Linear Synthesis of Chiral cycloSal-Pronucleotides
3
H-10), 4.49 (d, JH,H = 6.3 Hz, 1 H, H-14), 3.55–3.40 (m, 1 H, H-
7.32 (m, 5 H, ArH), 5.24–5.15 (m, 2 H, H-7), 4.74–4.68 (m, 1 H,
H-2), 3.67–3.50 (m, 2 H, H-5), 2.33–2.10 (m, 4 H, H-3 and H-
13), 2.95–2.85 (m, 1 H, H-13Ј), 2.21–1.85 (m, 2 H, H-11), 1.75–1.64
and 1.36–1.24 (m, 2 H, H-12) ppm. 31P NMR (162 MHz, CDCl3): δ 4) ppm. 31P NMR (162 MHz, CDCl3): δ = 53.7 ppm.
= 63.3 (major diastereoisomer), 63.7 (minor diastereoisomer) ppm.
(SC)/(SP)- and (SC)/(RP)-2-[2Ј-(Benzoxycarbonyl)pyrrolidin-1Ј-yl]-
(S)-N-Dichlorothiophosphoryl-2-proline Ethyl Ester (19): General 4H-1,3,2-benzodioxaphosphorin 2-Sulfide (24): General procedure B
procedure A with l-proline ethyl ester hydrochloride 16 (1.56 g,
8.69 mmol, 1.0 equiv.), thiophosphoryl chloride (1.33 mL, 2.21 g,
13.0 mmol, 1.5 equiv.) dissolved in dried Et2O (10 mL), and trieth-
ylamine (3.6 mL, 2.63 g, 13.0 mmol, 3.0 equiv.) dissolved in Et2O
(10 mL). The product 19 (1.55 g, 68%) was obtained as a colorless
oil. 1H NMR (400 MHz, CDCl3): δ = 4.66–4.62 (m, 1 H, H-2),
with potassium carbonate (120 mg, 0.89 mmol, 3.0 equiv.), 21
(100 mg, 0.30 mmol, 1.0 equiv.), and (40 mg, 0.30 mmol,
8
1.0 equiv.) in dried acetone (6 mL). The reaction mixture was
heated to reflux for 8 h and stirred at room temperature for 12 h.
The product 24 (70 mg, 57%, 60% de) was obtained as a colorless
oil. 1H NMR (400 MHz, CDCl3): δ (major diastereoisomer) =
3
2
3
4.22 (q, JH,H = 7.1 Hz, 2 H, H-7), 3.50–3.65 (m, 2 H, H-5), 2.31–
7.35–6.83 (m, 9 H, ArH), 5.50 (dd, JH,H = 14.0, JH,P = 7.0 Hz, 1
3
3
2
2.04 (4 H, H-3, H-4), 1.28 (t, JH,H = 7.1 Hz, 3 H, H-8) ppm. 31P H, H-4), 5.10 (s, 2 H, H-15), 4.99 (dd, JH,P = 25.1, JH,H
=
3
NMR (162 MHz, CDCl3): δ = 54.8 ppm.
14.0 Hz, 1 H, H-4Ј), 4.47 (ddd, 3JH,H = 3, 3JH,H = 5, JH,P = 9 Hz,
1 H, H-10), 3.45–3.30 (m, 2 H, H-13), 2.23–2.10 (m, 1 H, H-11),
2.00–1.92 (m, 2 H, H-11Ј), 1.92–1.80 (m, 1 H, H-12) ppm. 31P
NMR (162 MHz, CDCl3): δ = 62.4 (major diastereoisomer), 62.6
(minor diastereoisomer) ppm.
(SC)/(SP)- and (SC)/(RP)-2-[2Ј-(Ethoxycarbonyl)pyrrolidin-1Ј-yl]-4H-
1,3,2-benzodioxaphosphorin 2-Sulfide (22): General procedure B
with potassium carbonate (200 mg, 1.45 mmol, 3.8 equiv.), 19
(100 mg, 0.38 mmol, 1.0 equiv.), and
8 (48.0 mg, 0.38 mmol,
1.0 equiv.) in dried acetone (75 mL). The reaction mixture was
heated to reflux for 6 h and stirred at room temperature for 12 h.
The product 22 (60 mg, 48%, 65% de) was obtained as a yellow
oil. 1H NMR (400 MHz, CDCl3): δ (major diastereoisomer) =
N-Dichlorothiophosphoryl-2-(1Ј-methoxy-1Ј-ethylpropyl)pyrrolidine
(27): General procedure A with 25 (600 mg, 3.50 mmol, 1.0 equiv.),
thiophosphoryl chloride (1.10 mL, 1.78 g, 10.5 mmol, 3.0 equiv.)
dissolved in dried CHCl3 (10 mL), and triethylamine (534 μL,
390 mg, 3.85 mmol, 1.1 equiv.) dissolved in dried THF (10 mL).
