G. R. Geen et al. / Tetrahedron Letters 42 (2001) 1781–1784
1783
Scheme 4. (a) 1 M NaOH (aq), rt, 3 h, (87%); (b) DIBAL-H (15 equiv.), THF, rt, 48 h, (10%).
Scheme 5. (a) (i) BSA, DMF, rt, 1.5 h; (ii) 6, TMS–OTf, DMF, 0–5°C, 3 h, (81%); (b) NaOH, H2O, dioxan, rt, 4 h, (42%); (c)
(i) DIBAL-H (10 equiv.), THF, rt, 24 h; (ii) Ac2O, NEt3, DMAP, CH2Cl2, reflux, 2 h, (24%); (d) H2 (1 atm), 5% Pd/C, NEt3,
EtOAc, 50°C, 4 h, (81%) (see ref. 15).
In conclusion, we have developed a highly regioselective
alkylation of guanines and 2-aminopurines using 2-
acetoxytetrahydrofurans resulting in the formation of
intermediates which furnish famciclovir and penciclovir
after reductive cleavage of the tetrahydrofuran ring. It
appears that the regioselectivity of the alkylation is
influenced by both the substrate and the solvent in a
rather subtle manner, and is not simply dependent on
solvent polarity as has previously been suggested. This
work may have further applicability to the synthesis of
other purine nucleosides. The yields of acyclic purines
obtained from the reductive cleavage reactions are
modest at present, and additional work will be required
to optimise this stage.
5. The N-9 and N-7 isomers were separated by chromatog-
raphy and the position of alkylation determined by nmr.
Selected analytical data for 7b: lH (DMSO-d6) 2.13 (s,
3H, CH3), 2.35–2.72 (m, 2H, tetrahydrofuryl CH2), 2.92–
3.13 (m, 1H, tetrahydrofuryl CH), 3.84, 4.02, 4.12, 4.30
(4dd, 2H, tetrahydrofuryl CH2O), 4.33–4.47 (m, 2H,
CH2O), 6.14, 6.23 (2dd, 1H, tetrahydrofuryl CHO), 7.54
(dd, 2H, 2×aromatic CH), 7.67 (dd, 1H, aromatic CH),
7.99 (dd, 2H, 2×aromatic CH), 8.08, 8.15 (2s, 1H, H-8);
lC (DMSO-d6) 24.7 (CH3), 33.9 (tetrahydrofuryl CH2),
37.0, 38.3 (tetrahydrofuryl CH), 65.2, 65.5 (CH2O), 70.3,
70.5 (tetrahydrofuryl CH2O), 84.1 (tetrahydrofuryl
CHO), 120.1 (C-5), 128.7 (2×aromatic CH), 129.1 (2×aro-
matic CH), 129.5 (aromatic C), 133.3 (aromatic CH),
136.7, 136.9 (C-8), 148.9, 149.2 (C-4), 150.6 (C-2), 157.5
(C-6), 165.5 (C6 OPh), 174.3 (C6 OCH3); HRMS (ES) calcd
References
for [C19H20N5O5+H]+: 398.1464; found: 398.1501.
6. Selected analytical data for 7a: lH (DMSO-d6) 2.31–2.60
(m, 2H, tetrahydrofuryl CH2), 2.89–3.10 (m, 1H, tetra-
hydrofuryl CH), 3.79–4.29 (m, 2H, tetrahydrofuryl
CH2O), 4.29–4.51 (m, 2H, CH2O), 6.06, 6.14 (2dd, 1H,
tetrahydrofuryl CHO), 6.45 (br s, 2H, NH2), 7.57 (dd,
2H, 2×aromatic CH), 7.67 (dd, 1H, aromatic CH), 7.87,
7.93 (2s, 1H, H-8), 7.99 (dd, 2H, 2×aromatic CH), 10.62
(br s, 1H, NH); lC (DMSO-d6) 33.6, 33.9 (tetrahydrofuryl
CH2), 37.0, 38.3 (tetrahydrofuryl CH), 65.3, 65.5 (CH2O),
70.2, 70.4 (tetrahydrofuryl CH2O), 83.6, 83.7 (tetra-
hydrofuryl CHO), 116.8, 116.9 (C-5), 128.7 (2×aromatic
CH), 129.1 (2×aromatic CH), 129.5 (aromatic C), 133.3
(aromatic CH), 135.3 (C-8), 150.6, 150.8 (C-4), 153.4
1. Kjellberg, J.; Johansson, N. G. Nucleosides Nucleotides
1989, 8, 225–256.
2. (a) Dudycz, L. W.; Wright, G. E. Nucleosides Nucleotides
1984, 3, 33–44; (b) Vorbru¨ggen, H.; Krolikiewicz, K.;
Bennua, B. Chem. Ber. 1981, 114, 1234–1255; (c) Vor-
bru¨ggen, H.; Ho¨fle, G. Chem. Ber. 1981, 114, 1256–1268.
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4. Selected analytical data for 6: lH (DMSO-d6) 1.93–2.42
(m, 2H, tetrahydrofuryl CH2), 1.99, 2.01 (2s, 3H, CH3),
2.77–2.87 (m, 1H, tetrahydrofuryl CH), 3.80, 4.12 (2dd,
2H, tetrahydrofuryl CH2O), 4.23–4.29 (m, 2H, CH2O),
6.23, 6.25 (2dd, 1H, tetrahydrofuryl CHO), 7.53 (dd, 2H,
2×aromatic CH), 7.68 (dd, 1H, aromatic CH), 7.98 (d,
2H, 2×aromatic CH); lC (DMSO-d6) 21.0 (CH3), 34.5,
34.9 (tetrahydrofuryl CH2), 36.2, 36.3 (tetrahydrofuryl
CH), 65.6 (CH2O), 70.2, 70.4 (tetrahydrofuryl CH2O),
98.4 (tetrahydrofuryl CHO), 128.7 (2×aromatic CH),
129.2 (2×aromatic CH), 129.6 (aromatic C), 133.4 (aro-
(C-2), 156.6 (C-6), 165.5 (C6 OPh); HRMS (ES) calcd for
[C17H18N5O4+H]+: 356.1359; found: 356.1374.
7. Garner, P.; Ramakanth, S. J. Org. Chem. 1988, 53,
1294–1298.
8. Shiragimi, H.; Koguchi, Y.; Tanaka, Y.; Takamatsu, S.;
Uchida, Y.; Ineyama, T.; Izawa, K. Nucleosides Nucle-
otides 1995, 14, 337–340.
matic CH), 169.7 (C
6 OPh), 172.0 (C6 OCH3); HRMS (EI)
calcd for [C14H16O5]+: 264.0998; found: 264.0978.