Synthesis of cyclopropanoid nucleoside analogues possessing a flexible side chain

Article abstract of DOI:10.1515/znb-2003-0906

A novel class of cyclopropanoic nucleoside analogues containing an hydroxyethyl residue instead of a hydroxymethyl side chain has been prepared in an easy sequence. These compounds showed weak antitumor activity. The resolution of the racemates on an analytical scale was performed by HPLC using chiral stationary phases.

Full text of DOI:10.1515/znb-2003-0906

Synthesis of Cyclopropanoid Nucleoside Analogues
Possessing a Flexible Side Chain
Rene´ Csuk and Anja Kern
Institut fu¨r Organische Chemie, Martin-Luther-Universita¨t Halle-Wittenberg,
Kurt-Mothes-Str. 2, D-06120 Halle (Saale), Germany
Reprint requests to Prof. Dr. R. Csuk. E-mail: csuk@chemie.uni-halle.de
Z. Naturforsch. 58b, 843 – 852 (2003); received June 5, 2003
A novel class of cyclopropanoic nucleoside analogues containing an hydroxyethyl residue instead
of a hydroxymethyl side chain has been prepared in an easy sequence. These compounds showed
weak antitumor activity. The resolution of the racemates on an analytical scale was performed by
HPLC using chiral stationary phases.
Key words: Nucleoside Analogues, Cyclopropanes, HPLC
Introduction
under different reaction conditions invariably afforded
low yields of complex mixtures of stereomeric prod-
ucts that could not be separated by chromatography, its
treatment with ethyl chloroformate in the presence of
dry triethylamine followed by the reaction with ammo-
nia at −5 ◦C gave a mixture of the diastereomeric car-
boxamides cis-3 and trans-4 that were easily separated
by chromatography. Hofmann degradation of ( )-3
using di(acetoxyiodo)-benzene/methanolic potassium
hydroxide gave the corresponding methyl carbamate 5
that was conveniently hydrolysed to the amine ( )-6
[7, 8].
An attractive strategy in the development of new an-
titumor and/or antiviral active compounds consists in
the introduction of carbocyclic units into nucleosides
[1]. This concept has successfully been used for the
synthesis of numerous cyclobutane [2] and cyclopen-
tane [3] analogues of nucleosides, the so-called car-
bocyclic nucleosides analogues among which the cy-
clopropanoid derivatives play a most prominent role
[4 – 6]. Besides antitumor activity many of these cyclo-
propanoic compounds have been shown to be excellent
inhibitors of various enzymes.
In an analogous manner from 3 via the methyl car-
bamate 7 in good yields the amine 8 was obtained.
To obtain heterocycles of the purine type, ( )-6 was
treated with 5-amino-4,6-dichloropyrimidine in the
presence of n-butanol and triethylamine to yield 9 fol-
lowed by the reaction with triethyl orthoformate/conc.
hydrochloric acid [( )-10]. Finally after treatment
Results and Discussion
To obtain higher flexibility in the difluoro cyclo-
propanoid nucleoside analogues series the synthesis
of compounds possessing a flexible chain chain was
planned. During ongoing QSAR studies of antitumor
active cyclopropanoid nucleoside analogues we be-
came interested in the synthesis and biological eval-
uation of hydroxyethyl substituted derivatives.
The synthesis of cis as well as of trans configurated
compounds (with respect to the relative configuration
at the cyclopropane ring) started from well known
( )-ethyl 2-[2-(tetrahydro-2H-2-pyranyloxy)ethyl]-1-
cyclopropanoate (1) [6] as a racemic 1:1 mixture of the
corresponding cis/trans diastereomers to afford after
saponification the acids 2. The relative configuration
◦
with ammonia at 50 bar at 76 C in an autoclave, 97%
of the adenine analogue ( )-11 were obtained [5].
Similarly for the synthesis of the trans-configurated
compounds, reaction of amine 8 with 5-amino-4,6-
dichloropyrimidine as described above gave 12 whose
cyclization afforded the 6-chloro-purine( )-13 and 14
as a by-product. Treatment of ( )-13 with ammonia
in an autoclave finally afforded the adenine derivative
( )-15.
A thymine nucleoside analogue was synthesized in
of these comnpounds has been determined by NMR the cis-series starting from the amine ( )-6 that was
spectroscopy [6]. Whereas a Curtius degradation of 2 allowed to react with in situ prepared (3-methoxy-2-
c
0932–0776 / 03 / 0900–0843 $ 06.00 ꢀ 2003 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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R. Csuk – A. Kern · Synthesis of Cyclopropanoid Nucleoside Analogues
Scheme 1. Reactions and conditions:
a) NaOH; b) ClCO2Et/NH3; c) di(acet-
oxyiodo)benzene/KOH; d) KOH/MeOH;
e) 5-amino-4,6-dichloro-pyrimidine, n-
BuOH, NEt3; f) C(COEt) 3/HCl; g) NH3;
h) 3-methoxy-2-methyl-acryloyl chlo-
ride/AgOCN; i) H2SO4; j) 3-ethoxy-
acryloyl chloride/AgOCN.
Table 1. HPLC conditions for the separation of the enanti-
omers.
methyl-acryloyl)isocyanate [9] to afford ( )-16 fol-
lowed by a ring closure reaction mediated by 2 N sul-
phuric acid to yield the thymine derivative ( )-17. Fol-
lowing this strategy the trans amine ( )-8 gave under
the same conditions via ( )-18 the thymine derivative
( )-19. The uracil analogues were obtained by the re-
action of the amines with in situ prepared (3-ethoxy-
acryloyl)isocyanate (to afford ( )-20 and 18, respec-
tively) [9] followed by acid-mediated ring closure that
gave the cis-configurated uracil analogue ( )-21 and
trans ( )-19, respectively.
Preliminary biological screening of racemic 11, 15,
17, 19, 21 and 22 revealed weak antitumor activity
for several of these compounds. Since it is well estab-
lished that the biological activity of many nucleoside
analogues resides only in one enantiomer [10], the an-
alytical separation of the corresponding enantiomers
was accomplished by HPLC using chiral stationary
phases.
Column
Flow
Pressure
Detection
Chiralpak AD
0.5 ml/min
15.7 – 16.7 bar
UV/vis, λ = 267,
271, 276 nm
methanol
Chiralcel OD
1.0 ml/min
25.5 bar
UV/vis, λ = 271,
276 nm
Eluent
hexane/2-propanol
80:20
Temperature
20 ◦C
20 ◦C
22 was performed by HPLC on a Daicel Chiralcel OD
column using a hexane/2-propanol mixture or on a
Daicel Chiralpak AD column using methanol as the
eluent. The better results for these compounds were
obtained with the Chiralpak AD column. The results
of these separations are summarized in Tables 1 and 2.
For compound ( )-11 a semi-preparative separa-
tion using an analytical Chiralpak AD column was per-
formed using approx. 5 mg/2 ml of ( )-11 per in-
jection. Thus, sufficient enantiomerically pure material
The chromatographic separation of the enantiomers could be obtained; the CD-spectra of (+)-11 and (−)-
of ( )-11, ( )-25, ( )-17, ( )-19, ( )-21 and ( )- 11 are shown in Fig. 1 and are listed in Table 3.
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R. Csuk – A. Kern · Synthesis of Cyclopropanoid Nucleoside Analogues
845
Fig. 1. a) Typical chromatogram for the analytical separation of the enantiomers of ( )-11 by HPLC (Daicel, Chiralpak
AD); b) CD-spectra of (+)-11 and (−)-11.
Table 2. HPLC separation of the enantiomers.
Foss-Heraeus Vario EL instrument was used. TLC was per-
formed on silica gel (Merck 5554, detection by treatment
with a solution of 10% sulfuric acid, ammonium molyb-
date and cerium(IV) sulfate followed by gentle heating or by
UV/vis absorption); column chromatography was performed
on silica gel 60 (FLUKA, 0.04 – 0.06 mm). HPLC was per-
formed on a Merck-Hitachi L6200A/L4000/D2500 instru-
ment using either a Chiralcel OD (Daicel Chemical Indus-
tries, 4.6 × 250 mm, 10 µm) or a Chiralpak AD (Daicel
Chemical Industries, 4.6 × 250 mm, 10 µm) column.
Compound
Column
tR (+) [min]
8.75
tR (–) [min]
11.39
11
15
22
17
21
19
Chiralpak AD
Chiralpak AD
Chiralpak AD
Chiralcel OD
Chiralpak AD
Chiralcel OD
13.71
12.72
61.49
18.29
24.99
28.27
96.27
77.33
134.88
155.44
Table 3. Representative optical data for (-)-11 and (+)-11.
Compound
[α]2D0
∆ε
ee
(+)–11
(–)–11
+6.1
−6.2
−0.14 (226 nm)
> 99%
> 99%
( )-(1 RS, 2 RS)-cis-2-[2-(Tetrahydro-2H-2-pyranyloxy)-
ethyl]-1-cyclopropanecarboxylic acid (cis-( )-2) and
( )-(1 RS, 2 SR)-trans-2-[2-(tetrahydro-2H-2-pyranyloxy)-
ethyl]-1-cyclopropanecarboxylic acid (trans-( )-2)
+0.2 (230 nm)
Presently the separation of all enantiomeric forms
and their biological testing as well as a chemoenzy-
matic approach for the synthesis of the pure enan-
tiomers is under investigation in our labs.
