Carbocyclic 3Ј-Azidothymidine Analogues
FULL PAPER
(m, 1 H, H-1Ј), 3.76 (d, 1 H, J = 5.0 Hz, H-5Јa), 3.74 (d, 1 H, J =
5.0 Hz, H-5Јb), 2.37 (ddd, 1 H, J = 16.6 Hz, 6.0 Hz, 2.5 Hz, CHH–
C), 2.30 (ddd, 1 H, J = 16.6 Hz, 6.0 Hz, 2.5 Hz, CHH–C), 2.26–
6.94–6.90 (m, 2 H, 2 × H-5 arom.), 5.77–5.62 (m, 2 H,
2×CH=CH2), 5.42–5.25 (m, 4 H, 2×CH2 benzyl), 5.07–4.99 (m, 4
H, 2×CH=CH2), 4.96–4.87 (m, 2 H, 2×H-1Ј), 4.31–4.21 (m, 2 H,
2.20 (m, 2 H, H-3Ј, H-6Јa), 2.10–2.00 (m, 2 H, H-4Ј, H-2Јa), 1.99 2×H-5Јa), 4.20–4.11 (m, 2 H, 2×H-5Јb), 2.28 (s, 3 H, 3-CH3), 2.27
(dd, 1 H, J = 2.5 Hz, 2.5 Hz, CH alkyne), 1.98–1.93 (m, 1 H, H-
2Јb), 1.93 (d, 3 H, J = 1.2 Hz, H-7), 1.73–1.63 (m, 1 H, H-6Јb)
ppm. 13C NMR (101 MHz, CDCl3): δ = 164.3 (C-4), 151.3 (C-2),
137.3 (C-6), 111.4 (C-5), 82.7 (Cq alkyne), 70.2 (CH alkyne), 64.5
(C-5Ј), 55.1 (C-1Ј), 45.4 (C-4Ј), 38.7 (C-3Ј), 36.7 (C-2Ј), 35.2 (C-
(s, 3 H, 3-CH3), 2.26–2.20 (m, 4 H, 2×H-6Јa, 2×CH2–CH=), 2.10–
1.98 (m, 4 H, 2×H-4Ј, 2×H-3Ј), 1.91 (d, 3 H, J = 1.0 Hz, H-7),
1.91 (d, 3 H, J = 1.0 Hz, H-7), 1.88–1.81 (m, 4 H, 2×2Ј-CH2),
1,65–1.55 (m, 2 H, 2×H-6Јb) ppm. 13C NMR (101 MHz, CDCl3):
δ = 163.7 (C-4), 151.2 (C-2), 146.8 (C-2 arom), 136.8 (C-6), 136.2
(CH=CH2), 136.1 (CH=CH2), 131.7 (C-6 arom.), 128.6 (C-1
arom.), 124.4 (C-4 arom.), 123.3 (C-5 arom.), 122.7 (C-3 arom.),
117.5 (CH=CH2), 117.5 (CH=CH2), 111.6 (C-5), 70.7 (d, J =
6.0 Hz, 5Ј-CH2), 70.6 (d, J = 5.5 Hz, 5Ј-CH2), 69.0 (d, J = 6.6 Hz,
CH2 benzyl), 54.6 (C-1Ј), 54.6 (C-1Ј), 44.1 (d, J = 2.5 Hz, H-4Ј),
44.0 (d, J = 2.5 Hz, H-4Ј), 39.5 (CH2–CH=), 39.5 (CH2–CH=),
39.0 (C-3Ј), 36.2 (C-2Ј), 36.2 (C-2Ј), 35.4 (C-6Ј), 35.3 (C-6Ј), 15.8
(3-CH3), 15.8 (3-CH3), 13.0 (C-7) ppm. 31P NMR (162 MHz,
CDCl3): δ = –8.3, –8.4 ppm; UV: λmax = 263.9 nm (MeCN). IR
6Ј), 23.7 (CH –C), 13.0 (C-7) ppm. IR (KBr): ν = 3430, 3300, 3040,
˜
2
2925, 1685, 1470, 1430, 1395, 1370, 1270, 1130, 1040, 630, 590,
490, 420 cm–1. HRMS-FAB: m/z calcd. for C14H18N2O3 [M + H]:
263.1396; found: 263.1408.
Synthesis of the cycloSal-phosphate triesters: General Procedure
The nucleoside is dissolved in dry pyridine and 5 pieces of activated
molecular sieves (3 Å) are added. The mixture is cooled to –40 °C
under a nitrogen atmosphere and the 3-methyl-cycloSal-phosphor-
chloridate (1.23 in toluene) is added dropwise over a period of
2 hrs. Stirring is continued for an additional 0.5 hrs at –40 °C. The
reaction is warmed to room temperature and the pyridine is evapo-
rated off. The crude is purified by chromatography on a chromato-
tron (CH2Cl2/MeOH gradient 0–10%) to yield the cycloSal-phos-
phate triesters as colourless foams. After lyophilization (CH3CN/
H2O, 1:1) the products are obtained as colourless cottons.
