Access to Chiral Bisphenol Ligands (BPOL) through Desymmetrizing Asymmetric Ortho-Selective Halogenation

Full text of DOI:10.1016/j.chempr.2020.01.009

Article
Access to Chiral Bisphenol Ligands (BPOL)
through Desymmetrizing Asymmetric Ortho-
Selective Halogenation
Xiaodong Xiong, Tianyu Zheng,
Facile synthesis of potent privileged chiral bisphenol cores
Xinyan Wang, Ying-Lung Steve
R
R
R
Tse, Ying-Yeung Yeung
Br
Br
[Br
]
[Cl
]
OH
OH
OH
OH
OH
OH
stevetse@cuhk.edu.hk (Y.-L.S.T.)
yyyeung@cuhk.edu.hk (Y.-Y.Y.)
chiral catalyst
Cl
R
R
R
desymmetrizing
asymmetric
HIGHLIGHTS
ortho-halogenation
sequential
cross-coupling
Desymmetrizing asymmetric
ortho-halogenation of bisphenols
ortho-halogenation
R
Me
Ar1
Practical and scalable synthesis of
potent privileged chiral bisphenol
ligands
Me
OH
OH
Ph
Ph
O
O
chiral phosphoramidite
ligand
P
N
Ar2
R
Novel phosphoric acids and
phosphoramidite ligands for
catalytic asymmetric reactions
Me
bisphenol cores
Me
Me
CF3
O
P
OH
O
CF3
O
O
chiral phosphoric
acid catalyst
O
O
P
OH
Me
Me
Privileged chiral catalyst scaffolds are highly useful in chemical synthesis. Yeung
and colleagues describe the synthesis of a new class of potent privileged
bisphenol catalyst cores through the desymmetrizing asymmetric ortho-selective
mono-halogenation of phenol derivatives. The catalyst library can easily be
accessed via sequential cross-coupling of the halogen handles on the bisphenols.
The chiral bisphenols’ cores have been successfully applied to the preparation of
chiral phosphoric acid and phosphoramidite metal ligand for various catalytic
asymmetric reactions with excellent performance.
Xiong et al., Chem 6, 1–14
April 9, 2020 ª 2020 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2020.01.009

Please cite this article in press as: Xiong et al., Access to Chiral Bisphenol Ligands (BPOL) through Desymmetrizing Asymmetric Ortho-Selective
Halogenation, Chem (2020), https://doi.org/10.1016/j.chempr.2020.01.009
Article
Access to Chiral Bisphenol Ligands (BPOL)
through Desymmetrizing Asymmetric
Ortho-Selective Halogenation
1,3,
Xiaodong Xiong,1,2 Tianyu Zheng,1 Xinyan Wang,1 Ying-Lung Steve Tse,1, and Ying-Yeung Yeung
*
*
SUMMARY
The Bigger Picture
Asymmetric catalysis plays a
central role in the synthesis of
drugs and functional materials.
Many of the asymmetric reactions
rely on catalysts derived from a
few privileged cores such as
dihydroxyl compounds. Thus,
discovery of new potent
Privileged chiral catalyst scaffolds are highly useful in chemical synthesis such as
drug preparation. Substituted phenol ligands are among the most frequently
used scaffolds. However, the preparation of chiral phenol ligands commonly in-
volves tedious synthetic procedures. Herein, we describe a facile strategy to
prepare potent chiral bisphenols (BPOLs) through the desymmetrizing asym-
metric ortho-halogenation. Both theoretical and experimental studies were
conducted in order to shed light on the mechanistic picture. The halogen han-
dles in the BPOL products are manipulated to yield unsymmetrical chiral BPOL
ligands, which are potential privileged catalyst scaffolds and have been applied
in other asymmetric catalytic reactions.
privileged dihydroxyl catalyst
cores is still highly sought after,
but it is well understood that
identifying a new class of
INTRODUCTION
privileged catalyst cores is
Catalytic asymmetric synthesis is arguably one of the most active research areas in
chemistry.1–5 Nowadays, many important drug molecules are prepared through
asymmetric catalysis.6,7 In recent decades, small-molecule catalysts have played a
dominant role over enzymes in asymmetric catalysis, partly because of the ease of
preparation and modification of these catalyst systems for various transforma-
tions.8–10 Most of the practically useful catalytic enantioselective reactions, however,
are rooted in a handful of privileged catalyst cores.11,12 Some representative exam-
ples, e.g., 1,10-bi-2-naphthol (BINOL)13–21 and a,a,a0,a0-tetraaryl-2,2-disubstituted
1,3-dioxolane-4,5-dimethanol (TADDOL)22,23 derivatives, which are dihydroxyl com-
pounds that serve as the cores of organocatalysts or as ligands for metal complexes,
have been applied in a wide range of mechanistically unrelated reactions (Figure 1A).
