Enantioselective Desymmetrization of 2-Aryl-1,3-propanediols by Direct O-Alkylation with a Rationally Designed Chiral Hemiboronic Acid Catalyst That Mitigates Substrate Conformational Poisoning

Article abstract of DOI:10.1021/jacs.1c00759

Enantioselective desymmetrization by direct monofunctionalization of prochiral diols is a powerful strategy to prepare valuable synthetic intermediates in high optical purity. Boron acids can activate diols toward nucleophilic additions; however, the design of stable chiral catalysts remains a challenge and highlights the need to identify new chemotypes for this purpose. Herein, the discovery and optimization of a bench-stable chiral 9-hydroxy-9,10-boroxarophenanthrene catalyst is described and applied in the highly enantioselective desymmetrization of 2-aryl-1,3-diols using benzylic electrophiles under operationally simple, ambient conditions. Nucleophilic activation and discrimination of the enantiotopic hydroxy groups on the diol substrate occurs via a defined chairlike six-membered anionic complex with the hemiboronic heterocycle. The optimal binaphthyl-based catalyst 1g features a large aryloxytrityl group to effectively shield one of the two prochiral hydroxy groups on the diol complex, whereas a strategically placed "methyl blocker"on the boroxarophenanthrene unit mitigates the deleterious effect of a competing conformation of the complexed diol that compromised the overall efficiency of the desymmetrization process. This methodology affords monoalkylated products in enantiomeric ratios equal or over 95:5 for a wide range of 1,3-propanediols with various 2-aryl/heteroaryl groups.

Full text of DOI:10.1021/jacs.1c00759

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Communication
Enantioselective Desymmetrization of 2‑Aryl-1,3-propanediols by
Direct O‑Alkylation with a Rationally Designed Chiral Hemiboronic
Acid Catalyst That Mitigates Substrate Conformational Poisoning
Carl D. Estrada,‡ Hwee Ting Ang,‡ Kim-Marie Vetter, Ashley A. Ponich, and Dennis G. Hall*
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ABSTRACT: Enantioselective desymmetrization by direct monofunctionalization of prochiral diols is a powerful strategy to prepare
valuable synthetic intermediates in high optical purity. Boron acids can activate diols toward nucleophilic additions; however, the
design of stable chiral catalysts remains a challenge and highlights the need to identify new chemotypes for this purpose. Herein, the
discovery and optimization of a bench-stable chiral 9-hydroxy-9,10-boroxarophenanthrene catalyst is described and applied in the
highly enantioselective desymmetrization of 2-aryl-1,3-diols using benzylic electrophiles under operationally simple, ambient
conditions. Nucleophilic activation and discrimination of the enantiotopic hydroxy groups on the diol substrate occurs via a defined
chairlike six-membered anionic complex with the hemiboronic heterocycle. The optimal binaphthyl-based catalyst 1g features a large
aryloxytrityl group to effectively shield one of the two prochiral hydroxy groups on the diol complex, whereas a strategically placed
“methyl blocker” on the boroxarophenanthrene unit mitigates the deleterious effect of a competing conformation of the complexed
diol that compromised the overall efficiency of the desymmetrization process. This methodology affords monoalkylated products in
enantiomeric ratios equal or over 95:5 for a wide range of 1,3-propanediols with various 2-aryl/heteroaryl groups.
he catalytic enantioselective desymmetrization of simple
Tbifunctional substrates such as diols is an attractive
strategy to prepare useful optically enriched materials where,
unlike kinetic resolution strategies, quantitative yields can
theoretically be achieved.1,2 To this end, direct and selective
monofunctionalization of prochiral 1,3-diols can afford chiral
building blocks of great synthetic value, and nonenzymatic
methods often demonstrate a wider substrate scope (Figure
1A). Compared to meso-1,2-diols, available methodology for
enantioselective desymmetrization of 1,3-diols is limited.
