Total synthesis of 2'-O-methyl-β-L-arabinosyluridine and reassignment the nucleoside from penicillium sp. as 2'-O-methyl-β-L-uridine

Article abstract of DOI:10.1016/j.phytol.2020.01.018

In order to validate the structure of a rarely reported naturally occurring nucleoside isolated from the broth of Penicillium sp. (NO. 64), practical syntheses of 2′-O-methyl-β-L-arabinosyluridine, 2′-O-methyl-α-L-arabinosyluridine, and 2′-O-methyl-β-L-uridine were accomplished. Comparing their nuclear magnetic resonance (NMR) spectra and physical data, its structure was reassigned as 2′-O-methyl-β-L-uridine instead of former reported 2′-O-methyl-β-L-arabinosyluridine.

Full text of DOI:10.1016/j.phytol.2020.01.018

PhytochemistryLetters36(2020)68–72
Contents lists available at ScienceDirect
Phytochemistry Letters
journal homepage: www.elsevier.com/locate/phytol
Total synthesis of 2'-O-methyl-β-L-arabinosyluridine and reassignment the
nucleoside from penicillium sp. as 2'-O-methyl-β-L-uridine
Chunyang Shena, Haixin Dinga, Xueping Taoa, Ruchun Yanga, Jiang Baia, Ban-Peng Caoa,*,
Yi-Yuan Pengb, Qiang Xiaoa,*
a Jiangxi Key Laboratory of Organic Chemistry, Jiangxi Science & Technology Normal University, Nanchang, 330013, PR China
b Key Laboratory of Small Functional Organic Molecule, Ministry of Education, Jiangxi Key Laboratory of Green Chemistry and College of Chemistry & Chemical
Engineering, Jiangxi Normal University, Nanchang, 330022, PR China
A R T I C L E I N F O
A B S T R A C T
Keywords:
In order to validate the structure of a rarely reported naturally occurring nucleoside isolated from the broth of
Penicillium sp. (NO. 64), practical syntheses of 2′-O-methyl-β-L-arabinosyluridine, 2′-O-methyl-α-L-arabinosy-
luridine, and 2′-O-methyl-β-L-uridine were accomplished. Comparing their nuclear magnetic resonance (NMR)
spectra and physical data, its structure was reassigned as 2′-O-methyl-β-L-uridine instead of former reported 2′-
O-methyl-β-L-arabinosyluridine.
Naturally occurring nucleoside
L-arabinosyluridine
2'-O-methyl-β-L-uridine
Total synthesis
Penicillium sp
1. Introduction
nucleoside from nature was a breakthrough, which might change our
acknowledge about nucleoside’s natural occurrence. In addition, as we
Naturally occurring nucleosides have played extraordinarily im-
portant role for discovering new pharmaceutical and chemical iden-
tities (Aksoy et al., 2016; Ferrero and Goto, 2000; Li et al., 2018). In the
past century, large amount nucleosides have been isolated and identi-
fied from various natural resources, such as plants, microorganisms,
and recent marine origins. Reprehensive examples are antiviral drug
Vidarabine (Ara-A) and Cytarabine (Ara-C) from sponges, which are
still prescribed in clinical practice nowadays (Montaser and Luesch,
2011).
all know, L-arabinopyranoside and L-arabinofuranoside are widely
presented in nature, especially presence as the component of bacterial
cell wall (Zhao et al., 2017). However, to the best our knowledge, there
is very rare example of
cause only small amounLt-noufcnleuocsleidoesidreepo1rtwedasaissonlaattuerda,liptsrobdioulcot.giBcea-l
activity was not reported by the authors. As our continuous study on
total synthesis of naturally occurring nucleosides, we started to carry
out its synthesis and investigate its biological activities (Ding et al.,
2018, 2014; Ding et al., 2019; Hu et al., 2017; Li et al., 2017a; Sun
et al., 2016).
Investigating the chemical structures of all reported naturally oc-
curring nucleosides showed that almost all of them are D-nucleosides
(Liu et al., 2018). Actually, D-nucleosides are also the main components
of DNA and RNA. But in recent years, L-nucleosides have attracted
tremendous interests of medicinal chemists, because of their excellent
absorption, distribution, metabolism, and excretion (ADME) properties
(Ban et al., 2017). Since then, amount of nucleosides with the unnatural
β-L-configuration have been synthesized and their biological activities
were evaluated (Wang et al., 1999). Many have been found to possess
very potent antiviral activities (Patel et al., 2017). The most noble
compound is Lamivudine (3TC, Scheme 1), which is the first-line drug
for treating HBV at the moment (Dienstag et al., 1999).
