1774 Bull. Chem. Soc. Jpn., 75, No. 8 (2002)
Precursor of Spiro Carbocylic Nucleosides
(50 mL) and the combined organic phase was washed with brine,
then dried over MgSO4. The solvent was removed under vacuum
and the residue was chromatographed on silica gel (AcOEt/pen-
tane 5:95) to afford the diastereoisomeric mixture 16 (1R:1S =
1:1) as an oil (720 mg, 89%). TLC (AcOEt/pentane 3:97): Rf
0.33. 1H NMR: vide infra. 13C NMR (62 MHz, CDCl3) δ −5.4,
−4.7, −4.6 (4 C, Si(CH3)2), 18.0, 18.3 (2 C, SiC(CH3)3), 25.8,
25.9 (6 C, SiC(CH3)3), 28.4, 30.4 (C-5), 38.2, 38.6 (C-2), 39.9,
40.9 (C-1), 49.1, 50.8 (CH3O), 51.6, 51.7 (C-4), 62.7, 64.0 (C-6),
74.0, 74.6 (C-3), 176.4, 176.7 (CwO). MS (DCI, NH3 + isobu-
tane) m/z 403 [M]+. Anal. Calcd for C20H42O4Si2: C 59.65, H
10.51%; Found: C 59.13, H 10.42%.
SiC(CH3)3), 25.9, 26.0 (6 C, SiC(CH3)3), 33.8 (C-5), 43.0 (C-2),
48.9 (C-1), 50,2 (C-4), 63.4 (C-5), 66.4 (CH2Ar), 73.3 (C-3),
127.9, 128.3, 136.6 (arom. C), 155.5 (CwO). MS (FAB+, glycer-
ol) m/z 494 [M+H]+. Calcd for C26H47N1O4Si2: C 63.24, H 9.59 ,
N 2.84% ; Found: C 63.20 H 9.54 , N 2.89%.
Data for the (1S)-isomer: TLC (CH2Cl2): Rf 0.40. [α]2D5 = +
1
25.3 (c 1.02, CHCl3). H NMR (200 MHz, CDCl3) δ 0.01, 0.03,
0.04, 0.05 (4s, 12 H, SiCH3), 0.84, 0.86 (2s, 18 H, SiC(CH3)3),
1.45–2.70 (m, 2 H, H-5, H-2), 1.72–1.98 (m, 2 H, H-2, H-4), 2.17
(m, 1 H, H-5), 3.31 (dd, J = 6.9, 9.9 Hz, 1 H, H-6), 3.50 (dd, J =
5.1, 9.9 Hz, 1 H, H-6), 4.05–4.25 (m, 2 H, H-1 and H-3), 5.06 (s, 2
H, CH2), 5.65 (m, 1 H, NH), 7.25–7.35 (m, 5 H, arom. H). MS
(FAB+, glycerol) m/z 494 [M+H]+.
In order to determine the relative configuration at C-1 for each
diastereoisomer, a pure sample of each isomer (1R)-16 and (1S)-
16 was obtained by two successive chromatographies (using AcO-
Et/pentane 3:97 for the first column, CH2Cl2 for the second col-
umn). The compounds (1R)-16 and (1S)-16 were separately char-
acterized by 1H NMR 1D, NOE, and 2D COSY experiments.
