Visible-Light-Mediated Oxidative Debenzylation Enables the Use of Benzyl Ethers as Temporary Protecting Groups

Article abstract of DOI:10.1021/acs.orglett.0c04026

The cleavage of benzyl ethers by catalytic hydrogenolysis or Birch reduction suffers from poor functional group compatibility and limits their use as a protecting group. The visible-light-mediated debenzylation disclosed here renders benzyl ethers temporary protective groups, enabling new orthogonal protection strategies. Using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as a stoichiometric or catalytic photooxidant, benzyl ethers can be cleaved in the presence of azides, alkenes, and alkynes. The reaction time can be reduced from hours to minutes in continuous flow.

Full text of DOI:10.1021/acs.orglett.0c04026

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Letter
Visible-Light-Mediated Oxidative Debenzylation Enables the Use of
Benzyl Ethers as Temporary Protecting Groups
Cristian Cavedon, Eric T. Sletten, Amiera Madani, Olaf Niemeyer, Peter H. Seeberger,*
and Bartholomäus Pieber*
Cite This: Org. Lett. 2021, 23, 514−518
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ABSTRACT: The cleavage of benzyl ethers by catalytic hydrogenolysis or
Birch reduction suffers from poor functional group compatibility and limits
their use as a protecting group. The visible-light-mediated debenzylation
disclosed here renders benzyl ethers temporary protective groups, enabling
new orthogonal protection strategies. Using 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) as a stoichiometric or catalytic photooxidant, benzyl
ethers can be cleaved in the presence of azides, alkenes, and alkynes. The
reaction time can be reduced from hours to minutes in continuous flow.
he synthesis of complex molecules such as biopolymers
relies on protective groups to ensure chemo-, regio-, and
Scheme 1. Visible-Light-Mediated Oxidative Deprotection
Strategies of PMB and Benzyl Ethers
T
stereoselectivity.1 Protecting groups are of central importance
to carbohydrate construction, where a host of hydroxyl groups
have to be masked. Installation and selective removal are the
basis for orthogonal protecting group strategies that are key to
the synthesis of well-defined oligosaccharides.2−4 Benzyl ethers
are stable over a wide range of conditions, making them an
ideal protecting group that is removed only at the very end of
the synthesis.1 For this very reason, however, benzyl ether
cleavage requires harsh reduction/oxidation processes, such as
catalytic hydrogenolysis, Birch reduction, or oxidation with
ozone or BCl3, which are incompatible with many functional
groups1,5 and are hazardous.6,7 Methods for the mild and
selective cleavage of benzyl ethers would render them
attractive temporary protective groups that would conceptually
change the strategic approach toward the synthesis of complex
glycans.
example, was capable of hydrolyzing the benzyl ether, but
concomitant product degradation resulted in low yields (Table
S2).
Compared with benzyl ethers, p-methoxybenzyl (PMB)
ethers can be selectively cleaved using mild stoichiometric
oxidants.1,8−10 Photoredox catalysis was used to selectively
cleave PMB ethers (Scheme 1a).11−13 Benzyl ethers (EBn‑O‑Me
= 2.20 V vs saturated calomel electrode (SCE)14) have a
significantly higher oxidation potential compared with PMB
ethers (EPMB‑O‑Me = 1.60 V vs SCE14) and are stable during the
photocatalytic PMB cleavage.11−13
A photocatalyst (PC) with a sufficiently strong oxidizing
excited state could facilitate the oxidative cleavage of benzyl
ethers with high functional group tolerance (Scheme 1b). To
move this concept to practice, a suitable PC, H-atom acceptor,
and terminal oxidant had to be identified using the
debenzylation of C(3)-O-benzyl-tetraacetylglucoside (1a) as
a model reaction. Initial efforts with common PCs were not
successful. A combination of 4 mol % 9-mesityl-10-
methylacridinium as the PC and 5.0 equiv of CBr4, for
Full conversion of the starting material and excellent
selectivity toward the desired product (1b) were achieved
using stoichiometric amounts of 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) (E DDQ*/DDQ = 3.18 V vs SCE15) and
green-light irradiation (525 nm) in wet dichloromethane
(Table 1, entry 1). In contrast with photochemical PMB
deprotection,11−13 an additional H-atom acceptor is not
required, as the single electron transfer oxidation and the
hydrogen abstraction are executed by DDQ upon irradiation.16
3
−•
Received: December 4, 2020
Published: January 5, 2021
© 2021 The Authors. Published by
American Chemical Society
https://doi.org/10.1021/acs.orglett.0c04026
Org. Lett. 2021, 23, 514−518
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Table 1. Optimized Conditions and Control Experiments
for the Visible-Light-Mediated Oxidative Debenzylation
a
Using Catalytic and Stoichiometric Amounts of DDQ
a
Reaction conditions: 1a (50 μmol), DDQ (Protocol A: 75 μmol,
Protocol B: 12.5 μmol), TBN (Protocol B: 12.5 μmol), CH2Cl2 (5
b
1
mL), H2O (50 μL), 525 nm irradiation at rt. Determined by H
c
NMR using maleic acid as the internal standard. Not detected.
