One-pot conversion of proline derivatives into iodinated iminosugar-based nucleosides, useful precursors of highly functionalized nucleoside analogues

Article abstract of DOI:10.1002/ejoc.201000997

Readily available proline derivatives can be transformed in one step into β-iodinated iminosugar-based nucleosides, under very mild conditions. The method couples a tandem radical decarboxylation-oxidation-β-iodination to the addition of nitrogen bases. T

Full text of DOI:10.1002/ejoc.201000997

FULL PAPER
DOI: 10.1002/ejoc.201000997
One-Pot Conversion of Proline Derivatives into Iodinated Iminosugar-Based
Nucleosides, Useful Precursors of Highly Functionalized Nucleoside Analogues
Alicia Boto,*[a] Dácil Hernández,[a] and Rosendo Hernández*[a]
Keywords: Radical reactions / Amino acids / Nucleosides / Nitrogen heterocycles / Sequential processes
Readily available proline derivatives can be transformed in
one step into β-iodinated iminosugar-based nucleosides, un-
der very mild conditions. The method couples a tandem radi-
cal decarboxylation–oxidation–β-iodination to the addition of
nitrogen bases. The iodo group is introduced into the pre-
viously unfunctionalized 3-position. The resultant β-iodo de-
rivatives are useful precursors of highly functionalized
nucleoside analogues.
Due to their interesting biological properties, the synthe-
sis of these nucleoside analogues and related alkaloids has
received the attention of many research groups.[5] We rea-
soned that in order to prepare a diversity of highly func-
tionalized derivatives, the β-iodo compounds 4 could be
used as precursors, because the iodo group can be elimin-
ated or replaced by many other functional groups.
In a previous work, we reported the tandem radical de-
carboxylation–oxidation of proline derivatives 5a and 5b
(Scheme 1) to give the acyliminium ion 6, which was
Introduction
The structural modification of nucleosides and nucleo-
tides has allowed the discovery of new antiviral, antibiotic,
antitumoral, and antifungal agents.[1] In the iminosugar-
based nucleosides, the furanose ring is replaced by nitrogen
heterocycles; some examples are N-acetylazathymidine
(1),[2] which was incorporated to oligonucleotides to reduce
their degradation by 3Ј-exonucleases, and immucilin-H
(2),[3] which prevents the uncontrolled proliferation of T-
cells. Furthermore, some alkaloids resemble iminosugar-
based C-nucleosides, such as codonopsin (3),[4] isolated
from roots of Codonopsis sp, which has hypotensive activity
without any effect on the central nervous system (Figure 1).
Figure 1. Bioactive iminosugar-based nucleosides.
[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
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000997.
Scheme 1. One-pot conversion of proline derivatives into imino-
sugar-based nucleosides.
Eur. J. Org. Chem. 2010, 6633–6642
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6633

A. Boto, D. Hernández, R. Hernández
FULL PAPER
trapped by nitrogen bases to afford the nucleoside ana- conditions were assessed, and the best results were obtained
logues 7.[6] The one-pot process took place in high yields with dichloromethane as solvent, and 1 equiv. of iodine (ex-
under very mild conditions.
cess halogen gave complex product mixtures). Thus, the
In this article, we report a variation of the process that one-pot process afforded three isomeric nucleoside ana-
allows iodination of the previously unfunctionalized 3-posi- logues 15–17 (Scheme 3) in good global yield (66%). The
tion,[7] giving the acyliminium intermediate 8,[8,9] which re- major product was the 2,3-trans-diastereoisomer (Ϯ)-15
acts with nitrogen bases to give the iodinated iminosugar- (48%), which was obtained along with the 2-benzotriazole
based nucleosides 9. We also report the conversion of these isomer (Ϯ)-16 (7%). In this reaction, the 2,3-cis product
products into other 2,3,4-substituted nucleoside derivatives (Ϯ)-17 (11%) was also isolated.
and into tricyclic systems.
Results and Discussion
Development of the Radical Scission–Oxidation–
β-Iodination–Addition of Nitrogen Base Process
The process was initially studied with proline methyl
carbamate 10[10] (Scheme 2), which was treated with (di-
acetoxyiodo)benzene (DIB, also called BAIB) and iodine
under irradiation with visible light.[11] A radical decarboxyl-
ation ensued, generating a 2-pyrrolidinyl radical, which was
readily oxidized to the iminium ion 11.[8] This intermediate
isomerized to the encarbamate 12,[7] which, in the presence
of excess iodine, was halogenated to generate a second acyl-
iminium ion 13.[12] This ion was trapped by the nucleophile
bis(trimethylsilyl)fluorouracil,[13] yielding the iodinated 2,3-
trans-nucleoside analogue 14; the 2,3-cis-isomer was not de-
tected. Product 14 was isolated in 50% yield and, therefore,
Scheme 3. One-pot conversion of proline derivative 10 into the
iodinated nucleoside analogues 15–17.
each of the steps involved in the sequence took place in
excellent yield.
The process also worked with the purine bases trimethyl-
silyl-chloropurine
and
trimethylsilyl-benzyloxypurine
(Scheme 4). In these cases, the best results were obtained
when the intermediate acyliminium ion was trapped with
methanol to give (Ϯ)-18,[7b] followed by solvent removal
and replacement with acetonitrile. After addition of the si-
lylated base and the Lewis acid at 0 °C, separable mixtures
of non-halogenated and iodinated products were obtained.
In the case of the chloropurine derivatives, the non-halo-
genated product (Ϯ)-19 (11%)[6] and the desired 2,3-trans-
3-iodo-nucleoside analogue (Ϯ)-20 (47%) were readily sepa-
rated. The chloro group in 6-chloropurine can be replaced
by other groups (amino, aryl, or alkyl, etc) using spn–spn
couplings, radical reactions, etc.,[15] which allows the forma-
tion of libraries of nucleoside derivatives. Moreover, the in-
troduction of a halogen often results in interesting bio-
logical activities.[1g]
In a similar manner, the reaction with trimethylsilyl-
benzyloxypurine gave the non-iodinated derivative (Ϯ)-21
(10%)[6] and the desired β-iodo-nucleoside analogue (Ϯ)-22
(40%).
The manipulation of the iodo group introduced on C-3
is particularly interesting because it allows the preparation
of a range of nucleoside derivatives. Thus, dehalogenation
Scheme 2. One-pot conversion of proline derivative 10 into the
iodinated iminosugar-based nucleoside 14.
The process was also studied with trimethylsilyl-benzotri- could afford analogues of unsaturated antiviral drugs such
azole, because several triazolyl nucleosides are potent cyto- as abacavir or stavudine.[1,16] These unsaturated analogues
toxic, antiviral, and fungicide agents.[14] Several reaction could be further functionalized by dihydroxylation, amino-
6634
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6633–6642

Iodinated Iminosugar-Based Nucleosides
evaporation, yielding a residue, which was treated with
methanolic KOH, affording product 26. The yield obtained
in the simplified process (55%) was superior to the global
yield of the two-step method (37%).
The simplified methodology also allowed preparation of
the crude β-iodo-iminosugar-based nucleosides 23–25, de-
rived from iodouracil, thymine, and uracil, respectively.
These crude products were cyclized to give compounds 27
(50%), 28 (54%), and 29 (57%), respectively. To the best
of our knowledge, only one example of a related tricyclic
azacompound has been reported.[18a] In this manner, a sim-
ple amino acid derivative (substrate 10) was readily con-
verted into complex tricyclic systems in good global yields,
in a short period of time, while avoiding the purification of
reaction intermediates.
When the 4R-acetoxy proline derivative 30 (Scheme 6)
was used as the substrate, and bis(trimethylsilyl)fluorouracil
as the base, the reaction afforded the all-trans compound
33 as the major product (51%). Interestingly, the all-cis
product 34 was obtained as the minor product (15%),[19]
a
result which can be explained by using Woerpel’s model for
the addition of nucleophiles to cyclic iminium (or oxycarb-
enium) ions.[20]
Scheme 4. One-pot conversion of proline derivative 10 into the imino-
sugar-based nucleosides 19–22.
hydroxylation, or epoxidation followed by addition of nu-
cleophiles, etc.[17]
The iodo group can also be replaced by other functions,
as shown in Scheme 5 (conversions 14, 23–25 Ǟ 26–29).
Thus, by treatment of pure β-iodo derivative 14 with meth-
anolic KOH, an intramolecular SN2 reaction took place,
yielding the tricyclic compound 26[18] in 73% yield (37%
from proline substrate 10).
Scheme 6. One-pot conversion of hydroxyproline derivative 30 into
β-iodo-nucleoside analogues 33 and 34, and an explanation of the
stereoselectivity of the process.
Scheme 5. One-pot conversion of proline derivative 10 into tricyclic
compounds. a Intermediates 14, 23–25 were not isolated, but trans-
formed directly into products 26–29, respectively.
A simplified scission–β-iodination–base addition–cycli-
Thus, the possible acyliminium intermediates 31 or 32
zation process was then developed in which the β-iodo-nu- adopt envelope conformations in which the benzyloxy
cleoside analogue 14 was not purified. Thus, the proline group is in a pseudoaxial position, allowing stabilizing elec-
derivative 10 underwent the usual scission and addition of trostatic interactions between the oxygen lone electron pairs
the nitrogen base, followed by aqueous work-up and solvent and the iminium ion.
Eur. J. Org. Chem. 2010, 6633–6642
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6635

A. Boto, D. Hernández, R. Hernández
FULL PAPER
The silylated base adds preferentially from the inner face highly functionalized iminosugar-based nucleosides can be
because, in the resultant staggered structure, the substitu- prepared in a few steps, which can enable structure–bio-
ents at C-2 and C-3 are not eclipsed. Moreover, in the case logical activity relationships to be studied.[22]
of intermediate 31, addition from the inner face also avoids
repulsive interactions with the iodo group. In the case of
intermediate 32, the halogen is in a pseudoequatorial posi-
tion, and the interactions with the entering base are small.