(KBr): ν = 3440, 3180, 3060, 2950, 1685, 1470, 1395, 1300, 1190,
˜
1020, 940, 780 cm–1. HRMS-FAB: m/z calcd. for C22H27N2O6P [M
+ H]: 447.1685; found: 447.1691. HPLC: tR = 13.96, 14.17 min.
3-Methyl-cyclosSaligenyl-(6Ј-carba-2Ј,3Ј-dideoxy-3Ј-propargyl-
thymidinyl)monophosphate (3-Me-cycloSal-carba-3Ј-propargyl-
dTMP) (11): The reaction has been carried out according to the
described general procedure with nucleoside 6 (40.0 mg,
0.152 mmol), pyridine (400 µL) and 3-methyl-cycloSal-phosphor-
chloridate (260 µL). Yield: 46.0 mg, (69%) as a mixture of two dia-
stereomers. Rf (TLC) = 0.56 (CH2Cl2/MeOH, 9:1). 1H NMR
(500 MHz, CDCl3): δ = 8.31 (m, 2 H, 2×NH), 7.20–7.15 (m, 2 H,
2×H-6 arom.), 7.05–7.00 (m, 2 H, 2×H-4 arom.), 7.00 (q, 1 H, J
= 1.0 Hz, H-6), 6.99 (q, 1 H, J = 1.0 Hz, H-6), 6.94–6.90 (m, 2 H,
2×H-5 arom.), 5.43–5.25 (m, 4 H, 2×CH2 benzyl), 4.99–4.90 (m,
2 H, 2×H-1Ј), 4.34–4.19 (m, 4 H, 2×5Ј-CH2), 2.40–2.30 (m, 4 H,
2×CH2–C), 2.28 (s, 6 H, 2×3-CH3), 2.26–2.15 (m, 6 H, 2×H-3Ј,
2×H-4Ј, 2×H-6Јa), 2.09–2.00 (m, 2 H, 2×H-2Јa), 1.96 (dd, 1 H,
J = 2.5 Hz, 2.5 Hz, CH alkyne), 1.95 (dd, 1 H, J = 2.5 Hz, 2.5 Hz,
CH alkyne), 1.95–1.92 (m, 2 H, 2×H-2Јb), 1.92 (d, 6 H, J = 1.0 Hz,
2×H-7), 1.70–1.60 (m, 2 H, 2×H-6Јb) ppm. 13C NMR (101 MHz,
CDCl3): δ = 164.7 (C-4), 151.0 (C-2), 145.4 (C-2 arom.), 136.9 (C-
6), 131.7 (C-6 arom.), 129.1 (C-1 arom.), 124.4 (C-4 arom.), 123.3
(C-5 arom.), 121.0 (d, J = 2.0 Hz, C-3 arom.), 120.9 (d, J = 2.4 Hz,
C-3 arom.), 111.7 (C-5), 81.8 (Cq alkyne), 81.8 (Cq alkyne), 70.7
(CH alkyne), 70.7 (CH alkyne), 70.3 (d, J = 6.0 Hz, C-5Ј), 70.1 (d,
J = 6.0 Hz, C-5Ј), 69.1 (d, J = 6.8 Hz, CH2 benzyl), 54.8 (C-1Ј),
43.44 (C-4Ј), 43.4 (C-4Ј), 38.3 (C-3Ј), 38.2 (C-3Ј), 36.0 (C-2Ј) 36.0
(C-2Ј), 35.0 (C-6Ј), 35.2 (C-6Ј), 23.5 (CH2–C), 23.4 (CH2–C), 15.8
(3-CH3), 13.0 (C-7) ppm. 31PNMR (162 MHz, CDCl3): δ = –8.3,
3-Methyl-cycloSaligenyl-(3Ј-azido-6Ј-carba-2Ј,3Ј-dideoxythymidin-
yl)monophosphate (3-Me-cycloSal-carba-AZTMP) (9): The reac-
tion has been carried out according to the described general pro-
cedure with nucleoside 3 (50.0 mg, 0.19 mmol), pyridine (500 µL)
and 3-methyl-cycloSal-phosphorchloridate (330 µL). Yield:
72.0 mg, (85%) as a mixture of two diastereomers. Rf (TLC) = 0.62
(CH2Cl2/MeOH, 9:1) 1H NMR (500 MHz, CDCl3): δ = 8.70 (br.