The irradiation source is crucial for achieving high selectivity.
Shorter wavelengths (440 nm) result in the formation of
significant amounts of the corresponding benzoyl ester 1c
(entry 2). The cleavage of benzyl ethers using simple
substrates was previously reported using stoichiometric
amounts of DDQ under UV irradiation but suffered from
low functional group compatibility.17
To avoid the tedious separation of the stoichiometric
byproduct 2,3-dichloro-5,6-dicyano-1,4-hydroquinone
(DDQH2), we ultimately developed a catalytic protocol
using DDQ (25 mol %), tert-butyl nitrite (TBN, 25 mol %)
as the cocatalyst, and air as the terminal oxidant (Table 1,
entry 4).18−25 The nitrite thermally or photochemically
releases NO that is oxidized by O2 to NO2 and reoxidizes
DDQH2 to DDQ.16 Similar to the protocol with stoichiometric
amounts of DDQ, lower selectivities were observed at shorter
wavelengths (entry 5). Control studies confirmed that photons
and DDQ are necessary for productive catalysis (entries 3, 6,
and 7). Monitoring the reaction using an LED-NMR setup
supported the notion that the reaction ceases upon light source
removal (Figure 1a).26 When DDQ is used in catalytic
amounts and no TBN is added, the reaction stops after one
turnover (Table 1, entry 8). The late addition of TBN can
restore DDQ, and the reaction smoothly proceeds until
completion (Figure 1b). Under anaerobic conditions, the
reaction did not go to completion, confirming that O2 is
required (Table 1, entry 9).
Both protocols were evaluated using carbohydrate substrates
that carry multiple protecting groups (Scheme 2). The
protocol using catalytic amounts of DDQ (protocol B) was
slightly modified (2 equiv of TBN) to avoid long reaction
times. Substrates containing acetyl, isopropylidine, and benzoyl
protecting groups (1a−4a) were smoothly deprotected in <4 h
using both protocols and were isolated in excellent yield (84−
96%). Thioethers that could potentially poison palladium
catalysts during hydrogenolysis were unproblematic using both
Figure 1. In situ NMR studies using an LED-NMR setup. For
experimental details, see the Supporting Information.
photooxidative protocols, and no sulfoxide or sulfone side
products were identified (5a−11a). Several common protect-
ing groups that are not tolerated in hydrogenolysis or Birch
reduction, such as fluorenylmethoxycarbonyl (6a, 7a, 8a),
levulinic ester (8a), allyl carbonate (9a), propargyl carbonate
(10a), and benzylidene (12a), were well tolerated. Azides
(11a), which are essential for biorthogonal labeling, are stable
to the photooxidative benzyl ether cleavage. 2-Naphtylmethyl
ether (NAP, 12a) is routinely removed using stoichiometric
amounts of DDQ in the absence of light. The light-mediated
protocol using 25 mol % DDQ (protocol B) provides a
valuable alternative to avoid stoichiometric amounts of organic
oxidant. The benzyloxycarbonyl (Cbz) group was partially
cleaved using stoichiometric amounts of DDQ (protocol A),
resulting in a modest isolated yield of the desired product 13b.
Using the catalytic method (protocol B), longer reaction times
resulted in significant cleavage of the Cbz group. (See the
Supporting Information.) Phenylselenyl (14a) and tert-
butyldimethylsilyl (TBS, 15a)27 groups are not stable under
the conditions applied. Whereas the photocatalytic protocol
enables the use of benzyl ethers as temporary protective
groups, it is not the method of choice to globally deprotect
carbohydrates. Full deprotection of perbenzylated glucose
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a
Scheme 2. Substrate Scope and Limitations for the Visible-Light-Mediated Oxidative Cleavage of Benzyl Ethers
a
Reaction conditions: benzyl ether (100 μmol), DDQ (protocol A: 150 μmol/benzyl, protocol B: 25 μmol/benzyl), TBN (protocol B, 200 μmol),
b
c
CH2Cl2 (5 mL), H2O (50 μL), 525 nm irradiation at rt. Reaction on a 50 μmol scale. Reaction on a 1.5 mmol scale. Isolated yields are reported.
