Preparation of 2,2'-anhydronucleosides: Regio- and stereoselective modifications of the base and sugar moieties

Article abstract of DOI:10.1016/S0957-4166(00)00272-X

2'-Deoxy-2'-iodonucleosides 4-9, obtained from suitably protected furanoid glycals 1 and 2 with different silylated pyrimidine bases, were transformed into the corresponding 2,2'-anhydronucleosides 10-15 with inversion of the configuration at C-2', by hea

Full text of DOI:10.1016/S0957-4166(00)00272-X

Tetrahedron: Asymmetry 11 (2000) 3069±3077
Preparation of 2,20-anhydronucleosides: regio- and
stereoselective modi®cations of the base and sugar moieties
Rafael Robles,* Concepcion Rodrõguez, Isidoro Izquierdo, Marõa T. Plaza,
Antonio Mota and Luis Alvarez de Cienfuegos
Department of Organic Chemistry, University of Granada, 18071 Granada, Spain
Received 23 May 2000; accepted 10 July 2000
Abstract
20-Deoxy-20-iodonucleosides 4±9, obtained from suitably protected furanoid glycals 1 and 2 with di€erent
silylated pyrimidine bases, were transformed into the corresponding 2,20-anhydronucleosides 10±15 with
inversion of the con®guration at C-20, by heating in DMF with n-dibutyltin oxide. Regio- and stereo-
speci®c opening at C-20 of the 2,20-ring in compounds 10, 11, and 12 with sodium azide a€orded the related
20-azido-20-deoxynucleosides 16, 17 and 18, respectively. Action of sodium hydroxide on 12 caused the
regioselective opening of the above-mentioned ring at C-2 with retention of the con®guration at C-20 giving
19. Compound 19 could be transformed straightforwardly into 18 by well-established methodology. On the
other hand, compound 15 could be transformed into the related 20,30-anhydronucleoside 23 by a regio- and
stereoselective addition at N-3±C-20 of allyl bromide concomitant with 2,20-ring opening and inversion of
the con®guration at C-20 to a€ord the intermediate 20-bromo-20-deoxynucleoside 21, which was
subsequently treated with sodium methoxide giving 23. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Much attention has recently been paid to 2,20- and 2,30-anhydronucleosides due to the possibility
shown by these0compounds of being transformed by attack from a great variety of nucleophiles at
the C-20 or C-3 positions to a€ord compounds with anti-AIDS activity.1
Methods for the transformation of nucleosides into tricyclic 2,20-anhydro analogues have been
reported since 1958, when Fox2 treated 1-(30,50-O-isopropylidene-20-O-methanesulfonyl-b-d-
xylofuranosyl)thymine with sodium hydroxide in re¯uxing aqueous ethanol to a€ord the related
2,20-anhydro nucleoside. Lately, Watanabe,1d Rama Rao,1f Chen,1g Tolstikov,3 Musta®n,4 and
Hrebabecky5 used the action of a base (sodium hydrogen carbonate/DMF, sodium benzoate or
DBU) on the appropriated 20-O-phenyloxycarbonyl or 20-O-methanesulfonyl derivative of a
nucleoside, respectively, in order to promote anhydrization, whereas Chattopadhyaya1h treated a
* Corresponding author. E-mail: rrobles@platon.ugr.es
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00272-X

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R. Robles et al. / Tetrahedron: Asymmetry 11 (2000) 3069±3077
partially protected nucleoside with bis-(imidazol-1-yl)thiocarbonyl in re¯uxing toluene. We
report herein a new and mild method for the preparation, in high yield, of 2,20-anhydronucleosides
based on the easy access, from furanoid glycals,6 of 20-deoxy-20-iodonucleoside with a trans
disposition of substituents at C-10,20 and the subsequent elimination of hydrogen iodide by
n-dibutyltin oxide.
2. Results and discussion
As has been already stated, the starting nucleosides 6±9 for the present work were readily
synthesized7 from furanoid glycals 1 and 2 (see Scheme 1). Thus, compound 1 was prepared from
3 after heating with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine, whereas 2 was synthesized
from 3,5-di-O-benzoyl-d-xylose by reaction with I2/Ph3P/imidazole in dichloromethane. Both
glycals 1 and 2 had to be used at once, since they decomposed on standing. For the purposes of
this work nucleosides 4 and 5 are described for the ®rst time.
Scheme 1.
In a previous experiment of reductive dehalogenation of nucleoside 9 with n-tributyltin hydride
partial formation of 2,20-anhydronucleoside 15 was observed. Similar results were achieved by
Chen8 when 50-O-benzoyl-20-bromo-20-deoxy-30-O-methanesulfonylthymidine reacted with the
mentioned hydride giving a mixture of the normal dehalogenation product, together with the
2,30-anhydro-20-deoxy nucleoside as a minor component. These results could be explained as a
consequence of the presence of some oxidation product from the n-tributyltin hydride. Thus, we
treated nucleoside 9 with n-dibutyltin oxide and the corresponding 15 was isolated in high yield
by a clean reaction. In order to see the scope of this procedure, compounds 4±8 were prepared
and treated in the same way giving the expected 2,20-anhydronucleosides 10±14, indicating its
eciency.

