The Journal of Organic Chemistry
Note
THF (3.5 mL) was added 50% aqueous formic acid (50% aq.
HCOOH, 7.0 mL) dropwise at 23 °C. After stirring until 20a or 20b
was consumed, the reaction mixture was concentrated under reduced
pressure, and azeotroped with toluene. The resulting crude residue
flash column chromatography (hexanes:EtOAc, 3:2) to afford 8 (454
mg, 67%) as a white solid. TLC: (hexanes:EtOAc, 2:3), Rf = 0.19
(Anis); mp 60−63 °C; [α]25D: −75.5 (c 0.15, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.24−7.20 (m, 2H), 6.89−6.84 (m, 2H), 5.90−5.84
(m, 2H), 4.59−4.54 (m, 1H), 4.45 (s, 2H), 4.04−3.98 (m, 1H), 3.79
(s, 3H), 3.50 (dd, J = 9.2, 6.0 Hz, 1H), 3.44 (dd, J = 9.2, 6.8 Hz, 1H),
2.92−2.84 (m, 1H), 2.30 (brs, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ 159.4, 135.8, 132.4, 130.3, 129.4, 114.0, 75.2, 74.6, 73.1,
70.9, 55.4, 52.2; HRMS (ESI) m/z: [M + Na]+ Calcd for
C14H18O4Na 273.1097; Found 273.1104.
was purified by flash column chromatography (CH2Cl2
→
CH2Cl2:MeOH, 39:1) to afford 21a (126 mg, 70%) or 21b (128
mg, 86%) as a white solid. 21a: TLC: (CH2Cl2:MeOH, 9:1), Rf =
0.47 (Anis, PMA); mp 178−179 °C; [α]25D: −88.7 (c 0.21, MeOH);
1
UV (MeOH) λmax: 265.7 nm; H NMR (600 MHz, CD3OD) δ 8.71
(s, 1H), 8.64 (s, 1H), 4.52 (d, J = 14.6 Hz, 1H), 4.44 (d, J = 14.7 Hz,
1H), 4.22 (dd, J = 6.0, 1.1 Hz, 1H), 3.90 (t, J = 6.0 Hz, 1H), 2.07 (dt,
J = 13.8, 6.0 Hz, 1H), 1.76 (d, J = 14.4 Hz, 1H), 1.53 (dt, J = 7.8, 4.2
Hz, 1H), 1.34 (t, J = 4.2 Hz, 1H), 0.78−0.72 (m, 1H); 13C{1H} NMR
(100 MHz, CD3OD) δ 153.8, 153.0, 151.1, 148.9, 132.2, 77.3, 72.1,
50.1, 35.0, 33.7, 23.1, 15.0; HRMS (ESI) m/z: [M + H]+ Calcd for
C12H14ClN4O2 281.0800; Found 281.0802. 21b: TLC:
(CH2Cl2:MeOH, 9:1), Rf = 0.5 (Anis, PMA); mp 246−248 °C;
(1R,2R,3S,4S,5S)-4-(((4-Methoxybenzyl)oxy)methyl)bicyclo-
[3.1.0]hexane-2,3-diol (22). To a stirred solution of diethylzinc
(Et2Zn, 1.0 M in hexanes, 2.6 mL, 2.6 mmol, 2.0 equiv) in CH2Cl2 (5
mL) was added diiodomethane (CH2I2, 0.42 mL, 5.2 mmol, 4.0
equiv) dropwise at 0 °C. After 5 min, a solution of 8 (326 mg, 1.23
mmol, 1.0 equiv) in CH2Cl2 (3 mL) was added to the reaction
mixture, and warmed to 23 °C. After 24 h, the mixture was re-cooled
to 0 °C, and another 2.0 equiv of the Zn(CH2l)2 in CH2Cl2 was
added (preparation of Zn(CH2l)2 in CH2Cl2 as described above).
After stirring at 23 °C for 24 h, the reaction mixture was cooled to 0
°C, saturated NH4Cl aqueous solution and brine were added, and
diluted with CH2Cl2. The layers were separated, and the aqueous
layer was extracted with CH2Cl2. The combined organic layers were
dried over anhydrous MgSO4, and concentrated under reduced
pressure. The resulting crude residue was purified by flash column
chromatography (hexanes → hexanes:EtOAc, 3:2) to afford 22 (136
mg, 40%, 53% brsm) as a white solid and recovered 8 (83 mg, 25%).