In contrast, addition of the nucleophile from the outer
face of intermediates 31 and 32 is disfavored: in this case
the initially-formed trans product presents strong eclipsing
interactions between the substituents at C-2 and C-3.[6,20]
Due to this effect, the all-cis pyrrolidine 34 is formed in
spite of the steric hindrance posed by the iodo group once
the initially-formed trans product equilibrates to its other
conformations.
When the pure 4-acetoxy derivative 33 was treated under
basic conditions (methanolic KOH) the acetate was hy-
drolyzed (Scheme 7), and then an intramolecular SN2 took
place to give the epoxide 38 in 75% yield (38% from proline
substrate 30). When the simplified decarboxylation–base
addition–cyclization process was applied to the proline de-
rivative 30, the yield of epoxide 38 was notably increased
(50%). In a similar manner, proline 30 was transformed
into the epoxides 39 (53%), 40 (53%), and 41 (51%). In
preliminary screenings, the epoxy derivatives 38–40 dis-
played promising antifungal activity, which is currently un-
der study.
Scheme 8. Transformation of epoxy derivative 38 into a range of
2,3,4-substituted nucleoside analogues 42–45.
Conclusions
Readily available proline derivatives can be directly trans-
formed into β-iodinated iminosugar-based nucleosides by
using a radical scission–oxidation–β-iodination–addition of
nitrogen base process. The introduction of an iodo group
in a previously unfunctionalized position is remarkable, and
allows further derivatization of the products. Thus, by using
an intramolecular SN2 reaction, epoxy and other tricyclic
nucleoside analogues were obtained in good global yields.
The epoxy derivatives, which display interesting antifungal
activities, were useful precursors of highly functionalized
Scheme 7. One-pot conversion of hydroxyproline derivative 30 into
compounds bearing oxygen, nitrogen, and sulfur function-
alities. In this manner, by using simple proline precursors,
a library of nucleoside analogues can be prepared efficiently
in very few steps.
tricyclic iminosugar-based nucleosides 38–41. [a] Intermediates 35–
37 were not isolated, but transformed directly into products 39–41,
respectively.
The epoxides can be valuable precursors of a variety of
nucleoside analogues (Scheme 8).[21] For instance, by cleav-
age of epoxide 38 with sodium azide, the regioisomers 42
and 43 were isolated in good yield (75%), albeit as an in-
separable mixture (42/43, 4:1). When thiophenol was used
as the nucleophile, epoxide 38 underwent ring opening to
give the nucleoside analogues 44 (37%) and 45 (13%).
Experimental Section
Preparation of Trimethylsilyl Derivatives of the Nitrogen Bases:
Some trimethylsilyl derivatives from the nitrogen bases are com-
mercially available, but use of these products gave variable yields.
However, the reagents can be readily prepared by treatment of the
Therefore, from readily available amino acids, a library of bases (0.4 mmol) with N,O-bis(trimethylsilyl)acetamide (297 μL,
6636 Eur. J. Org. Chem. 2010, 6633–6642
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Iodinated Iminosugar-Based Nucleosides
244 mg, 1.2 mmol) under nitrogen. The mixture was heated to
130 °C and stirred for 1 h, then was cooled to 26 °C and anhydrous
toluene (1 mL) was added. The volatiles were removed under vac-
uum, and the operation was repeated twice. The silylated bases
were used in the next step without further purification.
(hexanes/EtOAc, 8:2 then 6:4), yielding the 2,3-trans product (Ϯ)-
15 (36 mg, 48%), its regioisomer (Ϯ)-16 (5 mg, 7%), and the 2,3-
cis product (Ϯ)-17 (8.3 mg, 11%).
Compound (؎)-15: Colorless oil; two rotamers at 26 °C (5:2), one
rotamer at 70 °C. IR (CDCl ): ν = 3095, 1707, 1614, 1591, 1132,
˜
3
1075 cm–1. 1H NMR (C6D6, 500 MHz): major rotamer δ = 1.71
(dd, J = 6.7, 14.8 Hz, 1 H), 2.81 (m, 1 H), 3.19 (s, 3 H), 3.37 (dd,
J = 9.0, 9.6 Hz, 1 H), 3.58 (m, 1 H), 4.02 (d, J = 5.2 Hz, 1 H), 6.73
(s, 1 H), 6.92 (dd, J = 7.6, 7.7 Hz, 1 H), 7.05 (dd, J = 7.6, 7.6 Hz,
1 H), 7.59 (d, J = 8.1 Hz, 1 H), 7.89 (d, J = 8.6 Hz, 1 H); minor
rotamer δ = 1.54 (dd, J = 6.2, 14.3 Hz, 1 H), 2.30 (m, 1 H), 3.01
(s, 3 H), 3.64 (m, 1 H), 3.75–3.82 (m, 2 H), 6.54 (s, 1 H), 6.92 (dd,
J = 7.6, 7.7 Hz, 1 H), 6.97 (d, J = 8.6 Hz, 1 H), 7.01 (dd, J = 6.7,
7.7 Hz, 1 H), 7.91 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR (C6D6,
125.7 MHz): major rotamer δ = 24.5 (CH), 36.4 (CH2), 45.7 (CH2),
52.6 (CH3), 79.6 (CH), 110.9 (CH), 119.9 (CH), 124.1 (CH), 127.7
(CH), 133.3 (C), 146.1 (C), 155.4 (C); minor rotamer δ = 25.5 (CH),
34.8 (CH2), 46.5 (CH2), 52.6 (CH3), 79.6 (CH), 109.7 (CH), 120.8
(CH), 124.1 (CH), 127.7 (CH), 136.3 (C), 146.3 (C), 155.4 (C) ppm.
MS: m/z (%) = 372 (7) [M+], 254 (84) [M+ + H – benzotriazole],
253 (24) [M+ – benzotriazole], 127 (100) [M+ + H – (benzotriazole
+ I)]. HRMS: calcd. for C12H13IN4O2 372.0083; found 372.0118;
calcd. for C6H9NO2 127.0633; found 127.0599. C12H13IN4O2
(372.17): calcd. C 38.73, H 3.52, N 15.05; found C 38.53, H 3.26,
N 14.78.
General Procedures for the One-Pot β-Scission–β-Iodination–Base
Addition Process
Method A (for Pyrimidine Bases): To a solution of l-proline methyl
carbamate 10 (35 mg, 0.2 mmol) or 4-acetoxyproline methyl carb-
amate 30 (46 mg, 0.2 mmol) in anhydrous CH3CN, were added
DIB (129 mg, 0.4 mmol) and iodine (102 mg, 0.4 mmol). The mix-
ture was stirred at 26 °C under irradiation with visible light (80-W
tungsten-filament lamp) for 3 h, then cooled to 0 °C and the freshly
prepared silylated base (0.4 mmol) was added dropwise, followed
by BF3·OEt2 (57 mg, 50 μL, 0.4 mmol). The mixture was allowed
to reach room temp. and stirring was continued for 1 h. The solu-
tion was poured into into 10% aqueous sodium thiosulfate and
saturated aqueous NaHCO3 (1:1) and extracted with dichlorometh-
ane. The organic layer was dried (Na2SO4), filtered and the solvents
evaporated under vacuum. The residue was purified by chromatog-
raphy on silica gel (hexanes/EtOAc), affording the β-iodo-nucleo-
side analogues.
Method B (for Benzotriazole): Similar to Method A, but using an-
hydrous CH2Cl2 (4 mL) as solvent and only 1 equiv. of iodine
(51 mg, 0.2 mmol).
Compound (؎)-16: Syrup, two rotamers at 26 °C (6:5), one rotamer
Method C (for Purine Bases): Similar to Method A, but the scission
was carried out in anhydrous CH2Cl2 heated to reflux. After 2 h,
the reaction mixture was cooled to r.t. (25 °C) and anhydrous meth-
anol was added (0.25 mL). Stirring was continued for 0.5 h and
then the solvent was removed under vacuum and the residue was
redissolved in anhydrous CH3CN, cooled to 0 °C, and treated with
the silylated base (0.4 mmol) and BF3·OEt2 (0.4 mmol) as described
in Method A. Usual work-up and purification by chromatography
on silica gel (hexanes/EtOAc), afforded the β-iodo-nucleoside ana-
logues.
at 70 °C. IR (CHCl ): ν = 3096, 3074, 3062, 1716, 1564, 1243,
˜
3
843 cm–1. 1H NMR (C6D6, 500 MHz): major rotamer δ = 1.48 (dd,
J = 5.9, 14.6 Hz, 1 H), 2.24 (m, 1 H), 3.10 (s, 3 H), 3.71 (m, 1 H),
3.81–3.91 (m, 2 H), 6.96–6.99 (m, 3 H), 7.69–7.73 (m, 2 H); minor
rotamer δ = 1.55 (dd, J = 6.3, 14.6 Hz, 1 H), 2.34 (m, 1 H), 3.26
(s, 3 H), 3.65 (m, 1 H), 3.81–3.91 (m, 2 H), 6.93–6.99 (m, 2 H),
7.30 (s, 1 H), 7.68–7.74 (m, 2 H) ppm. 13C NMR (C6D6,
125.7 MHz): major rotamer δ = 24.9 (CH), 33.9 (CH2), 46.6 (CH2),
52.8 (CH3), 86.1 (CH), 118.8 (2 ϫ CH), 127.0 (2 ϫ CH), 144.9
(2ϫC), 155.4 (C); minor rotamer δ = 23.8 (CH), 34.9 (CH2), 46.0
(CH2), 52.8 (CH3), 86.7 (CH), 118.8 (2ϫ CH), 126.8 (2 ϫ CH),
145.0 (2ϫC), 154.4 (C) ppm. MS: m/z (%) = 372 (7) [M+], 254
(100) [M+ + H – benzotriazole], 127 (68) [M+ + H – (benzotriazole
+ I)]. HRMS: calcd. for C12H13IN4O2 372.0083; found 372.0083;
calcd. for C6H9INO2 253.9678; found 253.9745. C12H13IN4O2
(372.17): calcd. C 38.73, H 3.52, N 15.05; found C 38.84, H 3.26,
N 14.76.