Fig. 1. Chemical structures of Lamivudine and the synthesized L-
nucleosides in present paper
From the synthetic point view, synthesis of β-L-arabinosyluridine
could be carried out in two different approaches shown in Fig. 2. The
most straightforward approach is selective methylation of β-L-arabino-
syluridine, which can be synthesized from 2,3,5-tri-O-benzyl-α-L-ara-
binofuranosyl chloride and uracil (Route A, Fig. 2). But, the glycosy-
lation always affords a mixture of anomers and their separation is
notorious. In addition, this approach needs tedious protection and de-
protection manipulations. Thus, the overall efficiency is low. The other
convenient approach is synthesis nucleoside 1 using Vorbrüggen gly-
cosylation of corresponding properly protected 2-O-methyl-L-arabino-
furanose with uracil (Route B, Fig. 2). However, because of 2-O-methyl
group lacking of neighboring participation effect, an anomeric mixture
In 2017, identification of 2′-O-methyl-β-L-arabinosyluridine (com-
pounds 1, Fig. 1) from the broth of Penicillium sp. (NO. 64) was reported
by Li et al. (2017b). We immediately realized that discovering L-
⁎ Corresponding authors.
E-mail addresses: caobanpeng@126.com (B.-P. Cao), xiaoqiang@tsinghua.org.cn (Q. Xiao).
https://doi.org/10.1016/j.phytol.2020.01.018
Received 7 November 2019; Received in revised form 18 December 2019; Accepted 16 January 2020
1874-3900/©2020PhytochemicalSocietyofEurope.PublishedbyElsevierLtd.Allrightsreserved.

C. Shen, et al.
PhytochemistryLetters36(2020)68–72
Scheme 1. Synthesis of 2′-O-methyl-L-arabinosyluridine and 2 from L-ribose.
Fig. 1. Chemical structures of Lamivudine and the synthesized L-nucleosides in present paper.
Fig. 2. Retrosynthetic analysis of 2′-O-methyl-β-L-arabinosyluridine 1.
of nucleosides 1 and 2 will be formed inevitably. Considering that the
corresponding α-configuration nucleoside was also not reported before
and the α-configuration nucleosides were attracted much interests in
recent years, we decided to use the second approach to synthesize 1 and
2 at the same time (Delbaere and James, 1973; Miah et al., 1998; Suck
and Saenger, 1973; Sweeney et al., 2019).
2. Results and discussion
Scheme 1. Synthesis of 2′-O-methyl-L-arabinosyluridine 1 and 2
from L-ribose
Our synthesis 2′-O-methyl-L-arabinosyluridine started from the
preparation of 1,3,5-tri-O-benzoyl-α-L-ribofuranose 4, which was syn-
thesized using L-ribose as starting material in four steps with 52 %
overall yield according to the reported literature (Scheme 1) (Jung
et al., 1999; Ma et al., 1996). Then 2-O-trifluoromethylsulfonyl-1,3,5-
tri-O-benzoyl-α-L-ribofuranose 5 was prepared with 90 % yield by
Fig. 2. Retrosynthetic analysis of 2′-O-methyl-β-L-arabinosyluridine
1
69

C. Shen, et al.
PhytochemistryLetters36(2020)68–72
esterification with trifluoromethanesulfonic anhydride in a mixture of
anhydrous pyridine and DCM. Subsequent nucleophilic substitution of
triflate 5 with KNO2 and simultaneous hydrolysis under H2O afforded
1,3,5-tri-O-benzoyl-α-L-arabinofuranose
6 with 52 % yield. En-
couragingly, a single crystal of L-arabinofuranose 6 suitable for X-ray
crystallography was obtained and its structure was ambiguously con-
firmed (Fig. 3)1 . Details of structure refinement for 6 was given in
supporting information (Table S1)
Fig. 3. ORTEP molecular structure of 1,3,5-tri-O-benzoyl-α-L-arabi-
nofuranose 6
Next, methylation of 2−OH of compound 6 was investigated.