R. Robles et al. / Tetrahedron: Asymmetry 11 (2000) 3069±3077
3071
Attempts at opening the 2,20-anhydro ring of the above compounds with sodium azide9 as the
nucleophile, clearly indicated the important role played by the protecting groups on the sugar
moiety on the course and result of the reaction. Thus, when benzoyloxyl groups were present on
the sugar moiety 13±15, complex reaction mixtures resulted and the expected products were
formed in low yield; however, in the case of the O-benzyl derivatives 10±12, the 20-azido-20-deoxy
derivatives 16±18 were isolated in moderate yield (33±55%).
^
In order to improve the yields of the I^!N3 interchange and using 12 as a model, a new
strategy was envisaged (see Scheme 2), consisting of the regioselective opening at C-2 by sod0ium
hydroxide1e to a€ord the d-lyxo nucleoside 19 which was transformed into the intermediate 2 -O-
tri¯ate derivative 20 which, on subsequent treatment with sodium azide in DMF, gave 18 in a
73% yield.
Scheme 2.
On the other hand, compound 15 was chosen as a model to be subjected to a series of trans-
formations leading to the related 20,30-anhydro analogues, due to the interest shown for this kind
of structure in nucleoside chemistry. With this aim, compound 15 was allowed to react with an
excess of allyl bromide (see Scheme 3) and two new products were isolated and identi®ed as
3-allyl- (21, major) and 1-(30,50-di-O-benzoyl-20-bromo-20-deoxy-b-d-xylofuranosyl)thymine
(22, minor), the former as the result of the addition, in a highly regioselective manner, of bromide
and the allyl group at the C-20 and N-3 positions, respectively.
Scheme 3.
Similar ring opening reactions, although on 2,30-anhydronucleosides, have been previously
reported by other authors.10 Finally, treatment of 21 with sodium methoxide in methanol
unequivocally led to 3-allyl-1-(20,30-anhydro-b-d-lyxofuranosyl)thymine 23, since the presence of
the allyl group at N-3 avoided the formation of the 2,20-anhydro nucleoside.