5-Fluoro-1-[(2R*,3S*)-3-iodo-N-(methoxycarbonyl)-2-pyrrolidinyl]-
uracil (14): Obtained from proline methyl carbamate 10 and bis(tri-
methylsilyl)-5-fluorouracil according to Method A (38.5 mg, 50%).
Two rotamers at 26 °C (2:1), one rotamer at 70 °C; crystalline solid;
m.p. 246–249 °C (from MeOH, decomposition). IR (film): ν =
˜
3547, 3378, 1713, 1664, 1259, 1177 cm–1 1H NMR (500 MHz,
.
CD3OD, 70 °C): δ = 2.22 (m, 1 H), 2.27 (m, 1 H), 3.72–3.87 (m, 5
H), 4.55 (br. band; d, J = 4.5 Hz at 26 °C, 1 H), 6.09 (br. s, 1 H),
7.71 (d, JF,H = 6.4 Hz, 1 H) ppm. 13C NMR (125.7 MHz, CD3OD,
26 °C): major rotamer δ = 24.5 (CH), 34.9 (CH2), 47.5 (CH2), 54.1
(CH3), 81.7 (CH), 125.5 (CH, d, JC,F = 34.7 Hz), 141.4 (C, d, JC,F
= 234.3 Hz), 150.7 (C), 156.8 (C), 159.4 (C, d, JC,F = 26.0 Hz);
minor rotamer δ = 25.1 (CH), 33.1 (CH2), 47.6 (CH2), 54.1 (CH3),
Compound (؎)-17: Colorless oil, two rotamers at 26 °C (3:2), one
rotamer at 70 °C. IR (CDCl ): ν = 3071, 1706, 1614, 1592, 1216,
˜
3
1081, 972 cm–1. 1H NMR (C6D6, 500 MHz): major rotamer δ =
1.82 (m, 1 H), 2.92 (m, 1 H), 3.06 (m, 1 H), 3.18 (s, 3 H), 3.42 (dd,
J = 9.4, 9.5 Hz, 1 H), 3.57 (m, 1 H), 6.17 (d, J = 6.0 Hz, 1 H), 6.93
(dd, J = 7.5, 7.7 Hz, 1 H), 7.13 (dd, J = 8.0, 8.0 Hz, 1 H), 7.48 (d,
J = 8.3 Hz, 1 H), 7.93 (d, J = 8.4 Hz, 1 H); minor rotamer δ = 1.76
(m, 1 H), 2.83 (m, 1 H), 3.00 (s, 3 H), 3.14 (m, 1 H), 3.59 (m, 1
H), 3.63 (m, 1 H), 5.82 (d, J = 5.9 Hz, 1 H), 6.93 (m, 1 H), 7.10–
7.20 (m, 2 H), 7.96 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR (C6D6,
100.6 MHz): major rotamer δ = 19.2 (CH), 34.9 (CH2), 46.6 (CH2),
52.6 (CH3), 72.7 (CH), 110.1 (CH), 120.4 (CH), 124.2 (CH), 127.6
(CH), 134.6 (C); minor rotamer δ = 20.3 (CH), 33.9 (CH2), 47.1
(CH2), 56.3 (CH3), 72.0 (CH), 109.4 (CH), 120.8 (CH), 124.2 (CH),
127.6 (CH), 134.6 (C) ppm; two (C) signals corresponding to an
aromatic carbon and the carbamate CO group were not clearly
observed. MS: m/z (%) = 372 (11) [M+], 254 (100) [M+ + H –
benzotriazole], 127 (79) [M+ + H – (benzotriazole + I)]. HRMS:
calcd. for C12H13IN4O2 372.0083; found 372.0077; calcd. for
81.0 (CH), 125.5 (CH, d, JC,F = 34.7 Hz), 141.4 (C, d, JC,F
=
234.3 Hz), 150.7 (C), 156.8 (C), 159.4 (C, d, JC,F = 26.0 Hz) ppm.
MS (EI): m/z (%) = 352 (1) [M+ – OMe], 254 (89) [M+ + H – 5-
fluorouracil], 127 (100) [M+ + H – (5-fluorouracil + I)]. HRMS:
calcd. for C9H8FIN3O3 351.9594; found 351.9581; calcd. for
C6H9NO2 127.0633; found 127.0629. C10H11FIN3O4 (383.12):
calcd. C 31.35, H 2.89, N 10.97; found C 31.54, H 2.96, N 10.77.
1-[(2R*,3S*)-3-Iodo-N-(methoxycarbonyl)-2-pyrrolidinyl]benzotri-
azole (15), 2-[(2R*,3S*)-3-Iodo-N-(methoxycarbonyl)-2-pyrrolidinyl-
]benzotriazole (16), and 1-[(2R*,3R*)-3-Iodo-N-(methoxycarbonyl)-
2-pyrrolidinyl]benzotriazole (17): Obtained from proline methyl
carbamate 10 and (trimethylsilyl)benzotriazole according to
Method B. The reaction mixture was purified by chromatography
Eur. J. Org. Chem. 2010, 6633–6642
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6637

A. Boto, D. Hernández, R. Hernández
C6H9INO2 253.9678; found 253.9659. C12H13IN4O2 (372.17): carbamate 10 (35 mg, 0.2 mmol) or 4-acetoxyproline methyl carb-
FULL PAPER
calcd. C 38.73, H 3.52, N 15.05; found C 39.01, H 3.28, N 14.96.
amate 30 (46 mg, 0.2 mmol) in anhydrous MeCN underwent the
tandem fragmentation–β-iodination–base addition process, as re-
ported for compounds 14 and 33. After usual work-up and solvent
evaporation, the residue was treated with 5% methanolic KOH
(2 mL) and the mixture was stirred at 26 °C for 2 h. The solvent
was partially removed under vacuum, followed by work-up and
purification as described in the previous procedure.
6-Chloro-9-[N-(methoxycarbonyl)-2-pyrrolidinyl]purine (؎-19) and
6-Chloro-9-[(2R*,3S*)-3-iodo-N-(methoxycarbonyl)-2-pyrrolidinyl]-
purine (؎)-20: Obtained from proline methyl carbamate 10 and (tri-
methylsilyl)chloropurine according to Method C. The reaction mix-
ture was purified by chromatography (hexanes/EtOAc, 7:3), yield-
ing the non-halogenated product (Ϯ)-19 (6 mg, 11%)[6] and the
iodinated compound (Ϯ)-20 (38 mg, 47%).
(3aR*,9aS*)-7-Fluoro-N-(methoxycarbonyl)-6-oxo-2,3,3a,9a-tetra-
hydropyrrolo[2Ј,3Ј:4,5][1,3]oxazolo[3,2-a]pyrimidine (26): Obtained
from substrate 10 and bis(trimethylsilyl)-5-fluorouracil, following
the simplified procedure for the synthesis of fused tricyclic com-
pounds (28 mg, 55%). Two rotamers at 26 °C (2:1), one rotamer at
70 °C; crystalline solid; m.p. 175–177 °C (from MeOH). IR
Compound (؎)-20: Syrup. IR (CHCl ): ν = 1693, 1592, 1561, 1454,
˜
3
1207, 1127, 985 cm–1. NMR (500 MHz, CD3OD, 70 °C): δ = 2.36
1
(dddd, J = 3.6, 3.6, 6.8, 14.2 Hz, 1 H), 2.71 (dddd, J = 5.8, 5.8,
8.2, 14.3 Hz, 1 H), 3.66 (br. s, 3 H), 3.87–3.97 (m, 2 H), 4.85 (ddd,
J = 2.3, 3.4, 5.7 Hz, 1 H), 6.57 (d, J = 2.2 Hz, 1 H), 8.50 (s, 1 H),
8.71 (s, 1 H) ppm. 13C NMR (CD3OD, 70 °C, 125.7 MHz): δ =
23.1 (CH), 36.2 (CH2), 48.5 (CH2), 53.8 (CH3), 80.5 (CH), 133.1
(C), 146.5 (CH), 152.3 (C), 153.1 (CH), 156.0 (C), 156.8 (C) ppm.
MS (EI): m/z (%) = 378/376 (0.58/1.52) [M+ – OMe], 254 (100)
[iodo-N-methylcarbamate-pyrrolidine – H]+, 127 (85) [2,3-dehy-
(CDCl ): ν = 1703, 1660, 1573, 1247, 1116 cm–1 1H NMR
.
˜
3
(500 MHz, CDCl3, 70 °C): δ = 2.30 (m, 1 H), 2.46 (dd, J = 6.1,
14.7 Hz, 1 H), 3.46 (ddd, J = 6.3, 11.1, 11.1 Hz, 1 H), 3.82 (s, 3
H), 3.93 (m, 1 H), 5.57 (dd, J = 5.9, 6.0 Hz, 1 H), 6.28 (d, J =
6.2 Hz, 1 H), 7.71 (br. band, 1 H) ppm. 13C NMR (125.7 MHz,
CDCl3, 70 °C): δ = 30.8 (CH2), 44.0 (CH2), 53.4 (CH3), 75.0 (CH),
83.8 (CH), 120.6 (CH, JC,F = 32 Hz), 146.2 (C, JC,F = 256 Hz),
152.8 (C), 157.9 (C), 163.9 (C, JC,F = 25.1 Hz) ppm. MS (EI): m/z
(%) = 255 (100) [M]+, 240 (5) [M+ – Me], 224 (6) [M+ – MeO], 125
(24) [methyl 1H-pyrrole-1-carboxylate]+. HRMS: calcd. for
C10H10FN3O4 255.0655; found 255.0651. C10H10FN3O4 (255.21):
calcd. C 47.06, H 3.95, N 16.47; found C 46.79, H 4.36, N 16.21.
dropyrrolidine-N-methylcarbamate]+.