Indirect,3 intramolecular (cyclative),4−8 and other catalytic
methods exist to desymmetrize narrow classes of substrates
such as 2-heteroatom substituted (halo, N, O) 1,3-diols.9−16
Direct intermolecular catalytic desymmetrization methods for
2-alkyl/aryl 1,3-diols include enantioselective monoacylations
of 2-aryl-1,3-propanediols catalyzed by a chiral dinuclear zinc
catalyst, from Trost and co-workers,17 the chiral 4-amino-
pyridine catalyzed method of Suga and co-workers,18 and the
aminophosphonite catalyzed benzoylation of Fujimoto and co-
workers19 (Figure 1B). While these methods produce
Figure 1. Direct and catalytic enantioselective intermolecular
desymmetrization of prochiral 1,3-diols.
monofunctionalized 1,3-diols with good to high enantioselec-
tivities, they are restricted by the use of cryogenic conditions,
variable selectivity, and/or competing difunctionalization.
Furthermore, these methods provide base-sensitive acylated
Received: January 20, 2021
Published: March 15, 2021
products. Consequently, there remains a need for mild catalytic
methods to access optically enriched derivatives of 2-
substituted-1,3-propanediols O-functionalized with comple-
mentary groups. Because of their stability and their ease of
removal using hydrogenolysis or Lewis acids, benzylic ethers
represent an ideal option.
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Activation of diols can be achieved using boron acids, under
basic conditions, by way of a transient tetravalent anionic
complex inducing an increase of the charge and nucleophilicity
of the diol’s oxygen atoms.20 Although great progress has been
made in regioselective monofunctionalization of carbohydrates
using diarylborinic acid catalysts,21 limitations include the
relative instability of borinic acids toward oxidation (typically
they must be handled as ethanolamine adducts) and the
considerable challenge to render this scaffold chiral.22
Compared to borinic acids, boronic acids are generally more
stable to ambient conditions and can be handled without
special precautions.23,24 However, to date very few examples of
chiral boronic acid catalyzed reactions exist, and selectivities
are moderate.25−30 In search of an improved catalyst scaffold,
we were drawn to evaluate cyclic hemiboronic acids. The 9-
hydroxy-9,10-boroxarophenanthrene 1a, a compound first
reported by Dewar in 1959,31 is known to exchange reversibly
with alcohols.32,33 Herein, we report the rational optimization
of a bench-stable chiral boroxarophenanthrene catalyst for the
highly enantioselective desymmetrization of 2-aryl-1,3-diols by
direct mono-O-alkylation using benzylic electrophiles under
operationally simple, ambient conditions (Figure 1C).
achieved in good yields and high selectivities. Remarkably,
using two distinct sets of reaction conditions, catalyst 1a was
found to be superior to borinate 4 in effecting the alkylation of
model 1,3-diol 2a to afford the monobenzylated product 3a in
good yield (entries 5−6). In all cases, poor conversions were
observed in the absence of a catalyst.
By analogy with borinic acid catalysts,21 diol activation by
catalyst 1a is expected to arise through a tetrahedral anionic
boron intermediate that imparts an increase in the oxygen’s
atomic charge. When mixing 1a with equimolar 1,3-diol 2a in
the presence of potassium carbonate, an upfield resonance of
2.8 ppm corresponding to a tetravalent intermediate (5a) can
be observed by 11B NMR spectroscopy, which was
corroborated by ESI HRMS, negative mode (Figure 2A).
At the onset, the capability of 9-hydroxy-9,10-boroxaro-
phenanthrene (1a) to catalyze the functionalization of polyols
was determined through a screen of different hemiboronic
heterocycles.34 The efficiency of 1a was subsequently assessed
in comparison with that of diphenylborinic acid, as the
borinate 4, using a diverse panel of model 1,2- and 1,3-diols
(Table 1). Using conditions reported by Taylor and co-
workers,35 catalytic monobenzylation of simple diols was
Table 1. Comparison of Boroxarophenanthrene 1a and
a
Borinate 4 in the Benzylation of 1,2- and 1,3-Diols
Figure 2. (A) Structure of the complex between boroxaro-
phenanthrene 1a and 1,3-diol 2a. (B) Catalytic cycle for
monoalkylation of 2-aryl-1,3-diols 2.
