Synthesis of nucleosides from 4-methylidenefuranoses: A non-classical electrophilic addition

Article abstract of DOI:10.1016/S0957-4166(02)00125-8

The reaction of persilylated bases (thymine, uracil, cytosine, and 5-fluorouracil) with either 3-O-benzoyl-5-deoxy-1,2-O-isopropylidene-α-D-erythro-pent-4-enofuranose 6 or its 3-O-benzyl analogue 7 in the presence of N-iodosuccinimide (NIS) afforded two types of product with high stereoselectivity; either (1′S,2′R,3′S)-3′-O-benzoyl- 8-10 or -3′-O-benzyl-5′-deoxy-5′-iodo-1′,2′-O- isopropylidene-4′-oxo-1′-yl-pyrimidines 11-13, respectively, from 1,4-addition with participation of the oxygen atom at the furanoid ring, and either 3′-O-benzoyl- 14-16, or 3′-O-benzyl-5′-deoxy-5′-iodo-1′,2′-O- isopropylidene-β-L-lyxo-4′-yl-pyrimidine and 17-19 resulting from normal electrophilic addition at the exocyclic methylene group. A third compound was isolated from the reaction of 7 with persilylated uracil/NIS and identified as the doubly N,N′-glycosylated pyrimidine 20.

Full text of DOI:10.1016/S0957-4166(02)00125-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 399–405
Synthesis of nucleosides from 4-methylidenefuranoses: a
non-classical electrophilic addition
Rafael Robles,* Isidoro Izquierdo, Concepcio´n Rodr´ıguez, Mar´ıa T. Plaza, Antonio J. Mota and
´
Lu´ıs Alvarez de Cienfuegos
Department of Organic Chemistry, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
Received 5 February 2002; accepted 11 March 2002
Abstract—The reaction of persilylated bases (thymine, uracil, cytosine, and 5-fluorouracil) with either 3-O-benzoyl-5-deoxy-1,2-O-
isopropylidene-a-D-erythro-pent-4-enofuranose 6 or its 3-O-benzyl analogue 7 in the presence of N-iodosuccinimide (NIS)
afforded two types of product with high stereoselectivity; either (1%S,2%R,3%S)-3%-O-benzoyl- 8–10 or -3%-O-benzyl-5%-deoxy-5%-iodo-
1%,2%-O-isopropylidene-4%-oxo-1%-yl-pyrimidines 11–13, respectively, from 1,4-addition with participation of the oxygen atom at the
furanoid ring, and either 3%-O-benzoyl- 14–16, or 3%-O-benzyl-5%-deoxy-5%-iodo-1%,2%-O-isopropylidene-b-L-lyxo-4%-yl-pyrimidine
and 17–19 resulting from normal electrophilic addition at the exocyclic methylene group. A third compound was isolated from the
reaction of 7 with persilylated uracil/NIS and identified as the doubly N,N%-glycosylated pyrimidine 20. © 2002 Elsevier Science
Ltd. All rights reserved.
1. Introduction
its benzoyl 4 or benzyl 58 derivative, in the usual
manner. 4,5-Dehydrohaloganation of either 4 or 5 by
classical methods in order to obtain the related 4-
methylenefuranoses 69 or 7 occurred in moderate or
very low yields, but treatment with caesium fluoride
afforded the required compounds in excellent yield
(Scheme 1).
In previous papers1 we reported on the highly regio-
and stereoselective synthesis of nucleosides from the
reaction of furanoid glycals with persilylated bases in
the presence of NIS. On the basis of the excellent
results obtained in our previous studies, we have
explored the same methodology but on an activated
enol ether-like exocyclic methylene group in order to
prepare nucleoside structurally related with the angust-
mycin A.2
Compounds 6 and 7 (see Scheme 2) have all sub-
stituents at the a-face and it can be expected that any
electrophilic attack at the exocyclic methylene group
must occur to the less hindered b-face in order to
produce the intermediate cyclic iodonium ion A that
would be attacked with high regio- and stereoselectivity
at C(4) by the persilylated base (PSB) at the a-face to
afford the related N-nucleosides. Nevertheless, when 6
and 7 were allowed to react with NIS, two unexpected
products were isolated from the reaction mixtures,
either 8–13, probably formed via SN1 anti approach of
the PSB at C(1) with respect to the C(2) substituent of
2. Results and discussion
Reaction of 1,2-O-isopropylidene-a-D 1
-xylofuranose3
with I2/Ph3P/imidazole in anhydrous dichloromethane
according to the Garegg–Samuelson procedure4 pro-
ceeded with high regioselectivity to afford 5-deoxy-5-
iodo-1,2-O-isopropylidene-a-
Compound 2 was transformed into its 3-epimer 36
-ribo) by a well established protocol consisting of
D
-xylofuranose
2.5
the stabilized oxocarbenium intermediate
D (see
(a-D
Scheme 2), or those from similar attack by the PSB at
the less hindered b-face, but at C(4) of the stabilized
oxocarbenium ion B. To the best of our knowledge,
there is no previous report in the literature about such
processes, although related processes where alkenyl
glycopyranosides and different promoters were used for
glycosidations are known.10
PCC oxidation of 2 to the corresponding ald-3-ulose
and subsequent sodium borohydride reduction.7 Com-
pound 3 was then straightforwardly 3-O-protected as
* Corresponding author. E-mail: rrobles@ugr.es
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00125-8

400
R. Robles et al. / Tetrahedron: Asymmetry 13 (2002) 399–405
Scheme 1.