HRMS:
calcd.
for
C10H837ClIN5O 377.9433/C10H835ClIN5O 375.9671; found
377.9439/375.9450; calcd. for C6H9INO2 253.9678; found 253.9671.
C11H11ClIN5O2 (407.60): calcd. C 32.41, H 2.72, N 17.18; found C
32.40, H 2.85, N 17.30.
6-(Benzyloxy)-9-[N-(methoxycarbonyl)-2-pyrrolidinyl]purine (؎)-21
and 6-(Benzyloxy)-9-[(2R*,3S*)-3-iodo-N-(methoxycarbonyl)-2-pyr-
rolidinyl]purine (؎)-22: Obtained from proline methyl carbamate
(10) and (trimethylsilyl)(benzyloxy)purine according to Method C.
The reaction mixture was purified by chromatography (hexanes/
EtOAc, 7:3 then 1:1), giving the non-halogenated product (Ϯ)-21
(7 mg, 10%)[6] and the iodinated compound (Ϯ)-22 (38 mg, 40%).
(3aR*,9aS*)-7-Iodo-N-(methoxycarbonyl)-6-oxo-2,3,3a,9a-tetrahydro-
pyrrolo[2Ј,3Ј:4,5][1,3]oxazolo[3,2-a]pyrimidine (27): Obtained from
substrate 10 and bis(trimethylsilyl)-5-iodouracil, following the sim-
plified procedure for the synthesis of fused tricyclic compounds
(36 mg, 50%).
Compound 27: Crystalline solid; m.p. 168–170 °C (from MeOH);
Compound (؎)-22: Syrup. IR (CHCl ): ν = 3089, 3066, 1705, 1601,
˜
3
two rotamers at 26 °C (2:1), one rotamer at 70 °C. IR (film): ν =
˜
1575, 1452, 1120, 1046 cm–1. NMR (500 MHz, CD3OD, 70 °C): δ
1
1
1702, 1690, 1264 cm–1. H NMR (CD3OD, 500 MHz, 70 °C): δ =
= 2.32 (dddd, J = 3.1, 3.2, 6.6, 13.9 Hz, 1 H), 2.66 (dddd, J = 8.0,
8.1, 8.2, 13.9 Hz, 1 H), 3.67 (s, 3 H), 3.87–3.97 (m, 2 H), 4.87 (m,
1 H), 5.68 (s, 2 H), 6.54 (d, J = 2.1 Hz, 1 H), 7.29 (dd, J = 7.3,
7.4 Hz, 1 H), 7.34 (J = 7.1, 7.7.2 Hz, 2 H), 7.50 (d, J = 7.2 Hz, 2
H), 8.22 (s, 1 H), 8.51 (s, 1 H) ppm. 13C NMR (CD3OD, 70 °C,
125.7 MHz): δ = 23.7 (CH), 36.1 (CH), 47.6 (CH2), 53.8 (CH3),
69.9 (CH2-Ph), 80.1 (CH), 122.8 (C), 129.2 (2ϫ CH), 129.3 (CH),
129.5 (2ϫ CH), 137.7 (C), 143.0 (CH), 152.8 (C), 153.4 (CH), 156.9
(C), 161.9 (C) ppm. MS (EI): m/z (%) = 479 (Ͻ1) [M+], 226 (17)
[benzyloxypurine]+, 128 (100) [2,3-dehydropyrrolidine methylcarb-
amate + H]+, 91 (45) [C7H7]+. HRMS: calcd. for C18H18IN5O3
479.0454; found 479.0470; calcd. for C6H10NO2 128.0712; found
128.0709. C18H18IN5O3 (479.28): calcd. C 45.11, H 3.79, N 14.61;
found C 45.30, H 3.99, N 14.68.
1.94 (m, 1 H), 2.19 (m, 1 H), 3.63 (ddd, J = 5.8, 7.9, 10.7 Hz, 1
H), 3.71 (s, 3 H), 3.72 (m, 1 H), 4.48 (dd, J = 5.7, 5.7, 5.7 Hz, 1
H), 6.09 (d, J = 5.5 Hz, 1 H), 7.67 (br. s, 1 H) ppm. 13C NMR
(CD3OD, 125.7 MHz, 70 °C): δ = 32.3 (CH2), 45.8 (CH2), 53.7
(CH3), 67.0 (C), 71.7 (CH), 73.3 (CH), 147.9 (CH), 152.5 (C), 157.2
(C), 162.7 (C) ppm. MS: m/z (%) = 363 (6) [M]+, 238 (36) [5-iodo-
uracil]+, 144 (100) [3-hydroxy-1-(methoxycarbonyl)pyrrolidine –
H]+. HRMS: calcd. for C10H10IN3O4 362.9716; found 362.9701;
calcd. for C6H10NO3 144.0661; found 144.0662. C10H10IN3O4
(363.11): calcd. C 33.08, H 2.78, N 11.57; found C 32.80, H 2.43,
N 11.30.
(3aR*,9aS*)-N-(Methoxycarbonyl)-7-methyl-6-oxo-2,3,3a,9a-tetra-
hydropyrrolo[2Ј,3Ј:4,5][1,3]oxazolo[3,2-a]pyrimidine (28): Obtained
from substrate 10 and bis(trimethylsilyl)thymine, following the sim-
plified procedure for the synthesis of fused tricyclic compounds
(27 mg, 54%). Two rotamers at 26 °C (2:1), one rotamer at 70 °C;
Conversion of β-Iodo-Nucleoside Analogues 14 or 33 into Polycyclic
Products 26 or 38: To a 5% methanolic solution of KOH (2 mL)
was added β-iodo-nucleoside analogue 14 (77 mg, 0.2 mmol) or 33
(88 mg, 0.2 mmol). The resulting suspension was stirred at 26 °C
for 2 h, then the solvent was partially removed under vacuum and
the mixture was poured into water and extracted with CH2Cl2. The
organic layer was dried, filtered and concentrated as usual, and
the residue was purified by chromatography on silica gel (CH2Cl2/
MeOH), affording the fused tricyclic compound 26 (37 mg, 73%
from substrate 14) or the epoxy derivative 38 (41 mg, 75% from
33).
crystalline solid; m.p. 175–177 °C (MeOH). IR (CHCl ): ν = 1693,
˜
3
1378, 1214, 1124 cm–1. H NMR (500 MHz, CD3OD, 70 °C): δ =
1
1.87 (s, 3 H), 1.93 (m, 1 H), 2.18 (m, 1 H), 3.59 (ddd, J = 6.7, 7.6,
10.6 Hz, 1 H), 3.69 (s, 3 H), 3.72 (ddd, J = 6.5, 7.4, 10.7 Hz, 1 H),
4.49 (ddd, J = 5.7, 6.0, 6.5 Hz, 1 H), 6.11 (d, J = 5.3 Hz, 1 H), 7.18
(s, 1 H) ppm. 13C NMR (125.7 MHz, CD3OD, 70 °C): δ = 12.2
(CH3), 32.2 (CH2), 45.6 (CH2), 53.5 (CH3), 71.8 (CH), 72.4 (CH),
110.6 (C), 139.1 (CH), 152.9 (C), 157.2 (C), 166.5 (C) ppm. MS
(EI): m/z (%) = 251 (24) [M]+, 144 (100) [3-hydroxy-1-(methoxycar-
bonyl)pyrrolidine – H]+, 126 (21) [thymine]+. HRMS: calcd. for
Simplified Procedure for the Synthesis of Fused Tricyclic Compounds
26–29 and Epoxy Compounds 38–41: A solution of proline methyl
C11H13N3O4 251.0906; found 251.0916; calcd. for C6H10NO3
6638
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6633–6642

Iodinated Iminosugar-Based Nucleosides
144.0661; found 144.0656. C11H13N3O4 (251.24): calcd. C 52.59, H
5.22, N 16.72; found C 52.21, H 5.53, N 16.40.
thesis of epoxy compounds (27 mg, 50%). Two rotamers at 26 °C
(2:1), one rotamer at 70 °C; syrup. [α]D = +10 (c = 0.41, CH3OH).
IR (CHCl ): ν = 3383, 1705, 1669, 1383, 1130, 1077 cm–1. 1H NMR
˜
3
(3aR*,9aS*)-N-(Methoxycarbonyl)-6-oxo-2,3,3a,9a-tetrahydropyr-
rolo[2Ј,3Ј:4,5][1,3]oxazolo[3,2-a]pyrimidine (29): Obtained from sub-
strate 10 and bis(trimethylsilyl)uracil, following the simplified pro-
cedure for the synthesis of fused tricyclic compounds (27 mg, 57%).
