Symmetry in Cascade Chirality-Transfer Processes: A Catalytic Atroposelective Direct Arylation Approach to BINOL Derivatives

Article abstract of DOI:10.1021/jacs.6b01458

Herein we disclose a scalable organocatalytic direct arylation approach for the regio- and atroposelective synthesis of non-C₂-symmetric 2,2′-dihydroxy-1,1′-binaphthalenes (BINOLs). In the presence of catalytic amounts of axially chiral phosphoric acids, phenols and naphthols are coupled with iminoquinones via a cascade process that involves sequential aminal formation, sigmatropic rearrangement, and rearomatization to afford enantiomerically enriched BINOL derivatives in good to excellent yields. Our studies suggest that the (local) symmetry of the initially formed aminal intermediate has a dramatic impact on the level of enantioinduction in the final product. Aminals with a plane of symmetry give rise to BINOL derivatives with significantly lower enantiomeric excess than unsymmetrical ones featuring a stereogenic center. Presumably asymmetric induction in the sigmatropic rearrangement step is significantly more challenging than during aminal formation. Sigmatropic rearrangement of the enantiomerically enriched aminal and subsequent rearomatization transfers the central chirality into axial chirality with high fidelity.

Full text of DOI:10.1021/jacs.6b01458

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Communication
Symmetry in Cascade Chirality-Transfer Processes: A Catalytic
Atroposelective Direct Arylation Approach to BINOL Derivatives
Jin-Zheng Wang, Jin Zhou, Chang Xu, Hongbin Sun, László Kürti, and Qing-Long Xu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b01458 • Publication Date (Web): 07 Apr 2016
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Symmetry in Cascade Chirality-Transfer Processes: A Cata-
lytic Atroposelective Direct Arylation Approach to BINOL De-
rivatives
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Jin-Zheng Wang†, Jin Zhou†, Chang Xu†, Hongbin Sun†*, László Kürti‡* and Qing-Long Xu†*
†Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State Key Laboratory of Natural Medicines, China
Pharmaceutical University 24 Tongjia Xiang, Nanjing 210009 (P.R. China)
‡Department of Chemistry, Rice University, BioScience Research Collaborative, 6500 Main Street, Rm 380, Houston, TX
77030 (USA)
Supporting Information Placeholder
scalable fashion.4 Current strategies5 include classical
ABSTRACT: Herein we disclose a scalable organocatalytic
resolution of racemic biaryls, desymmetrization of preformed
direct arylation approach for the regio- and atroposelective
prochiral biaryls, dynamic kinetic resolution of rapidly
synthesis
of
non-C2-symmetrical
2,2’-dihydroxy-1,1’-
racemizing preformed chiral biaryls5c,i, transition metal-
catalyzed aryl-aryl coupling4b,5d, de novo construction of an
aromatic ring5b,j and central-to-axial chirality exchange5f,h,k
(Fig. 1B).
binaphthalenes (BINOLs). In the presence of catalytic
amounts of axially chiral phosphoric acids, phenols and
naphthols are coupled with iminoquinones via a cascade
process that involves sequential aminal-formation, sigma-
tropic rearrangement and rearomatization to afford enanti-
omerically enriched BINOL derivatives in good to excellent
yield. Our studies suggest that the (local) symmetry of the
initially formed aminal intermediate has a dramatic impact
on the level of enantio-induction in the final product. Ami-
nals with a plane of symmetry gave rise to BINOL derivatives
with significantly lower enantiomeric excess than unsymmet-
rical ones featuring a stereogenic center. Presumably asym-
metric induction in the sigmatropic rearrangement step is
significantly more challenging than during aminal formation.
Sigmatropic rearrangement of the enantiomerically enriched
aminal and subsequent rearomatization transfers the central
chirality into axial chirality with high fidelity.
Biaryl compounds that exhibit axial chirality (i.e., hindered
rotation about the C-C bond) are common among natural
products, pharmaceuticals, ligands and catalysts (Fig. 1A).
