1,3-Dipolar cycloaddition reactions of 3′,5′-Bis-O-silyl thymidines. Synthesis of novel azabicyclic compounds

Article abstract of DOI:10.1081/SCC-120004847

An efficient one step procedure for the preparation of (4.3.0) bicyclic N-methylpyrrolidine thymidine derivatives 4, using cycloaddition reaction of the highly reactive non-stabilized azomethine ylide [Y] with 3′,5′-Bis-O-silylthymidines 3.

Full text of DOI:10.1081/SCC-120004847

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1,3-DIPOLAR CYCLOADDITION REACTIONS OF 3′,5′-
BIS-O-SILYL THYMIDINES. SYNTHESIS OF NOVEL
AZABICYCLIC COMPOUNDS
G. Negrón a , G. Calderón a , F. Vázquez a , L. Lomas b , J. Cárdenas c , C. Márquez c & R.
Gaviño c
a Area de Química Aplicada , Universidad Autónoma Metropolitana , Av. San Pablo No 180,
México, D.F., C.P. 02200, México
b Departamento de Química , Universidad Autónoma Metropolitana , Av. San Pablo No 180,
México, D.F., C.P. 02200, México
c Instituto de Química , Universidad Nacional Autónoma de México , Circuito Exterior, Ciudad
Universitaria, Coyoacán 04510, México, D.F., México
Published online: 16 Aug 2006.
To cite this article: G. Negrón , G. Calderón , F. Vázquez , L. Lomas , J. Cárdenas , C. Márquez & R. Gaviño (2002) 1,3-
DIPOLAR CYCLOADDITION REACTIONS OF 3′,5′-BIS-O-SILYL THYMIDINES. SYNTHESIS OF NOVEL AZABICYCLIC COMPOUNDS,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:13,
1977-1984, DOI: 10.1081/SCC-120004847
To link to this article: http://dx.doi.org/10.1081/SCC-120004847
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SYNTHETIC COMMUNICATIONS, 32(13), 1977–1984 (2002)
1,3-DIPOLAR CYCLOADDITION
REACTIONS OF 30,50-BIS-O-SILYL
THYMIDINES. SYNTHESIS OF NOVEL
AZABICYCLIC COMPOUNDS
G. Negron,1, G. Calderon,1 F. Vazquez,1 L. Lomas,2
*
y
J. Cardenas,3, C. Marquez,3 and R. Gavino3
1Area de Quımica Aplicada and Departamento de
2
Quımica, Universidad Autonoma Metropolitana, Av.
San Pablo No 180, C.P. 02200, Mexico D.F., Mexico
3Instituto de Quımica, Universidad Nacional Autonoma
de Mexico, Circuito Exterior, Ciudad Universitaria,
Coyoacan 04510, Mexico D.F., Mexico
ABSTRACT
An efficient one step procedure for the preparation of (4.3.0)
bicyclic N-methylpyrrolidine thymidine derivatives 4, using
cycloaddition reaction of the highly reactive non-stabilized
azomethine ylide [Y] with 30,50-Bis-O-silylthymidines 3.
Key Words: Bicyclic N-methylpyrrolidine; Nucleosides;
Cycloadditions; Non stabilized; Ylides
*Corresponding author. E-mail: gns@correo.uam.mx
yE-mail: rjcp@servidor.unam.mx
1977
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1978
NEGRON ET AL.
INTRODUCTION
After the discovery of 30-azido-30-deoxythymidine (AZT) as
antiretroviral agent[1] a large number of nucleoside analogues in which the
heterocyclic and/or the sugar moiety have been modified and evaluated for
their antiretroviral properties.