Scheme 2.
Finally, the reaction of 7 with persilylated uracil
afforded a third N,N%-dialkylated compound 20, iso-
lated in 23% yield. The analytical and spectroscopic
data allowed its complete structural elucidation. Thus,
in a HMBC experiment on 20, H-1¦ of the sugar
residue (6.62 ppm) (see Fig. 2) showed two strong
interactions with C(2) (149.5 ppm) and C(4) (162.6
ppm) of the ring, indicating that the open sugar moiety
was linked to N(3).
Our results could be explained on the basis of the
different nucleophilic character of the bases. Thus, the
most nucleophilic cytosine reacted giving only 16 and
19, whereas the less nucleophilic 5-fluorouracil afforded
only 10 and 13. The other bases, which have moderate
nucleophilic character (uracil and thymine) produced
mixtures of both types of product.
The structures for compounds 8–13 and 14–19 were
established on the basis of their analytical and spectro-
scopic data, and the stereochemistry of the new C(1%)
and C(4%) stereogenic centres was determined by
NOESY experiments. As an example, the definite NOE
effect between C(2%)H and C(6)H of thymine in 8 and
11, as well as C(1%)H and C(6)H of thymine in 14 and
17, indicates that the base and the mentioned protons
are in a cis disposition (see Fig. 1 below) in the 1,3-
dioxolane and furanose ring, respectively.
The presence of the iodomethylketone function (C(4%)
and C(5%) at 200 and 5 ppm, respectively) in compounds
8–13 was demonstrated by catalytic hydrogenation of
10 to the corresponding methylketone 21 (as evidenced
by NMR analyses).
Figure 1. NOE interaction for 8 and 14 (R=Bz), and 11 and
17 (R=Bn).

R. Robles et al. / Tetrahedron: Asymmetry 13 (2002) 399–405
401
Figure 2. HMBC experiment on 20.
3. Experimental
3.2. 5-Deoxy-5-iodo-1,2-O-isopropylidene-a-D-xylofura-
nose 2
3.1. General
Solutions were dried over MgSO4 before concentration
To a stirred solution of 1,2-O-isopropylidene-a-
D-xylo-
1
under reduced pressure. The H and 13C NMR spectra
furanose (4.3 g, 22.6 mmol) in anhydrous
1
were recorded with Bruker AMX-300, AM-300, and
ARX-400 spectrometers for solutions in CDCl3 (inter-
nal Me4Si). IR spectra were recorded with a Perkin–
dichloromethane (200 mL) were added iodine (14.35 g,
56.5 mmol), triphenylphosphine (14.8 g, 56.5 mmol),
and imidazole (8.6 g, 120 mmol) and the mixture was
heated under reflux for 8 h. TLC (ether–hexane, 3:1)
then revealed the presence of a new compound of
higher mobility. The reaction mixture was washed with
diluted aqueous hydrochloric acid and water until neu-
tral pH was reached, then concentrated and the residue
was chromatographed (ether–hexane, 1:1) to afford 2 as
a foam (6.6 g, 97%); [h]2D5 −38.4 (c 1), [lit.5 [h]2D0 −38 (c
1.07, chloroform)]. 13C NMR spectrum (100 MHz):
Elmer 782 instrument and mass spectra with
a
Micromass Mod. Platform II and Autospec-Q mass
spectrometers. Optical rotations were measured for
solutions in CHCl3 (1 dm tube) with a Jasco DIP-370
polarimeter. TLC was performed on precoated silica gel
60 F254 aluminium sheets and detection was by charring
with H2SO4. Column chromatography was performed
on silica gel (Merck, 7734).

