Site-Selective and Stereoselective C-H Alkylations of Carbohydrates via Combined Diarylborinic Acid and Photoredox Catalysis

Article abstract of DOI:10.1021/jacs.9b01531

Diphenylborinic acid serves as a cocatalyst for site- and stereoselective C-H alkylation reactions of carbohydrates under photoredox conditions using quinuclidine as the hydrogen atom transfer mediator. Products arising from selective abstraction of the equatorial hydrogens of cis-1,2-diol moieties, followed by C-C bond formation with net retention of configuration, are obtained. Computational modeling supports a mechanism involving formation of a tetracoordinate borinic ester, which accelerates hydrogen atom transfer with the quinuclidine-derived radical cation through polarity-matching and/or ion-pairing effects.

Full text of DOI:10.1021/jacs.9b01531

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Site-Selective and Stereoselective C−H Alkylations of Carbohydrates
via Combined Diarylborinic Acid and Photoredox Catalysis
Victoria Dimakos,‡ Hsin Y. Su,‡ Graham E. Garrett, and Mark S. Taylor*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario M5S 3H6, Canada
S
* Supporting Information
configuration. Control experiments and computational studies
ABSTRACT: Diphenylborinic acid serves as a cocatalyst
for site- and stereoselective C−H alkylation reactions of
carbohydrates under photoredox conditions using quinu-
clidine as the hydrogen atom transfer mediator. Products
arising from selective abstraction of the equatorial
hydrogens of cis-1,2-diol moieties, followed by C−C
bond formation with net retention of configuration, are
obtained. Computational modeling supports a mechanism
involving formation of a tetracoordinate borinic ester,
which accelerates hydrogen atom transfer with the
quinuclidine-derived radical cation through polarity-
matching and/or ion-pairing effects.
suggest a mechanism involving formation of a tetracoordinate
diarylborinic ester that is activated toward C−H abstraction by
the quinuclidine radical cation. The bicyclic nature of the
catalyst-bound radical intermediate influences the diastereose-
lectivity of the process.
Catalytic processes based on the nucleophilic reactivity of
tetracoordinate diarylborinic esters have been developed by
our group10 and by other researchers (Scheme 1, eq 1).11 We
Scheme 1. Reactivity of Carbohydrate-Derived
Diarylborinic Esters: O-Functionalization (1) and
Envisioned HAT (2)
hotoredox-mediated hydrogen atom transfer (HAT) has
Pemerged as a powerful mode of catalysis, enabling new
methods for C−H bond functionalization.1 The proposed
mechanism for this class of reactions involves one-electron
oxidation of a HAT mediator by the excited-state photo-
catalyst, generating a reactive intermediate that abstracts a
hydrogen atom from the organic substrate. After reaction of
the substrate-derived radical, reduction and proton transfer
steps close the catalytic cycle. The ability to influence the rate
and selectivity of hydrogen atom abstraction by variation of the
HAT mediator is an advantage of this approach.2 Oppor-
tunities exist to develop catalysts capable of interacting with
the substrate to accelerate hydrogen atom abstraction at a
particular site,3 or to influence stereoselectivity in reactions of
the resulting radical.4 A pioneering example of such a catalytic
process was reported by MacMillan and co-workers, who
achieved selective functionalizations of C−H bonds α to
hydroxyl groups using tetrabutylammonium dihydrogen
phosphate as catalyst.5 Hydrogen bond donation from the
OH group to the H2PO4− anion was proposed to enhance the
hydridic character of the α-C−H bond, accelerating HAT to
the electrophilic quinuclidine radical cation by polarity
matching.6 Other substrate activation modes for acceleration
of HAT include zinc alkoxide formation from alcohols,7
carboxylate formation from α-amino acids,8 and carbamate
formation from primary amines.9
hypothesized that borinic ester formation could also enable
site-selective HAT, through a combination of increased
hydridic character of the α-C−H bonds5,6 and electrostatic
attraction to a radical cation (eq 2).9,11 Selective oxidations of
diols via organotin12 and organoboron complexes13 constitute
support for the proposal that such species are activated toward
C−H bond cleavage.
