One-pot synthesis of azanucleosides from proline derivatives stereoselectivity in sequential processes

Article abstract of DOI:10.1002/ejoc.201000360

Common amino acid derivatives can be transformed in onestep fashion into N-azanucleosides. The method is a sequential process initiated, by a domino radical decarboxylation/ oxidation reaction; an acyliminium ion is formed as an intermediate and can be trapped by nitrogen bases (purines, pyrimidines, and benzotriazole). The mildness of the reaction conditions and the good, yields obtained make this procedure an interesting alternative to the conventional processes. Good stereoselectivities were obtained with 4-(silyloxy)proline derivatives as substrates.

Full text of DOI:10.1002/ejoc.201000360

FULL PAPER
DOI: 10.1002/ejoc.201000360
One-Pot Synthesis of Azanucleosides from Proline Derivatives –
Stereoselectivity in Sequential Processes
Alicia Boto,*[a] Dácil Hernández,[a] and Rosendo Hernández*[a]
Keywords: Radical reactions / Sequential processes / Amino acids / Nucleosides / Nitrogen heterocycles
Common amino acid derivatives can be transformed in one-
step fashion into N-azanucleosides. The method is a sequen-
tial process initiated by a domino radical decarboxylation/
oxidation reaction; an acyliminium ion is formed as an inter-
mediate and can be trapped by nitrogen bases (purines, pyr-
imidines, and benzotriazole). The mildness of the reaction
conditions and the good yields obtained make this procedure
an interesting alternative to the conventional processes.
Good stereoselectivities were obtained with 4-(silyloxy)pro-
line derivatives as substrates.
resulted in strong inhibition of their degradation by 3Ј-ex-
onucleases.[3] Compound 2, on the other hand, was found
to inhibit the vaccinia virus,[4] whereas the C-azanucleoside
immucilin-H (3) prevented the uncontrolled proliferation of
T-cells.[5] The isoxazolidine 4 was an efficient anti-HIV
agent, comparable to AZT in potency, but with low levels
of cytotoxicity.[6]
Recently we have started to study N-azanucleosides of
structures 5 and 6 (Figure 2) in order to find new pharma-
cological leads. In the case of compounds 5, the nitrogen
protecting group (such as certain acyl or amino acyl units)
could be removed in vivo, giving unstable derivatives which
could release a cytotoxic base (such as fluorouracil). In the
case of compounds 6, the hydroxy group on C-4 could be
phosphorylated and incorporated into oligonucleotides.
Chain extension of the nucleic acids would then be blocked,
because these compounds do not possess a second anchor-
ing unit.[1]
Introduction
In the search[1] for new antiviral, antitumor, and antifun-
gal agents, azanucleosides (Figure 1) have recently received
considerable attention. In these nucleoside analogues, the
furanose sugar is replaced by a nitrogen heterocycle; occa-
sionally, additional heteroatoms have been introduced. The
base has also been modified, and its position on the ring
has been shifted.[2]
Figure 1. Nucleoside analogues.
Figure 2. Target nucleoside analogues.
The work in this area has provided compounds with po-
tent biological activities. The incorporation of N-acetyl aza-
thymidine 1 (Figure 1) into oligonucleotides, for instance,
In previous works we have reported one-pot transforma-
tions of the proline derivatives 7 (Scheme 1) into the 2-sub-
stituted pyrrolidines 8,[7] via the acyliminium ions 9,
through domino radical fragmentation/oxidation reactions
coupled with the addition of nucleophiles. The process took
place in good yields and under very mild conditions. These
[a] Instituto de Productos Naturales y Agrobiología del CSIC,
Avda. Astrofísico Francisco Sánchez 3, 38206 La Laguna,
Tenerife, Spain
Fax: +34-922260135
E-mail: alicia@ipna.csic.es, rhernandez@ipna.csic.es
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A. Boto, D. Hernández, R. Hernández
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one-pot conversions[8] avoided the need for purification of
reaction intermediates, saving time and materials with re-
spect to other reported methods and reducing waste.
Scheme 1. One-pot conversions of proline derivatives into 2-substi-
tuted pyrrolidines.
Scheme 2. Conversion of the proline carbamate 10 into the azanu-
cleoside 12.
We reasoned that the addition of silylated nitrogen bases
to the acyliminium intermediates 9 should afford the de-
sired azanucleosides. The feasibility of this approach, with
use of model systems, is reported here.
ative 13 could be purified by chromatography and com-
pletely characterized. Once the N,O-acetal 13 was available,
it was used to optimize the addition of the nitrogen bases.
The best conditions were found for MeCN as the solvent,
BF3·OEt2 as the Lewis acid, and 0 °C as the addition tem-
perature, affording 12 in 99% yield.
Results and Discussion
Development of the Radical Scission/Oxidation/Addition of
Nitrogen Bases Reactions
We then returned to the development of the one-pot pro-
The one-pot scission/oxidation/addition of nitrogen cess. After considerable experimentation, it was found that
bases processes were explored with a proline-derived carb- the best solvent for the scission step was CH2Cl2, whereas
amate, N-(methoxycarbonyl)proline (10)[9] (Scheme 2), the best solvent for the addition step was MeCN. The ad-
which was treated with (diacetoxyiodo)benzene (DIB)[10] dition of methanol after the scission was also necessary to
and iodine at room temperature in the presence of visible obtain good yields; the alcohol probably deactivated excess
light (sunlight or tungsten-filament lamps).[11] Under these reagents (DIB/I2) from the scission step, and at the same
conditions, radical decarboxylation took place,[7] followed time generated the stable acetal 13. Finally, BF3·OEt2 again
by oxidation to the acyliminium intermediate 9a. This acyl- proved superior to TMSOTf as the Lewis acid.
iminium ion exists in equilibrium with the N,O-acetal 11,[12]
In the optimized one-pot procedure (Table 1), the scis-
as a result of the addition of acetate ions from DIB. On sion of the substrate 10 was carried out at room tempera-
addition of Lewis acids (BF3·OEt2 or TMSOTf), the acyl- ture in CH2Cl2 as solvent. Methanol was added after 3 h,
iminium ion was regenerated, and reacted with bis(tri- generating the N,O-acetal 13, which was not isolated. The
methylsilyl)fluorouracil[13,14] to afford the product 12.
solvent was removed under vacuum and replaced with
Several sets of reaction conditions were tried, with MeCN. The reaction mixture was then cooled to 0 °C, and
CH2Cl2 or MeCN as solvents, and with variation of the BF3·OEt2 and the nucleophile were added, affording the N-
reaction times and temperatures, but only moderate yields azanucleoside 12 in good yield (80%). The optimized condi-
were obtained (50–55%). In order to improve these results, tions were later applied with other silylated pyrimidine
the scission/oxidation reaction and the addition of nitrogen bases (Table 1). Some were derived from common pyrimid-
bases were studied separately (Scheme 2). In this approach, ines (uracil, thymine, cytosine); 5-iodouracil was also se-
the substrate 10 underwent the scission/oxidation reaction, lected, because the introduction of a halogen often results
and the N,O-acetal 11 was converted into the more stable in interesting biological activities[1g] and the iodo group can
α-methoxy pyrrolidine 13[15] by treatment with methanol also be replaced by other functionalities (through spn–spn
(80%). Unlike the acetoxy derivative 11, the methoxy deriv- couplings, radical reactions, etc.).[16]
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Azanucleosides from Proline Derivatives
Table 1. One-pot conversion of proline derivatives into azanucleos- fungicide agents.[19] The chosen purine bases were 6-chlo-
ides with pyrimidine bases.
ropurine, 6-benzyloxypurine, and N-benzyladenine. As has
been commented on before, the chloro group in 6-chloro-
purine is replaceable by other groups (amino, aryl, alkyl,
etc.)[16] affording collections of compounds.
Table 2. One-pot conversions of proline derivatives into azanucleos-
ides with purine bases.
[a] Base A: bis(trimethylsilyl)-5-fluorouracil; base B: bis(trimethyl-
silyl)-5-iodouracil; base C: bis(trimethylsilyl)thymine; base D: bis-
(trimethylsilyl)uracil; base E: bis(trimethylsilyl)-N-(benzoyl)cytos-
ine. [b] Yields of products purified by column chromatography.
[a] Base F: (trimethylsilyl)benzotriazole; base G: (trimethylsilyl)-6-
chloropurine; base H: (trimethylsilyl)-6-benzyloxypurine; base I:
bis(trimethylsilyl)-N-benzyladenine. [b] Yields of products purified
by column chromatography.
The sequential process was also studied with the hy-
droxyproline derivative 14 (Table 1).[9] Interestingly, the re-
action afforded the 2,4-cis diastereomers[17] as the major
products, as discussed later.
The one-pot method provided good overall yields of the
The scission/addition products 12 and 15–27 were ob- desired azanucleosides 28–38, even with the adenine deriva-
tained in good to excellent yields, and in the case of the 4- tives. When the hydroxyproline derivative 14 was used as
hydroxyazanucleosides the cis and trans diastereomers were substrate, the reactions gave mixtures of the 2,4-cis and 2,4-
usually readily separated by column chromatography.
trans azanucleosides, which in most cases were readily sepa-
The process was also studied with silylated derivatives of rated. Whereas the smaller pyrimidine bases gave a certain
benzotriazole and purine bases as nucleophiles diastereoselectivity, benzotriazole and the purine bases af-
(Table 2).[13,18] Benzotriazole was selected because several forded 1:1 mixtures of diastereomers. The stereoselectivity
triazolyl nucleosides are potent cytotoxic, antiviral, and of the reaction is discussed below.