A highly relevant and emerging class of privileged catalyst cores is 1,10-spirobiin-
enormously difficult. Here, we
report desymmetrizing
asymmetric halogenation of
bisphenols that gave rise to a new
class of chiral halo-bisphenols.
The halogen handles could be
modified at late-stage through
cross-coupling so that various
potent privileged dihydroxyl
catalyst cores could easily be
prepared. These catalyst cores
were successfully converted into
chiral phosphoric acid for
dane-7,70-diol (SPINOL), which features
a
spiro bisphenol system. The
high structural rigidity of SPINOL gives it tremendous utility in asymmetric catal-
ysis.24–35 However, the cores of most SPINOL catalysts are prepared through the
kinetic resolution of racemic mixtures using stoichiometric amounts of chiral
resolving agents.36,37 Tan et al. reported a seminal work on the catalytic preparation
of enantiopure SPINOL skeletons, but the synthesis of substituted SPINOLs has
proven somewhat challenging.38 Ding et al. also developed an enantioselective
approach toward cyclohexyl-fused SPINOL through a sequence of Ir-catalyzed asym-
metric hydrogenation and spiroannulation.39 Very recently, Tan and Houk developed
a new class of 1,10-(ethene-1,1-diyl)binaphthol scaffold, and its derivatives were suc-
cessfully applied in asymmetric catalysis.40 The search for potent privileged dihy-
droxyl catalyst cores is still highly active, although it is well understood that identi-
fying a new class of privileged catalyst cores is enormously difficult and often
requires a certain degree of serendipity.11,12 Herein, we are pleased to describe
organocatalysis and used as a
phosphoramidite ligand in metal
catalysis. This research sets a solid
foundation for the discovery of a
new class of bisphenol catalyst
core for the application in
asymmetric catalysis.
Chem 6, 1–14, April 9, 2020 ª 2020 Elsevier Inc.
1

Please cite this article in press as: Xiong et al., Access to Chiral Bisphenol Ligands (BPOL) through Desymmetrizing Asymmetric Ortho-Selective
Halogenation, Chem (2020), https://doi.org/10.1016/j.chempr.2020.01.009
A
R
R
R
R
Ar Ar
O
O
O
OH
OH
Me
Me
OH
OH
OH
OH
O
O
P
P
R1
O
O
OH
Ar Ar
R
R
R
R
SPINOL-derived
organocatalyst
SPINOL-derived
BINOL
TADDOL
SPINOL
ligand
B
Br
O
R
O
R
O
R
HN
HN
HN
OH
+
OH
OH
peptide
HO
OH
CH2OMe
HO
OH
CH2OMe
MeO
MeO
catalyst
R
Br
R
Br
R
HO
HO
Br
HO
1
2
3
4a
4b
up to e.r. = 95.0:5.0
C
controlling the
skeleton rigidity
R
R
R
R
Ar1
Br
Br
controlling the
steric and
electronic demands
[Br ]
[Cl ]
OH
OH
OH
OH
OH
OH
OH
OH
chiral
catalyst
Ar2
Cl
R
R
R
R
5
6
7
8
desymmetrizing
asymmetric
ortho-halogenation
sequential
ortho-halogenation
cross-coupling
simultaneous introduction of
facile synthesis of potent
point chirality and halogen handle
privileged chiral bisphenol core
Figure 1. Design of Privileged Dihydroxyl Catalyst Cores
(A) Privileged catalyst scaffolds containing dihydroxyl moieties.
(B) Examples from the literature of desymmetrization of phenols through asymmetric ortho-halogenation.
(C) Our design for the preparation of potent chiral BPOL catalyst core through desymmetrizing asymmetric ortho-halogenation.
the synthesis of a new class of potent bisphenol (BPOL) catalyst cores through the de-
symmetrizing asymmetric ortho-selective mono-halogenation of phenol derivatives.
Organocatalysis provides a promising opportunity for the ortho-halogenation of
phenols, and the resulting ortho-halogenated phenols are prevalent precursors for
catalyst modification.41–45 However, the ortho-halogenation of phenols in asym-
1Department of Chemistry and State Key
metric synthesis has been sporadic. Akiyama and co-workers described an inter-
esting approach in the desymmetrization/kinetic resolution of biaryl phenol deriva-
tives 1 through asymmetric ortho-bromination (Figure 1B).46 Recently, Miller and co-
workers reported a seminal work on using tailor-made peptide catalysts to fix the
conformation of diarylmethylamido BPOLs 3,47,48 which could then undergo desym-
metrizing ortho-bromination to give 4a with good enantioselectivity. However, the
yields were moderate as a result of the poor mono/dibromination (4a/4b) selectivity,
and kinetic resolution considerably contributed to the enantioselectivity of 4a.49–51
Relevant research was reported by Matsubara and co-workers, in which chiral amino
Laboratory of Synthetic Chemistry, The Chinese
University of Hong Kong, Shatin, NT, Hong Kong,
(China)
2Present address: School of Pharmacy, Nanchang
University, Nanchang 330006, China
3Lead Contact
*Correspondence:
stevetse@cuhk.edu.hk (Y.-L.S.T.),
yyyeung@cuhk.edu.hk (Y.-Y.Y.)