A number of nucleosides with modified pyrimidine moieties are cur-
rently undergoing evaluation as antiviral agents and modifications at the
5- or 6-position of the pyrimidine base have been extensively studied.[2]
However, to our knowledge, no report exists about an intermolecular
cycloaddition to the 5,6-double bond of pyrimidine nucleosides, which
will provide a route to a variety of adducts. These bicyclic compounds
might be useful for biological studies, especially those involving interaction
with repair enzymes.[3]
The [3þ2] cycloaddition reaction of azomethine ylides with alkene
represents an outstanding tool in organic synthesis to provide five
members nitrogen heterocycles, generally with high regio- and stereoselec-
tivities.[4]
We have discovered an efficient access to the non-stabilized azo-
methine ylide Y, generated from tertiary amine N-oxide (1) by reaction
with LDA, which can be usefully trapped with dipolarophiles to get a vari-
ety nitrogen heterocycles (2).[5]
Recently this method developed for non-stabilized ylide generations
has been used for the syntheses of bicyclic pirrolidine derivatives.[6]
Fourteen drugs are currently approved for treating HIV infections, but
there is still an urgent need for new medication. Up to 40% of current
theraphies fail, mainly because of toxicity resulting from taking the large
number of pills and, perhaps most significantly, the emergence of drug
resistance.[7] In our continuing research program on the synthesis of novel
analogues of nucleosides, we are interested in the design and synthesis of
various pyrrolidinyl nucleosides such as 4a–d to provide diverse models for
further search towards novel analogs.

30,50-BIS-O-SILYL THYMIDINES
RESULTS AND DISCUSSION
1979
When freshly sublimed trimethylamine N-oxide (1) was treated with
LDA at À78ꢀC in the presence of thymidine derivatives (3a–d), nucleoside
pyrrolidines (4a–d) were obtained. These products resulted from a cycload-
dition of the ylide Y to the 5,6-double bond of the thymine nucleosides.
This report constitutes the first synthesis of an isomeric pair of bicyclo
cis-fused-pyrrolidine nucleosides 4, and the first example of the intermole-
cular cycloaddition of ylide Y to the trisubstituted double bond.
Compound 4a was obtained as oil, the mass spectra is consistent with
the molecular formula C25H50N3Si2O5 (m/z 528FAB þ). The regiochemistry
of cycloaddition was established by NMR spectroscopy. Thus, the 1H NMR
spectrum of product 4a showed two anomeric protons ascribed to the sugar
moiety at d 6.35 (dd, J ¼ 8.4, 6.3 Hz) and 6.28 (dd, J ¼ 9.3, 5.4 Hz) as a
1
diastereoisomeric mixture (ca 3 : 1 ratio), respectively. Also the H NMR
spectra of 4a and 3a were very similar for the protons assigned to the
sugar moiety (see experimental). Other relevant signals in the 1H NMR
spectrum of 4a for the major isomer, are those due to an AB system at d
2.27 and 3.42 J ¼ 9 Hz (H-9, H-90), an ABX system at d 3.73 (dd, J ¼ 9.3,
6.3 Hz, H-6) 2.92 (dd, J ¼ 10.5, 6.3, H-7) and 2.75 (dd, J ¼ 10.5, 9.3 Hz, H-70)
and a methyl group attached to a nitrogen. These signals were assigned for a
1
N-methyl pyrrolidine, fused to the thymine ring. Similar H NMR spectra
were observed for 4b, 4c and 4d. The anomeric proton signals of these
compounds, led us to determinate the diastereoselectivity of the cycloaddi-
tion reaction. Compounds 4b and 4c were obtained as a diastereoisomeric
mixtures (ca 3 : 1 ratio), on the other hand, when the TBDPS is used as
1
protecting group (4d) no diastereoselectivity was observed in the H NMR
spectrum, because two anomeric proton signals of the same intensities at d
6.44 (dd, J ¼ 9.3, 5.4) and (dd, J ¼ 9.3, 5.1) were observed.

1980
NEGRON ET AL.
Diastereoisomeric separation and pharmacological evaluation of the
compounds synthesized here will be published elsewhere.
EXPERIMENTAL
All melting points were recorded on a Fisher–Johns melting point
apparatus and are uncorrected. 1H NMR spectra were measured on a
Varian UNITY-300 spectrometer. Chemical shifts are reported in parts
per million (d) with TMS as internal standard, coupling constants in Hz.
Infrared (IR) spectra were recorded on a Nicolet 5-SX FT IR spectro-
photometer. Mass spectra were obtained in a JEOL JMS-SX102A mass
spectrometer.
