An efficient chemical synthesis of nicotinamide riboside (NAR) and analogues

Article abstract of DOI:10.1016/S0960-894X(02)00125-7

A simple and efficient synthesis of nicotinamide riboside (NAR) 1 and derivatives 4 and 5 via trimethylsilyl trifluoromethanesulfonate (TMSOTf)-mediated N-glycosilation followed by spontaneous deacetylation by treating with methanol is reported.

Full text of DOI:10.1016/S0960-894X(02)00125-7

Bioorganic & Medicinal Chemistry Letters 12 (2002) 1135–1137
An Efficient Chemical Synthesis of Nicotinamide Riboside
(NAR) and Analogues
Shinji Tanimori,* Takeshi Ohta and Mitsunori Kirihata
Department of Applied Biological Chemistry, Graduate School of Agriculture and Life Sciences, Osaka Prefecture University,
1
-1 Gakuen-cho, Sakai, Osaka 599-8531, Japan
Received 17 December 2001; accepted 22 February 2002
Abstract—A simple and efficient synthesis of nicotinamide riboside (NAR) 1 and derivatives 4 and 5 via trimethylsilyl tri-
fluoromethanesulfonate (TMSOTf)-mediated N-glycosilation followed by spontaneous deacetylation by treating with methanol is
reported. # 2002 Elsevier Science Ltd. All rights reserved.
Nicotinamide riboside (NAR) 1 is important as a pre-
cursor of nicotinamide mononucleotide (b-NMN) 10,
which is a component for both chemical and enzy-
deacetylation on treatment with methanol as the key
steps.
1
2
matic preparation of nicotinamide adeninedinucleotide
+
The synthesis of NAR started from commercially avail-
able b-d-ribofuranose 1,2,3,5-tetraacetate 6 (Scheme 1).
Reaction of 6 with nicotinamide in the presence of
TMSOTf in acetonitrile at room temperature for 1 h
+
(
NAD ) 2. The importance of NAD and derivatives
+
such as NADP , NADH, and NADPH as coenzymes
for cellular oxidation and reduction reactions is well
3
+
1
known. In addition, NAD has been shown to be the
precursor to cyclic ADP-ribose (cADPR) 3, a newly
followed by the addition of methanol produced N -(b-
d-ribofuranosyl)-3-aminocarbamoylpyridinium triflate
1 via triacetate 9 (not isolated). The N-glycoside 1 thus
obtained contained upto 13% of the a-anomer as
2
+
discovered general mediator involved in Ca
signal-
4
ing. Although there are numerous cADPR analogues
synthesized previously due to their biological impor-
tance, to our knowledge, few examples concerning N-1-
1
determined by H NMR spectroscopy. The a-anomer
was removed by chromatography on activated charcoal
and crystallization to give b-1 in 58% isolated yield.
Along the same reaction pathway, the xylose and ara-
5
glycosidic derivatives have been reported. To obtain
these compounds, there was need for a reliable, prac-
tical synthesis of b-NMN and derivatives. Three essen-
tially different pathways to the preparation of b-NMN
1
0
binose derivatives (b-4 and a,b-mixture of 5 ) were also
prepared starting from the corresponding tetraacetate 7
+
6
11
are known: (i) enzymatic degradation of NAD ,
(a/b=33:67) and 8 (a/b=63:37) in 67 and 78% yield,
1
(
trophenyl)-3-aminocarbonylpyridinium halogenides,
ii) condensation of 1-amino sugars with N -(2,4-dini-
7
respectively (Scheme 2). In the latter case, the a-
anomeric isomer was predominantly produced (a/
b=61:39) due to neighboring group participation and
the mixture was not separable by chromatography on
activated charcoal.
and (iii) condensation of peracylated halo sugars with
8
nicotinamide. The biological process is not suitable
for analogue synthesis. The chemical synthesis using
halo sugars and/or 1-amino sugars was inefficient due to
their instability. We describe here a simple and efficient
synthesis of NAR 1 and its xylose and arabinose
derivatives 4 and 5 using trimethylsilyl trifluoro-
Thus, a simple and efficient method for the chemical
synthesis of NAR and derivatives via TMSOTf-medi-
ated N-glycosilation followed by spontaneous deacety-
lation by treating with methanol has been revealed in
one-pot manner. Synthetic studies of other NAR
9
methanesulfonate (TMSOTf)-mediated N-glycosilation
of tetraacetate 6, 7 and 8 followed by spontaneous
+
derivatives directed toward the synthesis of NAD
analogues for the enzymatic studies of ADP-ribosyl-
4
cyclase and NAD glycohydrolase are currently under
investigation.
*
9
Corresponding author. Tel.: +81-722-54-9469; fax: +81-722-54-
918; e-mail: tanimori@biochem.osakafu-u.ac.jp
0
960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00125-7