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Stereoselectivity of the Scission/Oxidation/Addition of
Nitrogen Bases Processes
When bulkier bases are used, the repulsive interactions
between the nucleophile entering from the inner face and
the 4-alkoxy group increase, and as a result, the stereoselec-
tivity decreases.[22]
The scission/oxidation/addition procedure was also car-
ried out with the substrates 42–45[23] (Table 3), in order to
determine the influence of the protecting group R on the
stereoselectivity. The results obtained with bis(trimethyl-
silyl)fluorouracil as the nucleophile were compared with the
conversion 14Ǟ15+16.
Interestingly, in those cases in which stereoselectivity is
observed (pyrimidine derivatives), the major products are
not the 2,4-trans compounds, but the more hindered 2,4-
cis isomers (cis/trans ratios from 1.5:1 to 2:1). A plausible
explanation can be found in Woerpel’s model for the ad-
dition of nucleophiles to cyclic oxycarbenium and acyl-
iminium ions.[20]
According to this model, the addition of nucleophiles to
C4-substituted, five-membered-ring iminium or oxycarben-
ium ions (intermediates 39, Scheme 3) is stereoselective and
the preferred face for the addition depends on the nature of
the substituent. In the case of 4-alkoxyl groups, the pre-
ferred envelope conformation is 39b, with a pseudoaxial
substituent, allowing stabilizing electrostatic interactions
between the oxygen lone electron pairs and the iminium
ion.
Table 3. Influence of the R group on the stereoselectivity of the
scission/oxidation/addition procedures.
Scheme 3. Stereoselectivity in the addition of nucleophiles to 4-sub-
stituted cyclic acyliminium or oxycarbenium ions.
As shown in Table 3, the processes took place with good
overall yields, affording the azanucleosides 46–53. A re-
The nucleophile adds preferentially from the inner face, markable increase in stereocontrol was achieved with R =
to avoid eclipsing interactions on the formation of the prod- TBS (78%, cis/trans 5:1), whereas increasing the volume of
uct. The addition generates a staggered structure 40 (2,4-cis the protecting group decreased both the yield and the
product) in which the substituents at C-2 and C-3 are not stereoselectivity (52%, 3:1 ratio for R = TBDPS). With the
eclipsed. The addition of the nucleophile from the outer acyl protecting groups, the best results corresponded to R
face of intermediate 39b is disfavored, due to the eclipsing = Ac (77%, cis/trans 1.7:1); a lower yield and stereoselecti-
interactions developed between the substituents at C-2 and vity were observed for R = Bz (67%, cis/trans 1.5:1), and
C-3 in the transition structure leading to the initially no stereoselectivity was achieved when R = Piv (57%,
formed trans product 41.[20,21]
cis/trans 1:1).
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Azanucleosides from Proline Derivatives
General Procedure for the One-Pot Scission/Oxidation/Base Ad-
dition Sequence: Iodine (25 mg, 0.1 mmol) and (diacetoxyiodo)ben-
zene (DIB, 129 mg, 0.4 mmol) were added to a solution of the pro-
line substrate 10 or the acetoxyproline substrate 14 (0.2 mmol) in
dry CH2Cl2 (2 mL). The reaction mixture was stirred at 25 °C for
3 h under irradiation with visible light (80 W tungsten-filament
lamp). MeOH was then added (0.25 mL) and the stirring was con-
tinued for 30 min. The solvent was removed under vacuum and the
residue was redissolved in dry CH3CN (2 mL). The solution was
cooled to 0 °C and freshly prepared silylated base (0.4 mmol) was
It should be noted that the stereoselectivity achieved
when R = Ac is lower than that seen with the bulkier silyl
protecting groups TBS and TBDPS. One possible explana-
tion is that the electron-donating silyl group favors the elec-
trostatic stabilization of the pseudoaxial conformer 39b, in-
creasing its population. In fact, it is known that when sub-
stituted benzoates are used as protecting groups, the stereo-
selectivity is related to the electron-withdrawing or electron-
donating natures of the substituents. A decrease in the elec-
tron density at the oxygen atom (EWG-BzO) leads to a de- injected, followed by dropwise addition of BF3·OEt2 (51 µL,
crease in the stereoselectivity.[20c,20g] On the other hand, the
0.4 mmol). After having been stirred for 1 h, the mixture was
poured into aqueous sodium thiosulfate (10%) and saturated aque-
longer length of the Si–O bond with respect to the C–O
ous NaHCO3 (1:1) and extracted with dichloromethane. The or-
bond would reduce the steric stress in the inner attack tran-
ganic layer was dried with Na2SO4 and filtered, and the solvents
sition state.
were evaporated under vacuum. The residue was purified by
Partial blockage of the inside face by neighboring ester
chromatography on silica gel (hexanes/EtOAc), to afford the azanu-
group participation is less likely but cannot be ruled out
cleosides.
completely.[24] Further studies will be carried out to address
5-Fluoro-1-[N-(methoxycarbonyl)-2-pyrrolidinyl]uracil (12): This
compound was obtained as a racemic mixture from N-(meth-
oxycarbonyl)--proline (10) and bis(trimethylsilyl)-5-fluorouracil
(80%); crystalline solid; two rotamers at 26 °C (9:1), one rotamer
this point. In any case, both steric and electronic effects
seem to influence the stereoselectivity of the process.
Finally, the development of this procedure for the direct
conversion of proline derivatives into azanucleosides has
opened the way to the creation of libraries of azanucleos-
ides 5 with different N-protecting groups (acyl, aminoacyl),
as well as the 4-hydroxyazanucleoside derivatives 6 with
a variety of O-protecting groups [such as phosphate,
(CH2)nP(O)(OMe)2, etc.]. These derivatives are currently
being prepared, in order to study structure/activity relation-
ships, as will be reported in due course.
at 70 °C; m.p. 248–250 °C (from MeOH, decomposition). 1H NMR
(500 MHz, DMSO, 70 °C): δH = 1.80–2.00 (m, 3 H), 2.26 (dddd, J
= 7.5, 7.9, 8.5, 13.2 Hz, 1 H), 3.42 (ddd, J = 7.4, 7.8, 10.1 Hz, 1
H), 3.61 (s, 3 H), 3.63–3.76 (m, 1 H), 5.90 (dd, J = 2.0, 6.5 Hz, 1
H), 7.76 (d, JF,H = 7.0 Hz, 1 H) ppm. 13C NMR (125.7 MHz,
DMSO, 70 °C): δC = 21.5 (CH2), 31.3 (CH2), 46.5 (CH2), 52.0
(CH3), 70.4 (CH), 124.8 (d, JC,F = 33.6 Hz, CH), 139.3 (d, JC,F
=
230.4 Hz, C), 148.3 (C), 153.9 (C), 156.5 (d, JC,F = 26.0 Hz,
C) ppm. IR (film): ν = 3441, 1692, 1674, 1197, 1102 cm–1. MS (EI,
˜
70 eV): m/z (%) = 226 (1) [M – OMe]+, 128 (100) [M + H – 5-
fluorouracil]+. HRMS (EI, 70 eV): calcd. for C9H9FN3O3
226.0628; found 226.0620; calcd. for C6H10NO2 128.0712; found
128.0651. C10H12FN3O4 (257.22): calcd. C 46.70, H 4.70, N 16.34;
found C 46.98, H 4.85, N 15.93.
Conclusions
In conclusion, readily available proline derivatives can be
directly transformed into N-azanucleosides by processes in-
volving radical scission/oxidation/addition of nitrogen
bases. The reactions proceed in good yields and under mild
conditions, and allow the introduction of a variety of purine
and pyrimidine bases, as well as benzotriazole.
1-[(2R,4R)- and 1-[(2S,4R)-4-Acetoxy-N-(methoxycarbonyl)-2-pyr-
rolidinyl]-5-fluorouracil (15 and 16): These compounds were ob-
tained from (4R)-4-acetoxy-N-(methoxycarbonyl)--proline (14)
and bis(trimethylsilyl)-5-fluorouracil as a separable diastereomer
mixture (chromatography on silica gel, hexanes/EtOAc, 7:3).
When 4-hydroxyproline derivatives and pyrimidine bases
are used as substrates and bases, respectively, the processes
afford mainly the 2,4-cis azanucleosides, due to stereoelec-
tronic effects. With use of appropriate O-protecting groups,
satisfactory stereoselectivities were achieved. In this way,
relatively inexpensive substrates can afford a variety of aza-
nucleosides for study of structure/activity relationships.