(+)-(1R,3S,4R)-3-Hydroxy-4-(hydroxymethyl)cyclopentyl-
amine ((+)-8). To a solution of (1R)-17 (140 mg, 0.284 mmol)
in THF (2 mL) was added a solution of 1 M TBAF in THF (0.70
mL). This solution was stirred at r.t. for 3.5 h. The solvent was
then removed under reduced pressure and the resulting residue
was chromatographed three times on silica gel (MeOH/CH2Cl2
10:90) in order to remove residual TBAF. The intermediate ben-
zyl carbamate was thus obtained as a white powder (55 mg, 72%):
mp 86–88 °C. TLC (MeOH/CH2Cl2 10:90): Rf 0.28. [α]2D5 +10.5
(c 0.82, CHCl3). IR (KBr) 3390, 3339, 3281, 2960, 1680, 1537,
1
Data for the isomer (1R)-16: TLC (CH2Cl2): Rf 0.59. H NMR
(300 MHz, CDCl3) δ 0.01 (s, 12 H, Si(CH3)2), 0.84, 0.86 (2s, 18
H, SiC(CH3)3), 1.48 (m, 1 H, H-5), 1.79 (m, 1 H, H-2), 1.85–2.05
(m, 2 H, H-2, H-4), 2.13 (m, 1 H, H-5), 2.99 (m, 1 H, H-1), 3.48
(d, J = 5.8 Hz, 2 H, H-6), 3.64 (s, 3 H, CH3O), 4.12 (m, 1 H, H-3).
1
Data for the isomer (1S)-16: TLC (CH2Cl2): Rf 0.53. H NMR
1352, 1284, 1267, 1218, 1155, 1036 cm−1 1H NMR (250 MHz,
.
(300 MHz, CDCl3) δ 0.01 (s, 12 H, Si(CH3)2), 0.84, 0.86 (2s, 18
H, SiC(CH3)3), 1.68 (m, 1 H, H-5), 1.83 (m, 1 H, H-2), 1.95 (m, 1
H, H-4), 2.05–2.15 (m, 2 H, H-2, H-5), 2.13 (m, 1 H, H-5), 2.62
(m, 1 H, H-1), 3.53 (d, J = 4.3 Hz, 2 H, H-6), 3.64 (s, 3 H, CH3O),
3.97 (m, 1 H, H-3).
CDCl3) δ 1.16 (m, 1 H, H-5), 1.62 (m, 1 H, H-2), 1.72–2.10 (m, 3
H, H-2, H-4 and OH), 2.10–2.30 (m, 2 H, H-5 and OH), 3.58 (dd,
J = 7.9, 10.3 Hz, 1 H, H-6), 3.79 (dd, J = 4.7, 10.3 Hz, 1 H, H-6),
4.11, 4.28 (m, 2 H, H-1 and H-3), 4.92 (m, 1 H, NH), 5.05 (s, 2 H,
CH2), 7.22–7.35 (2s, 5 H, arom. H). 13C NMR (62.5 MHz,
CDCl3) δ 34.3 (C-5), 41.5 (C-2), 48.7 (C-4), 49.6 (C-1), 63.8 (C-
6), 66.4 (CH2Ar), 73.6 (C-3), 127.9, 128.4, 136.5 (arom. C), 155.9
(CwO). MS (FAB−, glycerol) m/z 264 [M−H]. Anal. Calcd for
C14H19NO4: C 63.38, H 7.22, N 5.28%; Found: C 63.22 H 7.52, N
5.08%.
A solution of the above benzyl carbamate (48 mg, 0.19 mmol)
in MeOH (2 mL) was vigorously stirred for 2 h at r.t. under H2 at-
mosphere with Pd/C-10% (20 mg). This suspension was then fil-
tered on celite and the solid was thoroughly washed with MeOH.
The filtrate was concentrated under reduced pressure and the oily
residue was dried under high vacuum to afford (+)-8 as an oil (24
mg, 99%). [α]2D5 +30.8 (c 0.86, DMF). (lit.7b [α]2D5 +31.0 (c 1.0,
DMF)). 1H NMR (300 MHz, MeOD-d4) δ 1.14 (m, 1 H, H-5),
1.69 (m, 1 H, H-2), 1.82–2.05 (m, 2 H, H-2 and H-4), 2.21 (m, 1
H, H-5), 3.43–3.60 (m, 3 H, H-6 and H-1), 4.04 (m, 1 H, H-3).
