Synthesis of Isotopically Labeled, Spin-Isolated Tyrosine and Phenylalanine for Protein NMR Applications

Article abstract of DOI:10.1021/acs.orglett.1c02084

Isotopically labeled amino acids are widely used to study the structure and dynamics of proteins by NMR. Herein we describe a facile, gram-scale synthesis of compounds 1b and 2b under standard laboratory conditions from the common intermediate 7. 2b is ob

Full text of DOI:10.1021/acs.orglett.1c02084

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Letter
Synthesis of Isotopically Labeled, Spin-Isolated Tyrosine and
Phenylalanine for Protein NMR Applications
Brandon M. Young,* Paolo Rossi, P. Jake Slavish, Yixin Cui, Munia Sowaileh, Jitendra Das,
Charalampos G. Kalodimos, and Zoran Rankovic*
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ABSTRACT: Isotopically labeled amino acids are widely used to
study the structure and dynamics of proteins by NMR. Herein we
describe a facile, gram-scale synthesis of compounds 1b and 2b under
standard laboratory conditions from the common intermediate 7. 2b
is obtained via simple deprotection, while 1b is accessed through a
reductive deoxygenation/deuteration sequence and deprotection. 1b
and 2b provide improved signal intensity using lower amounts of
labeled precursor and are alternatives to existing labeling approaches.
noted. The syntheses of 3 and 4 diverge from the common
intermediate 5 at an early stage. The synthesis of 3 takes seven
steps from 5 and requires manipulation and purification of four
volatile intermediates. The preparation of 4 from 5 is carried
out in six steps, the final reaction of which requires rigorous
exclusion of oxygen to prevent product degradation. For the
same reason, pyruvate 4 requires storage at −80 °C, which
presents an additional barrier to its use.6 In addition, up to 200
mg of 3 and 4 per liter of culture may be needed to achieve
high levels of label incorporation into the protein for NMR
studies using existing protocols.4,7 In our hands, following the
recently reported protocol for aromatic labeling using stereo-
array isotope labeling (SAIL) amino acids,2e we found that 3
led to Phe 1a incorporation at high levels (>90%) in the
expressed protein at concentrations of 50 mg/mL (see the
Supporting Information and Figure 2). In contrast, the total
incorporation of 2a remained ∼7-fold lower in comparison to
1a despite the use of increasing concentrations of 4 in the
expression medium (Figure 2a). A similar experience was
reported by others,8 which led us to consider an alternative
strategy for the introduction of 1a and 2a into our labeling
experiments.
rotocols for the isotopic labeling of highly deuterated
1a−c
Pproteins to enable study by NMR are well established.
Of recent interest, the ability to produce proteins containing
isotopically labeled, spin-isolated aromatic amino acids has
provided enhanced structural detail and enabled the
mechanistic study of protein kinases.2 In protein kinases, the
knowledge of the Phe ring orientation in the conserved Asp-
Phe-Gly motif (DFG) in solution is of great interest, as it
correlates to the active vs inactive form.3 The isotope pattern
specificity and high levels of incorporation necessary for the
success of this method are achieved via the introduction of
advanced metabolic precursors that are transformed into the
desired amino acid during protein expression in situ.4
Phenylalanine 1a and tyrosine 2a are accessed via pyruvates
3 and 4 prepared from simple, commercially available isotopic
building blocks and assembled in such a way that the desired
isotope pattern is under complete synthetic control (Figure
1).5
In the course of preparing proteins incorporating spin-
isolated aromatic amino acids, literature-reported pyruvates 3
and 4 were synthesized in house and several challenges were
While unsure of the root cause of the low incorporation, we
hypothesized that incorporating amino acids 1a and 2a
directly, rather than their precursors, might increase the
labeling efficiency. Before initiating synthesis, we set the
following criteria that we believed were critical to the design of
Received: June 21, 2021
Published: August 11, 2021
Figure 1. Spin-isolated phenylalanine 1a and tyrosine 2a, their
corresponding pyruvate bioprecursors 3 and 4, and the common
synthetic intermediate 5.
