Rapid Entry into Biologically Relevant α,α-Difluoroalkylphosphonates Bearing Allyl Protection-Deblocking under Ru(II)/(IV)-Catalysis

Article abstract of DOI:10.1021/acs.orglett.9b03707

A convenient synthetic route to α,α-difluoroalkylphosphonates is described. Structurally diverse aldehydes are condensed with LiF₂CP(O)(OCH₂CH-CH₂)₂. The resultant alcohols are captured as the pentafluorophenyl thionocarbonates and efficiently deoxygenated with HSnBu₃, BEt₃, and O₂, and then smoothly deblocked with CpRu(IV)(π-allyl)quinoline-2-carboxylate (1-2 mol %) in methanol as an allyl cation scavenger. These mild deprotection conditions provide access to free α,α-difluoroalkylphosphonates in nearly quantitative yield. This methodology is used to rapidly construct new bis-α,α-difluoroalkyl phosphonate inhibitors of PTPIB (protein phosphotyrosine phosphatase-1B).

Full text of DOI:10.1021/acs.orglett.9b03707

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rapid Entry into Biologically Relevant α,α-
Difluoroalkylphosphonates Bearing Allyl Protection−Deblocking
under Ru(II)/(IV)-Catalysis
Kaushik Panigrahi,† Xiang Fei,† Masato Kitamura,*,‡ and David B. Berkowitz*,†
†Department of Chemistry, University of Nebraska, Lincoln, Nebraska 68588-0304, United States
‡Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan
S
* Supporting Information
ABSTRACT: A convenient synthetic route to α,α-difluoroalkylphosphonates
is described. Structurally diverse aldehydes are condensed with LiF2CP(O)-
(OCH2CHCH2)2. The resultant alcohols are captured as the pentafluor-
ophenyl thionocarbonates and efficiently deoxygenated with HSnBu3, BEt3,
and O2, and then smoothly deblocked with CpRu(IV)(π-allyl)quinoline-2-
carboxylate (1−2 mol %) in methanol as an allyl cation scavenger. These mild
deprotection conditions provide access to free α,α-difluoroalkylphosphonates
in nearly quantitative yield. This methodology is used to rapidly construct new
bis-α,α-difluoroalkyl phosphonate inhibitors of PTPIB (protein phosphotyr-
osine phosphatase-1B).
hosphate esters are ubiquitous in Nature, as they provide
binding handles and partitioning mechanisms for
phosphonate mimics of dTMP (G)17 and UMP (G′)18 are
useful building blocks for phosphonate nucleic acids,19 an area
of burgeoning contemporary interest, particularly for antisense
applications. Fluorophosphonate analogues of phospho-sugars
are useful tools in chemical biology as substrate mimics,20
mechanistic probes,21 or enzyme inhibitors.22 Glucose 6-
phosphate mimic H serves as both an alternate substrate for
G6PDH23 and as a mechansistic probe for phosphoglucomu-
tase by NMR.24 Finally, fluorinated phosphonate analogues of
phospholipids25 such as LPA (I)26 open up new avenues to
investigate and modulate phospholipid signaling mechanisms.
Previously, our lab and others have reported convergent
routes into the title compounds via PCF2−C bond formation.
Such routes include the following: (i) triflate displacement
chemistry with lithio difluoromethylphosphonate anion;27 (ii)
condensation of such (RO)2P(O)CF2M species with the
corresponding aldehydes28 and esters;12a,29 (iii) Pd(0)-
mediated addition of (RO)2P(O)CF2I to monosubstituted
alkenes followed by reductive deiodination;30 (iv) conjugate
addition of (RO)2P(O)CF2M reagents to (E)-nitroalkenes in
the presence of Ce(III);31 and (v) a series of radical-mediated
alkene addition approaches.32 Several other elegant routes are
specific for generating PCF2−C(sp2) bonds33 or directed at
allylic systems.34 Also, Piettre and co-workers have recently
described a convergent approach into the corresponding
fluorinated phosphinates.19a However, nearly all of these
studies lead to diethyl ester protected difluoroalkyl-
phosphonates. To date, these esters are typically deprotected
with TMSX reagents that combine both nucleophilic and
P
metabolites, as well as the backbone for nucleic acids and
phospholipids.1 The kinetic stability, yet thermodynamic
lability, of phosphate esters allows them to serve as on/off-
signals for protein regulation and signal transduction and
amplification. Since the pioneering work of Blackburn2 and
McKenna,3 there has been great interest in α,α-difluorinated
phosphonates as isopolar mimics of biological phosphates,
which are both hydrolytically stable and resistant to
phosphatase enzymes. Prior studies on difluorinated phospho-
nates support the notion of the isopolarity,4 reduced pKa,5 and
yet added hydrophobicity6 of these phosphate mimics.