The reaction mixture was stirred 12 h at room temperature. The
2
3
7.25–7.02 (m, 4 H, ArH), 5.58 (dd, JH,H = 14.0, JH,P = 6.6 Hz, 1
H, H-4), 5.14 (dd, 2JH,H = 14.1, 3JH,P = 24.8 Hz, 1 H, H-4Ј), 5.08–
4.46 (m, 1 H, H-10), 4.18 (q, 3JH,H = 7.0 Hz, 2 H, H-15), 3.44–3.53 product 27 (777 mg, 73%) was obtained as a colorless oil. 1H NMR
3
3
3
3
(m, 2 H, H-13), 2.27–1.92 (m, 4 H, H-11 and H-12), 1.27 (t, JH,H (400 MHz, CDCl3): δ = 4.38 (ddd, JH,H = 20.0, JH,H = 8.4, JH,P
= 7.0 Hz, 3 H, H-16) ppm. 31P NMR (162 MHz, CDCl3): δ = 60.9
= 2.5 Hz, 1 H, H-2), 3.83–3.70 (m, 1 H, H-5), 3.36–3.25 (m, 1 H,
H-5Ј), 3.23 (s, 3 H, H-9), 2.17–1.45 (m, 8 H, H-3, H-4, H-7 and H-
7Ј), 0.93 (t, 3JH,H = 7.4 Hz, 3 H, H-8), 0.85 ppm. (t, 3JH,H = 7.6 Hz,
3 H, H-8Ј). 31P NMR (162 MHz, CDCl3): δ = 64.7 ppm.
(major diastereoisomer), 63.7 (minor diastereoisomer) ppm.
(S)-N-Dichlorothiophosphoryl-2-proline Isopropyl Ester (20): Gene-
ral procedure A with l-proline isopropyl ester hydrochloride 17
(1.68 g, 8.69 mmol, 1.0 equiv.), thiophosphoryl chloride (1.33 mL,
2.21 g, 13.0 mmol, 1.5 equiv.) dissolved in dried Et2O (10 mL), and
triethylamine (3.6 mL, 2.63 g, 13.0 mmol, 3.0 equiv.) dissolved in
Et2O (10 mL). The base was added at –40 °C. The reaction mixture
was stirred 12 h at room temperature. The product 20 (1.4 g, 55%)
was obtained as a brown oil. 1H NMR (400 MHz, CDCl3): δ =
(SC)/(SP)- and (SC)/(RP)-2-[2Ј-(1ЈЈ-Ethyl-1ЈЈ-methoxypropyl)pyrrol-
idine-1Ј-yl]-4H-1,3,2-benzodioxaphosphorin 2-Sulfide (29): General
procedure B with potassium carbonate (114 mg, 0.820 mmol,
2.5 equiv.), 27 (100 mg, 0.330 mmol, 1.0 equiv.), and 8 (45 mg,
0.42 mmol, 1.1 equiv.) in dried acetone (10 mL). The reaction mix-
ture was first stirred at 0 °C and then for 12 h at room temperature.
The product 29 (93.8 mg, 80%, 90% de) was obtained as a yellow
oil. 1H NMR (400 MHz, CDCl3): δ (major diastereoisomer) =
7.53–7.45 (m, 1 H, ArH), 7.25–7.21 (m, 2 H, ArH), 7.19–7.18 (m,
3
5.10–5.02 (sept, JH,H = 6.2 Hz, 1 H, H-7), 4.63–4.59 (m, 1 H, H-
2), 3.63–3.45 (m, 2 H, H-5), 2.35–2.04 (m, 4 H, H-3 and H-4), 1.26–
1.22 (m, 6 H, H-8 and H-9) ppm. 31P NMR (162 MHz, CDCl3): δ
= 54.7 ppm.