402
R. Robles et al. / Tetrahedron: Asymmetry 13 (2002) 399–405
112.2 (CMe2), 105.6 (C-1), 85.1, 80.8, and 75.0 (C-
3.5. 3-O-Benzyl-5-deoxy-5-iodo-1,2-O-isopropylidene-a-
-ribofuranose 5
1
2,3,4), 26.9 and 26.3 (CMe2), and −1.1 (C-5). The H
D
NMR (400 MHz) spectroscopic data for 2 were iden-
tical to those already reported.5
To an ice-water cooled and stirred solution of 3 (3 g, 10
mmol) in anhydrous THF (50 mL) were added benzyl
bromide (1.2 mL, 50 mmol) and 60% oil dispersion
sodium hydride (1 g, 25 mmol) portionwise over 30
min. The reaction mixture was then stirred for an
additional 2 h. The reaction was quenched by cautious
addition of methanol (5 mL) and allowed to reach
room temperature. The solvents were removed and the
residue was partitioned between dichloromethane–
water. The organic phase was separated and concen-
trated to a residue that was submitted to column
chromatography (ether–hexane, 1:6“1:1) to afford
pure 58 as a colourless syrup (3.7 g, 95%); [h]2D4 +99 (c
3.3. 5-Deoxy-5-iodo-1,2-O-isopropylidene-a-D-ribofura-
nose 3
To a stirred solution of 2 (5 g, 15.8 mmol) in anhy-
drous dichloromethane (100 mL) were added molecu-
,
A powder, 10 g) and pyridinium
lar sieve (4
chlorochromate (10 g, 4.58 mmol). Stirring was main-
tained at room temperature overnight. TLC (ether–
hexane, 3:1) then revealed a new product of higher
mobility. The mixture was diluted with ether (300
mL), filtered through silica gel G and concentrated to
a residue that was chromatographed (ether) to afford
a compound that was not investigated but reduced at
−25°C in anhydrous methanol (75 mL) by portion
addition of sodium borohydride (1 g, 26.3 mmol)
over 1 h. The mixture was neutralised with acetic
acid and concentrated to a residue that was parti-
tioned between dichloromethane–water. The organic
phase was separated and concentrated to a residue
that was submitted to column chromatography
(ether–hexane, 2:1) to afford crystalline 3 as a colour-
less powder (4 g, 80%); mp 84–85°C; [h]2D2 +36.7 (c 1),
1
1.20), [lit.:8b [h]D20 +84.9 (c 4.7, dichloromethane)]. H
NMR data: (300 MHz), 7.40–7.30 (m 5H, PhCH2), 5.74
(d, 1H, J1,2=3.6 Hz, H-1), 4.67 (2d, 2H, J=11.9 Hz,
PhCH2), 4.56 (pt, 1H, J2,3=4.3 Hz, H-2), 3.73 (ddd,
1H, J3,4=8.5, J4,5a=3.0, J4,5b=4.3 Hz, H-4), 3.59 (dd,
1H, H-3), 3.51 (dd, 1H, J5a,5b=11.2, Hz, H-5a), 3.29
(dd, 1H, H-5b), 1.59 and 1.35 (2s, 6H, CMe2); 13C
NMR (80 MHz), 137.3, 128.6, 128.3, and 128.1 (Ph),
113.3 (CMe2), 104.0 (C-1), 81.7 (C-3), 77.4 and 76.3
(C-2,4), 72.4 (PhCH2), 26.7 and 26.6 (CMe2), and 7.4
(C-5).
1
[lit.:6 mp 84–85°C; [h]2D5 +20.6 (c 0.5, chloroform)]. H
3.6. Typical experimental procedure for the preparation
of 4-methylidenefuranoses 6 and 7
NMR data: (400 MHz): 5.83 (d, 1H, J1,2=3.9 Hz,
H-1), 4.60 (dd, 1H, J2,3=5.1 Hz, H-2), 3.75 (ddd, 1H,
J
3,4=10.5, J4,5a=8.1, J4,5b=5.6 Hz, H-4), 3.57–3.52
To a stirred solution of 4 or 5 (1 mmol) in dry DMF
(10 mL) was added caesium fluoride (304 mg, 2 mmol)
and the mixture was heated at 120°C for either 4 or 8
h, respectively. Most of the solvent was evaporated
under vacuum and the residue was partitioned into
toluene–water. The organic phase was separated and
concentrated to give a residue that was chromatograph
(ether–hexane, 1:5) to afford crystalline 6 and syrupy 7
(82%, in both cases), respectively.
(m, 2H, H-5a,3), 3.34 (dd, 1H, J5a,5b=12.0 Hz, H-5b),
2.45 (d, 1H, J3,OH=10.5 Hz, HO-3), 1.56 and 1.36
(2s, 6H, CMe2); 13C NMR (100 MHz): 112.2 (CMe2),
103.0 (C-1), 78.5 and 77.8 (C-2,3), 75.2 (C-4), 26.2
(CMe2), and 6.4 (C-5).