These postulates have gained significant experimental
support, for example, as illustrated in Figure 1. A is an
effective bisubstrate analogue inhibitor of purine nucleoside
phosphorylase (PNP),7 a target for gout, and B acts as an
analogue of phosphoenolpyruvate inactivating EPSP synthase,8
a key target for herbicide development. The β,γ-CF2-bridged
analogues of dATP (C) and ATP (C′) act as TS probes for
DNA polymerase9 and kinase enzymes,10 respectively. The
α,α-difluorinated phosphonate mimics of L-phosphoserine
(D),11 L-phosphothreonine (D′),12 and L-phosphotyrosine
(E) serve as useful tools for chemical biology.13 These
fluorinated phosphononates behave as “Teflon-phosphates”
being inert to biological phosphatase enzymes; when site-
specifically incorporated in peptides and proteins, they allow
for the study of kinase-mediated signal transduction pathways
of great interest to drug development.14 When incorporated
into cyclic peptides, the pTyr analogue F leads to effective, cell
permeable inhibitors of T-cell PTPase.15 The difluorinated
phosphonate mimic of PLP, F, has been shown to serve as a
useful proble of vitamin B6-active sites.16 Fluorinated
Received: October 19, 2019
© XXXX American Chemical Society
A
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Letter
Earlier, Martin and co-workers had reported the aldehyde
condensation route with diethyl lithio(difluoromethyl) phos-
phonate followed by deoxygenation.28b However, the most
significant limitation of the Martin route to (α,α-difluoroalkyl)-
phosphonate analogues is the need to carry ethyl phosphonate
ester protecting groups through the sequence. In order to best
mimic a natural phosphorus(V)-based biologically active
compound, these ethyl groups need to be removed, typically
using TMSX reagents. While Rabinowitz and co-workers had
reported the use of TMSCl37 for this purpose early on, the
groups of Olah,38 Jung,39 and Blackburn40 had described the
use of TMSI for such purposes. TMSCl only performs well at
elevated temperature, and TMSI is more effective for
carboxylate ester deprotection than for phosphonate ester
deprotection. This latter result was concretely evidenced in an
important study by Schmidhauser and McKenna,36a in which it
was shown that the TMSBr36b,41 is the TMSX agent of choice
for phosphonate ester deprotection.
While there are many examples of the successful use of
TMSBr for the deblocking of diethyl phosphonate protecting
groups, particularly for simple phosphonate esters, but also for
α,α-difluorinated congeners, we and others have encountered
deprotection problems with diethyl/dimethyl/dibutyl-phos-
phonate moieties by TMSBr/I when they are appended to
certain lactone, pyranose, or amino acid frameworks.42 To
expand the repertoire of existing deblocking conditions, the
corresponding dibenzyl-protected phosphonate reagents were
explored, and these proved to be useful in the sugar
phosphonate arena.43 However, due to a lack of stability, the
(BnO)2P(O)CF2Li reagent has not been used extensively for
fluorinated phosphonate synthesis. Therefore, we set out to
examine a new route into α,α-difluoroalkyl phosphonates that
utilizes the (H2CCHCH2O)2P(O)CF2Li reagent and that, if
successful, would offer medicinal chemists and chemical
biologists a streamlined, alternative synthetic entry in this
important class of phosphate mimics.
Figure 1. Bio-relevant α,α-difluorinated phosphonates.
Lewis acidic elements in the reagent itself or when generating
the reagent in situ from TMSX and NaBr of KI, for example.35
That said, the TMSX reagent of choice is TMSBr, as
delineated in a careful comparative study by McKenna and
co-workers,36 as is discussed in more detail below.
In this new approach, the diallyl (difluoromethyl)-
phosphonate anion is first added to a target aldehyde at low
temperature. The resulting β-hydroxy-α,α-difluoroalkyl phos-
phonates are then converted to the corresponding arylthiono-
carbonate esters. While this can be done in situ, if desired, we
chose to perform these operations in two steps, as it was felt
that the intermediate β-hydroxy-α,α-difluoroalkyl phospho-
nates might be of real interest for some chemical biology
applications, and so these were fully characterized. Unfortu-
nately, in model studies with benzaldehyde, deoxygenation of
the aryl thionocarbonate ester so obtained using typical Barton
conditions was largely unsuccessful (Scheme 1).44 The very
low yield of the desired product obtained led us to make a
crucial modification in the synthetic approach. In order to
prevent undesired side reactions, it was discovered that one
could lower the reaction temperature from 80 °C to ambient
temperature by replacing the usual AIBN initiator with BEt3/
air. The modified Barton conditions45 were found to be
successful. Under these conditions, the allyl phosphonate ester
protecting groups are stable to the radical tin chemistry and the
pentafluorophenyl thionocarbonate esters are cleanly reduced
off.