A solution of ( )-ethyl(1 RS, 2 RS)-cis-2-[2-(tetrahydro-
2H-2-pyranyloxy)ethyl]-1-cyclopropanecarboxylate
(cis-
( )-1) and ( )-ethyl(1 RS, 2 SR)-trans-2-[2-(tetrahydro-
2H-2-pyranyloxy)ethyl]-1-cyclopropanecarboxylate (trans-
( )-1) (9.65 g, 39.82 mmol) in ethanol (50 ml) was heated
Experimental Section
General methods: Melting points are uncorrected (Le- under reflux. To this mixture a solution of NaOH (3.02 g,
ica hot stage microscope), optical rotations were obtained 75.51 mmol) in water (15 ml) was added dropwise over
using a Perkin-Elmer 341 polarimeter (1 cm micro cell), a period of 2 h and stirring was continued for 1 h. After
NMR spectra (internal Me4Si) were recorded using the Var- cooling to room temperature the mixture was concentrated,
ian spectrometers Gemini 200, Gemini 2000 or Unity 500 (δ water was added (20 ml) and the mixture was concentrated
given in ppm, J in Hz, internal Me4Si for 1H and 13C NMR again. The yellowish residue was suspended in water (20 ml)
spectra, C’ correspond to the atoms of the heterocycle, C” and extracted with diethyl ether (3 × 50 ml). After adjusting
correspond to the atoms of the tetrahydropyranyl fragment), the pH of the aqueous phase to 3 by the addition of HCl
IR spectra (film or KBr pellet) were measured on a Perkin- (10%), the mixture was extracted with diethyl ether (5
Elmer FT-IR spectrometer Spectrum 1000, MS spectra were × 50 ml). The combined organic phases were dried over
taken on a Intectra GmbH AMD 402 (electron impact, 70 eV) MgSO4 and evaporated under reduced pressure to obtain 2
or on a Finnigan MAT LCQ 7000 (electrospray, voltage (8.42 g, 99%) as a yellowish oil. – RF (ethyl acetate/hexane
4.5 kV, under nitrogen) instrument; for elemental analysis a 3:1), cis-2: 0.52, trans-2: 0.44. – IR (film): ν = 2944s,
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R. Csuk – A. Kern · Synthesis of Cyclopropanoid Nucleoside Analogues
2872m, 1694s, 1456m, 1434m, 1385m, 1353m, 1324m, 11H19NO3 (213.27): calcd. C 61.95, H 8.98, N 6.57; found
C
1261m, 1228m, 1201s, 1185s, 1137s, 1120s, 1077m, 1034s C 61.85, H 9.02, N 6.63.
cm−1. – 1H NMR (200 MHz, CDCl3): δ = 7.99 (s, 1 H,
OH), 4.59 – 4.58 (m, 1 H, 2”-H), 3.87 – 3.64 (m, 2 H, 6”-HA,
OCHA), 3.53 – 3.35 (m, 2 H, 6”-HB, OCHB), 1.90 – 1.37
(m, 8 H, 3”-H2, 4”-H2, 5”-H2, CH2-ethyl), 1.26 – 0.94
(m, 3 H, 2-H, 1-H, 3-HA), 0.85 – 0.76 (m, 1 H, 3-HB). –
13C NMR (50 MHz, CDCl3): data for cis-2: δ = 178.94
(s, CO), 98.59 (d, C-2”), 66.50 (t, C-6”), 61.89 (t, OCH2),
33.02 (t, CH2-ethyl), 30.49 (t, C-3”), 27.10 (t, C-5”), 25.32
(t, C-4”), 19.24 (d, C-1) , 17.69 (d, C-2), 13.81 (t, C-3);
data for trans-2: δ = 180.09 (s, CO), 98.62 (d, C-2”), 66.90
(t, C-6”), 61.94 (t, OCH2), 33.02 (t, CH2-ethyl), 30.49 (t,
C-3”), 27.10 (t, C-5”), 25.32 (t, C-4”), 19.91 (d, C-1), 17.69
(d, C-2), 13.81 (t, C-3). – MS (EI, 70 eV): m/z (%) = 213
(0.7), 196 (2.1), 168 (0.7), 156 (0.7), 141 (3.6), 129 (2.1),
113 (33.6), 101 (23.6), 95 (12.9), 85 (100.0). – HRMS calcd.
for C11H18O4: 214.12050; found: 214.12050. – Analysis for
C11H18O4 (214.26): calcd. C 61.66, H 8.47; found C 61.72,
H 8.49.
Data for ( )-4: white solid. – M. p. 77.1 – 77.7 ◦C. – RF
(ethyl acetate/hexane 3:1) 0.16. – IR (KBr): ν = 3406 brm,
3204w, 2943m, 2871w, 1661m, 1622m, 1456w, 1428w,
1380w, 1353w, 1324w, 1284w, 1201w, 1184w, 1136m,
1120m, 1077w, 1030m cm−1. – 1H NMR (500 MHz,
CDCl3): δ = 5.79 (s, 2 H, NH2), 4.54 (dd, J = 4.32, 4.32 Hz,
1 H, 2”-H), 3.84 – 3.74 (m, 2 H, OCHA, 6”-HA), 3.48 – 3.39
(m, 2 H, OCHB, 6”-HB), 1.81 – 1.73 (m, 1 H, 4”-HA), 1.69 –
1.61 (m, 1 H, 3”-HA), 1.60 – 1.41 (m, 6 H, 4”-HB, 3”-HB,
5”-H2), CH2-ethyl), 1.40 – 1.33 (m, 1 H, 2-H), 1.22 (ddd, J =
8.16, 6.44, 4.18 Hz, 1 H, 1-H), 1.12 (ddd, J = 10.95, 4.31,
2.19 Hz, 1 H, 3-HA), 0.63 (ddd, J = 7.96, 6.24, 4.11 Hz,
1 H, 3-HB). – 13C NMR (100 MHz, CDCl3): δ = 177.13 (s,
CO), 99.98 (d, C-2”), 67.87 (t, OCH2), 63.28 (t, C-6”), 34.19
(t, CH2-ethyl), 31.62 (t, C-3”), 26.33 (t, C-5”), 22.21 (d, C-
1), 20.46 (d, C-2), 20.07 (t, C-4”), 15.07 (t, C-3). – MS (EI,
70 eV): m/z (%) = 212 (0.7), 184 (4.3), 158 (2.1), 141 (6.4),
130 (23.6), 113 (58.6), 99 (28.6), 85 (100.0). – HRMS calcd.
for C11H19NO3: 213.13648; found: 213.13648. – Analysis
for C11H19NO3 (213.27): calcd. C 61.95, H 8.98, N 6.57;
found C 61.83, H 9.00, N 6.68.
( )-(1 RS, 2 RS)-cis-2-[2-(Tetrahydro-2H-2-pyranyloxy)-
ethyl]-1-cyclopropanecarboxamide (( )-3) and ( )-(1 RS,
2 SR)-trans-2-[2-(tetrahydro-2H-2-pyranyloxy)ethyl]-1-cy-
clopropanecarboxamide (( )-4)
( )-Methyl(1 RS, 2 RS)-cis-2-[2-(tetrahydro-2H-2-pyranyl-
oxy)ethyl]-1-cyclopropylcarbamate (( )-5)
To a stirred solution of 2 (5.00 g, 23.34 mmol), triethy-
lamine (3.9 ml, 28.06 mmol) in dry THF (100 ml) ethyl
chloroformate (2.7 ml, 28.37 mmol) was added dropwise at
To a stirred solution of 3 (1.96 g, 9.19 mmol),
◦
−5 C and stirring was continued for 1 h at −5 ◦C. A satu- KOH (1.35 g, 24.06 mmol) in methanol (60 ml),
rated solution of NH3 in THF (250 ml) was then added care- di(acetoxyiodo)benzene (4.0 g, 12.42 mmol) was added in
fully at this temperature and stirring was pursued for 1 h at one portion at 5◦C. The solution was stirred at ice-bath tem-
◦
0 C. The reaction mixture was allowed to warm to room perature for 15 min followed by warming to room tem-
temperature, stirred for an additional 2 h and filtered. The perature for an additional 2 h. Methanol was removed un-
filtrate was concentrated and the residue was purified by col- der reduced pressure and the residue was partitioned be-
umn chromatography (silica gel, ethyl acetate/hexane 1:2 → tween water (70 ml) and dichloromethane (30 ml). The
2:1) to obtain 3 (2.01 g, 40%) and 4 (2.03 g, 40%). – Data aqueous layer was extracted with dichloromethane (4 ×
for ( )-3: white solid. – M. p. 103.6 – 104.8 ◦C. – RF (ethyl 30 ml). The combined organic phases were washed with