Quinuclidine-mediated C−H alkylation in the presence of a
photoredox catalyst5 was investigated to evaluate the effects of
diarylborinic acid complexation on HAT-based reactivity of
carbohydrates. Such C−H functionalizations of alcohols are
accelerated by formation of hydrogen-bonded complexes or
alkoxides,5,7 suggesting that the interaction of an organoboron
catalyst with a diol group might promote selective H-atom
abstraction. Witte and Minnaard have adapted MacMillan’s
Here, we disclose a method for stereo- and site-selective C−
H alkylation of carbohydrate derivatives, employing diphe-
nylborinic acid as a cocatalyst under photoredox conditions
with quinuclidine as the HAT mediator. In the presence of the
organoboron catalyst, C−H abstraction occurs selectively at
the equatorial hydrogens of cis-1,2-diol moieties, and the C−C
bond-forming step takes place with net retention of
Received: February 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b01531
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 2. Selective C−H Alkylation of 1a and Proposed Cocatalytic Cycle
−
H2PO4 -catalyzed protocol to achieve C3-selective C−H
alkylations of certain α-pyranosides.14 β-Glucopyranosides
resulted in mixtures of stereoisomers, while manno- and
galactopyranosides did not undergo selective alkylation under
these conditions.
Table 1. Effects of Catalyst Structure and Loading on C−H
Alkylation of Pyranoside 1a
yield of
a
entry
change(s) to conditions of Scheme 2
2a
b
1
2
3
3a omitted
5%
In the presence of diphenylborinic acid (3a, 10 mol %),
c
e
d
Bu4N+H2PO4 (25 mol %) used in place of 3a
<5%
b
−
quinuclidine (20 mol %) and Ir[dF(CF3)ppy]2(dtbbpy)-
Bu4N+H2PO4 (25 mol %) used in place of 3a
5%
−
15,16
PF6
(4, 1 mol %), irradiation of rhamnopyranoside 1a
4
5
6
7
8
9
10
3b used in place of 3a
3c used in place of 3a
3a (5 mol %)
3a (20 mol %)
Quinuclidine omitted
Bu4N+BzO− (20 mol %) in place of quinuclidine
Methyl thioglycolate (20 mol %) in place of
quinuclidine
46%
55%
54%
20%
<5%
<5%
<5%
and methyl acrylate with a blue LED in acetonitrile at 25 °C
generated spiro-fused butyrolactone17 2a in 72% yield (Scheme
2). The structure of 2a was established by nuclear magnetic
resonance (NMR) analysis (1H−1H COSY, H−13C HMBC
1
d
d
d
and NOE difference spectra). The outcome is consistent with
abstraction of the less hindered, equatorial α-hydrogen from
the cis-diol-derived borinic ester and approach of the acrylate
from the convex face of the resulting radical. The fact that
lactonization proceeded in situ, without the need for an acid
treatment,5 may reflect an accelerating effect of the borinic
ester group on C−O bond formation.18 A proposed catalytic
cycle is depicted in Scheme 2.
a
Yield determined by 1H NMR spectroscopy using a quantitative
b
internal standard. Obtained as a component of a mixture of C−H
c
alkylation products. 10 mol % quinuclidine, MeCN (0.8 M), 23 °C;
d
Amberlyst 15 resin, 50 °C (ref 6). <5% conversion of the pyranoside.
e
10 mol % quinuclidine, DMSO (0.5 M), 23 °C; Amberlyst 15, 50 °C
(ref 14).
Modifications of the reaction conditions were investigated
(Table 1). In the absence of Ph2BOH, 2a was generated in 5%
yield along its C-2 epimer (22%) and two dialkylated products
(18% combined yield, entry 1). The effect of the diarylborinic
acid on the stereochemical outcome of the reaction (>19:1 d.r.
versus 1:4.1 for the uncatalyzed process) is apparent from this
complexation10b) and HAT mediator. Inhibition by Ph2BOH
at higher loadings may result from a Lewis acid−base
interaction with quinuclidine, preventing oxidation of the
latter by the excited photocatalyst. No reaction was observed in
the absence of photocatalyst (data not shown) or quinuclidine
result. The hydrogen bond-acceptor catalyst Bu4N+H2PO4 ,
−
2g
(entry 8). Employing Bu4N+BzO− (O−H bond dissociation
under the conditions optimized by the MacMillan group,5 gave
<5% conversion of the pyranoside substrate (entry 2).