2
3
1 H, ArH), 5.80 (dd, JH,H = 14.1, JH,P = 6.0 Hz, 1 H, H-4), 5.35
2
3
3
(dd, JH,H = 14.1, JH,P = 24.4 Hz, 1 H, H-4Ј), 4.39 (ddd, JH,H
=
(SC)/(SP)- and (SC)/(RP)-2-[2Ј-(Isopropoxycarbonyl)pyrrolidin-1Ј-yl]-
4H-1,3,2-benzodioxaphosphorin 2-Sulfide (23): General procedure B
with potassium carbonate (200 mg, 1.45 mmol, 3.8 equiv.), 20
3
3
14.2, JH,H = 8.2, JH,P = 3.9 Hz, 1 H, H-10), 4.02–3.96 (m, 1 H,
H-13), 3.41 (s, 3 H, H-17), 3.34–3.26 (m, 1 H, H-13Ј), 2.30–2.24
(m, 1 H, H-11), 2.17–1.84 (m, 6 H, H-11Ј, H-12, H-15 and H-15Ј),
(110 mg, 0.38 mmol, 1.0 equiv.), and
8 (52 mg, 0.42 mmol,
3
1.75–1.68 (m, 1 H, H-12Ј), 1.13 (t, JH,H = 7.6 Hz, 3 H), 1.06 (t,
1.1 equiv.) in dried acetone (75 mL). The reaction mixture was
heated to reflux for 6 h and stirred at room temperature for 72 h.
The product 23 (65 mg, 50%, 62% de) was obtained as a yellow
oil. 1H NMR (400 MHz, CDCl3): δ (major diastereoisomer) =
3JH,H = 7.4 Hz, 3 H) ppm. 31P NMR (162 MHz, CDCl3): δ = 66.7
(major diastereoisomer), 69.9 (minor diastereoisomer) ppm.
N-Dichlorothiophosphoryl-2-(methoxydiphenylmethyl)pyrrolidine
(28): General procedure A with 26 (0.28 g, 1.0 mmol, 1.0 equiv.),
thiophosphoryl chloride (0.31 mL, 0.51 g, 3.0 mmol, 3.0 equiv.)
dissolved in dried CHCl3 (10 mL), and triethylamine (0.15 mL,
0.11 g, 1.1 mmol, 1.1 equiv.) dissolved in dried CHCl3 (10 mL). The
2
3
7.11–7.01 (m, 4 H, ArH), 5.58 (dd, JH,H = 14.2, JH,P = 6.6 Hz, 1
2
3
H, H-4), 5.14 (dd, JH,H = 14.2, JH,P = 25.4 Hz, 1 H, H-4Ј), 5.12
(sept., 3JH,H = 6.2 Hz, 1 H, H-15), 4.53–4.41 (m, 1 H, H-10), 3.51–
3.36 (m, 2 H, H-13), 2.31–2.17 and 2.07–1.92 (m, 4 H, H-11 and H-
12), 1.21–1.15 (m, 6 H, H16) ppm. 31P NMR (162 MHz, CDCl3): δ reaction mixture was first stirred at 0 °C and then for 12 h at room
= 63.8 (major diastereoisomer), 63.7 (minor diastereoisomer) ppm.
temperature. The product 28 (160 mg, 38%) was obtained as a col-
orless liquid. 1H NMR (400 MHz, CDCl3): δ = 7.27–7.60 (m, 10
(S)-N-Dichlorothiophosphoryl-2-proline Benzyl Ester (21): General
procedure A with l-proline benzyl ester hydrochloride 18 (0.50 g,
2.1 mmol, 1.0 equiv.), thiophosphoryl chloride (0.23 mL, 0.39 g,
2.3 mmol, 1.1 equiv.) dissolved in dried Et2O (50 mL), and triethyl-
amine (0.70 mL, 4.6 mmol, 2.2 equiv.) dissolved in Et2O (50 mL).
The base was added at –40 °C. The reaction mixture was stirred
12 h at room temperature. The product 21 (0.55 g, 78%) was ob-
tained as a pale-yellow oil. 1H NMR (400 MHz, CDCl3): δ = 7.39–
3
3
3
H, ArH), 5.32 (ddd, JH,H = 16.4, JH,H = 9.0, JH,P = 3.0 Hz, 1
H, H-2), 3.70–3.50 (m, 1 H, H-5), 2.98 (s, 3 H, H-11), 2.17–1.98
(m, 3 H, H-3 and H-5Ј), 1.73–1.66 (m, 1 H, H-4), 1.43–1.33 (m,
1 H, H-4Ј) ppm. 31P NMR (162 MHz, CDCl3): δ = 61.1 (major
diastereoisomer), 66.8 (minor diastereoisomer) ppm.
(SC)/(SP)- and (SC)/(RP)-2-[2Ј-(Methoxydiphenylmethyl)pyrrolidine-
1Ј-yl]-4H-1,3,2-benzodioxaphosphorin 2-Sulfide (30): General pro-
Eur. J. Org. Chem. 2011, 4397–4408
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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