The Journal of Organic Chemistry
ARTICLE
rotations were measured at ambient temperature and 589 nm. High
resolution mass spectra were performed using chemical ionization.
Melting points are uncorrected.
J = 3.2, 12.4 Hz, H-5), 4.61 (dd, 1H, J = 4.8, 12.4 Hz, H-50), 1.72 (d,
3H, J = 21.6 Hz, CH3); 13C NMR (100 MHz, CDCl3) δ 166.0, 165.8,
133.7, 133.4, 130.0, 129.7, 129.3, 128.8, 128.6, 128.5, 97.1 (d, J =
22.0 Hz), 94.8 (d, J = 209.3 Hz), 81.2, 73.4 (d, J = 15.9 Hz), 62.7, 22.8
(d, J = 25.8 Hz).
((2R,3R,4R,5R)-3-(Benzoyloxy)-4-fluoro-5-hydroxy-4-me-
thyltetrahydrofuran-2-yl)methyl Benzoate (14). To a dry 5 L
three neck round-bottom flask equipped with a mechanical stirrer,
addition funnel and thermometer were added the lactone 9 (379 g,
1.018 mol) and anhydrous THF (1.75 L). The solution was cooled to
ꢀ30 °C under a nitrogen atmosphere, and then was added a solution of
lithium tri-tert-butoxyaluminohydride (1.0 M in THF, 1.527 L, 1.527
mol), with stirring, over a period of 1 h. After completion of the addition,
the reaction mixture was allowed slowly to warm to ꢀ10 °C over 1 h
15 min. The reaction mixture was quenched with ethyl acetate (900 mL)
followed by saturated aq NH4Cl (40 mL) below 0 °C. The cloudy
supernant liquid was decanted, and the residue was washed with ethyl
acetate (2 ꢁ 200 mL) and decanted. The combined decants were
concentrated under reduced pressure to give an oily residue. The oil was
dissolved in ethyl acetate (2 L) and washed with 3 N HCl (600 mL). The
aqueous layer was back extracted with ethyl acetate (3 ꢁ 400 mL). The
combined organic layer was washed with water (3 ꢁ 800 mL), saturated
aq NaHCO3 (400 mL) and brine (400 mL). The organic layer was dried
over MgSO4, filtered and concentrated under reduced pressure to give a
light brown syrup. The residue was purified by column chromatography
(2.2 KG silica gel) using 5ꢀ30% ethyl acetate/hexanes gradient to give
lactol 10 as colorless syrup. The syrup was heated at 50 °C with seeds of
crystalline β-lactol for 20 h to give pure β-lactol 14 as a white solid
(293.8 g, 77%, β/R ratio 20:1). For 14: [R]20D = þ21 (c 1.0, MeOH);
mp 79ꢀ80 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.99 (m, 2 H), 7.93
(m, 2 H), 7.70 (m, 1 H), 7.61 (m, 1 H), 7.55 (m, 2 H), 7.42 (m, 2 H),
7.32 (d, J = 5.2 Hz, 1H), 5.54 (dd, J = 23.6, 7.2 Hz, 1H), 5.20 (dd, J =
10.8, 5.2 Hz, 1H, D2O exchangeable), 4.55ꢀ4.50 (m, 1H), 4.46ꢀ4.40
(m, 2H), 1.42 (d, J = 22.4 Hz, 3H). 13C NMR (DMSO-d6, 100 MHz) δ
166.4, 166.2, 134.9, 134.3, 130.5, 130.3, 130.2, 129.8, 129.6, 129.6, 101.2
(d, JCꢀF = 32 Hz), 101.1 (d, JCꢀF = 180 Hz), 77.1, 75.7 (d, JCꢀF = 15
Hz), 65.9, 17.6 (d, JCꢀF = 24 Hz). HRMS-ESI (m/z): calcd for
C20H19FO6 [M þ H]þ 375.1238, found 375.1243.