Reactivity was restored under the conditions of Witte and
Minnaard,14 but a mixture of products was generated (5% yield
of 2a (1:4.4 d.r.), two dialkylated products in a combined 33%
yield, entry 3). Boraaanthracenes 3b and 3c,19 which show
lower affinity for diols relative to 3a but form adducts of higher
oxygen-centered nucleophilicity, gave diminished yields of 2a
(entries 4 and 5). Changing the loading of Ph2BOH resulted in
appreciable decreases in yield (entries 6 and 7). Further
experiments (see the SI) revealed that a roughly 10 mol %
excess of quinuclidine relative to 3a was optimal across a range
of catalyst concentrations, perhaps reflecting a dual role for
quinuclidine as Brønsted base (to promote borinic acid−diol
enthalpy (BDE) of BzOH: 111 kcal/mol20) or methyl
thioglycolate1a,b (S−H BDE: 87 kcal/mol21) in place of
quinuclidine (N−H BDE of quinuclidinium: 99 kcal/mol22)
failed to give the C−H alkylation product. Of these HAT
mediators, only quinuclidine would result in a radical cation
capable of ion-pairing with the anionic diarylborinic ester as
proposed in Scheme 2.
The optimized protocol was applied to substrates having a
cis-1,2-diol moiety (Scheme 3). Two equivalents of diol
relative to methyl acrylate generally provided the highest yield,
but in cases where dialkylation was less problematic (e.g., 2f,
2g, 2h), a 1:1 or 1:2 diol:acrylate ratio was employed.
Activation of the equatorial C−H bond of a cis-1,2-diol motif
was observed consistently, leading to C2-alkylation of
B
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Journal of the American Chemical Society
Communication
when using acrylonitrile or phenyl vinyl sulfone in place of
methyl acrylate (see the SI).
Scheme 3. Site- and Stereoselective C−H Alkylations of
Diol and Triol Derivatives
Computational modeling was employed to probe the effect
of diarylborinic ester formation on the HAT reactivity of
rhamnopyranoside 1a. The BDEs were calculated to evaluate
changes in bond strength, while transition states for HAT with
the quinuclidine radical cation at various sites were modeled to
obtain insight into the kinetic origins of selectivity (Table 2).
The gas-phase DFT calculations (B97-D3/Def2-TZVP)23,24
were carried out using Gaussian 16.25
The calculated BDEs showed α-C−H bond weakening at
the 2- and 3-positions (by 4.5 and 4.2 kcal/mol, respectively)
Table 2. Calculated BDEs and Relative Activation Energies
a
(ΔΔG‡) for HAT with the Quinuclidine Radical Cation
a
b
5 mol % of 3a was used. 1 equiv of pyranoside to methyl acrylate
c
was employed. The product was acylated (RCOCl, pyridine) prior to
isolation. 18 h reaction time. 2 equiv of methyl acrylate to
carbohydrate substrate was employed. The reaction mixture was
treated with Amberlyst 15 resin (50 °C, 3 h) prior to isolation. 19 h
reaction time. 1 equiv of quinuclidine was employed.
d
e
f
g
h
mannopyranosides (2a−2c) and C4-alkylation of galactopyr-
anosides (2e, 2f). Transformations of 1,6-anhydrosugars
1
constrained to the C4 conformation enabled access to the
C3-alkylated mannopyranoside (2d) and galactopyranoside
(2g). The organoboron-catalyzed protocol was also applied to
a ribofuranoside (2h), cis-cycloalkanediols (2i, 2j) and glycerol
(2k). The relative configurations were determined by analysis
of the NOE difference spectra, and by single crystal X-ray
diffraction analysis for 2f. Results of control reactions
conducted in the absence of catalyst 3a are also reported.
The use of Ph2BOH consistently provided an enhancement in
the yield of the C−H alkylation reaction. Effects of the
organoboron catalyst on site-selectivity and diastereoselectivity
were also evident for several substrates, although relatively low
rates of uncatalyzed C−H alkylation, compounded by sluggish
lactonization and the formation of multiply alkylated side
products, hampered such assessments in other instances. For
α-fucopyranoside derivative 2e, the C4:C3 site-selectivity was
higher in the presence of 3a than in its absence. Whereas the
product of net retention of configuration of the C−H bond
was favored in the presence of Ph2BOH, the uncatalyzed
process gave a low diasteroselectivity for 2i (1.7:1 versus 12:1
d.r.) and favored the other diastereomer for 2g (0.6:1 versus
6:1 d.r.). Limitations of the current protocol were encountered
upon attempting C−H alkylations of α-N-acetylgalactosamine,
β-arabinopyranoside and α-ribopyranoside derivatives, and
rhamnopyranoside 1a
BDE (kcal/mol)
ΔΔG‡ for HAT (kcal/mol)
position
BDE
transition state
ΔΔG‡
H-1
H-2
H-3
H-4
H-5
89.2
89.6
90.2
87.4
91.7
1a-TSH1
1a-TSH2
1a-TSH3
1a-TSH4
1a-TSH5
+3.8
0.0
+4.0
+6.5
+5.4
diphenylborinate [1a·BPh2]−
BDE (kcal/mol)
ΔΔG‡ for HAT (kcal/mol)
position
BDE
transition state
ΔΔG‡
H-1
H-2
H-3
H-4
H-5
91.2
85.1
86.0
85.7
91.8
[1a·BPh2]−-TSH1
[1a·BPh2]−-TSH2
[1a·BPh2]−-TSH3
[1a·BPh2]−-TSH4
[1a·BPh2]−-TSH5
+15.3
0.0
+5.7
−
+22.0
a
Structures of 1a and [1a·BPh2]−, and transition state structures for H
atom abstraction by the quinuclidine radical cation, are depicted.