Early on, our lab reported the synthesis of biologically
relevant (α,α-difluoroalkyl)phosphonates bearing allyl ester
protecting groups35 by triflate displacement.27a In that study,
the fluorinated phosphonate esters thereby obtained were
deallylated under Pd(0)-catalysis in the presence of the
organic-soluble 2-methylhexanoate anion nucleophile as an
allyl cation scavenger. The unblocked phosphonates were
obtained with moderate to excellent (56−91%) yields,
depending on the case. While these results were promising,
there still were a couple of limitations to the chemistry
reported here. On the one hand, while triflate displacement
with (RO)2P(O)CF2Li provides for convergency, this
approach does have limitations: namely, (i) triflates are
generally not stable over long periods of time; (ii) molecules
containing highly acid sensitive functionalities may not
withstand triflate synthesis conditions; and (iii) triflates may
be incompatible with certain internal functionalities/protecting
groups (see the N-para-methoxybenzyl oxazolidinone case in
our early efforts to access the pCF2Ser-phosphonate mimic).27c
Therefore, there was a need for new methodology to
synthesize CF2-phosphonate analogues of biological phos-
phates under milder conditions, and ideally also with ester
deblocking conditions that would be exceptionally gentle to
streamline access to these chemical biological tools.
The overall streamlined entry into these fluorinated
phosphosphonates, featuring these mild deoxygenation con-
ditions, is summarized in Scheme 2. In the first step, the diallyl
lithio-α,α-difluoromethylphosphonate anion cleanly adds into
a range of aldehydes including those appended to protected
We set out to synthesize α,α-difluorinated phosphonates
bearing allyl blocking groups via condensation of diallyl
lithio(difluoromethyl)phosphonate with a series of aldehydes.
B
DOI: 10.1021/acs.orglett.9b03707
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Letter
Scheme 1. Standard Deoxygenation Conditions Fail
Table 1. P−CF2−C Bond Formation/Thionocarbonate
Capture
Scheme 2. Streamlined Route into α,α-Difluorinated
Phosphonates
carbohydrate, purine, and vitamin B6-cofactor scaffolds. The
resultant α,α-difluorinated β-hydroxyphosphonates were deriv-
atized as pentafluorophenyl thionocarbonates. As can be seen
from Table 1, the method displays broad substrate scope and
provides two-step yields of the corresponding thionocarbonate
derivatives that are over 63% (>80% average per step) for all
but one densely functionalized protected guanine system 4f.
The BEt3/O2-initiated radical Bu3SnH-mediated deoxygena-
tion step proceeds particularly efficiently in this sequence. As
can be seen from Table 2, for the model system (4a →5a)
described above, one sees a dramatic improvement in yield
(86%) over that obtained under traditional AIBN-initiated
deoxygenation conditions at elevated temperature (20%).
These findings lead us to hypothesize that, at the higher
deoxygenation temperature initially employed, the intermedi-
ate tributyltin radical reacts with the allyl protecting group
centers in competition with Sn−S bond formation, the desired
Finally, as is depicted in Table 3, we have deblocked a set of
allyl-protected α,α-difluorinated phosphonate mimics of bio-
logical phosphates using the novel Cp-Ru(II)-2-quinolinecar-
boxylate catalyst developed in the Kitamura group.46 To our
knowledge, these are the first examples of the use of this
catalyst to provide access to this class of “ teflon” phosphate
mimics. The deallylation proceeds under exceptionally mild
conditions, using the cationic Ru(IV)-PF6 precatalyst shown, at
moderate loading (1−2%). In addition, with this catalyst
system, addition of an exogenous allyl cation acceptor is
unnecessary, since the reaction solvent, MeOH, fills this role,
affording methyl allyl ether as a volatile, readily removable
byproduct. By using this methodology we have demonstrated a
streamlined synthesis of a variety of “teflon” phosphonates in
fully deprotected form.
́
entree into the deoxygenation reaction manifold. Indeed, the
deoxygenation conditions described (ambient temperature,
oxygen-triethylborane initiation) are a key cog in the
methodology presented herein as they are robustly tolerated
across all substrates in our library, giving an average
deoxygenation yield of ∼80%.