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R. Robles et al. / Tetrahedron: Asymmetry 11 (2000) 3069±3077
3. Experimental
3.1. General
Melting points were determined with a Gallenkamp apparatus and are uncorrected. Solutions
1
were dried over MgSO4 before concentration under reduced pressure. The H and 13C NMR
spectra were recorded with Bruker AMX-300, AM-300 and ARX-400 spectrometers for solutions
in CDCl3 (internal Me4Si). IR spectra were recorded with a Perkin±Elmer 782 instrument and
mass spectra with a Hewlett±Packard HP-5988-A and Fisons mod. Platform II and VG
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 by charring with 5% conc. H2SO4 in ethanol. Column
chromatography was performed on silica gel (Merck, 7734).
3.2. 1-(30,50-Di-O-benzyl-20-deoxy-20-iodo-ꢀ-d-xylofuranosyl)uracil 4 or its 5-¯uoro derivative 5
To a stirred solution of glycal 16 (2 mmol) in dry dichloromethane (15 mL) was added
N-iodosuccinimide (2 mmol) and the appropriate silylated base (2.5 mmol) in the same solvent,
and the mixture was kept at room temperature for 2 h, when TLC (ether) revealed the absence of
2 and the presence of a compound of lower mobility. The solvent was removed and the residue
supported on silica gel and chromatographed (ether:hexane=3:! ether) to a€ord the corresponding
20-deoxy-20-iodonucleoside derivatives 4 and 5.
Compound 4: (1.05 g, quantitative), m.p. 113±114ꢀC, ‰ꢁŠD22: +21.5 (c 1); ꢂKmBaxr 1705, 1679, 1663,
and 1267 cm^1. NMR data: 1H, 9.67 (bs, 1H, H-3), 7.51 (d, 1H,0J5,6=7.2 Hz, H-6), 7.34±7.30 and
0
7.18±7.12 (2 m, 10H, aromatic), 6.31 (d, 1H, J1 ,2 =1.9 Hz, H-1 ), 5.52 (d, 1H, H-5), 4.77 (dt, 1H,
0
0
0
0
0
0
J4 ,5 =5.5, J3 ,4 =3.6 Hz, H-4 ), 4.61 and 4.55 (2d, 2H, J=11.9 Hz, PhCH2), 4.53 and 4.44 (2d,
2H, J=11.6 Hz, PhCH2), 4.28±4.25 (m, 2H, H-20,30), and 3.82 (d, 2H, H-50,50); 13C, 163.7 (C-4),
150.4 (C-2), 139.7 (C-6), 137.5, 136.4, 128.8, 128.6, 128.1, and 127.9 (PhCH2), 101.5 (C-5), 93.9
(C-10), 84.6 and 81.4 (C-30,40), 73.7 and 72.6 (PhCH2), 67.7 (C-50), and 24.9 (C-20). Anal. calcd for
C23H23IN2O5: C, 51.69; H, 4.34; N, 5.24. Found: C, 51.73; H, 4.53; N, 5.37.
Compound 5: (995 mg, 90%), m.p. 154±155ꢀC, ‰ꢁŠD22: +21.8 (c 1); ꢂmKaBxr 1718, 1706, and 1646
cm^1. NMR data: 1H, 9.51 (bs, 1H, H-3), 7.66 (d, 1H, J6,F=6.4 Hz, H-6), 7.35±7.28 and 7.16±7.12
(2 m, 10H, aromatic), 6.32 (t, 1H, J1 ,2 =J1 ,F=1.7, H-10), 4.75 (dt, 1H, J4 ,5 =5.4, J3 ,4 =3.5 Hz,
0
0
0
0
0
0
0
H-40), 4.63 and 4.57 (2d, 2H, J=11.9 Hz, PhCH2), 4.55 and 4.49 (2d, 2H, J=101.6 Hz, PhCH2),
0
0
0
4.27 (t, 1H, J2 ,3 =1.6 Hz, H-2 ), 4.26 (bd, 1H, H-3 ), and 3.83 (d, 2H, H-5 ,5 ); 13C, 157.0 (d,
J4,F= 28.5 Hz, C-4), 148.8 (C-2), 140.0 (d, J5,F=235 Hz, C-5), 137.4, 136.3, 128.9, 128.6, 128.1,
and 128.0 (PhCH2), 124.2 (d, J6,F=37.1 Hz, C-6), 93.9 (C-10), 84.5 and 81.5 (C-30,40), 73.6 and
72.8 (PhCH2), 67.7 (C-50), and 29.5 (C-20). Anal. calcd for C23H22FIN2O5: C, 50.01; H, 4.01; N,
5.07. Found: C, 49.69; H, 4.17; N, 5.20.
0
0
3.3. Reaction of 4±9 with n-dibutyltin oxide. Preparation of 2,20-anhydronucleosides 10±15
To a well stirred solution of 4±9 (1 mmol) in DMF (5 mL), n-dibutyltin oxide (249 mg, 1 mmol)
was added and the mixture was heated at 120ꢀC for 3 h. TLC (ether:acetone=3:2) then revealed
the presence of a product of much lower mobility. The reaction mixture was concentrated and the
residue dissolved in dichloromethane (20 mL) and the solution was washed with a slightly

R. Robles et al. / Tetrahedron: Asymmetry 11 (2000) 3069±3077
3073
alkaline water solution (10 mL), and water (10 mL). Concentration of the solvent gave a residue
that was supported on silica gel and chromatographed (ether:acetone=3.1) to yield the corresponding
2,20-anhydro derivative 10±15.
Compound 10: (317 mg, 78%), m.p. 163±164ꢀC, ‰ꢁŠD27: ^84.3 (c 1); ꢂmKaBxr 1666, 1646, 1549, and
1478 cm^1. NMR data: see Tables 1 and 2. Anal. calcd for C23H22N2O5: C, 67.96; H, 5.45; N,
6.89. Found: C, 67.68; H, 5.48; N, 6.90.
Table 1
1H NMR data for compounds 10±18