((2R,3R,4R,5R)-3-(Benzoyloxy)-5-bromo-4-fluoro-4-meth-
yltetrahydrofuran-2-yl)methyl Benzoate (16). To a stirred
solution of PPh3 (205.4 g, 0.783 mol) in dichloromethane (5.6 L) was
added the β-lactol 14 (209.4 g, 0.559 mol) below ꢀ20 °C under N2
atmosphere. After the mixture stirred for 15 min, CBr4 (278.2 g, 0.839
mol) was added portion-wise while maintaining the reaction tempera-
ture between ꢀ25 and ꢀ20 °C under N2 flow. After completion of the
addition, the reaction mixture was stirred below ꢀ17 °C for 20 min.
Silica gel (230 g) was added to the mixture, filtered through a pad of silica
gel (680 g) and washed with dichloromethane. The combined filtrates
were concentrated under reduced pressure at room temperature to give
colorless oil. 1H NMR of a crude sample at this stage indicated 10:1 R/β
mixture. The residue was purified by column chromatography (2.1 kg
silica gel) using 0ꢀ25% EtOAc/hexanes gradient to give 16 as colorless
oil which solidified upon standing to give waxy solid. (197 g, 81%, R/β
ratio 20:1). For 16: [R]20D = þ136 (c 1.0, CHCl3); mp 59ꢀ61 °C; 1H
NMR (CDCl3, 400 MHz) δ 8.13 (d, J = 7.2 Hz, 2H), 8.02 (d, J = 7.6 Hz,
2H), 7.63ꢀ7.56 (m, 2H), 7.50ꢀ7.42 (m, 4H), 6.34 (s, 1H), 5.29 (dd, J =
5.3, 2.8 Hz, 1H), 4.89ꢀ4.86 (m, 1H), 4.80ꢀ4.76 (m, 1H), 4.65ꢀ4.61
(m, 1H), 1.72 (d, J = 21.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz) δ
165.9, 165.7, 133.7, 133.4, 130.0, 129.6, 129.2, 128.8, 128.5, 128.5, 94.6
(d, J = 210 Hz), 92.0 (d, J = 23 Hz), 81.9, 73.3 (d, J = 15 Hz), 62.4, 22.8
(d, J = 27 Hz). HRMS-ESI (m/z): calcd for C20H18BrFO5
[M þ H]þ 437.0394, found 437.0393.
(2R,3R,4R,5S)-5-Bromo-2-(((4-chlorobenzoyl)oxy)meth-
yl)-4-fluoro-4-methyltetrahydrofuran-3-yl 4-Chlorobenzo-
ate (19). Under similar reaction conditions lactol 18 (23.5 g, 53 mmol)
gave bromide 19 (21.23 g, 79% yield, R/β ratio 65:1, contaminated with
2% of triphenylphosphine) as a white solid after crystallization of the
crude product from the mixture of ether/hexanes (3.4:1). For 19:
1
[R]20D = þ133 (c 1.0, CHCl3); mp 122ꢀ124 °C; H NMR (CDCl3,
((2R,3R,4R,5R)-3-((4-Chlorobenzoyl)oxy)-4-fluoro-5-hydr-
oxy-4-methyltetrahydrofuran-2-yl)methyl 4-Chlorobenzoate
(18). Under similar reaction conditions reduction of the lactone 17
(50 g, 113 mmol) followed by crystallization of the crude product from the
mixture of methanol/water (4.5:1) gave lactol 18 as a white solid (30.5 g,
61% yield, β/R ratio 35:1). For 18: [R]20D = þ53 (c 1.0, MeOH); mp
101ꢀ104 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.96ꢀ7.93 (m, 2H),
7.92ꢀ7.88 (m, 2H), 7.61ꢀ7.58 (m, 2H), 7.52ꢀ7.48 (m, 2H), 7.31 (dd,
J = 5.2, 0.8 Hz, 1H), 5.50 (dd, J = 24, 7.2 Hz, 1H), 5.19 (dd, J = 10.8, 5.6
Hz, 1H), 4.58ꢀ4.54 (m, 1H), 4.45ꢀ4.40 (m, 2H), 1.42 (d, J = 22.8 Hz,
3H). 13C NMR (DMSO-d6, 100 MHz) δ 165.5, 165.3, 139.8, 139.3,
132.25, 131.9, 129.9, 129.7, 129.1, 128.4, 101.1 (d, J = 31.8 Hz), 101.0 (d,
J = 179.8 Hz), 76.9, 75.9 (d, J = 15.1 Hz), 65.9, 17.6 (d, J = 23.5 Hz).
