetric synthesis. Further
work encompassing the application of other 4,4’ꢀdisubstituted
SPINOLꢀderived phosphoric acids for enantioselective reacꢀ
tions is currently in progress in our laboratory.
Scheme 3. Control Experiments and Proposed Mechanism.
Scheme 2. Synthesis and Application of 4,4’-Dimethyl
SPINOL-Phosphoric Acid (R)-C3a.
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We are thankful for the financial support from the National Natuꢀ
ral Science Foundation of China (Nos. 21572095 & 21602097),
Shenzhen special funds for the development of biomedicine, inꢀ
CONCLUSION
1
2
3
4
5
6
7
8
We have successfully developed the asymmetric synthesis
of SPINOL derivatives by means of chiral phosphoric acid for
the first time. With this methodology, a wide range of axially
chiral SPINOLs were synthesized in good results with high
level of enantioselectivity, delivering a practical and straightꢀ
forward approach to this fundamental and important privileged
structure. Notably, the preparative scale synthesis can be conꢀ
ducted very well with only 0.1 mol% of catalyst loading.
Furthermore, the 4,4’ꢀdimethyl SPINOLꢀphosphoric acid was
synthesized and applied to catalyze the model reaction for
synthesis of enantioenriched SPINOL derivative, indicating
that the newly developed phosphoric acid has the potential
application in asymmetric synthesis. Application of this strateꢀ
gy to other substrate classes and mechanistic studies for better
understanding the asymmetric induction in this transformation
are ongoing in our laboratory.
ternet,
new
energy,
and
new
material
industries
(JCYJ20150430160022510). B.T. thanks the Thousand Young
Talents Program for financial support. Dedicated to prof. QiꢀLin
Zhou for his great contribution on development and application of
axially chiral SPINOL and its derivatives as ligands on asymmetꢀ
ric catalysis.
9
REFERENCES
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(1) For typical reviews, see: (a) Chen, Y.; Yekta, S.; Yudin, A. K.
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METHODS
General procedure for the asymmetric synthesis of the
SPINOL Derivatives (R)-3a-3o from ketal substrates. Unꢀ
der argon atmosphere, 2 (0.1 mmol), (S)ꢀC2 (1 mol% or 5
mol%) and 3 mL of anhydrous CHCl3 were added to a 10 mL
ovenꢀdried pressure Schlenk tube (purchased from Beijing
Synthware Glass) with a magnetic stirring bar. Then the
sealed reaction proceeded at 60℃ or 70℃ (the temperature of
oil bath) until the substrate was consumed completely. After
evaporation of the solvent, the residue was purified by flash
chromatography eluted with PE/EA (8/1ꢀ4/1) to afford the
product (R)ꢀ3.
General procedure for the asymmetric synthesis of the
6,6’-diaryl-SPINOL Derivatives (S)-3p-3s. Under argon
atmosphere, 2 (0.1 mmol), (R)ꢀC3 (10 mol%) and 5 mL of
anhydrous CHCl3 were added to a 10 mL ovenꢀdried pressure
Schlenk tube (purchased from Beijing Synthware Glass)
with a magnetic stirring bar. Then the sealed reaction proceedꢀ
ed at 100℃(the temperature of oil bath) for five days. After
evaporation of the solvent, the residue was purified by flash
chromatography eluted with PE/EA (50/1ꢀ20/1) to afford the
corresponding product (S)ꢀ3.
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S. J. J. Am. Chem. Soc. 2013, 135, 2963. (d) Ros, A.; Estepa, B.; Ramírezꢀ
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization of all new compounds,
Table S1, Table S2. This information is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
tanb@sustc.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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