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R. Robles et al. / Tetrahedron: Asymmetry 11 (2000) 3069±3077
Table 2
13C NMR data for compounds 10±18
Compound 11: (301 mg, 71%), m.p. 155±156ꢀC, ‰ꢁŠD27: ^76.5 (c 1); ꢂmKaBxr 1661, 1577, and 1495
cm^1. NMR data: see Tables 1 and 2. Anal. calcd for C23H21FN2O5: C, 65.08; H, 4.98; N, 6.60.
Found: C, 64.74; H, 5.05; N, 6.72.
Compound 12: (315 mg, 75%), m.p. 160±161ꢀC, ‰ꢁŠD27: ^97.3 (c 1); ꢂmKaBxr 1671, 1638, 1635, 1565,
and 1491 cm^1. NMR data: see Tables 1 and 2. Anal. calcd for C24H24N2O5: C, 68.55; H, 5.75; N,
6.66. Found: C, 68.28; H, 5.86; N, 6.81.
Compound 13: (348 mg, 80%), m.p. 85±86ꢀC, ‰ꢁŠD22: ^6 (c 1); ꢂmKaBxr 1728, 1660, 1647, and 1542
cm^1. NMR data: see Tables 1 and 2. Anal. calcd for C23H18N2O7: C, 63.58; H, 4.17; N, 6.45.
Found: C, 63.35; H, 4.23; N, 6.38.
Compound 14: (407 mg, 90%), m.p. 104±105ꢀC, [ꢁ]42075: +46.8 (c 1); ꢂmKaBxr 1733, 1725, 1662, 1650,
and 1576 cm^1. NMR data: see Tables 1 and 2, which were in accordance with those found in the
literature.3 Anal. calcd for C23H17FN2O7: C, 61.06; H, 3.78; N, 6.12. Found: C, 60.78; H, 3.87; N,
6.16.
Compound 15: (372 mg, 83%), m.p. 90±91ꢀC, ‰ꢁŠD27: ^33 (c 1); ꢂKmaBxr 1729, 1646, 1565, and 1482
cm^1. NMR data: see Tables 1 and 2. Anal. calcd for C24H20N2O7: C, 64.27; H, 4.49; N, 6.24.
Found: C, 64.05; H, 4.45; N, 6.35.
3.4. Preparation of 1-(20-azido-30,50-di-O-benzyl-20-deoxy-ꢀ-d-xylofuranosyl)-2,4-dioxo-1,2,3,4-
tetrahydropyrimidines 16±18
To a stirred solution of nucleosides 10±12 (1 mmol) in dry DMF (5 mL) was added sodium
azide (65 mg, 1 mmol) and the mixture was heated at 120ꢀC for 48 h. TLC (ether:acetone=3:2)
then showed the presence of a faster-running product. The mixture was concentrated and the