Product 15: Colorless oil (48%); two rotamers at 26 °C (9:1), one
rotamer at 70 °C. [α]D = +80.5 (c = 0.48, CH3OH). 1H NMR
(500 MHz, CDCl3, 70 °C): δH = 2.01 (s, 3 H), 2.25 (d, J = 15.6 Hz,
1 H), 2.61 (ddd, J = 5.4, 7.6, 15.5 Hz, 1 H), 3.75 (s, 3 H), 3.77 (d,
J = 12.7 Hz, 1 H), 3.80 (dd, J = 4.0, 12.3 Hz, 1 H), 5.34–5.38 (m,
1 H), 6.16 (d, J = 7.7 Hz, 1 H), 7.43 (d, JF,H = 6.5 Hz, 1 H) ppm.
13C NMR (125.7 MHz, CDCl3, 26 °C): δC = 20.7 (CH3), 38.7
(CH2), 53.5 (CH3), 54.0 (CH2), 70.3 (CH), 71.3 (CH), 124.0 (d,
JC,F = 35.1 Hz, CH), 140.3 (d, JC,F = 237.6 Hz, C), 149.1 (C), 154.8
(C), 156.8 (d, JC,F = 26.5 Hz, C), 169.4 (C) ppm. IR (CHCl ): ν =
˜
3
3377, 3192, 1703, 1668, 1266, 1237 cm–1. MS (EI, 70 eV): m/z (%)
= 315 (Ͻ1) [M]+, 186 (38) [M + H – 5-fluorouracil]+, 126 (100)
[M – (5-fluorouracil + MeCO2)]+. HRMS (EI, 70 eV): calcd. for
C12H14FN3O6 315.0867; found 315.0879; calcd. for C6H8NO2
126.0555; found 126.0554. C12H14FN3O6 (315.26): calcd. C 45.72,
H 4.48, N 13.33; found C 45.59, H 4.78, N 13.20.
Experimental Section
Preparation of Trimethylsilyl Derivatives of the Nitrogen Bases:
Some trimethylsilyl derivatives of the nitrogen bases are commer-
cial products, but they gave variable yields. However, the reagents
can be readily prepared by treatment of the bases (0.4 mmol) with
N,O-bis(trimethylsilyl)acetamide (297 µL, 244 mg, 1.2 mmol) under
nitrogen. The mixtures were heated to 130 °C and stirred for 1 h;
they were then cooled to 26 °C and dry toluene (1 mL) was added.
The volatiles were removed under vacuum, and the operation was
repeated twice. The silylated bases were used in the next step with-
out further purification.
Product 16: Colorless oil (29%); two rotamers at 26 °C (2:1), one
rotamer at 70 °C. [α]D = –5.1 (c = 0.39, CH3OH). 1H NMR
(500 MHz, CDCl3, 70 °C): δH = 2.04 (s, 3 H), 2.54–2.60 (m, 2 H),
3.74 (s, 3 H), 3.75 (d, J = 12.2 Hz, 1 H), 3.92 (dd, J = 5.0, 12.3 Hz,
1 H), 5.40 (dddd, J = 2.2, 4.5, 4.8, 5.0 Hz, 1 H), 5.83–5.89 (m, 1
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H), 7.28 (d, JF,H = 5.7 Hz, 1 H) ppm. 13C NMR (CDCl3,
125.7 MHz, 70 °C): δC = 20.8 (CH3), 37.6 (CH2), 53.3 (CH3), 53.4
(CH2), 72.3 (CH), 73.3 (CH), 126.5 (d, JC,F = 33.7 Hz, CH), 140.4
(C), 73.9 (CH), 75.0 (CH), 149.8 (CH), 151.9 (C), 156.7 (C), 163.1
(C), 172.1 (C) ppm. IR (film): ν = 3381, 1718, 1696, 1228 cm–1. MS
˜
(EI, 70 eV): m/z (%) = 423 (Ͻ1) [M]+, 186 (29) [M + H – 5-iodoura-
cil]+, 126 (100) [M – (5-iodouracil + MeCO2)]+. HRMS (EI, 70 eV):
(d, JC,F = 237.3 Hz, C), 148.7 (C), 155.1 (C), 156.9 (d, JC,F
=
24.7 Hz, C), 170.0 (C) ppm. IR (CHCl ): ν = 3381, 3188, 1725, calcd. for C12H14IN3O6 422.9927; found 422.9936; calcd. for
˜
3
1707, 1673, 1201 cm–1. MS (EI, 70 eV): m/z (%) = 284 (Ͻ1) [M –
MeO]+, 186 (10) [M + H – 5-fluorouracil]+, 126 (100) [M – (5-
fluorouracil
C11H11FN3O5 284.0683; found 284.0693; calcd. for C6H8NO2
126.0555; found 126.0560. C12H14FN3O6 (315.26): calcd. C 45.72,
H 4.48, N 13.33; found C 45.67, H 4.49, N 13.41.
C6H8NO2 126.0555; found 126.0551. C12H14IN3O6 (423.16): calcd.
C 34.06, H 3.33, N 9.93; found C 34.01, H 3.31, N 10.06.
+
MeCO2)]+. HRMS (EI, 70 eV): calcd. for
1-(N-Methoxycarbonyl-2-pyrrolidinyl)thymine (20): This compound
was obtained as a racemic mixture from N-(methoxycarbonyl)--
proline (10) and bis(trimethylsilyl)thymine as described in the Ge-
neral One-Pot Procedure; crystalline solid (83%); two rotamers at
26 °C (1.5:1); one rotamer at 70 °C; m.p. 219–221 °C (from
5-Iodo-1-[N-(methoxycarbonyl)-2-pyrrolidinyl]uracil (17): This com-
pound was obtained as a racemic mixture from N-(methoxycarb-
onyl)--proline (10[2]) and bis(trimethylsilyl)-5-iodouracil (80%) as
described in the General One-Pot Procedure; crystalline solid; m.p.
179–181 °C (from MeOH); two rotamers at 26 °C (1.5:1), one rot-
amer at 70 °C. 1H NMR (CD3OD, 500 MHz, 70 °C): δH = 1.90–
2.05 (m, 2 H), 2.07–2.14 (m, 1 H), 2.36 (dddd, J = 7.9, 7.9, 8.1,
15.9 Hz, 1 H), 3.58 (ddd, J = 7.9, 8.1, 15.8 Hz, 1 H), 3.72 (s, 3 H),
4.30–4.50 (m, 1 H), 5.96 (dd, J = 2.9, 7.2 Hz, 1 H), 7.79 (s, 1
1
MeOH). H NMR ([D6]DMSO, 500 MHz, 70 °C): δH = 1.78 (s, 3
H), 1.85–1.95 (m, 3 H), 2.20–2.30 (m, 1 H), 3.45 (ddd, J = 7.2, 7.4,
10.8 Hz, 1 H), 3.60 (s, 3 H), 3.67 (ddd, J = 4.9, 7.2, 10.4 Hz, 1 H),
5.94 (dd, J = 2.5, 7.1 Hz, 1 H), 7.24 (s, 1 H), 10.90 (br. s, 1 H) ppm.
13C NMR ([D6]DMSO, 125.7 MHz, 70 °C): δC = 11.5 (CH3), 21.7
(CH2), 31.6 (CH2), 46.7 (CH2), 52.0 (CH3), 69.8 (CH), 108.4 (C),
135.9 (CH), 149.8 (C), 154.0 (C), 163.6 (C) ppm. IR (film): ν =
˜
3394, 1703, 1684, 1379, 1224 cm–1. MS (EI, 70 eV): m/z (%) = 253
H) ppm. 13C NMR (CD3OD, 125.7 MHz): major rotamer δC
=
(1) [M]+, 128 (100) [M + H – thymine]+, 126 (9) [thymine]+. HRMS
31.9 (CH2), 39.0 (CH3), 40.7 (CH2), 56.4 (CH2), 62.1 (CH), 81.2 (EI, 70 eV): calcd. for C11H15N3O4 253.1063; found 253.1069;
(C), 156.4 (CH), 159.5 (C), 164.0 (C), 170.0 (C) ppm; minor rot- calcd. for C6H10NO2 128.0712; found 128.0712. C11H15N3O4
amer δC = 31.1 (CH2), 39.0 (CH3), 41.9 (CH2), 56.8 (CH2), 61.5 (253.26): calcd. C 52.17, H 5.97, N 16.59; found C 52.49, H 6.19,
(CH), 80.1 (C), 154.9 (CH), 160.7 (C), 163.7 (C), 170.9 (C) ppm.
N 16.28.
IR (film): ν = 3381, 1707, 1694, 1222 cm–1. MS (EI, 70 eV): m/z
˜
1-[(2S,4R)- and 1-[(2R,4R)-4-Acetoxy-N-(methoxycarbonyl)-2-pyr-
rolidinyl]thymine (21 and 22): These compounds were obtained
from 4-acetoxy-N-(methoxycarbonyl)proline (14) and bis(trimeth-
ylsilyl)thymine as described in the General One-Pot Procedure. The
products were purified by column chromatography (hexanes/
EtOAc, 1:1).
(%) = 365 (2) [M]+, 238 (30) [iodouracil]+, 128 (100) [M + H –
iodouracil]+. HRMS (EI, 70 eV): calcd. for C10H12IN3O4 364.9873;
found 364.9882; calcd. for C6H10NO2 128.0712; found 128.0716.
C10H12IN3O4 (365.13): calcd. C 32.90, H 3.31, N 11.51; found C
32.80, H 3.33, N 11.27.
