The Journal of Organic Chemistry
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= 3.0, 11.5 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 12.6, 13.1,
13.3, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 48.2, 55.5, 58.4, 64.7, 70.7, 75.0;
HRMS (EI) calcd for (C18H36O5Si2 + H)+ 389.2180, found 389.2171.
(+)-(6aS,6bR,7aR,8R,8aR)-8-Fluoro-2,2,4,4-tetraisopropyl-
hexahydrooxireno[2′,3′:3,4]cyclopenta[1,2-f ][1,3,5,2,4]-
trioxadisilocine (12). To a solution of compound 11 (11.5 g, 29.6
mmol) in anhydrous dichloromethane (DCM) was added dieth-
ylaminosulfur trifluoride (DAST; 19.0 mL, 118.5 mmol) slowly at −20
°C, and the mixture was warmed to room temperature with stirring for
30 min. The reaction mixture was quenched with ice−water at −20
°C, the organic layer was collected, and the aqueous phase was
extracted with DCM (200 mL × 2). The combined organic layers were
dried over Na2SO4, and the solvent was removed under reduced
pressure. The crude residue was purified by flash silica gel column
chromatography (1% EtOAc/99% hexane) to give 12 (6.1 g, 53.0%) as
an oil: [α]24D = +3.58° (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ
0.93−1.12 (m, 28H), 2.15−2.19 (m, 1H), 3.39 (s, 1H), 3.56 (dd, J =
1.5, 3.0 Hz, 1H), 4.03−4.11 (m, 2H), 4.15−4.18 (m, 1H), 4.86−4.98
(ddd, J = 1.5, 5.5, and 52.0 Hz, 1H); 19F NMR (500 MHz, CDCl3) δ
−201.73 (dd, J = 21.0, 52.5 Hz, 1F); 13C{1H} NMR (125 MHz,
CDCl3) δ 12.6, 13.1, 13.3, 16.9, 17.01, 17.06, 17.13, 17.4, 17.6, 29.7,
47.6 (d, J = 6.2 Hz), 52.5 (dd, J = 7.2, 20.5 Hz), 54.9, 64.2 (d, J = 17.6
Hz), 75.5 (d, J = 19.5 Hz), 100.4 (dd, J = 28.1, 187.8 Hz); HRMS (EI)
calcd for (C18H35FO4Si2 + H)+ 391.2136, found 391.2131.
1H), 4.47 (dd, J = 4.5, 13.5 Hz, 1H), 4.65 (dt, J = 8.0, 55.0 Hz, 1H),
5.16 (d, J = 2.5 Hz, 1H), 5.35 (s, 1H); 19F NMR (500 MHz, CDCl3) δ
−195.8 (dt, J = 17.5, 59.5 Hz, 1F); 13C{1H} NMR (100 MHz, CDCl3)
δ 12.5, 12.7, 13.3, 13.4, 16.88, 16.89, 16.95, 17.06, 17.37, 17.43, 17.54,
49.1 (d, J = 6.1 Hz), 63.7, 73.7 (d, J = 19.1 Hz), 74.6 (d, J = 21.4 Hz),
102.3 (d, J = 189.7 Hz), 111.5, 144.9 (d, J = 9.1 Hz); HRMS (EI)
(C19H37FO4Si2 + H)+ 405.2293, found 405.2287.
(+)-9-[(1′R,2′R,3′R,4′R)-2′-Fluoro-3′,4′-methyl[1,3,5,2,4]-
trioxadisilocine-5′-methylenecyclopentan-1′-yl]-6-N,N-diboca-
denine (15). To a stirred solution of triphenylphosphine (1.4 g, 5.56
mmol), in THF (20 mL) at −10 °C, was added DIAD (1.12 mL, 5.56
mmol) dropwise, the reaction mixture was stirred at this temperature
for 30 min, and then a solution of N,N-diBoc-protected adenine (1.5 g,
4.46 mmol) in THF (10 mL) was added; this mixture was stirred for
30 min at 0 °C. Compound 14 (0.75 g, 1.85 mmol) in THF (5 mL)
was then added, and the reaction mixture was stirred for 3 h at room
temperature. The solvent was removed under reduced pressure, and
the residue was purified by silica gel column chromatography (EtOAc/
hexane 1/20 to 1/10) to give 15 (0.87 g, 65%) as a colorless oil:
[α]26D = +15.6° (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 0.95−
1.06 (m, 28H), 1.36 (s, 18H), 2.61−2.69 (m, 1H), 3.94 (dd, J = 7.5,
11.5 Hz, 1H), 4.15 (dd, J = 4.5, 11.5 Hz, 1H), 4.47−4.53 (ddd, J = 4.0,
6.0, and 20.5 Hz, 1H), 4.81 (s, 1H), 4.93 (t, J = 6.0 Hz, 1H), 4.99 (dt, J
= 4.5, 52.5 Hz, 1H), 5.82 (dd, J = 4.5, 19.5 Hz, 1H), 8.07 (d, J = 2.0
Hz, 1H), 8.80 (s, 1H); 19F NMR (500 MHz, CDCl3) δ −192.9 (dt, J =
21.0, 56.5 Hz, 1F); 13C{1H} NMR (125 MHz, CDCl3) δ 12.4, 13.1,
13.2, 13.4, 16.90, 16.94, 17.0, 17.3, 17.4, 17.6, 21.7, 21.9, 27.7, 50.1,
69.9, 75.1, 84.4, 111.5, 128.2, 143.7, 144.8, 150.0, 153.8; HRMS (EI)
calcd for (C34H56FN5O7Si2 + H)+ 722.3781, found 722.3770.