The X-ray crystallographic structure of a tetrahedral boron
complex between 1a and neopentyl alcohol was successfully
resolved as the tetrabutyl ammonium salt 6. Close inspection
of its structure reveals a defined six-membered chairlike
conformation in which the aryloxy B−O bond of the
stereogenic boron atom occupies the axial position and the
larger aryl B−C fragment is placed equatorially. Presumably,
once the activated anionic species 5 forms in solution, one of
the bound oxygen atoms is functionalized by the electrophile,
with catalytic turnover arising from exchange of intermediate 7
with another molecule of diol 2 that concomitantly releases the
monofunctionalized product (3) (Figure 2B). Functionaliza-
tion occurs at one of the two alkoxy ligands as opposed to the
less nucleophilic phenoxy ligand, and double alkylation is
a
Conditions: 0.20 mmol of polyol, 0.30 mmol BnBr, 10 mol % 4 or
b
1a, in 1 mL of CH3CN (except entry 6: 0.10 mmol scale). Isolated
yields. A single regioisomer was observed. Reaction without catalyst
(NMR yield): entry 5: 7.5% monobenzylated, 3.5% dibenzylated; 15%
monobenzylated, 5.5% dibenzylated. Conditions: BnCl (1.5 equiv),
K2CO3 (1.7 equiv), KI (1.0 equiv) (rr, regioisomer ratio).
c
d
e
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prevented as two hydroxy groups are required for effective
substrate activation with the catalyst.
Realizing the potential for enantioselective desymmetriza-
tion, we sought to design a chiral variant of catalyst 1a. To this
end, we first evaluated the 1,1′-bi-2-naphthol (BINOL)-
derived axially chiral bis(boroxarophenanthrene) 1b reported
by Hosoya and co-workers (Table 2).36 Utilizing (R)-1b as a
Table 2. Initial Optimization of Alkylation Conditions and
Chiral Catalyst
Figure 3. Stereochemical model for the monobenzylation of 1,3-diol
2a using catalyst (R)-1e.
A final round of optimization was attempted to further
increase the catalyst’s enantioselectivity. Using catalyst 1e,
lowering the temperature, or a switch to other polar solvents
and carbonate bases, provided no improvement.34 Control
experiments suggested that the background reaction is not
competing under these conditions and that the enantioselec-
tivity is truly limited by the structure of the catalyst.34 A crucial
clue for further improving the catalyst’s enantioselectivity
a
b
entry
conditions
catalyst
yield (%)
er
1
2
3
4
5
A
B
B
B
B
1b
1b
1c
1d
1e
97
99
62
83
94
80:20
83:17
69:31
79:21
93:7
1
emerged from the H NMR analysis of complex 5a, which
showed a second, minor set of resonances likely attributable to
another slow-exchanging conformer.34 As inferred from the
above X-ray crystallographic structure (6, Figure 2A), the
conformer of 5a with a pseudoaxial aryloxy group is expected
to be favored; however, the diol’s phenyl group may be
positioned either pseudoequatorial or pseudoaxial (Figure 4A).
In the absence of H⇔Ph 1,3-diaxial interactions (such as in
phenylcyclohexane), the pseudoaxial conformer II may be very
close in energy relative to the pseudoequatorial conformer I.
As shown with catalyst (R)-1e in Figure 4B, this minor
conformer can cause a significant erosion of the enantiose-
lectivity of the desymmetrization because it is expected to lead,
by alkylation of the least hindered O atom, to the antipode of
product (S)-3a. The four possible conformers of 4 were
minimized computationally using density functional theory
(DFT) calculations (B3LYP/6-31G*). Although the relative
energies of the conformers are to be considered approximate,
the calculations confirmed the large preference for the two
conformers with the pseudoaxial aryloxy group, I and II
(Figure 4A). However, the desired conformer I with the
pseudoequatorial phenyl substituent is only slightly lower in
energy (∼0.5 kJ/mol). It was hypothesized that the addition of
a “methyl blocker” in position 1 of the boroxarophenanthrene
scaffold would cause unfavorable nonbonded interactions in
the minor, undesired conformer II that would help minimize
this conformer and its deleterious effect on the reaction’s
enantioselectivity. Computations evaluating the effect of 1-
methyl substitution are in full agreement with this proposal,
revealing a larger energy difference in favor of conformer I
(Figure 4A, R = Me). These calculations are corroborated by
NMR spectroscopic studies comparing the conformer ratio
between 1a and the methylated derivative 1f (Figure 4C).