3.4. 3-O-Benzoyl-5-deoxy-5-iodo-1,2-O-isopropylidene-
a-D-ribofuranose 4
Conventional benzoylation of 3 (4 g, 13.3 mmol) with
benzoyl chloride (2.3 mL, 20 mmol) and triethylamine
(5.5 mL, 40 mmol) in anhydrous dichloromethane (75
mL) for 4 h, and quenching with methanol for 30
min, gave after usual work-up and column chro-
matography (ether–hexane, 1:4) colourless crystalline
4 (5.4 g, 93%); mp 60–61°C; [h]2D5 +111.6 (c 1.02);
3.6.1. 3-O-Benzoyl-5-deoxy-1,2-O-isopropylidene-a-
erythro-pent-4-enofuranose 6. Mp 54–55°C (from ether–
hexane); [h]2D1 +151.6 (c 1.1); wKBr
2990, 1720 (CꢀO,
D-
max
1
benzoate), 1680 (CꢀC), 1385 and 1375 cm−1 (CMe2). H
NMR data (inter alia): (400 MHz), 6.02 (d, 1H, J1,2
3.6 Hz, H-1), 5.57 (dt, 1H, J2,3=5.3, J3,5a=2.2, J3,5b
=
=
2.2 Hz, H-3), 4.99 (dd, 1H, H-2), 4.62 (dt, 1H,
wKBr
1745 (CꢀO, benzoate) and 1275 cm−1 (CMe2).
J
5a,5b=2.4, Hz, H-5a), and 4.31 (t, 1H, H-5b); 13C
max
1H NMR data: (400 MHz), 8.08 (dd, 2 H, Jo-,m-
6.28, Jo-,p-=1.10 Hz, H-ortho), 7.60 (tt, 1H, J =6.9
=
NMR (100 MHz), 165.8 (CꢀO), 156.8 (C-4), 114.5
(CMe2), 105.1 (C-1), 84.8 (C-5), 77.6 and 72.1 (C-2,3),
27.9 and 27.5 (CMe2). Mass spectrum (LSIMS): m/z:
299.0894 [M++Na] for C15H16O5Na 299.0895 (deviation
+0.4 ppm). Anal. calcd for C15H16O5: C, 65.20; H, 5.83.
Found: C, 65.05; H, 5.94%.
m-,p-
Hz, H-para), 7.47 (dt, 2H, H-meta), 5.92 (d, 1H,
J
J
1,2=3.8 Hz, H-1), 4.98 (t, 1H, H-2), 4.81 (dd, 1H,
2,3=4.9, J3,4=8.6 Hz, H-3), 4.16 (dt, 1H, H-4), 3.52
(dd, 1H, J4,5a=4.2, J5a,5b=11.1, Hz, H-5a), 3.37 (dd,
1H, J4,5b=4.9 Hz, H-5b), 1.55 and 1.33 (2s, 6H,
CMe2); 13C NMR (100 MHz), 165.7 (CꢀO), 133.6,
130.6, 129.2, 128.6 (Ph), 113.4 (CMe2), 104.2 (C-1),
77.9, 76.8, and 76.4 (C-2,3,4), 26.8 (CMe2), and 5.2
(C-5). Mass spectrum (LSIMS): m/z: 427.0023 [M++
Na] for C15H17O5INa 427.0018 (deviation −1.0 ppm).
Anal. calcd for C15H17O5I: C, 44.57; H, 4.24. Found:
C, 44.64; H, 4.59%.
3.6.2.
3-O-Benzyl-5-deoxy-1,2-O-isopropylidene-a-D-
max
erythro-pent-4-enofuranose 7. [h]2D5 +98.9 (c 1.1); wfilm
2990, 1680 (CꢀC), 1385 and 1375 cm−1 (CMe2). 1H
NMR data (inter alia): (400 MHz), 5.80 (d, 1H, J1,2
=
3.3 Hz, H-1), 4.84 and 4.68 (2d, 2H, J=12.4, CH2Ph),
4.56 (t, 1H, J2,3=3.8, H-2), 4.48 (bs, 1H, H-5a), 4.30 (t,
1H, J5a,5b=1.8 Hz, H-5b), 4.28 (m, 1H, J3,5a=2.1,

R. Robles et al. / Tetrahedron: Asymmetry 13 (2002) 399–405
403
J
3,5b=2.2 Hz, H-3), 1.54 and 1.41 (2s, 6H, CMe2); 13C
slightly contaminated with succinimide (1H NMR evi-
dence). This could be removed by dissolving in
dichloromethane and washing with a saturated aqueous
sodium hydrogen carbonate solution and water to give
the corresponding pure compounds.
NMR (100 MHz), 158.8 (C-4), 137.4, 128.5, 128.1, and
128.0 (Ph), 114.8 (CMe2), 104.3 (C-1), 83.9 (C-5), 77.4
and 76.9 (C-2,3), 72.4 (CH2Ph), 27.9 and 27.3 (CMe2).
Mass spectrum (LSIMS): m/z: 262.1281 [M++H] for
C15H19O4 263.1283 (deviation +0.8 ppm).
24
405
Compound 8: (253 mg, 16%) solid foam; [h] −93.2 (c
0.93); wfilm
1690 (CꢀO) and 1260 cm−1. For NMR
max
3.7. Typical experimental procedure for nucleosidation
of 6 and 7
data, see Tables 1 and 2. Mass spectrum (LSIMS): m/z:
551.0296 [M++Na] for C20H21N2O7INa 551.0291 (devia-
tion −0.9 ppm). Anal. calcd for C20H21N2O7I: C, 45.47;
H, 4.00; N, 5.30. Found: C, 45.28; H, 3.81; N, 5.37%.
