Convenient synthesis of C-aza-2,3-dideoxynucleosides

Article abstract of DOI:10.1039/a900689c

l-Aryl-l,2,3,4-tetradeoxy-l,4-imino-D-pentitols 5 and 9f are easily synthesized from TV-Boc-L-pyroglutamate 1 via a successive procedure involving regioselective ring-opening, recyclization with dehydration, stereoselective reduction, and reduction of the

Full text of DOI:10.1039/a900689c

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Convenient synthesis of C-aza-2,3-dideoxynucleosides
Atsuya Momotake,b Hideo Togoab and Masataka Yokoyama*ab
a Department of Chemistry, Faculty of Science, b Graduate School of Science and Technology,
Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba City 263-8522, Japan
Received (in Cambridge) 26th January 1999, Accepted 12th March 1999
1-Aryl-1,2,3,4-tetradeoxy-1,4-imino--pentitols 5 and 9f are easily synthesized from N-Boc--pyroglutamate
1 via a successive procedure involving regioselective ring-opening, recyclization with dehydration, stereoselective
reduction, and reduction of the ester group. Their structures are determined mainly by X-ray crystallography
and NMR measurements. Their bioassay is also described.
O
Boc
N
Introduction
A
The importance of modification of the sugar moiety in nucleo-
O
L-Glutamic Acid
EtO
sides has long been recognized to improve their antiviral or
anticancer activities. The 2,3-dideoxynucleosides1 are typical
sugar-modified nucleosides, which have been used as both anti-
cancer and antiviral drugs, because DNA synthesis is termin-
ated when they are incorporated into the end of a growing
DNA chain. Recently, they have received increased attention
1
B
O
O
O
due to their activity against the human immunodeficiency virus
(HIV).2 Thus, compounds which would substantially mimic the
2,3-dideoxynucleoside structures have been synthesized and
employed as enzyme inhibitors in chemotherapy. In order to
provide a new type of potentially active analogue the further
modification of nucleoside subunits to a variety of derivatives
with potentially different activities is considered to be desirable.
In this respect, we chose the azafuranopentose analogues, in
which the ring oxygen of furanoses is replaced with nitrogen.
Azasugars such as nojirimycin are well known as glycosidase
inhibitors. Their activity is ascribed to both the charge–charge
interaction and the hydrogen bonding between an enzyme and a
protonated azasugar at physiological pH.3 In the case of the
azafuranopentose system, the 1,4-imino group on the sugar
ring is protonated to give the corresponding immonium com-
pound like the oxocarbenium ion. Azasugar-containing nucleo-
sides such as C-azanucleosides and N-azanucleosides have been
reported in the literature.4 However, their synthesis requires
multi-step or tedious methods.
C
N
Ar
EtO
Ar
EtO
NHBoc
3
2
D
O
O
H
N
H
N
HO
HO
E
EtO
EtO
Ar
Ar
4 (α-form)
5 (α-form)
H
E
H
Ar
Ar
N
N
4 (β-form)
5 (β-form)
From the above standpoint, we intended to synthesize the
C-aza-2,3-dideoxynucleosides on a large scale by a convenient
method. Recently, we have developed a short-step synthesis of
some C-azanucleosides having 1,4-dideoxy-1,4-imino--lyxitol
and 1,2,4-trideoxy-1,4-imino--lyxitol as the sugar moiety,5 and
it was possible to modify the amino group in the azasugar
moiety of these C-azanucleosides with an alkyl or acyl group.
Therefore, it is expected that functionalization of this amino
group would render it a potential linker for attachment to other
molecules.
Scheme 1 Reagents and conditions: A, Ref. 6; B, Ar-Metal, THF, Ϫ78
to Ϫ40 ЊC, 1 h; C, CF3CO2H, CHCl3, rt, 2 h; D, NaBH3CN, HCl,
PriOH, rt, 2 h; E, LiAlH, Et2O, 0 ЊC, 3 h.
procedure, and the carbonyl group of its amide was attacked
regioselectively by aryl metal reagents because of the electron-
withdrawing Boc group. Thus, the ring-opening reaction of
1 was achieved with a variety of nucleophiles.7 Before the
reaction of 1 with aromatic metal reagents, we examined the
enantiomeric excess7b of the starting material 1 by using chiral
column chromatography. It was revealed that some racemiz-
ation occurred to an extent of 4% (92% ee) when -glutamic
acid was treated with SOCl2 and refluxed in ethanol solution.
Compound 1 was treated with Grignard reagents (ArMgX)
to give 5-aryl-substituted derivatives 2 in a regioselective
manner (Table 1, a and b). In this reaction, we used the easily
available lithium reagents of heterocyclic substituents to intro-
duce various kinds of heteroaromatics. The thienyllithium
reagent reacted in the same way as the corresponding Grignard
reagent (Table 1, c). The lithium reagents of other hetero-
aromatics such as benzofuran, N-(phenylsulfonyl)indole, and
In this report, we describe the synthesis of other analogues,
C-aza-2,3-dideoxynucleosides, their structure determination
mainly with X-ray crystallography and NMR measurements,
and, furthermore, their biological activities.
Results and discussion
For the synthesis of 1-aryl-1,2,3,4-tetradeoxy-1,4-imino-
-pentitol (C-aza-2,3-dideoxynucleoside), we chose N-Boc-
-pyroglutamate6 1 as the starting material (Scheme 1).
Pyroglutamate 1 was prepared from -glutamic acid by the usual
J. Chem. Soc., Perkin Trans. 1, 1999, 1193–1200
1193

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Table 1 Preparation of compounds 2, 3, 4 and 5
Table 2 Introduction of pyrimidinyl group by using some metal
reagents
Yields (%)a
ee (%)
Ar
2
3
4α/4β (total)
5α
5β
Ar-Metal
Conditions
Yield (%)
49
1
3
92b
64b
89
19/44 (63)
81
83
a:
OMe
N
rt, 10 min, THF
92 65
92 72
Me
b:
c:
94
94
18/48 (66)
33/46 (79)
98
65
67
70
MeO
N
Li
84b
84c
a
OMe
S
N
N
rt, 30 min, THF
29
MeO
MeO
N
CeCl2
MgCl
51c
78
90
63
29/47 (76)
36/36 (72)
27/59 (86)
89
49
71
66
75
73
d:
e:
OMe
O
N
rt, 8 h, THF
rt, 1 h, THF
40
40
92 60
92 92



63c
N
a CeCl3, THF, Ϫ78 ЊC, 30 min.
SO2Ph
N
OMe
17c
54b
f:
O
Boc
N
N
OMetal
Ar
Ar-Metal
OMe
N
1
EtO
H
OBut
g:
e
78c
84d
1'
N
OBut
Boc
O
a Isolated yield. b Aryl Grignard reagent was used. c Aryllithium reagent
was used. d Ar 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl. e see Table 4.
NMetal
quenching
OH
Ar
2
EtO
Scheme 2 Plausible mechanism for racemization.
2,4-di(tert-butoxy)pyrimidine were also employed for the
ring-opening reaction.
Here, the yield of 2,4-dimethoxypyrimidine derivative 2f was
poor with the corresponding lithium reagent because of the
decomposition of its lithium salt at above Ϫ78 ЊC. To improve
the yield of 2f, the Grignard reagent of 2,4-dimethoxy-
pyrimidine was prepared from the reaction of 5-bromo-2,4-di-
methoxypyrimidine with EtMgBr via halogen–metal exchange.8
Unlike its lithium reagent, the pyrimidine Grignard reagent did
not decompose even at room temperature and the ring-opening
reaction proceeded cleanly in a regioselective manner. How-
ever, no improvement in the yield of 2f was observed, perhaps
because of the small equilibrium constant of the halogen–metal
exchange between 5-bromo-2,4-dimethoxypyrimidine and
EtMgCl. When this Grignard reagent was prepared in Et2O,
it did not work at all due to its insolubility. Therefore, it
should be prepared in THF solution. Next, 2a–f were treated
with trifluoroacetic acid to remove the Boc group followed
by intramolecular cyclization resulting in the formation of 2-
aryl-∆1-pyrroline-5-carboxylates 3 in good yields. Since it was
possible to separate the enantiomers of 3 (only at analytical
level) by chiral column chromatography, the ee-values were
rechecked. Compared with the ee-value of 1, that of 3 was
diminished as shown in Table 2, perhaps because 5-H of 1 or
1Ј was somewhat removed by alkyl or aromatic lithium reagents
in the ring-opening reaction with aromatic lithium reagents in
the preparation of 2 (Scheme 2). To prevent this racemization,
the reaction was carried out again by using less basic reagents
such as pyrimidine cerium or magnesium reagents. Compared
with the lithium reagent, the racemization decreased when
the cerium reagent9 was used. Further, no racemization was
observed with the use of the magnesium reagent for 1 h (chiral
transfer 100%). In the case of other heterocycles, the reaction
proceeded in the same manner as for 2f. It was confirmed that
the ee-value did not change during the process 1 → 4, by
using chiral column chromatography.
acidic conditions to give α- and β-forms of 2-arylpyrrolidine-5-
carboxylates 4. As shown in entries 1–5 in Table 3, the reaction
showed some β-selectivity probably due to the steric hindrance
of the 2-ethoxycarbonyl group. When amine–borane com-
plexes10 were used as reducing agents (entries 6 and 7), the
stereoselectivity was reversed to give the α-form of 4 preferen-
tially. Further, the use of trifluoroacetic acid in place of HCl
gave the same result. When this reduction was performed in
AcOH, an unexpected (5S)-2-aryl-5-ethoxycarbonyl-N-ethyl-
pyrrolidine was obtained as the main product, which might be
produced by the reaction of 4 with acetaldehyde generated
under these reaction conditions. In the case of 2g, the elimin-
ation of two tert-butoxy groups took place under acidic con-
ditions to give 3g, which was then reduced in a 1,4-reductive
manner to give an undesired product 7 (Table 4). The reduction
with Pd/C11 or with NaBH4–CeCl3 12 also gave only 7 in place of
isomer 8.