s, 2 H, 2 ×NH), 7.19–7.16 (m, 2 H, 2×H-6 arom.), 7.05–7.01 (m,
2 H, 2×H-4 arom.), 6.97 (q, 1 H, J = 1.0 Hz, H-6), 6.95 (q, 1 H,
J = 1.0 Hz, H-6), 6.94–6.90 (m, 2 H, 2×H-5 arom.), 5.42–5.30 (m,
4 H, 2×CH2 benzyl), 4.85–4.77 (m, 2 H, 2×H-1Ј), 4.26 (ddd, 1 H,
J = 10.8 Hz, 6.8 Hz, 4.6 Hz, H-5Јa), 4.22–4.19 (m, 2 H, 5Ј-CH2),
4.17 (ddd, 1 H, J = 10.8 Hz, 7.7 Hz, 5.2 Hz, H-5Јb), 4.12–4.09 (m,
2 H 2×H-3Ј), 2.23 (s, 6 H, 2×3-CH3), 2.22–2.11 (m, 6 H, 2×H-
4Ј; 2×H-6Јa, 2×H-2Јa), 2.10–2.04 (m, 2 H, 2×H-2Јb), 1.85 (d, 6
H, J = 1.0 Hz, 2×H-7), 1.74–1.68 (m, 2 H, 2×H-6Јb) ppm. 13C
NMR (101 MHz, CDCl3): δ = 163.9 (C-4), 151.0 (C-2), 150.9 (C-
2), 148.9 (C-2 arom.), 137.9 (C-6), 137.9 (C-6), 131.8 (C-6 arom.),
128.4 (C-1 arom.), 128.3 (C-1 arom.), 124.5 (C-4 arom.), 124.5 (C-
4 arom.), 123.3 (C-5 arom.), 122.4 (C-3 arom.), 69.2 (d, J = 6.5 Hz,
CH2 benzyl), 69.2 (d, J = 6.5 Hz, CH2 benzyl), 68.8 (d, J = 6.0 Hz,
C-5Ј), 68.7 (d, J = 5.6 Hz, C-5Ј), 62.0 (C-3Ј), 62.0 (C-3Ј), 56.0 (C-
1Ј), 56.0 (C-1Ј), 36.5 (C-2Ј), 36.4 (C-2Ј), 32.1 (C-6Ј), 32.0 (C-6Ј),
15.8 (3-CH3), 12.9 (C-7) ppm. 31P NMR (162 MHz, CDCl3): δ = –
–8.4 ppm; UV: λmax = 264.5 nm (MeCN). IR (KBr): ν = 3440,
˜
3245, 3050, 2950, 1685, 1470, 1370, 1300, 1190, 1020, 940, 870,
820, 780, 650, 590, 480, 420 cm–1. HRMS-FAB: m/z calcd. for
8.7, –8.8 ppm; UV: λmax = 262.8 nm (CH CN); IR (KBr): ν = 3440,
˜
3
3180, 3050, 2950, 2105, 1690, 1470, 1270, 1295, 1190, 1020, 940,
C22H25N2O6P [M + H]: 445.1529; found: 445.1523. HPLC: tR
13.21, 13.35 min.
=
870, 820, 770, 650, 495, 415 cm–1. HRMS-FAB: m/z calcd. for
C19H22N5O6P [M + H]: 448.1386; found: 448.1397. HPLC: tR
13.05, 13.20 min.
=
3-Methyl-cycloSaligenyl-(6Ј-carba-2Ј,3Ј-dideoxythymidinyl)mono-
phosphate (3-Me-cycloSal-carba-ddTMP) (12): The reaction has
been carried out according to the described general procedure with
nucleoside 7 (45.0 mg, 0.20 mmol), pyridine (500 µL) and 3-methyl-
cycloSal-phosphorchloridate (350 µL). Yield: 63.0 mg, (78%) as a
mixture of two diastereomers. Rf (TLC) = 0.54 (CH2Cl2/MeOH,
9:1) 1H NMR (400 MHz, CDCl3): δ = 8.44 (br. s, 2 H, 2×NH),
7.19–7.15 (m, 2 H, 2 × H-6 arom.), 7.05–7.00 (m, 4 H, 2 × H-6,
3-Methyl-cycloSaligenyl-(3Ј-allyl-6Ј-carba-2Ј,3Ј-dideoxythymidin-
yl)monophosphate (3-Me-cycloSal-carba-3Ј-allyl-dTMP) (10): The
reaction has been carried out according to the described general
procedure with nucleoside 5 (50.0 mg, 0.19 mmol), pyridine
(500 µL) and 3-methyl-cycloSal-phosphorchloridate (330 µL).
Yield: 55.0 mg, (65%) as a mixture of two diastereomers. Rf (TLC)
= 0.57 (CH2Cl2/MeOH, 9:1). 1H NMR (400 MHz, CDCl3): δ = 2×H-4 arom.), 6.94–6.98 (m, 2 H, 2×H-5 arom.), 5.41–5.25 (m, 4
8.36 (br. s, 2 H, 2×NH), 7.20–7.15 (m, 2 H, 2×H-6 arom.), 7.05– H, 2×CH2 benzyl), 4.93–4.84 (m, 2 H, 2×H-1Ј), 4.25–4.12 (m, 4
7.00 (m, 3 H, 2×H-4 arom., H-6), 6.99 (q, 1 H, J = 1.0 Hz, H-6), H, 2×5Ј-CH2), 2.46–2.35 (m, 2 H, 2×H-4Ј), 2.29 (s, 3 H, 3-CH3),
Eur. J. Org. Chem. 2006, 932–940
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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