1-[(2S,4R)- and 1-[(2R,4R)-4-Acetoxy-N-(methoxycarbonyl)-2-pyr-
rolidinyl]-5-iodouracil (18 and 19): These compounds were obtained
Product 21: Colorless oil (48%); two rotamers at 26 °C (5:1), one
rotamer at 70 °C. [α]D = +61.4 (c = 0.49, MeOH). 1H NMR
(CD3OD, 500 MHz, 70 °C): δH = 1.90 (s, 3 H), 1.98 (s, 3 H), 2.18
(ddd, J = 1.5, 1.5, 1.5, 14.7 Hz, 1 H), 2.66 (ddd, J = 5.7, 7.7,
15.3 Hz, 1 H), 3.73 (s, 3 H), 3.80 (ddd, J = 1.6, 1.6, 12.3 Hz, 1 H),
3.84 (dd, J = 4.7, 12.4 Hz, 1 H), 5.31 (dddd, J = 1.7, 2.4, 4.9,
5.2 Hz, 1 H), 6.13 (dd, J = 1.5, 7.7 Hz, 1 H), 7.40 (s, 1 H) ppm.
13C NMR (CD3OD, 125.7 MHz): major rotamer δC = 12.4 (CH3),
21.0 (CH3), 38.9 (CH2), 53.8 (CH3), 54.6 (CH2), 71.6 (CH), 73.7
(CH), 110.2 (C), 138.1 (CH), 152.4 (C), 156.7 (C), 166.5 (C), 171.5
(C) ppm; minor rotamer δC = 12.4 (CH3), 21.0 (CH3), 39.7 (CH2),
53.8 (CH3), 54.6 (CH2), 70.9 (CH), 72.9 (CH), 110.2 (C), 138.1
from 4-acetoxy-N-(methoxycarbonyl)proline (14[2]
) and bis(tri-
methylsilyl)-5-iodouracil as described in the General One-Pot Pro-
cedure. The products were purified by column chromatography
(hexanes/EtOAc, 7:3).
Product 18: Colorless oil (47%); two rotamers at 26 °C (1:1), one
rotamer at 70 °C. [α]D = +34.8 (c = 0.64, MeOH). 1H NMR
(CD3OD, 500 MHz, 70 °C): δH = 2.06 (s, 3 H), 2.19 (d, J = 15.4 Hz,
1 H), 2.61–2.69 (m, 1 H), 3.75 (s, 3 H), 3.80–3.82 (m, 2 H), 5.32–
5.36 (m, 1 H), 6.15 (dd, J = 0.8, 7.8 Hz, 1 H), 7.93 (s, 1 H) ppm.
13C NMR (CD3OD, 125.7 MHz, 70 °C): δC = 21.3 (CH3), 39.4
(CH2), 54.0 (CH3), 55.0 (CH2), 67.1 (C), 72.0 (CH), 73.4 (CH),
(CH), 152.1 (C), 156.7 (C), 166.5 (C), 172.1 (C) ppm. IR (film): ν
˜
146.8 (CH), 152.2 (C), 156.8 (C), 162.6 (C), 171.5 (C) ppm. IR = 3393, 1743, 1716, 1686, 1379, 1237 cm–1. MS (EI, 70 eV): m/z
(film): ν = 3381, 1710, 1688, 1212 cm–1. MS (EI, 70 eV): m/z (%) (%) = 311 (Ͻ1) [M]+, 219 (8) [M – (MeCO2H + MeOH)]+, 186 (9)
= 424 (1) [M + H]+, 238 (5) [5-iodouracil]+, 186 (16) [M + H – 5- [M + H – thymine]+, 126 (100) [M – (thymine + MeCO2)]+. HRMS
iodouracil]+, 126 (100) [M – (5-iodouracil + MeCO2)]+. HRMS
(EI, 70 eV): calcd. for C13H17N3O6 311.1117; found 311.1129;
˜
(EI, 70 eV): calcd. for C12H15IN3O6 424.0006; found 424.0010; calcd. for C6H8NO2 126.0555; found 126.0554. C13H17N3O6
calcd. for C6H8NO2 126.0555; found 126.0553. C12H14IN3O6 (311.29): calcd. C 50.16, H 5.50, N 13.50; found C 50.33, H 5.58,
(423.16): calcd. C 34.06, H 3.33, N 9.93; found C 34.36, H 3.51, N
9.88.
N 13.33.
Product 22: Two rotamers at 26 °C (5:1), one rotamer at 70 °C;
colorless oil. [α]D = +4.7 (c = 0.32, MeOH). 1H NMR (CD3OD,
500 MHz, 70 °C): δH = 1.88 (s, 3 H), 2.04 (s, 3 H), 2.55 (br. dd, J
= 4.9, 6.5 Hz, 2 H), 3.70 (s, 3 H), 3.72 (d, J = 13.3 Hz, 1 H), 3.97
(dd, J = 4.8, 12.2 Hz, 1 H), 5.38 (dddd, J = 1.7, 4.2, 4.5, 4.6 Hz, 1
Product 19: Colorless oil (36%); two rotamers at 26 °C (5:1), one
rotamer at 70 °C. [α]D = +9.1 (c = 0.55, MeOH). 1H NMR
(CD3OD, 500 MHz, 70 °C): δH = 2.02 (s, 3 H), 2.55 (dd, J = 8.1,
13.8 Hz, 1 H), 2.64 (ddd, J = 6.0, 6.0, 14.5 Hz, 1 H), 3.70 (d, J =
13.2 Hz, 1 H), 3.71 (s, 3 H), 3.97 (dd, J = 4.9, 12.1 Hz, 1 H), 5.36– H), 5.99 (dd, J = 6.5, 6.8 Hz, 1 H), 7.33 (s, 1 H) ppm. 13C NMR
5.41 (m, 1 H), 5.95 (dd, J = 6.8, 7.2 Hz, 1 H), 7.94 (s, 1 H) ppm.
(CD3OD, 125.7 MHz): major rotamer δC = 12.3 (CH3), 20.9 (CH3),
37.7 (CH2), 53.5 (CH3), 54.0 (CH2), 72.1 (CH), 73.6 (CH), 111.0
13C NMR (CD3OD, 100.6 MHz): major rotamer δC = 20.9 (CH3),
37.5 (CH2), 53.6 (CH3), 54.2 (CH2), 67.8 (C), 73.8 (CH), 74.4 (CH), (C), 140.7 (CH), 152.1 (C), 156.7 (C), 166.5 (C), 172.1 (C) ppm;
150.2 (CH), 151.7 (C), 156.8 (C), 163.0 (C), 172.1 (C) ppm; minor minor rotamer δC = 12.4 (CH3), 21.0 (CH3), 38.8 (CH2), 53.6
rotamer δC = 20.9 (CH3), 38.6 (CH2), 53.7 (CH3), 54.3 (CH2), 67.8
(CH3), 54.1 (CH2), 72.1 (CH), 74.2 (CH), 111.0 (C), 139.7 (CH),
3852
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3847–3857

Azanucleosides from Proline Derivatives
152.1 (C), 156.7 (C), 166.5 (C), 172.1 (C) ppm. IR (film): ν = 3391,
(C), 129.1 (2ϫCH), 129.3 (2ϫCH), 133.5 (CH), 134.1 (C), 146.2
(CH), 155.0 (C), 155.4 (C), 163.8 (C), 168.1 (C) ppm; minor rot-
amer δC = 21.8 (CH2), 33.6 (CH2), 48.2 (CH2), 53.5 (CH3), 72.3
˜
1738, 1714, 1687, 1387, 1244 cm–1. MS (EI, 70 eV): m/z (%) = 311
(Ͻ1) [M]+, 126 (100) [M – (thymine + MeCO2)]+. HRMS (EI,
70 eV): calcd. for C13H17N3O6 311.1117; found 311.1107; calcd. for (CH), 96.6 (C), 129.3 (4ϫCH), 133.5 (CH), 134.1 (C), 146.2 (CH),
C6H8NO2 126.0555; found 126.0559. C13H17N3O6 (311.29): calcd.
C 50.16, H 5.50, N 13.50; found C 50.22, H 5.64, N 13.37.
155.0 (C), 155.4 (C), 163.7 (C), 168.0 (C) ppm. IR (film): ν = 3532,
˜
3414, 1703, 1675, 1241 cm–1. MS (EI, 70 eV): m/z (%) = 342 (1)
[M]+, 215 (15) [N-benzoylcytosine]+, 128 (42) [M + H – N-benzoyl-
cytosine]+, 105 (100) [PhCO]+, 77 (90) [Ph]+. HRMS (EI, 70 eV):
calcd. for C17H18N4O4 342.1328; found 342.1342; calcd. for C7H5O
105.0340; found 105.0341. C17H18N4O4 (342.35): calcd. C 59.64, H
5.30, N 16.37; found C 59.68, H 5.30, N 16.48.
1-(N-Methoxycarbonyl-2-pyrrolidinyl)uracil (23): This compound
was obtained as a racemic mixture from N-(methoxycarbonyl)--
proline (10) and bis(trimethylsilyl)uracil as described in the General
One-Pot Procedure; colorless oil (81%); two rotamers at 26 °C
1
(1:1), one rotamer at 70 °C. H NMR (500 MHz, CD3OD, 70 °C):
1-[(2R,4R)- and 1-[(2S,4R)-4-Acetoxy-N-(methoxycarbonyl)-2-pyr-
rolidinyl]-4-N-benzoylcytosine (26 and 27): These compounds were
obtained from 4-acetoxy-N-(methoxycarbonyl)proline (14) and bis-
(trimethylsilyl)-N-(benzoyl)cytosine as described in the General
One-Pot Procedure. The products were purified by column
chromatography (hexanes/EtOAc, 70:30).
