The Journal of Organic Chemistry
NOTE
The yellow oil was then recrystallized in petroleum ether to afford
compound (+)-4 (1.37 g, 2.95 mmol, 72%) as a white powder.
Recrystallization from ethanol afforded the pure product as a solid: mp
152ꢀ154 °C; [α]20D +85 (c 1, MeOH); 1H NMR (CDCl3) δ 7.11 (m,
1H, H-5), 6.05 (d, 1H, NH, J = 9.6 Hz), 5.53 (s, 1H, H-3), 4.02 (m, 1H,
H-7), 3.79 (s, 3H, OCH3), 3.45 (m, 2H, H-3a, H-1 menthyl), 3.32 (m,
1H, H-7a), 2.56 (m, 1H, H-6), 2.22ꢀ2.08 (m, 2H, menthyl), 2.03 (m,
1H, H-60), 1.72ꢀ1.59 (m, 3H, menthyl), 1.40ꢀ1.22 (m, 2H, menthyl),
1.45 (s, 9H, C(CH3)3), 1.04ꢀ0.97 (m, 2H, menthyl), 0.95 (d, 3H,
menthyl, J = 6.5 Hz), 0.89 (d, 3H, menthyl, J = 6.5 Hz), 0.76 (d, 3H,
menthyl, J = 6.8 Hz); 13C NMR (CDCl3) δ 177.7 (CdO), 165.6
(CdO), 155.2 (CdO), 141.7 (C-5), 126.3 (C-4), 103.2 (C-1), 79.7
(C(CH3)3 Boc), 52.0 (OCH3), 47.6 (C-1 menthyl), 44.7 (C-3a), 43.5
(C-7), 40.8 (C-7a), 39.5 (CH2 menthyl), 34.2 (CH2 menthyl), 31.3 (CH
Menthyl), 28.9 (C-6), 28.3 (C(CH3)3 Boc), 25.5 (CH menthyl), 23.0
(CH2 menthyl), 22.2 (CH(CH3)2), 20.8 (CH(CH3)2), 15.9 (CH3
menthyl). Anal. Calcd for C25H39NO7: C, 64.49; H, 8.44; N, 3.01.
Found: C, 64.29; H, 8.75; N, 2.97.
N-tert-Butoxycarbonyl((1R,5R,6S)-4,5,6-tris(hydroxymethyl)-
cyclohex-3-en-1-yl)amine (6). To a stirred, cooled (ꢀ78 °C)
solution of adduct (+)-4 (1.56 g, 3.35 mmol) in dry toluene (8 mL)
was added dropwise DIBAL-H (1 M in toluene, 29 mL, 29.00 mmol)
under argon atmosphere. The reaction mixture was stirred for 3 h at the
same temperature, warmed to rt for 24 h, and then treated with a 1.2 M
aqueous solution of Rochelle’s salts (potassium sodium tartrate salts)
(60 mL). After vigorous stirring for 3 h, the toluene layer was removed,
and then water was added to the residue. The aqueous layer was
extracted with cyclohexane (3 ꢁ 50 mL) and then continuously
extracted with EtOAc for 12 h. The combined organic layers were dried
over MgSO4, filtered, and concentrated to give compound 6 (546.00 mg,
1.91 mmol, 57% crude) as a colorless oil: 1H NMR (CDCl3) δ 5.89 (s,
1H, NH), 5.80 (m, 1H, dCH), 4.16ꢀ3.66 (m, 10H, CH2OH and
ꢀCHNHBoc), 2.61ꢀ2.55 (m, 1H, ꢀCHCH2OH), 2.44ꢀ2.31 (m, 1H,
ꢀCH2ꢀ), 2.28ꢀ2.19 (m, 1H, ꢀCHCH2OH), 2.10ꢀ1.98 (m, 1H,
ꢀCH2ꢀ), 1.43 (s, 9H, C(CH3)3); 13C NMR (CDCl3) δ 156.5
(CdO), 136.2 (dC), 126.7 (dCH), 79.4 (C(CH3)3), 66.0 (C-7),
60.4 (CH2OH), 60.2 (CH2OH), 45.9 (CHNBoc), 42.4 (CH), 41.3
(CH), 30.7 (CH2), 28.4 (C(CH3)3).