© 2021 The Authors. Published by
American Chemical Society
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Scheme 1. Retrosynthetic Design of Spin-Isolated Amino
Acids 1b and 2b from a Single Advanced Intermediate
transformation had no direct examples in the literature. We
anticipated that the access to 7 could be accomplished by
Negishi cross-coupling of iodoalanine 8 with iodophenol 9.
The preparation of 9 by a Sandmeyer iodination of 10, an
intermediate in the production of 4, would allow access to the
desired labeling chemistry. Though the use of 8 would produce
isotopologues 1b and 2b with benzylic (Hβ) 1H in place of 2H,
this change improves overall synthetic viability and maintains
spin isolation while facilitating aromatic assignment by
providing a probe to connect intraresidue amide and Cε via
13C-edited and 15N-edited NOESY experiments (Figure 2b).9
Before the isotopically labeled synthesis was attempted, the
optimal conditions for the key reductive deuteration/
deoxygenation of 7 were required. A survey of the literature
revealed no examples of the desired transformation utilizing a
deuterium source, although several examples of the reductive
deoxygenation of Tyr or its derivatives with a proton source
were found.10a−g However, these methods were deemed
unsuitable for our purpose due to poor atom economy,10b,c
the requirement for difficult to remove protecting group-
s,10a,e−g or challenges incorporating deuterium under standard
laboratory conditions.10d Ultimately, this survey did suggest
that Tyr triflate 11a would provide the most direct path to the
desired transformation.
1
Figure 2. Aromatic H,13C-TROSY of the 36 kDa recombinant ALK
extracellular domain (673−1025) prepared with a 50 mg/L culture of
precursor 3 and 4 (pyruvate type) (top panel, a) and 32 kDa
recombinant Src kinase domain (248−531) using 15 mg/L of
precursors 1 and 2 (amino acid type) (bottom panel, a). Up to 7-fold
higher Phe incorporation was found vs Tyr when 3 and 4 were used.
In contrast, 1b and 2b gave equal and high incorporations of both Tyr
and Phe. (b) Resonance assignment of Phe and Tyr in highly
deuterated proteins up to 50 kDa obtained by NOESY matching the
intrabenzylic proton (Hβ) using reagents 1b and 2b in this work.
While examples of aryl triflate reduction have been quite
commonly reported in the literature,11 only three of these
reports provided examples of deuterium incorporation.10c,12,13
We focused our attention on the work of Sajiki,13 who
described an operationally simple Pd/C-catalyzed reduction of
aryl triflates using Mg0 turnings in MeOH at rt. A notable rate
acceleration was observed upon addition of a variety of
ammonium salts, specifically 1 equiv of NH4OAc. In the course
of mechanistic experiments, CH3OD and CD4OD were
reported to provide regioselective deuterium incorporation,
suggesting that the hydroxyl proton was the source of
deuterium in the reaction.
an optimal synthetic approach to the target molecules: (1)
identify a key intermediate suitable to provide both final
products to minimize the number of overall synthetic steps
required, (2) eliminate handling and purification of volatile
intermediates, and (3) utilize existing intermediates from the
synthesis of 3 and 4 when possible.
With these goals in mind, we began our retrosynthetic
analysis with a regioselective reductive deuteration/deoxyge-
nation. This would allow the production of 6 directly from 7,
addressing our desire for a single advanced intermediate
capable of providing both 1 and 2 (Scheme 1). However, this
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Before employing these conditions, we opted to exchange
NH4OAc for NH4Cl. Although both salts were reported to
provide similar reaction rate enhancements, the latter was
expected to be less hygroscopic than the former, reducing the
chance of undesired hydrogen incorporation later. When
11a10e was exposed to the reported conditions, we observed
30% conversion to 6a after overnight stirring by UPLC-MS
(entry 1, Figure 3). The reaction was quickly optimized after
Scheme 2. Synthesis of Spin-Isolated Tyr 2b from
Intermediate 10
Figure 3. Reaction screening to prepare 6a,b from 11a.