https://doi.org/10.1016/j.chempr.2020.01.009
2
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Please cite this article in press as: Xiong et al., Access to Chiral Bisphenol Ligands (BPOL) through Desymmetrizing Asymmetric Ortho-Selective
Halogenation, Chem (2020), https://doi.org/10.1016/j.chempr.2020.01.009
ureas were used to fix the conformation of isoquinoline N-oxide for enantioselective
electrophilic tri-bromination of the phenol moiety.52 Nonetheless, these works
inspired us to consider the desymmetrization of BPOL system 5 through asymmetric
organocatalytic ortho-halogenation.
RESULTS
We envisioned that catalytic asymmetric ortho-selective mono-halogenation of 5 using
a stoichiometric amount of an achiral electrophilic halogen (e.g., bromine) source
would selectively halogenate one of the enantiotopic phenol moieties to give com-
pound 6. The point-chirality and the halogen handle could be introduced simulta-
neously (Figure 1C). We reasoned that the bulky substituent at the stereogenic center
could restrict the rotation of the phenols, furnishing a rigid BPOL system potentially
useful as a catalyst core. Subsequent ortho-halogenation of 6 with another halogen
(e.g., chlorine) source would result in compound 7, which has two halogens with
different reactivity toward cross-coupling. The halogen handles at the ortho-positions
of the BPOL could readily be modified through cross-coupling to give 8, enabling
various substituents to be introduced in close proximity to the OH. This is of particular
importance to catalyst design because it is believed that close communication be-
tween the substituents and the phenol moiety can effectively shape the reaction
pocket.11,12 In addition, this strategy allows for late-stage modification of the BPOL
ligands so that a large library of analogs can easily be accessed. Moreover, our
approach to the preparation of chiral diarylmethine compounds could be potentially
useful in drug discovery and natural product synthesis,53–57 as has been demonstrated
by several elegant catalytic desymmetrization methodologies.58–70
Reaction Optimization
Initially, halogenation of symmetrical BPOL 5a was examined using N-bromosuccini-
mide (NBS) as the halogen source. It was rationalized that the acidity of the hydroxyl
proton could be enhanced through intramolecular hydrogen bonds.71,72 We envi-
sioned that an amino organocatalyst could activate the halogen source and the
phenol substrate (through hydrogen bonds with the acidic proton) simultaneously
and enantioselectively deliver the halogen atom.73 Thus, various bifunctional
amino-urea52 catalysts 9 were examined (Figure 2). Amino-urea 9a bearing an
N,N-dimethylamine unit could desymmetrize 5a to give 6a in a promising enantio-
meric ratio (e.r.) of 67.5:32.5 (Figure 2, Entry 1). Changing the amine from an N,N-
dimethyl to an N,N-di-n-pentyl group (catalyst 9b) significantly improved the e.r.
of 6a (Figure 2, Entry 2). Considerable diminishment of the reaction efficiency and
enantioselectivity was encountered when replacing the urea moiety with a squara-
mide (catalyst 9c) (Figure 2, Entry 3).74 A lower reactant concentration favored the
desymmetrization of 5a (Figure 2, Entry 4). To our delight, both the reaction yield
˚
and e.r. of 6a were dramatically improved when a 4 A molecular sieve (MS) was
used as an additive (Figure 2, Entry 5). A 91% yield and 97.5:2.5 e.r. of the desired
product 6a were obtained after fine-tuning the reaction media (Figure 2, Entry 6).
Further modification of the catalyst by introducing an (S)-BINOL-amine derivative
(i.e., catalyst 9d) gave rise to 6a in excellent e.r. (Figure 2, Entry 7). The chirality of
the BINOL core was found to be crucial, and the yield of 6a diminished significantly
when using the mismatched catalyst 9e bearing the (R)-BINOL-amine substituent
(Figure 2, Entry 8). The reaction was readily scalable at 1 or 5 mmol scale using
2.5 mol % of 9d as the catalyst (Figure 2, Entries 9 and 10). An enantiopure sample
of 6a could be obtained by a simple recrystallization, which is important for prepar-
ing chiral BPOL cores for other catalytic applications (vide infra). The absolute
configuration of 6a was confirmed unambiguously by X-ray crystallography.