δH = 1.95–2.01 (m, 2 H), 2.05 (dddd, J = 3.0, 6.0, 8.7, 10.7 Hz, 1
H), 2.29–2.39 (m, 1 H), 3.56 (ddd, J = 5.1, 7.6, 10.4 Hz, 1 H), 3.69
(s, 3 H), 3.70 (ddd, J = 3.8, 9.1, 10.7 Hz, 1 H), 5.63 (d, J = 8.0 Hz,
1 H), 6.01 (dd, J = 2.8, 7.1 Hz, 1 H), 7.43 (d, J = 8.1 Hz, 1 H) ppm.
13C NMR (125.7 MHz, CD3OD, 70 °C): δC = 23.4 (CH2), 33.4
(CH2), 49.5 (CH2), 53.5 (CH3), 72.8 (CH), 102.3 (CH), 142.4 (CH),
152.2 (C), 156.8 (C), 166.1 (C) ppm. IR (film): ν = 3392, 1698,
˜
Product 26: Crystalline solid (54%); two rotamers at 26 °C (3:1),
1636, 1265, 1185 cm–1. MS (EI, 70 eV): m/z (%) = 239 (1) [M]+, 128
(100) [M + H – uracil]+. HRMS (EI, 70 eV): calcd. for C10H13N3O4
239.0906; found 239.0896; calcd. for C6H10NO2 128.0712; found
128.0708. C10H13N3O4 (239.23): calcd. C 50.21, H 5.48, N 17.56;
found C 49.95, H 5.77, N 17.40.
one rotamer at 70 °C; m.p. 226–228 °C (from MeOH). [α]D
=
1
+135.5 (c = 0.20, MeOH). H NMR (CDCl3, 500 MHz, 70 °C): δH
= 1.93 (s, 3 H), 2.42 (d, J = 15.5 Hz, 1 H), 2.64 (ddd, J = 5.2, 7.4,
15.5 Hz, 1 H), 3.73 (s, 3 H), 3.84 (d, J = 12.7 Hz, 1 H), 3.89 (dd,
J = 4.6, 12.7 Hz, 1 H), 5.37 (dd, J = 4.8, 4.8 Hz, 1 H), 6.24 (d, J
= 7.3 Hz, 1 H), 7.50 (dd, J = 7.5, 7.8 Hz, 3 H), 7.58 (dd, J = 7.4,
7.5 Hz, 1 H), 7.75 (d, J = 7.5 Hz, 1 H), 7.95 (d, J = 7.5 Hz, 2
H) ppm. 13C NMR (CDCl3, 125.7 MHz, 70 °C): δC = 20.8 (CH3),
38.7 (CH2), 53.4 (CH3), 54.3 (CH2), 71.8 (2ϫCH), 95.8 (CH),
127.8 (2ϫCH), 129.0 (2ϫCH), 133.1 (CH), 133.3 (C), 143.9 (CH),
154.8 (C), 155.0 (C), 162.6 (C), 167.0 (C), 169.4 (C) ppm. IR
1-[(2R/S,4R)-4-Acetoxy-N-(methoxycarbonyl)-2-pyrrolidinyl]uracil
(24): This compound was obtained from 4-acetoxy-N-(methoxy-
carbonyl)proline (14) and bis(trimethylsilyl)uracil as described in
the General One-Pot Procedure, as an inseparable diastereomer
mixture (cis/trans 2:1, 89%); colorless oil; two rotamers at 26 °C
(and one at 70 °C) for each diastereomer. 1H NMR ([D6]DMSO,
500 MHz): major diastereomer δH = 2.01 (s, 3 H), 2.41–2.51 (m, 1
H), 2.56–2.60 (m, 1 H), 3.34 (s, 3 H), 3.41–3.78 (m, 2 H), 5.12–5.22
(m, 1 H), 5.52 (d, J = 7.9 Hz, 1 H), 5.93 (br. b, 1 H), 7.60 (d, J =
8.1 Hz, 1 H), 11.29 (s, 1 H) ppm; minor diastereomer δH = 1.91 (s,
3 H), 2.41–2.51 (m, 1 H), 2.56–2.60 (m, 1 H), 3.31 (s, 3 H), 3.51–
3.68 (m, 2 H), 5.20–5.25 (m, 1 H), 5.55 (d, J = 7.0 Hz, 1 H), 5.95
(br. b, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 11.26 (s, 1 H) ppm. Some
minor bands corresponding to the minor rotamers are observed.
13C NMR ([D6]DMSO, 125.7 MHz, 70 °C): major diastereomer δC
= 20.2 (CH3), 37.3 (CH2), 52.2 (CH3), 52.6 (CH2), 69.2 (CH), 71.2
(CH), 99.8 (CH), 140.2 (CH), 150.0 (C), 153.5 (C), 162.7 (C), 169.0
(C) ppm; minor diastereomer δC = 20.2 (CH3), 36.6 (CH2), 52.2
(CH3), 52.6 (CH2), 69.2 (CH), 71.6 (CH), 100.7 (CH), 142.2 (CH),
(CHCl ): ν = 3414, 1738, 1705, 1664, 1377, 1239 cm–1. MS (EI,
˜
3
70 eV): m/z (%) = 400 (1) [M]+, 214 (16) [N-benzoylcytosine –
H]+, 186 (28) [M + H – N-benzoylcytosine]+, 105 (100) [PhCO]+.
HRMS (EI, 70 eV): calcd. for C19H20N4O6 400.1383; found
400.1390; calcd. for C7H5O 105.0340; found 105.0342. C19H20N4O6
(400.39): calcd. C 57.00, H 5.03, N 13.99; found C 56.61, H 5.39,
N 13.84.
Product 27: Colorless oil (27%); two rotamers at 26 °C (2:1), one
rotamer at 70 °C. [α]D = –36.1 (c = 0.18, MeOH). 1H NMR
(CD3OD, 500 MHz, 70 °C): δH = 2.05 (s, 3 H), 2.60–2.70 (m, 2 H),
3.69 (s, 3 H), 3.77 (dd, J = 3.1, 11.6 Hz, 1 H), 4.05 (dd, J = 5.1,
12.1 Hz, 1 H), 5.42 (dddd, J = 2.4, 2.5, 3.3, 5.2 Hz, 1 H), 6.10 (dd,
J = 6.4, 6.7 Hz, 1 H), 7.49 (br. b, 1 H), 7.51 (dd, J = 7.5, 7.9 Hz,
2 H), 7.59 (dd, J = 7.4, 7.4 Hz, 1 H), 7.95 (d, J = 7.2 Hz, 2 H),
7.99 (d, J = 7.4 Hz, 1 H) ppm. 13C NMR (CD3OD, 125.7 MHz,
70 °C): δC = 20.8 (CH3), 38.6 (CH2), 53.7 (CH3), 54.4 (CH2), 74.0
(CH), 75.4 (CH), 98.3 (CH), 129.1 (2ϫCH), 129.7 (2ϫCH), 134.0
(CH), 134.8 (C), 148.5 (CH), 156.6 (C), 157.4 (C), 164.9 (C), 169.3
149.6 (C), 153.5 (C), 162.7 (C), 169.4 (C) ppm. IR (film): ν = 3450,
˜
3392, 1738, 1691, 1376, 1237 cm–1. MS (EI, 70 eV): m/z (%) = 297
(Ͻ1) [M]+, 186 (20) [M + H – uracil]+, 126 (100) [M – (uracil +
MeCO2)]+. HRMS (EI, 70 eV): calcd. for C12H15N3O6 297.0961;
found 297.0953; calcd. for C6H8NO2 126.0555; found 126.0560.
C12H15N3O6 (297.27): calcd. C 48.49, H 5.09, N 14.14; found C
48.82, H 5.19, N 13.87.
(C), 172.2 (C) ppm. IR (film): ν = 3413, 1739, 1703, 1672, 1325,
˜
1240 cm–1. MS (EI, 70 eV): m/z (%) = 400 (Ͻ1) [M]+, 215 (50) [N-
benzoylcytosine]+, 105 (100) [PhCO]+, 91 (58) [PhCH2]+. HRMS
(EI, 70 eV): calcd. for C19H20N4O6 400.1383; found 400.1382;
calcd. for C7H5O 105.0340; found 105.0343. C19H20N4O6 (400.39):
calcd. C 57.00, H 5.03, N 13.99; found C 57.31, H 5.40, N 13.84.