(−)-(6aR,8R,9R,9aR)-9-Fluoro-2,2,4,4-tetraisopropyl-7-meth-
ylenehexahydrocyclopenta[f ][1,3,5,2,4]trioxadisilocin-8-ol
(13). To a suspension of trimethylsulfonium iodide (30.5 g, 138.4
mmol) in THF (150 mL) at −20 °C was added n-BuLi (2.5 M
solution in hexane; 55.3 mL, 138.4 mmol). After 30 min, the epoxide
12 (6.0 g, 15.5 mmol) in THF (30 mL) was introduced at −20 °C and
the reaction mixture was slowly warmed to 0 °C over 1 h. The mixture
was then stirred at ambient temperature for 2 h, quenched with water,
and then extracted with ethyl acetate (200 mL × 3). The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (10% EtOAc/90% hexane) to give
(+)-9-[(1′R,2′R,3′R,4′R)-2′-Fluoro-3′-hydroxy-4′-(hydroxy-
methyl)-5′-methylenecyclopentan-1′-yl]adenine (FMCA, 1). To
a solution of compound 15 (1.0 g, 1.38 mmol) in THF was added
trifluoroacetic acid (0.10 mL, 1.80 mmol), and the mixture was stirred
for 16 h at ambient temperature. To this reaction mixture was added
tetrabutylammonium fluoride (TBAF, 1 M solution in THF) (1.3 mL,
1.38 mmol), and this mixture was stirred at room temperature for 16 h.
The solvent was removed under reduced pressure; the residue was
dissolved in a mixture of isopropyl alcohol and chloroform (4/1, 200
mL) and washed with water (2 × 50 mL). The organic layer was
collected, dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (methanol/DCM 0.2/10 to 0.6/10) to give 1 (0.33 g, 85%)
as a white solid: mp 215−218 °C; [α]25D = +152.10° (c 0.5, MeOH);
UV (H2O) λmax 259.0 nm (ε 14000, pH 2), 260.0 nm (ε 15600, pH 7),
the allylic alcohol 13 (5.1 g, 81%) as an oil: [α]26 = −0.54° (c 0.5,
D
1
MeOH); H NMR (500 MHz, CDCl3) δ 0.93−1.08 (m, 28H), 2.01
(dd, J = 2.0, 5.5 Hz, 1H, OH), 2.54−2.59 (m, 1H), 3.84 (dd, J = 9.0,
11.0 Hz, 1H), 4.08 (dd, J = 5.0, 12.0 Hz, 1H), 4.43−4.49 (m, 2H),
4.73 (dt, J = 9.0, 52.0 Hz, 1H), 5.09 (s, 1H), 5.34−5.35 (m, 1H); 19F
NMR (500 MHz, CDCl3) δ −202.9 (ddd, J = 14.0, 21.0, and 56.0 Hz,
1F); 13C{1H} NMR (100 MHz, CDCl3) δ 12.5, 12.9, 13.4, 13.5, 16.9,
17.0, 17.3, 17.43, 17.47, 17.6, 50.1 (d, J = 4.0 Hz), 65.4, 72.5 (d, J =
17.4 Hz), 97.3 (d, J = 185.0 Hz), 111.9, 146.8; HRMS (EI) calcd for
(C19H37FO4Si2 + H)+ 405.2293, found 405.2287.