Literature survey revealed that CH3I/Ag2O and trimethylsilyl diazo-
methane (TMSCHN2)/HBF4 were frequently used for the O-methylation
of alcohols (Purdie and Irvine, 1903; Shioiri et al., 2001). At first, the
method of CH3I/Ag2O in DMF was applied. Because Ag2O are weak
base, transesterification of benzoyl to 2−OH occurred and a compli-
cated mixtures was obtained (Shohda et al., 2000). Therefore, the
method of TMSCHN2/HBF4 was further employed. In our preliminary
experiment, L-arabinose methyl ether 7 was successfully obtained but in
low yield accompanied by unreacted starting material. After extensive
optimization of solvents, reaction temperature, equivalence ratios of
TMSCHN2 and HBF4, it was found that the best condition was using of
1.0 equiv. 1,3,5-tri-O-benzoyl-α-L-arabinofuranose 6, 2.0 equiv. of
TMSCHN2, and 1.0 equiv. of HBF4 in DCM at room temperature. The
results are depicted in supporting information (Table S2). It affords
methyl ether 7 in 70 % yield accompanied with 20 % unreacted starting
material arabinose 6.
Fig. 3. ORTEP molecular structure of 1,3,5-tri-O-benzoyl-α-L-arabinofuranose
6.
Table 1
13C Chemical shifts of nucleosides 1, 2, 3 and the reported nucleosidea.
Subsequent, vorbrüggen glycosylation of uracil with methyl ether 7
was performed in MeCN/BSA/TMSOTf. It afforded the β-L-arabinosy-
luridine 8 and α-L-arabinosyluridine 9 (approximation ratio of 3:1) as
expected in 74 % yield. Careful recrystallization of the mixed isomers
can give part of nucleoside 8 as a white solid. The remaining residue
containing the mixed isomers 8 and 9 was difficult to separate using
silica gel chromatography. Thus, the mixture was subjected to a satu-
rated solution of ammonia in methanol directly to afforded nucleoside 1
and 2, which can be separated successfully by HPLC. Discrimination of
the α-anomer and β-anomer was done based on 3JH1′,H2′ coupling
constant. The resonances for the anomeric hydrogens of α/β-L-arabi-
nosyluridine appeared as a doublet (3JH1′,H2′ =2.9 Hz) at δ 5.81 ppm
and a doublet (3JH1′,H2′ =5.6 Hz) at δ 6.13 ppm, respectively (Remin
and Shugar, 1973). It is noteworthy that the small value of 3JH1′,H2′ is a
characteristic trans-relationship between H1' and H2' in ribose nucleo-
side (Sivets, 2018).
1/CD3OD [α]eq
2/ CD3OD [α]eq 3/CD3OD [α]eq Reported/CD3OD
\o(\s\up 6(20),
\o(\s\up 6(20),
\o(\s\up 6(20),
[α]eq \o(\s\up
6(20),\s\do 2())
-68a
\s\do 2()) -136b \s\do 2()) -16.7b \s\do 2()) -44b
1
2
3
4
5
6
7
8
9
59.0
61.8
74.6
85.1
85.6
87.0
101.3
144.1
152.2
58.5
58.8
58.8
62.8
61.6
61.8
75.5
69.7
69.8
90.3
85.0
85.2
91.5
86.1
86.2
92.0
88.8
88.9
100.2
143.1
152.1
166.4
102.5
142.4
152.1
166.2
102.8
142.6
152.0
166.6
10 166.2
a
b
Nucleoside reported (Ref. Li et al., 2017b).
Recorded at c = 0.050 in CH3OH.
Table 1 13C Chemical shifts of nucleosides 1, 2, 3 and the reported
nucleosidea
uridine 11 was obtained in 80 % yield. Next, 2,2′-anhydro-β-L-arabi-
nosyluridine 12 was prepared in 70 % yield by refluxing nucleoside 11
with diphenyl carbonate. In addition, a single crystal of nucleoside 12
suitable for X-ray crystallography was also obtained and its structure
was ambiguously confirmed. The molecules form stacked dimers which
are linked by two hydrogen bonds (Fig. 4)2 . Details of structure re-
finement for 12 was given in supporting information (Table S3). At last,
2′-O-methyl-β-L-uridine 3 was prepared by refluxing nucleoside 12 with
freshly prepared magnesium methoxide in 75 % yield.