acetate/hexane 3:1) 0.21. – IR (KBr): ν = 3360s, 3186m, water (50 ml) and brine (50 ml), dried (MgSO4), evapo-
2941m, 2869m, 2359w, 1353m, 1324w, 1301m, 1260w, rated and the residue was subjected to column chromatogra-
1201m, 1183w, 1166m, 1139m, 1120m, 1080m, 1060m, phy (silica gel, hexane → ethyl acetate/hexane 1:2 → 2:1)
1036s cm−1. – 1H NMR (500 MHz, CDCl3): δ = 5.57 (s, to afford 5 (2.02 g, 90%) as a white solid. – M. p. 65.1 –
◦
1 H, NH), 5.31 (s, 1 H, NH), 4.57 (dd, J = 7.37, 3.13 Hz, 66.3 C. – RF (ethyl acetate/hexane 1:1) 0.54. – IR (KBr):
1 H, 2”-H), 3.88 – 3.83 (m, 1 H, OCHA), 3.79 – 3.74 (m, 1 H, ν = 3288m, 2949m, 2869m, 1712s, 1691s, 1540m, 1454w,
6”-HA), 3.50 – 3.41 (m, 2 H, OCHB, 6”-HB), 1.89 – 1.76 (m, 1354w, 1324w, 1274m, 1236m, 1202m, 1186w, 1137m,
4 H, 4”-H2, 3”-H2), 1.72 – 1.67 (m, 1 H, CHA-ethyl), 1.57 – 1119m, 1095m, 1078m, 1063m, 1033m cm−1. – 1H NMR
1.48 (m, 4 H, 1-H, CHB-ethyl, 5”-H2), 1.37 – 1.24 (m, 1 H, (200 MHz, CDCl3): δ = 5.79 (s, 1 H, NH), 4.60 – 4.57 (m,
2-H), 1.00 – 0.92 (m, 2 H, 3-H2). – 13C NMR (100 MHz, 1 H, 2ꢀꢀ-H), 3.96 – 3.64 (m, 2 H, 6ꢀꢀ-HA, OCHA), 3.60 (s,
CDCl3): δ = 175.23 (s, CO), 99.89 (d, C-2”), 68.21 (t, C- 3 H, OCH3), 3.51 – 3.23 (m, 2 H, 6ꢀꢀ-HB), OCHB), 2.51
6”), 63.35 (t, OCH2), 31.67 (t, CH2-ethyl), 28.08 (t, C-3”), (ddd, J = 10.89, 5.52, 5.52 Hz, 1 H, 1-H), 1.90 – 1.67 (m,
26.37 (t, C-5”), 20.57 (t, C-4”), 20.02 (d, C-1), 19.17 (d, C- 2 H, 3ꢀꢀ-HA, 4ꢀꢀ-HA), 1.64-1.50 (m, 6 H, 3ꢀꢀHB, 4ꢀꢀ-HB, 5ꢀꢀ-
2), 12.62 (t, C-3). – MS (EI, 70 eV): m/z (%) = 184 (8.6), 142 H2), CH2-ethyl), 0.96 – 0.77 (m, 2 H, 2-H, 3-HA), 0.18 –
(0.7), 128 (28.6), 113 (19.3), 112 (100.0). – HRMS calcd. for 0.35 (m, 1 H, 3-HB). – 13C NMR (50 MHz, CDCl3): δ =
C11H19NO3: 213.13648; found: 213.13648. – Analysis for 158.12 (s, CO), 99.47 (d, C-2ꢀꢀ), 67.30 (t, OCH2), 61.77 (t,
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R. Csuk – A. Kern · Synthesis of Cyclopropanoid Nucleoside Analogues
847
C-6ꢀꢀ), 51.78 (q, CH3), 30.46 (t, CH2-ethyl), 28.65 (t, C- 2 H, 6ꢀꢀ-HB, OCHB), 2.38 – 2.50 (m, 1 H, 1-H), 1.81 – 1.74
3ꢀꢀ), 26.76 (d, C-1), 25.26 (t, C-5ꢀꢀ), 19.29 (t, C-4ꢀꢀ), 15.32 (m, 1 H, 4ꢀꢀ-HA), 1.71 – 1.63 (m, 1 H, 3ꢀꢀ-HA), 1.58 – 1.42
(d, C-2), 12.82 (t, C-3); MS (EI, 70 eV): m/z (%) = 159 (m, 6 H, 3ꢀꢀ-HB, 4ꢀꢀ-HB, 5ꢀꢀ-H2), CH2-ethyl), 0.95 – 0.87 (m,
(19.3), 142 (11.4), 128 (7.1), 114 (13.6), 110 (2.9), 100 1 H, 2-H), 0.64 (ddd, J = 9.23, 4.54, 4.54 Hz, 1 H, 3-HA),
(2.1), 88 (7.9), 85 (100.0). – HRMS calcd. for C12H21NO4: 0.57 – 0.52 (m, 1 H, 3-HB). – 13C NMR (100 MHz, CDCl3):
243.14705; found: 243.14704. – Analysis for C12H21NO4 δ = 157.69 (s, CO), 98.94 (d, C-2ꢀꢀ), 66.64 (t, OCH2),
(243.30): calcd. C 59.24, H 8.70, N 5.76; found C 59.17, 62.31 (t, C-6ꢀꢀ), 51.94 (q, CH3), 32.37 (t, CH2-ethyl),
H 8.89, N 5.87.
30.63 (t, C-3ꢀꢀ), 29.34 (d, C-1), 25.33 (t, C-5ꢀꢀ), 19.53 (t,
C-4ꢀꢀ), 17.71 (d, C-2), 13.47 (t, C-3). – MS (EI, 70 eV):
m/z (%) = 242 (5.7), 212 (2.1), 184 (2.1), 159 (18.6), 142
(3.6), 128 (8.6), 114 (20.7), 110 (2.9), 101 (2.9), 88 (8.6), 85
(100.0). – HRMS calcd. for C12H21NO4: 243.14706; found:
243.14706. – Analysis for C12H21NO4 (243.30): calcd.
C 59.24, H 8.70, N 5.76; found C 58.98, H 8.70, N 5.89.
( )-(1 RS, 2 RS)-cis-2-[2-(Tetrahydro-2H-2-pyranyl-oxy)-
ethyl]-1-cyclopropylamine (( )-6)
A solution of 5 (3.36 g, 13.81 mmol), KOH (14.6 g,
260.2 mmol), methanol (100 ml) and water (30 ml) was
heated under reflux for 48 h. The solvents were removed
under reduced pressure and water (50 ml) was added. The
aqueous layer was extracted with dichloromethane (5 ×
50 ml). The combined organic phases were washed with
brine (50 ml), dried (MgSO4) and evaporated in vacuo to
( )-(1 RS, 2 SR)-trans-2-[2-(Tetrahydro-2H-2-pyranyl-oxy)-
ethyl]-1-cyclopropylamine (( )-8)
According to the preparation of 6 from 7 (2.00 g,
obtain 6 (2.12 g, 83%) as a colorless oil. – RF (ethyl ac- 8.22 mmol), KOH (8.72 g, 155.41 mmol), methanol (40 ml)
etate/hexane 1:1) 0.05. – IR (film): ν = 3375w, 3068w, 2942s, and water (10 ml) 8 (1.41 g, 93%) was obtained as a col-
2870m, 1576m, 1442m, 1384m, 1352m, 1323m, 1284m, orless oil. – RF (ethyl acetate/hexane 1:1) 0.05. – IR (film):
1261m, 1201m, 1184m, 1164m, 1136s, 1119s, 1076m, ν = 3361w, 3071w, 2941s, 2869m, 2360w, 1578w, 1454m,
1033s cm−1. – 1H NMR (400 MHz, CDCl3): δ = 4.58 – 1353m, 1323w, 1261w, 1201m, 1184w, 1165m, 1136m,
4.57 (m, 1 H, 2”-H), 3.87 – 3.74 (m, 2 H, 6ꢀꢀ-HA, OCHA), 1120m, 1077m, 1033s cm−1. – 1H NMR (400 MHz, CDCl3):
3.47 – 3.39 (m, 2 H, 6ꢀꢀ-HB, OCHB), 2.31 (ddd, J = 13.33, δ = 4.53 – 4.48 (m, 1 H, 2ꢀꢀ-H), 3.85 – 3.68 (m, 2 H, 6ꢀꢀ-HA,
6.10, 5.03 Hz, 1 H, 1-H), 1.81 – 1.65 (m, 4 H, 3ꢀꢀ-H2, 4ꢀꢀ- OCHA), 3.47 – 3.34 (m, 2 H, 6ꢀꢀ-HB, OCHB), 2.02 (ddd, J =
H2), 1.58 – 1.37 (m, 4 H, CH2-ethyl, 5ꢀꢀ-H2), 0.70 – 0.59 (m, 6.78, 3.37, 3.37 Hz, 1 H, 1-H), 1.80 – 1.58 (m, 2 H, 3ꢀꢀ-HA,
2 H, 2-H, 3-HA), −0.06 (ddd, J = 7.62, 3.42, 3.42 Hz, 1 H, 4ꢀꢀ-HA), 1.55 – 1.29 (m, 6 H, 3ꢀꢀ-HB, 4ꢀꢀ-HB, 5ꢀꢀ-H2, CH2-
3-HB). – 13C NMR (100 MHz, CDCl3): δ = 98.61 (d, C- ethyl), 0.74 – 0.67 (m, 1 H, 2-H), 0.42 (ddd, J = 10.98, 4.88,
2ꢀꢀ), 67.69 (t, OCH2), 61.97 (t, C-6ꢀꢀ), 30.59 (t, CH2-ethyl), 2.78 Hz, 1 H, 3-HA), 0.24 (ddd, J = 7.18, 4.74, 4.74 Hz, 1 H,
27.74 (t, C-3ꢀꢀ), 27.11 (d, C-1), 25.36 (t, C-5ꢀꢀ), 19.41 (t, 3-HB). – 13C NMR (100 MHz, CDCl3): δ = 98.81 (d, C-
C-4ꢀꢀ), 14.96 (d, C-2), 13.00 (t, C-3); MS (EI, 70 eV): m/z 2ꢀꢀ), 67.06 (t, OCH2), 62.14 (t, C-6ꢀꢀ), 32.62 (t, CH2-ethyl),
(%) = 186 (1.4), 168 (0,7), 154 (1.4), 140 (3.6), 126 (3.6), 30.71 (t, C-3ꢀꢀ), 30.57 (d, C-1), 25.30 (t, C-5ꢀꢀ), 19.35 (t, C-
112 (4.3), 101 (16.4), 100 (32.1), 85 (100.0). – HRMS calcd. 4ꢀꢀ), 18.45 (d, C-2), 14.27 (t, C-3). – MS (EI, 70 eV): m/z
for C10H19NO2: 185.14157; found: 185.14158. – Analysis (%) = 184 (1.4), 149 (0.7), 126 (1.4), 112 (0,7), 101 (2.9),
for C10H19NO2 (185.26): calcd. C 64.83, H 10.34, N 7.56; 100 (19.3), 85 (100.0). – HRMS calcd. for C10H19NO2:
found C 64.69, H 10.18, N 7.31.