(16a) was not feasible, and a complex mixture of partially
deprotected derivatives precipitated during the reaction.
The relatively long reaction times for some substrates are a
major limitation, especially using the catalytic protocol. This is
a result of the long wavelengths used, as DDQ absorbs only
weakly above 450 nm (Figure S9). When a 440 nm irradiation
source was applied, we observed significantly shorter reaction
times but had severe selectivity issues due to overoxidation and
product degradation.
Slowing down a chemical reaction to avoid selectivity
problems is a common strategy in batch. Continuous-flow
chemistry can help to overcome selectivity issues, as it offers
precise control over the reaction time and better irradi-
ation.28,29 A two-feed setup introduced the homogeneous
reaction mixture and air into the reactor unit, which consisted
of fluorinated ethylene propylene (FEP) tubing (0.8 mm i.d.)
and a 440 nm light source. A short optimization study using
C(3)-O-benzyl-glucofuranose 2a resulted in a significant
reduction of the reaction time (2.5 min in flow at 440 nm
versus 3 h in batch at 525 nm) while maintaining excellent
selectivity (Figure 2a). An experiment using a longer residence
time showed that selectivity issues indeed arise from prolonged
reaction times at low wavelengths (Figure 2b)
The flow approach was subsequently tested for other
substrates (Figure 2c). The reaction time for the debenzylation
of 10a was significantly reduced to 3 min, whereas
dibenzylated compounds 4a and 6a required 10 min.
In conclusion, we developed a mild, photocatalytic
debenzylation protocol that is significantly more functional-
group-tolerant than traditional methods. The proper choice of
irradiation source is crucial for reaching high selectivities of
benzyl ether cleavage in batch. Green-light irradiation (525
Figure 2. Visible-light-mediated oxidative cleavage of benzyl ethers
using a continuous-flow system.
nm) was superior over blue light (440 nm) in suppressing the
formation of side products during batch reactions. A biphasic
continuous-flow system helped to reduce the reaction times.
Precise control of the reaction time and efficient irradiation in
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flow enabled the use of 440 nm to significantly reduce reaction
times while maintaining high selectivities. The photooxidative
debenzylation overcomes the current limitations of benzyl
ethers as protecting groups that arise from the harsh conditions
necessary for their cleavage. The methodology enables the use
of benzyl ethers as a temporary protective group and is
attractive for the development of new synthetic routes in
glycan synthesis.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Max-Planck Society for
generous financial support. A.M. and B.P. acknowledge the
Deutsche Forschungsgemeinschaft (DFG, German Research
Foundation) under Germany’s Excellence Strategy−EXC
2008/1 (UniSysCat)−390540038 for financial support. B.P.
acknowledges financial support from a Liebig Fellowship of the
German Chemical Industry Fund (Fonds der Chemischen
Industrie, FCI). E.T.S. acknowledges financial support from
the Alexander von Humboldt Foundation.
ASSOCIATED CONTENT
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* Supporting Information
REFERENCES
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04026.
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(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
(2) Wang, T.; Demchenko, A. V. Synthesis of carbohydrate building
blocks via regioselective uniform protection/deprotection strategies.
Org. Biomol. Chem. 2019, 17, 4934−4950.
Detailed experimental procedures and characterization
data for all compounds (PDF)
(3) Krasnova, L.; Wong, C.-H. Oligosaccharide Synthesis and
Translational Innovation. J. Am. Chem. Soc. 2019, 141, 3735−3754.
(4) Guberman, M.; Seeberger, P. H. Automated Glycan Assembly: A
Perspective. J. Am. Chem. Soc. 2019, 141, 5581−5592.
(5) Crawford, C.; Oscarson, S. Optimized Conditions for the
Palladium-Catalyzed Hydrogenolysis of Benzyl and Naphthylmethyl
Ethers: Preventing Saturation of Aromatic Protecting Groups. Eur. J.
