Protection of the amino group of adenosine and guanosine derivatives by elaboration into a 2,5-dimethylpyrrole moiety

Article abstract of DOI:10.1021/ol035264f

(Matrix presented) Protection of the amino group of adenine and guanine nucleosides was effected by heating the substrates in 2,5-hexanedione. The resulting 2,5-dimethylpyrrole adducts were stable toward bases but were hydrolyzed with TFA/H₂O to regenerate the amino function.

Full text of DOI:10.1021/ol035264f

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3345-3348
Protection of the Amino Group of
Adenosine and Guanosine Derivatives
by Elaboration into a
2,5-Dimethylpyrrole Moiety†
Ireneusz Nowak and Morris J. Robins*
Department of Chemistry and Biochemistry, Brigham Young UniVersity,
ProVo, Utah 84602-5700
morris_robins@byu.edu
Received July 8, 2003
ABSTRACT
Protection of the amino group of adenine and guanine nucleosides was effected by heating the substrates in 2,5-hexanedione. The resulting
2,5-dimethylpyrrole adducts were stable toward bases but were hydrolyzed with TFA/H O to regenerate the amino function.
2
Multistep syntheses of modified nucleosides depend on the
protection/deprotection of functional groups. During the
course of a synthetic scheme, which required addition of a
carbene to unsaturated nucleoside derivatives, the need arose
to mask the 6-amino group of adenosine. Usual protecting
groups that were investigated did not survive the basic
conditions employed for generation of the nucleoside alkene.
We previously elaborated the 6-amino group of adenine-type
nucleosides into a 6-(1,2,4-triazol-1-yl) moiety,1 and we
employed a modified Appel reaction for introduction of a
6-(imidazol-1-yl) group into purine nucleosides.2 However,
these triazole and imidazole heterocycles are weakly basic
enough to function as leaving groups for SNAr reactions with
nitrogen, oxygen, or sulfur nucleophiles.1,2 Elaboration of
the 6-amino function into a 2,5-dimethylpyrrole attracted our
attention because this transformation has been used for
protection of primary amines of aliphatic,3,4 aromatic,3,5
heterocyclic,3,6 and carbohydrate7,8 origin. Applications in
medicinal chemistry have included syntheses of benzolac-
tam,9 amino alcohol,4 and serotonin6 analogues, and it was
found that substitution of a pyrrole ring at C6 of a purine
derivative resulted in enhancement of biological activity.10
(3) (a) Breukelman, S. P.; Meakins, G. D.; Tirel, M. D. J. Chem. Soc.,
Chem. Commun. 1982, 800-801. (b) Breukelman, S. P.; Leach, S. E.;
Meakins, G. D.; Tirel, M. D. J. Chem. Soc., Perkin Trans. 1 1984, 2801-
2807.
(4) Kashima, C.; Maruyama, T.; Fujioka, Y.; Harada, K. J. Chem. Soc.,
Perkin Trans. 1 1989, 1041-1046.
(5) Davis, A. P.; Egan, T. J. Tetrahedron Lett. 1992, 33, 8125-8126.
(6) Macor, J. E.; Chenard, B. L.; Post, R. J. J. Org. Chem. 1994, 59,
7496-7498.
(7) Bowers, S. G.; Coe, D. M.; Boons, G.-J. J. Org. Chem. 1998, 63,
4570-4571.
(8) Yan, F.; Mehta, S.; Eichler, E.; Wakarchuk, W. W.; Gilbert, M.;
Schur, M. J.; Whitfield, D. M. J. Org. Chem. 2003, 68, 2426-2431.
(9) Sakamuri, S.; Kozikowski, A. P. Chem. Commun. 2001, 475-476.
(10) Estep, K. G.; Josef, K. A.; Bacon, E. R.; Carabateas, P M.; Rumney,
S., IV; Pilling, G. M.; Krafte, D. S.; Volberg, W. A.; Dillon, K.; Dugrenier,
N.; Briggs, G. M.; Canniff, P. C.; Gorczyca, W. P.; Stankus, G. P.; Ezrin,
A. M. J. Med. Chem. 1995, 38, 2582-2595.
† Nucleic Acid Related Compounds. 120. Paper 119: Janeba, Z.;
Francom, P.; Robins, M. J. J. Org. Chem. 2003, 68, 989-992.
(1) (a) Samano, V.; Miles, R. W.; Robins, M. J. J. Am. Chem. Soc. 1994,
116, 9331-9332. (b) Miles, R. W.; Samano, V.; Robins, M. J. J. Am. Chem.
Soc. 1995, 117, 5951-5957.
(2) Lin, X.; Robins, M. J. Org. Lett. 2000, 2, 3497-3499.
10.1021/ol035264f CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/05/2003