Chem 6, 1–14, April 9, 2020
3

Please cite this article in press as: Xiong et al., Access to Chiral Bisphenol Ligands (BPOL) through Desymmetrizing Asymmetric Ortho-Selective
Halogenation, Chem (2020), https://doi.org/10.1016/j.chempr.2020.01.009
Me
Me
Br
O
Catalyst
Solvent, -78 oC, 5 d
OH
OH
OH
OH
+
N
Br
O
Me
6a
Me
5a
NBS (1.05 equiv)
XRD structure of 6a
catalysts
F3C
O
CF3
F3C
CF3
F3C
O
F3C
O
CF3
F3C
CF3
CF3
N
H
O
N
H
H
H
N
H
O
N
N
H
N
N
N
N
O
N
H
H
H
N
N
N
N
H
Me
Me
N
Me
Me
9a
9b
9c
9d
9e
Entry Catalyst Loading (mol %)
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Concentration (M)
0.05
Additive
-
Yield (%)
79
E.r.
1
2
9a
9b
9c
9b
9b
9b
9d
9e
9d
9d
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
2.5
2.5
67.5:32.5
79.5:20.5
59.5:40.5
83.5:16.5
94.0:6.0
97.5:2.5
98.5:1.5
95.5:4.5
99.0:1.0
0.05
-
77
3
0.05
-
50
4
0.025
-
38
5
0.025
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
94
6
Toluene/CCl4 (5:1 v/v)
Toluene/CCl4 (5:1 v/v)
Toluene/CCl4 (5:1 v/v)
Toluene/CCl4 (5:1 v/v)
Toluene/CCl4 (5:1 v/v)
0.025
91
7
0.025
96
8
0.025
64
9*
10†
0.025
99
0.025
98
98.5:1.5 (>99.9:0.1)‡
Figure 2. Optimization of the Desymmetrizing Asymmetric Ortho-Halogenation of BPOL
Conditions: the reactions were conducted with 5a (0.2 mmol), catalyst 9, and NBS (0.21 mmol) in the indicated solvent at ꢀ78ꢁC for 5 days in the absence
of light. Footnotes: *The reaction was conducted at 1.0 mmol scale. yThe reaction was conducted at 5 mmol scale. zRecrystallized from hexanes. Me,
methyl; e.r., enantiomeric ratio; MS, molecular sieves.
Desymmetrizing Asymmetric Ortho-Bromination of BPOLs
Next, the substrate scope was examined (Figure 3). To our delight, the reaction worked
well with 5b bearing no substituent at the 4-position, giving 6b in 92% yield and 99.5:0.5
e.r. The strong preference of the ortho-bromination at the phenol suggested that the
hydroxyl unit in 5 might be crucial in directing the halogenation (vide infra). A range
of alkyl- or aryl-substituted substrates 5c–5g were examined and the corresponding
ortho-brominated product 6b–6g were obtained in good-to-excellent e.r. BPOL 5h
with ether at the 4-position of the phenol moiety was also compatible, giving
product 6h smoothly. Substrates 5i and 5j with electron-withdrawing substituents also
gave the desired mono-brominated products 6i and 6j with high efficiency and enantio-
selectivity. 3-Substituted BPOL 5k furnished 6k smoothly. A range of multi-substituted
substrates 5l–5o were also ortho-brominated smoothly using the catalytic protocol,
4
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Halogenation, Chem (2020), https://doi.org/10.1016/j.chempr.2020.01.009
R
R
Br
O
R
9d (5 mol%), 4Å MS, Solvent
OH
OH
OH
OH
+
N
Br
Temperature, 5 d
R
O
5
NBS (1.05 equiv)
6
Me Ph
Me
Ph
nBu
tBu
Ph
Br
Br
Br
Br
Br
Br
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Ph
6c
nBu
tBu
Ph
Me
Ph
Me
6b
* 92%
6d
6e
-78 oC,
6f
6g
-78 oC,
-40 oC,* 86%
-78 oC,† 95%
e.r. = 99.5:0.5
-78 oC,† 97%
e.r. = 99.0:1.0
-78 oC,* 95%
* 95%
e.r. = 99.5:0.5
e.r. = 96.0:4.0
e.r. = 99.2:0.8
e.r. = 99.0:1.0
Me
Br
Me
Me
PhO
F
Cl
Br
Br
Br
Br
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Me
PhO
F
Cl
6j
Me
Me
6h
6i
6k
* 92%
6l
-78 oC,* 89%
-78 oC,* 94%
-78 oC,* 87%
-78 oC,
e.r. = 95.0:5.0
-78 oC,‡ 92%
e.r. = 95.0:5.0
e.r. = 98.0:2.0
e.r. = 95.0:5.0
e.r. = 94.0:6.0
F
Cl
Br
Me
Br
Me
Me
F
MeO
AcO
Br
Br
Br
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
MeO
AcO
Me
6m
Me
F
Me
F
Cl
6n
6o
6p
6q
-40 oC,* 92%
-40 oC,* 94%
-40 oC,* 97%
-78 oC,* 92%
-78 oC,* 90%
e.r. = 95.0:5.0
e.r. = 96.0:4.0
e.r. = 94.0:6.0
e.r. = 96.5:3.5
e.r. = 96.0:4.0
Figure 3. Desymmetrizing Asymmetric Ortho-Selective Mono-Bromination of BPOL 5
˚
Conditions: the reactions were conducted with 5 (0.1 mmol), catalyst 9d (5 mol %), NBS (0.105 mmol), and 4A MS in the indicated solvent (4 mL) and
temperature for 5 d in the absence of light. Footnotes: *In toluene/CCl4 (2:1 v/v). y In toluene/CCl4 (5:1 v/v). zIn toluene. Ph, phenyl; nBu, n-butyl; Me,
methyl; Ac, acetyl.