13C NMR (75 MHz, MeOD-d4) δ 37.3 (C-5), 43.9 (C-2), 51.0 (C-
4), 51.3 (C-1), 64.7 (C-6), 74.6 (C-3). MS (IE) m/z 131 [M]+, 114
[M − OH], 100 [M − CH2OH], 96 [M − 2OH], 72, 69, 56, 44.
Benzyl (+)-(1R, 3S, 4R)-N-[3-(t-Butyldimethylsiloxy)-4-(t-
butyldimethylsiloxymethyl)cyclopentyl]carbamate (17).
A
solution of the diastereoisomeric mixture 16 (680 mg, 1.7 mmol)
in ethanolic KOH (310 mg in 17 mL) was stirred at 30 °C for 20 h.
The solvent was then removed under vacuum and the resulting
residue was dissolved in Et2O (100 mL). This solution was cooled
at 4 °C, then washed with a solution of 0.05 M HCl (100 mL).
The aqueous phase was extracted three times with Et2O, and the
combined organic phase was dried over MgSO4. The solvent was
then removed under reduced pressure to give the intermediate
crude acid (660 mg, 99%).
To a solution of the above acid in toluene (17 mL) were added
at 0 °C, diphenoxyphosphoryl azide (0.42 mL) and Et3N (0.28
mL). The mixture was stirred at 0 °C for 30 min, then at r.t. for 1
h, and finally at 80 °C for 2 h. The solution was cooled at 10 °C
and benzyl alcohol (0.40 mL) and dibutyltin dilaurate (40 µL)
were added. This solution was stirred at 80 °C for 3 h, then at 100
°C for 30 min. After being cooled to r.t., the mixture was diluted
with Et2O. The organic phase was washed with a solution of 1 M
NaHCO3. The aqueous phase was extracted three times with
Et2O, the combined organic phase was washed with brine, and
then dried over MgSO4. The solvent was removed under reduced
pressure and the resulting residue was chromatographed on silica
gel (CH2Cl2, three successive columns) to afford the (1R)-isomer
17 (201 mg, 27%) and the (1S)-isomer (220 mg, 31%), both as
oils.
References
1
a) C. Périgaud, G. Gosselin, and J.-L. Imbach, Nucleosides
Nucleotides, 11, 903 (1992). b) E. De Clercq, Nucleosides Nucle-
otides, 13, 1271 (1994).
2
M. Nakajima, K. Itoi, Y. Takamatsu, T. Kinoshita, T.
Okazaki, K. Kawakubo, M. Shindo, T. Honma, M. Tohjigamori,
and T. Haneishi, J. Antibiot., 44, 293 (1991).
Data for the (1R)-isomer 17: TLC (CH2Cl2): Rf 0.33. [α]2D5
1
+26.4 (c 0.97, CHCl3). H NMR (200 MHz, CDCl3) δ 0.01, 0.03,
3
a) D. R. Heim, C. Cseke, B. C. Gerwick, M. G. Murdoch,
0.04, 0.05 (4s, 12 H, SiCH3), 0.84, 0.86 (2s, 18 H, SiC(CH3)3),
1.23 (m, 1 H, H-5), 1.65–2.10 (m, 3 H, H-2, H-4), 2.16 (m, 1 H,
H-5), 3.55 (m, 2 H, H-6), 4.05–4.22 (m, 2 H, H-1 and H-3), 5.06
(s, 2 H, CH2), 7.25–7.35 (m, 5 H, arom. H). 13C NMR (62 MHz,
CDCl3) δ −5.3, −4.7, −4.4 (4 C, SiCH3), 18.0, 18.5 (2 C,
and S. B. Green, Pestic. Biochem. Physiol., 53, 138 (1995). b) D.
L. Siehl, M. V. Subramanian, E. W. Walters, S.-F. Lee, R. J.
Anderson, and A. G. Toschi, Plant Physiol., 110, 753 (1996). c)
R. Fonné-Pfister, P. Chemla, E. Ward, M. Girardet, K. E. Kreuz, R.
B. Honzatko, H. J. Fromm, H.-P. Schär, M. G. Grütter, and S. W.