A
solution of persilylated base (thymine, uracil,
cytosine, or 5-fluorouracil, 4 mmol) in anhydrous
dichloromethane (50 mL) was added to a flask contain-
ing either 6 or 7 (3 mmol), and to the resulting stirred
and cooled (ice-water) solution was added NIS (675
mg, 13 mmol) and the reaction mixture was left for 18
h. During this time the reaction mixture was allowed to
reach room temperature. The solvent was evaporated
and the residue submitted to column chromatography
(ether–hexane, 2:1“ether in all cases, except with
cytosine where dichloromethane–methanol, 20:1, was
used as eluent) to afford, first compounds 8–13 and
secondly compounds 14–19, respectively, all of them
Compound 9: (107 mg, 7%) solid foam; [h]2D5 −5.5 (c 1);
max
wfilm
2960, 1690 (CꢀO), 1660, and 1250 cm−1. For
NMR data, see Tables 1 and 2. Mass spectrum
(LSIMS): m/z: 537.0125 [M++Na] for C19H19N2O7INa
537.0134 (deviation +1.8 ppm). Anal. calcd for
C19H19N2O7I: C, 44.37; H, 3.72; N, 5.44. Found: C,
44.69; H, 3.98; N, 5.38%.
Compound 10: (1.2 g, 75%) solid foam; [h]2D6 −14.4 (c
max
1.1); wfilm
3060, 1720 (CꢀO), 1700, and 1250 cm−1.
Table 1. 1H NMR chemical shifts (l) and J (Hz) values for compounds 8–13
Compound
H-1%
H-2%
H-3%
H-5%a
H-5%b
4.04d
4.07d
4.02d
H-3
H-5
H-6
Me
1.96d
–
CMe2
8a
6.32d
J1%,2% 6.6
6.34d
J1%,2% 6.4
6.28dd
J1%,2% 6.4
J1%,F 1.6
6.23d
J1%,2% 6.4
6.20d
J1%,2% 6.2
6.17dd
J1%,2% 6.3
J1%,F 1.4
4.54dd
J2%,3% 4.1
4.59dd
J2%,3% 3.8
4.55dd
J2%,4% 3.5
6.17d
6.23d
6.24d
4.25d
J5%a,5%b 11.5
4.28d
J5%a,5%b 11.5
4.23d
J5%a,5%b 11.4
9.24s
8.61s
–
7.19d
7.47d
1.55
1.38
1.58
1.44
1.56
1.39
9b
5.87d
J5,6 8.2
–
10b
8.92d
J3,F 4.5
7.47d
J6,F 5.7
–
11b
12a
13a
4.33dd
J2%,3% 4.2
4.37dd
J2%,3% 3.8
4.36dd
J2%,3% 3.7
4.65d
4.70d
4.69d
4.25d
J5%a,5%b 10.7
4.27d
J5%a5%b 10.6
4.26d
J5%a,5%b 10.6
3.91d
3.92d
3.90d
8.95s
9.50s
9.23s
–
7.14s
1.92
–
1.53
1.47
1.51
1.50
1.53
1.50
5.78d
J5,6 8.2
–
7.37m*
7.39m*
–
a Recorded at 400 MHz.
b Recorded at 300 MHz.
*Signals overlapping with those of benzyl group and also containing the coupling with fluorine.
Table 2. 13C NMR chemical shifts (l) for compounds 8–13
Compound
C(2)
C(4)
C(5)
C(6)
C(1%)
C(2%)
C(3%)
C(4%)
C(5%)
Me
8a
150.7
150.3
149.0
150.5
150.5
149.0
164.9
164.9
156.0c
163.4
163.1
156.5f
111.5
103.5
141.0d
111.4
103.1
140.8g
134.2
138.6
122.8e
134.4
138.9
123.1h
82.7
83.3
83.2
83.5
83.8
83.7
79.5
80.1
80.1
80.3
80.3
80.0
73.4
73.5
73.4
81.1
81.7
81.5
198.6
198.4
198.6
202.5
202.6
202.6
4.2
3.8
3.7
4.9
4.8
4.7
12.9
–
–
12.8
–
–
9b
10b
11b
12a
13a
a Recorded at 100 MHz.
b Recorded at 80 MHz.
c JC-4,F=26.6 Hz.
d JC-5,F=239.0 Hz.
e JC-6,F=34.2 Hz.
f JC-4,F=21.7 Hz.
g JC-5,F=238.0 Hz.
h JC-6,F=34.0 Hz.