The ease of racemization in enantiopure biaryls depends on
the magnitude of the rotational barrier that is determined by
both the size and number of substituents at the ortho posi-
tions flanking the aryl-aryl bond.1 During the past two dec-
ades, both C2- and non-C2-symmetrical axially chiral biaryl
compounds1a-c (e.g., BINAP, BINOL, BINAM, NOBIN and
their derivatives, Fig. 1A) have played key roles as ligands for
transition-metals in the development of catalytic enantiose-
lective transformations.2 In addition to being referred to as
“privileged chiral catalysts”2j, recently it was recognized that
controlling the chirality of functionalized biaryl structures
will have enormous implications in the future development
of pharmaceuticals.3 Given the importance of biaryls, it is
surprising that relatively few methods are available for their
atroposelective synthesis in an operationally simple and
Figure 1. Organocatalytic atroposelective direct arylation of
hydroxyarenes to afford non-C2-symmetrical BINOLs.
As part of an ongoing program in the Kürti group to devel-
op new and practical TM-free direct arylation methods for
the preparation of highly functionalized symmetrical and
unsymmetrical biaryls6a,5h,6b, we recently successfully exploit-
ed quinone and imino-quinone monoacetals as arylating
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agents to access both BINOL/NOBIN-type of functionalized
yield and with 49% ee. Encouraged by this initial result, we
1
2
3
4
5
6
7
8
biaryls, that are atropoisomeric but non-C2-symmetrical,
from phenols and naphthols under organocatalytic condi-
tions (1 + 2 → 5; Fig. 2A).6b We also briefly explored the pos-
sibility of using chiral BINOL-derived phosphoric acids as
catalysts to obtain the biaryl products in an enantiomerically
enriched form. Unfortunately, despite achieving moderate to
good isolated yields, the level of enantio-induction was very
poor (3-10% enantiomeric excess, ee), which we partially at-
tributed to interference by MeOH that is liberated during the
formation of a mixed-acetal intermediate (1 + 2 → 3; Fig.
2A);6b addition of 3 Ǻ molecular sieves (MS) did not improve
the ee. We observed similar interference by proton-donors
(i.e., H2O) during the catalytic synthesis of BINAM deriva-
tives;5h in this case the addition of 4 Ǻ MS was advantageous.
conducted a survey of structurally diverse BINOL-derived
chiral phosphoric acid catalysts2d,9 and solvents to find the
optimum conditions that maximizes the enantiomeric excess
of the product (Table 1; see SI for a detailed discussion of the
screening results).
Table 1. Catalyst Screen for the Atroposelective Syn-
thesis of 9a from 6a and 2a.
i-Pr
i-Pr
TsHN
Me
Me
O
9
Me
OH
i-Pr
OH
O
i-Pr
solvent
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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O
O
+
OH
OH
(S)
P
room
temperature
Me
2a
NTs
6a
i-Pr
i-Pr
9a
7c (10 mol%)
Entrya
Time (h)
erb
ee (%)
Solvent
A. Organocatalytic Synthesis of BINOL/NOBIN-Type Biaryls (Kürti):
1
2
3
4
5
48
48
48
48
84
60
24
48
8
77
72
88
81
94
86
88
92
82
CH2Cl2
toluene
1,2ꢀdichloroethane (DCE)
CHCl3
chlorobenzene
1,3ꢀdiꢀCF3ꢀbenzene
1,2ꢀdichloroethane (DCE)
chlorobenzene
88.5:11.5
86:14
94:6
90.5:9.5
97:3
93:7
94:6
96:4
91:9
88.5:11.5
TFA (20 mol%)
MeO
X
toluene, 100 o
C
OR
OH
R1
XH
OH
R2
+
R1
(PhO)2PO2H (20 mol%)
R2
MeO OMe
CF3CH2OH, r.t.
1
2
6
X = O, NMs, NTs; R = alkyl
7c
8c
9d
5
loss of
MeOH
acetal
formation
re-
aromati-
zation
1,2ꢀdichloroethane (DCE)
R2
10c,e 1,2ꢀdichloroethane (DCE)
100
77
X
6
aReaction conditions: 2a (0.075 mmol), 6a (0.05 mmol), cat. (10 mol%), solvent (1 mL).
Reactions were stopped when all of 6a was consumed. bEnantiomeric ratio was
determined by HPLC analysis. cReacted at 50 oC. dReacted at 80 oC. eUsing 5 mol% 7c.
4
MeO
X
H
1
2
4
5
[3,3]
6
1
R1
O
5
R1
6
R2
1
X
H
O
3
H
OMe
H
2
R1
5
O
3
3
4
2
3
R2
OMe
4
Based on the optimization studies (described in Table 1),
we selected DCE as the preferred solvent, chiral phosphoric
acid 7c (at 10 mol% loading) as the preferred catalyst and
either 25 ˚C or 50 ˚C as the optimum reaction temperature.