(+)-N-tert-Butoxycarbonyl((1R,5R,6S)-4,5,6-tris(acetyloxy-
methyl)cyclohex-3-en-1-yl)amine ((+)-7). A solution of crude 6
(546 mg, 1.91 mmol), acetic anhydride (30 mL), and DMAP (100 mg,
0.82 mmol) in pyridine (15 mL) was stirred for 24 h at rt under argon
atmosphere. Evaporation of the solvents under reduced pressure
followed by column chromatography on silica gel (cyclohexane/EtOAc
8/2) afforded compound (+)-7 (705 mg, 1.70 mmol, 90%, 51% from
(+)-4) as a colorless oil: [α]20D +22 (c 1.75, CHCl3); 1H NMR (CDCl3)
δ 5.89ꢀ5,85 (m, 1H, dCH), 5.50 (d, 1H, NH, J = 8.5 Hz), 4.56 (d, 1H,
dCCH2OAc, J = 12.6 Hz), 4.49 (d, 1H, CH2OAc, J = 12.6 Hz), 4.35
(dd, 1H, CH2OAc, J = 6.2, 12.2 Hz), 4.21 (dd, 1H, CH2OAc, J = 6.7, 11.
Hz), 4.16ꢀ4.06 (m, 2H, CH2OAc), 4.05ꢀ3.95 (m, 1H, CHNHBoc),
2.89ꢀ2.81 (m, 1H, CH), 2.54ꢀ2.37 (m, 2H, CH and CH2), 2.16ꢀ2.03
(m, 1H, CH2), 2.11 (s, 3H, OAc), 2.07 (s, 3H, OAc), 2.05 (s, 3H, OAc),
1.44 (s, 9H, Boc); 13C NMR (CDCl3) δ 170.8 (CdO, OAc), 170.6
(CdO, OAc), 170.2 (CdO, OAc), 155.4 (CdO, Boc), 130.9 (dC),
128.4 (dCH), 79.4 (C(CH3)3), 66.5 (CH2OAc), 62.6 (CH2OAc), 61.8
(CH2OAc), 45.2 (CHNHBoc), 38.1 (CH), 36.8 (CH), 31.0 (CH2),
28.4 (C(CH3)3), 20.9 (3 ꢁ CH3 OAc); HRMS calcd for C20H32NO8
[M + H]+ 414.2128, found 414.2133.
of the organic phase (MgSO4), filtration, and then evaporation afforded
compound 8 (580 mg, 1.85 mmol, 95% crude) as a pale yellow oil: 1H
NMR (CDCl3) δ 5.81ꢀ5.69 (m, 1H, =CH), 4.48 (m, 2H, =CCH2OAc),
4.31 (dd, 1H, CH2OAc, J = 5.2, 11.4 Hz), 4.22 (d, 2H, CH2OAc, J = 6.5
Hz), 4.05 (dd, 1H, CH2OAc, J = 7.5, 11.4 Hz), 3.27ꢀ3.07 (m, 1H,
CHNHBoc), 2.82ꢀ2.64 (m, 1H, CH), 2.41ꢀ2.09 (m, 3H, CH and
CH2), 2.01 (s, 3H, OAc), 1.99 (s, 3H, OAc), 1.98 (s, 3H, OAc).
(+)-((1R,5R,6S)-4,5,6-Tris(hydroxymethyl)cyclohex-3-en-1-
yl)adenine ((+)-12). A solution of amine 8 (0.305 g, 0.974 mmol),
N-(2,6-dichlorophenyl)formamide 9 (0.380 g, 1.999 mmol), and Et3N
(0.8 mL, 5.730 mmol) in dry dioxane (6 mL) was refluxed for 12 h under
argon atmosphere. After evaporation of the solvent, the mixture was
dissolved in diethoxymethyl acetate (10 mL), heated at 120 °C for 24 h,
and then concentrated. The residue was dissolved in MeOH (6 mL), and
then 30% aqueous NH4OH solution (0.6 mL) was added. After being
stirred for 1 h, the mixture was concentrated. The crude product 11 was
taken in a saturated methanolic ammonia solution (40 mL), and the
mixture was heated at 80 °C for 24 h in steel bomb under 11 bar.
Evaporation of the solvent and then column chromatography on silica gel
(EtOAc/MeOH: 90/10 to 80/20) afforded compound (+)-12 (0.060 g,
0.197 mmol, 20%) as a pale yellow solid: [α]20D +60 (c 0.64, MeOH); 1H
NMR (CD3OD) δ 8.22 (s, 1H, CHdN), 8.21 (s, 1H, CHdN),
5.95ꢀ5.91 (m, 1H, dCH), 4.94ꢀ4.86 (m, 1H, CHNHBoc), 4.21 (d,
1H, dCCH2OH, J = 13.0 Hz), 4.11 (d, 1H, dCCH2OH, J = 13.0 Hz),
3.79 (dd, 1H, CH2OH), 3.72 (dd, 1H, CH2OH), 3.69 (dd, 1H,
CH2OH), 3.58 (dd, 1H, CH2OH), 3.04ꢀ2.89 (m, 2H, CH),
2.71ꢀ2.58 (m, 2H, CH2); 13C NMR (CD3OD) δ 158.8 (CNH2),
155.1 (NCHdN), 152.4 (CdCN), 142.8 (NCHdN), 140.8 (dCCH2-
OH), 124.9 (CHd), 121.7 (CdCN), 66.9 (dCCH2OH), 63.4 (CH2-
OH), 60.6 (CH2OH), 56.0 (CHNH), 44.9 (CH), 44.6 (CH), 29.6
(CH2); HRMS calcd for C14H20N5O3 [M + H]+ 306.1566, found
306.1578.