The reduction of 4 with LiAlH4 in Et2O gave α- and β-forms
of 1-aryl-1,2,3,4-tetradeoxy-1,4-imino--pentitols 5. Although
we could obtain an α/β-mixture of 5 directly from 3 or via 2-
aryl-5-hydroxymethyl-∆1-pyrrolines such as 6 (Scheme 3), their
yields were low. In addition, it was difficult to separate the α-
and β-isomers of 5. On the other hand, the α- and β-isomers of
3 were found to be separated easily on preparative TLC (PLC).
Finally, the α- and β-isomers of 5f were deprotected by
treatment with HCl in MeOH at 60 ЊC for 3 h to afford the
desired α- and β-form of 9f (C-aza-2,3-dideoxyribonucleosides)
as HCl salts, respectively (Scheme 4).
1
In the H NMR data of C-aza-2,3-dideoxyribonucleosides
5a–e and 9f, differential nuclear Overhauser effects (NOEs)
were observed and the spectral data of the α- and β-forms were
compared. Fig. 1 shows the NOEs observed in 9f as a typical
example. A difference between the α- and β-forms is pointed out
as follows: In the α-form, an NOE is observed between 1-H and
CH2OH, while in the β-form NOEs are observed between 1-H
The imino group of 3 was reduced with NaBH3CN under
1194
J. Chem. Soc., Perkin Trans. 1, 1999, 1193–1200

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Table 3 Reductive conditions of imino group under acidic conditions
(3c → 4c)
O
H
HN
H
H
H
H
H
NH
O
N
H
H
H
HO
H
O
Entry
Conditions
HCl (M)
Yield (%) (α/β)
N
HO
1
2
3
4
5
6
7
NaBH3CN, EtOH, HCl
NaBH3CN, EtOH, HCl
NaBH3CN, EtOH, HCl
NaBH3CN, PriOH, HCl
NaBH3CN, ButOH, HCl
Me2NHؒBH3, AcOH
0.5
1
2
1
1
22 (4/18)
NH
O
69 (26/43)
35 (13/22)
79 (33/46)
63 (28/35)
51 (38/13)
60 (40/20)
HN
9f (α-form)
9f (β-form)
Fig. 1 Observed NOEs in 9f.
ButNH2ؒBH3, AcOH
3g
reductive conditions
H
H
O
N
O
O
N
O
O
O
H
N
H
N
NH
NH
EtO
EtO
7
8
Table 4 Reduction of compound 3g
Yields (%)
Reductive conditions
7
8
Hϩ, NaBH3CN, EtOH
H2, Pd/C, MeOH
CeCl3, NaBH4, MeOH
55
100
30
0
0
0
A
3c
5c (α, β-mixture)
B
S
C
HO
N
Fig. 2 Top structure: X-ray molecular structure of β-form of 9f.
Bottom structure: 9f and its enantiomer in the same crystal.
6
Scheme 3 Reagents and conditions: A, 15% LiAlH4, THF, 0 ЊC, 2 h; B,
22% excess NaBH4, EtOH, rt, 8 h; C, 70% NaBH3CN, HCl, EtOH, rt,
2 h.
Table 5 Crystallographic data for 9f†
Empirical formula
Formula relative molecular mass
Crystal dimensions/mm
Crystal system
Space group
Lattice parameters
C9H14ClN3O3
247.68
Cl
0.20 × 0.25 × 0.02
monoclinic
C2/c (#15)
a = 13.741(1) Å
b = 7.2000(7) Å
c = 24.483(2) Å
β = 109.322(5)Њ
8
1.439
29.73
23.0
1.42 ϩ 0.30 tanθ
135.1
H2
HO
N
O
HCl-MeOH,
5f (α-form)
60 °C, 3h, 92%
NH
HN
9f (α-form)
O
O
Z
Dc (g cmϪ3
)
µ(Mo-Kα) (cmϪ1
Temp. (T/ЊC)
Scan width (Њ)
2θ/max (Њ)
)
HN
NH
O
Cl
H2
N
HO
HCl-MeOH,
No. of reflections measured
Total
5f (β-form)
4199
60 °C, 3h, 89%
With I > 2σ (I)
2006
No. of refinement variables
Final R; Rw
150
0.066; 0.094
9f (β-form)
Scheme 4 Deprotection of pyrimidine moiety.
pure 9f. Compound 9f obtained by the first reprecipitation
([α]D25 Ϫ30.5Њ) was purified by the second reprecipitation (see
Experimental section) to give 9f showing the specific rotation of
[α]D25 Ϫ33.1Њ, and was considered to be fully resolved. Attempted
and 4-H, and between uracil 6-H and CH2OH. In all other C-
aza-2,3-dideoxyribonucleosides 5a–e, NOEs were observed in
the same manner as those of 9f.
The crystal of 9f, which was obtained from ethanol–H2O for
X-ray analysis, was found to be a racemic mixture (Fig. 2, Table
5). Judging from the easy crystallization of the racemic com-
pound, reprecipitation seemed appropriate to obtain enantio-
† CCDC reference number 207/309. See http://www.rsc.org/suppdata/
p1/1999/1193 for crystallographic files in .cif format.
J. Chem. Soc., Perkin Trans. 1, 1999, 1193–1200
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diastereomeric resolution with salts of 9f and -(ϩ)-tartaric
acid or 9f and (S)-(ϩ)-camphor-10-sulfonic acid was unsuc-
cessful. Furthermore, the transfer from 4 to 5 turned out to pro-
ceed without racemization by the isolation of enantiopure 9f.
The anti-HIV activities of 3g and 9f (β-form) were examined.
Very little activity was found (3g: EC50 > 25 m; EC90 > 25 m;
CC50 = 7.9 m; 9f: EC50 > 30 m; EC90 > 30 m; CC50 = 14.9
m) like that of a typical anti-HIV drug, 3Ј-azido-2Ј,3Ј-
dideoxythymidine (AZT: EC50 = 0.056 µ; EC90 = 0.153 µM;
CC50 = 48.0 µ).
In summary, both the α- and β-forms of C-aza-2,3-
dideoxynucleosides 5 and 9f were synthesized from -glutamic
acid in 5 or 6 steps. The use of Grignard reagents of hetero-
aromatics totally prevented the racemization in the reaction of
1 → 2. Under the acidic conditions used, compounds 3 were
reduced with NaBH3CN in a β-selective manner and the select-
ivity was reversed with amine–borane complexes. Enantiopure
9f could be also obtained by the reprecipitation method.
with saturated aqueous NH4Cl and the product was extracted
with AcOEt. The extract was dried (Na2SO4) and concentrated.
The residue was purified by column chromatography [eluent:
hexane–AcOEt (3:1)] to give 2.
Ethyl (S)-2-(tert-butoxycarbonylamino)-5-phenyl-5-oxopent-
anoate 2a. Solid; mp 82–83 ЊC (Found: C, 64.56; H, 7.61; N,
4.17. Calc. for C18H25NO5: C, 64.46; H, 7.51; N, 4.18%);
νmax(KBr)/cmϪ1 740, 1180, 1220, 1280, 1420, 1590, 1650, 2980,
3370; δH(CDCl3) 1.28 (3H, t, J 7.0, CH3CH2), 1.42 (9H, s, Boc),
2.09 (1H, m, 3-Ha), 2.31 (1H, m, 3-Hb), 3.02–3.17 (2H, m, 4-H2),
4.20 (2H, q, J 7.0, CH3CH2), 4.37 (1H, m, 2-H), 5.16 (1H, d,
J 7.0, NH), 7.16 (2H, m, Ph), 7.57 (1H, m, Ph), 7.95 (2H, m, Ph).
Ethyl
(S)-2-(tert-butoxycarbonylamino)-5-oxo-5-(p-tolyl)-
pentanoate 2b. Solid; mp 74–75 ЊC (Found: C, 65.36; H, 7.75;
N, 3.91. Calc. for C19H27NO5: C, 65.31; H, 7.79; N, 4.01%);
νmax(KBr)/cmϪ1 780, 1060, 1160, 1350, 1520, 1680, 1710, 1740,
2980, 3350; δH(CDCl3) 1.25 (3H, t, J 7.0, CH3CH2), 1.42 (9H, s,
Boc), 2.09 (1H, m, 3-Ha), 2.29 (1H, m, 3-Hb), 2.38 (3H, s,
PhCH3), 2.98–3.16 (2H, m, 4-H2), 4.18 (2H, q, J 7.0, CH3CH2),
4.35 (1H, m, 2-H), 5.51 (1H, d, J 8.1, NH), 7.23 (2H, d, J 7.7,
3Ј- and 5Ј-H), 7.84 (2H, d, J 7.7, 2Ј- and 6Ј-H).
Experimental
All reactions requiring anhydrous conditions were conducted
in oven-dried (120 ЊC) apparatus under dry argon. Ether and
THF were distilled from sodium in the presence of benzo-
phenone ketyl. Microanalyses were performed at the Chemical
Ethyl (S)-2-(tert-butoxycarbonylamino)-5-oxo-5-(2-thienyl)-
pentanoate 2c. Solid; mp 101–102 ЊC (Found: C, 56.42; H, 6.87;
N, 4.02. Calc. for C16H23NO5S: C, 56.29; H, 6.79; N, 4.10%);
νmax(KBr)/cmϪ1 720, 1060, 1160, 1340, 1520, 1660, 1710, 1740,
3000, 3350; δH(CDCl3) 1.28 (3H, t, J 7.0, CH3CH2), 1.42 (9H, s,
Boc), 2.09 (1H, m, 3-Ha), 2.30 (1H, m, 3-Hb), 2.95–3.11 (2H, m,
4-H2), 4.20 (2H, q, J 7.0, CH3CH2), 4.35 (1H, m, 2-H), 5.16
(1H, d, J 5.8, NH), 7.13 (1H, dd, J 5.0, 3.9, 4Ј-H), 7.64 (1H, dd,
J 5.0, 1.0, 3Ј-H), 7.72 (1H, dd, J 3.9, 1.0, 5Ј-H); δC(CDCl3) 14.02
(p), 27.03 (s), 28.14 (C(CH3)3), 35.14 (s), 53.03 (t), 61.38 (p),
79.76 (C(CH3)3), 128.01 (t), 131.84 (t), 133.57 (t), 143.76 (q, Ar),
155.35 (q, CO), 172.16 (q, CO), 191.70 (q, CO).
1
Analysis Center of Chiba University. H NMR spectra were
recorded on a JNM-LA-500 (500 MHz) spectrometer. J-Values
are in Hz. 13C NMR spectra were recorded on a JEOL
JNM-LA-500 (125 MHz) spectrometer. X-ray crystallographic
data were collected on a Rigaku AFC7S diffractometer with
graphite-monochromated Mo-Kα radiation. IR spectra were
measured with a JASCO FT/IR-200. Mass spectra were
recorded on a JEOL JMS-HX 110 mass spectrometer. For fast-
atom bombardment (FAB) mass spectra, NBA refers to
m-nitrobenzyl alcohol matrix. Specific rotations were measured
with a JASCO DIP-370. Mps were measured using a Yamano
Melting Points Apparatus Model MP-21 and uncorrected.
Wakogel C-200, C-300 and Silicagel 60 (Kanto Chemical Co.,
Inc.) were used for column chromatography, Kieselgel 60 F254
(Merck) for TLC, and Wakogel B-5F for PLC.
Ethyl (S)-5-(2-benzofuryl)-2-(tert-butoxycarbonylamino)-5-
oxopentanoate 2d. Oil; νmax/cmϪ1 (neat) 750, 1030, 1160, 1370,
1520, 1680, 1710, 1750, 2980, 3370; HRMS (FAB, NBA) Calc.
for C20H26O6N: m/z (M ϩ H) 376.1760. Found: m/z, 376.1788;
δH(CDCl3) 1.28 (3H, t, J 7.1, CH3CH2), 1.42 (9H, s, Boc), 2.13
(1H, m, 3-Ha), 2.34 (1H, m, 3-Hb), 3.00–3.18 (2H, m, 4-H2),
4.22 (2H, q, J 7.1, CH3CH2), 4.39 (1H, m, 2-H), 5.23 (1H, d,
J 8.0, NH), 7.30 (1H, m, benzofuran), 7.45–7.59 (3H, m, benzo-
furan), 7.70 (1H, m, benzofuran); δC(CDCl3) 14.13 (p), 26.75
(s), 28.23 (C(CH3)3), 34.83 (s), 53.06 (t), 61.57 (s), 79.98
(C(CH3)3), 112.42 (t), 112.81 (t), 123.29 (t), 123.92 (t), 126.96
(q, Ar), 128.29 (t), 152.25 (q), 155.45 (q), 155.57 (q, CO), 172.24
(q, CO), 190.03 (q, CO).
Preparation of Grignard reagents [bromobenzene and p-bromo-
toluene]
A solution of an aryl bromide (5 mmol) in THF (5 ml) was
added dropwise to activated magnesium (5.5 mmol) at 0 ЊC and
the solution was allowed to attain rt and stirred for 2 h.
Preparation of lithium reagents (i) [thiophene, benzofuran and N-
(phenylsulfonyl)indole]
To a solution of an aromatic heterocycle (5 mmol) in THF (20
ml) was added n-butyllithium (1.0 mol equiv.) dropwise at 0 ЊC.
The solution was allowed to attain rt and stirred for 1 h.
Ethyl (S)-2-(tert-butoxycarbonylamino)-5-oxo-5-[N-(phenyl-
sulfonyl)indol-2-yl]pentanoate 2e. Oil; νmax/cmϪ1 (neat) 690, 730,
1180, 1370, 1450, 1520, 1700, 2980, 3380; HRMS (FAB, NBA)
Calc. for C26H31O7N2S: m/z (M ϩ H) 515.1852. Found: m/z,
515.1837; δH(CDCl3) 1.28 (3H, t, J 7.1, CH3CH2), 1.43 (9H, s,
Boc), 2.12 (1H, m, 3-Ha), 2.33 (1H, m, 3-Hb), 3.02–3.15 (2H, m,
4-H2), 4.20 (2H, q, J 7.1, CH3CH2), 4.35 (1H, m, 2-H), 5.19
(1H, d, J 7.9, NH), 7.09 (1H, s, 3Ј-H), 7.28–8.14 (9H, m, indole
and Ph); δC(CDCl3) 14.18 (p), 27.25 (s), 28.31 (C(CH3)3), 38.40
(s), 53.06 (t), 61.57 (s), 79.98 (C(CH3)3), 115.65 (t), 116.85 (t),
122.83 (t), 124.48 (t), 127.35 (t), 127.59 (t), 128.52 (q), 128.90
(t), 129.12 (t), 129.63 (t), 133.86 (t), 138.06 (q), 138.60 (q),
139.42 (q), 155.52 (q), 172.33 (q, CO), 193.66 (q, CO).
Preparation of lithium reagents (ii) [2,4-di(tert-butoxy)pyr-
imidine and 2,4-dimethoxypyrimidine]
To a solution of 5-bromo-2,4-di(tert-butoxy)pyrimidine or 5-
bromo-2,4-dimethoxypyrimidine (5 mmol) in THF at Ϫ78 ЊC
(20 ml) was added dropwise a hexane solution of n-butyllithium
(1.0 mol equiv.) which was kept at Ϫ78 ЊC using a cannula. The
solution was stirred at the same temperature for 5 min.
The nucleophilic ring opening of ethyl N-Boc-pyroglutamate 1 to
give ethyl (S)-5-aryl-2-(tert-butoxycarbonylamino)-5-oxopent-
anoates 2
Ethyl (S)-2-(tert-butoxycarbonylamino)-5-(2,4-dimethoxypyr-
imidin-5-yl)-5-oxopentanoate 2f. Oil; νmax/cmϪ1 (neat) 1010,
1170, 1390, 1580, 1720, 2980, 3370; HRMS (FAB, NBA) Calc.
for C18H28O7N3: m/z (M ϩ H) 398.1927. Found: m/z, 398.1924;
δH(CDCl3) 1.28 (3H, t, J 7.0, CH3CH2), 1.43 (9H, s, Boc), 2.00
(1H, m, 3-Ha), 2.24 (1H, m, 3-Hb), 2.96–3.12 (2H, m, 4-H2),
Typical procedure. To a solution of 1 (1 mmol) in THF (2 ml)
was added dropwise a THF solution of an organomagnesium
or organolithium reagent (1.1 mol equiv.) at Ϫ78 ЊC. The mix-
ture was allowed to warm slowly to Ϫ40 ЊC. After stirring at the
same temperature for 1 h, the reaction mixture was quenched
1196
J. Chem. Soc., Perkin Trans. 1, 1999, 1193–1200

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4.06 (3H, s, OCH3), 4.10 (3H, s, OCH3), 4.21 (2H, q, J 7.0,
CH3CH2), 4.33 (1H, m, 2-H), 5.15 (1H, d, J 8.0, NH), 8.84 (1H,
s, pyrimidine 6Ј-H); δC(CDCl3) 14.24 (p), 27.10 (s), 28.35 (p),
39.32 (s), 53.20 (OCH3), 54.59 (t), 55.56 (OCH3), 61.53 (s),
79.94 (C(CH3)3), 113.45 (q), 155.54 (q), 162.91 (t), 166.69 (q),
169.41 (q), 172.57 (q, CO), 196.27 (q, CO).
(1H, m, 3-Ha), 3.19 (1H, m, 3-Hb), 4.25 (2H, q, J 7.0, CH3CH2),
4.96 (1H, m, 5-H), 7.24 (1H, s, 3Ј-H), 7.26 (1H, m, benzofuran),
7.38 (1H, m, benzofuran), 7.53 (1H, m, benzofuran), 7.67 (1H,
m, benzofuran); δC(CDCl3) 14.14 (p), 26.23 (s), 35.43 (s), 61.21
(s), 75.02 (t), 110.66 (t), 111.98 (t), 122.03 (t), 123.32 (t), 126.60
(t), 127.62 (q), 150.36 (q), 155.55 (q), 167.10 (q), 172.41 (q).
(S)-5-Ethoxycarbonyl-2-[N-(phenylsulfonyl)indol-2-yl]-∆1-
pyrroline 3e. Oil; νmax/cmϪ1 (neat) 730, 760, 1090, 1180, 1370,
1450, 1630, 1740, 2980, 3070, 3450; HRMS (FAB, NBA) Calc.
for C21H21O4N2S: m/z (M ϩ H) 397.1222. Found: m/z, 397.1227;
δH(CDCl3) 1.34 (3H, t, J 7.2, CH3CH2), 2.23 (1H, m, 4-Ha), 2.48
(1H, m, 4-Hb), 3.13 (1H, m, 3-Ha), 3.27 (1H, m, 3-Hb), 4.29 (2H,
q, J 7.2, CH3CH2), 4.95 (1H, m, 5-H), 6.87 (1H, s, 3Ј-H), 7.20–
8.12 (9H, m, indole and Ph); δC(CDCl3) 14.23 (p), 27.44 (s),
40.61 (s), 61.13 (s), 74.36 (t), 114.98 (t), 115.65 (t), 121.74 (t),
124.56 (t), 125.94 (t), 127.20 (t), 128.80 (t), 130.14 (q), 133.78
(t), 136.08 (q), 136.29 (q), 137.82 (q), 172.47 (q), 172.70 (q).
Ethyl (S)-2-(tert-butoxycarbonylamino-5-[2,4-di(tert-butoxy)-
pyrimidin-5-yl]-5-oxopentanoate 2g. Solid; mp 71–72 ЊC;
(Found: C, 59.89; H, 8.32; N, 8.82. Calc. for C24H39N3O7: C,
59.86; H, 8.16; N, 8.73%); νmax(KBr)/cmϪ1 1050, 1070, 1370,
1420, 1580, 1700, 2980, 3400; δH(CDCl3) 1.28 (3H, t, J 7.0,
CH3CH2), 1.42 (9H, s, Boc), 1.63 (9H, s, OBut), 1.70 (9H, s,
OBut), 2.00 (1H, m, 3-Ha), 2.23 (1H, m, 3-Hb), 2.95–3.15 (2H,
m, 4-H2), 4.20 (2H, q, J 7.0, CH3CH2), 4.32 (1H, m, 2-H), 5.11
(1H, d, J 8.3, NH), 8.74 (1H, s, pyrimidine 6Ј-H); δC(CDCl3)
14.10 (p), 26.87 (s), 28.23 (C(CH3)3), 28.28 (C(CH3)3), 28.55
(C(CH3)3), 39.53 (s), 53.15 (t), 61.33 (s), 79.72 (C(CH3)3), 81.76
(C(CH3)3), 83.94 (C(CH3)3), 114.18 (q), 155.32 (q), 162.15 (t),
165.39 (q), 168.30 (q), 172.49 (q, CO), 197.20 (q, CO).
(S)-5-Ethoxycarbonyl-2-(2,4-dimethoxypyrimidin-5-yl)-Ä1-
pyrroline 3f. Oil; νmax/cmϪ1 (neat) 800, 1010, 1190, 1350, 1390,
1470, 1600, 1740, 2960, 3450; HRMS (FAB, NBA) Calc. for
C13H18O4N3: m/z (M ϩ H) 280.1297. Found: m/z, 280.1298;
δH(CDCl3) 1.32 (3H, t, J 7.1, CH3CH2), 2.18 (1H, m, 4-Ha), 2.30
(1H, m, 4-Hb), 2.99 (1H, m, 3-Ha), 3.17 (1H, m, 3-Hb), 4.04 (3H,
s, OCH3), 4.05 (3H, s, OCH3), 4.24 (2H, q, J 7.1, CH3CH2), 4.82
(1H, m, 5-H), 8.86 (1H, s, uracil 6Ј-H); δC(CDCl3) 16.07 (p),
28.40 (s), 40.05 (s), 56.07 (p), 57.05 (p), 63.03 (s), 75.45 (t),
111.78 (q), 162.23 (t), 168.02 (q), 170.86 (q), 174.04 (q), 174.75
(q).
Deprotection of N-Boc group of 2 to give (S)-ethoxycarbonyl-2-
aryl-Ä1-pyrrolines‡ 3
Typical procedure. To a solution of 2 (2 mmol) in CH2Cl2 (30
ml) was added trifluoroacetic acid (30 mmol equiv.) at 0 ЊC and
the resulting solution was allowed to warm to rt. After being
stirred for 2 h, the mixture was neutralized with triethylamine
(35 mmol), water was added to the mixture, and the organic
phase was separated. The aqueous phase was extracted with
CHCl3, and the combined organic phase was dried (Na2SO4)
and concentrated. The residue was purified by PLC
[developer:hexane–AcOEt (3:1)] to give the corresponding
ethyl 2-aryl-∆1-pyrroline-5-carboxylate 3.
(S)-5-Ethoxycarbonyl-2-(2,4-dioxo-1,2,3,4-tetrahydropyr-
imidin-5-yl)-Ä1-pyrroline 3g. Powder; mp 210 ЊC (decomp.);
νmax/cmϪ1 (neat) 830, 1300, 1400, 1460, 1520, 1600, 1690, 1740,
2790, 2850, 2970, 3060, 3240, 3450; HRMS (FAB, NBA) Calc.
for C11H14O4N3: m/z (M ϩ H) 252.0984. Found: m/z, 252.0957;
δH(D2O) 1.30 (3H, t, J 7.1, CH3CH2), 2.40 (1H, m, 4-Ha), 2.69
(1H, m, 4-Hb), 3.45 (2H, m, 3-H2), 4.30 (2H, q, J 7.1, CH3CH2),
5.05 (1H, dd, J 9.8 and 5.4, 5-H), 8.61 (1H, s, uracil 6Ј-H);
δC(D2O) 13.95 (p), 24.20 (s), 33.60 (s), 64.40 (s), 66.71 (t), 101.33
(q), 151.19 (q), 157.13 (t), 163.70 (q), 171.36 (q), 181.26 (q).
(S)-5-Ethoxycarbonyl-2-phenyl-Ä1-pyrroline 3a. Oil; νmax/cmϪ1
(neat) 700, 760, 1040, 1190, 1270, 1350, 1450, 1620, 1740, 2980;
HRMS (FAB, NBA) Calc. for C13H16O2N: m/z (M ϩ H)
218.1181. Found: m/z, 218.1201; δH(CDCl3) 1.31 (3H, t, J 7.1,
CH3CH2), 2.24 (1H, m, 4-Ha), 2.35 (1H, m, 4-Hb), 2.99 (1H, m,
3-Ha), 3.16 (1H, m, 3-Hb), 4.24 (2H, q, J 7.1, CH3CH2), 4.91
(1H, m, 5-H), 7.39–7.47 (3H, m, 3Ј-, 4Ј- and 5Ј-H), 7.89 (2H, m,
2Ј- and 6Ј-H).
Reduction of imino group of 3 to give (5S)-2-aryl-5-(ethoxycarb-
onyl)pyrrolidines 4
(S)-5-Ethoxycarbonyl-2-(p-tolyl)-Ä1-pyrroline 3b. Oil; νmax
/
cmϪ1 (neat) 820, 1040, 1180, 1260, 1340, 1460, 1610, 1740, 2980;
HRMS (FAB, NBA) Calc. for C14H17O2N: m/z (M ϩ H)
232.1338. Found: m/z, 232.1328; δH(CDCl3) 1.27 (3H, t, J 7.1,
CH3CH2), 2.16–2.37 (2H, m, 4-H2), 2.36 (3H, s, PhCH3), 2.95
(1H, m, 3-Ha), 3.12 (1H, m, 3-Hb), 4.20 (2H, q, J 7.1, CH3CH2),
4.86 (1H, m, 5-H), 7.19 (2H, d, J 8.1, 3Ј- and 5Ј-H), 7.76 (2H, d,
J 8.1, 2Ј- and 6Ј-H).
Typical procedure. To a solution of 3 (1 mmol) in conc. HCl–
PriOH (1 ml:11 ml) was added NaBH3CN (5.0 mol equiv.) at rt.
After being stirred for 2 h, the reaction mixture was quenched
with saturated aqueous NaHCO3 and extracted with AcOEt.
The extract was dried (Na2SO4) and concentrated. The residue
was purified and α- and β-isomers of 4 were separated by PLC
[developer:hexane–AcOEt (2:1)].
(S)-5-Ethoxycarbonyl-2-(2-thienyl)-Ä1-pyrroline 3c. Oil; νmax
/
(S)-5-Ethoxycarbonyl-2-phenylpyrrolidine§ 4a. (α-Form) oil;
νmax/cmϪ1 (neat) 700, 1030, 1120, 1210, 1370, 1450, 1730, 2980,
3350; MS (EI) Calc. for C13H18O2N: m/z (M ϩ H) 220. Found:
m/z, 220; δH(CDCl3) 1.30 (3H, t, J 7.1, CH3CH2), 1.74 (1H, m,
3-Ha), 1.98 (1H, m, 4-Ha), 2.20 (2H, m and br s, 3-Hb and NH),
2.35 (1H, m, 4-Hb), 4.03 (1H, dd, J 8.4 and 5.8, 5-H), 4.21 (2H,
q, J 7.1, CH3CH2), 4.37 (1H, dd, J 8.3 and 6.8, 2-H), 7.20–7.40
(5H, m, Ph); δC(CDCl3) 14.23 (p), 29.78 (s), 34.60 (s), 59.58 (t),
60.95 (s), 61.72 (t), 126.44 (t), 126.84 (t), 128.29 (t), 144.47 (q),
175.92 (q, CO); (β-form) oil; νmax/cmϪ1 (neat) 700, 1030, 1170,
1210, 1370, 1450, 1730, 2980, 3370; HRMS (FAB) Calc. for
C13H18O2N: m/z (M ϩ H) 220.1338. Found: m/z, 220.1327;
δH(CDCl3) 1.30 (3H, t, J 7.1, CH3CH2), 1.70 (1H, m, 3-Ha),
2.05–2.26 (3H, m, 3-Hb, 4-H2), 2.52 (1H, br s, NH), 3.87 (1H,
dd, J 8.7 and 4.4, 5-H), 4.16 (1H, dd, J 9.2 and 5.8, 2-H), 4.21
cmϪ1 (neat) 720, 1040, 1190, 1260, 1430, 1610, 1740, 2980;
HRMS (FAB, NBA) Calc. for C11H14O2NS: m/z (M ϩ H)
224.0745. Found: m/z, 224.0742; δH(CDCl3) 1.30 (3H, t, J 7.1,
CH3CH2), 2.19–2.39 (2H, m, 4-H2), 2.98 (1H, m, 3-Ha), 3.14
(1H, m, 3-Hb), 4.23 (2H, q, J 7.1, CH3CH2), 4.86 (1H, m, 5-H),
7.07 (1H, m, 4Ј-H), 7.39 (1H, m, 3Ј-H), 7.46 (1H, m, 5Ј-H);
δC(CDCl3) 14.10 (p), 26.78 (s), 35.96 (s), 61.02 (s), 74.30 (t),
127.38 (t), 129.84 (t), 130.07 (t), 138.46 (q), 170.30 (q), 172.70 (q).
(S)-2-(2-Benzofuryl)-5-ethoxycarbonyl-Ä1-pyrroline 3d. Oil;
νmax/cmϪ1 (neat) 760, 810, 1030, 1060, 1190, 1260, 1380, 1630,
1740, 2960; HRMS (FAB, NBA) Calc. for C15H16O3N: m/z
(M ϩ H) 258.1130. Found: m/z, 258.1132; δH(CDCl3) 1.32 (3H,
t, J 7.0, CH3CH2), 2.28 (1H, m, 4-Ha), 2.37 (1H, m, 4-Hb), 3.02
‡ IUPAC-preferrednomenclature:5-aryl-2-ethoxycarbonyl-3,4-dihydro-
2H-pyrroles.
§ Non-systematic numbering scheme.
J. Chem. Soc., Perkin Trans. 1, 1999, 1193–1200
1197

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(2H, q, J 7.1, CH3CH2), 7.22–7.45 (5H, m, Ph); δC(CDCl3)
14.13 (p), 30.63 (s), 34.09 (s), 60.01 (t), 60.96 (s), 63.51 (t),
126.66 (t), 127.12 (t), 128.38 (t), 143.11 (q), 175.09 (q, CO).
1210, 1370, 1450, 1730, 2980, 3360; MS (FAB) Calc. for
C21H23O4N2S: m/z (M ϩ H) 399. Found: m/z, 399; δH(CDCl3)
1.31 (3H, t, J 7.1, CH3CH2), 2.00 (2H, m, 3- and 4-Ha), 2.20–
2.42 (2H, m, 3- and 4-Hb), 3.98 (1H, dd, J 8.4 and 4.8, 5-H),
4.23 (2H, q, J 7.1, CH3CH2), 5.05 (1H, m, 2-H), 6.74 (1H, s,
indole 3Ј-H), 7.17–7.52 (6H, m, indole and Ph), 7.75 (2H, m,
Ph), 8.12 (1H, m, indole 4Ј-H); δC(CDCl3) 14.22 (p), 29.25 (s),
32.80 (s), 55.82 (t), 59.60 (t), 61.10 (s), 108.80 (t), 114.85 (t),
120.62 (t), 123.71 (t), 124.22 (t), 126.27 (t), 129.15 (t), 129.56
(q), 133.61 (t), 137.61 (q), 137.76 (q), 145.48 (q), 175.52 (q, CO);
(β-form) oil; νmax/cmϪ1 (neat) 730, 750, 1020, 1170, 1370, 1450,
1730, 2980, 3390; HRMS (FAB) Calc. for C21H23O4N2S: m/z
(M ϩ H) 399.1379. Found: m/z, 399.1361; δH(CDCl3) 1.26 (3H,
t, J 7.1, CH3CH2), 2.00–2.09 (2H, m, 3- and 4-Ha), 2.20 (1H, m,
3-Hb), 2.35 (1H, m, 4-Hb), 3.96 (1H, dd, J 5.3 and 4.1, 5-H),
4.17 (2H, q, J 7.1, CH3CH2), 4.96 (1H, m, 2-H), 6.89 (1H, s, 3Ј-
H), 7.18–7.52 (6H, m, indole and Ph), 7.76 (2H, m, Ph), 8.11
(1H, m, indole 4Ј-H); δC(CDCl3) 16.07 (p), 30.85 (s), 35.16 (s),
58.07 (t), 61.81 (t), 62.84 (s), 111.05 (t), 116.71 (t), 122.69 (t),
125.63 (t), 126.25 (q), 128.15 (t), 131.08 (t), 131.38 (t), 135.54
(t), 139.42 (q), 140.76 (q), 146.82 (q), 176.71 (q, CO).
(S)-5-Ethoxycarbonyl-2-(p-tolyl)pyrrolidine§ 4b. (α-Form)
oil; νmax/cmϪ1 (neat) 810, 1040, 1120, 1210, 1730, 2980, 3350;
MS (FAB, NBA) Calc. for C14H20O2N: m/z (M ϩ H) 234.
Found: m/z, 234; δH(CDCl3) 1.29 (3H, t, J 7.1, CH3CH2), 1.72
(1H, m, 3-Ha), 1.97 (1H, m, 4-Ha), 2.17 (1H, m, 3-Hb), 2.33 (3H,
s, PhCH3), 2.34 (1H, m, 4-Hb), 4.02 (1H, dd, J 8.7 and 6.1, 5-H),
4.21 (2H, q, J 7.1, CH3CH2), 4.32 (1H, dd, J 8.4 and 6.8, 2-H),
7.13 (2H, d, J 8.0, 3Ј- and 5Ј-H), 7.26 (2H, d, J 8.0, 2Ј- and 6Ј-
H); δC(CDCl3) 14.24 (p), 21.02 (p), 29.76 (s), 34.61 (s), 59.53 (t),
60.94 (s), 61.54 (t), 126.37 (t), 128.99 (t), 136.45 (q), 141.37 (q),
175.96 (q); (β-form) oil; νmax/cmϪ1 (neat) 820, 1030, 1110, 1210,
1730, 2980, 3350; HRMS (FAB, NBA) Calc. for C14H20O2N:
m/z (M ϩ H) 234.1494. Found: m/z, 234.1499; δH(CDCl3) 1.30
(3H, t, J 7.1, CH3CH2), 1.70 (1H, m, 3-Ha), 2.02–2.23 (3H, m,
3-Hb, 4-H2), 2.33 (3H, s, PhCH3), 3.90 (1H, dd, J 8.7 and 4.8,
5-H), 4.16 (1H, dd, J 9.4 and 5.8, 2-H), 4.21 (2H, q, J 7.1,
CH3CH2), 7.15 (2H, d, J 8.1, 3Ј- and 5Ј-H), 7.33 (2H, d, J 8.1,
2Ј- and 6Ј-H); δC(CDCl3) 14.21 (p), 21.03 (p), 30.76 (s), 34.16
(s), 60.16 (t), 61.02 (s), 63.44 (t), 126.67 (t), 129.14 (t), 136.83
(q), 140.15 (q), 175.21 (q).
(S)-5-Ethoxycarbonyl-2-(2,4-dimethoxypyrimidin-5-yl)pyrrol-
idine 4f. (α-Form) oil; νmax/cmϪ1 (neat) 800, 1020, 1080, 1200,
1380, 1470, 1570, 1600, 1730, 2980, 3350; MS (FAB) Calc. for
C13H20O4N3: m/z (M ϩ H) 282. Found: m/z, 282; δH(CDCl3)
1.30 (3H, t, J 7.2, CH3CH2), 1.67 (1H, m, 3-Ha), 1.96 (1H, m,
4-Ha), 2.14–2.33 (2H, m, 3- and 4-Hb), 3.97 (1H, m, 5-H),
3.98 (3H, s, OCH3), 3.99 (3H, s, OCH3), 4.22 (2H, q, J 7.1,
CH3CH2), 4.43 (1H, m, 2-H), 8.33 (1H, s, uracil 6Ј-H);
δC(CDCl3) 14.18 (p), 29.55 (s), 31.58 (s), 53.79 (p), 54.23 (t),
54.57 (p), 59.28 (t), 61.00 (s), 117.37 (q), 155.34 (t), 164.33 (q),
168.91 (q), 175.68 (q, CO); (β-form) oil; νmax/cmϪ1 (neat) 800,
1020, 1080, 1200, 1380, 1470, 1570, 1600, 1730, 2980, 3360;
HRMS (FAB) Calc. for C13H20O4N3: m/z (M ϩ H) 282.1454.
Found: m/z, 282.1454; δH(CDCl3) 1.29 (3H, t, J 7.1, CH3CH2),
1.77 (1H, m, 3-Ha), 2.05 (1H, m, 4-Ha), 2.10–2.24 (2H, m, 3-
and 4-Hb), 3.89 (1H, dd, J 8.3 and 6.0, 5-H), 3.98 (3H, s,
OCH3), 4.01 (3H, s, OCH3), 4.21 (2H, q, J 7.1, CH3CH2), 4.27
(1H, m, 2-H), 8.37 (1H, s, uracil 6Ј-H); δC(CDCl3) 14.15 (p),
29.66 (s), 31.27 (s), 53.82 (p), 54.61 (p), 55.61 (t), 59.76 (t), 60.88
(s), 116.25 (q), 155.91 (t), 164.44 (q), 168.81 (q), 174.52 (q, CO).
(S)-5-Ethoxycarbonyl-2-(2-thienyl)pyrrolidine§ 4c. (α-Form)
oil; νmax/cmϪ1 (neat) 700, 1030, 1120, 1310, 1730, 2980, 3350;
MS (EI) Calc. for C11H16O2NS: m/z (M ϩ H) 226. Found: m/z,
226; δH(CDCl3) 1.29 (3H, t, J 7.1, CH3CH2), 1.85 (1H, m, 3-Ha),
1.98 (1H, m, 4-Ha), 2.20 (1H, m, 3-Hb), 2.35 (1H, m, 4-Hb), 2.69
(1H, br s, NH), 4.00 (1H, dd, J 8.5 and 5.4, 5-H), 4.21 (2H, q,
J 7.1, CH3CH2), 4.66 (1H, t, J 5.0 , 2-H), 6.92 (2H, m, 3Ј- and
4Ј-H), 7.16 (1H, dd, J 4.9 and 1.2, 5Ј-H); δC(CDCl3) 14.20 (p),
29.60 (s), 35.04 (s), 57.62 (t), 59.27 (t), 60.99 (s), 122.83 (t),
123.58 (t), 126.65 (t), 149.84 (q), 175.57 (q, CO); (β-form) oil;
νmax/cmϪ1 (neat) 700, 1030, 1100, 1210, 1380, 1440, 1740, 2980,
3360; HRMS (FAB) Calc. for C11H16O2NS: m/z (M ϩ H)
226.0902. Found: m/z, 226.0903; δH(CDCl3) 1.29 (3H, t, J 7.0,
CH3CH2), 1.83 (1H, m, 3-Ha), 2.07–2.28 (3H, m, 3-Hb, 4-H2),
2.38 (1H, br s, NH), 3.88 (1H, dd, J 8.5 and 5.9, 5-H), 4.21 (2H,
q, J 7.0, CH3CH2), 4.46 (1H, dd, J 8.8 and 5.9, 2-H), 6.95 (1H,
dd, J 5.1 and 3.4, 4Ј-H), 7.01 (1H, d, J 3.4, 3Ј-H), 7.20 (1H, dd,
J 5.1 and 1.0, 5Ј-H); δC(CDCl3) 14.33 (p), 30.49 (s), 34.83 (s),
59.02 (t), 60.28 (t), 61.16 (s), 122.87 (t), 124.10 (t), 126.73 (t),
147.70 (q), 174.76 (q, CO).
Reduction of the ester group of 4 to give 1-aryl-1,2,3,4-tetradeoxy-
1,4-imino-D-pentitols 5
Typical procedure. To a solution of 4 (0.5 mmol) in Et2O (5
ml) was added LiAlH4 (1 mol equiv.) at 0 ЊC and the mixture
was stirred at the same temperature for 3 h. After the mixture
was quenched with water, the organic phase was separated and
the aqueous phase was extracted with Et2O. The combined
organic phases were dried (Na2SO4) and concentrated. The
residue was purified PLC [developer:CHCl3–MeOH (9:1)] to
give the corresponding (5S)-2-aryl-5-(hydroxymethyl)pyrrol-
idine 5.
(S)-5-Ethoxycarbonyl-2-(2-benzofuryl)pyrrolidine 4d. (α-
Form) oil; νmax/cmϪ1 (neat) 760, 1030, 1160, 1210, 1370, 1460,
1730, 2980, 3350; MS (FAB) Calc. for C15H18O3N: m/z (M ϩ H)
260. Found: m/z, 260; δH(CDCl3) 1.30 (3H, t, J 7.0, CH3CH2),
1.97–2.13 (2H, m, 3- and 4-Ha), 2.20 (1H, m, 3-Hb), 2.37 (1H,
m, 4-Hb), 4.02 (1H, dd, J 8.2 and 5.2, 5-H), 4.22 (2H, q, J 7.0,
CH3CH2), 4.59 (1H, t, J 6.9, 2-H), 6.56 (1H, s, 3Ј-H), 7.16–7.24
(2H, m, 5Ј- and 6Ј-H), 7.43 (1H, m, 7Ј-H), 7.49 (1H, m, 4Ј-H);
δC(CDCl3) 14.21 (p), 29.55 (s), 30.60 (s), 55.72 (t), 59.55 (t),
61.08 (s), 102.10 (t), 111.08 (t), 120.65 (t), 122.55 (t), 123.64 (t),
128.41 (q), 154.97 (q), 160.11 (q), 175.34 (q, CO); (β-form)
oil; νmax/cmϪ1 (neat) 760, 1030, 1170, 1210, 1370, 1460, 1730,
2980, 3360; HRMS (FAB) Calc. for C15H18O3N: m/z (M ϩ H)
260.1287. Found: m/z, 260.1292; δH(CDCl3) 1.26 (3H, t, J 7.1,
CH3CH2), 2.01–2.28 (5H, m, 3-, 4-H2, and NH), 3.91 (1H, dd,
J 8.2 and 6.7, 5-H), 4.19 (2H, q, J 7.1, CH3CH2), 4.43 (1H, t,
J 6.5, 2-H), 6.65 (1H, s, 3Ј-H), 7.16–7.25 (2H, m, 5Ј- and 6Ј-H),
7.42 (1H, m, 7Ј-H), 7.50 (1H, m, 4Ј-H); δC(CDCl3) 14.15 (p),
29.70 (s), 31.26 (s), 56.81 (t), 60.17 (t), 61.08 (s), 102.34 (t),
111.03 (t), 120.74 (t), 122.59 (t), 123.74 (t), 128.39 (q), 154.86
(q), 159.59 (q), 174.58 (q, CO).
1-Phenyl-1,2,3,4-tetradeoxy-1,4-imino-D-pentitol 5a. (α-
Form) oil; νmax/cmϪ1 (neat) 700, 760, 1040, 1450, 1490, 2870,
2930, 3320; MS (FAB) Calc. for C11H16ON: m/z (M ϩ H) 178.
Found: m/z, 178; δH(CDCl3) 1.57 (1H, m, 3-Ha), 1.75 (1H, m,
2-Ha), 2.03 (1H, m, 3-Hb), 2.23 (1H, m, 2-Hb), 3.39 (1H, dd,
J 10.5 and 7.5, 5-Ha), 3.53–3.62 (2H, m, 4-H and 5-Hb), 4.17
(1H, dd, J 8.6 and 6.6, 1-H), 7.23–7.35 (5H, m, Ph); δC(CDCl3)
27.97 (s), 34.68 (s), 29.67 (t), 61.72 (t), 64.98 (s), 126.39 (t),
127.13 (t), 128.53 (t), 143.73 (q); (β-form) oil; νmax/cmϪ1 (neat)
700, 760, 1050, 1460, 1490, 2870, 2950, 3330; HRMS (FAB)
Calc. for C11H16ON: m/z (M ϩ H) 178.1232. Found: m/z,
178.1233; δH(CDCl3) 1.63–1.77 (2H, m, 2- and 3-Ha), 1.94 (1H,
m, 3-Hb), 2.14 (1H, m, 2-Hb), 3.43–3.50 (2H, m, 4-H and 5-Ha),
3.63 (1H, dd, J 9.9 and 3.2, 5-Hb), 4.24 (1H, dd, J 8.9 and 6.7,
1-H), 7.22–7.39 (5H, m, Ph); δC(CDCl3) 27.72 (s), 34.50 (s),
(S)-5-Ethoxycarbonyl-2-[N-(phenylsulfonyl)indol-2-yl])pyrrol-
idine§ 4e. (α-Form) oil; νmax/cmϪ1 (neat) 730, 750, 1020, 1170,
1198
J. Chem. Soc., Perkin Trans. 1, 1999, 1193–1200

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58.65 (t), 62.69 (t), 65.22 (s), 126.46 (t), 126.93 (t), 128.30 (t),
144.26 (q).
1-H), 6.59 (1H, s, indole 3Ј-H), 7.20–7.54 (6H, m, indole and
Ph), 7.75 (2H, m, Ph), 8.15 (1H, m, indole 4Ј-H); δC(CDCl3)
26.72 (s), 32.41 (s), 55.37 (t), 58.28 (t), 65.23 (s), 108.23 (t),
114.96 (t), 120.64 (t), 123.80 (t), 124.51 (t), 126.23 (t), 129.19 (t),
129.30 (q), 133.69 (t), 137.57 (q), 138.89 (q), 144.82 (q); (β-
form) oil; νmax/cmϪ1 (neat) 730, 750, 1020, 1090, 1170, 1370,
1450, 2940, 3390; HRMS (FAB) Calc. for C19H21O3N2S: m/z
(M ϩ H) 357.1273. Found: m/z, 357.1275; δH(CDCl3) 1.75 (1H,
m, 3-Ha), 1.91–2.02 (2H, m, 2-Ha and 3-Hb), 2.30 (1H, m, 2-Hb),
3.38 (1H, dd, J 10.3 and 5.5, 5-Ha), 3.51 (1H, m, 4-H), 3.57 (1H,
dd, J 10.3 and 4.1, 5-Hb), 4.85 (1H, t, J 7.0, 1-H), 6.73 (1H, s,
indole 3Ј-H), 7.18–7.52 (6H, m, indole and Ph), 7.72 (2H, m,
Ph), 8.09 (1H, m, indole 4Ј-H); δC(CDCl3) 27.41 (s), 32.29 (s),
55.65 (t), 58.61 (t), 65.39 (s), 108.24 (t), 114.83 (t), 120.76 (t),
123.76 (t), 124.36 (t), 126.12 (t), 129.16 (t), 129.48 (q), 133.61
(t), 137.49 (q), 139.00 (q), 145.36 (q).
1-(p-Tolyl)-1,2,3,4-tetradeoxy-1,4-imino-D-pentitol 5b. (α-
Form) oil; νmax/cmϪ1 (neat) 810, 1050, 1460, 1520, 2870, 2920,
3300; HRMS (FAB) Calc. for C12H18ON: m/z (M ϩ H) 192.
Found: m/z, 192; δH(CDCl3) 1.55 (1H, m, 3-Ha), 1.73 (1H, m,
2-Ha), 2.02 (1H, m, 3-Hb), 2.20 (1H, m, 2-Hb), 2.33 (3H, s,
PhCH3), 3.38 (1H, dd, J 10.5 and 7.4, 5-Ha), 3.53 (1H, dd,
J 10.5 and 3.1, 5-Hb), 3.57 (1H, m, 4-H), 4.13 (1H, dd, J 8.7 and
6.3, 1-H), 7.13 (2H, d, J 8.1, 3Ј- and 5Ј-H), 7.20 (2H, d, J 8.1, 2Ј-
and 6Ј-H); δC(CDCl3) 21.23 (p), 28.25 (s), 34.99 (s), 59.92 (t),
61.73 (t), 65.25 (s), 126.54 (t), 129.43 (t), 136.99 (q), 140.90 (q);
(β-form) oil; νmax/cmϪ1 (neat) 810, 1050, 1460, 1520, 2870,
2950, 3330; HRMS (FAB) Calc. for C12H18ON: m/z (M ϩ H)
192.1388. Found: m/z, 192.1380; δH(CDCl3) 1.60–1.77 (2H, m,
2- and 3-Ha), 1.94 (1H, m, 3-Hb), 2.11 (1H, m, 2-Hb), 2.33 (3H,
s, PhCH3), 3.40–3.48 (2H, m, 4-H and 5-Ha), 3.63 (1H, dd, J 9.8
and 3.2, 5-Hb), 4.20 (1H, dd, J 8.9 and 6.6, 1-H), 7.12 (2H, d,
J 8.1, 3Ј- and 5Ј-H), 7.26 (2H, d, J 8.1, 2Ј- and 6Ј-H); δC(CDCl3)
20.99 (p), 27.74 (s), 34.45 (s), 58.55 (t), 62.49 (t), 65.17 (s),
126.40 (t), 128.98 (t), 136.54 (q), 141.15 (q).
1-(2,4-Dimethoxypyrimidin-5-yl)-1,2,3,4-tetradeoxy-1,4-
imino-D-pentitol 5f. (α-Form) oil; νmax/cmϪ1 (neat) 800, 1040,
1220, 1450, 1670, 2970, 3280; MS (FAB) Calc. for C11H18O3N3:
m/z (M ϩ H) 240. Found: m/z, 240; δH(CDCl3) 1.56 (1H, m, 3-
Ha), 1.79 (1H, m, 2-Ha), 2.00 (1H, m, 3-Hb), 2.14 (1H, m, 2-Hb),
3.42 (1H, dd, J 10.1 and 6.7, 5-Ha), 3.53 (1H, m, 4-H), 3.56 (1H,
dd, J 10.1 and 6.0, 5-Hb), 3.97 (3H, s, OMe), 4.00 (3H, s, OMe),
4.22 (1H, t, J 7.2, 1-H), 8.18 (1H, s, uracil 6Ј-H); δC(CDCl3)
29.51 (s), 33.82 (s), 55.74 (p), 56.50 (p), 56.77 (t), 61.11 (t), 66.83
(s), 118.28 (q), 157.45 (t), 166.39 (q), 170.72 (q); (β-form) oil;
νmax/cmϪ1 (neat) 800, 1020, 1200, 1380, 1470, 1570, 1600, 2960,
3450; HRMS (FAB) Calc. for C11H18O3N3: m/z (M ϩ H)
240.1348. Found: m/z, 240.1350; δH(CDCl3) 1.63–1.76 (2H, m,
2- and 3-Ha), 1.94 (1H, m, 3-Hb), 2.16 (1H, m, 2-Hb), 3.43
(1H, dd, J 10.1 and 5.5, 5-Ha), 3.47 (1H, m, 4-H), 3.62 (1H,
dd, J 10.1 and 3.6, 5-Hb), 3.97 (3H, s, OMe), 4.00 (3H, s,
OMe), 4.32 (1H, dd, J 7.0 and 6.4, 1-H), 8.33 (1H, s, uracil
6Ј-H); δC(CDCl3) 27.56 (s), 31.49 (s), 53.89 (p), 54.72 (p),
55.19 (t), 58.42 (t), 65.67 (s), 117.45 (q), 155.44 (t), 164.52 (q),
169.02 (q).
1-(2-Thienyl)-1,2,3,4-tetradeoxy-1,4-imino-D-pentitol 5c. (α-
Form) oil; νmax/cmϪ1 (neat) 700, 1040, 1400, 1550, 2870, 2940,
3310; MS (FAB) Calc. for C9H14ONS: m/z (M ϩ H) 184. Found:
m/z, 184; δH(CDCl3) 1.60 (1H, m, 3-Ha), 1.86 (1H, m, 2-Ha),
2.09 (1H, m, 3-Hb), 2.30 (1H, m, 2-Hb), 3.39 (1H, dd, J 10.5 and
7.0, 5-Ha), 3.55 (1H, dd, J 10.5 and 5.1, 5-Hb), 3.58 (1H, m, 4-
H), 4.46 (1H, t, J 6.9, 1-H), 6.92–6.96 (2H, m, 3Ј- and 4Ј-H),
7.19 (1H, dd, J 4.8 and 4.9, 5Ј-H); δC(CDCl3) 27.78 (s), 35.34
(s), 57.51 (t), 59.00 (t), 65.12 (s), 123.50 (t), 123.83 (t), 126.75 (t),
148.62 (q); (β-form) oil; νmax/cmϪ1 (neat) 700, 1050, 1440, 1610,
2870, 2940, 3330; HRMS (FAB) Calc. for C9H14ONS: m/z
(M ϩ H) 184.0796. Found: m/z, 184.0798; δH(CDCl3) 1.73–1.87
(2H, m, 2- and 3-Ha), 1.94 (1H, m, 3-Hb), 2.20 (1H, m, 2-Hb),
3.42 (1H, dd, J 10.3 and 5.5, 5-Ha), 3.48 (1H, m, 4-H), 3.61 (1H,
dd, J 10.3 and 3.6, 5-Hb), 4.59 (1H, t, J 6.8, 1-H), 6.90–6.96
(2H, m, 3Ј- and 4Ј-H), 7.16 (1H, dd, J 4.9 and 1.3, 5Ј-H);
δC(CDCl3) 27.74 (s), 35.56 (s), 58.22 (t), 58.65 (t), 65.21 (s),
122.60 (t), 123.45 (t), 126.75 (t), 150.07 (q).
(S)-5-Hydroxymethyl-2-(2-thienyl)-Ä1-pyrroline¶ 6. Solid; mp
95–96 ЊC; νmax/cmϪ1 (neat) 740, 1090, 1340, 1430, 1610, 2950,
3060, 3230 (Found: C, 59.35; H, 6.08; N, 7.63. Calc. for
C9H11NOS: C, 59.64; H, 6.12; N, 7.73%); MS (FAB) Calc. for
C9H11NOS: m/z (M ϩ H) 181. Found: m/z, 181; δH(CDCl3) 1.89
(1H, m, 3-Ha), 2.12 (1H, m, 3-Hb), 2.88 (1H, m, 4-Ha), 3.03 (1H,
m, 4-Hb), 3.66 (1H, dd, J 11.4 and 5.6, CHHOH), 4.00 (1H, dt,
J 11.4 and 4.1, CHHOH), 4.32 (1H, m, 5-H), 7.04 (1H, m,
4Ј-H), 7.29 (1H, m, 3Ј-H), 7.40 (1H, m, 5Ј-H); δC(CDCl3) 26.42
(s), 38.02 (s), 67.20 (s), 76.34 (t), 129.09 (t), 130.98 (t), 131.29
(t), 140.54 (q), 170.41(q).
1-(2-Benzofuryl)-1,2,3,4-tetradeoxy-1,4-imino-D-pentitol 5d.
(α-Form) oil; νmax/cmϪ1 (neat) 750, 1050, 1260, 1460, 1580, 1740,
2870, 2940, 3320; MS (FAB) Calc. for C13H16O2N: m/z (M ϩ H)
218. Found: m/z, 218; δH(CDCl3) 1.63 (1H, m, 3-Ha), 1.99–2.11
(2H, m, 2-Ha and 3-Hb), 2.22 (1H, m, 2-Hb), 3.42 (1H, dd,
J 11.7 and 7.8, 5-Ha), 3.55–3.63 (2H, m, 4-H and 5-Hb), 4.40
(1H, t, J 6.2, 1-H), 6.52 (1H, s, 3Ј-H), 7.17–7.26 (2H, m, 5Ј- and
6Ј-H), 7.42 (1H, m, 7Ј-H), 7.50 (1H, m, 4Ј-H); δC(CDCl3) 27.37
(s), 31.32 (s), 55.76 (t), 58.92 (t), 64.97 (s), 101.95 (t), 111.03 (t),
120.70 (t), 122.68 (t), 123.83 (t), 128.32 (q), 154.81 (q), 159.86
(q); (β-form) oil; νmax/cmϪ1 (neat) 750, 1050, 1260, 1460, 1600,
1740, 2870, 2940, 3330; HRMS (FAB) Calc. for C13H16O2N:
m/z (M ϩ H) 218.1181. Found: m/z, 218.1176; δH(CDCl3) 1.73
(1H, m, 3-Ha), 1.93 (1H, m, 3-Hb), 2.02 (1H, m, 2-Ha), 2.17
(1H, m, 2-Hb), 3.41–3.49 (2H, m, 4-H and 5-Ha), 3.61 (1H, m,
5-Hb), 4.42 (1H, t, J 7.3, 1-H), 6.56 (1H, s, 3Ј-H), 7.15–7.26
(2H, m, 5Ј- and 6Ј-H), 7.42 (1H, m, 7Ј-H), 7.49 (1H, m, 4Ј-H);
δC(CDCl3) 27.48 (s), 31.08 (s), 56.07 (t), 59.40 (t), 65.21 (s),
101.66 (t), 110.97 (t), 120.65 (t), 122.55 (t), 123.60 (t), 128.40
(q), 154.83 (q), 160.62 (q).
(S)-5-Ethoxycarbonyl-2-(2,4-dioxo-1,2,3,4,5,6-hexahydro-
pyrimidin-5-ylidene)pyrrolidine§ 7. Powder; νmax/cmϪ1 (neat)
1220, 1460, 1560, 1700, 2980, 3230 (Found: C, 52.25; H, 5.99;
N, 16.73. Calc. for C11H15N3O4: C, 52.17; H, 5.97; N, 16.59%);
MS (FAB) Calc. for C11H15N3O4: m/z (M ϩ H) 254. Found: m/z,
254; δH(DMSO) 1.19 (3H, t, J 7.1, CH3CH2), 1.91 (1H, m,
4-Ha), 2.24 (1H, m, 4-Hb), 2.55 (2H, m, 3-H2), 3.77 (2H, d, J 1.9,
CCH2NH), 4.11 (2H, q, J 7.1, CH3CH2), 4.40 (1H, dd, J 8.9 and
4.8, 5-H), 7.10 (1H, br s, pyrimidine 1Ј-NH), 8.79 (1H, br s,
NH), 9.20 (1H, br s, NH); δC(DMSO) 14.02 (p), 25.27 (s), 29.13
(s), 39.23 (s), 60.29 (t), 60.67 (s), 81.30 (q), 154.35 (q), 161.27
(q), 166.49 (q), 172.41(q).
1-(2,4-Dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-1,2,3,4-tetra-
deoxy-1,4-imino-D-pentitol 9f
1-[N-(Phenylsulfonyl)indol-2-yl]-1,2,3,4-tetradeoxy-1,4-
imino-D-pentitol 5e. (α-Form) oil; νmax/cmϪ1 (neat) 730, 750, 1020,
1090, 1170, 1370, 1450, 2940, 3400; MS (FAB) Calc. for C19-
H21O3N2S: m/z (M ϩ H) 357. Found: m/z, 357; δH(CDCl3) 1.63
(1H, m, 3-Ha), 1.95–2.04 (2H, m, 2-Ha and 3-Hb), 2.33 (1H, m,
2-Hb), 3.46 (1H, dd, J 10.4 and 6.4, 5-Ha), 3.50 (1H, m, 4-H),
3.60 (1H, dd, J 10.4 and 3.6, 5-Hb), 4.94 (1H, dd, J 6.8 and 4.6,
To a MeOH solution (3.0 ml) of 5f (50 mg) was added conc.
HCl (3.0 ml). After being refluxed for 3 h, the reaction solution
was evaporated to give a residue, which was then dissolved in a
¶ IUPAC-preferred nomenclature: (S)-2-hydroxymethyl-5-(2-thienyl)-
3,4-dihydro-2H-pyrrole.
J. Chem. Soc., Perkin Trans. 1, 1999, 1193–1200
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small amount of MeOH. The resulting solution was dropped
into ether to afford 9f as the HCl salt (the first reprecipitation).
This compound was resolved by the following procedure: (1)
dissolve in MeOH and reprecipitate with the minimum quantity
of ether; (2) separate the supernatant from the precipitate; (3)
evaporate the supernatant, and reprecipitate to give the fully
resolved 9f as its HCl salt.
calorimetric assay that monitored the ability of the viable cells
to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium
bromide (MTT) to a blue formazan product. The absorbances
were read in a microcomputer-controlled photometer (Titertek
MultiskanR; Labsystem Oy, Helsinki, Finland) at two wave-
lengths (540 and 690 nm). The absorbance measured at 690 nm
was automatically subtracted from that at 540 nm, to eliminate
the effects of non-specific absorption. All data represent the
mean values of triplicate wells. These values were then trans-
lated into percentage cytotoxicity and percentage antiviral pro-
tection, from which the 50% cytotoxic concentration (CC50), the
50% effective concentration (EC50), and the selectivity indexes
(SI) were calculated.13
(α-Form) powder; mp 212 ЊC (decomp.); νmax(KBr)/cmϪ1
1040, 1220, 1450, 1670, 1690, 2970, 3280; MS (FAB) Calc. for
C9H14O3N3: m/z (M ϩ H) 212. Found: m/z, 212; δH(D2O) 1.90
(1H, m, 3-Ha), 2.26–2.35 (3H, m, 2-H2 and 3-Hb), 3.77 (1H, dd,
J 12.3 and 7.0, 5-Ha), 3.91 (1H, dd, J 12.3 and 3.8, 5-Hb), 3.97
(1H, m, 4-H), 4.58 (1H, dd, J 9.3 and 7.8, 1-H), 7.72 (1H, s,
uracil 6Ј-H); δC(D2O) 29.20 (s), 30.81 (s), 59.96 (t), 62.97 (s),
64.35 (t), 109.90 (q), 145.41 (t), 155.47 (q), 167.98 (q); (β-form)
powder; mp 212 ЊC (decomp.); [α]D25 Ϫ33.1 (c 0.42 in 1 
HCl); νmax(KBr)/cmϪ1 1010, 1030, 1680, 1710, 2960, 3420;
MS (FAB) Calc. for C9H14O3N3: m/z (M ϩ H) 212. Found:
m/z, 212; δH(D2O) 2.04 (1H, m, 3-Ha), 2.20–2.40 (3H, m, 2-H2
and 3-Hb), 3.79 (1H, dd, J 12.4 and 6.6, 5-Ha), 3.86–4.02 (2H, m,
4-H and 5-Hb), 4.56 (1H, t, J 8.3, 1-H), 7.72 (1H, s, uracil 6Ј-H);
δC(D2O) 28.01 (s), 29.97 (s), 60.52 (t), 63.14 (s), 64.08 (t), 109.51
(q), 145.27 (t), 155.37 (q), 168.24 (q).
Acknowledgements
We thank Professor Hiroshi Takaku (Chiba Institute of
Technology) for the assay test of HIV, and Dr Hiroko Seki
and Miss Rituko Hara (Chemical Analysis Center of Chiba
University) for measurements of NMR and mass spectra.
This work was supported by a Grant-in-Aid No. 07554085 for
Scientific Research from the Ministry of Education, Science
and Culture, Japan and a Fund for Researching Assistant of
Chiba University (A. M.).
Enantiomeric excess (ee) determinations. Chiral column HPLC
References
Column: Daicel OD-H (0.46 cm diam. × 25 cm) and OC (0.46
cm diam. × 25 cm). UV Detector: Hitachi L-4000. Pump:
Hitachi L-6000.
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(S)-5-Ethoxycarbonyl-2-(2,4-dimethoxypyrimidin-5-yl)-
pyrrolidine 4f. (β-Form) column: OC, detection: 254 nm, EtOH–
hexane (1:1), flow = 0.15 ml minϪ1. t1 = 47.12 min, t2 = 49.42
min.
Bio-assay test
Cell lines. The human T lymphotropic virus type I (HTLV-I)-
positive human T cell line, MT-4, was subcultured twice weekly
at a density of 3 × 105 cells mlϪ1 in RPMI-1640 medium
supplemented with 10% heat-inactivated fetal calf serum
(FCS), 100 IU mlϪ1 penicillin, and 100 mg mlϪ1 streptomycin.
Virus. The HTLV-IIIB strain was used in the anti-HIV assay.
The virus was prepared from the culture supernatants of
MOLT-4/HTLV-IIIB cells, which were persistently infected
with HTLV-IIIB. HIV stocks were titrated in MT-4 cells as
determined by 50% tissue culture infectious doses (TCID50) and
plaque-forming units, and stored at Ϫ80 ЊC until use.
Anti-HIV assay. The anti-HIV activity of test compounds in
a fresh, cell-free HIV infection was determined as protection
against HIV-induced cytopathic effects (CPE). Briefly, MT-4
cells were infected with HTLV-IIIB at a multiplicity of infection
(MOI) of 0.01. HIV-infected or mock-infected MT-4 cells
(1.5 × 105 ml, 200 ml) were placed into 96-well microtiter plates
and incubated in the presence of various concentrations of test
compounds. The dilution ranged from one-to five-fold and nine
concentrations of each compound were examined. All experi-
ments were performed in triplicate. After a 5-day incubation at
37 ЊC in a CO2 incubator, the cell viability was quantified by a
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|| IUPAC-preferred name: (S)-5-(2,4-dimethoxypyrimidin-5-yl)-2-
ethoxycarbonyl-3,4-dihydro-2H-pyrrole.
Paper 9/00689C
1200
J. Chem. Soc., Perkin Trans. 1, 1999, 1193–1200