General Procedure for the Synthesis of Compounds 3a–d
A typical procedure for protection of hydroxyl groups as disilyl deri-
vatives of thymidine is given by the preparation of 3a. To a stirred solution
of thymidine (1.00 g, 4.13 mmol) in DMF (20 mL) were added imidazole
(2.81 g, 41.32 mmol) and tert-butyldimethylsilyl chloride (4.98g,
33.05 mmol) at room temperature, and the whole reaction mixture was
stirred at reflux for 24 h. After dilution with brine, the aqueous layer was
extracted with dichloromethane. The combined organic extracts were
washed with water, dried over anhydrous MgSO4, filtered and eva-
porated to afford a residue, which was purified by silica gel column
chromatography (2/98methanol/dichloromethane) to give the disilyl ether
3a (1.81 g, 83%).[8]
30,50-Bis-O-(tert-butyldimethylsilyl)-thymidine 3a: Colorless solid[8]
m.p. 140–141ꢀC. IR (CHCl3) 3730, 1697, 1479, 1262, 1111, 841, 775 cmÀ1
.
1H NMR (CDCl3) d 0.058(s, 3H, CH 3SiO), 0.065 (s, 3H, CH3SiO), 0.095 (s,
6H, (CH3)2SiO), 0.87 (s, 9H, (CH3)3CSi), 0.91 (s, 9H, (CH3)3CSi), 1.89 (d,
3H, J ¼ 0.60, 5-CH3), 1.98(ddd, 1H, J ¼ 2.7, 7.8, 12.9, H-20), 2.21 (ddd, 1H,
2.7, 5.7, 12.9, H-200), 3.73 (dd, 1H, J ¼ 6.0, 11.7, 50-H), 3.84 (dd, 1H, J ¼ 6.0,
11.7, 500-H), 3.90 (dt, 1H, J ¼ 2.4, 2.7, 40-H), 4.39 (dt, 1H, J ¼ 2.4, 6.0, 30-H),
6.30 (dd, 1H, J ¼ 5.7, 7.8, 10-H), 7.43 (q, 1H, J ¼ 0.60, 6-H), 8.07 (m, 1H,
NH). MS: (CI) m/z 471 (Mþ þ 1) (100%), 155, 145, 127, 81.
30,50-Bis-O-(triisopropylsilyl)-thymidine 3b: White solid m.p.
123–124ꢀC. IR (CHCl3) 3030, 1689, 1467, 1281, 1110, 882, 677 cmÀ1
.
1H NMR d (CDCl3) 1.069 (m, 42H, 6[(CH3)2CH]), 1.90 (d, 1H, J ¼ 1.2, 5-
CH3), 2.30 (ddd, 1H, J ¼ 1.5, 5.7, 13.2, H-20), 2.03 (ddd, 1H, 5.70, 8.70, 13.2,
H-200), 3.94 (dd, 1H, J ¼ 2.7, 11.7, 50-H), 3.88 (dd, 1H, J ¼ 2.7, 11.7, 500-H),

30,50-BIS-O-SILYL THYMIDINES
1981
4.015 (c, 1H, J ¼ 2.7, 40-H), 4.61 (dt, 1H, J ¼ 1.5, 5.7, 30-H), 6.34 (dd, 1H,
J ¼ 5.1, 8.7, 10-H), 7.45 (c, 1H, J ¼ 1.2, 6-H), 8.05 (m, NH). MS: (FAB) m/z
555 (Mþ þ 1), 337, 187, 145 (100%).
30,50-Bis-O-(dimethylthexylsilyl)-thymidine 3c: White solid m.p.
113–114ꢀC. IR (CHCl3) 3036, 1697, 1460, 1261, 1124, 833, 781, 669 cmÀ1
.
1H NMR (CDCl3) d 0.085 (s, 3H, CH3SiO), 0.093 (s, 3H, CH3SiO), 0.128(s,
3H, CH3SiO), 0.131 (s, 3H, CH3SiO), 0.823 (s, 12H, 2(CH3)2CSi), 0.87 (d,
6H, J ¼ 6.6, (CH3)2CH), 0.86 (d, 6H, J ¼ 6.6, (CH3)2CH), 1.622 (Hept, 1H,
J ¼ 6.6, (CH3)2CH), 1.628(Hept, 1H,
J ¼ 6.6, (CH3)2CH), 1.92 (d,
1H, J ¼ 1.2, 5-CH3), 1.96 (ddd, 1H, J ¼ 3.0, 6.0, 13.2, H-20), 2.10 (ddd,
1H, 2.7, 6.0, 13.2, H-200), 3.72 (dd, 1H, J ¼ 2.7, 11.4, 50-H), 3.815 (dd, 1H,
J ¼ 3.0, 11.4, 500-H), 3.90 (dt, 1H, J ¼ 2.7, 6.0, 40-H), 4.38(dt, 1H, J ¼ 3.0,
6.0, 30-H), 6.26 (dd, 1H, J ¼ 5.4, 7.8, 10-H), 7.38(c, 1H, J ¼ 1.2, 6-H), 8.03
(m, NH). MS: (FAB) m/z 527 (Mþ þ 1), 173, 89, 73 (100%).
30,50-Bis-O-(tert-butyldiphenylsilyl)-thymidine 3d: Colorless solid[8] m.p.
65–66ꢀC. IR (CHCl3) 3192, 1703, 1466, 1433, 1281, 1117, 748, 709 cmÀ1
.
1H NMR (CDCl3) d 0.927 (s, 9H, (CH3)3CSi), 1.073 (s, 9H, (CH3)3CSi) 1.49
(d, 3H, J ¼ 0.60, 5-CH3), 1.94 (ddd, 1H, J ¼ 2.7, 9.0, 13.2, H-20), 2.32 (ddd,
1H, 2.7, 5.7, 13.2, H-200), 3.31 (dd, 1H, J ¼ 5.7, 11.4, 50-H), 3.73 (dd, 1H,
J ¼ 5.7, 11.4, 500-H), 3.98(dt, 1H, J ¼ 2.4, 2.7, 40-H), 4.54 (dt, 1H, J ¼ 2.4,
5.7, 30-H), 6.49 (dd, 1H, J ¼ 5.7, 9.0, 10-H), 7.4 (m, 21H, (Ph)2SiO, (Ph)2SiO,
6-H), 8.57 (m, NH). MS: (FAB) m/z 719 (Mþ þ 1), 269, 197, 135 (100%).
General Procedure for Cycloaddition Compounds 4a–d
A typical procedure for cycloaddition of 30,50-Bis-O-(tert-butyldi-
methylsilyl)-thymidine is given by the preparation of 4a. To a mixture of
3a (470 mg, 1 mmol) and trimethylamine N-oxide 1 (375 mg, 5 mmol) in
THF (10 mL) under nitrogen atmosphere, was added dropwise a solution
of LDA (18.5 mmol) in THF (10 mL) at À78ꢀC. The reaction mixture was
stirred for 7 h and then allowed to warm to rt. Stirring was continued for
48h. The yellow solution was diluted with water and extracted with CH 2Cl2.
The extractives dried over anhydrous Na2SO4, and evaporated under
reduced pressure. Chromatographic separation on preparative TLC plates
using MeOH/CH2Cl2 (5 : 95) as eluent gave 4a (296 mg, 0.56 mmol, 56%) as
a mixture of diastereoisomers A : B in a 75 : 25 ratio (1H NMR).
2-(20-Deoxy-30,50-Bis-O-tert-butyldimethylsilyl-ꢀ-D-ribofuranosyl)-8-aza-
5,8-dimethyl-cis-5,6-diazabicyclo [4.3.0] nonane-2,4-dione IR (CHCl3) 3030,
.
1700, 1462, 1251, 1092, 1041, 838, 776, 673 cmÀ1 1H NMR 4a (major)
(CDCl3) d 0.04 (s, 6H, (CH3)2SiO), 0.08(s, 6H, (CH ) SiO), 0.86 (s, 9H,
3 2
(CH3)3CSi), 0.91 (s, 9H, (CH3)3CSi), 1.25 (s, 3H, 5-CH3), 1.89 (m, 2H, H-2,

1982
NEGRON ET AL.
H-20), 2.25 (s, 3H, N-Me), 2.27 (d, 1H, J ¼ 9.0, H-9), 2.45 (dd, 1H, J ¼ 9.3,
10.5, H-7), 2.92 (dd, 1H, J ¼ 6.3, 10.5, H-70), 3.42 (d, 1H, J ¼ 9.0, H-90), 3.69
(m, 2H, H-5, H-50), 3.73 (dd, 1H, J ¼ 6.3, 9.3, H-6), 3.81 (m, 1H, H-40), 4.30
(m, 1H, H-30), 6.35 (dd, 1H, J ¼ 6.3, 8.4, H-10), 7.75 (s, 1H, NH). H NMR
1
4a (minor) (CDCl3) d 0.04 (s, 6H, (CH3)2SiO), 0.08(s, 6H, (CH 3)2SiO), 0.86
(s, 9H, (CH3)3CSi), 0.91 (s, 9H, (CH3)3CSi), 1.25 (s, 3H, 5-CH3), 1.89 (m,
2H, H-20), 2.25 (d, J ¼ 9, H-9), 2.26 (s, 3H, N-Me), 2.67 (dd, 1H, J ¼ 9.3, 9.9,
H-7), 2.92 (H-70), 3.50 (d, 1H, J ¼ 9.0, H-90), 3.69 (m, 2H, H-5, H-50), 3.77
(m, 1H, H-40), 3.98(dd, 1H, J ¼ 6.0, 9.0, H-6), 4.30 (m, 1H, H-30), 6.28(dd,
1H, J ¼ 5.4, 9.3, H-10), 8.12 (s, 1H, NH). MS: (FAB) m/z 528(M þ 1)þ
(100%), 182, 73, 57. HRMS (FAB) m/z calcd for C25H50N3Si2O5
(Mþ þ 1) 528.3295, found 528.3280.
2-(20-Deoxy-30,50-Bis-O-(triisopropylsilyl)-ꢀ-D-ribofuranosyl)-8-aza-5,8-
1
dimethyl-cis-5,6-diazabicyclo [4.3.0] nonane-2,4-dione H NMR 4b (major)
d (CDCl3) 1.03–1.08(m, 42H, 6[(CH ) CH]), 1.25 (s, 1H, 5-CH3), 1.95 (m,
3 2
2H, H-20), 2.23 (s, 3H, N-Me), 2.24 (d, 1H, J ¼ 9.0, H-9), 2.80 (br-t, H-7),
2.90 (dd, 1H, J ¼ 6.0, 10.0, H-70), 3.40 (d, 1H, J ¼ 9.0, H-90), 3.73 (dd, 1H,
J ¼ 6.0, 9.6, H-6), 3.79 (m, 2H, H-5, H-50), 3.89 (m, 1H, H-40), 4.49 (br d,
1H, J ¼ 4.5, H-30), 6.34 (dd, 1H, J ¼ 5.4, 9.0, H-10), 7.40 (s, 1H, NH).
1H NMR 4b (minor) d (CDCl3) 1.03–1.08(m, 42 H, 6[(CH ) CH]), 1.27
3 2
(s, 1H, 5-CH3), 1.95 (m, 2H, H-20), 2.24 (d, 1H, J ¼ 9.0, H-9), 2.25 (s,
3H, N-Me), 2.67 (t, J ¼ 9.6, H-7), 2.85 (dd, 1H, J¼6.0, 9.6, H-70), 3.47 (d,
1H, J ¼ 9.0, H-90), 3.80 (m, 2H, H-5, H-50), 3.87 (m,1H, H-40), 3.97 (dd, 1H,
J ¼ 6.0, 9.6, H-6), 4.52 (br d, 1H, J ¼ 5.4, H-30), 6.30 (dd, 1H, J ¼ 4.8, 9.9,
H-10), 7.40 (s, 1H, NH). MS: (FAB) m/z 612 (M þ 1)þ, 182, 145 (100%).
HRMS (FAB) m/z calcd for C31H62N3Si2O5 (Mþ þ 1) 612.4221, found
612.4228.
2-(20-Deoxy-30,50-Bis-O-(dimethylthexylsilyl)-ꢀ-D-ribofuranosyl)-8-aza-
5,8-dimethyl-cis-5,6-diazabicyclo [4.3.0] nonane-2,4-dione IR (CHCl3) 2956,
1696, 1458, 1385, 1245, 1088, 1024, 965, 820, 769, 667 823, 739, 670 cmÀ1
.
1H NMR 4c (major) (CDCl3) d 0.10 (s, 6H, (CH3)2SiO), 0.14 (s, 6H,
(CH3)2SiO), 0.83 (s, 12H, 2(CH3)2CSi), 0.87 (d, 6H, J¼6.6, (CH3)2CH),
0.89 (d, 6H, J ¼ 6.6, (CH3)2CH) 1.29 (s, 3H, 5-CH3), 154–1.70 (m, 2H,
CH3)2CH), 1.87–1.92 (m, 2H, H-2, H-20), 2.28(d, 1H, J ¼ 9.0, H-9), 2.30
(s, 3H, N-Me), 2.83 (m, 1H, H-7), 2.92 (dd, 1H, J ¼ 6.3, 10.5, H-70), 3.46 (d,
1H, J ¼ 9.0, H-90), 3.69 (m, 2H, H-5, H-50), 3.74 (m, H-6), 3.83 (m, 1H, H-
40), 4.33 (m, 1H, H-30), 6.35 (dd, 1H, J ¼ 6.3, 8.4, H-10), 7.60 (br s, 1H, NH).
1H NMR 4c (minor) (CDCl3) d 0.10 (s, 6H, (CH3)2SiO), 0.14 (s, 6H,
(CH3)2SiO), 0.826 (s, 12H, 2(CH3)2CSi), 0.87 (d, 6H, J ¼ 6.6, (CH3)2CH),
0.89 (d, 6H, J ¼ 6.6, (CH3)2CH) 1.29 (s, 3H, 5-CH3), 1.54–1.70 (m, 2H,
CH3)2CH), 1.87–1.92 (m, 2H, H-2, H-20), 2.28(d, 1H, J ¼ 9.0, H-9), 2.30
(s, 3H, N-Me), 2.83 (m, 1H, H-7), 2.92 (dd, 1H, J ¼ 6.3, 10.5, H-70), 3.50

30,50-BIS-O-SILYL THYMIDINES
1983
(d, 1H, J ¼ 9.0, H-90), 3.69 (m, 2H, H-5, H-50), 3.74 (m, H-6), 3.83 (m, 1H,
H-40), 4.33 (m, 1H, H-30), 6.20 (dd, 1H, J ¼ 5.1, 9.0, H-10), 7.60 (br s, 1H,
NH). (FAB) m/z 584 (M þ 1)þ, 182, 96, 73 (100%), 57. HRMS (FAB) m/z
calcd for C29H58N3Si2O5 (Mþ þ 1) 584.3927, found 584.3915.
2-(20-Deoxy-30,50-Bis-O-(tert-butyldiphenylsilyl)-ꢀ-D-ribofuranosyl)-8-aza-
5,8-dimethyl-cis-5,6-diazabicyclo [4.3.0] nonane-2,4-dione IR (CHCl3) 3069,
1
1690, 1470, 1426, 1250 823, 739, 670 cmÀ1. H NMR (4d mixture) (CDCl3)
0.92 (s, 9H, (CH3)3CSi), 0.93 (s, 9H, (CH3)3CSi), 1.04 (s, 9H, (CH3)3CSi),
1.05 (s, 9H, (CH3)3CSi), 1.10 (s, 3H, 5-CH3), 1.13 (s, 3H, 5-CH3), 1.60–2.40
(m, 8H, H-2, H-20, H-2, H-20, H-7, H-7, H-9, H-9), 2.14 (s, 3H, NMe), 2.15
(s, 3H, NMe), 2.69 (dd, 1H, J ¼ 6.0, 10.5, H-70), 2.88 (dd, 1H, J ¼ 6.0, 10.5,
H-70), 3.31 (d, 1H, J ¼ 9.0, H-90), 3.31 (d, 1H, J ¼ 9.0, H-90), 3.56 (m, H-6),
3.66 (m, 2H, H-5, H-50), 3.66 (m, 2H, H-5, H-50), 3.79 (dd, J ¼ 3.6, 9.0, H-6),
3.88 (m, 1H, H-40), 3.88 (m, 1H, H-40), 4.39 (m, 1H, H-30), 4.45 (m, 1H, H-
30), 6.40 (dd, 1H, J ¼ 5.1, 9.3, H-10), 6.44 (dd, 1H, J ¼ 5.4, 9.3, H-10), 7.16–
7.80 (m, NH, Ph). ). (FAB) m/z 776 (M þ 1)þ.
ACKNOWLEDGMENTS
The authors are indebted to Consejo Nacional de Ciencia y Tecnologıa
(CONACyT) for partial financial support (Project No 33366-E). Messrs, A.
Acosta and L. Velasco for their technical assistance.
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Received in the USA June 23, 2001