1
[α]25D: −86.3 (c 0.25, MeOH); UV (MeOH) λmax: 275.3 nm; H
NMR (400 MHz, CD3OD) δ 8.62 (s, 1H), 4.51 (d, J = 14.4 Hz, 1H),
4.32 (d, J = 14.8 Hz, 1H), 4.21 (dd, J = 6.4, 1.2 Hz, 1H), 3.90 (t, J =
6.4 Hz, 1H), 2.14−2.04 (m, 1H), 1.75 (d, J = 14.0 Hz, 1H), 1.51 (dt,
J = 8.4, 4.4 Hz, 1H), 1.34 (t, J = 4.4 Hz, 1H), 0.77−0.72 (m, 1H);
13C{1H} NMR (100 MHz, (CD3)2SO) δ 153.8, 150.8, 149.3, 148.8,
130.3, 75.0, 69.9, 48.5, 33.8, 32.2, 21.0, 13.9; HRMS (ESI) m/z: [M +
H]+ Calcd for C12H13Cl2N4O2 315.0410; Found 315.0404.
(1S,2S,3R,5S)-1-((6-((3-Iodobenzyl)amino)-9H-purin-9-yl)-
methyl)bicyclo[3.1.0]hexane-2,3-diol (3a) and (1S,2S,3R,5S)-1-((2-
Chloro-6-((3-iodobenzyl)amino)-9H-purin-9-yl)methyl)bicyclo-
[3.1.0]hexane-2,3-diol (3b). To a stirred suspension of 21a (19.8 mg,
0.07 mmol, 1.0 equiv) or 21b (31.6 mg, 0.1 mmol, 1.0 equiv) in
EtOH (2 mL) were added 3-iodobenzylamine hydrochloride (3-I-Bn-
NH2-HCl, 47.3 mg for 3a or 67.9 mg for 3b, 2.5 equiv) and
triethylamine (Et3N, 0.05 mL for 3a or 0.07 mL for 3b, 5.0 equiv) at
23 °C. The reaction mixture in a sealed tube was placed under
microwave irradiation at 100 °C for 4 h. The reaction mixture was
concentrated under reduced pressure. The resulting crude residue was
TLC: (hexanes:EtOAc, 3:2), Rf = 0.17 (Anis); mp 57−58 °C; [α]25
:
D
1
+10.0 (c 0.23, CHCl3); H NMR (600 MHz, CDCl3) δ 7.23−7.21
(m, 2H), 6.88−6.84 (m, 2H), 4.51−4.45 (m, 1H), 4.43 (s, 2H),
3.87−3.83 (m, 1H), 3.78 (s, 3H), 3.42 (dd, J = 9.6, 6.0 Hz, 1H), 3.34
(dd, J = 9.0, 6.6 Hz, 1H), 2.28−2.24 (m, 1H), 2.19 (brs, 2H), 1.58−
1.53 (m, 1H), 1.19−1.15 (m, 1H), 0.92−0.88 (m, 1H), 0.49 (td, J =
7.8, 4.8 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ 159.1, 130.3,
129.1, 113.7, 74.8, 73.4, 72.8, 72.1, 55.2, 48.4, 22.5, 18.0, 7.9; HRMS
(ESI) m/z: [M + H]+ Calcd for C15H21O4 265.1434; Found
265.1434.
purified by flash column chromatography (CH2Cl2
→
CH2Cl2:MeOH, 39:1) to afford 3a (26.1 mg, 78%) or 3b (47.6 mg,
93%) as a white solid. 3a: TLC: (CH2Cl2:MeOH, 9:1), Rf = 0.50
(Anis, PMA); mp 74−75 °C; [α]25D: +49.9 (c 0.09, MeOH); UV
(1R,2R,3S,4S,5S)-4-(((4-Methoxybenzyl)oxy)methyl)bicyclo-
[3.1.0]hexane-2,3-diyl Diacetate (23). To a stirred solution of 22
(188 mg, 0.71 mmol, 1.0 equiv) in CH2Cl2 (6 mL) were added
triethylamine (Et3N, 0.6 mL, 4.3 mmol, 6.0 equiv) and 4-
dimethylaminopyridine (DMAP, 8.6 mg, 0.071 mmol, 0.1 equiv) at
23 °C. The reaction mixture was cooled to 0 °C, and acetic anhydride
(Ac2O, 0.2 mL, 2.13 mmol, 3.0 equiv) was added dropwise. After
stirring at 23 °C for 2 h, the reaction mixture was cooled to 0 °C,
saturated NaHCO3 aqueous solution was added, and diluted with
CH2Cl2. The layers were separated, and the aqueous layer was
extracted with CH2Cl2. The combined organic layers were dried over
anhydrous MgSO4, and concentrated under reduced pressure. The
resulting crude residue was purified by flash column chromatography
(hexanes → hexanes:EtOAc, 9:1) to afford 23 (188 mg, 76%) as a
1
(MeOH) λmax: 271.7 nm; H NMR (600 MHz, CD3OD) δ 8.24 (s,
1H), 8.14 (s, 1H), 7.73 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.36 (d, J =