1136
S. Tanimori et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1135–1137
Typical Experimental Procedure
colorless syrupafter removal of the solvent. The syrup
was dissolved in minimum amount of methanol and
then ethyl acetate was added to produce b-1 (0.15 g,
58%) as a white solid. R =0.41 (n-BuOH/H O/
Synthesis of 3-(N-D-ribofuranosylcarbamoyl)pyridinium
triflate (ꢀ-1). To a stirred solution of tetraacetate 6 (0.2
g, 0.63 mmol) and nicotinamide (86 mg, 0.70 mmol) in
dry acetonitrile (5 mL), TMSOTf (1.0 mL, 5.17 mmol)
was added dropwise at room temperature and the mix-
ture was stirred for 1 h at the same temperature.
Methanol (2.5 mL) was added to the mixture and stirred
for 30 min, then the solvent was evaporated in vacuo.
The residue was chromatographed on activated char-
coal (eluted with H O to 10% MeOH in H O) to give a
f
2
ꢀ
1
AcOH=5:3:2); IR nmax cm : 3410, 3101, 2934, 2112,
1739, 1698, 1639, 1591, 1553, 1411, 1229, 1167, 1100,
1
1032, 913, 840, 763, 679, 642, 577, 520; H NMR d
(D O): 9.23 (1H, s, H-2), 8.96 (1H, d, J=6.1 Hz, H-4),
8.81 (1H, d, J=7.9 Hz, H-6), 8.06 (1H, dd, J=6.7, 7.6
2
0
Hz, H-5), 5.70 (1H, d, J=8.9 Hz, H-1 ), 4.13–4.08 (1H,
m, H-2 ), 3.96–3.87 (2H, m, H-3 , H-4 ), 3.78 (1H, dd,
0
J=12.2, 12.5 Hz, H-5 ), 3.63 (1H, dd, J=2.6, 9.0 Hz,
0
0
0
0
+
H-5 ); TOF-MS (DHBA): m/z 255.2 ([MꢀOTf] ).
2
2
Scheme 1.
Scheme 2.

S. Tanimori et al. / Bioorg. Med. Chem. Lett. 12 (2002) 1135–1137
1137
3
4
-(N-D-Xylofuranosylcarbamoyl)pyridinium triflate (ꢀ-
1
References and Notes
). R =0.32 (n-BuOH/H O/AcOH=5:3:2); H NMR d
1. For a general survey, see: Jeck, R.; Woenckhaus, C. In
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Academic: New York, 1979; Vol. 66, p62.
. Suhadolnik, R. J.; Lennon, M. B.; Uematsu, T.; Monahan,
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3. For a comprehensive review, see: Woenckhaus, C. Top.
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f
2
(
D O): 9.33 (1H, s, H-2), 8.99 (1H, d, J=6.1 Hz, H-4),
2
8.82 (1H, d, J=8.8 Hz, H-6), 8.10 (1H, dd, J=7.0, 7.3
0
Hz, H-5), 5.58 (1H, d, J=8.5 Hz, H-1 ), 4.12 (1H,
dd, J=5.4, 11.5 Hz, H-2 ), 3.64–3.85 (1H, m, H-4 ),
3
2
2
0
.54–2.95 (3H, m, H-3 , H-5 ); TOF-MS (DHBA): m/z
0
0
0
+
54.6 ([MꢀOTf] ).
4
3
-(N-D-Arabinofuranosylcarbamoyl)pyridinium triflate
a,b-5). R =0.38 and 0.27 (n-BuOH/H O/
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5
(
1999, 7, 653.
f
2
1
6. Takei, S. Agric. Biol. Chem. 1970, 34, 23.
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2
9
.22 (0.4H, s, H-2), 9.03–8.97 (1H, m, H-4), 8.83 (0.4H,
d, J=7.9 Hz, H-6), 8.75 (0.6H, d, J=5.3 Hz, H-6), 8.09
(
8
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0.6H, dd, J=7.0, 7.3 Hz, H-5), 8.00 (0.4H, dd, J=7.3,
.3 Hz, H-5), 6.16 (0.4H, d, J=3.1 Hz, H-1 ), 5.52
0
0.6H, d, J=8.5 Hz, H-1 ), 4.46 (0.4H, dd, J=5.4, 8.7
Akhrem, A. A. Synthesis 1981, 388. Lee, J.; Churchil, H.;
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7
(
0
Hz, H-4 ), 4.32 (0.6H, dd, J=3.4, 4.3 Hz, H-4 ), 4.13–
0
.05 (1H, m, H-2 ), 3.88 (0.6H, s, H-3 ), 3.83 (0.4H, s, H-
0
9
1
0
0
4
3
0
0
0
), 3.79–3.70 (1H, m, H-5 ), 3.69–3.60 (1H, m, H-5 );
+
N. J. Biochemistry 1987, 26, 3453.
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TOF-MS (DHBA): m/z 255.9 ([MꢀOTf] ).