Negishi reagent of 8 with 9 occurred with a slight modification
of Jackson’s procedure16 using 2.5 mol % of Pd2(dba)3 and 5
mol % of S-Phos. After the Negishi reagent was prepared in
DMF at 25 °C, the catalyst components and 9 were added
followed by heating at 40 °C overnight. After aqueous workup
and chromatography, 7 was isolated in 85% yield. The specific
rotation of 7 was found to be in line (50.3°) with that of a
commercial sample (49.9°), as confirmed by chiral chromatog-
raphy. Interestingly, when the reaction was carried out using
preformed Gen 3 S-Phos precatalyst instead of Pd2(dba)3 and
S-Phos, the resulting yield dropped to 38%. We attributed this
surprising result to the low basicity of the Negishi reagent that,
while compatible with the free hydroxyl present in 9, may
therefore be insufficiently basic to deprotonate the precatalyst
and consequently fail to produce the active catalytic species.
The synthesis of 2b was completed after a standard sequence
of LiOH·H2O ester hydrolysis17 followed by removal of the
Boc group with 4 M HCl in dioxane18 to give the HCl salt in
96% yield over two steps. Overall, 2b was obtained from 10 in
a 57% total yield over four steps.
With the route to prepare 2b in hand, we turned our
attention to the preparation of 1b (Scheme 3). As before,
triflate 11b was prepared from 7 under the standard
conditions,10e subjected to a brief aqueous workup, and
carried forward directly into the reduction step. An amount of
10% Pd/C, 2 equiv of Mg0 turnings, and 1 equiv of ND4Cl
were introduced and placed under nitrogen at rt. After dilution
with CD3OD, the reaction mixture was stirred 3 h at room
temperature, wherein a second bolus of 2 equiv of Mg0 and 1
equiv of ND4Cl were introduced, followed by a further 3 h of
stirring. After an aqueous workup with 1 M citric acid and
column chromatography, 6c was isolated in 86% yield over
both steps. The observed specific rotation of 6c again
compared favorably with that of the commercial standard
(−4.5 and −4.4°, respectively), no loss of optical activity being
demonstrated by chiral chromatography. The synthesis was
completed as before with ester hydrolysis and Boc depro-
observing the effect of 2 equiv of Mg0 resulted in an essentially
complete reaction after 3 h (entries 2 and 3, Figure 3).
Addition of a second bolus of 2 equiv of Mg0 and 1 equiv of
NH4Cl after 3 h resulted in quantitative conversion to 6a after
an additional 3 h at rt (entry 4, Figure 3) producing the desired
product in 92% yield. Concerned that the presence of basic
Mg(OMe)2 may lead to racemization, we were delighted to
find that 6a displayed the same specific rotation as a
commercial standard (−4.7 and −4.4°, respectively), which
was confirmed by chiral chromatography. In a final
modification, 11a was taken forward after a brief aqueous
workup directly into the reduction reaction, leading to isolated
6a in 88% overall yield for both steps from Boc-Tyr-OMe. We
were gratified to find that the procedure was well-adapted to
the incorporation of deuterium. Using crude 11a, substitution
of ND4Cl and CD3OD into the protocol produced 6b in
similar yield with a deuterium incorporation of over 90% on
1
the basis of H NMR integration (entry 5, Figure 3).
With the conditions for our key transformation secured, we
turned our attention to the fully isotopically labeled synthesis
(Scheme 2). Key to the success of the scheme would be
conditions that did not alter the isotopic distributions already
installed in 10.5 A Sandmeyer iodination of 10 proved
unexpectedly complex, as the reported conditions had poor
reproducibility with regard to yield or purity.14 During the
optimization efforts we noted that, in the time between the
final addition of nitrite and the introduction of iodide, the
reaction began to take on a gritty consistency, suggesting that
the diazonium salt was no longer soluble in the aqueous
medium. This difficulty was overcome by the use of DMSO as
a cosolvent, demonstrated in Zhu’s high-yielding synthesis of
2,3-trifluoromethyl-4-iodophenol,15 circumventing these issues
and giving 9 in 70% yield reproducibly with a high chemical
purity after chromatography. Despite the strongly acidic
conditions, we were pleased to observe no change in aromatic
peak integrations between 10 and 9. Cross-coupling of the
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Scheme 3. Preparation of Spin-Isolated 1b from
Intermediate 7
Complete synthetic details and characterization data of
all novel compounds and NMR experimental data
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Brandon M. Young − Department of Chemical Biology and
Therapeutics, St. Jude Children’s Research Hospital,
Memphis, Tennessee 38105, United States;
Email: brandon.young@stjude.org
Zoran Rankovic − Department of Chemical Biology and
Therapeutics, St. Jude Children’s Research Hospital,
Memphis, Tennessee 38105, United States; orcid.org/
0000-0001-6866-4290; Email: zoran.rankovic@stjude.org
Authors
Paolo Rossi − Department of Structural Biology, St. Jude
Children’s Research Hospital, Memphis, Tennessee 38105,
United States
P. Jake Slavish − Department of Chemical Biology and
Therapeutics, St. Jude Children’s Research Hospital,
Memphis, Tennessee 38105, United States
Yixin Cui − Department of Structural Biology, St. Jude
Children’s Research Hospital, Memphis, Tennessee 38105,
United States
Munia Sowaileh − Department of Structural Biology, St. Jude
Children’s Research Hospital, Memphis, Tennessee 38105,
United States
Jitendra Das − Department of Structural Biology, St. Jude
Children’s Research Hospital, Memphis, Tennessee 38105,
United States
Charalampos G. Kalodimos − Department of Structural
Biology, St. Jude Children’s Research Hospital, Memphis,
Tennessee 38105, United States
tection to give 1b in 87% yield over the final two steps. With
10 as the starting material, 1b was obtained in 47% total yield
over six steps.