As shown in Table 3, the deallylation reaction provides
essentially quantitative conversion with all the selected
substrates. This methodology provides a practical route into
analogues of several biologically relevant phosphates, such as
6b, an analogue of pyridoxal phosphate (PLP) of proven
C
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Table 2. Deoxygenation with Retention of Allyl PGs
Table 3. Deallylation to the Free α,α-Difluorophosphonates
These results highlight the advantage of the bis-phosphonates
over their monomeric congeners (Figure 2) in binding to
PTP1B.
utility,16 at a time when modified PLP analogues are finding
expanded use in chemical biology,47 and 5e, an analogue of
ribose-5-phosphate that could be used to synthesize non-
hydrolyzable RNA mimics as discussed.17,19b,e,g Heterocycle 5f
is a precursor to potent bisubstrate analogue inhibitors of
purine nucleoside phosphorylase,7a and 5j is a building block
for constructing conjugates of the CF2-phosphonate mannose-
6-phosphate (M6P) mimic.48 This phosphatase-inert M6P-
surrogate is of great interest as an unnatural ligand for the
insulin-like growth factor-II receptor (IGFIIR). Polyvalent
versions of such ligands may promote the dimerization of this
receptor and thereby stimulate internalization of circulating
IGF-II growth factor, a potential approach to cancer therapy
currently under investigation.49
Finally, we have rapidly constructed a set of α,α-
difluorinated mono- and bis-phosphonates (6d, 6i and 6g,
6h) to demonstrate how this chemistry can be used to
assemble targeted libaries, here a set of protein tyrosine
phosphatase-1B inhibitor candidates. PTP1B is a high value
potential therapeutic target for type II diabetes.14,15,50 In fact,
for such rapidly assembled scaffolds, significant inhibition was
observed in the midmicromolar range with 6h, in particular.
Figure 2. Comparison of rapidly assembled mono- and bivalent
fluorinated phosphonate PTP1B inhibitors.
A docked structure of 6h, bound to the PTP1B active site
(from pdb 2B07),51 is presented in Figure 3 (AutodockVina;52
best of 25 poses shown). Each difluorinated phosphonate
group is seen to engage in favorable electrostatic/H-bonding
interactions with R24 and K120, with each arene ring of the
inhibitor available for edge-to-face π−π interactions with F182
and Y46, respectively. Thus inhibitor 6h is expected to be a
useful tool for chemical biology; it is a potential lead scaffold
for PTP inhibitor development to facilitate the study of signal
transduction via protein (de)phosphorylation.13a
In conclusion, a practical route for the synthesis of α,α-
difluoroalkyl)phosphonates bearing allyl ester protection has
been established, by exploiting the favorable low temperature
D
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Letter
Fellowship to D.B.B. that brought D.B.B. and M.K. together
and were facilitated by the IR/D program for D.B.B.’s
appointment at the NSF. The authors thank Martin Osinde
and Ranjeet Dhokale (both of the University of Nebraska) for
assistance with modeling and data analysis, respectively; the
NIH (SIG-1-510-RR-06307) and NSF (CHE-0091975 and
MRI-0079750) for NMR instrumentation; and the NIH
(RR016544) for facilities.
REFERENCES
■
(1) Westheimer, F. H. Science 1987, 235, 1173−1178.
(2) (a) Blackburn, G. M.; Brown, D.; Martin, S. J.; Parratt, M. J. J.
Chem. Soc., Perkin Trans. 1 1987, 1, 181−186. (b) Blackburn, G. M.;
Taylor, G. E.; Tattershall, R. H.; Thatcher, G. R. J.; McLennan, A.
Bioactive Molecules 1987, 3, 451−464. (c) Blackburn, G. M.; Parratt,
M. J. J. Chem. Soc., Perkin Trans. 1 1986, 1, 1417−1424.
(3) McKenna, C. E.; Shen, P.-D. J. Org. Chem. 1981, 46, 4573−4576.
(4) (a) Meanwell, N. A. J. Med. Chem. 2018, 61, 5822−5880.
(b) Panigrahi, K.; Nelson, D. L.; Berkowitz, D. B. Chem. Biol. 2012,
19, 666−667.
Figure 3. Inhibitor 6h docked in the PTP1B active site.
(5) Rodriguez, J. B.; Gallo-Rodriguez, C. ChemMedChem 2018, 14,
190−216.
condensation of the (H2CCHCH2O)2P(O)CF2Li reagent
with a set of functionalized aldehydes appended to diverse
biologically relevant scaffolds. A modified Barton deoxygena-
tion is then employed, compatible with the presence of allyl
phosphonate ester functionality. Fluorinated phosphonate
deprotection is achieved under exceptionally mild conditions
with the Ru(II)-catalyst pioneered in the Kitamura lab. The
new method has been applied to the synthesis of CF2-
phosphonate mimics of PLP (vitamin B6), D-mannopyranosyl
and D-ribofuranosyl phosphates, and an established purine-
based phosphonate scaffold for PNP inhibition. Finally, this
chemistry has been deployed in a parallel, bidirectional fashion
using aromatic bis-aldehyde substrates to provide rapid access
to simple bis-α,α-difluoromethylene phosphonates that display
midmicromolar inhibitory potency against PTP1B. Indeed,
PTP inhibitor 6h provides an attractive and readily accessible
scaffold from which to potentially build out specificity and
enhanced affinity across the PTP family of signal-transducing
enzymes.
(6) Hoffmann, W.; Langenhan, J.; Huhmann, S.; Moschner, J.;
Chang, R.; Accorsi, M.; Seo, J.; Rademann, J.; Meijer, G.; Koksch, B.;
Bowers, M. T.; von Helden, G.; Pagel, K. Angew. Chem., Int. Ed. 2019,
58, 8216−8220.
(7) (a) Halazy, S.; Ehrhard, A.; Danzin, C. J. Am. Chem. Soc. 1991,
113, 315−317. (b) Halazy, S.; Eggenspiller, A.; Ehrhard, A.; Danzin,
C. Bioorg. Med. Chem. Lett. 1992, 2, 407−410.
(8) Phillion, D. P.; Cleary, D. G. J. Org. Chem. 1992, 57, 2763−2764.
(9) (a) Oertell, K.; Florian, J.; Haratipour, P.; Crans, D. C.;
Kashemirov, B. A.; Wilson, S. H.; McKenna, C. E.; Goodman, M. F.
Biochemistry 2019, 58, 1764−1773. (b) Haratipour, P.; Minard, C.;
Nakhjiri, M.; Negahbani, A.; Kashemirov, B. A.; McKenna, C. E.
Phosphorus, Sulfur Silicon Relat. Elem. 2019, 194, 329−330. (c) Oertell,
K.; Kashemirov, B. A.; Negahbani, A.; Minard, C.; Haratipour, P.;
Alnajjar, K. S.; Sweasy, J. B.; Batra, V. K.; Beard, W. A.; Wilson, S. H.;
McKenna, C. E.; Goodman, M. F. Biochemistry 2018, 57, 3925−3933.
(10) Ni, F.; Kung, A.; Duan, Y.; Shah, V.; Amador, C. D.; Guo, M.;
Fan, X.; Chen, L.; Chen, Y.; McKenna, C. E.; Zhang, C. J. Am. Chem.
Soc. 2017, 139, 7701−7704.
(11) (a) Tarrant, M. K.; Rho, H.-S.; Xie, Z.; Jiang, Y. L.; Gross, C.;
Culhane, J. C.; Yan, G.; Qian, J.; Ichikawa, Y.; Matsuoka, T.; Zachara,
N.; Etzkorn, F. A.; Hart, G. W.; Jeong, J. S.; Blackshaw, S.; Zhu, H.;
Cole, P. A. Nat. Chem. Biol. 2012, 8, 262−269. (b) Panigrahi, K.;
Eggen, M.; Maeng, J.-H.; Shen, Q.; Berkowitz, D. B. Chem. Biol. 2009,
16, 928−936. (c) Zheng, W.; Schwarzer, D.; LeBeau, A.; Weller, J. L.;
Klein, D. C.; Cole, P. A. J. Biol. Chem. 2005, 280, 10462−10467.
(d) Higashimoto, Y.; Saito, S. i.; Tong, X.-H.; Hong, A.; Sakaguchi,
K.; Appella, E.; Anderson, C. W. J. Biol. Chem. 2000, 275, 23199−
23203.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b03707.
■
S
Detailed experimental procedures (synthesis and en-
zyme kinetics assays) and characterization data (1H, 13C,
19F, and 31P NMR spectra) (PDF)
(12) (a) Berkowitz, D. B.; Eggen, M.; Shen, Q.; Shoemaker, R. K. J.
Org. Chem. 1996, 61, 4666−4675. (b) Chen, H.-X.; Kang, J.; Chang,
R.; Zhang, Y.-L.; Duan, H.-Z.; Li, Y.-M.; Chen, Y.-X. Org. Lett. 2018,
20, 3278−3281.
(13) (a) Lu, C. H. S.; Liu, K.; Tan, L. P.; Yao, S. Q. Chem. - Eur. J.