R. Robles et al. / Tetrahedron: Asymmetry 11 (2000) 3069±3077
3075
reaction crude partitioned into toluene±water, the organic phase was separated, concentrated and
the residue supported on silica gel and chromatographed (ether) to give the corresponding 20-azido-
20-deoxy derivatives 16±18.
Compound 16: (128 mg, 55%), m.p. 86±87ꢀC, ‰ꢁŠD22: ^8.3 (c 1.3); ꢂKmBaxr 2113 (N3), 1696, and 1455
cm^1. NMR data: see Tables 1 and 2. Anal. calcd for C23H23N5O5: C, 61.46; H, 5.16; N, 15.58.
Found: C, 61.22; H, 5.35; N, 15.29.
Compound 17: (77 mg, 33%), m.p. 51±52ꢀC, ‰ꢁŠD24: +7.5 (c 1); ꢂmKBaxr 2113 (N3), 1714, and 1456
cm^1. NMR data: see Tables 1 and 2. Anal. calcd for C23H22FN5O5: C, 59.09; H, 4.74; N, 14.98.
Found: C, 59.31; H, 5.05; N, 15.06.
Compound 18: (110 mg, 47%), m.p. 94±95ꢀC, ‰ꢁŠD22: ^22 (c 1); ꢂmKBaxr 2110 (N3), 1700, and 1684
cm^1. NMR data: see Tables 1 and 2. Anal. calcd for C24H25N5O5: C, 62.19; H, 5.44; N, 15.11.
Found: C, 62.43; H, 5.25; N, 15.20.
3.5. Preparation of 1-(30,50-di-O-benzyl-ꢀ-d-lyxofuranosyl)thymine 19
To a warmed solution of 12 (460 mg, 1.1 mmol) in acetonitrile (20 mL) was added 1N aqueous
sodium hydroxide solution (1 mL) and the mixture kept at room temperature for 2 h. TLC
(ether:acetone=3:1) then showed the presence of a faster-running product. The reaction mixture
was neutralized with Amberlite-IR 120 (H+, form), the solvent removed and the crude percolated
(ether:acetone=3:1) through a short silica gel column to yield 19 (460 mg, 95%) as a colourless
thick syrup, ‰ꢁŠ2D7: +25 (c 0.8); ꢂ®mlmax 1720, 1711, 1455, and 1280 cm^1. NMR data: 1H, 9.31 (bs, 1H,
0
0
0
H-3), 7.49 (s, 1H, H-6), 7.30 (m, 10H, aromatic), 6.04 (d, 1H, J1 ,2 =3.5 Hz, H-10), 4.64 (2 d, 2H,
0
0
0
0
J=11.2 Hz, PhCH2), 4.60 (s, 2H, PhCH2), 4.39 (t, 1H, J2 ,3 =J3 ,4 =3.9 Hz, H-3 ), 4.35±4.28 (m,
2H, H-20,40), 3.83 (dd, 1H, J4 ,5 a=3.4, J5 a,5 b=10.5 Hz, H-50a), and 3.71 (dd, 1H, J4 ,5 b=2.7 Hz,
H-50b); 13C, 164.2 (C-4), 150.8 (C-2), 137.8 (C-6), 137.2, 136.7, 128.7, 128.6, 128.3, 128.2, 128.0,
and 127.9 (PhCH2), 109.0 (C-5), 85.2 (C-10), 78.0 and 77.2 (C-30,40), 73.9 and 72.9 (PhCH2), 69.2
(C-20), 68.0 (C-50), and 12.5 (Me). Mass spectrum (LSIMS): m/z 461.16895 (M++Na). For
C24H26N2O6Na 461.16886 (deviation ^0.2 ppm).
0
0
0
0
0
0
3.6. Preparation of 1-(20-azido-30,50-di-O-benzyl-20-deoxy-ꢀ-d-xylofuranosyl)thymine 18
To an ice±water cooled and stirred solution of 19 (246 mg, 0.56 mmol) in dry dichloro-
methane:pyridine=1:1 (10 mL) was added dropwise a solution of tri¯uoromethanesulfonyl
anhydride (130 mmol) in dry dichloromethane (2 mL). The mixture was then allowed to reach
room temperature and kept for 30 min when TLC (ether) revealed the presence of a faster-running
product. The reaction mixture was diluted with dichloromethane (20 mL) and washed with 3N
aqueous hydrochloric acid, water, aqueous 10% sodium hydrogencarbonate, and water.
Concentration of the solvent gave a residue, presumably the 20-O-tri¯uromethanesulfonyl
derivative 20, that was used in the next step without further puri®cation.
Compound 20 was taken-up in dry DMF (5 mL) and treated with sodium azide (56 mg, 0.86
mmol) at 120ꢀC with stirring overnight. The solvent was removed and the residue partitioned in
dichloromethane±water, the organic phase was separated, concentrated and the residue
supported on silica gel and chromatographed (ether:hexane=1:1) to a€ord the title compound
(18, 190 mg, 73%).