In summary, we have developed a concise, flexible, high-
1
yielding synthesis to attain spin-isolated labeled Hε,13Cε Phe
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02084
1b and Tyr 2b for NMR studies. In developing this route, we
were able to overcome several challenges encountered during
the preparation and utilization of late-stage metabolic
precursors 3 and 4, which currently provide the best means
of access to spin-isolated labeled proteins. With the previously
reported aminophenol 10 as the starting material, the advanced
labeled intermediate 7 is prepared in two steps, allowing access
to either 1b or 2b in a further two or four steps, respectively.
Key to the flexibility of the route were conditions allowing for
the regioselective deuteration of 7 while maintaining stereo-
chemical purity. On activation as its triflate, we demonstrated
that 7 was quantitatively reduced by Mg0 turnings with 10%
Pd/C in MeOH accelerated by ammonium salts. These
conditions were readily adapted to incorporate deuterium
regiospecifically at levels of above 90%. Finally, we
demonstrated that 1b and 2b can be used to efficiently label
Phe and Tyr residues in an expressed protein at concentrations
of 15 mg/mL. We feel that the convenient synthesis coupled
with high levels of Phe and Tyr residue labeling makes 1b and
2b valuable reagents to enable the future application of spin-
isolated aromatic labeling in protein NMR.
Author Contributions
B.M.Y. and P.J.S. carried out synthetic chemistry. B.M.Y. and
Z.R. designed the study. P.R., Y.C., M.S., J.D., and C.G.K.
performed protein expression and protein NMR experiments.
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by U.S. National Institutes of Health
grant R35 GM122462 (C.G.K.), the American Lebanese
Syrian Associated Charities (ALSAC) and St. Jude Children’s
Research Hospital (SJCRH). We also thank Dr. Stephanie
Reeve at SJCRH for her assistance in obtaining hi-res MS data.
REFERENCES
■
(1) (a) Gardner, K. H.; Kay, L. E. Production and incorporation of
15N, 13C, 2H (1H-δ1 methyl) isoleucine into proteins for multidimen-
sional NMR studies. J. Am. Chem. Soc. 1997, 119, 7599−7600.
(b) Monneau, Y. R.; Ishida, Y.; Rossi, P.; Saio, T.; Tzeng, S.-R.;
Inouye, M.; Kalodimos, C. G. Exploiting E. coli auxotrophs for leucine,
valine, and threonine specific methyl labeling of large proteins for
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NMR applications. J. Biomol. NMR 2016, 65, 99−108. (c) Schuetz, S.;
Sprangers, R. Methyl TROSY spectroscopy: A versatile NMR
approach to study challenging biological systems. Prog. Nucl. Magn.
Reson. Spectrosc. 2020, 116, 56−84.
Selective Hydrogenation of C-O Bonds with a Simple Sodium
Formate Catalyzed by Nickel. Chem. Commun. 2018, 54, 1521−1524.
(11) Qiu, Z. H.; Li, C. J. Transformations of Less-Activated Phenols
and Phenol Derivatives via C-O Cleavage. Chem. Rev. 2020, 120,
10454−10515.