Table 1. Elaboration of the Amino Group in Nucleosides 1 into the 2,5-Dimethylpyrrole Moiety of Products 2a,b
a Reactions were performed by the general procedure (ref 14) unless noted otherwise. b Substrates and products had clean UV and 1H and 13C NMR
spectra and HRMS data. c Isolated yields. d Reaction performed at 130 °C.
Subsequent removal of the pyrrole ring to regenerate the
amine can be effected readily by ozonolysis or by treatment
with hydroxylamine hydrochloride. Electron-rich pyrrole
rings do not survive in the presence of oxidizing agents or
3346
Org. Lett., Vol. 5, No. 18, 2003

strong electrophiles, but their usefulness has been demon-
strated when a need exists to mask weakly acidic NH2 groups
for reactions that employ strongly basic (e.g., Grignard or
organolithium) reagents.3-6 An additional practical conse-
quence for nucleoside chemistry involves the enhanced
lipophilicity of 2,5-dimethylpyrrole derivatives, especially
with respect to the solubility of guanine-containing nucleo-
sides, which are notorious for self-aggregation by hydrogen
bonding. We now report reactions of adenine and guanine
nucleosides with 2,5-hexanedione, which give new acid-
sensitive but base-stable 2,5-dimethylpyrrole adducts for
further synthetic manipulations.
The nucleoside or sugar-protected derivative was heated
in neat 2,5-hexanedione (∼10 equiv) for 2 days. The excess
diketone was removed under oil-pump vacuum, and the
product was purified by chromatography. It is noteworthy
that this method was applied successfully to unprotected as
well as sugar-protected nucleosides (Table 1).14 The major
limitations were solubility of the nucleoside and stability of
the starting material and/or product for an extended period
at elevated temperatures. The majority of adenine and
guanine derivatives tested gave the elaborated pyrrole
products, but cytidine and its sugar-protected derivatives
failed to give the 4-(2,5-dimethylpyrrol-1-yl) adducts under
the same conditions. The apparent thermal instability of the
(CDCl3) δ 13.5, 20.3, 20.4, 20.6, 62.8, 70.3, 73.1, 80.2, 86.8, 109.0, 129.1,
129.7, 143.1, 150.4, 152.5, 152.9, 169.3, 169.5, 170.2; EI-MS m/z 471 ([M+]
20%), 470, 258, 226, 212, 139 (100%), 97; HRMS calcd for C22H25N5O7
471.1753, found 471.1756. (f) 9-[3,5-Bis-O-(tert-butyldimethylsilyl)-2-
deoxy-â-D-erythro-pentofuranosyl]-6-(2,5-dimethylpyrrol-1-yl)purine (2f).
UV (MeOH) max 283 nm (ꢀ 11 900), min 245 nm (ꢀ 3700); 1H NMR
(CDCl3) δ 0.06 (s, 3H), 0.08 (s, 3H), 0.13 (s, 6H), 0.89 (s, 9H), 0.93 (s,
9H), 2.20 (s, 6H), 2.43-2.56 (ddd, J ) 3.7, 6.2, 13.2 Hz, 1H), 2.66-2.81
(m, 1H), 3.80 (dd, J ) 3.1, 11.0 Hz, 1H), 3.89 (dd, J ) 4.0, 11.0 Hz, 1H),
4.04-4.11 (m, 1H), 4.63-4.72 (m, 1H), 5.97 (s, 2H), 6.57 (t, J ) 6.6 Hz,
1H), 8.39 (s, 1H), 8.91 (s, 1H); 13C NMR (CDCl3) δ -5.6, -5.5, -4.9,
-4.8, 13.4, 17.9, 18.3, 25.6, 25.8, 41.0, 62.6, 71.9, 84.5, 88.0, 108.7, 129.0,
129.6, 143.3, 150.0, 152.0, 152.9; EI-MS m/z 557 ([M+] 75%), 500, 368,
287, 213 (100%), 155; HRMS calcd for C28H47N5O3Si2 557.3217, found