Two rotamers at 26 °C (8:1); one rotamer at 70 °C; crystalline solid;
(500 MHz, DMSO, 70 °C): δ = 3.57 (dd, J = 2.0, 12.3 Hz, 1 H),
3.58 (s, 3 H), 3.85 (d, J = 12.3 Hz, 1 H), 3.96 (dd, J = 2.3, 2.8 Hz,
1 H), 4.04 (dd, J = 2.4, 2.7 Hz, 1 H), 6.19 (dd, J = 1.7, 1.7 Hz, 1
H), 7.63 (d, J = 7.0 Hz, 1 H), 11.63 (br. band, 1 H) ppm. 13C NMR
(125.7 MHz, DMSO, 26 °C): major rotamer δ = 48.0 (CH2), 52.6
m.p. 155–157 °C (MeOH). IR (CDCl ): ν = 1702, 1648, 1385, 1214,
˜
3
(CH3), 54.9 (CH), 57.2 (CH), 67.9 (CH), 126.1 (CH, d, JC,F
=
1186, 1037 cm–1. H NMR (CDCl3, 400 MHz): δ = 2.28 (m, 1 H),
1
34.1 Hz), 140.0 (C, d, JC,F = 229.6 Hz), 149.0 (C), 155.0 (C), 156.8
(C, d, JC,F = 26.0 Hz); minor rotamer δ = 48.6 (CH2), 52.7 (CH3),
54.9 (CH), 57.8 (CH), 67.6 (CH), 126.0 (CH, d, JC,F = 34.1 Hz),
140.0 (C, d, JC,F = 229.6 Hz), 149.0 (C), 155.0 (C), 157.0 (C, d,
JC,F = 26.0 Hz) ppm. MS (EI): m/z (%) = 271 (98) [M]+, 141 (100)
[M+ – 5-fluorouracil], 59 (85) [MeOCO]. HRMS: calcd. for
C10H10FN3O5 271.0604; found 271.0602; calcd. for C6H7NO3
141.0426; found 141.0424. C10H10FN3O5 (271.20): calcd. C 44.29,
H 3.72, N 15.49; found C 44.59, H 3.45, N 15.21.
2.49 (dd, J = 6.1, 14.8 Hz, 1 H), 3.46 (ddd, J = 6.1, 11.4, 11.4 Hz,
1 H), 3.78 (s, 3 H), 3.88 (m, 1 H), 5.49 (dd, J = 5.7, 5.8 Hz, 1 H),
5.99 (d, J = 7.5 Hz, 1 H), 6.26 (d, J = 6.2 Hz, 1 H), 7.74 (d, J =
7.6 Hz, 1 H) ppm. 13C NMR (CDCl3, 100.6 MHz, 70 °C): δ = 30.6
(CH2), 43.8 (CH2), 53.3 (CH3), 74.1 (CH), 82.7 (CH), 109.9 (CH),
136.3 (CH), 160.2 (C), 171.8 (C) ppm; the (C) signal corresponding
to the carbamate is missing. MS (EI): m/z (%) = 237 (100)
[M]+, 125 (37) [methyl 1H-pyrrole-1-carboxylate]+. HRMS: calcd.
for C10H11N3O4 237.0750; found 237.0754. C10H11N3O4 (237.22):
calcd. C 50.63, H 4.67, N 17.71; found C 51.03, H 4.53, N 17.40.
1-[(2R,3S,4R)-3,4-Epoxy-N-(methoxycarbonyl)-2-pyrrolidinyl]-5-
iodouracil (39): Obtained from substrate 30 and bis(trimethylsilyl)-
5-iodouracil, following the simplified procedure for the synthesis
of epoxy compounds (40 mg, 53%). Crystalline solid, m.p. 118–
120 °C (MeOH); colorless crystals; two rotamers at 26 °C (3:1), one
1-[(2S,3R,4S)-4-Acetoxy-3-iodo-N-(methoxycarbonyl)-2-pyrrolidin-
yl]-5-fluorouracil (33) and 1-[(2R,3S,4S)-4-Acetoxy-3-iodo-N-(meth-
oxycarbonyl)-2-pyrrolidinyl]-5-fluorouracil (34): Obtained from 4-
acetoxyproline 30 and bis(trimethylsilyl)-5-fluorouracil as a separa-
ble diastereomer mixture (chromatography on silica gel; hexanes/
EtOAc, 7:3).
rotamer at 70 °C. [α]D = +77 (c = 0.41, MeOH). IR (CHCl ): ν =
˜
3
3379, 1716, 1690, 1255, 1129, 1052 cm–1 1H NMR (CD3OD,
.
500 MHz, 70 °C): δ = 3.47 (dd, J = 2.0, 12.6 Hz, 1 H), 3.57 (s, 3
H), 3.71 (dd, J = 2.1, 3.1 Hz, 1 H), 3.76 (d, J = 12.6 Hz, 1 H), 3.85
(dd, J = 2.1, 3.0 Hz, 1 H), 6.19 (d, J = 2.0 Hz, 1 H), 7.28 (s, 1 H),
7.79 (s, 1 H) ppm. 13C NMR (CD3OD, 125.7 MHz, 26 °C): major
rotamer δ = 49.2 (CH2), 53.6 (CH3), 55.8 (CH), 58.2 (CH), 68.3
(C), 69.5 (CH), 147.0 (CH), 152.0 (C), 156.9 (C), 162.3 (C); minor
rotamer δ = 49.5 (CH2), 54.1 (CH3), 55.7 (CH), 58.8 (CH), 68.3
(C), 71.0 (CH), 147.0 (CH), 152.0 (C), 156.9 (C), 162.3 (C) ppm.
MS: m/z (%) = 379 (14) [M]+, 142 (100) [M+ + H – 5-iodouracil].
HRMS: calcd. for C10H10IN3O5 378.9665; found 378.9671; calcd.
for C6H8NO3 142.0504; found 142.0502. C10H10IN3O5 (379.11):
calcd. C 31.68, H 2.66, N 11.08; found C 31.48, H 2.63, N 10.68.
Compound 33: Yield 45 mg (51%); two rotamers at 26 °C (1:1), one
rotamer at 70 °C; colorless oil. [α]D = –20 (c = 0.25, CH3OH). IR
(film): ν = 3375, 1721, 1751, 1723, 1666, 1376, 1262, 1228,
˜
1198 cm–1. 1H NMR (500 MHz, CD3OD, 70 °C): δ = 1.99 (s, 3 H),
3.79 (s, 3 H), 3.91 (br. d, J = 12.5 Hz, 1 H), 4.26 (dd, J = 4.9,
12.5 Hz, 1 H), 4.48 (br. s, 1 H), 5.39 (br. d, J = 4.9 Hz, 1 H), 6.20
(s, 1 H), 7.74 (d, JF,H = 6.7 Hz, 1 H) ppm. 13C NMR (125.7 MHz,
CD3OD, 70 °C): δ = 20.5 (CH3), 23.8 (CH), 52.6 (CH2), 54.3
(CH3), 79.7 (CH), 81.3 (CH), 126.0 (CH, d, JC,F = 35.2 Hz), 142.0
(C, d, JC,F = 233 Hz), 150.9 (C), 152.7 (C), 170.7 (C) ppm. The
(C) signal corresponding to the uracil amide (C-4Ј) was not clearly
observed. MS (EI): m/z (%) = 410 (1) [M+ – MeO], 312 (29) [M+
+ H – fluorouracil], 252 (74) [M+ – (5-fluorouracil + MeCO2)],
125 (100) [M+ – (5-fluorouracil + MeCO2 + I)]. HRMS: calcd.
for C11H10FIN3O5 409.9649; found 409.9643; calcd. for C6H7NO2
125.0477; found 125.0475. C12H13FIN3O6 (441.15): calcd. C 32.67,
H 2.97, N 9.53; found C 33.06, H 3.18, N 9.26.
1-[(2R,3S,4R)-3,4-Epoxy-N-(methoxycarbonyl)-2-pyrrolidinyl]thym-
ine (40): Obtained from substrate 30 and bis(trimethylsilyl)thymine,
following the simplified procedure for the synthesis of epoxy com-
pounds (28 mg, 53%). Two rotamers at 26 °C (4:1); one rotamer at
70 °C; syrup. [α]D = +44 (c = 0.24, MeOH). IR (CHCl ): ν = 3395,
˜
3
1703, 1689, 1376, 1257, 1132 cm–1. H NMR (CD3OD, 500 MHz,
1
Compound 34: Yield 13.5 mg (15%); colorless oil; two rotamers at
26 °C (1:1), one rotamer at 70 °C. [α]D = +25 (c = 0.10, MeOH).
70 °C): δ = 1.84 (s, 3 H), 3.64 (dd, J = 2.1, 12.6 Hz, 1 H), 3.65 (s,
3 H), 3.88 (dd, J = 2.1, 2.5 Hz, 1 H), 3.90 (d, J = 12.5 Hz, 1 H),
3.99 (dd, J = 2.6, 2.6 Hz, 1 H), 6.26 (d, J = 2.0 Hz, 1 H), 7.29 (s,
1 H) ppm. 13C NMR (CD3OD, 125.7 MHz, 70 °C): δ = 12.3 (CH3),
49.9 (CH2), 53.7 (CH3), 55.8 (CH), 58.9 (CH), 69.1 (CH), 111.2
(C), 138.6 (CH), 166.1 (C) ppm. Two (C) signals corresponding to
the carbamate and the urea were not clearly observed at 70 °C; at
26 °C they appeared at δ = 152.6 and 157.2 ppm. MS (EI): m/z (%)
= 267 (63) [M]+, 142 (100) [M+ + H – thymine], 126 (78) [thymine].
HRMS: calcd. for C11H13N3O5 267.0855; found 267.0845; calcd.
for C6H8NO3 142.0504; found 142.0506. C11H13N3O5 (267.24):
calcd. C 49.44, H 4.90, N 15.72; found C 49.70, H 5.23, N 15.40.
IR (CHCl ): ν = 3377, 3192, 1747, 1725, 1673, 1266, 1237 cm–1. 1H
˜
3
NMR (CD3OD, 500 MHz, 70 °C): δ = 2.11 (s, 3 H), 3.72 (s, 3 H),
3.75 (dd, J = 3.5, 11.9 Hz, 1 H), 4.00 (dd, J = 4.7, 11.7 Hz, 1 H),
4.92 (dd, J = 4.7, 5.9 Hz, 1 H), 5.10 (ddd, J = 3.6, 4.6, 4.7 Hz, 1
H), 6.05 (d, J = 6.1 Hz, 1 H), 7.73 (d, JF,H = 6.3 Hz, 1 H) ppm.
