One-pot synthesis of azanucleosides from proline derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.11.113

Common cyclic amino acids, derived from proline and hydroxyproline, can be readily transformed into azanucleosides. The mildness of the reaction conditions, and the good yields obtained, make this procedure an interesting alternative to the conventional p

Full text of DOI:10.1016/j.tetlet.2007.11.113

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 455–458
One-pot synthesis of azanucleosides from proline derivatives
*
*
´
´
´
Alicia Boto , Dacil Hernandez, Rosendo Hernandez
Instituto de Productos Naturales y Agrobiologı´a CSIC, Avda. Astrofı´sico Fco. Sa´nchez 3, 38206-La Laguna, Tenerife, Spain
Received 21 August 2007; revised 2 November 2007; accepted 20 November 2007
Available online 24 November 2007
Abstract
Common cyclic amino acids, derived from proline and hydroxyproline, can be readily transformed into azanucleosides. The mildness
of the reaction conditions, and the good yields obtained, make this procedure an interesting alternative to the conventional processes.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Azanucleosides; Nucleoside analogues; Radical reactions; Decarboxylation; Iminium ions
The synthesis of nucleoside analogues has proven very
Ac
N
H
N
valuable to discover new antiviral, antibiotic, antifungal,
and antitumoral drugs. Both the base and the carbohydrate
chain have been modified: in the case of the azanucleosides,
the sugar ring oxygen has been replaced by a nitrogen func-
tion (Fig. 1).1,2
NH
O
O
N
NH
HO
HO
NH
N
O
HO
HO
OH
The heterocyclic ring can be attached to a nitrogen base
(N-azanucleosides) or to an aromatic ring (C-azanucleo-
sides). An example of the former is N-acetyl azathymidine
(1) (Fig. 1), which was incorporated to oligonucleotides to
decrease their degradation by 30-exonucleases.3 On the
other hand, immucillin-H (2) is a C-azanucleoside,4 which
is being studied to control T-cell proliferative disorders.
An intermediate example is the adenosine analogue 3 that
once incorporated to DNA (product 4), strongly inhibits
MutY, a glycosylase which repairs damaged DNA.5
In the present work, we will focus on the synthesis of N-
azanucleosides 5 (Scheme 1) from readily available amino
acids 6, using a combination of tandem and sequential pro-
cesses to achieve a one-pot transformation, avoiding inter-
mediate purifications. Such method would save time and
materials and would give access to many derivatives for
structure–activity studies.
N
-Azanucleoside
C
-Azanucleoside
N-Acetyl Azathymidine (1)
Immucillin-H (2)
NH2
N
N
H
N
3
4
R = H
R = DNA
N
N
RO
RO
Fig. 1. Azanucleoside families.
In previous articles,6 we have reported that on treatment
with (diacetoxy)iodobenzene (DIB) and iodine and visible
light irradiation, amino acids (such as 4-acetoxyproline
substrate 7, Scheme 2) undergo a radical decarboxylation
process. The resulting C-radical 8 probably reacts with
iodine giving an unstable a-iodopyrrolidine 9. Extrusion
of iodide generates an acyliminium ion 10, which can be
trapped by acetate ions from the reagent, affording the
*
Corresponding authors. Tel.: +34 922 260112; fax: +34 922 260135
(A.B.).
E-mail addresses: alicia@ipna.csic.es (A. Boto), rhernandez@ipna.
´
csic.es (R. Hernandez).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.113

456
A. Boto et al. / Tetrahedron Letters 49 (2008) 455–458
One-Pot
CO2Me
N
CO2Me
PhI(OAc)2, I2,
CH2Cl2, hν, rt,
Z
N
Z
N
Decarboxylation−
Base Addition
N
CO2H
OMe
B
CO2H
then MeOH, 1 h
B
AcO
AcO
(X)n
(X)n
6
13
B = pyrimidine or
purine base
7
5
X = H, OH, alkyl,
then volatiles ; MeCN,
O-alkyl, etc
.
0 ºC, BF3 OEt2
Z = acyl, CO2R
Scheme 1. Azanucleosides from proline derivatives.
CO2Me
N
CO2Me
N
+
CO2Me
H
B
N
B
B
AcO
+
F
H
PhI(OAc)2, I2,
CH2Cl2, hν, rt,
then 0 ºC,
AcO
AcO
MeO2C
N
CO2Me
N
O
14
12a, 15a−19a
12b, 15b−19b
CO2H
N
NH
(major)
(minor)
2
.