404
R. Robles et al. / Tetrahedron: Asymmetry 13 (2002) 399–405
Compound 14: (1.03 g, 65%) solid foam; [h]2D5 +26.3 (c
0.92); wfilm 1770 (CꢀO), 1710, and 1260 cm−1. For
NMR data, see Tables 3 and 4. Mass spectrum
(LSIMS): m/z: 551.0287 [M++Na] for C20H21N2O7INa
551.0291 (deviation +0.8 ppm). Anal. calcd for
C20H21N2O7I: C, 45.47; H, 4.00; N, 5.30. Found: C,
45.82; H, 4.26; N, 5.44%.
For NMR data, see Tables 1 and 2. Mass spectrum
(LSIMS): m/z: 555.0040 [M++Na] for C19H18N2O7FINa
555.0040. Anal. calcd for C19H18N2O7FI: C, 42.87; H,
3.41; N, 5.26. Found: C, 43.11; H, 3.65; N, 5.16%.
max
Compound 11: (350 mg, 23%) solid foam; [h]2D5 −26.2 (c
max
1.02); wfilm
3200, 3000, 1700 (CꢀO), and 1680 cm−1.
For NMR data, see Tables 1 and 2. Mass spectrum
(LSIMS): m/z: 537.0503 [M++Na] for C20H23N2O6INa
537.0498 (deviation −0.9 ppm). Anal. calcd for
C20H23N2O6I: C, 46.70; H, 4.51; N, 5.44. Found: C,
46.99; H, 4.82; N, 5.51%.
Compound 15: (1.315 g, 85%) solid foam; [h]2D4 +42.4 (c
max
For NMR data, see Tables 3 and 4. Mass spectrum
(LSIMS): m/z: 537.0128 [M++Na] for C19H19N2O7INa
537.0135 (deviation +1.3 ppm). Anal. calcd for
C19H19N2O7I: C, 44.37; H, 3.72; N, 5.44. Found: C,
44.21; H, 3.95; N, 5.50%.
1.1); wfilm
2960, 1740 (CꢀO), 1690, and 1660 cm−1.
Compound 12: (320 mg, 21%) white crystals; mp 125–
126°C (from ether–hexane); [h]2D4 −33.4 (c 0.8); wKBr
max
3050, 2920, 1720 (CꢀO), and 1680 cm−1. For NMR
data, see Tables 1 and 2. Mass spectrum (LSIMS): m/z:
523.0331 [M++Na] for C19H21N2O6INa 523.0342 (devia-
tion +2.1 ppm). Anal. calcd for C19H21N2O6I: C, 45.62;
H, 4.23; N, 5.60. Found: C, 45.89; H, 4.43; N, 5.58%.
Compound 16: (1.393 g, 90%) white crystals; mp 165°C
dec.; [h]2D7 +60.6 (c 1); wKBr
3080, 1720 (CꢀO), and
1640 cm−1. For NMR data,msaxee Tables 3 and 4. Mass
spectrum (LSIMS): m/z: 536.0290 [M++Na] for
C19H20N3O6INa 536.0294 (deviation +0.8 ppm). Anal.
calcd for C19H20N3O6I: C, 44.37; H, 4.11; N, 8.17.
Found: C, 44.29; H, 3.83; N, 8.09%.
Compound 13: (950 mg, 61%) solid foam; [h]2D5 −43.6 (c
max
1.1); wfilm
2020, 1720 (CꢀO), and 1700 cm−1. For
Compound 17: (1.065 g, 69%) solid foam; [h]2D4 −31 (c
max
1.1); wfilm
3220, 3080, 1750 (CꢀO), and 1700 cm−1.
NMR data, see Tables 1 and 2. Mass spectrum
(LSIMS): m/z: 541.0248 [M++Na] for C19H20N2O6FINa
541.0248 (deviation −0.1 ppm). Anal. calcd for
C19H20N2O6I: C, 44.03; H, 3.89; N, 5.40. Found: C,
44.29; H, 4.03; N, 5.42%.
For NMR data, see Tables 3 and 4. Mass spectrum
(LSIMS): m/z: 537.0498 [M++Na] for C20H23N2O6INa
537.0498. Anal. calcd for C20H23N2O6I: C, 46.70; H,
4.51; N, 5.44. Found: C, 47.02; H, 4.68; N, 5.36%.