185.14157; found: 185.14157. – Analysis for C10H19NO2
(185.26): calcd. C 64.83, H 10.34, N 7.56; found C 64.78,
H 10.54, N 7.69.
( )-Methyl(1 RS, 2 SR)-trans-2-[2-(tetrahydro-2H-2-pyr-
anyloxy)ethyl]-1-cyclopropylcarbamate (( )-7)
( )-4N-{(1 RS, 2 RS)-cis-2-[2-(Tetrahydro-2H-2-pyranyl-
oxy)ethyl]cyclopropyl}-6-chloro-4,5-pyrimidine-diamine
(( )-9)
Following the procedure given for the prepara-
tion of compound 5 using 4 (5.23 g, 24.52 mmol),
KOH (3.45 g, 61.49 mmol), methanol (75 ml) and
bis(acetoxy)iodobenzene (8.10 g, 25.15 mmol) 7 (5.67 g,
A
suspension of 6 (2.0 g, 10.8 mmol), triethyl-
95%) was obtained after purification by column chromatog- amine (25 ml), 5-amino-4,6-dichloro-pyrimidine (3.55 g,
raphy (silica gel, hexane → ethyl acetate/hexane 1:2 → 2:1) 21.65 mmol) in n-butanol (50 ml) was heated under re-
as a colorless oil. – RF (ethyl acetate/hexane 1:1) 0.54. – IR flux for 24 h. After cooling to room temperature the sol-
(film): ν = 3323m, 2944m, 2869m, 1708s, 1527m, 1455m, vent was removed under reduced pressure and the remain-
1354m, 1264m, 1217m, 1201m, 1136m, 1119m, 1076m, ing oil subjected to column chromatography (silica gel,
1064m, 1032s cm−1. – 1H NMR (400 MHz, CDCl3): δ = ethyl acetate/hexane 1:1 → 2:1) to afford 9 (3.15 g, 93%)
4.87 (s, 1 H, NH), 4.57 – 4.54 (m, 1 H, 2ꢀꢀ-H), 3.86 – 3.76 (m, as a yellowish oil. – RF (ethyl acetate/hexane 3:1) 0.5. –
2 H, 6ꢀꢀ-HA), OCHA), 3.62 (s, 3 H, OCH3), 3.50 – 3.44 (m, UV/vis (methanol): λmax (lg ε) = 302 nm (4.28). – IR (film):
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R. Csuk – A. Kern · Synthesis of Cyclopropanoid Nucleoside Analogues
ν = 3354s, 2942s, 2870m, 1733m, 1644m, 1574s, 1495s, ( )-2-[(1 RS, 2 RS)-cis-2-(6-Amino-9H-9-purinyl)cyclo-
1454s, 1418s, 1358s, 1244m, 1202m, 1184m, 1119s, 1074s, propyl]-1-ethanol (( )-11)
1032s cm−1. – 1H NMR (400 MHz, CDCl3): δ = 8.07 (d,
A solution of 10 (0.9 g, 3.77 mmol) in liquid ammo-
J = 7.81 Hz,1 H, 2ꢀ-H), 6.03 (s, 2 H, NH2), 4.62 (s, 1 H,
◦
nia (100 ml) was heated at 76 C for 20 h in an autoclave
NH), 4.52 (dd, J = 6.64, 2.34 Hz, 1 H, 2ꢀꢀ-H), 3.96 – 3.80 (m,
(50 bar). After removal of the ammonia the residue was dis-
2 H, 6ꢀꢀ-HA, OCHA), 3.61 – 3.46 (m, 2 H, 6ꢀꢀ-HB, OCHB),
solved in methanol. The solvent was removed in vacuo to
2.77 (ddd, J = 9.27, 4.30, 3.52 Hz, 1 H, 1-H), 1.98 – 1.47
afford 11 (0.80 g, 97%) as a white solid. – M. p. 185.4 –
(m, 8 H, 3ꢀꢀ-H2), 4ꢀꢀ-H2, 5ꢀꢀ-H2, CH2-ethyl), 1.11 – 1.05 (m,
186.1 ◦C. – RF(ethyl acetate/methanol 10:1) 0.23. – UV/vis
2 H, 2-H, 3-HA), 0.23 – 0.20 (m, 1 H, 3-HB). – 13C NMR
(methanol): λmax (lg ε) = 264 nm (4.28). – IR (KBr): ν =
(100 MHz, CDCl3): δ = 155.30 (s, C-6ꢀ), 148.97 (d, C-
3296s, 3125s, 2931m, 1677s, 1608s, 1577m, 1480m, 1404m,
2ꢀ), 141.01 (s, C-4ꢀ), 122.74 (s, C-5ꢀ), 101.56 (d, C-2ꢀꢀ),
1335m, 1307m, 1262w, 1194w, 1111w, 1048m cm−1. –
69.16 (t, OCH2), 64.38 (t, C-6ꢀꢀ), 30.85 (t, CH2-ethyl), 29.11
1H NMR (500 MHz, CD3OD): δ = 8.21 (s, 1 H, 2ꢀ-H), 8.08
(t, C-3ꢀꢀ), 27.65 (d, C-1), 25.10 (t, C-5ꢀꢀ), 20.68 (t, C-4ꢀꢀ),
15.83 (d, C-2), 13.27 (t, C-3). – MS (EI, 70 eV): m/z (%) =
312 (9.3), 239 (6.4), 227 (25.0), 211 (21.4), 201 (15.7),
183 (15.0), 156 (27.7), 144 (15.7), 130 (5.7), 101 (5.7),
85 (100.0). – HRMS calcd. for C14H21ClN4O2: 312.13529;
found: 312.13529. – Analysis for C14H21ClN4O2 (312.80):
(s, 1 H, 8ꢀ-H), 4.79 (s, 1 H, OH), 3.60 – 3.52 (m, 3 H, 2-H,
OCH2), 1.59 – 1.52 (m, 1 H, CHA-ethyl), 1.48 – 1.35 (m, 2 H,
1-H, 3-HA), 1.21 (ddd, J = 7.29, 4.21, 4.21 Hz, 1 H, 3-HB),
0.89 – 0.83 (m, 1 H, CHB-ethyl). – 13C NMR (100 MHz, d6-
DMSO): δ = 156.15 (s, C-6ꢀ), 152.67 (d, C-2ꢀ), 151.20 (s,
C-4ꢀ), 141.77 (d, C-8ꢀ), 119.18 (s, C-5ꢀ), 60.26 (t, OCH2),
calcd. C 53.76, H 6.77, Cl 11.33, N 17.91; found C 53.49,
30.75 (d, C-2), 29.28 (t, CH2-ethyl), 14.34 (d, C-1), 9.20 (t,
H 6.86; Cl 11.56, N 17.64.
C-3). – MS (EI, 70 eV): m/z (%) = 219 (41.4), 202 (7.9),
189 (33.6), 188 (100.0). – HRMS calcd. for C10H13N5O:
219.11199; found: 219.11200. – Analysis for C10H13N5O
(219.25): calcd. C 54.78, H 5.98, N 31.94; found C 54.52,
H 5.71, N 31.69.