Further comparing the reported 13C NMR chemical shift of 2′-O-
methyl-β-L-arabinosyluridine isolated from the broth of Penicillium sp.
(NO. 64) with the synthetic sample, it clearly showed different data
(Table 1). This inconsistency proved that the nucleoside structure from
the broth of Penicillium (NO. 64) is not 2′-O-methyl-β-L-arabinosylur-
idine indeed.
Revisiting the two-dimensional NMR data, we supposed that the
uridine might be 2′-O-methyl-β-L-uridine instead of the former reported
2′-O-methyl-β-L-arabinosyluridine. Although 2′-O-methyl-β-D-uridine
was commercially available, 2′-O-methyl-β-L-uridine was not reported
yet. In order to further verify its structure, synthesis of 2′-O-methyl-β-L-
uridine was accomplished (Scheme 2).
Fig. 4. ORTEP molecular structure of 2,2′-anhydro-β-L-arabinosy-
luridine 12
After 2′-O-methyl-β-L-uridine was obtained, we were glad to find
that all the NMR spectroscopy of synthesized are in accordance with the
nucleoside isolated from Penicillium sp. (NO. 64) (Table 1). Further-
more, the specific optical rotations of nucleosides isolated from Peni-
cillium sp. (NO. 64) and synthesized by L-ribofuranose are [α]eq \o(\s
\up 6(20),\s\do 2(-68 and [α]eq \o(\s\up 6(20),\s\do 2(-44 (c =
0.050) respectively. Therefore, we reassigned the nucleoside isolated
from Penicillium sp. (NO. 64) as 2′-O-methyl-β-L-uridine. To the best of
Scheme 2. Synthesis of 2′-O-methyl-β-L-uridine 3
Synthesis of 2′-O-methyl-β-L-uridine started from 1,2,3,5-tetra-O-
acetyl-β-L-ribofuranose, which was conveniently prepared using L-ri-
bose as starting material in 3 steps (Mehta et al., 2015). Vorbrüggen
glycosylation between 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose and ur-
acil gave L-nucleoside 10 in 60 % yield. After Zemplén saponification, L-
1 CCDC 1940346 Contains the Supplementary Crystallographic Data.
2 CCDC 1940359 Contains the Supplementary Crystallographic Data.
70

C. Shen, et al.
PhytochemistryLetters36(2020)68–72
Scheme 2. Synthesis of 2′-O-methyl-β-L-uridine 3.
Fig. 4. ORTEP molecular structure of 2,2′-anhydro-β-L-arabinosyluridine 12.
our knowledge, it is still the first naturally occurring L-nucleoside and
its synthesis was firstly accomplished.
3.2. Synthesis of 2′-O-methyl-β-L-arabinosyluridine (1)
A solution of 8 (0.37 g, 0.8 mmol) in methanolic ammonia (MeOH
saturated with NH3 at 0 °C, 6 mL) was placed in an autoclave and
stirred at 130 °C for 12 h. After cooling, the mixture was concentrated
to dryness and the residue was purified by column chromatography on
silica gel to give 1 (0.16 g, 80 %) as a white solid.
3. Experimental
3.1. General
Yield: 80 %, Rf =0.3 (DCM:MeOH = 10:1), m.p. 167−168 °C, [α]
eq \o(\s\up 6(20),\s\do 2(= −136.0 (c = 0.050, CH3OH).