Although the minor conformer is still observed with 1f, its
a
b
Conditions: 0.10 mmol of diol 2a in 0.5 mL of CH3CN. Isolated
yields.
chiral catalyst and model substrate 2a under the mono-
benzylation conditions of Table 1 (entries 5−6), the
desymmetrized product 3a was isolated in good yield with
moderate enantioselectivity (Table 2, entry 1, “conditions A”).
Because it delivered monobenzylated diol 3a with higher
enantioselectivity (entry 2), conditions B (BnCl, K2CO3, KI)
were selected for further optimization of the catalyst.
In consideration of the dimeric structure of catalyst 1b, we
posited that a single boronyl unit may be sufficient to complex
the diol. To test this hypothesis, monohemiboronic acid 1c
was synthesized using a similar sequence starting from (R)-3-
bromo-2,2′-dimethoxy-1,1′-binaphthalene.34 Moreover, ether-
ification of the hydroxy group of 1c with a large group may
provide a catalyst that can differentiate more efficiently the two
diol oxygen atoms bound in the tetravalent boronate complex.
Thus, whereas catalyst 1c and 1d provided the desymmetrized
product with poorer enantioselectivity compared to 1b (Table
2, entries 3−4), the trityl ether of catalyst 1e provides much
greater steric hindrance, and it led to a significantly higher er of
93:7 (entry 5). According to a stereochemical induction model
informed by the above X-ray crystallographic structure of
adduct 6, which assumes a pseudoequatorial 2-aryl group in
the chairlike complex, alkylation of the most accessible oxygen
atom would result in formation of (S)-3a (Figure 3). Indeed,
the (S) absolute stereochemistry of the major enantiomer was
confirmed by the X-ray crystallographic analysis of the 3,5-
dinitrobenzoyl derivative of 3a.34
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Table 3. Scope of 2-Substituted 1,3-Diol Substrates with
a
Catalyst (R)-1g
b
entry diol
R1
R2
yield (%)
er
95:5
5:95
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
2a
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
90
95
86
90
88
84
91
93
95
84
85
76
81
88
73
81
81
91
90
70
89
87
88
74
50
c
2-MeC6H4
3-MeC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-FC6H4
4-FC6H4
2-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
4-CF3C6H4
4-NO2C6H4
3-indolyl
3-thienyl
1-naphthyl
t-Bu
96:4
94.5:5.5
95.5:4.5
95.5:4.5
95:5
95:5
95:5
95:5
95:5
95:5
95:5
94.5:5.5
93.5:6.6
93.5:6.5
92.5:7.5
94:6
92.5:7.5
92:8
75:25
95.6:4.4
94.2:5.8
95.7:4.3
91.8:8.2
d
2j
2k
2l
d
d
2m
2n
2o
2p
2q
2r
2s
2t
CH2Ph
2a
2a
2a
2u
Ph
Ph
Ph
4-CF3C6H4
4-MeOC6H4
2-naphthyl
Ph
N-Phthalamido
a
b
Conditions: 0.10 mmol of diol 2 in 0.5 mL of CH3CN. Isolated
c
d
yields. With catalyst (S)-1g, affording product (R)-3a. With
recycled catalyst.
Figure 4. Analysis (A) and stereochemical implications (B) of
possible conformations of catalysts 1 complexed with diol 1a. (C)
NMR study of the effect of a “methyl blocker” on the conformational
equilibrium (ax., axial; eq., equatorial).
substituted at all positions. For example, all three positional
isomers of tolyl and methoxyphenyl groups provided er’s of
95:5 and over (entries 3−8). Halogenated 2-aryl 1,3-diols are
suitable substrates regardless of the position of the halide
substituent (entries 9−14). Strong electron-withdrawing
substituents like trifluoromethyl and nitro lead to slightly
decreased enantioselectivities (entries 15−16), as are the 2-
heteroaryl substrates (entries 17−18). In contrast, aliphatic
groups such as tert-butyl (entry 20) and benzyl (entry 21) led
to significantly lower er’s. Overall the obtained er’s roughly
parallel substituent A values (e.g., Bn 1.9, Ph 3.0 kcal/mol).