and good e.r. of 6l–6o were obtained. Moreover, functional groups including methyl
ether and acetate (5p and 5q) were tolerated under the reaction conditions.
Desymmetrizing Asymmetric Ortho-Chlorination of BPOLs
After examining the scope of ortho-bromination, we turned our focus to the desym-
metrizing asymmetric ortho-chlorination of BPOL 5 to give the mono-chlorinated
BPOL product 10. The chlorine handle in 10 further diversified the choice of
Chem 6, 1–14, April 9, 2020
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Halogenation, Chem (2020), https://doi.org/10.1016/j.chempr.2020.01.009
R
R
Cl
O
Ph
N
R
9d (5 mol%), 4Å MS, Solvent
OH
OH
Ph
Cl
OH
OH
+
N
Cl
Temperature, 4 d
O
R
5
DCDPH (1.05 equiv)
nBu
10
Ph
Ph
Me
tBu
Cl
Cl
Cl
Cl
Cl
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Me
10a
-40 oC,* 85%
nBu
tBu
Ph
10b
-70 oC,† 83%
Ph
10e
10c
-78 oC,† 85%
10d
-70 oC,† 83%
-40 oC, 85%
*
e.r. = 95.5:4.5
e.r. = 98.5:1.5
e.r. = 97.5:2.5
e.r. = 94.0:6.0
e.r. = 96.0:4.0
Me
Cl
Cl
Cl
Me
Cl
Me
Me
Me
Cl
Cl
Cl
Cl
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
Me
Me
Cl
10j
Cl
Me
Cl
Me
Me
10f
10g
10h
-40 oC,* 86%
10i
-60 oC,† 93%
-40 oC,† 90%
e.r. = 92.0:8.0
-70 oC,† 90%
e.r. = 95.0:5.0
-70 oC,† 91%
e.r. = 95.0:5.0
e.r. = 97.0:3.0
e.r. = 95.0:5.0
Figure 4. Desymmetrizing Asymmetric Ortho-Selective Mono-Chlorination of BPOL 5
˚
Conditions: the reactions were conducted with 5 (0.1 mmol), catalyst 9d (5 mol %), DCDPH (0.105 mmol), and 4A MS in the indicated solvent (4 mL) and
temperature for 4 d in the absence of light. Footnotes: *In toluene. y In toluene/CCl4 (2:1 v/v).
substituents during the coupling reactions or relevant transformations. To our
delight, the ortho-chlorination of BPOL 5 also proceeded smoothly after a brief sur-
vey of the chlorinating sources, in which 1,3-dichloro-5,5-diphenylhydantoin
(DCDPH) gave superior performance (Figure 4). Similar to the ortho-bromination,
the desymmetrizing asymmetric ortho-chlorination was found to be compatible
with a range of BPOL substrates with various alkyl, aryl, and electron-withdrawing
substituents.
Application
To explore the potential of BPOL 6 as a potent catalyst core, 6 was further function-
alized by introducing various substituents in close proximity to the hydroxyl groups.
Thus, 6a was ortho-chlorinated to give 7 in excellent yield (Figure 5A).41–45 Com-
pound 7 contains two halogen handles that have different reactivity toward cross-
coupling reactions. For instance, 7 could undergo consecutive palladium-catalyzed
cross-coupling with 1-naphthyl and 2-naphthyl boronic acids at the aryl bromide and
chloride, respectively, to give substituted BPOL 8a. By the same strategy,
substituted BPOLs 8b and 8c, which have different steric and electronic demands,
could readily be prepared. This strategy allows fast access to a library of chiral
BPOL ligands.