At first we evaluated the coupling of iminoquinone 6a with
fourteen (14) structurally different hydroxyarenes that in-
cluded eleven (11) naphthols (Table 2, entries 1-11) and three
(3) monocyclic phenols (Table 2, entries 12-14).
mixed
acetal
doubly deꢀaromatized
intermediate
4
B. New Design to Utilize N-Sulfonyl Iminoquinones (Xu, Sun & Kürti):
SiPh3
TsHN
Me
Me
O
O
O
O
(S)
P
TsHN
Me
Me
OH
6a
+
SiPh3
[3,3]
OH
OH
O
O
7b (10 mol%)
re-
OH
Me
CH2Cl2, rt, 48 h
Me
aromati-
zation
enantioselective
aminal formation
TsHN
For 2-naphthols the biaryl products were formed in good
to excellent yield and the observed enantioselectivities
ranged between 78-96% ee. There is no clear pattern that can
be discerned how electron-withdrawing and electron-
donating groups on the naphthalene ring influence the level
of enantio-induction.
8a
9a
85%; 49% ee
2a
chiral aminal
C. Atroposelective Synthesis of Axially Chiral Biaryldiols (Tan):
2,4,6-(i-Pr)3C6H2
O
HO
X
HO
X
O
O
O
re-
aromati-
zation
P
X
O
OH
10
+
O
O
OH
OH
2,4,6-(i-Pr)3C6H2
OH
The nearly perfect enantioselectivity (99% ee) obtained
during the formation of terphenyl compound 9ea’ from 2,3-
dihydroxynapthalene (Table 2, entry 15) is remarkable and
suggests that significant substrate stereocontrol occurs as the
second biaryl linkage is established (see discussion in SI).
7c (5 mol%)
R
R
R
CH2Cl2, ꢀ78 oC, 24 h
enantioselective
1,4-addition
2
11
proposed 1,4ꢀadduct
12
up to 97% ee
X = CO2R, Cl, Br
Figure 2. Development of our catalytic atroposelective direct
arylation approach to non-C2-symmetrical BINOL deriva-
tives (A6b & B). A recent report by Tan et al. (C).5k
With one exception (Table 2, entry 14), the use of monocy-
clic phenols resulted in good levels of enantio-induction (en-
tries 12 & 13). In a few cases (Table 2, entries 1 & 5) the use of
chlorobenzene as the solvent instead of DCE improved the
enantioselectivities.
Based on these findings6b, we decided to redesign the qui-
none monoacetal coupling partner in a way to avoid the gen-
eration of a proton source (i.e., MeOH) and thereby remove
this potentially detrimental factor from the catalytic cycle.7
We selected readily available N-sulfonyl-protected iminoqui-
nones as substrates as these were expected to undergo acid-
catalyzed in-situ aminal-formation8 and subsequent [3,3]-
rearrangement/rearomatization (Fig. 2B). In contrast, a 1,4-
addition mechanism has been proposed recently by Tan et al.
for a related reaction (Fig. 2C).5k We were pleased to observe
that 10 mol% of chiral phosphoric acid 7b catalyzed the cou-
pling of 6a with 2a under mild conditions and led to the
formation of functionalized biaryl 9a in excellent isolated
Next, we explored how the structural changes (i.e., sym-
metry as well as size and nature of the substituents) in the
iminoquinones (6b-j) influence the yields and enantioselec-
tivities of the biaryl products (Table 3).
Among the unsymmetrical iminoquinones 6b-e that were
coupled with 2,3-dihydroxynaphthalene (2e), the presence of
a large substituent (i.e, i-Pr) in the ortho position of the N-Ts
imine moiety led to somewhat lower the isolated yield and ee
of 9ed (entry 18) compared to the isomeric 9eb and 9ec (en-
tries 16 & 17) in which a smaller methyl (Me) substituent is in
the ortho position.