( )-2-[(1 RS, 2 RS)-cis-2-(6-Chloro-9H-9-purinyl)cyclo-
propyl]-1-ethanol (( )-10)
A suspension of 9 (2.38 g, 7.61 mmol) in triethyl ortho-
formate (18.0 g, 121.46 mmol) and hydrochloric acid (36%,
0.9 g, 9.0 mmol) was stirred for 4 h at room temperature. By
addition of sodium hydrogen carbonate and water (50 ml) the
pH of the reaction mixture was adjusted to 7 – 8 and the aque-
ous solution was extracted with ethyl acetate (5 × 100 ml),
( )-N4-{trans-2-[2-(Tetrahydro-2H-2-pyranyloxy)-ethyl]-
cyclopropyl}-6-chloro-4,5-pyrimidinediamine (( )-12)
The reaction was performed under the conditions as
the combined organic phases were dried (MgSO4) and the described for 9 using 8 (2.00 g, 10.80 mmol), triethyl-
solvent was removed. The crude product was purified by col- amine (50 ml), 5-amino-4,6-dichloro-pyrimidine (2.93 g,
umn chromatography (silica gel, ethyl acetate → ethyl ac- 17.87 mmol) in n-butanol (100 ml). After evaporation of the
etate/methanol 10:1) to obtain 10 (0.97 g, 53%) as a white solvents and purification by column chromatography (silica
solid. – M. p. 122.4 – 122.9 ◦C; UV/vis (methanol): λmax gel, ethyl acetate/hexane 1:1 → 2:1) 12 (2.94 g, 87%) was
(lg ε) = 269 nm (4.23). – RF(ethyl acetate/methanol 10:1) obtained as a yellowish oil. – RF(ethyl acetate/hexane 3:1)
0.52. – IR (KBr): ν = 3343m, 3103w, 2939w, 2863w, 1594s, 0.5. – UV/vis (methanol): λmax (lg ε) = 302 nm (3.98). –
1569m, 1498w, 1441m, 1404m, 1342s, 1234m, 1150w, IR (film): ν = 3355s, 3251s, 2941s, 2870m, 1737m, 1644m,
1045m cm−1. – H NMR (500 MHz, CDCl3): δ = 8.71 (s, 1574s, 1496s, 1467s, 1450s, 1419s, 1342m, 1299m, 1238m,
1
1 H, 2ꢀ-H), 8.10 (s, 1 H, 8ꢀ-H), 3.69 – 3.64 (m, 2 H, OCH2), 1200m, 1184m, 1162m, 1119s, 1075s, 1030s cm−1. –
3.55 (ddd, J = 7.36, 7.36, 4.16 Hz, 1 H, 2-H), 2.31 (brs, 1H NMR (400 MHz, CDCl3): δ = 8.07 (s, 1 H, 2ꢀ-H), 5.37
1 H, OH), 1.59 – 1.52 (m, 2 H, CHA-ethyl, 1-H), 1.46 (ddd, (s, 1 H, NH), 4.55 (dd, J = 4.59, 2.83 Hz, 1 H, 2ꢀꢀ-H),
J = 7.64, 5.96, 3.81 Hz, 1 H, 3-HA), 1.15 (ddd, J = 6.28, 3.88 – 3.80 (m, 2 H, 6ꢀꢀ-HA, OCHA), 3.66 – 3.42 (m, 2 H,
6.28, 4.36 Hz, 1 H, 3-HB), 1.00 (dddd, J = 17.98, 8.38, 6ꢀꢀ-HB, OCHB), 2.59 (ddd, J = 7.91, 5.57, 3.22 Hz, 1 H, 1-
4.50, 4.26 Hz, 1 H, CHB-ethyl). – 13C NMR (100 MHz, H), 1.81 – 1.45 (m, 8 H, 3ꢀꢀ-H2, 4ꢀꢀ-H2, 5ꢀꢀ-H2, CH2-ethyl),
CDCl3): δ = 153.19 (s, C-6ꢀ), 152.16 (d, C-2ꢀ), 151.34 (s, 1.03 – 0.94 (m, 1 H, 2-H), 0.73 – 0.67 (m, 2 H, 3-H2). –
C-4ꢀ), 146.68 (d, C-8ꢀ), 131.94 (s, C-5ꢀ), 61.70 (t, OCH2), 13C NMR (100 MHz, CDCl3): ν = 155.71 (s, C-6ꢀ), 149.54
30.63 (d, C-2), 30.08 (t, CH2-ethyl), 15.10 (d, C-1), 10.26 (t, (d, C-2ꢀ), 142.44 (s, C-4ꢀ), 122.15 (s, C-5ꢀ), 99.34 (d, C-2ꢀꢀ),
C-3). – MS (EI, 70 eV): m/z (%) = 239 (3.6), 237 (2.9), 221 66.97 (t, OCH2), 62.70 (t, C-6ꢀꢀ), 32.45 (t, CH2-ethyl), 30.67
(3.6), 219 (3.6), 209 (11.4), 207 (67.1), 205 (7.1), 194 (25.0), (t, C-3ꢀꢀ), 30.46 (d, C-1), 25.30 (t, C-5ꢀꢀ), 19.73 (t, C-4ꢀꢀ),
183 (5.7), 167 (7.9), 157 (37.1), 155 (100.0). – HRMS calcd. 17.83 (d, C-2), 13.99 (t, C-3). – MS (EI, 70 eV): m/z (%) =
for C10H11ClN4O: 238.06213; found: 238.06214. – Analysis 312 (14.3), 239 (7.9), 228 (32.9), 212 (27.1), 197 (20.7),
for C10H11ClN4O (238.68): calcd. C 50.32, H 4.65, Cl 14.85, 183 (21.4), 175 (19.3), 169 (25.0), 156 (30.0), 144 (18.6),
N 23.47; found C 50.21, H 4.81, Cl 15.02, N 23.51.
130 (6.4), 119 (4.3), 101 (5.0), 85 (100.0). – HRMS calcd.
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R. Csuk – A. Kern · Synthesis of Cyclopropanoid Nucleoside Analogues
849
for C14H21ClN4O2: 312.13529; found: 312.13527. – Anal- 169 (100.0). – HRMS calcd. for C9H13ClN4O: 228.07778;
ysis for C14H21ClN4O2 (312.80): calcd. C 53.76, H 6.77, found: 228.07777. – Analysis for C9H13ClN4O (228.68):
Cl 11.33, N 17.91; found C 53.41, H 6.82, Cl 11.49, N 17.69. calcd. C 47.27, H 5.73, N 24.50; found C 47.03, H 5.53,
N 24.34.
( )-2-{(1 RS, 2 SR)-trans-2-(6-Chloro-9H-9-purinyl)-cyclo-
propyl}-1-ethanol (( )-13) and ( )-2-{(1 RS, 2 SR)-trans-
2-(5-Amino-6-chloro-4-pyrimidinyl-amino)cyclopropyl}-1-
ethanol (( )-14)
( )-2-{(1 RS, 2 SR)-trans-2-(6-Amino-9H-9-purinyl)-cyclo-
propyl}-1-ethanol (( )-15
A solution of 13 (0.29 g, 1.22 mmol) in liquid ammo-
nia (25 ml) was heated at 76 ◦C for 20 h in an auto-
clave (30 bar). After removal of the ammonia the residue
was dissolved in methanol. The solvent was removed in
vacuo and the residue was subjected to column chromato-
graphy (silica gel, ethyl acetate/methanol 10:1) to obtain
15 (0.17 g, 64%) as a yellowish solid. – M. p. 192.2 –
193.0 ◦C. – RF(ethyl acetate/methanol 10:1) 0.23. – UV/vis
(methanol): λmax (lg ε) = 266 nm (3.90). – IR (KBr):
ν = 3284s, 3135s, 2930m, 2872m, 1728m, 1675s, 1608s,
1573m, 1515w, 1480m, 1457m, 1422m, 1404m, 1382m,
1336m, 1300s, 1256m, 1198m, 1120m, 1064m, 1026m,
1006m cm−1. – 1H NMR (500 MHz, CDCl3): δ = 8.33 (s, 1
H, 2ꢀ-H), 7.76 (s, 1 H, 8ꢀ-H), 5.91 (s, 2 H, NH2), 3.95 – 3.86
(m, 2 H, OCH2), 3.20 (ddd, J = 7.05, 3.53, 3.53 Hz, 1 H,
2-H), 1.30 – 1.21 (m, 2 H, CHA-ethyl, 1-H), 1.10 – 1.02 (m,
1 H, 3-HA), 0.96 (ddd, J = 7.94, 4.33, 3.05 Hz, 1 H, 3-HB),
0.91 – 0.85 (m, 1 H, CHB-ethyl). – 13C NMR (100 MHz,
CDCl3): δ = 156.76 (s, C-6ꢀ), 153.97 (d, C-2ꢀ), 152.17 (s,
C-4ꢀ), 142.13 (d, C-8ꢀ), 120.63 (s, C-5ꢀ), 62.64 (t, OCH2),
35.83 (d, C-2), 31.49 (t, CH2-ethyl), 19.18 (d, C-1), 11.91 (t,
C-3). – MS (EI, 70 eV): m/z (%) = 219 (35.0), 202 (7.9),
189 (65.7), 188 (100.0). – HRMS calcd. for C10H13N5O:
219.11200; found: 219.11201. – Analysis for C10H13N5O
(219.25): calcd. C 54.78, H 5.98, N 31.94; found C 54.92,
H 5.99, N 31.85.
The same experimental procedure as given for 10 start-
ing from 12 (2.72 g, 8.70 mmol), triethyl orthoformate
(21.47 g, 144.87 mmol) and hydrochloric acid (36%, 1.11 g,
11.10 mmol) led to the crude products. Column chromatogra-
phy (silica gel, ethyl acetate → ethyl acetate/methanol 10:1)
of the residue yielded 13 (0.31 g, 15%) and 14 (1.05 g, 53%).
Data for ( )−13: yellowish oil.
– RF (ethyl ac-
etate/methanol 10:1) 0.52. – UV/vis (methanol): λmax (lg
ε) = 270 nm (3.70). – IR (film): ν = 3346brm, 3061w,
2933m, 2239w, 1797w, 1724m, 1592s, 1564s, 1496m,
1438m, 1412m, 1337m, 1226s, 1172m, 1120m, 1094m,
1
1063m cm−1. – H NMR (400 MHz, CDCl3): δ = 8.74 (s,
1 H, 8ꢀ-H), 8.13 (s, 1 H, 2ꢀ-H), 3.73 – 3.63 (m, 2 H, OCH2),
3.57 (ddd, J = 7.32, 7.32, 4.30 Hz, 1 H, 2-H), 2.29 (s, 1 H,
OH), 1.61 – 1.45 (m, 3 H, 1-H, 3-HA), CHA-ethyl), 1.16
(ddd, J = 6.98, 5.23, 5.22 Hz, 1 H, 3-HB), 1.06 – 1.00 (m, 1 H,
CHB-ethyl). – 13C NMR (100 MHz, CDCl3): δ = 154.24 (s,
C-6ꢀ), 153.20 (d, C-2ꢀ), 152.39 (s, C-4ꢀ), 147.70 (d, C-8ꢀ),
132.99 (s, C-5ꢀ), 62.75 (t, OCH2), 31.67 (d, C-2), 31.13 (t,
CH2-ethyl), 16.15 (d, C-1), 11.30 (t, C-3). – MS (EI, 70 eV):
m/z (%) = 239 (2.9), 238 (0.7), 237 (3.6), 221 (2.1), 219 (2.9),
209 (21.4), 207 (59.3), 205 (6.4), 194 (24.3), 183 (12.5),
167 (21.8), 157 (38.2), 155 (100.0), 129 (7.9), 119 (8.6), 104
(15.0), 84 (4.3), 77 (4.6). – HRMS calcd. for C10H11ClN4O:
238.06213; found: 238.06213. – Analysis for C10H11ClN4O
(238.68): calcd. C 50.32, H 4.65, N 23.47; found C 50.21,
H 4.39, N 23.23.