Org. Chem. 2020, 2020, 3332−3337.
AUTHOR INFORMATION
■
Corresponding Authors
Bartholomäus Pieber − Department of Biomolecular Systems,
Max Planck Institute of Colloids and Interfaces, 14476
Potsdam, Germany; orcid.org/0000-0001-8689-388X;
Email: bartholomaeus.pieber@mpikg.mpg.de
(6) Van Ornum, S. G.; Champeau, R. M.; Pariza, R. Ozonolysis
Applications in Drug Synthesis. Chem. Rev. 2006, 106, 2990−3001.
(7) Joshi, D. K.; Sutton, J. W.; Carver, S.; Blanchard, J. P.
Experiences with Commercial Production Scale Operation of
Dissolving Metal Reduction Using Lithium Metal and Liquid
Ammonia. Org. Process Res. Dev. 2005, 9, 997−1002.
Peter H. Seeberger − Department of Biomolecular Systems,
Max Planck Institute of Colloids and Interfaces, 14476
Potsdam, Germany; Department of Chemistry and
Biochemistry, Freie Universität Berlin, 14195 Berlin,
Germany; Email: peter.seeberger@mpikg.mpg.de
(8) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
On the selectivity of deprotection of benzyl, mpm (4-methoxybenzyl)
and dmpm (3,4-dimethoxybenzyl) protecting groups for hydroxy
functions. Tetrahedron 1986, 42, 3021−3028.
(9) Classon, B.; Garegg, P. J.; Samuelsson, B.; Lawesson, S.-O.;
Norin, T. The p-Methoxybenzyl Group as Protective Group of the
Anomeric Centre. Selective Conversions of Hydroxy Groups into
Bromo Groups in p-Methoxybenzyl 2-Deoxy-2-phthalimido-beta-D-
glucopyranoside. Acta Chem. Scand. 1984, 38b, 419−422.
(10) Vaino, A. R.; Szarek, W. A. Iodine in Methanol: a Simple
Selective Method for the Cleavage of p-Methoxybenzyl Ethers. Synlett
1995, 1995, 1157−1158.
(11) Tucker, J. W.; Narayanam, J. M. R.; Shah, P. S.; Stephenson, C.
R. J. Oxidative photoredox catalysis: mild and selective deprotection
of PMB ethers mediated by visible light. Chem. Commun. 2011, 47,
5040−5042.
(12) Liu, Z.; Zhang, Y.; Cai, Z.; Sun, H.; Cheng, X. Photoredox
Removal of p-Methoxybenzyl Ether Protecting Group with Hydrogen
Peroxide as Terminal Oxidant. Adv. Synth. Catal. 2015, 357, 589−
593.
(13) Ahn, D. K.; Kang, Y. W.; Woo, S. K. Oxidative Deprotection of
p-Methoxybenzyl Ethers via Metal-Free Photoredox Catalysis. J. Org.
Chem. 2019, 84, 3612−3623.
(14) Mayeda, E. A.; Miller, L. L.; Wolf, J. F. Electrooxidation of
benzylic ethers, esters, alcohols, and phenyl epoxides. J. Am. Chem.
Soc. 1972, 94, 6812−6816.
(15) Ohkubo, K.; Fujimoto, A.; Fukuzumi, S. Visible-Light-Induced
Oxygenation of Benzene by the Triplet Excited State of 2,3-Dichloro-
5,6-dicyano-p-benzoquinone. J. Am. Chem. Soc. 2013, 135, 5368−
5371.
Authors
Cristian Cavedon − Department of Biomolecular Systems,
Max Planck Institute of Colloids and Interfaces, 14476
Potsdam, Germany; Department of Chemistry and
Biochemistry, Freie Universität Berlin, 14195 Berlin,
Germany
Eric T. Sletten − Department of Biomolecular Systems, Max
Planck Institute of Colloids and Interfaces, 14476 Potsdam,
Germany
Amiera Madani − Department of Biomolecular Systems, Max
Planck Institute of Colloids and Interfaces, 14476 Potsdam,
Germany; Department of Chemistry and Biochemistry, Freie
Universität Berlin, 14195 Berlin, Germany
Olaf Niemeyer − Department of Biomolecular Systems, Max
Planck Institute of Colloids and Interfaces, 14476 Potsdam,
Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04026
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
A preprint of this research was previously posted to ChemRxiv
on October 27, 2020: Cavedon, C.; Sletten, E. T.; Madani, A.;
Niemeyer, O.; Seeberger, P. H.; Pieber, B. Visible Light-
Mediated Oxidative Debenzylation. ChemRxiv 2020, DOI: 10.