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R. Robles et al. / Tetrahedron: Asymmetry 11 (2000) 3069±3077
3.7. Reaction of 15 with allyl bromide. Preparation of 3-allyl- (21) and 1-(30,50-di-O-benzoyl-20-
bromo-20-deoxy-ꢀ-d-xylofuranosyl)thymine 22
A solution of 15 (400 mg, 0.9 mmol) in dry DMF (5 mL) was treated with allyl bromide (500
mL, 5.8 mmol) and heated in a sealed tube at 80ꢀC overnight. TLC (ether) then revealed two new
faster-running products. Concentration of the solvent, followed by column chromatography
(ether:hexane=1:1) of the residue a€orded ®rst crystalline 21 (380 mg, 74%), m.p. 58±59ꢀC (from
27
D
KBr
max
ether±hexane), ‰ꢁŠ : +90 (c 1); ꢂ
1730, 1700, 1656, and 1259 cm^1. NMR data: 1H, (inter alia)
0
0
0
0
0
0
0
6.29 (d, 1H, J1 ,2 =1.5 Hz, H-1 ), 5.82 (m, 1H, ˆCH), 5.77 (dd, 1H, J2 ,3 =1.3, J3 ,4 =3.3 Hz, H-
30), 5.18±5.09 (m, 3H, H-40 and CˆCH2), 4.88 (dd, 1H, J4 ,5 a=6.9, J5 a,5 b=12.1 Hz, H-50a), 4.67
0
0
0
0
(dd, 1H, J4 ,5 b=4.3 Hz, H-50b), 4.49 (m, 2H, N-CH2), 4.41 (t, 1H, H-20), and 1.86 (d, 3H,
J6,Me=1.1 Hz, Me); 13C, 166.2 and 164.6 (2 PhCO), 162.8 (C-4), 150.6 (C-2), 134.4, 133.6, 129.8,
129.7, 129.2, 128.9, 128.6, and 128.1 (PhCO), 132.5 (C-6), 131.4 (ˆCH), 118.1 (ˆCH2), 110.0 (C-
5), 93.1 (C-10), 79.7 (C-40), 77.7 (C-30), 61.5 (C-50), 50.7 (C-20), 43.3 (N-CH2), and 13.3 (Me). Anal.
calcd for C27H25BrN2O7: C, 56.94; H, 4.42; N, 4.92. Found: C, 56.78; H, 4.61; N, 4.66.
0
0
Eluted second was crystalline 22 (21 mg, 25%), m.p. 176±177ꢀC (from ether±hexane), ‰ꢁŠD27:
KBr
max
+76.2 (c 1); ꢂ
1717, 1684, and 1279 cm^1. NMR data: 1H, (inter alia) 8.83 (s, 1H, H-3), 6.31 (d,
0
0
0
0
0
0
0
0
0
1H, J1 ,2 =1.9 Hz, H-1 ), 5.78 (dd, 1H, J2 ,3 =2.4, J3 ,4 =3.5 Hz, H-3 ), 5.10 (dt, 1H, H-4 ), 4.87
(dd, 1H, J4 ,5 a=6.9, J5 a,5 b=12.1 Hz, H-50a), 4.69 (dd, 1H, J4 ,5 b=4.3 Hz, H-50b), 4.42 (t, 1H, H-
20), and 1.83 (d, 3H, J6,Me=1.2 Hz, Me); 13C, 166.2 and 164.7 (2 PhCO), 163.5 (C-4), 150.1 (C-2),
134.5 (C-6), 134.4, 133.6, 129.8, 129.7, 129.2, 128.9, 128.6, and 128.1 (PhCO), 110.9 (C-5), 92.4
(C-10), 79.6 (C-40), 77.8 (C-30), 61.5 (C-50), 50.4 (C-20), and 12.5 (Me). Anal. calcd for
C24H21BrN2O7: C, 54.45; H, 4.00; N, 5.29. Found: C, 54.23; H, 3.85; N, 5.10.
0
0
0
0
0
0
3.8. Treatment of 21 with sodium methoxide
To a solution of 21 (210 mg, 0.37 mmol) in dry methanol (5 mL) was added 0.5N sodium
methoxide solution (1 mL) and the mixture was kept at room temperature for 5 h. TLC (ether)
showed the presence of a slower-running product. The reaction mixture was neutralized with
acetic acid, concentrated and the residue subjected to column chromatography (ether) to give 23
(91 mg, 88%) as a colourless syrup, ‰ꢁŠ2D7: +23 (c 0.7); ꢂ®mlmax 3451, 1701, 1477, and 1114 cm^1. NMR
data: H, 7.42 (s, 1H, H-6), 6.21 (s, 1H, H-10), 5.86 (m, 1H, ˆCH), 5.28±5.15 (4m, 2H, ˆCH2),
1
0
4.55 and 4.53 (2s, 2H, H-20,30), 4.14 (t, 1H, J4 ,5 =5.6 Hz, H-4 ), 3.98±3.87 (m, 4H, N-CH2,H-
50,50), 2.05 (bs, 1H, OH), and 1.93 (s, 3H, Me); 13C, 163.1 (C-4), 151.0 (C-2), 134.8 (C-5), 131.6
(ˆCH), 118.1 (ˆCH2), 110.5 (C-6), 82.0 (C-10), 77.5 (C-40), 61.4 (C-50), 55.8 and 55.4 (C-20,30),
43.5 (N-CH2), and 13.4 (Me). Mass spectrum (LSIMS): m/z 303.09541 (M++Na). For
C13H16N2O5Na 303.09569 (deviation 0.9 ppm).
0
0
Acknowledgements
The authors are deeply grateful to the Ministerio de Educacion y Cultura (Spain) (Project
PB98-1321) for ®nancial support and (L. Alvarez de Cienfuegos) for a grant from the same
institution.

R. Robles et al. / Tetrahedron: Asymmetry 11 (2000) 3069±3077
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