C
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Journal of the American Chemical Society
Communication
ORCID
upon diarylborinate formation, and comparatively small
changes (≤2 kcal/mol) at the other positions. Contrary to
our initial expectations,26 the lowest calculated C−H BDE for
1a was at the 4-position, not the anomeric center: the results
suggest that intramolecular hydrogen bonding causes stabiliza-
tion of radicals α to OH groups. For borinic ester [1a·BPh2]−,
the 2-position was calculated to have the weakest C−H bond,
consistent with the observed site-selectivity, although the BDE
at C4 was only marginally (0.6 kcal/mol) higher. The
calculated energies of activation gave a more definitive result,
revealing an appreciable kinetic preference for abstraction of
H-2 from [1a·BPh2]− by the quinuclidine radical cation
(ΔΔG‡ of −5.7 kcal/mol relative to abstraction of H-3). A
transition state for abstraction of H-4 from [1a·BPh2]− could
not be identified, likely due to steric hindrance at this position.
The 2-position was also calculated to be the kinetically favored
site of HAT for the unbound substrate, but to a lesser extent
(see the ΔΔG‡ data for 1a). For this pyranoside, it appears that
diarylborinic ester formation accentuates an intrinsic level of
site-selectivity while also increasing the rate of the C−H
alkylation process. Although the calculations did not provide a
direct estimate of the relative rates of catalyzed versus
uncatalyzed HAT, the exergonic formation of a prereactive
complex from [1a·BPh2]− and the radical cation suggests a
significant level of acceleration (see the SI). Further computa-
tional modeling to account for ion pairing and solvent effects,
along with experimental studies of reaction rates, would be of
interest.
In conclusion, diphenylborinic acid has a significant effect on
quinuclidine-mediated C−H alkylations of cis-1,2-diol groups
under photoredox conditions. The patterns of site-selectivity,
along with computational modeling of the proposed
intermediate, suggest acceleration of HAT between a
tetracoordinate diarylborinic ester and the quinuclidine radical
cation due to polarity matching and/or ion pairing effects.
Association of the borinic acid with the resulting radical
intermediate is likely responsible for the observed retention of
configuration upon C−C bond formation. Considering that
carbohydrate-derived radicals have been implicated in
synthetic and enzyme-catalyzed transformations,27 the ability
to use a small-molecule catalyst to influence the rate and site-
selectivity of H atom abstraction from a sugar-derived substrate
(and to remain associated with the radical during subsequent
transformations) is a significant advance. Opportunities exist to
gain additional mechanistic insight into this activation mode,
and to develop extensions that enable other useful trans-
formations of carbohydrates and related molecules.
Graham E. Garrett: 0000-0001-8558-2027
Mark S. Taylor: 0000-0003-3424-4380
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSERC (Discovery Grant and
Canada Research Chairs programs, doctoral scholarship to
V.D.), the McLean Foundation and University of Toronto
(McLean Award to M.S.T.), the Canada Foundation for
Innovation (project nos. 17545 and 19119) and the Govern-
ment of Ontario. Dr. Alan Lough (University of Toronto) is
acknowledged for solving the X-ray crystal structure of 2f.
Computations were performed on resources and with support
provided by the Centre for Advanced Computing (CAC) at
Queen’s University in Kingston, Ontario. The CAC is funded
by the Canada Foundation for Innovation, the Government of
Ontario, and Queen’s University.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b01531.
■
S
Experimental and computational details, additional data
regarding optimization and substrate scope, character-
1
ization data for new compounds, copies of H and 13C
1
1
1
NMR, H−1H COSY, H−13C HSQC, H−13C HMBC
and H−1H NOE difference spectra (PDF)
1
X-ray crystal structure data of 2f (CIF)
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AUTHOR INFORMATION
Corresponding Author
*mtaylor@chem.utoronto.ca
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Journal of the American Chemical Society
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DOI: 10.1021/jacs.9b01531
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX