Organic Letters
Letter
Table 3. Isotope Labeling via Base Exchange
AUTHOR INFORMATION
Corresponding Author
■
Yong Gong − Discovery Sciences, Janssen Research &
Development, Johnson & Johnson, Spring House, Pennsylvania
Authors
i
entry
1(R1)
[13C,15N2]2a (equiv)
yield (%)
de
1a:[13C,15N2]1a
Lu Chen − Discovery Sciences, Janssen Research & Development,
Johnson & Johnson, Spring House, Pennsylvania 19477,
United States
Wei Zhang − Discovery Sciences, Janssen Research &
Development, Johnson & Johnson, Spring House, Pennsylvania
19477, United States
Rhys Salter − Discovery Sciences, Janssen Research &
Development, Johnson & Johnson, Spring House, Pennsylvania
19477, United States
a
,
1
2
3
4
5
1a
1a
1b
1b
1b
1
42
61
63
68
74
1:1
1:2
−
−
−
b
df
,
2
a
d
g
1
b
2
c
g h
,
0.5
a
b
1(R1):BSA:TMSOTf = 1:3:1.5, 2 h. 1(R1):BSA:TMSOTf = 1:5:3,
2 h. 1b:BSA:TMSOTf = 2:3:3, 1 h. HPLC yield. Calibrated with 1a
c
d
e
standard. Calculated from a 50% enriched isotopic mixture of
f
[13C,15N2]1a and 1a. Calculated from a 66% enriched isotopic
g
h
i
mixture. Isolated yield. Based on [13C,15N2]2a. Equilibrated molar
ratio. Determined by mass peak area ratio of 1a:[13C,15N2]1a in
LC−MS.
Complete contact information is available at:
Notes
The authors declare no competing financial interest.
enriched [13C,15N2]1a in 63% yield (Table 3, entry 3). Minor
unreacted 1b was separable from [13C,15N2]1a. An isolated
yield of 68% was achieved when 2 equiv of [13C,15N2]2a was
used (Table 3, entry 4). An even higher isolated yield (74%)
was obtained when 2 equiv of 1b was used (Table 3, entry 5).
5-Nitrouridine 1b not only improved the exchange yield, but
also prevented the isotopic dilution from direct usage of 1a in
entries 1 and 2 in Table 3.
The potential isotopic effects on the equilibration were
evaluated from the equilibrated 1a:[13C,15N2]1a ratios via
LC−MS analysis. The observed 1:1 ratio of 1a:[13C,15N2]1a in
entry 1 in Table 3 and the 1:2 ratio in entry 2 in Table 3
indicated the absence of any significant isotopic effect. The
marginal difference between the isolated yields of 1a in
Scheme 2 and [13C,15N2]1a in entry 4 in Table 3 reflected
experimental variations between two reactions.
ACKNOWLEDGMENTS
■
The authors are grateful to Ronghui Lin and Fengbin Song
(Discovery Sciences, Janssen Research & Development,
Johnson & Johnson) for their helpful chemistry discussions.
REFERENCES
■
(1) Nucleosides and Nucleotides as Antitumor and Antiviral Agents;
Chu, C. K., Baker, D. C., Eds.; Plenum Press: New York, 1993.
(2) (a) De Clercq, E.; Li, G. Clin. Microbiol. Rev. 2016, 29, 695−747.
(b) Jordan, P. C.; Stevens, S. K.; Deval, J. Antivir. Chem. Chemother.
2018, 26, 1−19.
(3) (a) Chemical Synthesis of Nucleoside Analogues; Merino, P., Ed.;
Wiley: Hoboken, NJ, 2013. (b) Downey, A. M.; Richter, C.; Pohl, R.;
Mahrwald, R.; Hocek, M. Org. Lett. 2015, 17, 4604−4607.
(4) Vorbruggen, H.; Ruh-Pohlenz, C. Org. React. 1999, 55, 1−630.
̈
In summary, the above work has demonstrated the viability
of an activation-exchange approach for the modification of
pyrimidine nucleosides via inductive activation of parent
uridine 1a to 5-nitrouridine 1b as a more reactive glycosyl
donor, followed by transglycosylation with substituted uracils.
The reactivity of uridines, nucleophilicity of uracil nucleobases,
and reaction conditions on exchange equilibration were
investigated under microwave irradiation. The optimized
(5) (a) Liao, J.; Sun, J.; Yu, B. Tetrahedron Lett. 2008, 49, 5036−
5038. (b) Yu, B.; Sun, J. Chem. Commun. 2010, 46, 4668−4679.
(c) Rao, B. V.; Manmode, S.; Hotha, S. J. Org. Chem. 2015, 80, 1499−
1505.
(6) (a) Zhang, Q.; Sun, J.; Zhu, Y.; Zhang, F.; Yu, B. Angew. Chem.,
Int. Ed. 2011, 50, 4933−4936. (b) Shirouzu, H.; Morita, H.;
Tsukamoto, M. Tetrahedron 2014, 70, 3635−3639. (c) Basu, N.;
Oyama, K.; Tsukamoto, M. Tetrahedron Lett. 2017, 58, 1921−1924.
(7) Bozhok, T. S.; Sivets, G. G.; Baranovsky, A. V.; Kalinichenko, E.
N. Tetrahedron 2016, 72, 6518−6527.
(8) (a) Crisp, G. T.; Flynn, B. L. Tetrahedron Lett. 1990, 31, 1347−
1350. (b) Flynn, B. L.; Macolino, V.; Crisp, G. T. Nucleosides
Nucleotides 1991, 10, 763−779.
(9) (a) Nowak, I.; Robins, M. J. Org. Lett. 2005, 7, 4903−4905.
(b) Nowak, I.; Cannon, J. F.; Robins, M. J. Org. Lett. 2006, 8, 4565−
4568. (c) Klier, L.; Aranzamendi, E.; Ziegler, D.; Nickel, J.;
Karaghiosoff, K.; Carell, T.; Knochel, P. Org. Lett. 2016, 18, 1068−
1071.
(10) (a) Boryski, J. Curr. Org. Chem. 2008, 12, 309−325.
(b) Lapponi, M. J.; Rivero, C. W.; Zinni, M. A.; Britos, C. N.;
Trelles, J. A. J. Mol. Catal. B: Enzym. 2016, 133, 218−233. (c) Kaspar,
F.; Giessmann, R. T.; Hellendahl, K.; Neubauer, P.; Wagner, A.;
Gimpel, M. ChemBioChem 2020, 21, 1428−1432.
(11) (a) Hatano, A.; Kurosu, M.; Yonaha, S.; Okada, M.; Uehara, S.
Org. Biomol. Chem. 2013, 11, 6900−6905. (b) Drenichev, M. S.;
Alexeev, C. S.; Kurochkin, N. N.; Mikhailov, S. N. Adv. Synth. Catal.
2018, 360, 305−312. (c) Alexeev, C. S.; Drenichev, M. S.; Dorinova,
Vorbruggen conditions were used in the synthesis of 5-
̈
substituted uridine derivatives. The one-pot protocol was
illustrated successfully in a gram-scale conversion under
thermal heating. The approach also enabled the fully isotope
labeling of the parent uridine 1a. The strategy and developed
conditions provide convenient access to nucleoside analogues
and isotopologues that can be otherwise difficult to synthesize.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
1
Experimental procedures, characterization data, H and
13C NMR spectra of all the isolated compounds, and a
representative HPLC chromatogram of transglycosyla-
D
Org. Lett. XXXX, XXX, XXX−XXX