4-N-Benzoyl-1-[N-(methoxycarbonyl)-2-pyrrolidinyl]cytosine (25):
This compound was obtained as a racemic mixture from N-(meth-
oxycarbonyl)--proline (10) and bis(trimethylsilyl)-N-(benzoyl)-
cytosine (80%) as described in the General One-Pot Procedure;
crystalline solid; two rotamers at 26 °C (3:2), one rotamer at 70 °C;
m.p. 223–225 °C (from MeOH). H NMR ([D6]DMSO, 500 MHz, pound was obtained as a racemic mixture from N-(methoxycarb-
70 °C): δH = 1.80–1.92 (m, 3 H), 2.22–2.32 (m, 1 H), 3.44 (ddd, J onyl)--proline (10) and (trimethylsilyl)benzotriazole as described
1-(N-Methoxycarbonyl-2-pyrrolidinyl)benzotriazole (28): This com-
1
= 8.2, 8.9, 8.9 Hz, 1 H), 3.57 (s, 3 H), 3.69 (ddd, J = 3.4, 7.5,
in the General One-Pot Procedure (51%); syrup; two rotamers at
10.5 Hz, 1 H), 5.97 (dd, J = 1.1, 7.0 Hz, 1 H), 7.22 (br. s, 1 H), 26 °C (2:1); one rotamer at 70 °C. 1H NMR (CD3OD, 500 MHz,
7.46 (dd, J = 7.7, 7.7 Hz, 2 H), 7.57 (dd, J = 7.3, 7.4 Hz, 1 H), 7.90
(d, J = 7.3 Hz, 1 H), 7.95 (d, J = 7.6 Hz, 2 H), 10.86 (br. s, 1
70 °C): δH = 2.12–2.21 (m, 1 H), 2.32–2.39 (m, 1 H), 2.43–2.53 (m,
1 H), 2.55–2.64 (m, 1 H), 3.58 (br. b, 3 H), 3.65–3.73 (m, 1 H),
3.84 (ddd, J = 3.6, 8.5, 10.4 Hz, 1 H), 6.72 (dd, J = 2.0, 6.9 Hz, 1
H) ppm. 13C NMR ([D6]DMSO, 100.6 MHz): major rotamer δC
=
22.7 (CH2), 32.6 (CH2), 47.8 (CH2), 53.5 (CH3), 73.1 (CH), 96.6 H), 7.42 (dd, J = 8.0, 8.1 Hz, 1 H), 7.56 (dd, J = 7.8, 7.9 Hz, 1 H),
Eur. J. Org. Chem. 2010, 3847–3857
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3853

A. Boto, D. Hernández, R. Hernández
FULL PAPER
7.77–7.90 (m, 1 H), 7.94 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR
2.44–2.48 (m, 2 H), 3.59 (s, 3 H), 3.57–3.65 (m, 1 H), 3.80 (ddd, J
(CD3OD, 125.7 MHz): major rotamer δC = 24.8 (CH2), 33.9 (CH2), = 4.1, 7.9, 10.3 Hz, 1 H), 6.31 (dd, J = 5.4, 5.7 Hz, 1 H), 8.12 (s, 1
48.4 (CH2), 53.4 (CH3), 72.6 (CH), 112.1 (CH), 119.8 (CH), 125.6 H), 8.65 (s, 1 H) ppm. 13C NMR (CDCl3, 125.7 MHz, 70 °C): δC
(2ϫCH), 128.8 (C), 146.4 (C) ppm; minor rotamer δC = 23.8
= 23.1 (CH2), 32.5 (CH2), 47.1 (CH2), 52.8 (CH3), 69.8 (CH), 132.4
(CH2), 35.0 (CH2), 48.0 (CH2), 53.4 (CH3), 72.0 (CH), 111.6 (CH), (C), 144.3 (CH), 151.0 (2ϫC), 151.6 (CH), 154.9 (C) ppm. IR
120.0 (CH), 125.6 (2ϫCH), 129.0 (C), 146.4 (C) ppm. The (C) sig-
nal of the carbamate was not observed. IR (CHCl ): ν = 1702,
(film): ν = 1705, 1592, 1560, 1205, 1120, 945 cm–1. MS (EI, 70 eV):
˜
m/z (%) = 283/281 (1/3) [M]+, 252/250 (4/12) [M – OMe]+, 154/156
˜
3
1614, 1493, 1116 cm–1. MS (EI, 70 eV): m/z (%) = 246 (4) [M]+, (15/44) [6-chloropurine]+, 128 (100) [M + H – 6-chloropurine]+.
128 (100) [M + H – benzotriazole]+, 119 (55) [benzotriazole]+.
HRMS (EI, 70 eV): calcd. for C12H14N4O2 246.1117; found
246.1123; calcd. for C6H10NO2 128.0712; found 128.0719.
C12H14N4O2 (246.27): calcd. C 58.53, H 5.73, N 22.75; found C
58.46, H 5.36, N 22.56.
HRMS (EI, 70 eV): calcd. for C11H1237ClN5O2/C11H1235ClN5O2
283.0650/281.0680; found 283.0659/281.0687; calcd. for C6H10NO2
128.0712; found 128.0712. C11H12ClN5O2 (281.70): calcd. C 46.90,
H 4.29, N 24.86; found C 47.26, H 4.52, N 24.53.
9-[(2R/S,4R)-4-Acetoxy-N-(methoxycarbonyl)-2-pyrrolidinyl]-6-chlo-
ropurine (32): This compound was obtained from 4-acetoxy-N-
(methoxycarbonyl)proline (14) and (trimethylsilyl)-6-chloropurine
as described in the General One-Pot Procedure as an inseparable
diastereomer mixture (61%, cis/trans 1:1). Each diastereomer exists
as two rotamers at 26 °C (1:1), one rotamer at 70 °C; colorless oil.
1H NMR (CD3OD, 500 MHz, 70 °C): two sets of signals were ob-
served, each corresponding to one diastereomer δH = 1.87 (s, 3 H),
2.07 (s, 3 H), 2.54 (d, J = 15.1 Hz, 1 H), 2.73–2.82 (m, 1 H), 2.86
(ddd, J = 5.7, 7.6, 15.2 Hz, 1 H), 3.03 (ddd, J = 5.7, 5.7, 14.8 Hz,
1 H), 3.59 (s, 3 H), 3.66 (s, 3 H), 3.82 (d, J = 12.3 Hz, 1 H), 3.94
(d, J = 12.2 Hz, 1 H), 3.97 (dd, J = 4.9, 12.3 Hz, 1 H), 4.18 (dd, J
= 4.9, 12.0 Hz, 1 H), 5.40–5.44 (m, 1 H), 5.62–5.66 (m, 1 H), 6.52
(dd, J = 5.7, 8.2 Hz, 1 H), 6.56 (dd, J = 1.6, 7.6 Hz, 1 H), 8.52 (s,
1 H), 8.55 (s, 1 H), 8.68 (s, 1 H), 8.70 (s, 1 H) ppm. 13C NMR
(CD3OD, 125.7 MHz, 70 °C): Two sets of signals were observed,
each corresponding to one diastereomer δC = 20.7/20.7 (CH3), 38.8/
39.4 (CH2), 53.2/53.5 (CH3), 53.8/54.4 (CH2), 70.2/70.2 (CH), 73.5/
73.9 (CH), 133.0/133.3 (C), 146.2/146.9 (CH), 148.1/148.6 (C),
152.8/152.9 (C), 153.0/153.0 (CH), 157.4/157.4 (C), 171.6/172.1
1-[(2R,4R)- and 1-[(2S,4R)-4-Acetoxy-N-(methoxycarbonyl)-2-pyr-
rolidinyl]benzotriazole (29 and 30): These compounds were obtained
from 4-acetoxy-N-(methoxycarbonyl)proline (14) and (trimethyl-
silyl)benzotriazole as described in the General One-Pot Procedure.
The products were purified by column chromatography (hexanes/
EtOAc, 8:2).
Product 29: Syrup (43%); two rotamers at 26 °C (1:1), one rotamer
at 70 °C. [α]D = +111.1 (c = 0.31, MeOH). 1H NMR (CD3OD,
500 MHz, 70 °C): δH = 1.73 (s, 3 H), 2.61 (d, J = 15.0 Hz, 1 H),
2.99 (ddd, J = 6.3, 7.4, 14.7 Hz, 1 H), 3.73 (s, 3 H), 3.89 (dd, J =
2.5, 12.3 Hz, 1 H), 4.10 (dd, J = 5.9, 12.2 Hz, 1 H), 5.36–5.41 (m,
1 H), 6.83 (dd, J = 2.0, 7.6 Hz, 1 H), 7.35 (dd, J = 7.6, 7.7 Hz, 1
H), 7.58 (dd, J = 7.4, 8.1 Hz, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.98
(d, J = 8.4 Hz, 1 H) ppm. 13C NMR (CD3OD, 100.6 MHz): δC
=
21.2 (CH3/CH3), 40.1/41.1 (CH2/CH2), 54.4 (CH3/CH3), 54.5/54.8
(CH2/CH2), 73.8 (CH/CH), 74.1 (CH/CH), 113.0 (CH/CH), 120.6
(CH/CH), 126.2 (CH/CH), 129.4 (CH/CH), 133.0 (C/C), 147.5 (C/
C), 154.0 (C/C), 172.6 (C/C) ppm. IR (film): ν = 1739, 1714, 1452,
˜
1382, 1242 cm–1. MS (EI, 70 eV): m/z (%) = 304 (4) [M]+, 126 (100)
[M – (benzotriazole + MeCO2)]+. HRMS (EI, 70 eV): calcd. for
C14H16N4O4 304.1172; found 304.1181; calcd. for C6H8NO2
126.0555; found 126.0551. C14H16N4O4 (304.31): calcd. C 55.26, H
5.30, N 18.41; found C 55.06, H 5.66, N 18.74.
(C) ppm. IR (film): ν = 1738, 1708, 1592, 1561, 1234, 1203 cm–1.