( )-{(1 RS, 2 SR)-trans-2-[2-(Tetrahydro-2H-2-pyranyl-
oxy)ethyl]cyclopropyl}-3-(3-methoxy-2-methyl-acryloyl)-
urea (( )-16)
Data for ( )−14: yellowish solid. – M. p. 161.2 –
163.0 ◦C. – RF(ethyl acetate/methanol 10:1) 0.56. – UV/vis
(methanol): λmax (lg ε) = 272 nm (3.74). – IR (KBr):
ν
= 3447m, 3351m, 3254m, 2941m, 2864w, 1668m,
Following the procedure given for the preparation of
1636m, 1592s, 1503m, 1475m, 1449m, 1414m, 1396w, compound 23 using 3-methoxy-2-methylacryloyl chloride
1341m, 1300m, 1236m, 1198w, 1164w, 1100m, 1068m, (1.80 g, 13.38 mmol), silver cyanate (2.30 g, 15.34 mmol)
1010w cm−1. – 1H NMR (400 MHz, CD3OD): δ = 7.79 (s, in dry benzene (15 ml) and 8 (0.80 g, 4.32 mmol), com-
1 H, 2ꢀ-H), 4.84 (s, 1 H, OH), 3.84 – 3.71 (m, 2 H, OCH2), pound 16 (1.02 g, 72%) was obtained after purification by
2.55 (ddd, J = 7.18, 3.57, 3.57 Hz, 1 H, 2-H), 1.97 – 1.91 (m, column chromatography (silica gel, ethyl acetate/hexane 1:1)
1 H, CHA-ethyl), 1.10 (dddd, J = 15.65, 9.01, 4.37, 4.37 Hz, as a yellowish oil. – RF(ethyl acetate/hexane 1:1) 0.19. –
1 H, CHB-ethyl), 0.87 (ddd, J = 9.18, 5.28, 3.90 Hz, 1 H, UV/vis (methanol): λmax (lg ε) = 259 nm (4.13). – IR
3-HA), 0.80 – 0.72 (m, 1 H, 1-H), 0.63 (ddd, J = 7.37, 5.52, (film): δ = 3270m, 2941m, 2869m, 1689s, 1615m, 1538s,
5.52 Hz, 1 H, 3-HB). – 13C NMR (100 MHz, CD3OD): δ = 1454m, 1402m, 1369w, 1352m, 1295m, 1244s, 1184m,
155.09 (s, C-6ꢀ), 146.96 (d, C-2ꢀ), 138.66 (s, C-4ꢀ), 125.63 1130s, 1076m, 1034s cm−1. – 1H NMR (400 MHz, CDCl3):
(s, C-5ꢀ), 63.51 (t, OCH2), 36.36 (t, CH2-ethyl), 31.23 (d, δ = 8.71 (s, 1 H, OCNHCO), 8.64 (s, 1 H, NH), 7.33 (d,
C-2), 20.54 (d, C-1), 11.62 (t, C-3). – MS (EI, 70 eV): m/z J = 1.17 Hz, 1 H, CH=), 4.56 – 4.53 (m, 1 H, 2ꢀꢀ-H), 3.84 –
(%) = 229 (12.9), 228 (6.1), 227 (3.6), 213 (12.1), 211 (30.0), 3.74 (m, 2 H, 6ꢀꢀ-HA, OCHA), 3.81 (s, 3 H, OCH3), 3.48 –
199 (21.4), 197 (65.0), 186 (30.7), 184 (95.7), 171 (37.1), 3.40 (m, 2 H, 6ꢀꢀ-HB, OCHB), 2.46 (ddd, J = 5.66, 4.49,
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850
R. Csuk – A. Kern · Synthesis of Cyclopropanoid Nucleoside Analogues
2.54 Hz, 1 H, 1-H), 1.80 – 1.74 (m, 2 H, 4ꢀꢀ-H2), 1.72 (d, 1345m, 1325m, 1244s, 1184s, 1151s, 1076m, 1062m, 1031s,
1
J = 0.98 Hz, 3 H, CH3), 1.70 – 1.61 (m, 1 H, 3ꢀꢀ-HA), 1.55 – 1000m cm−1. – H NMR (400 MHz, CDCl3): δ = 9.97 (s,
1.44 (m, 5 H, 3ꢀꢀ-HB, 5ꢀꢀ-H2, CH2-ethyl), 1.00 – 0.93 (m, 1 H, OCNHCO), 8.64 (s, 1 H, NH), 7.56 (d, J = 12.30 Hz,
1 H, 2-H), 0.69 (ddd, J = 9.28, 5.37, 3.91 Hz, 1 H, 3-HA), 1 H, OCH=), 5.36 (d, J = 12.30 Hz, 1 H, CH=), 4.54 – 4.52
0.56 (ddd, J = 9.37, 9.37, 3.71 Hz, 1 H, 3-HB). – 13C NMR (m, 1 H, 2ꢀꢀ-H), 3.91 (q, J = 6.40 Hz, 2 H, OCH2-ethyl),
(100 MHz, CDCl3): δ = 169.63 (s, CO), 158.40 (d, CH=), 3.83 – 3.73 (m, 2 H, 6ꢀꢀ-HA, OCHA), 3.47 – 3.39 (m, 2 H,
155.43 (s, NHCONH), 107.50 (s, Cq), 98.75 (d, C-2ꢀꢀ), 66.48 6ꢀꢀ-HB, OCHB), 2.44 (ddd, J = 3.42, 3.42, 2.05 Hz, 1 H,
(t, OCH2), 62.09 (t C-6ꢀꢀ), 61.27 (q, OCH3), 32.49 (t, CH2- 1-H), 1.79 – 1.71 (m, 1 H, 4ꢀꢀ-HA), 1.69 – 1.62 (m, 2 H, 3ꢀꢀ-
ethyl), 30.57 (t, C-3ꢀꢀ), 28.59 (d, C-1), 25.32 (t, C-5ꢀꢀ), 19.37 HA, CHA-ethyl), 1.52 – 1.35 (m, 5 H, 3ꢀꢀ-HB, 4ꢀꢀ-HB, 5ꢀꢀ-H2,
(t, C-4ꢀꢀ), 17.16 (d, C-2), 13.19 (t, C-3), 8.56 (q, CH3). – CHB-ethyl), 1.28 (t, J = 4.69 Hz, 3 H, CH3), 1.00 – 0.93
MS (EI, 70 eV): m/z (%) = 327 (3.6), 311 (4.3), 279 (0.7), (m, 1 H, 2-H), 0.70 (ddd, J = 9.28, 5.27, 4.10 Hz, 1 H, 3-
243 (2.9), 227 (5.7), 211 (3.6), 197 (7.9), 178 (4.3), 159 HA), 0.57 – 0.53 (m, 1 H, 3-HB). – 13C NMR (100 MHz,
(39.3), 141 (7.1), 116 (7.1), 99 (100.0). – HRMS calcd. for CDCl3): δ = 168.38 (s, CO), 162.54 (d, OCH=), 156.48
C16H26N2O5: 326.18416; found: 326.18417. – Analysis for (s, NHCONH), 98.74 (d, OC-CH=), 98.06 (d, C-2ꢀꢀ), 67.01
C16H26N2O5 (326.39): calcd. C 58.88, H 8.03, N 8.58; found (t, OCH2-ethyl), 66.45 (t, OCH2), 62.08 (t, C-6ꢀꢀ), 32.43 (t,
C 58.97, H 7.85, N 8.55.
CH2-ethyl), 30.53 (t, C-3ꢀꢀ), 28.45 (d, C-1), 25.27 (t, C-5ꢀꢀ),
19.35 (t, C-4ꢀꢀ), 17.31 (d, C-2), 14.20 (q, CH3), 12.92 (t,
C-3). – MS (EI, 70 eV): m/z (%) = 327 (0.4), 297 (0.7),
285 (0.7), 256 (0.4), 242 (44.3), 226 (4.3), 211 (8.6), 197
(6.4), 185 (6.4), 172 (5.7), 159 (100.0). – HRMS calcd. for
C16H26N2O5: 326.18416; found: 326.18416. – Analysis for
C16H26N2O5 (326.39): calcd. C 58.88, H 8.03, N 8.58; found
C 58.71, H 7.98, N 8.48.
( )-1-{(1 RS, 2 SR)-trans-2-(2-Hydroxyethyl)cyclopropyl}-
5-methyl-1,2,3,4-tetrahydro-pyrimidine-2,4-dione (( )-17)
According to the preparation of 22 from 16 (0.47 g,
1.44 mmol) and sulfuric acid (2 N, 20 ml), compound 17
(0.21 g, 68%) was obtained as a yellowish solid. – M. p.