1H NMR (400 MHz, CD3OD) δ: 7.79 (d, J =8.1 Hz, 1 H), 6.23 (d, J
=5.2 Hz, 1 H), 5.65 (d, J =8.1 Hz, 1 H), 4.16 (t, J =4.4 Hz, 1 H),
3.90(t, J =4.5 Hz, 1 H), 3.83-3.78 (m, 2 H), 3.72 (dd, J = 11.8, 5.0 Hz,
1 H), 3.36 (s, 3 H).
All reagents and catalysts were purchased from commercial sources
(Energy Chemical Co. Ltd. or Sigma-Aldrich Co. Ltd.) and used without
purification. DCM, MeCN, DMF, and Pyridine were dried with CaH2 and
distilled prior to use. Thin layer chromatography was performed using
silica gel GF-254 plates (Qing-Dao Chemical Company, China) with
detection by UV (254 nm) or charring with 10 % sulfuric acid in
ethanol. Column chromatography was performed on silica gel (200–300
mesh, Qing-Dao Chemical Company, China). NMR spectra were re-
corded on a Bruker AV400 spectrometer, and chemical shifts (δ) are
reported in ppm. 1H NMR and 13C NMR spectra were calibrated with
TMS as an internal standard, and coupling constants (J) are reported in
Hz. The ESI-HRMS were obtained on a Bruker Dalton microTOFQ II
spectrometer in positive ion mode. Melting points were measured on an
electrothermal apparatus uncorrected. Optical rotation was measured
on a Rudolph Autopol IV at a wavelength of 589 nm. Synthesis and
characterization of intermediate products were present in support in-
formation.
13C NMR (101 MHz, CD3OD) δ: 166.2, 152.2, 144.1, 101.3, 87.0,
85.6, 85.1, 74.6, 61.8, 59.0.
HRMS (ESI): M/Z calculated for C10H14N2O6, [M+H]+: 259.0930,
found: 259.0930.
3.3. Synthesis of 2′-O-methyl-α-L-arabinosyluridine (2)
The nucleoside 2 was synthesized as described for 1 starting from
crude nucleoside 9. The reaction mixture was concentrated to dryness
and the residue was purified by column chromatography on silica gel to
give a crude product. The nucleoside 2 (0.04 g, 14 %) was obtained by
71

C. Shen, et al.
PhytochemistryLetters36(2020)68–72
preparative HPLC purification from crude product.
Yield: 14 % (two steps), Rf =0.2 (DCM:MeOH = 10:1), [α]eq \o(\s
\up 6(20),\s\do 2(= -16.7 (c = 0.050, CH3OH).
1H NMR (400 MHz, CD3OD) δ: 7.75 (d, J =8.1 Hz, 1 H), 5.92 (d, J
=5.2 Hz, 1 H), 5.69 (d, J =8.1 Hz, 1 H), 4.34-4.30 (m, 1 H), 4.17(t, J
=2.7 Hz, 1 H), 3.92 (t, J =2.3 Hz, 1 H), 3.64 (d, J =5.9 Hz, 1 H), 3.48
(s, 3 H).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the
online version, at https://doi.org/10.1016/j.phytol.2020.01.018.
References
13C NMR (101 MHz, CD3OD) δ: 166.4, 152.1, 143.1, 102.0, 92.0,
91.5, 90.3, 75.5, 62.8, 58.5.
Aksoy, S.C., Uzel, A., Bedir, E., 2016. Cytosine-type nucleosides from marine-derived
Streptomyces rochei 06CM016. J. Antibiot. (Tokyo) 69, 51–56.
Ban, J., Shabbir, S., Lim, M., Lee, B., Rhee, H., 2017. Synthesis of l-Ribose from d-Ribose
by a Stereoconversion through Sequential Lactonization as the Key Transformation.
Synthesis 49, 4299–4302.
ESI-TOF-MS: M/Z calculated for C10H14N2O6, [M+H]+: 259.0930,
found: 259.0936.
Delbaere, L.T.J., James, M.N.G., 1973. Crystal and molecular structure of 2,2’-anhydro-1-
β-D-arabinofuranosyluracil. Acta Crystallogr. Sect. B 29, 2905–2912.
Dienstag, J.L., Schiff, E.R., Wright, T.L., Perrillo, R.P., Hann, H.W.L., Goodman, Z.,
Crowther, L., Condreay, L.D., Woessner, M., Rubin, M., 1999. Lamivudine as initial
treatment for chronic hepatitis B in the United States. N. Engl. J. Med. 341,
1256–1263.
3.4. Synthesis of 2′-O-methyl-β-L-uridine (3)
2,2′-Anhydrouridine 12 (0.57 g, 2.5 mmol) was added to a freshly
prepared solution of 12 % magnesium methoxide (7 mL, 9.8 mmol) in
anhydrous methanol. The reaction mixture was refluxed under ni-
trogen. Once TLC monitoring showed disapperance of the starting
material, the reaction was quenched with sat. NH4Cl. After cooling, the
mixture was concentrated to dryness and the residue was purified by
column chromatography on silica gel to give nucleoside 3 as a white
solid (0.48 g, 75 %).