7.8 Hz, 1H), 7.05 (t, J = 7.8 Hz, 1H), 4.75 (brs, 2H), 4.42 (d, J = 14.7
Hz, 1H), 4.26 (d, J = 14.6 Hz, 1H), 4.18 (d, J = 5.5 Hz, 1H), 3.90 (t, J
= 6.2 Hz, 1H), 2.04 (dt, J = 14.2, 5.5 Hz, 1H), 1.73 (d, J = 14.2 Hz,
1H), 1.47 (dt, J = 8.2, 4.6 Hz, 1H), 1.31 (t, J = 4.5 Hz, 1H), 0.65−
0.61 (m, 1H); 13C{1H} NMR (200 MHz, CD3OD) δ 156.6, 154.5,
151.1, 143.9, 143.6, 138.3, 138.1, 132.1, 128.6, 120.9, 95.7, 77.6, 72.8,
49.5, 45.0, 35.6, 34.7, 23.6, 15.3; HRMS (ESI) m/z: [M + H]+ Calcd
for C19H21IN5O2 478.0734; Found 478.0728. 3b: TLC:
(CH2Cl2:MeOH, 9:1), Rf = 0.54 (Anis, PMA); mp 175−176 °C;
1
[α]25D: +135.1 (c 0.09, MeOH); UV (MeOH) λmax: 273.8 nm; H
colorless oil. TLC: (hexanes:EtOAc, 3:2), Rf = 0.68 (Anis); [α]25
:
D
NMR (600 MHz, CD3OD) δ 8.11 (s, 1H), 7.77 (s, 1H), 7.59 (d, J =
7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 4.69
(brs, 2H), 4.35 (d, J = 14.4 Hz, 1H), 4.23 (d, J = 14.4 Hz, 1H), 4.17
(d, J = 6.0 Hz, 1H), 3.91 (t, J = 6.0 Hz, 1H), 2.10−2.02 (m, 1H), 1.74
(d, J = 14.4 Hz, 1H), 1.48 (dt, J = 8.4, 4.3 Hz, 1H), 1.31 (t, J = 4.2
Hz, 1H), 0.67−0.63 (m, 1H); 13C{1H} NMR (150 MHz, (CD3)2SO)
δ 154.6, 152.8, 150.2, 142.0, 141.8, 136.0, 135.5, 130.4, 126.8, 117.8,
94.6, 74.5, 70.0, 47.1, 42.4, 33.9, 32.5, 20.8, 13.6; HRMS (ESI) m/z:
[M + H]+ Calcd for C19H20ClIN5O2 512.0345; Found 512.0350.
(1S,2R,5S)-5-(((4-Methoxybenzyl)oxy)methyl)cyclopent-3-ene-
1,2-diol (8). To a stirred solution of 9 (783.1 mg, 2.7 mmol, 1.0
equiv) in MeOH (27 mL) was added 1 N HCl aqueous solution (3
mL) dropwise at 0 °C. After stirring at 50 °C for 2 h, the reaction
mixture was cooled to 0 °C, solid NaHCO3 was added for
neutralization, and diluted with EtOAc. The layers were separated,
and the aqueous layer was extracted with EtOAc. The combined
organic layers were dried over anhydrous MgSO4, and concentrated
under reduced pressure. The resulting crude residue was purified by
−9.6 (c 0.14, CHCl3); 1H NMR (600 MHz, CDCl3) δ 7.25−7.22 (m,
2H), 6.88−6.84 (m, 2H), 5.44 (t, J = 5.9 Hz, 1H), 5.09 (d, J = 6.4 Hz,
1H), 4.47−4.41 (m, 2H), 3.78 (s, 3H), 3.46−3.38 (m, 2H), 2.29 (t, J
= 4.6 Hz, 1H), 2.01 (s, 3H), 1.99 (s, 3H), 1.68−1.62 (m, 1H), 1.32−
1.27 (m, 1H), 0.90−0.86 (m, 1H), 0.59 (tdd, J = 7.8, 5.4, 1.2 Hz,
1H); 13C{1H} NMR (125 MHz, CDCl3) δ 170.4, 169.7, 159.1, 130.2,
129.1, 113.8, 74.9, 73.7, 72.9, 71.3, 55.2, 47.0, 20.87, 20.82, 19.8, 17.9,
7.9; HRMS (ESI) m/z: [M + H]+ Calcd for C19H25O6 349.1646;
Found 349.1654.
(1R,2R,3S,4S,5S)-4-(Hydroxymethyl)bicyclo[3.1.0]hexane-2,3-diyl
Diacetate (7). To a stirred solution of 23 (142 mg, 0.41 mmol, 1.0
equiv) in CH2Cl2/H2O (4.4 mL, 10:1, v/v) was added 2,3-dichloro-
5,6-dicyano-p-benzoquinone (DDQ, 110.7 mg, 0.49 mmol, 1.2 equiv)
at 23 °C. After 2 h, saturated NaHCO3 aqueous solution was added,
and diluted with CH2Cl2. The layers were separated, and the aqueous
layer was extracted with CH2Cl2. The combined organic layers were
dried over anhydrous MgSO4, and concentrated under reduced
pressure. The resulting crude residue was purified by flash column
9834
J. Org. Chem. 2021, 86, 9828−9837