26434/chemrxiv.13135814.
(16) For a discussion of possible mechanisms, see the Supporting
Information.
(17) Rahim, M. A.; Matsumura, S.; Toshima, K. Deprotection of
benzyl ethers using 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ)
under photoirradiation. Tetrahedron Lett. 2005, 46, 7307−7309.
The authors declare no competing financial interest.
517
https://doi.org/10.1021/acs.orglett.0c04026
Org. Lett. 2021, 23, 514−518

Organic Letters
pubs.acs.org/OrgLett
Letter
(18) Song, C.; Yi, H.; Dou, B.; Li, Y.; Singh, A. K.; Lei, A. Visible-
light-mediated C2-amination of thiophenes by using DDQ as an
organophotocatalyst. Chem. Commun. 2017, 53, 3689−3692.
(19) Rusch, F.; Schober, J.-C.; Brasholz, M. Visible-Light Photo-
catalytic Aerobic Benzylic C(sp3)−H Oxygenations with the
3DDQ*/tert-Butyl Nitrite Co-catalytic System. ChemCatChem
2016, 8, 2881−2884.
(20) Wang, Y.; Wang, S.; Chen, B.; Li, M.; Hu, X.; Hu, B.; Jin, L.;
Sun, N.; Shen, Z. Visible-Light-Induced Arene C(sp2)−H Lactoniza-
tion Promoted by DDQ and tert-Butyl Nitrite. Synlett 2020, 31, 261−
266.
(21) Das, S.; Natarajan, P.; König, B. Teaching Old Compounds
New Tricks: DDQ-Photocatalyzed C−H Amination of Arenes with
Carbamates, Urea, and N-Heterocycles. Chem. - Eur. J. 2017, 23,
18161−18165.
(22) Pan, D.; Pan, Z.; Hu, Z.; Li, M.; Hu, X.; Jin, L.; Sun, N.; Hu, B.;
Shen, Z. Metal-Free Aerobic Oxidative C−O Coupling of C(sp3)−H
with Carboxylic Acids Catalyzed by DDQ and tert-Butyl Nitrite. Eur.
J. Org. Chem. 2019, 2019, 5650−5655.
(23) Song, C.; Dong, X.; Yi, H.; Chiang, C.-W.; Lei, A. DDQ-
Catalyzed Direct C(sp3)−H Amination of Alkylheteroarenes: Syn-
thesis of Biheteroarenes under Aerobic and Metal-Free Conditions.
ACS Catal. 2018, 8, 2195−2199.
(24) Shen, Z.; Dai, J.; Xiong, J.; He, X.; Mo, W.; Hu, B.; Sun, N.; Hu,
X. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)/tert-Butyl
Nitrite/Oxygen: A Versatile Catalytic Oxidation System. Adv. Synth.
Catal. 2011, 353, 3031−3038.
(25) Shen, Z.; Sheng, L.; Zhang, X.; Mo, W.; Hu, B.; Sun, N.; Hu, X.
Aerobic oxidative deprotection of benzyl-type ethers under atmos-
pheric pressure catalyzed by 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ)/tert-butyl nitrite. Tetrahedron Lett. 2013, 54, 1579−
1583.
(26) Feldmeier, C.; Bartling, H.; Riedle, E.; Gschwind, R. M. LED
based NMR illumination device for mechanistic studies on photo-
chemical reactions − Versatile and simple, yet surprisingly powerful. J.
Magn. Reson. 2013, 232, 39−44.
(27) Tanemura, K.; Suzuki, T.; Horaguchi, T. Deprotection of silyl
ethers using 2,3-dichloro-5,6-dicyano-p-benzoquinone. J. Chem. Soc.,
Perkin Trans. 1 1992, 22, 2997−2998.
(28) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. The
Hitchhiker’s Guide to Flow Chemistry. Chem. Rev. 2017, 117,
11796−11893.
(29) Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.;
Noël, T. Applications of Continuous-Flow Photochemistry in Organic
Synthesis, Material Science, and Water Treatment. Chem. Rev. 2016,
116, 10276−10341.
NOTE ADDED AFTER ISSUE PUBLICATION
This article was initially published with an incorrect copyright
statement and was corrected on or around May 5, 2021.
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