1
260.0 nm (ε 15600, pH 11); H NMR (500 MHz, CD3OD) δ 2.81
(bs, 1H), 38.1−3.91 (m, 2H), 4.44 (dt, J = 3.0, 14.0 Hz, 1H), 4.95 (s,
1H), 4.96 (dt, J = 2.5, 52.5 Hz, 1H), 5.46. (s, 1H), 5.90 (d, J = 25.0 Hz,
1H), 8.10 (d, J = 2.5 Hz, 1H), 8.26 (s, 1H); 19F NMR (500 MHz,
DMSO-d6) δ −192.93 (ddd, J = 14.0, 28.0, and 56.0 Hz, 1F); 13C{1H}
NMR (125 MHz, CD3OD) δ 51.0, 57.5 (d, J = 17.4 Hz), 61.7, 72.9 (d,
J = 23.6 Hz), 95.9 (d, J = 184.0 Hz), 111.7, 117.9, 141.1, (d, J = 5.3
Hz), 146.0, 149.9, 152.5, 156.0. Anal. Calcd for C12H14FN5O2: C,
51.61; H, 5.05; N, 25.08; Found: C, 51.74; H, 5.09; N, 24.92.
(−)-(6aR,8S,9R,9aR)-9-Fluoro-2,2,4,4-tetraisopropyl-7-meth-
ylenehexahydrocyclopenta[f ][1,3,5,2,4]trioxadisilocin-8-ol
(14). To a stirred solution of allylic alcohol 13 (5 g, 12.3 mmol) was
added the Dess−Martin periodinane reagent (7.8 g, 18.5 mmol) at 0
°C. The mixture was warmed to ambient temperature and stirred for l
h. The mixture was then passed through a Celite bed, and the filtrate
was concentrated under reduced pressure to give a crude allylic ketone,
which was used as such in the next step without further purification.
The crude ketone (4.5 g, 11.1 mmol) was dissolved in anhydrous
methanol, the solution was cooled to −78 °C, CeCl3·7H2O (5.5 g,
14.7 mmol) was added at −78 °C, and then after 10 min of stirring,
NaBH4 (0.54 g, 14.3 mmol) was added in one portion. After 15 min of
stirring at −78 °C, the reaction mixture was warmed to 0 °C, a
saturated solution of ammonium chloride (30 mL) and a 10% aqueous
solution of acetic acid were added, and then the mixture was allowed
to stand for 1 h with stirring. The organic solvent was removed under
reduced pressure, and the residue was extracted with DCM (200 mL ×
2). The combined DCM extracts were washed with brine (50 mL ×
2), dried (anhydrous Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash silica gel column
(−)-(6aR,8S,9S,9aR)-8-Bromo-9-fluoro-2,2,4,4-tetraisoprop-
yl-7-methylenehexahydrocyclopenta[f ][1,3,5,2,4]trioxadisilo-
cine (16). To a stirred solution of compound 13 (0.5 g, 1.23 mmol) in
dry DCM was added carbon tetrabromide (1.63 g, 4.9 mmol),
followed by the addition of triphenylphosphine (1.29 g, 4.9 mmol) at 0
°C. The mixture was warmed to room temperature and stirred for 3 h.
The reaction mixture was neutralized with triethylamine and passed
through a small bed of silica gel. The filtrate was concentrated under
reduced pressure, and the residue was purified by flash silica gel
column chromatography (4% EtOAc/96% hexane) to give allyl
1
bromide 16 (0.49 g, 86%) as an oil: H NMR (500 MHz, CDCl3) δ
0.93−1.01 (m, 28H), 2.65−2.63 (m, 1H), 3.87 (dd, J = 4.5, 14.0 Hz,
1H), 3.96 (dd, J = 4.0, 12.0 Hz, 1H), 4.11−4.07 (m, 1H), 4.60 (ddd, J
= 2.0, 6.5, and 17.0 Hz, 1H), 4.95 (dt, J = 6.5, 54.5 Hz, 1H), 5.22 (d, J
= 2.0 Hz, 1H), 5.40 (s, 1H); 19F NMR (500 MHz, CDCl3) δ −187.0
(dt, J = 17.5, 56.0 Hz, 1F); 13C{1H} NMR (125 MHz, CDCl3) δ
11.50, 11.53, 11.7, 11.8, 12.2, 12.4, 15.8, 15.9, 16.02, 16.05, 16.2, 16.3,
chromatography (5% EtOAc/95% hexane) to give compound 14 (4.3
1
g, 86%) as an oil: [α]26 = −88.1° (c 0.5, MeOH); H NMR (500
D
MHz, CDCl3) δ 0.93−1.08 (m, 28H), 2.63−2.69 (m, 1H), 3.89 (dd, J
= 6.0, 11.5 Hz, 1H), 3.99 (dd, J = 4.5, 12.0 Hz, 1H), 4.19−4.26 (m,
3922
dx.doi.org/10.1021/jo500382v | J. Org. Chem. 2014, 79, 3917−3923