BF3 OEt2 or
O
4
Scheme 3. Optimized reaction conditions (see Table 1).
TMSOTf,
bis(trimethylsilyl)
fluorouracil
AcO
AcO
12a (2,4-cis
12b (2,4-trans
)
7
)
afforded azanucleosides 12a,b (5:3) in 92% yield (79% for
the two steps).
OTMS
N
Having optimized the two-step procedure, a one-pot
variation was developed. Thus, the scission of substrate 7
was carried out for 3 h, and then methanol was added.10
The N,O-acetal 13 was not isolated, but the solvent and
excess methanol were removed under vacuum and the
crude residue was redissolved in dry MeCN and treated
with bis(trimethylsilyl)-5-fluorouracil and BF3ꢀOEt2 at
0 °C. Under these conditions, products 12a,b were isolated
in good yield (78%, 12a,b 5:3). This one-pot procedure was
later applied to the other nucleophiles (see Table 1).
As shown in Scheme 3 and Table 1, the addition of the
silylated nitrogen bases to the acyliminium ion 14 gave sep-
arable mixtures of the 2,4-cis and 2,4-trans-azanucleosides.
Interestingly, the cis diastereomers 12a and 15a–19a pre-
dominated over trans isomers 12b and 15b–19b. We have
previously obtained similar results by using carbon
nucleophiles.6c,11
The scope of this procedure can be further expanded by
modification of the reaction conditions. When excess
iodine was added, and MeCN was used as the solvent both
in the scission and the base addition steps, a one-pot
scission–b-iodination–base addition process took place
(Scheme 4). The increased solvent polarity favored the
isomerization of the acyliminium intermediate 10 to the
encarbamate 20,12 which reacted with iodine generating a
second acyliminium ion 21, precursor of acetate 22. The
addition of boron trifluoride regenerated intermediate 21,
which was trapped by the base (bis(trimethylsilyl)-5-
fluorouracil), affording the iodinated 2,3-trans-3,4-trans
azanucleoside 23 (51%). Since the whole process involves
at least six reaction steps, each of them must take place
in excellent yield to account for the final results.
F
Lewis
acid
N
O TMS
CO2Me
CO2Me
N
I
CO2Me
N +
CO2Me
N
N
OAc
.
I2
AcO
AcO
AcO
AcO
9
8
10
11
Scheme 2. Synthesis of azanucleosides such as 12a,b.
unstable N,O-acetal 11.7 In the presence of a Lewis acid,
this acetal regenerates the acyliminium ion. We reasoned
that intermediate 10 could be trapped by silylated nitrogen
bases, affording N-azanucleosides (such as products 12a,b).
In a first approach, substrate 7 in CH2Cl2 was treated
with DIB and iodine, and the scission was carried out for
3 h; then bis(trimethylsilyl)-5-fluorouracil8 and BF3ꢀOEt2
were added. The reaction gave products 12a,b, although
in moderate yields (40–50%, 12a:12b, 5:3).
To improve the yields, different conditions were tried. A
two-step procedure was studied first (Scheme 3). Thus,
addition of methanol after the scission step generated a-
methoxypyrrolidine 13.9 This product is more stable than
the a-acetoxypyrrolidines, and could be isolated in 86%
yield.6c Then product 13 was redissolved (CH2Cl2 or
MeCN) and treated with the nitrogen base and a Lewis
acid (BF3ꢀOEt2 or TMSOTf) at different temperatures.
MeCN gave better results than CH2Cl2, BF3ꢀOEt2 proved
to be superior to TMSOTf, and the best temperature for
the addition was 0 °C. Thus, treating 13 with BF3ꢀOEt2
and bis(trimethylsilyl)-5-fluorouracil in MeCN at 0 °C,
This methodology allows to introduce an iodo group in
a previously non-functionalized position. The manipula-
tion of the halo function can generate a variety of azanucleo-

A. Boto et al. / Tetrahedron Letters 49 (2008) 455–458
457
Table 1
Azanucleosides 12a,b, and 15a/b–19a/b produced via Scheme 3
F
F
MeO
AcO
O
I
MeO
O
O
O
Productsa (%)
5% KOH,
MeOH, 1 h
Entry
Base
B
N
N
O
N
NH
N
NH
O
N
X
O
O
HN
O
24 (75%)
23
Scheme 5. Conversion of the b-iodo-pyrrolidine 23 into the epoxy
derivative 24.