(+)-((1R,5R,6S)-4,5,6-Tris(acetyloxymethyl)cyclohex-3-en-
1-yl)-3-((E)-3-methoxy-2-methylacryloyl)urea ((+)-14). A so-
lution of 3-methoxy-2-methylacryloyl chloride12 (0.418 g, 3.1 mmol)
and silver cyanate (0.8 g, 5.3 mmol, previously dried in vacuo over P2O5
at 100 °C for 3 h in the dark), in dry benzene (3.3 mL), was refluxed for
30 min and then cooled to 0 °C. The supernatant liquor was added
dropwise to a solution of amine 8 (0.360 g, 1.100 mmol) in dry DMF
(4 mL) at ꢀ15 °C. The reaction mixture was stirred at ꢀ15 °C for 2 h
and then at rt overnight. The solvents were removed under reduced
pressure, and the residue was purified by column chromatography on
silica gel (cyclohexane/EtOAc 1/1) to afford compound (+)-14 (0.240
g, 0.539 mmol, 49%) as a colorless oil: [α]20D +9 (c 2.7, CHCl3); 1H
NMR (CD3OD) δ 9.08 (d, 1H, NH, J = 8.3 Hz), 7.79 (br s, 1H,
(CO)NH(CO)), 7.31 (d, 1H, MeOCHd, J = 1.3 Hz), 5.87ꢀ5.83 (m,
1H, dCH), 4.52 (br s, 2H, dCCH2OAc), 4.35ꢀ4.08 (m, 5H, CHNH,
CH2OAc), 3.86 (s, 3H, OCH3), 3.04ꢀ2.95 (m, 1H, CH), 2.62ꢀ2.56
(m, 1H, CH), 2.55ꢀ2.45 (m, 1H, CH2), 2.18ꢀ2.03 (m, 1H, CH2), 2.12
(m, 3H, OAc), 2.07 (m, 3H, OAc), 2.05 (m, 3H, OAc), 1.77 (d, 3H,
CH3thymine, J = 1.3 Hz); 13C NMR (CD3OD) δ 171.2 (OCOCH3),
170.7 (OCOCH3), 170.6 (OCOCH3), 169.3 (NCONH), 158.5
(MeOCHd), 154.1 (HNCO), 131.5 (dCCH2OAc), 127.9 (CHd),
107.3 (CH3Cd), 66.4 (dCCH2OAc), 63.2 (CH2OAc), 61.5 (CH2-
OAc, OCH3), 47.3 (CHNH), 38.9 (CH), 37.5 (CH), 29.3 (CH2), 20.9
(OCOCH3), 8.8 (CH3thymine); HRMS calcd for C21H31N2O9 [M + H]+
455.2033, found 455.2030.
(+)-((1R,5R,6S)-4,5,6-Tris(hydroxymethyl)cyclohex-3-en-
1-yl)thymine ((+)-15). A solution of urea (+)-14 (0.170 g, 0.397
mmol) in a 1/1 mixture of 30% aqueous NH4OH solution and MeOH
(30 mL) was heated at 100 °C in a sealed tube for 24 h. Evaporation of
the solvents then column chromatography on silica gel (CH2Cl2/
MeOH 95/5 to 85/15) led to compound (+)-15 (0.059 g, 0.199 mmol,
((1R,5R,6S)-4,5,6-Tris(acetyloxymethyl)cyclohex-3-en-1-yl)-
amine (8). To a stirred, cooled (0 °C) solution of compound 7 (801
mg, 1.94 mmol) in dry CH2Cl2 (10 mL) was added TMSOTf (0.70 mL,
5.53 M, 3.87 mmol) under argon atmosphere. The reaction mixture was
stirred at the same temperature for 4 h and then treated with a saturated
aqueous solution of NaHCO3 (35 mL). Extraction with CH2Cl2, drying
50%) as a colorless oil: [α]20 +70 (c 0.55, MeOH); 1H NMR
D
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dx.doi.org/10.1021/jo2012708 |J. Org. Chem. 2011, 76, 8059–8063