13C NMR (CD3OD, 125.7 MHz, 70 °C): δ = 20.8 (CH3), 24.4 (CH),
51.8 (CH2), 54.2 (CH3), 73.1 (CH), 81.1 (CH), 126.1 (CH, br. d,
JC,F = 35.0 Hz), 141.8 (C, d, JC,F = 235 Hz), 150.7 (C), 159.2 (C,
d, JC,F = 25.0 Hz), 171.2 (C) ppm. The (C) signal corresponding to
the methyl carbamate was not clearly observed. MS: m/z (%) = 410
(1) [M+ – OMe], 312 (100) [M+ + H – 5-fluorouracil], 126 (84) [M+
+ H – (5-fluorouracil + MeCO2 + I)]. HRMS: calcd. for
C11H10FIN3O5 409.9649; found 409.9650; calcd. for C8H11INO4
311.9733; found 311.9735. C12H13FIN3O6 (441.15): calcd. C 32.67,
H 2.97, N 9.53; found C 32.97, H 3.19, N 9.33.
1-[(2R,3S,4R)-3,4-Epoxy-N-(methoxycarbonyl)-2-pyrrolidinyl]uracil
(41): Obtained from substrate 30 and bis(trimethylsilyl)uracil, fol-
lowing the simplified procedure for the synthesis of epoxy nucleo-
side analogues (26 mg, 51%). Two rotamers at 26 °C (1:1); one rot-
amer at 70 °C; syrup. [α]D = +40 (c = 0.11, MeOH). IR (CHCl3):
1-[(2R,3S,4R)-3,4-Epoxy-N-(methoxycarbonyl)-2-pyrrolidinyl]-5-
fluorouracil (38): Obtained from substrate 30 and bis(trimethyl- ν = 3389, 1715, 1693, 1374, 1258, 1131, 1093 cm–1
.
1H NMR
˜
silyl)-5-fluorouracil, following the simplified procedure for the syn-
(CDCl3, 500 MHz, 70 °C): δ = 3.66 (dd, J = 2.1, 12.9 Hz, 1 H),
Eur. J. Org. Chem. 2010, 6633–6642
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6639

A. Boto, D. Hernández, R. Hernández
FULL PAPER
3.70 (s, 3 H), 3.83 (dd, J = 2.5, 2.5 Hz, 1 H), 3.94 (d, J = 12.8 Hz,
1 H), 3.99 (dd, J = 2.2, 2.5 Hz, 1 H), 5.66 (d, J = 8.2 Hz, 1 H),
(2ϫCH), 133.7 (2ϫCH), 134.2 (C), 143.5 (C, d, JC,F = 237.0 Hz),
152.0 (C), 157.2 (C), 160.3 (C, d, JC,F = 29.0 Hz) ppm. MS: m/z
6.34 (d, J = 1.9 Hz, 1 H), 7.31 (d, J = 8.2 Hz, 1 H), 8.07 (br. s, 1 (%) = 381 (25) [M]+, 252 (87) [M+ + H – 5-fluorouracil], 234 (78)
H) ppm. 13C NMR (CDCl3, 125.7 MHz, 26 °C): δ = 48.8/48.9
(CH2), 53.3/53.5 (CH3), 54.5 (CH), 58.1/58.2 (CH), 67.2/67.3 (CH),
[M+ + H – (5-fluorouracil + H2O)], 142 (100) [M+ + H – (5-fluoro-
uracil + PhSH)]. HRMS: calcd. for C16H16FN3O5S 381.0795;
102.3/102.3 (CH), 140.8/140.8 (CH), 150.5/150.5 (C), 155.2/155.2 found 381.0789; calcd. for C6H8NO3 142.0504; found 142.0501.
(C), 162.7/126.7 (C) ppm. MS (EI): m/z (%) = 253 (41) [M]+, 142
(100) [M+ + H – uracil]. HRMS: calcd. for C10H11N3O5 253.0699;
found 253.0698; calcd. for C6H8NO3 142.0504; found 142.0503.
C10H11N3O5 (253.21): calcd. C 47.43, H 4.38, N 16.59; found C
47.10, H 4.50, N 16.22.
C16H16FN3O5S (381.38): calcd. C 50.39, H 4.23, N 11.02; found C
50.34, H 4.57, N 11.40.
Compound 45: Isolated as a mixture with the major regioisomer
(44/45, 2:1). Two rotamers at 26 °C (1:1), one rotamer at 70 °C. 1H
NMR (CD3OD, 500 MHz, 70 °C): δ = 3.60 (m, 1 H), 3.70 (s, 3 H),
3.77 (br. s, 1 H), 3.83 (dd, J = 5.1, 11.4 Hz, 1 H), 4.23 (m, 1 H),
5.95 (d, J = 1.6 Hz, 1 H), 7.27–7.36 (m, 3 H), 7.51–7.54 (m, 2 H),
7.72 (d, JF,H = 6.6 Hz, 1 H) ppm. 13C NMR (CD3OD, 125.7 MHz,
70 °C): δ = 51.8 (CH3), 55.3 (CH2), 59.0 (CH), 73.9 (CH), 77.6
(CH), 127.2 (CH, d, JC,F = 36.3 Hz), 129.4 (CH), 130.3 (2ϫCH),
133.7 (2ϫCH), 134.1 (C), 160.2 (C). Several signals of product 45
were not clearly observed, even with the aid of 2D-NMR experi-
ments, and are not described.
Preparation of 1-[(2R,3S,4R)-4-Azido-3-hydroxy-N-(methoxycarb-
onyl)-2-pyrrolidinyl]-5-fluorouracil (42) and 1-[(2R,3S,4S)-3-Azido-
4-hydroxy-N-(methoxycarbonyl)-2-pyrrolidinyl]-5-fluorouracil (43):
To a solution of epoxide 38 (35 mg, 0.13 mmol) in acetone/water
(4 mL, 8:1) were added NH4Cl (16.0 mg, 0.3 mmol) and NaN3
(42.0 mg, 0.65 mmol). The mixture was stirred at 60 °C for 14 h,
then poured into water and extracted with EtOAc. The organic
layers were dried and evaporated, and the residue was purified by
chromatography (hexanes/EtOAc, 3:7), yielding hydroxy azides 42
and 43 as an inseparable mixture of regioisomers (30 mg, 75%; 42/
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra of the the new compounds
43, 4:1). Colorless oil. IR (CHCl ): ν = 3383, 2114, 1706, 1257,
˜
3
14–17, 20, 22, 26–29, 33, 34, and 38–45.
1130, 1088 cm–1. H NMR (CD3OD, 500 MHz, 70 °C): two rota-
1
mers/regioisomers at 26 °C (1:1), one rotamer/regioisomer at 70 °C;
major regioisomer δ = 3.50 (dd, J = 4.7, 11.4 Hz, 1 H), 3.71 (s, 3
H), 3.93 (dd, J = 5.7, 11.4 Hz, 1 H), 4.13 (ddd, J = 4.7, 5.1, 5.7 Hz,
1 H), 4.34 (dd, J = 5.4, 5.4 Hz, 1 H), 6.05 (d, J = 5.6 Hz, 1 H),
7.54 (d, JF,H = 6.6 Hz, 1 H); minor regioisomer δ = 3.65 (dd, J =
2.5, 11.4 Hz, 1 H), 3.74 (s, 3 H), 3.76 (dd, J = 4.7, 11.4 Hz, 1 H),
4.20–4.30 (m, 2 H), 5.81 (br. s, 1 H), 7.70 (d, JF,H = 7.0 Hz, 1
H) ppm. 13C NMR (CD3OD, 125.7 MHz, 70 °C): major re-
gioisomer δ = 50.0 (CH2), 53.9 (CH3), 65.6 (CH), 72.7 (CH), 75.4
(CH), 127.8 (CH, d, JC,F = 35.4 Hz), 141.5 (C, d, JC,F = 233.3 Hz),
151.2 (C), 157.0 (C), 159.3 (C, d, JC,F = 25.4 Hz); minor re-
gioisomer δ = 55.1 (CH3), 71.7 (CH), 73.3 (CH), 76.2 (CH), 126.8
(CH, d, JC,F = 33.6 Hz), 141.5 (C, d, JC,F = 233.3 Hz), 151.0 (C),
157.0 (C), 159.3 (C, d, JC,F = 25.4 Hz). One (CH2) signal is over-
lapped by the solvent signal. MS: m/z (%) = 314 (3) [M]+, 254 (12)
[M+ – (N3 + H2O)], 185 (100) [M+ + H – 5-fluorouracil], 130 (46)
[5-fluorouracil+], 59 (91) [MeOCO+]. HRMS: calcd. for
Acknowledgments
This work was supported by the Spanish Ministerio de Educación
y Ciencia (MEC) and Ministerio de Ciencia e Innovación (MIC-
INN), Investigation Programmes CTQ2006-14260/PPQ and
CTQ2009-07109 of the Plan Nacional de Investigación Científica,
Desarrollo e Innovación Tecnológica. The authors also acknow-
ledge financial support from the European Regional Development
Funds (FEDER funds). D. H. thanks the MEC for a fellowship
and the Gobierno de Canarias (ACIISI)-BIOSIGMA SL for a re-
search contract.
[1] a) Modified Nucleosides in Biochemistry Biotechnology and
Medicine (Ed.: P. Herdewijn), Wiley-VCH, Weinheim, 2008; b)
L. A. Agrofoglio, S. R. Challand, Acyclic, Carbocyclic and l-
Nucleosides, Chapman and Hall, 1998; c) See also: A.