(12) Korvinson, K. A.; Akula, H. K.; Malinchak, C. T.; Sebastian, D.;
Wei, W.; Khandaker, T. A.; Andrzejewska, M. R.; Zajc, B.; Lakshman,
M. K. Catalytic Reductions Without External Hydrogen Gas: Broad
Scope Hydrogenations with Tetrahydroxydiboron and a Tertiary
Amine. Adv. Synth. Catal. 2020, 362, 166−176.
(13) (a) Sajiki, H.; Mori, A.; Mizusaki, T.; Ikawa, T.; Maegawa, T.;
Hirota, K. Pd/C-Catalyzed Deoxygenation of Phenol Derivatives
Using Mg Metal and MeOH in the Presence of NH4OAc. Org. Lett.
2006, 8, 987−990. (b) Mori, A.; Mizusaki, T.; Ikawa, T.; Maegawa,
T.; Monguchi, Y.; Sajiki, H. Mechanistic Study of a Pd/C-Catalyzed
Reduction of Aryl Sulfonates Using the Mg-MeOH-NH4OAc system.
Chem. - Eur. J. 2007, 13, 1432−1441.
(14) (a) Dains, F. B.; Eberly, F. p-Iodophenol. Org. Synth. 1935, 15,
39. (b) Maity, S.; Das, D.; Sarkar, S.; Samanta, R. Direct Pd(II)-
Catalyzed Site-Selective C5-Arylation of 2-Pyridone Using Aryl
Iodides. Org. Lett. 2018, 20, 5167−5171.
(15) Zhu, G.-D.; Staeger, M. A.; Boyd, S. A. Diels-Alder Reactions of
Hexafluoro-2-butyne with 2-Heterosubstituted Furans: A Facile and
General Synthesis of 1,4-Disubstituted 2,3-Di(trifluoromethyl)-
benzenes. Org. Lett. 2000, 2, 3345−3348.
(16) Ross, A. J.; Lang, H. L.; Jackson, R. F. Much Improved
Conditions for the Negishi Cross-Coupling of Iodoalanine Derived
Zinc Reagents with Aryl Halides. J. Org. Chem. 2010, 75, 245−248.
(17) Khan, R. A. Synthesis of Met-enkephalin by Solution-Phase
Peptide Synthesis Methodology Utilizing Para-toluene Sulfonic Acid
as N-terminal Masking of L-methionine Amino Acid. Chem. Biol. Drug
Des. 2016, 88, 884−888.
(18) Han, G.; Tamaki, M.; Hruby, V. J. Fast, effcient and selective
deprotection of the tert-butoxycarbonyl (Boc) group using HCl/
dioxane (4 M). J. Pept. Res. 2001, 58, 338−341.
(2) (a) Wagner, G.; Demarco, A.; Wuthrich, K. Dynamics of
aromatic amino acid residues in globular conformation of basic
pancreatic trypsin-inhibitor (BPTI). Biophys. Struct. Mech. 1976, 2,
139−158. (b) Pervushin, K.; Riek, R.; Wider, G.; Wuthrich, K.
Transverse relaxation-optimized spectroscopy (TROSY) for NMR
studies of aromatic spin systems in 13C-labeled proteins. J. Am. Chem.
Soc. 1998, 120, 6394−6400. (c) Gautier, A.; Mott, H. R.; Bostock, M.
J.; Kirkpatrick, J. P.; Nietlispach, D. Structure determination of the
seven-helix transmembrane receptor sensory rhodopsin II by solution
NMR spectroscopy. Nat. Struct. Mol. Biol. 2010, 17, 768−774.
(d) Weininger, U.; Modig, K.; Akke, M. Ring Flips Revisited: 13C-
Relaxation Dispersion Measurements of Aromatic Side Chain
Dynamics and Activation Barriers in Basic Pancreatic Trypsin
Inhibitor. Biochemistry 2014, 53, 4519−4525. (e) Miyanoiri, Y.;
Takeda, M.; Terauchi, T.; Kainosho, M. Recent developments in
isotope-aided NMR methods for supramolecular protein complexes
-SAIL aromatic TROSY. Biochim. Biophys. Acta, Gen. Subj. 2020,
1864, 129439. (f) Xie, T.; Saleh, T.; Rossi, P.; Kalodimos, C. G.