2012, 18, 28−39. (b) Yun, S.-M.; Moulaei, T.; Lim, D.; Bang, J. K.;
Park, J.-E.; Shenoy, S. R.; Liu, F.; Kang, Y. H.; Liao, C.; Soung, N.-K.;
Lee, S.; Yoon, D.-Y.; Lim, Y.; Lee, D.-H.; Otaka, A.; Appella, E.;
McMahon, J. B.; Nicklaus, M. C.; Burke, T. R., Jr.; Yaffe, M. B.;
Wlodawer, A.; Lee, K. S. Nat. Struct. Mol. Biol. 2009, 16, 876−882.
(14) Groves, M. R.; Yao, Z.-J.; Roller, P. P.; Burke, T. R., Jr.; Barford,
D. Biochemistry 1998, 37, 17773−17783.
(15) Liao, H.; Pei, D. Org. Biomol. Chem. 2017, 15, 9595−9598.
(16) Stirtan, W. G.; Withers, S. G. Biochemistry 1996, 35, 15057−
15064.
(17) Garvey, E. P.; Lowen, G. T.; Almond, M. R. Biochemistry 1998,
37, 9043−9051.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: dberkowitz1@unl.edu.
*E-mail: kitamura@os.rcms.nagoya-u.ac.jp.
ORCID
Masato Kitamura: 0000-0002-0543-8795
David B. Berkowitz: 0000-0001-7550-0112
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported in part by NSF CHE-1500076 and
CHE-1800574. These studies were initiated by a JSPS
■
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Letter
(18) Matulic-Adamic, J.; Haeberli, P.; Usman, N. J. Org. Chem. 1995,
60, 2563−2569.
(33) (a) Singsardar, M.; Mondal, S.; Laru, S.; Hajra, A. Org. Lett.
2019, 21, 5606−5610. (b) Liu, D.; Jiao, M.-J.; Wang, X.-Z.; Xu, P.-F.
Org. Lett. 2019, 21, 4745−4749.
(19) (a) Zhang, J.; Lambert, E.; Xu, Z.-F.; Brioche, J.; Remy, P.;
Piettre, S. R. J. Org. Chem. 2019, 84, 5245−5260. (b) Pfund, E.;
Dupouy, C.; Rouanet, S.; Legay, R.; Lebargy, C.; Vasseur, J.-J.;
Lequeux, T. Org. Lett. 2019, 21, 4803−4807. (c) Arangundy-Franklin,
S.; Taylor, A. I.; Porebski, B. T.; Genna, V.; Peak-Chew, S.; Vaisman,
A.; Woodgate, R.; Orozco, M.; Holliger, P. Nat. Chem. 2019, 11,
533−542. (d) Liu, C.; Cozens, C.; Jaziri, F.; Rozenski, J.; Marechal,
A.; Dumbre, S.; Pezo, V.; Marliere, P.; Pinheiro, V. B.; Groaz, E.;
Herdewijn, P. J. Am. Chem. Soc. 2018, 140, 6690−6699. (e) Pomeisl,
K.; Beier, P.; Pohl, R.; Krecmerova, M. ChemistrySelect 2016, 1,
2102−2106. (f) Prakash, T. P.; Lima, W. F.; Murray, H. M.; Li, W.;
Kinberger, G. A.; Chappell, A. E.; Gaus, H.; Seth, P. P.; Bhat, B.;
Crooke, S. T.; Swayze, E. E. Nucleic Acids Res. 2015, 43, 2993−3011.
(g) Shen, G. H.; Hong, J. H. Nucleosides, Nucleotides Nucleic Acids
2014, 33, 1−17.
(34) Lebargy, C.; De Schutter, C.; Legay, R.; Pfund, E.; Lequeux, T.
Synlett 2018, 29, 46−50.
(35) Kamber, M.; Just, G. Can. J. Chem. 1985, 63, 823−827.
(36) (a) McKenna, C. E.; Schmidhauser, J. J. Chem. Soc., Chem.
Commun. 1979, 739. (b) McKenna, C. E.; Higa, M. T.; Cheung, N.
H.; McKenna, M. C. Tetrahedron Lett. 1977, 18, 155−158.
(37) Rabinowitz, R. J. Org. Chem. 1963, 28, 2975−2978.
(38) Ho, T.-L.; Olah, G. A. Angew. Chem. 1976, 88, 847.
(39) Jung, M. F.; Lyster, M. A. J. Am. Chem. Soc. 1977, 99, 968−969.
(40) Blackburn, G. M.; Ingleson, D. J. Chem. Soc., Chem. Commun.
1978, 870−871.
(41) Hata, T.; Yamada, K.; Futatsugi, T.; Sekine, M. Synthesis 1979,
1979, 189−191.