1
2
3
Bis(TMS)-5-fluorouracil
Bis(TMS) thymine
Bis(TMS) uracil
X = F
X = Me
X = H
12a (49), 12b (29)
15a (48), 15b (39)
16a (59), 16b (30)
purified. After the aqueous work-up and solvent evapora-
tion, the residue was treated with 5% methanolic KOH giv-
ing epoxide 24 in better global yield (50%). Compound 24
can generate many other azanucleosides by epoxide cleav-
age with different nucleophiles.13
NHBz
N
4
5
Bis(TMS) cytosine
17a (54), 17b (27)
O
N
N
In a related example (Scheme 6), substrate 25 underwent
the one-pot scission–b-iodination–base addition process,
affording exclusively the 2,3-trans b-iodo-azanucleoside
26 (50%). When pure compound 26 was treated with meth-
anolic KOH, an intramolecular SN2 reaction took place,
affording the tricyclic derivative 27 in 73% yield (37% for
the two steps). Satisfactorily, the simplified scission–iodin-
ation–basic treatment protocol afforded compound 27 in
55% yield. To our knowledge, only one example of related
tricyclic azacompounds has been reported,14 and the bio-
logical activity was not studied. We are currently using this
protocol to prepare other derivatives and to study their
antiviral and antifungal properties.
The iodinated pyrrolidine 26 is also interesting as a pos-
sible precursor of unsaturated azanucleosides, which are
analogues of antiviral compounds such as stavudine
(D4T) or abacavir.15 The formation of olefinic azanucleo-
sides and their transformation into dihydroxylated or
amino hydroxylated azanucleosides2b,16 currently under
study, and will be reported in due time.
N
TMS-benzo triazole
18a (43), 18b (33)
19a (34), 19b (31)
N
OBn
N
N
N
6
TMS-benzyl oxypurine
N
a
Yields for products purified by chromatography on silica gel.
F
PhI(OAc)2, I2, hν,
CH3CN, rt, 3 h;
rt to 0 ºC,
MeO
AcO
O
MeO
O
O
N
N
CO2H
N
NH
2
.
BF3 OEt2,
O
4
AcO
I
bis(trimethylsilyl)
-5-fluorouracil
23 (51%)
7
F
OTMS
N
F
PhI(OAc)2, I2, hν,
CH3CN, rt, 3 h;
rt to 0 ºC,
MeO
O
MeO
O
.
BF3 OEt2
O
N
N
N
CO2H
N
NH
O−TMS
O
2
.
BF3 OEt2,
O
3
MeO
O
MeO
O
MeO
AcO
O
MeO
AcO
I
bis(trimethylsilyl)
-5-fluorouracil
+
+
N
( )-26 (50%)
( )-25
N
N
N
OAc
I2
5% KOH,
Refs.
13,15
AcO
AcO
I
Simplified
procedure
I
MeOH, 1 h,
73%
10
20
21
22
55%
Unsaturated
Scheme 4. Synthesis of b-iodo-pyrrolidines such as 23.
MeO
O
azanucleosides
F
sides to study structure–activity relationships. For instance,
when compound 23 was treated with 5% methanolic KOH
(Scheme 5), the acetate was hydrolyzed, and the epoxy
derivative 24 was formed (75%; 38% from amino acid 7).
In a simplified version of this process, the scission–iodin-
ation was carried out but iodoazanucleoside 23 was not
N
Ref. 16
N
O
N
O
3,4-disubstituted
azanucleosides
( )-27
Scheme 6. Synthesis of tricyclic compound 27.

458
A. Boto et al. / Tetrahedron Letters 49 (2008) 455–458
5. (a) Deng, L.; Scharer, O. D.; Verdine, G. L. J. Am. Chem. Soc. 1997,
In summary, this work illustrates how readily available
119, 7865–7866. For related examples, see: (b) Mayer, A.; Ha¨berli, A.;
Leumann, C. J. Org. Biomol. Chem. 2005, 3, 1653–1658; (c) Ha¨berli,
A.; Leumann, C. J. Org. Lett. 2002, 4, 3275–3278.
substrates can be directly converted into potential drugs
by combination of tandem and sequential processes. Thus,
proline and hydroxyproline derivatives were transformed
into azanucleosides, using a one-pot fragmentation–base
addition process. The method is versatile, and allows the
introduction of an iodo group in previously non-function-
alized positions. The manipulation of the halo substituent
can generate new compounds to study structure–activity
relationships; thus, the iodinated azanucleosides were
transformed into epoxy and fused tricyclic derivatives.