6
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A
B
C
D
E
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Halogenation, Chem (2020), https://doi.org/10.1016/j.chempr.2020.01.009
Figure 5. Application of the BPOL Core in Asymmetric Catalysis
(A) Preparation of chiral phosphoric acids 11 using BPOL core 6.
(B) DFT-calculated geometry of 11a.
(C) Asymmetric addition of indole to imine catalyzed by chiral phosphoric acids 11.
(D) Biginelli reaction.
(E) Addition of diethyl zinc to 20.
Conditions: (a) iPr2NH2Cl (5 mol %), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), toluene, 0ꢁC, 2 h; (b) Ar1-B(OH)2, Pd(PPh3)4 (6 mol %), Na2CO3 (aq.),
toluene/EtOH (2:1 v/v), reflux, 24 h (11a, Ar1 = 1-naphthyl; 11b, Ar1 = 3,5-bis(trifluoromethyl)phenyl; 11c, Ar1 = 4-nitrophenyl); (c) Ar2-B(OH)2, Pd(OAc)2
(6 mol %), S-Phos (12 mol %), K3PO4, THF, 80ꢁC, 18 h (11a, Ar2 = 2-naphthyl; 11b, Ar2 = 1-naphthyl; 11c, Ar2 = 1-naphthyl); (d) POCl3, pyridine, reflux, 3 h,
then H2O, reflux 3 h; (e) NaH, MeI, DMF, 23ꢁC, 12 h; (f) nBuLi, EtI, THF, ꢀ78ꢁC, 12 h; (g) BBr3, CH2Cl2, 23ꢁC, 12 h; (h) (+)-bis[(R)-1-phenylethyl]amine, PCl3,
Et3N, THF, ꢀ78–23ꢁC, 24 h.
We then attempted to prepare chiral phosphoric acids using the BPOL cores 8 to
evaluate the asymmetric performance. Treatment of BPOLs 8a–8c with oxophospho-
rus trichloride gave chiral phosphoric acid catalysts 11a–11c. Based on the density
functional theory (DFT) calculation on 11a, an optimized geometry with a structurally
well-defined phosphoric acid catalyst pocket was identified (Figure 5B). The calcula-
tion also showed that the geometry resembled that of the SPINOL system.32–35
Experimentation indicated that chiral phosphoric acid 11a could catalyze the asym-
metric addition of indole 12 to imine 13 to give the corresponding adduct 14 with
appreciable enantioselectivity (Figure 5C). By further screening other catalysts,
11b and 11c, with substituents that have different steric and electronic demands,
the enantioselectivity of 14 could be enhanced dramatically to 98.0:2.0 e.r. (using
11b). The yield of 14a could be improved by decreasing the reaction temperature.
The reaction was compatible with a range of substituted indoles 12 and imine part-
ners 13, giving products 14b–14i in excellent yields and e.r. 11a was also found to be
potentially useful in catalyzing the Biginelli reaction among aldehyde 15, thiourea
(16), and ethyl acetoacetate (17), giving 3,4-dihydropyrimidin-2(1H)-one 18
smoothly (Figure 5D). We also explored the possibility of applying the BPOL core
in metal catalysis. Phosphoramidite ligand 19a was readily prepared from 6a. A pre-
liminary study showed that ligand 19a together with copper(II) acetate could cata-
lyze the enantioselective addition of diethyl zinc to chalcone 20 to give 21 in good
yield and e.r. (Figure 5E). It was also found that performance of the BPOL catalysts
were superior to the state-of-the-art BINOL-derived catalysts (11d, 11e, and 19b)
and SPINOL-derived catalysts (11f, 11g, and 19c) in the abovementioned reactions.
These results suggest that BPOLs 6 and 8 could be potential privileged cores and
open a new avenue for the design and application of BPOL catalysts.
DISCUSSION
Mechanistic Studies
Several control experiments were conducted to shed light on the reaction mechanism.
First, mono-O-methylated substrate racemic-22 was prepared and subjected to the
ortho-halogenation. The reaction was found to be sluggish and gave product 23 and
enantioenriched 22 with low enantioselectivity (Figure 6A). When the same reaction con-
ditions were applied to the di-O-methylated substrate 24, no reaction was observed,
and the starting material was recovered quantitatively (Figure 6B). We speculated that
the two phenol moieties in 5 might work synergistically to achieve the enantioselective
mono-ortho-halogenation. Based on the data from the crystallographic analysis of 6a, it
appears that the two oxygen atoms were linked through an intramolecular hydrogen
1
bond (see Figure S1). We also conducted a H NMR experiment in which the catalyst
was mixed with the halogen source NBS. The protons adjacent to the tertiary amine’s
nitrogen exhibited a significant downfield shift. We speculate that the amine might co-
ordinate to the electrophilic Br, whereas the succinimide anion might form hydrogen
bonds to the urea moiety (see Figure S2).