Table 3. 1H NMR chemical shifts (l) and J (Hz) values for compounds 14–19
Compound
14a
H-1%
H-2%
H-3%
H-5%a
H-5%b
3.89d
3.95d
3.84d
3.74d
3.76d
3.53d
H-3
H-5
H-6
NH2
Me
CMe2
5.97d
J1%,2% 2.6
5.98d
J1%,2% 2.7
6.00d
J1%,2% 3.1
5.72d
J1%,2% 2.8
5.71d
J1%,2% 2.9
5.83d
4.99dd
J2%,3% 4.9
5.03dd
J2%,3% 4.9
4.94dd
J2%,4% 5.3
4.53dd
J2%,3% 5.0
4.54dd
J2%,3% 5.0
4.76dd
J2%,3% 4.8
5.85d
5.89d
5.74d
4.50d
4.50d
4.53d
4.40d
J5%a,5%b 11.4
4.43d
J5%a,5%b 11.5
4.52d
J5%a,5%b 11.0
4.28d
J5%a,5%b 11.8
4.29d
J5%a5%b 11.8
4.47d
9.29bs
9.40bs
–
–
7.56s
7.76d
7.37d
7.51s
7.70d
7.67d
–
1.87s
1.60
1.36
1.64
1.40
1.47
1.28
1.60
1.39
1.61
1.40
1.46
1.32
15b
5.68d
J5,6 8.2
5.73d
J5,6 7.7
–
–
–
16a*
17a
7.20s
–
–
9.30bs
9.50bs
–
1.94s
18b
5.73d
J5,6 8.4
5.70d
–
–
–
19a*
7.16
J1%,2% 3.0
J5%a,5%b 11.0
J5,6 7.6
a Recorded at 400 MHz.
b Recorded at 300 MHz.
*Recorded in DMSO-d6.
Table 4. 13C NMR chemical shifts (l) for compounds 8–13
Compound
C(2)
C(4)
C(5)
C(6)
C(1%)
C(2%)
C(3%)
C(4%)
C(5%)
Me
14a
149.8
149.8
154.7
149.9
149.9
154.7
164.3
165.0
166.1
164.4
163.9
166.0
109.2
100.9
93.0
109.4
101.1
92.9
136.1
140.3
141.4
136.4
138.9
141.4
103.9
103.9
104.0
103.8
103.8
103.5
79.9
79.9
79.8
80.4
80.4
80.2
76.9
76.7
76.5
82.5
82.5
82.4
96.3
96.5
95.8
97.7
98.0
96.8
10.0
10.1
11.5
10.4
10.5
12.0
12.8
–
–
12.8
–
–
15b
16a*
17a
18b
19a*
a Recorded at 100 MHz.
b Recorded at 80 MHz.
*Recorded in DMSO-d6.

R. Robles et al. / Tetrahedron: Asymmetry 13 (2002) 399–405
405
Compound 18: (620 mg, 41%) solid foam; [h]2D4 −21.6 (c
1); wfilmmax 3050, 1690 (CꢀO), and 1670 cm−1. For NMR
data, see Tables 3 and 4. Mass spectrum (LSIMS): m/z:
523.0340 [M++Na] for C19H21N2O6INa 523.0342 (devia-
tion +0.2 ppm). Anal. calcd for C19H21N2O6I: C, 45.62;
H, 4.23; N, 5.60. Found: C, 45.82; H, 4.08; N, 5.71%.
27.0 (CMe2). Mass spectrum (LSIMS): m/z: 429.1078
[M++Na] for C19H19N2O7FNa 429.1074 (deviation −0.9
ppm). Anal. calcd for C19H19N2O7F: C, 56.16; H, 4.71;
N, 6.89. Found: C, 55.98; H, 5.00; N, 6.51%.
Acknowledgements
Compound 19: (1.424 g, 93%) white crystals; mp 132–
133°C (from ether); [h]2D5 −32 (c 1.1, methanol); wfilm
max
2940, 1650 (CꢀO), and 1630 cm−1. For NMR data, see
Tables 3 and 4. Mass spectrum (LSIMS): m/z: 522.0501
[M++Na] for C19H22N3O5INa 522.0502 (deviation +0.1
ppm). Anal. calcd for C19H22N3O5I: C, 45.70; H, 4.44;
N, 8.41. Found: C, 45.52; H, 4.36; N, 8.39%.
The authors are deeply grateful to Ministerio de Educa-
cio´n y Cultura (Spain) for financial support (Project
´
PB98-1321) and for a grant (L. Alvarez de Cienfuegos).
References
Compound 20: (350 mg, 23%) was also isolated as a
syrup from the reaction of 7 with persilylated uracil and
had [h]2D2 +32.5 (c 1.1); wfilm
2940, 1720 (CꢀO), and
1. (a) Robles, R.; Rodr´ıguez, C.; Izquierdo, I.; Plaza, M.-T.;
Mota, A.-J. Tetrahedron: Asymmetry 1997, 8, 2959–2965;
(b) Robles, R.; Rodr´ıguez, C.; Izquierdo, I.; Plaza, M.-T.;
Mota, A.-J.; Alvarez de Cienfuegos, L. Tetrahedron:
Asymmetry 2000, 11, 3069–3077.