Mieczkowski, V. Roy, L. A. Agrofoglio, Chem. Rev. 2010, 110,
1828–1856; d) E. de Clercq, J. Med. Chem. 2010, 53, 1438–
1450; e) V. B. Kurteva, C. A. M. Afonso, Chem. Rev. 2009, 109,
6809–6857; f) J. Stambasky, M. Hocek, P. Kocovský, Chem.
Rev. 2009, 109, 6729–6764; g) W. B. Parker, Chem. Rev. 2009,
109, 2880–2893, and references cited therein.
C
10H11FN6O5 314.0775; found 314.0770; calcd. for C6H9N4O3
185.0675; found 185.0666. C10H11FN6O5 (314.23): calcd. C 38.22,
H 3.53, N 26.74; found C 38.42, H 3.23, N 26.84.
Preparation of 5-Fluoro-1-[(2R,3R,4R)-3-hydroxy-N-(methoxycarb-
onyl)-4-phenylthio-2-pyrrolidinyl]uracil (44) and 5-Fluoro-1-
[(2R,3S,4S)-4-hydroxy-N-(methoxycarbonyl)-3-phenylthio-2-pyrrol-
idinyl]uracil (45): To a solution of epoxide 38 (27.1 mg, 0.1 mmol)
in anhydrous acetone (4 mL) were added Et3N (41 μL, 0.3 mmol)
and PhSH (30 μL, 0.3 mmol). The mixture was stirred under nitro-
gen at 50 °C for 14 h, then poured into water and extracted with
EtOAc. The organic layers were dried, concentrated under vacuum
and the residue was purified by chromatography (CH2Cl2/MeOH,
9.8:0.2), giving compounds 44 (14 mg, 37%) and 45 (4.9 mg, 13%).
[2] For N-Acetylazathymidine (1), see: K. H. Altmann, S. M. Fre-
ier, U. Pieles, T. Winkler, Angew. Chem. Int. Ed. Engl. 1994, 33,
1654–1657.
[3] For Immucilin-H and analogues, see: a) G. B. Evans, R. H.
Furneaux, H. Hausler, J. S. Larsen, P. C. Tyler, J. Org. Chem.
2004, 69, 2217–2220; b) V. P. Kamath, S. Ananth, S. Bantia,
P. E. Morris Jr., J. Med. Chem. 2004, 47, 1322–1324; c) See
also: K. Clinch, G. B. Evans, R. F. G. Fröhlich, R. H. Fur-
neaux, P. M. Kelly, L. Legentil, A. S. Murkin, L. Li, V. L.
Schramm, P. C. Tyler, A. D. Woolhouse, J. Med. Chem. 2009,
52, 1126–1143; d) A. S. Murkin, K. Clinch, J. M. Mason, P. C.
Tyler, V. L. Schramm, Bioorg. Med. Chem. Lett. 2008, 18,
5900–5903; e) E. A. Taylor, K. Clinch, P. M. Kelly, L. Li, G. B.
Evans, P. C. Tyler, V. L. Schramm, J. Am. Chem. Soc. 2007,
129, 6984–6985; f) For an orally active immunosuppressant,
see: S. Bantia, P. J. Miller, C. D. Parker, S. L. Ananth, L. L.
Horn, J. M. Kilpatrick, P. E. Morris, T. L. Hutchison, J. A.
Montgomery, J. S. Sandhu, Int. Immunopharmacol. 2001, 1,
1199–1210.
Compound 44: Colorless oil, two rotamers at 26 °C (1:1), one rot-
amer at 70 °C. [α]D = +35 (c = 0.26, CHCl ). IR (CHCl ): ν =
˜
3
3
1
3384, 1705, 1550, 1203, 1126 cm–1. H NMR (CD3OD, 500 MHz,
70 °C): δ = 3.61 (dd, J = 4.4, 11.7 Hz, 1 H), 3.69 (s, 3 H), 3.70 (m,
1 H), 4.05 (dd, J = 6.0, 11.4 Hz, 1 H), 4.31 (dd, J = 4.7, 5.4 Hz, 1
H), 6.19 (d, J = 5.7 Hz, 1 H), 7.27–7.35 (m, 3 H), 7.47–7.50 (m, 2
H), 7.52 (d, JF,H = 6.6 Hz, 1 H) ppm. 13C NMR (CD3OD,
125.7 MHz, 70 °C): δ = 51.5 (CH2), 51.8 (CH3), 53.8 (CH), 73.0
(CH), 75.6 (CH2), 127.6 (CH, d, JC,F = 31.8 Hz), 129.0 (CH), 130.3
6640
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6633–6642

Iodinated Iminosugar-Based Nucleosides
[4]
[5]
Chem. Rev. 2004, 104, 2311–2352; h) B. E. Maryanoff, H. C.
Zhang, J. H. Cohen, I. J. Turchi, C. A. Maryanoff, Chem. Rev.
2004, 104, 1431–1628.
A. Boto, R. Hernández, E. Suárez, J. Org. Chem. 2000, 65,
4930–4937.
For Codonopsin, see: D. F. Oliveira, E. A. Severino, C. R. D.
Correia, Tetrahedron Lett. 1999, 40, 2083–2086.
a) For reviews on iminosugar-based nucleosides, see: M.
Yokoyama, A. Momotake, Synthesis 1999, 1541–1554; b) V. L.
Schramm, P. C. Tyler, Curr. Top. Med. Chem. 2003, 5, 525–
540; c) For recent work on the subject, see: M. Rueping, B. J.
Nachtsheim, Synlett 2010, 119–122; d) U. Chiacchio, L. Bor-
rello, L. Crispino, A. Rescifina, P. Merino, B. Macchi, E. Bales-
trieri, A. Mastino, A. Piperno, G. Romeo, J. Med. Chem. 2009,
52, 4054–4057; e) G. Enderlin, C. Taillefumier, C. Didierjean,
Y. Chapleur, J. Org. Chem. 2009, 74, 8388–8391; f) R. Flores,
R. Alibés, M. Figueredo, J. Font, Tetrahedron 2009, 65, 6912–
6917; g) M. Koszytkowska-Stawinska, E. De Clercq, J. Balzar-
ini, Bioorg. Med. Chem. 2009, 17, 3756–3762; h) V. Vanek, M.
[10]
[11]
Any source of visible light can be used. However, to obtain
reproducible results, we carried out the scission reaction with
commonly available 80-W tungsten-filament lamps.
The formation of the acyliminium intermediate 13 from the
enecarbamate 12 probably proceeds via an iodonium ion.
a) The nucleophiles were prepared from commercial bases 5-
fluorouracil, benzotriazole, 6-(benzyloxy)purin, and 6-chlo-
ropurin according to a protocol described by Vorbrüggen, see:
H. Vorbrüggen, Acta Biochim. Pol. 1996, 43, 25–36; b) M. G. B.
Drew, S. Gorsuch, J. H. M. Gould, J. Mann, J. Chem. Soc. Per-
kin Trans. 1 1999, 969–978.
a) C. Nájera, J. M. Sansano, Org. Biomol. Chem. 2009, 7, 4567–
4581; b) F. Amblard, J. H. Cho, R. F. Schinazi, Chem. Rev.
2009, 109, 4207–4220; c) J. Wan, Y. Xia, Y. Liu, M. Wang, P.
Rocchi, J. Yao, F. Qu, J. Neyts, J. L. Iovanna, L. Peng, J. Med.
Chem. 2009, 52, 1144–1155; d) S. Bae, M. K. Lakshman, J.
Am. Chem. Soc. 2007, 129, 782–789; e) D. S. Im, C. S. Cheong,
S. H. Lee, B. H. Youn, S. C. Kim, Tetrahedron 2000, 56, 1309–
1314.
a) M. Stefko, L. Slavetínska, B. Klepetarova, M. Hocek, J. Org.
Chem. 2010, 75, 442–449; b) R. Pratap, D. Parrish, P. Gunda,
D. Venkataraman, M. K. Lakshman, J. Am. Chem. Soc. 2009,
131, 12240–12249; c) J. Pschierer, H. Plenio, Org. Lett. 2009,
11, 2551–2554.
For Abacavir and stavudine (D4T), see: a) H. Kumamoto, H.
Tanaka, J. Org. Chem. 2002, 67, 3541–3547; b) M. Ferrero, V.
Gotor, Chem. Rev. 2000, 100, 4319–4347, and references cited
therein.
a) For the formation of olefinic nucleoside analogues and their
transformation into dihydroxy or amino-hydroxy derivatives,
see: D. F. Oliveira, E. A. Severino, C. R. D. Correia, Tetrahe-
dron Lett. 1999, 40, 2083–2086; b) G. Rassu, L. Pinna, P.
Spanu, F. Ulgheri, G. Casiraghi, Tetrahedron Lett. 1994, 35,
4019–4022.
a) To the best of our knowledge, only one example of related
tricyclic aza compounds has been reported, see: E. R. Costen-
aro, L. A. M. Fontoura, D. F. Oliveira, C. R. D. Correia, Tetra-
hedron Lett. 2001, 42, 1599–1602; b) For tricyclic systems from
conventional nucleosides, see: Y. Oeda, Y. Ijima, H. Taguchi,
A. Ohkubo, K. Seio, M. Sekine, Org. Lett. 2009, 11, 5582–
5585, and references cited therein.
[12]
[13]
Budesinský, M. Rinnová, I. Rosenberg, Tetrahedron 2009, 65,
ˇ
862–876; i) M. Nakano, M. Terada, Synlett 2009, 1670–1674;
j) B. Hélal, F. Ferreira, C. Botuha, F. Chemla, A. Pérez-Luna,
Synlett 2009, 3115–3118; k) A. Goeminne, M. Berg, M. Mc-
Naughton, G. Bal, G. Surpateanu, P. Van der Veken, S.