8
Chem 6, 1–14, April 9, 2020

Please cite this article in press as: Xiong et al., Access to Chiral Bisphenol Ligands (BPOL) through Desymmetrizing Asymmetric Ortho-Selective
Halogenation, Chem (2020), https://doi.org/10.1016/j.chempr.2020.01.009
A
B
Me
Me
Me
Me
Br
9d (5 mol%)
NBS (1.05 equiv)
4Å MS, Toluene
-78 oC, 5 d
9d (5 mol%)
NBS (0.55 equiv)
4Å MS, Toluene
-78 oC, 5 d
OH
OMe
OMe
OH
OMe
OH
OMe
no reaction
+
OMe
Me
23
53%, e.r. = 61:39
Me
22
42%, e.r. = 63:37
Me
Me
rac-22
24
C
Me
Me
Me
Br
O
Br
Br
9d (5 mol%), 4Å MS
toluene/CCl4 (5:1 v/v), -78 oC, 5 d
OH
OH
+
+
OH
OH
N
Br
OH
OH
O
Br
Me
rac-6a
Me
unreacted 6a
48%, e.r. = 50:50
Me
NBS (0.5 equiv)
25
49%
Figure 6. Control Experiments
(A) Ortho-bromination of mono-methylated BPOL rac-22.
(B) Attempt to halogenate 24 with catalyst 9d.
(C) Ortho-bromination of rac-6a with NBS.
When bromination of racemic 6a was conducted with 0.5 equiv of NBS under the
optimized conditions, dibrominated product 25 (49%) was obtained. The unreacted
6a (48%) was recovered and the e.r. was found to be negligible (Figure 6C). This
result indicates that the second step of bromination is unlikely to be a kinetic reso-
lution, and the high enantioselectivity of 6a appears not to be derived from the ki-
netic resolution of the mono-brominated compound 6a.
Theoretical Studies
DFT calculations on the reaction with substrate 5a, catalyst 9d, and NBS were con-
ducted to gain further insight into the catalytic cycle. Based on the results of kinetic
studies (0.2th order on substrate 5, 0th order on catalyst 9, and 1st order on NBS) and
non-linear effect experiments (linear relationship), a single molecule from each of the
reaction components was used in the calculation model (see Supplemental Informa-
tion for details). All DFT calculations were carried out using Gaussian 09 (ver. D.01)75
at the level of M06-2X hybrid-exchange correlation functional76 with Grimme D3
dispersion correction77,78 and 6–311G(d,p) basis set. All the thermodynamic proper-
ties were evaluated at 195 K. The study began with the two most commonly pro-
posed activation models of NBS (Figure 7), which involve: Lewis basic nitrogen acti-
vation of Br (intermediate A in WAY-1) and dihydrogen bond activation of NBS
(intermediate A0 in WAY-2).73 In the calculated free energy profiles, WAY-1 and
WAY-2 give the same phenonium intermediate B before the formation of product
6a. In the two pathways, when intermediates A and A0 are equally populated,
WAY-1 is the predominant reaction avenue toward product 6 because the rate-
determining step of WAY-2 encounters a significantly higher energy barrier (A0/
TS10, 29.5 kcal/mol). It is possible that WAY-2 becomes the predominant pathway
when A0 is significantly more populated than A, which will happen when the barrier
associated with the formation of A is considerably higher than that of A0 (see
Chem 6, 1–14, April 9, 2020
9

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Halogenation, Chem (2020), https://doi.org/10.1016/j.chempr.2020.01.009
tBu
Me
Me
WAY-1
tBu
Me
Me
tBu
tBu
H
H
H
H
H
H
H
H
O
O
O
O
H
H
O
O
O
H
H
R1
R1
R1
R1
R1R1
O
H
O
O
O
O
N(R1)2
N
H
N
NR
Br
N
Br
Me
H
Br
Me
H
NR
NR
H
N
Me
NR
N
N
Br
N
Me
N
20
0
H
H
H
H
H
H
H
O
O
O
O
N
N
N
O
O
O
O
A
TS-1
R = 3,5-(CF3)2-C6H3
B
TS-2
0.0
TS-1' -4.3
5a + 9d
+ NBS
-4.9
TS-1
-10.8
-13.5
TS-2
N-Br intermediate A
-20
-40
-60
-28.4
Phenonium intermediate B
-33.8
urea-NBS intermediate A'
Me
tBu
WAY-2
tBu
Me
-51.7
H
H
H
H
(S)-6a + 9d
+
succinimide
O
O
O
H
O
H
O
R1
R1
O
N
NR
N
NR
H
R1
R1
N
H
N
H
H
Me
Me
Br
H
H
O
Br
O
N
N
A'
TS-1'
O
O
Figure 7. DFT Calculations on the Desymmetrizing Asymmetric Ortho-Halogenation
Figure S3 in Supplemental Information for a comprehensive discussion). However,
this situation seems less likely because the 1H NMR experiment suggests that forma-
tion of the N-Br species is favorable (see Figure S2).