Ding, H., Li, W., Ruan, Z., Yang, R., Mao, Z., Xiao, Q., Wu, J., 2014. Concise total synthesis
of two marine natural nucleosides: trachycladines A and B. Beilstein J. Org. Chem.
10, 1681–1685.
Ding, H., Li, C., Dong, X., Cao, B., Zhang, N., Hong, S., Xiao, Q., 2018. First total synthesis
of marine natural nucleoside kipukasin d. Chinese J. Org. Chem. 38, 3351.
Ding, H., Ruan, Z., Kou, P., Dong, X., Bai, J., Xiao, Q., 2019. Total synthesis of mycalisine
B. Mar. Drugs 17, 226.
Ferrero, M., Goto, V., 2000. Chemoenzymatic transformations in nucleoside chemistry.
Monatsh. Chem. 131, 59–90.
Hu, C., Ruan, Z., Ding, H., Zhou, Y., Xiao, Q., 2017. An expedient total synthesis of
Triciribine. Molecules 22, 643.
Yield: 75 %, Rf = 0.3 (DCM:MeOH = 10:1), m.p. 158−159 °C, [α]
eq \o(\s\up 6(20),\s\do 2(= -44.0 (c = 0.050,CH3OH).
1H NMR (400 MHz, CD3OD) δ: 8.10 (d, J =8.1 Hz, 1 H), 5.94 (d, J
=3.4 Hz, 1 H), 5.69 (d, J =8.1 Hz, 1 H), 4.24 (t, J =5.6 Hz, 1 H), 4.04
– 3.94 (m, 1 H), 3.91-3.82 (m, 2 H), 3.74 (dd, J = 12.3, 2.6 Hz, 1 H),
3.52 (s, 3 H).
Jung, M.E., Nichols, C.J., Kretschik, O., Xu, Y., 1999. Synthesis and testing of new
modified nucleosides. Nucleosides Nucleotides Nucleic Acids 18, 541–546.
Li, C., Ding, H., Ruan, Z., Zhou, Y., Xiao, Q., 2017a. First total synthesis of kipukasin A.
Beilstein J. Org. Chem. 13, 855–862.
Li, X.-S., Tan, M.-H., Lv, M.-M., Liu, C.-X., Guo, Z.-Y., Zhang, L., Zou, K., Chen, H.-Y.,
Proksch, P., 2017b. New γ-pyranone and nucleoside derivatives from Penicillium sp.
Phytochem. Lett. 20, 285–288.
13C NMR (101 MHz, CD3OD) δ: 166.2, 152.1, 142.4, 102.5, 88.8,
86.1, 85.0, 69.7, 61.6, 58.8.
Li, H., Zhu, S., Zheng, G., 2018. Promiscuous (+)-γ-lactamase activity of an amidase from
nitrile hydratase pathway for efficient synthesis of carbocyclic nucleosides inter-
mediate. Bioorg. Med. Chem. Lett. 28, 1071–1076.
HRMS (ESI): M/Z calculated for C10H14N2O6, [M+H]+: 259.0930,
found: 259.0935.
Liu, J., Ingale, S.A., Seela, F., 2018. Guanine and 8-Azaguanine in anomeric DNA hybrid
base pairs: stability, fluorescence sensing, and efficient mismatch discrimination with
α-d-Nucleosides. Bioconjug. Chem. 29, 2265–2277.
Ma, T., Pai, S.B., Zhu, Y.L., Lin, J.S., Shanmuganathan, K., Du, J., Wang, C., Kim, H.,
Newton, M.G., Cheng, Y.C., 1996. Structure− activity relationships of 1-(2-Deoxy-2-
fluoro-β-l-arabino-furanosyl) pyrimidine nucleosides as anti-hepatitis B virus agents.
J. Med. Chem. 39, 2835–2843.
4. Conclusion
In summary, total synthesis of 2′-O-methyl-β-L-arabinosyluridine, 2′-
O-methyl-α-L-arabinosyluridine, and 2′-O-methyl-β-L-uridine were ac-
complished in present paper. The key intermediates were confirmed by
X-ray crystallography. The developed protocol for synthesis 2′-O-me-
thyl-β-L-arabinosyluridine and 2′-O-methyl-α-L-arabinosyluridine could
be extended to preparation other 2′-O-methyl-nucleosides. After de-
tailed comparison of their spectra, the nucleoside isolated from
Penicillium sp (64) was reassigned as 2′-O-methyl-β-L-uridine instead of
the reported 2′-O-methyl-β-L-arabinosyluridine. To the best of our
knowledge, this is the first reported naturally occurring L-nucleoside.