De Prol, W. Versées, J. Steyaert, A. Haemers, K. Augustyns,
Bioorg. Med. Chem. 2008, 16, 6752–6763; l) X. Yue, X. L. Qiu,
F. L. Qing, J. Fluorine Chem. 2008, 129, 866–874; m) E. L.
Tsou, S. Y. Chen, M. H. Yang, S. C. Wang, T. R. R. Cheng,
W. C. Cheng, Bioorg. Med. Chem. 2008, 16, 10198–10204; n)
[14]
[15]
D. Rejman, P. Kocalka, M. Budesinský, R. Pohl, I. Rosenberg,
ˇ
ˇ
Tetrahedron 2007, 63, 1243–1253; o) S. Castellano, H. D. G.
Fiji, S. S. Kinderman, M. Watanabe, P. de Leon, F. Tamanoi,
O. Kwon, J. Am. Chem. Soc. 2007, 129, 5843–5845; p) G. Bur-
ton, T. W. Ku, T. J. Carr, T. Kiesow, R. T. Sarisky, J. Lin-Go-
erke, G. A. Hofmann, M. J. Slater, D. Haigh, D. Dhanak, V. K.
Johnson, N. R. Parry, P. Thommes, Bioorg. Med. Chem. Lett.
[16]
[17]
2007, 17, 1930–1933; q) P. Kocalka, R. Pohl, D. Rejman, I.
ˇ
Rosenberg, Tetrahedron 2006, 62, 5763–5774, and references
cited therein.
[6]
[7]
A. Boto, D. Hernández, R. Hernández, Eur. J. Org. Chem.
2010, 3847–3857.
a) For a preliminary communication of this work, see: A. Boto,
D. Hernández, R. Hernández, Tetrahedron Lett. 2008, 49, 455–
458; b) See also: A. Boto, R. Hernández, Y. León, E. Suárez,
J. Org. Chem. 2001, 65, 7796–7803.
[18]
[19]
[8]
a) For other related work from our group, see: C. Saavedra, R.
Hernandez, A. Boto, E. Alvarez, J. Org. Chem. 2009, 74, 4655–
4665; b) A. Boto, D. Hernández, R. Hernández, Tetrahedron
Lett. 2009, 50, 3974–3977; c) A. Boto, D. Hernández, R.
Hernández, A. Montoya, E. Suárez, Eur. J. Org. Chem. 2007,
325–334; d) A. Boto, D. Hernández, R. Hernández, Org. Lett.
2007, 9, 1721–1724; e) A. Boto, D. Hernández, R. Hernández,
E. Álvarez, J. Org. Chem. 2007, 72, 9523–9532; f) C. J. Saa-
vedra, R. Hernández, A. Boto, E. Álvarez, Tetrahedron Lett.
2006, 47, 8757–8760; g) A. Boto, J. A. Gallardo, R. Hernández,
C. J. Saavedra, Tetrahedron Lett. 2005, 46, 7807–7811; h) A.
Boto, R. Hernández, Y. León, J. R. Murguía, A. Rodríguez-
Afonso, Eur. J. Org. Chem. 2005, 673–682; i) For related work,
see: B. R. Díaz-Sánchez, M. A. Iglesias-Arteaga, R. Melgar-
Fernández, E. Juaristi, J. Org. Chem. 2007, 72, 4822–4825; j)
T. Maruyama, Y. Mizuno, I. Shimizu, S. Suga, J. I. Yoshida, J.
Am. Chem. Soc. 2007, 129, 1902–1903; k) For a review on the
modification of amino acids and carbohydrates through radical
chemistry, see: S. G. Hansen, T. Skrydstrup, Top. Curr. Chem.
2006, 264, 135–162; l) For a review covering radical chemistry
with hypervalent iodine reagents, see: V. V. Zhdankin, P. J.
Stang, Chem. Rev. 2008, 108, 5299–5358.
a) Theoretical calculations performed with Macromodel 7.0
support the assigned stereochemistries. Thus, the experimental
coupling constants for compound 33 are J2,3 = 0 Hz, J3,4
=
1 Hz, and J4,5 = 0, 4.9 Hz and for its isomer 34 the constants
are J2,3 = 5.9 Hz, J3,4 = 4.7 Hz, and J4,5 = 3.5, 4.7 Hz. The
theoretical constants for the (2R,3S,4S) diastereoisomer are
J2,3 = 0 Hz, J3,4 = 0 Hz, and J4,5 = 1.2, 4.9 Hz; for the
(2S,3S,4S) diastereoisomer are J2,3 = 7 Hz, J3,4 = 9 Hz, and
J4,5 = 8.5, 8.5 Hz; for the (2S,3R,4S) diastereoisomer are J2,3
= 1 Hz, J3,4 = 5.5 Hz, and J4,5 = 8.0, 9.0 Hz; and for the
(2R,3R,4S) diastereoisomer are J2,3 = 7 Hz, J3,4 = 4 Hz, and
J4,5 = 2.0, 4.7 Hz. Therefore, the experimental constants of
products 33 and 34 match the theoretical constants of the
(2R,3S,4S) and the (2R,3R,4S) isomers, respectively; b) Calcu-
lations were made using an AMBER force-field model im-
planted in the Macromodel 7.0 program. The calculations were
also performed with an MMFF force field, by using high qual-
ity parameters. Similar results were obtained in both cases. The
theoretical coupling constants were calculated over the mini-
mized structures for all possible isomers, by using the Karplus–
Altone equation implemented in Macromodel.
[9]
a) For the addition of nucleophiles to iminium ions, see: A.
Yazici, S. G. Pyne, Synthesis 2009, 339–368 (part I); A. Yazici,
S. G. Pyne, Synthesis 2009, 513–541 (part 2); b) D. Ferraris,
Tetrahedron 2007, 63, 9581–9597; c) G. K. Friestad, A. K.
Mathies, Tetrahedron 2007, 63, 2541–2569; d) S. E. Schaus, A.
Ting, Eur. J. Org. Chem. 2007, 5797–5815; e) M. Petrini, E.
Torregiani, Synthesis 2007, 159–186; f) M. Petrini, Chem. Rev.
2005, 105, 3949–3977; g) J. Royer, M. Bonin, L. Micouin,
[20]
a) C. H. Larsen, B. H. Ridgway, J. T. Shaw, K. A. Woerpel, J.
Am. Chem. Soc. 1999, 121, 12208–12209; b) D. M. Smith,
M. B. Tran, K. A. Woerpel, J. Am. Chem. Soc. 2003, 125,
Eur. J. Org. Chem. 2010, 6633–6642
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6641

A. Boto, D. Hernández, R. Hernández
FULL PAPER
14149–14152; c) C. H. Larsen, B. H. Ridgway, J. T. Shaw,
D. M. Smith, K. A. Woerpel, J. Am. Chem. Soc. 2005, 127,
10879–10884; d) D. Smith, K. A. Woerpel, Org. Biomol. Chem.
2006, 4, 1195–1201; e) K. M. Bonger, T. Wennekes, D. V. Filip-
pov, G. Lodder, G. A. van der Marel, H. S. Overkleeft, Eur. J.
Org. Chem. 2008, 3678–3688; f) For similar studies in six-mem-
bered-ring oxocarbenium ions, see: J. A. C. Romero, S. A. Tab-
acco, K. A. Woerpel, J. Am. Chem. Soc. 2000, 122, 168–169; g)
L. Ayala, C. G. Lucero, J. A. C. Romero, S. A. Tabacco, K. A.
Woerpel, J. Am. Chem. Soc. 2003, 125, 15521–15528; h) S. R.
Shenoy, K. A. Woerpel, Org. Lett. 2005, 7, 1157–1160.
d) D. P. Schumacher, S. S. Hall, J. Am. Chem. Soc. 1982, 104,
6076–6080.
[22]
a) Because commercially available 4R-hydroxyproline can be
easily transformed into 4-(S)-hydroxy, alkoxy, or acyloxy deriv-
atives, this methodology would also afford the opposite series
of enantiomers, see: A. Kamal, D. R. Reddy, P. S. M. M.
Reddy, Bioorg. Med. Chem. Lett. 2007, 17, 803–806; b) A. K.
Mandal, J. Hines, K. Kuramochi, C. M. Crews, Bioorg. Med.
Chem. Lett. 2005, 15, 4043–4047; c) M. Doi, Y. Nishi, N. Kiri-
toshi, T. Iwata, M. Nago, H. Nakano, S. Uchiyama, T. Nakaz-
awa, T. Wakamiya, Y. Kobayashi, Tetrahedron 2002, 58, 8453–
8459; d) J. A. Gómez-Vidal, R. B. Silverman, Org. Lett. 2001,
3, 2481–2484; e) B. Bellier, I. McCort-Tranchepain, B. Ducos,
S. Danascimento, H. Meudal, F. Noble, C. Garbay, B. P. Ro-
ques, J. Med. Chem. 1997, 40, 3947–3956.
[21] a) For the synthesis of other epoxy-pyrrolidines and their con-
version into 3,4-disubstituted pyrrolidines, see: A. Kamal,
A. A. Shaik, M. Sandbhor, M. Shaheer-Malik, H. Kaga, Tetra-
hedron Lett. 2004, 45, 8057–8059; b) B. G. Davis, M. A. T.
Maughan, T. M. Chapman, R. Villard, S. Courtney, Org. Lett.
2002, 4, 103–106; c) J. K. Robinson, V. Lee, T. D. W. Claridge,
J. E. Baldwin, C. J. Schofield, Tetrahedron 1998, 54, 981–996;
Received: July 15, 2010
Published Online: October 20, 2010
6642
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 6633–6642