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Table 3. Expansion of the Substrate Scope by Cou-
Table 2. Exploration of the Substrate Scope by Cou-
1
pling 6a with Structurally Diverse Hydroxyarenes
pling Structurally Diverse Iminoquinones
2
3
4
5
6
7
8
R5
X
N
catalyst 7c
(10 mol%)
XHN
R3
R4
R3
R5
R4
OH
R2
R1
+
OH
OH
DCE
(or chlorobenzene)
O
R1
2a, 2e, 2l
(3 hydroxyarenes)
6b-j
R2
X = Ts, Ms, Ac, PNB
(9 iminoquinones)
9
Structure of Non-C2-Symmetrical BINOLs
(Entry)[a]: Compound #, Isolated Yield (%)[b], ee[c], T and Time
9
MsHN
Me
Me
TsHN
Me
iPr
TsHN
iPr
Me
TsHN
Me
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
(16) 9eb
(17) 9ec
68%; 91% ee
(rt, 2 h)
(18) 9ed
63%; 73% ee
(rt, 48 h)
(19) 9ee
98%; 87% ee
(rt, 1 h)
56%; 78% ee
(rt, 1h)
Me
TsHN
iPr
Me
AcHN
Me
Me
TsHN
Me
Me
TsHN
Me
Me
MeO
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OMe
(22) 9lc
OH
(20) 9ef
(21) 9eg
68%; 21% ee
(rt, 3 h)
(23) 9eh
31%; 4% ee
98%; 75% ee
(rt, 3.5 h)
48%; 83% ee
(50 oC, 15 h)
(rt, 24h)
O2N
Me
H
N
Me
TsHN
Me
TsHN
O
Me
OH
OH
OH
OH
OH
OH
OH
(25) 9aj'[d]
(24) 9ei
69%, 58% ee
(rt, 24 h)
(25) 9aj
combined: 99%; (9aj/9aj' = 1/2)
82% ee for 9aj; 25% ee for 9aj'
[a]Reaction conditions: 2 (0.225 mmol), 3a (0.15 mmol), cat. 1c (10 mol%), DCE or chloroꢀ
benzene (3 mL), rt or 50 oC. [b]Reactions were stopped when all of 6b-j was consumed.
[c]Determined by HPLC analysis. [d]Compound 9aj' was found to racemize easily; even at
room temperature overnight the initial 25% ee was decreased to 12% ee.
A. SymmetricalQuinone Monoacetal Leads to SymmetricalMixed Acetal(Ref. 6b):
O
O
Me
MeO
chiral
acid
catalyst
Me
Me
OMe
1a
(symmetrical)
Me
Me
OMe
[3,3]
Me
OH
OH
MeO
O
mixed
acetal-
formation
+
OH
symmetrical
intermediate
5a (11% ee)
"a missed opportunity"
2a
B. UnsymmetricalIminoquinones Lead to Unsymmetrical(i.e., Chiral) Aminals:
O
O
R2
iPr
R2
TsHN
Me
chiral
acid
catalyst
R1
OH
OH
R1
NTs
6b, 6c, 6d
[3,3]
O
NHTs
aminal-
formation
(usymmetrical)
OH
9ec 91% ee
9eb(87% ee) &
9ed(73% ee)
+
OH
OH
Presumably, the larger i-Pr group slows down aminal for-
mation and also lowers the enantioselectivity of this step.
The nature of the acyl/sulfonyl group on the N atom also
appears to be important - enantioselectivities increase as
more electron withdrawing groups are used (i.e., Ts ≥ Ms >
Ac > p-NO2-benzoyl; compare 9aa in Table 1 with entries 16,
23 & 24 in Table 2).
'unsymmetrical'
centrally chiral
aminal intermediate
OH
2e
C. Symmetrical& (Pseudo)SymmetricalIminoquinones Lead to Symmetrical
Aminals:
O
O
O
R1
R1
R1
Me
TsHN
[3,3]
chiral
acid
R1
R1
R1
R1
R1
NTs
6f
NTs
6g
catalyst
Me
OH
OH
O
NHTs
The most dramatic drop in the level of enantio-induction
occurred when symmetrical (6f) and pseudosymmetrical (6g)
iminoquinones were utilized as coupling partners (Table 3,
entries 20 & 21). In fact, the poor ee’s observed for biaryls 9ef
and 9eg provided us with a very valuable clue that helped us
establish if indeed aminal-formation versus 1,4-addition is
involved in the key stereochemistry-determining step.
aminal-
formation
(symmetrical) (pseudoꢀ
symmetrical)
OH
OH
9ef(4% ee)
symmetrical
&
pseudo-symmetrical
aminal intermediate
OH
+
See also:
9eg (21% ee)
OH
2e
Figure 3. The symmetry of intermediates in chirality transfer
processes has a dramatic impact on the final product’s ee.