˜
MS (EI, 70 eV): m/z (%) = 341/339 (0.3/1) [M]+, 282/280 (5/15)
[M – MeCO2]+, 186 (69) [M + H – 6-chloropurine]+, 126 (100)
[M – (6-chloropurine + MeCO2)]+. HRMS (EI, 70 eV): calcd. for
C13H1437ClN5O4/C13H1435ClN5O4
341.0705/339.0548;
found
Product 30: Crystalline solid (33%); two rotamers at 26 °C (1:1),
one rotamer at 70 °C; m.p. 204–206 °C (from MeOH). [α]D = +5.2
(c = 0.20, MeOH). 1H NMR (CD3OD, 500 MHz, 70 °C): δH = 2.09
(s, 3 H), 2.82 (ddd, J = 4.8, 7.5, 14.4 Hz, 1 H), 2.96 (ddd, J = 4.2,
6.1, 14.4 Hz, 1 H), 3.56 (s, 3 H), 3.81 (dd, J = 2.2, 11.9 Hz, 1 H),
4.09 (dd, J = 5.7, 12.0 Hz, 1 H), 5.72 (dddd, J = 3.8, 4.5, 5.6,
5.7 Hz, 1 H), 6.88 (dd, J = 4.3, 7.8 Hz, 1 H), 7.42 (dd, J = 7.7,
7.9 Hz, 1 H), 7.57 (dd, J = 7.4, 7.9 Hz, 1 H), 7.83 (br. b, 1 H), 7.97
341.0708/ 339.0533; calcd. for C6H8NO2 126.0555; found 126.0555.
C13H14ClN5O4 (339.74): calcd. C 45.96, H 4.15, N 20.61; found C
45.69, H 4.51, N 20.90.
6-Benzyloxy-9-[N-(methoxycarbonyl)-2-pyrrolidinyl]purine
(33):
This compound was obtained as a racemic mixture from N-(meth-
oxycarbonyl)--proline (10) and (trimethylsilyl)-6-(benzyloxy)-
purine as described in the General One-Pot Procedure (72%); two
rotamers at 26 °C (1:1), one rotamer at 70 °C; colorless oil. 1H
NMR (CDCl3, 500 MHz, 70 °C): δH = 1.93–2.02 (m, 1 H), 2.17–
2.26 (m, 1 H), 2.32–2.45 (m, 2 H), 3.56 (s, 3 H), 3.52–3.61 (m, 1
H), 3.76 (ddd, J = 4.1, 7.9, 10.4 Hz, 1 H), 5.62 (s, 2 H), 6.26 (dd,
J = 3.2, 6.7 Hz, 1 H), 7.20 (dd, J = 7.3, 7.3 Hz, 1 H), 7.25 (dd, J
= 7.0, 7.9 Hz, 2 H), 7.45 (d, J = 7.3 Hz, 2 H), 7.86 (s, 1 H), 8.44
(s, 1 H) ppm. 13C NMR (CDCl3, 125.7 MHz, 70 °C): δC = 23.0
(CH2), 32.8 (CH2), 47.1 (CH2), 52.7 (CH3), 68.4 (CH2), 69.3 (CH),
122.4 (C), 127.9 (CH), 128.2 (2ϫCH), 128.3 (2ϫCH), 136.5 (C),
141.0 (CH), 151.6 (C), 151.8 (CH), 154.9 (C), 160.7 (C) ppm. IR
(d, J = 8.4 Hz, 1 H) ppm. 13C NMR (CD3OD, 125.7 MHz): δC
=
20.8 (CH3/CH3), 39.2/40.2 (CH2/CH2), 52.9 (CH3/CH3), 53.3/53.5
(CH2/CH2), 70.5/70.9 (CH/CH), 73.2/73.8 (CH/CH), 111.7/112.2
(CH/CH), 119.9/120.1 (CH/CH), 125.7 (CH/CH), 128.9/129.1 (CH/
CH), 134.2/134.3 (C/C), 146.4 (C/C), 154.0/156.2 (C/C), 172.2 (C/
C) ppm. IR (film): ν = 1741, 1709, 1452, 1385, 1242 cm–1. MS (EI,
˜
70 eV): m/z (%) = 304 (1) [M]+, 273 (1) [M – MeO]+, 126 (100)
[M – (benzotriazole + MeCO2)]+. HRMS (EI, 70 eV): calcd. for
C14H16N4O4 304.1172; found 304.1186; calcd. for C6H8NO2
126.0555; found 126.0554. C14H16N4O4 (304.31): calcd. C 55.26, H
5.30, N 18.41; found C 55.12, H 5.45, N 18.24.
(film): ν = 3196, 3064, 1705, 1601, 1319, 1118 cm–1. MS (EI, 70 eV):
˜
m/z (%) = 353 (4) [M]+, 226 (26) [6-benzyloxypurine]+, 128 (100)
[M + H – benzyloxypurine]+. HRMS (EI, 70 eV): calcd. for
C18H19N5O3 353.1488; found 353.1493; calcd. for C6H10NO2
128.0712; found 128.0712. C18H19N5O3 (353.38): calcd. C 61.18, H
5.42, N 19.82; found C 60.81, H 5.52, N 20.20.
6-Chloro-9-[N-(methoxycarbonyl)-2-pyrrolidinyl]purine (31): This
compound was obtained as a racemic mixture from N-(meth-
oxycarbonyl)--proline (10) and (trimethylsilyl)-6-chloropurine as
described in the General One-Pot Procedure; crystalline solid
(69%); two rotamers at 26 °C (1:1), one rotamer at 70 °C; m.p. 155–
157 °C (from MeOH, decomposition). 1H NMR (CDCl3, 6-Benzyloxy-9-[(2S,4R)- and 6-Benzyloxy-9-[(2R,4R)-4-acetoxy-N-
500 MHz, 70 °C): δH = 2.02–2.10 (m, 1 H), 2.25–2.35 (m, 1 H), (methoxycarbonyl)-2-pyrrolidinyl]purine (34 and 35): These com-
3854
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3847–3857

Azanucleosides from Proline Derivatives
pounds were obtained from 4-acetoxy-N-(methoxycarbonyl)proline
(14) and (trimethylsilyl)-6-benzyloxypurine as described in the Ge-
neral One-Pot Procedure. The products were purified by column
chromatography (hexanes/EtOAc, 7:3).
N-Benzyl-9-[(2S,4R)- and N-Benzyl-9-[(2R,4R)-4-acetoxy-N-(meth-
oxycarbonyl)-2-pyrrolidinyl]adenine (37 and 38): These compounds
were obtained from (4R)-4-acetoxy-N-(methoxycarbonyl)--proline
(14) and bis(trimethylsilyl)-N-benzyladenine as a separable dia-
stereomer mixture (column chromatography, CH2Cl2/MeOH, 9:1).
Product 34: Colorless oil (34%); two rotamers at 26 °C (1:1), one
rotamer at 70 °C. [α]D = –4.5 (c = 0.89, CHCl3). 1H NMR
(CD3OD, 500 MHz, 70 °C): δH = 1.86 (s, 3 H), 2.51 (dd, J = 2.9,
15.1 Hz, 1 H), 2.82 (ddd, J = 5.5, 7.4, 15.0 Hz, 1 H), 3.65 (s, 3 H),
3.92 (dd, J = 2.0, 12.3 Hz, 1 H), 3.96 (dd, J = 4.6, 12.3 Hz, 1 H),
5.40 (dddd, J = 1.9, 1.9, 4.5, 4.5 Hz, 1 H), 5.69 (s, 2 H), 6.51 (dd,
J = 1.5, 7.5 Hz, 1 H), 7.28 (dd, J = 7.3, 7.3 Hz, 1 H), 7.34 (dd, J
= 7.1, 7.7 Hz, 2 H), 7.50 (d, J = 7.3 Hz, 2 H), 8.31 (s, 1 H), 8.52
(s, 1 H) ppm. 13C NMR (125.7 MHz, CD3OD, 70 °C): δC = 21.0
(CH3), 39.1 (CH2), 53.4 (CH3), 53.7 (CH2), 67.9 (CH), 68.7 (CH2),
71.9 (CH), 122.2 (C), 128.2 (2ϫCH), 128.1 (CH), 128.4 (2ϫCH),
136.8 (C), 140.6 (CH), 152.1 (C), 152.4 (CH), 161.0 (C), 162.6 (C),
Product 37: Colorless oil (32%); two rotamers at 26 °C (1:1), one
rotamer at 70 °C. [α]D = = +7.1 (c = 1.26, MeOH). 1H NMR
(CD3OD, 500 MHz, 26 °C): δH = 1.86 (s, 3 H), 2.43 (d, J = 15.2 Hz,
1 H), 2.72–2.81 (m, 1 H), 3.60 (rotamer A)/3.70 (rotamer B) (br. s,
3 H), 3.88–3.97 (m, 2 H), 4.70–4.90 (m, 2 H), 5.36–5.40 (m, 1 H),
6.41 (d, J = 6.7 Hz, 1 H), 7.22 (dd, J = 7.3, 7.6 Hz, 1 H), 7.29 (dd,
J = 7.6, 7.6 Hz, 2 H), 7.37 (d, J = 7.3 Hz, 2 H), 8.17 (s, 1 H), 8.26
(s, 1 H) ppm. 13C NMR (CD3OD, 125.7 MHz, 70 °C): δC = 20.3
(CH3), 42.4 (CH2), 45.5 (CH2), 53.4 (CH3), 57.4 (CH2), 69.4 (CH),
70.2 (CH), 120.8 (C), 128.2 (CH), 128.6 (2ϫCH), 129.5 (2ϫCH),
140.4 (CH), 141.8 (C), 149.4 (C), 153.5 (CH), 156.2 (C), 157.1 (C),
170.0 (C) ppm. IR (film): ν = 3095, 3067, 1739, 1706, 1451, 1383,
˜
173.3 (C) ppm. IR (film): ν = 3426, 3095, 3067, 1703, 1620,
˜
1235 cm–1. MS (EI, 70 eV): m/z (%) = 411 (2) [M]+, 352 (4) [M –
MeCO2]+, 226 (36) [6-benzyloxypurine]+, 126 (100) [M – (6-benzyl-
oxypurine + MeCO2)]+, 91 (64) [PhCH2]+. HRMS (EI, 70 eV):
calcd. for C20H21N5O5 411.1543; found 411.1556; calcd. for
C6H8NO2 126.0555; found 126.0551. C20H21N5O5 (411.42): calcd.