Toward the formation of the major (S)-enantiomer of 6a, the Lewis base activation
pathway initially gives the N-Br intermediate A stabilized by ꢀ13.5 kcal/mol. Inter-
mediate A features hydrogen bond interactions between: (1) phenol substrate 5a
and the urea’s oxygen and (2) the urea N-Hs and the succinimide anion. Based on
the optimized geometry, the Br on the amine is attacked by the enantiotopic
phenolic moiety to produce the phenonium cationic intermediate B through transi-
tion state TS-1 (Figure 8). The theoretical studies reveal that the intramolecular
hydrogen bond between the two phenols in 5 plays a crucial role in fixing the geom-
etry during the enantio-determining step TS-1. We believe that the acidity of one of
the protons in the intramolecular hydrogen bond in 5 is enhanced potentially
through the Brønsted-acid-assisted-Brønsted-acid mechanism,71,72 which can facil-
itate the interaction between 5a and the urea’s oxygen of catalyst 9d. In addition, it is
subsequent deprotonation of the proton at the phenonium cation B by the succini-
mide anion accompanied by internal proton transfer through transition state TS-2
that gives the product (S)-6a. It is calculated that TS2 is the rate-determining step
of WAY-1, which has an energy barrier of 17.6 kcal/mol.
Reaction pathway toward the minor (R)-enantiomer of 6a based on the Lewis basic
nitrogen activation of Br was also calculated (see Supplemental Information, Figures
S3 and S5). It was found that the free energy profile of (R)-6a is similar to that in the
10
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Halogenation, Chem (2020), https://doi.org/10.1016/j.chempr.2020.01.009
Br
Br
Br
N-Br intermediate A
TS-1
Phenonium intermediate B
(model showing the Br interaction)
Br
Br
Phenonium intermediate B
TS-2
(model showing the hydrogen bonds)
(the 3,5-(CF3)2-C6H3 moiety was removed for clarity)
Figure 8. Optimized Geometries of the Intermediates and Transition States
formation of (S)-6a except the rate-determining step is 1.4 kcal/mol higher than the
TS-2 in the formation of (S)-6a. At the experimental temperature 195 K, the lower
barrier for (S)-6a is associated with a rate constant that is at least 40 times larger.
This calculated enantioselectivity is in good agreement with the experimental value.
While a more detailed study is needed to elucidate the complete mechanism, our
proposed pathway provides a self-consistent mechanistic picture that is in good
agreement with the experimental results.
Conclusions
Desymmetrizing asymmetric halogenation of BPOL has been disclosed, yielding a range
of chiral BPOL ligands with enantiomeric ration up to 99.5:0.5. The chiral BPOLs are
potent privileged catalyst cores that have been successfully applied to the preparation
of chiral phosphoric acid and phosphoramidite metal ligand for various catalytic
Chem 6, 1–14, April 9, 2020
11

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Halogenation, Chem (2020), https://doi.org/10.1016/j.chempr.2020.01.009
asymmetric reactions. The catalyst library can easily be accessed because late-stage
modification of the scaffold can readily be executed through cross-coupling of the
halogen handles on the BPOLs. This research sets a solid foundation for the discovery
of a new class of BPOL catalyst core for the application in asymmetric catalysis. We fore-
see that our work can initiate further application of new BPOL cores in other catalytic
processes.
DATA AND CODE AVAILABILITY
The accession number for the X-ray structure of 6a reported in this paper is CCDC:
1905582.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2020.01.009.
ACKNOWLEDGMENTS
Supported by Hong Kong Special Administrative Region General Research Funding
(grant nos. CUHK14315716 and CUHK14304918), the Chinese University of Hong
Kong (grant nos. 4053203 and 4053327), and Innovation and Technology Commis-
sion to the State Key Laboratory of Synthetic Chemistry (GHP/004/16GD). X.X.
thanks the Chinese University of Hong Kong Research Fellowship Scheme for finan-
cial support.
AUTHOR CONTRIBUTIONS
Y.-Y.Y. conceived of and directed the project; X.X. and T.Z. performed the experi-
mental works; Y.-L.S.T. directed the DFT calculations and mechanism analysis;
X.W. performed the DFT calculations; X.X., T.Z., X.W., Y.-L.S.T., and Y.-Y.Y. co-wrote
the manuscript.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: August 2, 2019
Revised: November 19, 2019
Accepted: January 15, 2020
Published: February 10, 2020
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Halogenation, Chem (2020), https://doi.org/10.1016/j.chempr.2020.01.009
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