Studies on its biological activity and biosynthetic pathway in Penicillium
sp. (NO. 64) are undergoing.
Mehta, A.P., Abdelwahed, S.H., Fenwick, M.K., Hazra, A.B., Taga, M.E., Zhang, Y., Ealick,
S.E., Begley, T.P., 2015. Anaerobic 5-hydroxybenzimidazole formation from ami-
noimidazole ribotide: an unanticipated intersection of thiamin and vitamin B12
biosynthesis. J. Am. Chem. Soc. 137, 10444–10447.
Miah, A., Reese, C.B., Song, Q., Sturdy, Z., Neidle, S., Simpson, I.J., Read, M., Rayner, E.,
1998. 2’,3’-Anhydrouridine. A useful synthetic intermediate. J. Chem. Soc., Perkin
Trans. 1, 3277–3284.
Montaser, R., Luesch, H., 2011. Marine natural products: a new wave of drugs? Future
Med. Chem. 3, 1475–1489.
Patel, M.J., Akhani, R.C., Patel, A.T., Dedania, S.R., Patel, D.H.J., 2017. A single and two
step isomerization process for D-tagatose and L-ribose bioproduction using L-arabi-
nose isomerase and D-lyxose isomerase. Enzyme Microb. Technol. 97, 27–33.
Purdie, T., Irvine, J.C., 1903. C.—the alkylation of sugars. J. Chem. Soc.Trans 83,
1021–1037.
Remin, M., Shugar, D., 1973. Conformational analysis of cytidine, 1-beta-D-(arabinofur-
anosyl) cytosine and their O’-methyl derivatives by proton magnetic resonance
spectroscopy. J. Am. Chem. Soc. 95, 8146–8156.
Declaration of Competing Interest
Shioiri, T., Aoyama, T., Snowden, T., Lee, D., Gupta, S., 2001.
Trimethylsilyldiazomethane.
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
Shohda, K., Okamoto, I., Wada, T., Seio, K., Sekine, M., 2000. Synthesis and properties of
2’-O-methyl-2-thiouridine and oligoribonucleotides containing 2’-O-methyl-2-
thiouridine. Bioorg. Med. Chem. Lett. 10, 1795–1798.
Sivets, G.G., 2018. Regio- and stereoselective syntheses of L-pentose derivatives from L-
arabinose. Tetrahedron 74, 920–931.
Suck, D., Saenger, W., 1973. Crystal and molecular structure of O2,2’-cyclouridine.
Influence of O(2)-C(2’) cyclization on the sugar conformation of pyrimidine nucleo-
sides. Acta Crystallogr. Sect. B 29, 1323–1330.
Acknowledgements
Sun, Z., Zhu, Y., Huang, H., Song, X., Xiao, Q., 2016. Studies on the total synthesis of iso-
L-Cystidine. Chinese J Org. Chem. 36, 2729.
This work is supported by the National Natural Science Foundation
of China (No. 21676131 and No. 21462019), the Science Foundation of
Jiangxi Province (20161BAB213085, 20192BBHL80017), Education
Department of Jiangxi Province (GJJ170689, GJJ170672), and Jiangxi
Science & Technology Normal University (2017BSQD020). We also
thank Prof. Zhi-Yong Guo for providing the original NMR fid data of the
naturally occurring nucleoside.
Sweeney, J.B., Bethel, P.A., Gill, D.M., Ochocinska, A.M., Walsh, A.E.J., Walton, S.M.,
2019. Synthesis of a protected keto-lysidine analogue via improved preparation of
arabino-isocytosine nucleosides. Org. Lett. 21, 2004–2007.
Wang, P., Agrofoglio, L.A., Newton, M.G., Chu, C.K., 1999. Chiral synthesis of carbocyclic
analogues of L-ribofuranosides. J. Org. Chem. 64, 4173–4178.
Zhao, H., Bai, H., Jing, Y., Li, W., Yin, S., Zhou, H., 2017. A pair of taxifolin-3-O-arabi-
nofuranoside isomers from Juglans regia L. Nat. Prod. Res. 31, 945–950.
72