(42) (a) Piettre, S. R.; Raboisson, P. Tetrahedron Lett. 1996, 37,
2229−2232. (b) Gordeev, M. F.; Patel, D. V.; Barker, P. L.; Gordon,
E. M. Tetrahedron Lett. 1994, 35, 7585−7588. (c) Wang, M. F.;
Crilley, M. M. L.; Golding, B. T.; McInally, T.; Robinson, D. H.;
Tinker, A. J. Chem. Soc., Chem. Commun. 1991, 667−668.
(43) Berkowitz, D. B.; Bhuniya, D.; Peris, G. Tetrahedron Lett. 1999,
40, 1869−1872.
(20) (a) Bartee, D.; Wheadon, M. J.; Freel Meyers, C. L. J. Org.
Chem. 2018, 83, 9580−9591. (b) Cocaud, C.; Nicolas, C.; Poisson,
T.; Pannecoucke, X.; Legault, C. Y.; Martin, O. R. J. Org. Chem. 2017,
82, 2753−2763.
(21) Forget, S. M.; Bhattasali, D.; Hart, V. C.; Cameron, T. S.;
Syvitski, R. T.; Jakeman, D. L. Chem. Sci. 2012, 3, 1866−1878.
(22) Cocaud, C.; Zheng, R. B.; Lowary, T. L.; Poisson, T.;
Pannecoucke, X.; Nicolas, C.; Martin, O. R. Carbohydr. Res. 2018,
461, 45−50.
(23) Berkowitz, D. B.; Bose, M.; Pfannenstiel, T. J.; Doukov, T. J.
Org. Chem. 2000, 65, 4498−4508.
(44) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1, 1574−1585.
(45) Barton, D. H. R.; Jaszberenyi, J. C. Tetrahedron Lett. 1989, 30,
2619−2622.
(46) (a) Tanaka, S.; Kitamura, M. e-EROS Encycl. Reagents Org.
Synth. 2010, 1−3. (b) Tanaka, S.; Saburi, H.; Murase, T.; Ishibashi,
Y.; Kitamura, M. J. Organomet. Chem. 2007, 692, 295−298.
(c) Tanaka, S.; Saburi, H.; Kitamura, M. Adv. Synth. Catal. 2006,
348, 375−378. (d) Tanaka, S.; Saburi, H.; Ishibashi, Y.; Kitamura, M.
Org. Lett. 2004, 6, 1873−1875.
(24) Baxter, N. J.; Bowler, M. W.; Alizadeh, T.; Cliff, M. J.;
Hounslow, A. M.; Wu, B.; Berkowitz, D. B.; Williams, N. H.;
Blackburn, G. M.; Waltho, J. P. Proc. Natl. Acad. Sci. U. S. A. 2010,
107, 4555−4560.
(47) Fux, A.; Pfanzelt, M.; Kirsch, V. C.; Hoegl, A.; Sieber, S. A. Cell
Chem. Biol. 2019, 26, 1461−1468e7.
(25) (a) Prasad, V. P.; Wagner, S.; Keul, P.; Hermann, S.; Levkau,
B.; Schaefers, M.; Haufe, G. Bioorg. Med. Chem. 2014, 22, 5168−5181.
(b) Nikitopoulou, I.; Kaffe, E.; Sevastou, I.; Sirioti, I.; Samiotaki, M.;
Madan, D.; Prestwich, G. D.; Aidinis, V. PLoS One 2013, 8,
No. e70941. (c) Jiang, G.; Xu, Y.; Fujiwara, Y.; Tsukahara, T.;
Tsukahara, R.; Gajewiak, J.; Tigyi, G.; Prestwich, G. D. Chem-
MedChem 2007, 2, 679−690. (d) Zhang, H.; Xu, Y.; Zhang, Z.;
Liman, E. R.; Prestwich, G. D. J. Am. Chem. Soc. 2006, 128, 5642−
5643. (e) Zhang, H.; Tsukuhara, R.; Tigyi, G.; Prestwich, G. D. J. Org.
Chem. 2006, 71, 6061−6066. (f) Xu, Y.; Lee, S. A.; Kutateladze, T. G.;
Sbrissa, D.; Shisheva, A.; Prestwich, G. D. J. Am. Chem. Soc. 2006,
128, 885−897. (g) Xu, Y.; Aoki, J.; Shimizu, K.; Umezu-Goto, M.;
Hama, K.; Takanezawa, Y.; Yu, S.; Mills, G. B.; Arai, H.; Qian, L.;
Prestwich, G. D. J. Med. Chem. 2005, 48, 3319−3327.
(48) (a) Barragan-Montero, V.; Awwad, A.; Combemale, S.; de
Santa Barbara, P.; Jover, B.; Moles, J.-P.; Montero, J.-L.