Conformational states dynamically populated by a kinase determine
its function. Science 2020, 370, eabc2754.
(3) Modi, V.; Dunbrack, R. L., Jr. Defining a new nomenclature for
the structures of active and inactive kinases. Proc. Natl. Acad. Sci. U. S.
A. 2019, 116, 6818−6827.
(4) Schorghuber, J.; Geist, L.; Platzer, G.; Feichtinger, M.; Bisaccia,
M.; Scheibelberger, L.; Weber, F.; Konrat, R.; Lichtenecker, R. J. Late
Metabolic Precursors for Selective Aromatic Residue Labeling. J.
Biomol. NMR 2018, 71, 129−140.
(5) Lichtenecker, R. J. Synthesis of Aromatic 13C/2H-alpha-Ketoacid
Precursors to be Used in Selective Phenylalanine and Tyrosine
Protein Labelling. Org. Biomol. Chem. 2014, 12, 7551−7560.
(6) (a) Billek, G. Synthesis of phenylpyruvic acids 2. A new synthesis
of 4-hydroxyphenylpyruvic acid. Monatsh. Chem. 1961, 92, 335−342.
(b) Billek, G. p-Hydroxyphenylpyruvic acid. Org. Synth. 1963, 43, 49.
(7) Lichtenecker, R. J.; Weinhaupl, K.; Schmid, W.; Konrat, R.
alpha-Ketoacids as Precursors for Phenylalanine and Tyrosine
Labelling in Cell-based Protein Overexpression. J. Biomol. NMR
2013, 57, 327−331.
(8) Raum, H. N.; Schorghuber, J.; Dreydoppel, M.; Lichtenecker, R.
1
J.; Weininger, U. Site-selective H/2H Labeling Enables Artifact-Free
1H CPMG Relaxation Dispersion Experiments in Aromatic Side
Chains. J. Biomol. NMR 2019, 73, 633−639.
(9) Rossi, P.; Xia, Y.; Khanra, N.; Veglia, G.; Kalodimos, C. G. 15N
and 13C-SOFAST-HMQC editing enhances 3D-NOESY sensitivity in
highly deuterated, selectively 1H,13C-labeled proteins. J. Biomol. NMR
2016, 66, 259−271.
(10) (a) Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar, G. Palladium
Catalyzed Triethylammonium Formate Reduction of Aryl Triflates. A
Selective Method for the Deoxygenation of Phenols. Tetrahedron Lett.
1986, 27, 5541−5544. (b) Walker, T. E.; Matheny, C.; Storm, C. B.;
Hayden, H. An Efficient Chemomicrobiological Synthesis of Stable
Isotope-Labeled L-Tyrosine and L-Phenylalanine. J. Org. Chem. 1986,
51, 1175−1179. (c) Wang, H.; Janowick, D. A.; Schkeryantz, J. M.;
Liu, X.; Fesik, S. W. A Method for Assigning Phenylalanines in
Proteins. J. Am. Chem. Soc. 1999, 121, 1611−1612. (d) Tsukamoto,
H.; Suzuki, R.; Kondo, Y. Revisiting Benzenesulfonyl Linker for the
Deoxygenation and Multifunctionalization of Phenols. J. Comb. Chem.
2006, 8, 289−292. (e) Iimura, S.; Wu, W. Palladium-catalyzed
Borylation of L-tyrosine Triflate Derivative with Pinacolborane:
Practical Route to 4-Borono-L-phenylalanine (l-BPA) Derivatives.
Tetrahedron Lett. 2010, 51, 1353−1355. (f) Tobisu, M.; Yamakawa,
K.; Shimasaki, T.; Chatani, N. Nickel-Catalyzed Reductive Cleavage
of Aryl-oxygen Bonds in Alkoxy- and Pivaloxyarenes Using Hydro-
silanes as a Mild Reducing Agent. Chem. Commun. 2011, 47, 2946−
2948. (g) Xi, X.; Chen, T.; Zhang, J.-S.; Han, L.-B. Efficient and
6292
https://doi.org/10.1021/acs.orglett.1c02084
Org. Lett. 2021, 23, 6288−6292