196.4 – 197.0 ◦C. – RF(ethyl acetate/methanol 10:1) 0.59. –
UV/vis (methanol): λmax (lg ε) = 275 nm (4.11). – IR (film):
ν = 3382s, 3156m, 3016m, 2923s, 1667s, 1454m, 1425m,
1387m, 1321m, 1297m, 1163m, 1074m, 1018m cm−1. –
1H NMR (500 MHz, CDCl3): δ = 9.17 (s, 1 H, NH), 7.05
(s, 1 H, 6ꢀ-H ), 3.83 – 3.78 (m, 2 H, OCH2), 2.87 (ddd,
J = 7.11, 3.51, 3.51 Hz, 1 H, 1-H), 2.07 – 2.03 (m, 1 H,
CHA-ethyl), 1.88 (s, 3 H, CH3), 1.18 – 1.14 (m, 1 H, 2-
H), 1.07 – 1.01 (m, 1 H, CHB-ethyl), 0.96 (ddd, J = 9.80,
6.12, 3.73 Hz, 1 H, 3-HA), 0.80 – 0.76 (m, 1 H, 3-HB). –
13C NMR (100 MHz, CDCl3): δ = 163.80 (s, C-4ꢀ), 152.87
(s, C-2ꢀ), 140.78 (d, C-6ꢀ), 111.16 (s, C-5ꢀ), 61.97 (t, OCH2),
36.47 (d, C-1), 35.21 (t, CH2-ethyl), 19.63 (d, C-2), 12.13
(q, CH3), 11.30 (t, C-3). – MS (EI, 70 eV): m/z (%) = 210
(13.6), 182 (17.1), 180 (7.9), 166 (12.1), 154 (2.9), 140 (6.1),
136 (16.4), 127 (100.0). – HRMS calcd. for C10H14N2O3:
210.10043; found: 210.10042. – Analysis for C10H14N2O3
(210.23): calcd. C 57.13, H 6.71, N 13.33; found C 57.33,
H 6.58, N 12.87.
( )-1-[(1 RS, 2 SR)-trans-2-(2-Hydroxyethyl)cyclopropyl]-
1,2,3,4-tetrahydro-pyrimidine-2,4-dione (( )-19)
The reaction was performed under the conditions as de-
scribed for 21 using 18 (0.80 g, 2.46 mmol) in sulfu-
ric acid (2 N, 25 ml). After neutralisation and evapora-
tion of the solvents under reduced pressure, the residue was
extracted with ethyl acetate (300 ml). The combined or-
ganic phases were dried over MgSO4 and evaporated in
vacuo. The residue was purified by column chromatogra-
phy (silica gel, ethyl acetate/methanol 10:1) to afford com-
poun◦d 19 (0.32 g, 66%) as a yellowish solid. – M. p. 227 –
228 C. – RF(ethyl acetate/methanol 10:1) 0.50. – UV/vis
(methanol): λmax (lg ε) = 270 nm (3.91). – IR (KBr):
ν = 3376m, 3134m, 3010m, 2957m, 2876w, 2810m, 1675s,
1616m, 1470m, 1420m, 1396m, 1354w, 1320m, 1298s,
1
1238w, 1192w, 1123w, 1093w, 1075m, 1022w cm−1. – H
NMR (500 MHz, d6-DMSO): δ = 11.16 (s, 1 H, NH), 7.49
(d, J = 8.01 Hz, 1 H, 6ꢀ-H ), 5.47 (d, J = 7.91 Hz, 1 H,
5ꢀ-H ), 3.56 – 3.51 (m, 2 H, OCH2), 2.77 (ddd, J = 7.24,
3.66, 3.64 Hz, 1 H, 1-H), 1.58 – 1.52 (m, 1 H, CHA-ethyl),
1.38-1.31 (m, 1 H, CHB-ethyl), 1.14-1.10 (m, 1 H, 2-H),
( )-{(1 RS, 2 SR)-trans-2-[2-(Tetrahydro-2H-2-pyranyl-
oxy)ethyl]cyclopropyl}-3-(3-ethoxy-acryloyl)urea (( )-18)
Similarly as described for compound 23 using 3-ethoxy- 0.97 (ddd, J = 9.71, 5.81, 3.91 Hz, 1 H, 3-HA), 0.76 – 0.72
acryloyl chloride (2.00 g, 14.86 mmol), silver cyanate (m, 1 H, 3-HB). – 13C NMR (100 MHz, d6-DMSO): δ =
(3.36 g, 22.42 mmol) in dry benzene (20 ml) and 8 (1.09 g, 163.66 (s, C-4ꢀ), 152.03 (s, C-2ꢀ), 145.63 (d, C-6ꢀ), 100.72
5.88 mmol), 18 (1.39 g, 72%) was obtained as a yellowish (d, C-5ꢀ), 60.25 (t, OCH2), 36.12 (d, C-1), 34.67 (t, CH2-
◦
solid. – M. p. 102.6 – 103.9 C. – RF (ethyl acetate/hexane ethyl), 17.42 (d, C-2), 12.10 (t, C-3). – MS (EI, 70 eV): m/z
3:1) 0.45. – UV/vis (methanol): λmax (lg ε) = 252 nm (%) = 196 (7.1), 179 (1.4), 168 (20.7), 152 (12.9), 140 (3.6),
(4.25). – IR (KBr): δ 3272m, 3091m, 2940m, 2869m, 1704s, 122 (13.6), 113 (100.0). – HRMS calcd. for C9H12N2O3:
1676s, 1606s, 1537s, 1499s, 1473m, 1455m, 1396m, 1370w, 196.08478; found: 196.08477. – Analysis for C9H12N2O3
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R. Csuk – A. Kern · Synthesis of Cyclopropanoid Nucleoside Analogues
851
(196.20): calcd. C 55.10, H 6.16, N 14.28; found C 55.18, δ = 7.52 (d, J = 7.91 Hz, 1 H, 6ꢀ-H ), 5.47 (d, J = 7.91, 1 H,
H 6.32, N 14.09.
5ꢀ-H ), 3.44 – 3.41 (m, 2 H, OCH2), 3.06 (ddd, J = 7.49, 7.49,
4.43, 1 H, 1-H), 1.55 – 1.49 (m, 1 H, CHA-ethyl), 1.19 – 1.15
(m, 1 H, C-2), 1.01 (ddd, J = 9.51, 5.71, 5.71, 1 H, 3-HA),
0.91 – 0.84 (m, 1 H, CHB-ethyl), 0.73 (ddd, J = 6.33, 6.33,
4.53, 1 H, 3-HB). – 13C NMR (100 MHz, d6-DMSO): δ =
163.77 (s, C-4ꢀ), 152.07 (s, C-2ꢀ), 146.23 (d, C-6ꢀ), 100.41
(d, C-5ꢀ), 60.47 (t, OCH2), 34.98 (d, C-1), 30.58 (t, CH2-
ethyl), 15.06 (d, C-2), 9.61 (t, C-3). – MS (EI, 70 eV): m/z
(%) = 196 (2.5), 179 (1.4), 168 (6.4), 166 (6.4), 151 (7.9),
140 (2.5), 126 (4.3), 122 (18.6), 113 (100.0). – HRMS calcd.
for C9H12N2O3: 196.08478; found: 196.08478. – Analysis
for C9H12N2O3 (196.20): calcd. C 55.10, H 6.16, N 14.28;
found C 55.13, H 6.23, N 14.00.
( )-{(1 RS, 2 RS)-cis-2-[2-(Tetrahydro-2H-2-pyranyl-oxy)-
ethyl]cyclopropyl}-3-(3-ethoxy-acryloyl)urea (( )-20)
The reaction was performed under the conditions as de-
scribed for 23 using 3-ethoxy-acryloyl chloride (1.79 g,
13.2 mmol), silver cyanate (2.6 g, 17.28 mmol) in dry ben-
zene (20 ml) and the amine 6 (0.8 g, 4.32 mmol). Af-
ter evaporation of the solvents and purification by column
chromatography (silica gel, ethyl acetate/hexane 1:1) 20
(1.06 g, 75%) was obtained as a yellowish solid. – M. p.
78.9 – 79.3 ◦C. – RF(ethyl acetate/hexane 3:1) 0.45. – UV/vis
(methanol): λmax (lg ε) = 252 nm (4.29). – IR (film): ν =
3233m, 3088m, 2942s, 2868m, 2247w, 1707s, 1673s, 1606s,
1548s, 1496s, 1396m, 1346m, 1246s, 1162s, 1076m, 1060m,
1032s cm−1. – 1H NMR (400 MHz, CDCl3): δ = 9.19 (s,
1 H, OCNHCO), 8.63 (s, 1 H, NH), 7.60 (d, J = 12.30 Hz,
( )-1-[(1 RS, 2 RS)-cis-2-(2-Hydroxyethyl)cyclopropyl]-5-
methyl-1,2,3,4-tetrahydro-pyrimidine-2,4-dione (( )-22)
Compound 23 (0.6 g, 1.84 mmol) was dissolved in sulfu-
1 H, OCH=), 5.32 (d, J = 12.30 Hz, 1 H, CH=), 4.59 (dd, ric acid (2 N, 20 ml) and stirred for 2 h at 76 ◦C. After cooling
J = 12.30, 7.23 Hz, 1 H, 2ꢀꢀ-H), 3.95 (q, J = 7.13 Hz, 2 H, in an ice-bath the mixture was neutralised with NaOH (8 N)
OCH2-ethyl), 3.86 – 3.80 (m, 2 H, 6ꢀꢀ-HA, OCHA), 3.49 – and concentrated under reduced pressure. The residue was
3.44 (m, 2 H, 6ꢀꢀ-HB, OCHB), 2.79 (ddd, J = 7.37, 7.37, extracted with ethyl acetate (300 ml). The organic phase was