C 58.39, H 5.14, N 17.02; found C 58.59, H 5.41, N 16.71.
1205 cm–1. MS (EI, 70 eV): m/z (%) = 410 (Ͻ1), [M]+, 351 (22)
[M – MeCO2]+, 226 (100) [N-benzyladenine + H]+, 91 (63)
[PhCH2]+. HRMS (EI, 70 eV): calcd. for C20H22N6O4 410.1703;
found 410.1707; calcd. for C12H12N5 226.1093; found 226.1098.
C20H22N6O4 (410.43): calcd. C 58.53, H 5.40, N 20.48; found C
58.19, H 5.08, N 20.21.
Product 35: Colorless oil (31%); two rotamers at 26 °C (2:1), one
rotamer at 70 °C. [α]D = –20.2 (c = 0.58, CHCl3). 1H NMR
(CD3OD, 500 MHz, 70 °C): δH = 2.07 (s, 3 H), 2.74 (ddd, J = 2.5,
7.9, 12.5 Hz, 1 H), 3.00 (ddd, J = 5.7, 5.8, 12.5 Hz, 1 H), 3.56 (s,
3 H), 3.82 (dd, J = 6.1, 12.7 Hz, 1 H), 4.19 (dd, J = 4.9, 12.1 Hz,
1 H), 5.61–5.65 (m, 1 H), 5.65 (br. s, 2 H), 6.46 (dd, J = 5.7, 8.0 Hz,
1 H), 7.28 (dd, J = 7.2, 7.3 Hz, 1 H), 7.34 (dd, J = 7.7, 7.9 Hz, 2
H), 7.49 (d, J = 7.3 Hz, 2 H), 8.29 (s, 1 H), 8.49 (s, 1 H) ppm. 13C
NMR (CD3OD, 125.7 MHz, 70 °C): δC = 20.7 (CH3), 38.7 (CH2),
53.4 (CH3), 53.8 (CH2), 69.5 (CH2 + CH), 73.9 (CH), 122.7 (C),
129.0 (CH), 129.1 (2ϫCH), 129.3 (2ϫCH), 137.5 (C), 144.5 (CH),
152.4 (C), 152.9 (CH), 156.5 (C), 161.6 (C), 172.1 (C) ppm. IR
Product 38: Syrup (29%); two rotamers at 26 °C (1:1), one rotamer
at 70 °C. [α]D = = –3.3 (c = 0.97, MeOH). 1H NMR (CD3OD,
500 MHz, 70 °C): δH = 2.06 (s, 3 H), 2.67–2.73 (m, 1 H), 2.97 (ddd,
J = 5.7, 6.0, 14.9 Hz, 1 H), 3.59 (s, 3 H), 3.80 (d, J = 11.4 Hz, 1
H), 4.17 (dd, J = 4.7, 11.9 Hz, 1 H), 4.83 (d, J = 6.4 Hz, 2 H),
5.56–5.61 (m, 1 H), 6.39 (dd, J = 6.0, 7.9 Hz, 1 H), 7.21 (dd, J =
7.0, 7.3 Hz, 1 H), 7.28 (dd, J = 7.0, 7.3 Hz, 2 H), 7.36 (d, J =
7.9 Hz, 2 H), 8.05 (s, 1 H), 8.24 (s, 1 H) ppm. 13C NMR (CD3OD,
125.7 MHz, 70 °C): δC = 20.8 (CH3), 39.1 (CH2), 45.5 (CH2), 53.4
(CH3), 53.9 (CH2), 69.4 (CH), 74.0 (CH), 121.2 (C), 128.2 (CH),
128.6 (2ϫCH), 129.5 (2ϫCH), 140.4 (CH), 141.8 (C), 149.7 (C),
154.2 (CH), 156.2 (C), 156.7 (C), 172.2 (C) ppm. IR (film): ν =
˜
(film): ν = 3095, 3067, 1739, 1706, 1383, 1235 cm–1. MS (EI, 70 eV):
3428, 3095, 3067, 1737, 1705, 1618, 1230 cm–1. MS (EI, 70 eV):
m/z (%) = 410 (1) [M]+, 225 (100) [N-benzyladenine]+, 106 (66)
[PhCH2NH]+, 91 (41) [PhCH2]+. HRMS (EI, 70 eV): calcd. for
C20H22N6O4 410.1703; found 410.1706; calcd. for C12H11N5
225.1014; found 225.1019. C20H22N6O4 (410.43): calcd. C 58.53, H
5.40, N 20.48; found C 58.57, H 5.53, N 20.27.
˜
m/z (%) = 411 (19) [M]+, 352 (22) [M – MeCO2]+, 226 (100) [6-
benzyloxypurine]+, 91 (63) [PhCH2]+. HRMS (EI, 70 eV): calcd.
for C20H21N5O5 411.1543; found 411.1537; calcd. for C12H10N4O
226.0855; found 226.0850. C20H21N5O5 (411.42): calcd. C 58.39, H
5.14, N 17.02; found C 58.33, H 5.35, N 17.18.
N-Benzyl-9-[1-(methoxycarbonyl)-2-pyrrolidinyl]adenine (36): This
compound was obtained as a racemic mixture from N-(meth-
oxycarbonyl)--proline (10) and bis(trimethylsilyl)-N-benzyl-
adenine (purification by chromatography with CH2Cl2/MeOH
98:2); syrup (67%); two rotamers at 26 °C (1:1). 1H NMR
(CD3OD, 400 MHz, 26 °C): δH = 1.98–2.08 (m, 1 H), 2.10–2.30 (m,
2 H), 2.41 (br. s, 1 H), 3.54–3.64 (br. b, 3 H), 3.60–3.73 (m, 1 H),
3.84 (ddd, J = 3.7, 7.9, 11.4 Hz, 1 H), 4.79 (br. s, 2 H), 6.30 (dd, J
= 1.8, 6.6 Hz, 1 H), 7.21 (dd, J = 7.1, 7.4 Hz, 1 H), 7.27 (dd, J =
7.2, 7.4 Hz, 2 H), 7.34 (d, J = 7.2 Hz, 2 H), 8.05 (s, 1 H), 8.24 (s,
1 H) ppm. 13C NMR (CD3OD, 125.7 MHz, 26 °C): δC = 23.2/24.1
(CH2/CH2), 33.7/34.7 (CH2/CH2), 45.1 (CH2/CH2), 48.5/48.8 (CH2/
CH2), 53.5 (CH3/CH3), 69.9/70.7 (CH/CH), 120.9 (C/C), 128.2
(2ϫCH/CH), 128.5 (2ϫCH/CH), 128.6 (CH/CH), 140.3 (CH/
CH), 140.6 (C/C), 149.3 (C/C), 153.8 (C/C), 156.0 (CH/CH), 156.5
Supporting Information (see also the footnote on the first page of
this article): Preparation of proline precursor 45, synthesis and
spectroscopic data for products 46–53. 1H and 13C NMR spectra
of the new compounds 12, 15–38, 46–53.
Acknowledgments
This work was supported by the Investigation Programmes
CTQ2006-14260/PPQ and CTQ2009-07109 of the Plan Nacional
de Investigación Científica, Desarrollo e Innovación Tecnológica,
Ministerio de Educación y Ciencia (MEC) and Ministerio de Cien-
cia e Innovación (MICINN), Spain. We also acknowledge financial
support from FEDER funds. D. H. thanks MEC for an FPU fel-
lowship, and the Gobierno de Canarias (ACIISI)ϪBIOSIGMA SL
for a research contract.
(C/C) ppm. IR (film): ν = 3428, 3325, 3030, 3019, 1701, 1618, 1226,
˜
1205 cm–1. MS (EI, 70 eV): m/z (%) = 352 (10) [M]+, 225 (91) [N-
benzyladenine]+, 128 (100) [M + H – N-benzyladenine]+, 106 (48)
[PhCH2NH]+. HRMS (EI, 70 eV): calcd. for C18H20N6O2
352.1648; found 352.1641; calcd. for C6H10NO2 128.0712; found
128.0708. C18H20N6O2 (352.40): calcd. C 61.35, H 5.72, N 23.85;
found C 61.29, H 6.07, N 24.13.
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DIB is also known as bis(acetoxyiodo)benzene (BAIB).
Any source of visible light can be used. However, to obtain
reproducible results, we carried out the scission with 80 W
tungsten-filament lamps, available in DIY shops.
[10]
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3856
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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,
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Received: March 16, 2010
Published Online: May 19, 2010
Eur. J. Org. Chem. 2010, 3847–3857
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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