HRMS-ESI (m/z): calcd for C20H17Cl2FO6 [M þ Na]þ 465.0278,
found 465.0293.
((2R,3R,4R,5S)-3-(Benzoyloxy)-5-chloro-4-fluoro-4-meth-
yltetrahydrofuran-2-yl)methyl Benzoate (15). To a solution of
of the lactol 14 (1.0 g, 2.67 mmol) and PPh3 (1.4 g, 5.34 mmol) in
CH2Cl2 (15 mL) was added N-chlorosuccimide (1.07 g, 8.01 mmol)
portion-wise at 0 °C. Then the resulting mixture was stirred at rt for 1 h
and poured into a silica gel column and eluted with a mixture of EtOAc/
hexanes (1:4). The collected fractions were combined, concentrated
under reduced pressure, coevaporated two times with CH2Cl2 and used
in the next step without further purification (1.0 g, 95%, R/β ratio 7:1).
For major R-isomer 15: 1H NMR (400 MHz, CDCl3) δ 8.12ꢀ8.10 (m,
4H, aromatic), 8.04 (m, 4H, aromatic), 7.63ꢀ7.56 (m, 2H,
aromatic), 7.50ꢀ7.42 (m, 4H, aromatic), 6.00 (broad s, 1H, H-1),
5.27 (dd, 1H, J = 3.6, 5.6 Hz, H-3), 4.87 (m, 1H, H-4), 4.76 (dd, 1H,
400 MHz) δ 8.06ꢀ8.03 (m, 2H), 7.96ꢀ7.93 (m, 2H), 7.46ꢀ7.40 (m,
4H), 6.33 (s, 1H), 5.22 (dd, J = 5.6, 1H), 4.86ꢀ4.83 (m, 1H), 4.78ꢀ4.74
(m, 1H), 4.64ꢀ4.60 (m, 1H), 1.69 (d, J = 21.6 Hz, 3H). 13C NMR
(CDCl3, 100 MHz) δ 165.1, 164.8, 140.3, 140.0, 131.4, 131.0, 127.6,
127.1, 94.5 (d, J = 209.4 Hz), 91.8 (d, J = 23.5 Hz), 81.7, 73.5 (d, J = 15.2
Hz), 62.5, 22.8 (d, J = 26.6 Hz). HRMS-ESI (m/z): calcd for
C20H16BrCl2FO5 [M þ Na]þ 528.9412, found 528.9431.
(2R,3R,4R,5R)-5-(2-Amino-6-chloro-9H-purin-9-yl)-2-(be-
nzoyloxymethyl)-4-fluoro-4-methyltetrahydrofuran-3-yl Be-
nzoate (12). A 12 L three-neck round-bottomed flask was charged
with 6-chloro-2-aminopurine (225.4 g, 1.329 mol) followed by anhy-
drous tBuOH (4.5 L) with stirring with a mechanical stirrer. To the
above stirred solution was added potassium tert-butoxide (151.6 g, 1.35
mol) portion-wise at room temperature under N2 flow. After 30 min, a
solution of 1-R-bromo ribofuranose 16 (197 g, 0.451 mol) in anhydrous
acetonitrile (4 L) was added in one lot over a period of 5 min at room
temperature. The mixture was slowly heated to 50 °C with a heating
mantle at which temperature it was stirred for 22 h. To the reaction
mixture was added solid NH4Cl (75 g) followed by water (200 mL), and
the mixture was filtered through a short pad of Celite and washed with
toluene (3 ꢁ 200 mL). The filtrate was neutralized with 6 N HCl and
concentrated under reduced pressure to a volume of 800 mL. The
mixture was filtered through Celite to remove additional salts that were
precipitated during the concentration, washed with toluene (200 mL)
and concentrated. The residue was purified by column chromatography
(1.6 kg silica gel) using 40ꢀ45% EtOAc/hexanes gradient to give
6-chloropurine 12 as a white foamy solid (150.7 g, 64% yield, β/R ratio
14:1). A portion of the solid was crystallized from methanol to give pure
3787
dx.doi.org/10.1021/jo200060f |J. Org. Chem. 2011, 76, 3782–3790