4.05 Hz, 1 H, 1-H), 1.82 – 1.65 (m, 3 H, 3ꢀꢀ-HA, 4ꢀꢀ-HA, dried over MgSO4 and evaporated under reduced pressure.
CHA-ethyl), 1.61 – 1.46 (m, 5 H, 3ꢀꢀ-HB, 4ꢀꢀ-HB, 5ꢀ-H2, CHB- The remaining residue was purified by column chromatog-
ethyl), 1.32 (t, J = 7.13 Hz, 3 H, CH3), 1.07 – 0.88 (m, 2 H, raphy (silica gel, ethyl acetate/methanol 10:1) to obtain 22
2-H, 3-HA), 0.28 (ddd, J = 6.44, 5.76, 3.03 Hz, 1 H, 3-HB). – (0.33 g, 85%) as a white solid. – M. p. 145.3 – 145.9 ◦C. –
13C NMR (100 MHz, CDCl3): ν = 168.13 (s, CO), 162.82 (d, RF(ethyl acetate/methanol 10:1) 0.48. – UV/vis (methanol):
OCH=), 156.44 (s, NHCONH), 98.93 (d, OC-CH=), 98.09 λmax (lg ε) = 276 nm (4.28). – IR (KBr): ν = 3491s,
(d, C-2ꢀꢀ), 67.18 (t, OCH2-ethyl), 66.99 (t, OCH2), 61.96 (t, 3148m, 3085m, 3019m, 2940m, 2885m, 2820m, 2360w,
C-6ꢀꢀ), 30.58 (t, CH2-ethyl), 28.19 (t, C-3ꢀꢀ), 26.53 (d, C- 1704s, 1652s, 1474m, 1454m, 1426m, 1399w, 1373m,
1), 25.38 (t, C-5ꢀꢀ), 19.41 (t, C-4ꢀꢀ), 14.52 (d, C-2), 14.32 1355m, 1306s, 1246w, 1192w, 1142w, 1111w, 1065m,
1
(q, CH3), 11.63 (t, C-3). – MS (EI, 70 eV): m/z (%) = 327 1032m cm−1. – H NMR (500 MHz, CDCl3): δ = 9.60 (s,
(0.4), 242 (32.9), 225 (6.4), 213 (7.1), 197 (6.8), 185 (4.3), 1 H, NH), 7.02 (s, 1 H, 6ꢀ-H ), 3.70 – 3.68 (m, 2 H, OCH2),
172 (3.6), 159 (100.0). – HRMS calcd. for C16H26N2O5: 3.12 (ddd, J = 7.41, 7.41, 4.50, 1 H, 1-H), 2.62 (s, 1 H,
326.18416; found: 326.18416. – Analysis for C16H26N2O5 OH), 1.86 (s, 3 H, CH3), 1.69 – 1.62 (m, 1 H, CHA-ethyl),
(326.39): calcd. C 58.88, H 8.03, N 8.58; found C 58.66, 1.36 – 1.30 (m, 1 H, 2-H), 1.26 – 1.21 (m, 1 H, CHB-ethyl),
H 8.25, N 8.69.
1.17 (ddd, J = 14.81, 7.36, 7.36, 1 H, 3-HA), 0.62 (ddd,
J = 6.38, 6.38, 4.67, 1 H, 3-HB). – 13C NMR (100 MHz,
CDCl3): δ = 165.34 (s, C-4ꢀ), 153.60 (s, C-2ꢀ), 142.09 (d, C-
6ꢀ), 111.47 (s, C-5ꢀ), 63.04 (t, OCH2), 36.70 (d, C-1), 31.55
(t, CH2-ethyl), 17.09 (d, C-2), 13.21 (q, CH3), 11.27 (t, C-
3). – MS (EI, 70 eV): m/z (%) = 210 (9.6), 193 (1.4), 182
(17.1), 179 (9.3), 165 (20.0), 154 (3.6), 149 (5.0), 140 (6.4),
136 (21.4), 127 (100.0). – HRMS calcd. for C10H14N2O3:
210.10043; found: 210.10043. – Analysis for C10H14N2O3
(210.23): calcd. C 57.13, H 6.71, N 13.33; found C 57.09,
H 6.80, N 12.96.
( )-1-[(1 RS, 2 RS)-cis-2-(2-Hydroxyethyl)cyclopropyl]-
1,2,3,4-tetrahydro-pyrimidine-2,4-dione (( )-21)
A solution of 20 (0.86 g, 2.63 mmol) in sulfuric acid (2 N,
20 ml) was stirred for 2 h at 75 ◦C then cooled to 5 ◦C neu-
tralised with NaOH (8 N) and concentrated under reduced
pressure. The precipitate was washed with ethyl acetate
(300 ml). The washings were dried (MgSO4), the solvent
was removed in vacuo and the residue subjected to column
chromatography (silica gel, ethyl acetate/methanol 10:1) to
afford 21 (0.37 g, 71%) as a yellowish solid. – M. p. 142.7 –
143.5 ◦C. – RF(ethyl acetate/methanol 10:1) 0.49. – UV/vis
(methanol): λmax (lg ε) = 271 nm (4.00). – IR (KBr): ν =
3412s, 3162w, 3087w, 3036m, 2932w, 2877w, 1731s, 1666s,
1462w, 1427w, 1387m, 1364w, 1306m, 1247w, 1120w,
( )-[(1 RS,2 RS)-cis-2-[2-(Tetrahydro-2H-2-pyranyl-oxy)-
ethyl]cyclopropyl]-3-(3-methoxy-2-methylacryloyl)-urea
(( )-23)
A suspension of 3-methoxy-2-methylacryloyl chloride
1058w, 1023m cm−1. – 1H NMR (500 MHz, d6-DMSO): (1.73 g, 12.86 mmol) and silver cyanate (2.3 g, 15.27 mmol)
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852
R. Csuk – A. Kern · Synthesis of Cyclopropanoid Nucleoside Analogues
in dry benzene (10 ml) was heated under reflux for 30 min. 2 H, 2-H, 3-HA), 0.23 (ddd, J = 4.83, 4.83, 2.39, 1 H, 3-
◦
The mixture was cooled to 0 C and the supernatant liquor HB). – 13C NMR (100 MHz, CDCl3): δ = 169.82 (s, CO),
was rapidly added to the amine 6 (0.8 g, 4.32 mmol). The 158.26 (d, CH), 156.25 (s, NHCONH), 107.26 (s, Cq), 98.78
solution was stirred for 20 h at room temperature and con- (d, C-2ꢀꢀ), 67.03 (t, OCH2), 61.87 (t, C-6ꢀꢀ), 61.12 (q, OCH3),
centrated. The residue was purified by column chromatogra- 30.48 (t, CH2-ethyl), 28.09 (t, C-3ꢀꢀ), 26.42 (d, C-1), 25.29
phy (silica gel, ethyl acetate/hexane 1:1) to yield 23 (0.95 g, (t, C-5ꢀꢀ), 19.30 (t, C-4ꢀꢀ), 14.26 (d, C-2), 11.56 (t, C-3),
67%) as a yellowish solid. – M. p. 93.3 – 94.0 ◦C. – RF(ethyl 8.50 (q, CH3). – MS (EI, 70 eV): m/z (%) = 327 (0.7), 242
acetate/hexane 1:1) 0.18. – UV/vis (methanol): λmax (lg ε) = (21.4), 225 (6.1), 211 (4.3), 197 (2.9), 159 (65.0), 116 (8.2),
259 nm (4.27). – IR (KBr): ν = 3362m, 3258s, 3072w, 2947s, 100 (14.3), 99 (100.0). – HRMS calcd. for C16H26N2O5:
2870m, 2786w, 2651w, 2361w, 1687s, 1659s, 1543s, 1489s, 326.18416; found: 326.18415. – Analysis for C16H26N2O5
1455s, 1405m, 1370m, 1296s, 1247s, 1159s, 1078s, 1068m, (326.39): calcd. C 58.88, H 8.03, N 8.58; found C 58.80,
1036s, 1024m cm−1
–
1H NMR (400 MHz, CDCl3): δ = H 8.15, N 8.32.
9.07 (s, 1 H, OCNHCO), 8.79 (brs, 1 H, NH), 7.40 (d, J =
1.17, 1 H, CH=), 4.54 (dd, J = 7.42, 7.42, 1 H, 2ꢀꢀ-H), 3.83 –
3.74 (m, 2 H, 6ꢀꢀ-HA, OCHA), 3.80 (s, 3 H, OCH3), 3.46 –
3.39 (m, 2 H, 6ꢀꢀ-HB, OCHB), 2.74 (ddd, J = 7.37, 7.37,
4.05, 1 H, 1-H), 1.78 – 1.72 (m, 1 H, 4ꢀꢀ-HA), 1.70 (s, 3 H,
CH3), 1.68 – 1.63 (m, 2 H, 3ꢀꢀ-HA, CHA-ethyl), 1.60 – 1.42
(m, 5 H, 3ꢀꢀ-HB, 4ꢀꢀ-HB, 5ꢀ’-H2, CHB-ethyl), 0.99 – 0.87 (m,
Acknowledgements
Financial support by the European Communities (SC1*-
CT92-0780) and the Fonds der Chemischen Industrie is
gratefully acknowledged. We like to thank Dr. K. Mohr and
Mrs. R. Ziehn for their help with the HPLC separations and
Dr. D. Stro¨hl for his help with the NMR spectra.
[6] R. Csuk, A. Kern, Tetrahedron 55, 8409 (1999).
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(1970).
[8] N. Gauvry, F. Huet, Tetrahedron 55, 1321 (1999).
[9] R. Csuk, R. Y. von Scholz, Tetrahedron 51, 7193
(1995).
[1] A. D. Borthwick, K. Biggadike, K. Tetrahedron 48, 571
(1992).
[2] G. A. Jacobs, J. A. Tino, R. Zahler, Tetrahedron Lett. 30,
6955 (1989).
[3] G. R. Geen, M. R. Harnden, M. Parrat, J. Bioorg. Med.
Chem. Lett. 1, 347 (1991).
[10] P. Herdewijn, J. Balzarini, E. De Clercq, J. Vander-
haeghe, J. Med. Chem. 28, 1385 (1985).
[4] M. G. Lee, J. F. Du, M. W. Chun, C. K. Chu, J. Org.
Chem. 62, 1991 (1997).
[5] R. Csuk, Y. von Scholz, Tetrahedron 52, 6383 (1996).
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