ChemMedChem 2011, 6, 1771−1774. (b) Clavel, C.; Barragan-
Montero, V.; Garric, X.; Moles, J.-P.; Montero, J.-L. Farmaco 2005,
60, 721−725. (c) Khanjin, N. A.; Montero, J.-L. Tetrahedron Lett.
2002, 43, 4017−4020. (d) Barragan, V.; Menger, F. M.; Caran, K. L.;
Vidil, C.; Morere, A.; Montero, J.-L. Chem. Commun. 2001, 85−86.
(49) (a) Fei, X.; Zavorka, M. E.; Malik, G.; Connelly, C. M.;
MacDonald, R. G.; Berkowitz, D. B. Org. Lett. 2017, 19, 4267−4270.
(b) Fei, X.; Connelly, C. M.; MacDonald, R. G.; Berkowitz, D. B.
Bioorg. Med. Chem. Lett. 2008, 18, 3085−3089. (c) Berkowitz, D. B.;
Maiti, G.; Charette, B. D.; Dreis, C. D.; MacDonald, R. G. Org. Lett.
2004, 6, 4921−4924.
(26) Xu, Y.; Prestwich, G. D. Org. Lett. 2002, 4, 4021−4024.
(27) (a) Berkowitz, D. B.; Sloss, D. G. J. Org. Chem. 1995, 60,
7047−50. (b) Shen, Q. R.; Sloss, D. G.; Berkowitz, D. B. Synth.
Commun. 1994, 24, 1519−1530. (c) Berkowitz, D. B.; Shen, Q. R.;
Maeng, J. H. Tetrahedron Lett. 1994, 35, 6445−6448. (d) Berkowitz,
D. B.; Eggen, M.; Shen, Q.; Sloss, D. G. J. Org. Chem. 1993, 58,
6174−6176.
(28) (a) Panigrahi, K.; Applegate, G. A.; Malik, G.; Berkowitz, D. B.
J. Am. Chem. Soc. 2015, 137, 3600−3609. (b) Martin, S. F.; Dean, D.
W.; Wagman, A. S. Tetrahedron Lett. 1992, 33, 1839−1842.
(29) Lequeux, T. P.; Percy, J. M. J. Chem. Soc., Chem. Commun.
1995, 2111−2112.
(30) Yang, Z. Y.; Burton, D. J. J. Org. Chem. 1992, 57, 4676−4683.
(31) Lequeux, T. P.; Percy, J. M. Synlett 1995, 1995, 361−362.
(32) (a) Yin, G.; Zhu, M.; Yang, G.; Wang, X.; Fu, W. J. Fluorine
Chem. 2016, 191, 63−69. (b) Xia, X.-F.; Zhu, S.-L.; Li, Y.; Wang, H.
RSC Adv. 2016, 6, 51703−51709. (c) Zhu, M.; Fu, W.; Zou, G.; Xu,
C.; Wang, Z. J. Fluorine Chem. 2015, 180, 1−6. (d) De Schutter, C.;
Pfund, E.; Lequeux, T. Tetrahedron 2013, 69, 5920−5926.
(e) Lequeux, T.; Lebouc, F.; Lopin, C.; Yang, H.; Gouhier, G.;
Piettre, S. R. Org. Lett. 2001, 3, 185−188.
(50) (a) Kobzar, O. L.; Shevchuk, M. V.; Lyashenko, A. N.;
Tanchuk, V. Y.; Romanenko, V. D.; Kobelev, S. M.; Averin, A. D.;
Beletskaya, I. P.; Vovk, A. I.; Kukhar, V. P. Org. Biomol. Chem. 2015,
13, 7437−7444. (b) Zhang, S.; Zhang, Z.-Y. Drug Discovery Today
2007, 12, 373−381. (c) Nichols, A. J.; Mashal, R. D.; Balkan, B. Drug
Dev. Res. 2006, 67, 559−566. (d) Shen, K.; Keng, Y.-F.; Wu, L.; Guo,
X.-L.; Lawrence, D. S.; Zhang, Z.-Y. J. Biol. Chem. 2001, 276, 47311−
47319.
(51) Moretto, A. F.; Kirincich, S. J.; Xu, W. X.; Smith, M. J.; Wan, Z.
K.; Wilson, D. P.; Follows, B. C.; Binnun, E.; Joseph-McCarthy, D.;
Foreman, K.; Erbe, D. V.; Zhang, Y. L.; Tam, S. K.; Tam, S. Y.; Lee, J.
Bioorg. Med. Chem. 2006, 14, 2162−2177.
(52) Trott, O.; Olson, A. J. J. Comput. Chem. 2009, 31, 455−461.
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DOI: 10.1021/acs.orglett.9b03707
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