´
´
´
6. (a) Boto, A.; Hernandez, D.; Hernandez, R.; Montoya, A.; Suarez, E.
´
Eur. J. Org. Chem. 2007, 325–334; (b) Boto, A.; De Leon, Y.;
´
Gallardo, J. A.; Hernandez, R. Eur. J. Org. Chem. 2005, 3461–3468;
(c) Boto, A.; Herna´ndez, R.; Sua´rez, E. J. Org. Chem. 2000, 65, 4930–
4937. For a review, see: (d) Hansen, S. G.; Skrydstrup, T. Top. Curr.
Chem. 2006, 264, 135–162.
7. Although the a-acetoxy amides are usually unstable and decompose
during isolation, we have been able to purify an a-acetoxyglycine
derived from the fragmentation of serine derivatives: (a) Boto, A.;
´
´
Gallardo, J. A.; Hernandez, D.; Hernandez, R. J. Org. Chem. 2007,
72, 7260–7269; Acetoxy acetals are also formed during the radical
Acknowledgments
´
fragmentation of carbohydrates: (b) Boto, A.; Hernandez, D.;
´
´
Hernandez, R.; Suarez, E. J. Org. Chem. 2003, 68, 5310–5319.
8. The nucleophiles were prepared from commercial bases (5-fluoroura-
cil, thymine, uracil, benzoylcytosine, benzotriazole, and benzyloxy-
This work was supported by the Research Programs
PPQ2003-01379 and CTQ2006-14260/PPQ (Plan Nacional
purin) according to Vorbruggen protocol: (a) Vorbruggen, H. Acta
¨
¨
´
´
´
de Investigacion Cientıfica, Desarrollo e Innovacion Tec-
Biochem. Pol. 1996, 43, 25–36; (b) Drew, M. G. B.; Gorsuch, S.;
Gould, J. H. M.; Mann, J. J. Chem. Soc., Perkin Trans. 1 1999, 969–
978.
´
´
nologica, Ministerios de Ciencia y Tecnologıa y de Educa-
´
cion y Ciencia, Spain). We also acknowledge financial
support from FEDER funds. D.H. thanks the Ministerio
9. (a) The a-methoxypyrrolidine 13 was obtained as a diastereomer
mixture (2,4-cis:2,4-trans, 1:1). For examples on the generation of a-
methoxy nitrogen heterocycles by electrochemical methods, see: (b)
Shono, T. Tetrahedron 1984, 40, 811–850; (c) Matsumura, Y.; Kanda,
Y.; Shirai, K.; Onomura, O.; Maki, T. Tetrahedron 2000, 56, 7411–
7422; (d) Kardassis, G.; Brungs, P.; Steckhan, E. Tetrahedron 1998,
54, 3471–3478; (e) Shono, T.; Matsumura, Y.; Onomura, O.; Sato, M.
J. Org. Chem. 1988, 53, 4118–4121; (f) Nishitani, T.; Horikawa, H.;
Iwasaki, T.; Matsumoto, K.; Inoue, I.; Miyoshi, M. J. Org. Chem.
1982, 47, 1706–1712.
10. The addition of methanol improved the yields. When it was omitted,
(the other conditions remaining the same) the products were isolated
in lower yields (50–55%).
11. For a related example, see: (a) Renaud, P.; Seebach, D. Helv. Chim.
Acta 1986, 69, 1704–1710. For a related acyliminium intermediate,
see: (b) Durand, J.-O.; Larcheveˆque, M.; Petit, Y. Tetrahedron Lett.
1998, 39, 5743–5746.
´
de Educacion y Ciencia for a FPU fellowship and Gobi-
´
erno de Canarias (Consejerıa de Industria)-CSIC for a
research contract.
Supplementary data
General procedure for the one-pot fragmentation–base
addition reaction, spectroscopic data of compounds 12a,
12b, 23, 24, 26, and 27. Supplementary data associated with
this article can be found, in the online version, at doi:
10.1016/j.tetlet.2007.11.113.
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