2. Prisbe, E. J.; Smajkal, J.; Verheyden, J. P. H.; Moffatt, J.
max
1670 cm−1. H NMR data: (400 MHz), 7.58 (d, 1H,
1
J
J
5,6=8.4 Hz, H-6). 7.37–7.31 (m, 5H, Ph), 6.62 (d, 1H,
1¦,2¦=6.5 Hz, H-1¦), 5.62 (d, 1H, H-5), 5.57 (d, 1H,
´
J1%,2%=2.9 Hz, H-1%), 5.00 (t, 1H, J2¦,3¦=6.3 Hz, H-2¦),
4.81–4.63 (m, 4H, 2CH2Ph), 4.51 (t, 1H, J2%,3%=3.7 Hz,
H-2%), 4.50 (d, 1H, H-3¦), 4.42 (d, 1H, H-3%), 4.22 (d,
1H, J5%a,5%b=11.7 Hz, H-5%a), 4.08 (d, 1H, J5¦a,5¦b=10.9
Hz, H-5¦a), 3.96 (d, 1H, H-5¦b), 3.72 (d, 1H, H-5%b),
1.62, 1.59, 1.50 and 1.39 (4s, 12H, 2CMe2); 13C NMR
(100 MHz), 202.2 (C-4¦), 162.6 (C-4), 149.5 (C-2), 139.0
(C-6), 137.5, 136.7, 128.6, 128.5, 128 4, 128.3, 128.2,
and 128.1 (Ph), 116.1 and 111.8 (2CMe2), 103.8 (C-5),
100.5 (C-1¦), 98.2 (C-4%), 82.3, 81.9, 81.7, 81.2, and 75.8
(C-1¦,2¦,3¦,2%,3%), 28.6, 27.8, 27.1 and 26.4 (2CMe2),
10.3 (C-5%), 5.2 (C-5¦). Mass spectrum (LSIMS): m/z:
911.0515 [M++Na] for C34H38N2O10I2Na 911.0514
(deviation −0.1 ppm).
G. J. Org. Chem. 1976, 41, 1836–1846.
3. Compound 1 was prepared by partial hydrolysis of
1,2:3,5-di-O-isopropylidene-a-D-xylofuranose with 50%
aqueous acetic acid.
4. (a) Garegg, J.; Samuelson, B. Synthesis 1979, 813–814;
(b) Robles, R.; Rodr´ıguez, C.; Izquierdo, I.; Plaza, M.-T.
Carbohydr. Res. 1997, 300, 375–380.
5. Achab, S.; Das, B. C. J. Chem. Soc., Perkin Trans. 1
1990, 2863–2873.
6. Kiss, J.; D’Souza, R.; Koeveringe, J. A. van; Arnold, W.
Helv. Chim. Acta 1982, 65, 1522–1537.
7. Ness, R. K.; Fletcher, H. G. J. Org. Chem. 1963, 28,
435–437.
8. (a) Musicki, B.; Widlanski, T. S. J. Org. Chem. 1990, 55,
4231–4233; (b) Fu¨rstner, A.; Jumbam, D.; Teslic, J.;
Weidmann, H. J. Org. Chem. 1991, 50, 2213–2217.
9. Product 6 was recorded by the MDL Information System
GmbH (Beilstein) but reading the original paper by
Hough, L.; Otter, B. J. Chem. Soc., Chem. Commun.
1966, 173–174, the compound reported was actually its
3-epimer.
10. (a) Fraser-Reid, B.; Udodong, U. E.; Wu, Z.; Ottosson,
H.; Merrit, J. R.; Rao, C. S.; Roberts, C.; Madsen, R.
Synlett 1992, 927–942; (b) Raadt, A. de; Ferrier, F. J.
Carbohydr. Res. 1991, 216, 93–107; (c) Marra, A.;
Esnault, J.; Veyrie`res, A.; Sinay¨, P. J. Am. Chem. Soc.
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5031.
3.8. Catalytic hydrogenation of 10
Compound 10 (50 mg, 0.09 mmol) in anhydrous
methanol (15 mL) was hydrogenated at room tempera-
ture over 10% Pd–C at 4 atm for 2 h to afford
crystalline 21 (38 mg, quantitative); mp 207–208°C
(from ether–hexane); [h]2D2 +15 (c 1); wKBr
3070, 1730
max
1
(CꢀO), and 1670 cm−1. H NMR data (inter alia): (400
MHz), 7.47 (d, 1H, J6,F=5.7 Hz, H-6), 6.34 (dd, 1H,
J1%,2%=6.4, J1%,F=1.5 Hz, H-1%), 5.80 (d, 1H, J2%,3%=4.0
Hz, H-3%), 4.54 (dd, 1H, H-2%), and 2.29 (s, 3H, MeCO);
13C NMR (100 MHz), 204.5 (MeCO), 165.3 (PhCO),
156.5 (d, JC-4,F=26.9 Hz, C-4), 149.1 (C-2), 141.0 (d,
JC-5,F=238.7 Hz, C-5), 134.1, 130.0, 128.9, and 128.5
(Ph), 123.0 (d, JC-6,F=34 Hz, C-6), 111.9 (CMe2), 83.3
(C-1%), 79.4 and 76.0 (C-2%,3%), 28.0 (MeCO), 27.4 and