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Based on several experimental findings (Fig. 3), it appears
(BK20150688), and program for Changjiang Scholars and
1
2
3
4
5
6
7
8
that in catalytic enantioselective processes where sequential
chirality-transfer steps are involved, the highest level of en-
antio-induction will most likely take place in those cases
where the catalyst does not “miss/skip” an opportunity to
transfer chiral information. One way to “lose” or “skip” an
opportunity for chirality-transfer is when one or more sym-
metrical intermediates are formed along the pathway (see
Fig. 3A & 3C). Naturally, symmetrical (i.e., prochiral) inter-
mediates can be desymmetrized using chiral catalysts, how-
ever, the level of enantio-induction in these desymmetriza-
tions must be very high which is often difficult to achieve. In
particular, organocatalytic asymmetric versions of the
Claisen rearrangement are challenging and there are only a
few highly enantioselective examples in the literature.10
Innovative Research Team in University (IRT1193). L.K. grate-
fully acknowledges the generous financial support of Rice
University, National Institutes of Health (R01 GM-114609-01),
National Science Foundation (CAREER:SusChEM CHE-
1455335), the Robert A. Welch Foundation (Grant C-1764),
ACS-PRF (Grant 51707-DNI1), Amgen (2014 Young Investiga-
tors’ Award for LK) and Biotage (2015 Young Principle Inves-
tigator Award) that are greatly appreciated.
9
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D. A.; Bhayana, B.; Buchwald, S. L. J Am Chem Soc 2010, 132, 11278.
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H.; Kürti, L. J. Am. Chem. Soc. 2013, 135, 7414. (i) Mori, K.; Ichikawa,
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Ess, D. H.; Kürti, L. Angew. Chem., Int. Ed. 2016, 55, 566.
(7) Intriguingly, when the coupling between 2a and 6a to form biaryl 9a
was conducted in the presence of catalyst 7c ( 10 mol%) and 1 equivalent
of MeOH (in DCE as the solvent), no detrimental impact on either the
isolated yield (97%) or the enantiomeric excess (86% ee) was observed.
However, when 20 equivalents of MeOH were added, the reaction slowed
down dramatically while the isolated yield and ee also dropped to 35%
and 62%, respectively (at 50% conversion).
In light of the enantio-induction levels for biaryls 9ea
(96% ee) and 9eg (21% ee), we can make a convincing mech-
anistic case for the involvement of sequential aminal-
formation/[3,3]-rearrangement. Figure 4 clearly shows that if
a direct 1,4-addition was operational, the influence of the
highlighted extra methyl group could not account for the
dramatic loss of enantioselectivity.
1,4-
addi-
tion
X
Me
Me
O
TsHN
Me
HO
HO
[3,3]
O
O
H
HO
Me
O
H
Me
O
Me
Me
TsHN
Me
TsN
OH
Me
centrally chiral
intermediate
(21% ee)
pseudo-symmetrical
aminal intermediate
direct 1,4-addition
Figure 4. The case is made for the aminal-formation/[3,3]-
rearrangement sequence as opposed to a 1,4-direct addition.
In conclusion, we have successfully developed a practical
organocatalytic atroposelective synthesis of non-C2-
symmetrical BINOL derivatives starting from readily availa-
ble hydroxyarenes and iminoquinones. The nearly two dozen
axially chiral and structurally diverse functionalized biaryl
products represent new chemical space and expected to find
broad utility in asymmetric catalysis, drug discovery and
materials science.
ASSOCIATED CONTENT
Supporting Information
Complete experimental procedures and characterization data
including 1H and 13C NMR spectra and chiral HPLC traces.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
hbsun2000@yahoo.com; qlxu@cpu.edu.cn; kur-
ti.laszlo@rice.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from National Natural Science Foundation
of China (grants 81373303, 81473080, 81573299 and 21502230)
is gratefully acknowledged. This project was also supported
by the Jiangsu Province Natural Science Foundation
(8) Li, G.; Fronczek, F. R.; Antilla, J. C. J. Am. Chem. Soc. 2008, 130,
12216.
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