Satisfactorily, high selectivities are maintained when using
other electrophiles like functionalized benzylic chlorides and
even a naphthyl derivative (entries 22−24). Finally, a 2-amino
derivative (entry 25) and a 1,3-disubstituted 1,3-diol34
demonstrate potential toward other substrate classes. Notably,
catalyst 1g is recyclable (cf. entries 8, 12, 15).
proportion is significantly reduced from 1:4 to 1:9. Addition-
ally, due to the additional steric hindrance of a pseudoaxial aryl
group in the approach of the electrophile, it is plausible that
the minor conformer II is intrinsically less reactive. To test the
idea of substrate conformational control, chiral catalyst 1g with
the “methyl blocker” was prepared.34 When compared with
catalyst 1e in the benzylation of diol 2a, the methylated
derivative 1g afforded a reproducible increase of enantiose-
lectivity from 93:7 (cf. Table 2, entry 5) to 95:5 er with both
the (R) (Table 3, entry 1) and (S) catalyst (entry 2). Further
supporting its ability to control the substrate’s conformation,
the methylated catalyst 1g was found to consistently
outperform catalyst 1e when compared with several other
substrates (e.g., 2f: 95:5 vs 92:8; 2g: 95:5 vs 93:7; 2m: 94.5:4.5
vs 91:9).34
In summary, highly enantioselective desymmetrization of 2-
aryl-1,3-propanediols by direct O-alkylation was achieved
under mild ambient conditions using a novel class of chiral
hemiboronic acid organocatalyst derived from BINOL.
Nucleophilic activation and discrimination of the enantiotopic
hydroxy groups on the substrate occurs via a defined, chairlike
The scope of the 2-substituent was examined with the
optimal catalyst (R)-1g. High yields and consistently high
enantioselectivity ratios were obtained for aryl groups
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Communication
six-membered anionic boronate complex. Catalyst optimiza-
tion featured the judicious addition of a steric blocking group
to help disfavor a poisoning conformer, leading to higher
enantiomeric ratios equal or over 95:5 for a wide range of 2-
aryl/heteroaryl groups embodying various, synthetically useful
substituents. It can be anticipated that the chiral boroxar-
ophenanthrene scaffold will be amenable to further improve-
ments, along with applications with other electrophiles and
transformations.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00759.
■
sı
Full experimental details, analytical data, and spectral
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of catalyst 1a; further reaction optimization studies;
details of molecular modeling (PDF)
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Accession Codes
CCDC 2051073 and 2063743 contain the supplementary
crystallographic data for this paper. These data can be obtained
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emailing data_request@ccdc.cam.ac.uk, or by contacting The
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AUTHOR INFORMATION
Corresponding Author
■
Dennis G. Hall − Department of Chemistry, Centennial Centre
for Interdisciplinary Science, University of Alberta, Edmonton,
Alberta, Canada T6G 2G2; orcid.org/0000-0001-8555-
6400; Email: dennis.hall@ualberta.ca
Authors
Carl D. Estrada − Department of Chemistry, Centennial
Centre for Interdisciplinary Science, University of Alberta,
Edmonton, Alberta, Canada T6G 2G2
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Hwee Ting Ang − Department of Chemistry, Centennial
Centre for Interdisciplinary Science, University of Alberta,
Edmonton, Alberta, Canada T6G 2G2
Kim-Marie Vetter − Department of Chemistry, Centennial
Centre for Interdisciplinary Science, University of Alberta,
Edmonton, Alberta, Canada T6G 2G2
Ashley A. Ponich − Department of Chemistry, Centennial
Centre for Interdisciplinary Science, University of Alberta,
Edmonton, Alberta, Canada T6G 2G2
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00759
Author Contributions
‡C.D.E. and H.T.A. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the Natural Sciences and Engineering
Research Council (NSERC) of Canada (Discovery Grant
RGPIN-2017-05086 to D.G.H.). We thank Mr. Ed Fu for help
with chiral HPLC analysis of the enantiomeric ratio and Dr.
Michael Ferguson (X-ray Crystallography Laboratory, Uni-
versity of Alberta) for X-ray crystallographic analyses.
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