557.3223. (g) 9-(3,5-Di-O-acetyl-2-deoxy-â-D-erythro-pentofuranosyl)-
6-(2,5-dimethylpyrrol-1-yl)purine (2g). UV (MeOH) max 283 nm (ꢀ
1
12 100), min 247 nm (ꢀ 4400); H NMR (CDCl3) δ 2.10 (s, 3H), 2.17 (s,
3H), 2.21 (s, 6H), 2.69 (ddd, J ) 2.7, 6.1, 14.2 Hz, 1H), 3.06 (ddd, J )
6.3, 7.8, 14.2 Hz, 1H), 4.37-4.48 (m, 3H), 5.47-5.50 (m, 1H), 5.99 (s,
2H), 6.55 (dd, J ) 6.3, 7.8 Hz, 1H), 8.28 (s, 1H), 8.94 (s, 1H); 13C NMR
(CDCl3) δ 13.1, 20.4, 20.5, 36.8, 63.3, 74.0, 82.3, 84.5, 108.5, 128.8, 129.3,
143.0, 149.8, 151.9, 152.6, 169.9, 170.0; FAB-MS (thioglycerol) m/z 414
([M + H+] 100%), 437 ([M + Na + H+] 15%); HRMS calcd for
C20H24N5O5 414.1777, found 414.1785. (h) 9-[2(3),5-Bis-O-(tert-butyldi-
methylsilyl)-â-D-ribofuranosyl]-6-(2,5-dimethylpyrrol-1-yl)purine (2h).
UV (MeOH) max 283 nm (ꢀ 12 200), min 244 nm (ꢀ 3900); FAB-MS m/z
573 ([M+] 100%), 516, 497, 423, 370, 343, 301; HRMS calcd for
C28H47N5O4Si2 573.3166, found 573.3173. (i) 9-(2,3-O-Isopropylidene-â-
D-ribofuranosyl)-2-(2,5-dimethylpyrrol-1-yl)purin-6-one (2i). Mp 184-
186 °C; UV (MeOH) max 254 nm (ꢀ 11 800), 276 nm (ꢀ 8600), min 232
(11) Brown, D. M.; Haynes, L. J.; Todd, A. R. J. Chem. Soc. 1950,
3299-3304.
(12) Acedo, M.; Fabrega, C.; Avino, A.; Goodman, M.; Fagan, P.;
Wemmer, D.; Eritja, R. Nucleic Acids Res. 1994, 22, 2982-2989.
(13) Forman, S. L.; Fettinger, J. C.; Pieraccini, S.; Gottarelli, G.; Davis,
J. T. J. Am. Chem. Soc. 2000, 122, 4060-4067.
(14) General Procedure. A solution of 2′,3′-O-isopropylideneadenosine
(1b) (1.0 g, 3.26 mmol) in 2,5-hexanedione (4 mL) was heated at 150-
160 °C for 2 days. Volatiles were evaporated in vacuo, and the oily residue
was dissolved in CH2Cl2 (5 mL) and deposited on silica gel. Chromatog-
raphy (EtOAc/hexanes, 1:1) gave pyrrole adduct 2b (56%) as an orange
oil.
1
(15) (a) 6-(2,5-Dimethylpyrrol-1-yl)-9-(â-D-ribofuranosyl)purine (2a).
UV (MeOH) max 284 nm (ꢀ 12 100), min 245 nm (ꢀ 4100); 1H NMR
(CDCl3) δ 2.18 (s, 6H), 3.32 (br s, 1H), 3.78 (d, J ) 12.6 Hz, 1H), 3.80 (br
s, 1H), 3.98 (dd, J ) 0.9, 12.6 Hz, 1H), 4.36 (s, 1H), 4.48 (d, J ) 5.4 Hz,
1H), 4.98 (dd, J ) 5.4, 7.3 Hz, 1H), 5.50 (br s, 1H), 5.93 (d, J ) 7.3 Hz,
1H), 5.99 (s, 2H), 8.21 (s, 1H), 8.86 (s, 1H); 13C NMR (CDCl3) δ 13.2,
62.3, 71.3, 74.1, 86.9, 90.7, 109.1, 129.4, 129.7, 145.2, 150.3, 151.6, 152.1;
EI-MS m/z 345 ([M+] 25%), 256, 213 (100%), 198; HRMS calcd for
C16H19N5O4 345.1437, found 345.1431. (b) 9-(2,3-O-Isopropylidene-â-D-
ribofuranosyl)-6-(2,5-dimethylpyrrol-1-yl)purine (2b). UV (MeOH) max
283 nm (ꢀ 12 100), min 247 nm (ꢀ 4200); 1H NMR (CDCl3) δ 1.42 (s,
3H), 1.69 (s, 3H), 2.22 (s, 6H), 3.82-3.88 (m, 1H), 4.02 (dd, J ) 12.7, 1.5
Hz, 1H), 4.60 (s, 1H), 5.17 (dd, J ) 1.5, 5.8 Hz, 1H), 5.31 (dd, J ) 4.4,
5.8 Hz, 1H), 5.46 (d, J ) 10.7 Hz, 1H), 6.00 (s, 2H), 6.03 (d, J ) 4.4 Hz,
1H), 8.22 (s, 1H), 8.93 (s, 1H); 13C NMR (CDCl3) δ 13.0, 24.7, 26.9, 62.2,
81.2, 83.6, 86.2, 92.3, 108.6, 113.6, 128.8, 129.2, 144.2, 149.8, 151.6, 152.1;
MS m/z 385 ([M+] 80%), 370, 354, 296, 213 (100%), 198; HRMS calcd
for C19H23O4N5 385.1750, found 385.1753. (c) 9-(5-O-tert-Butyldimeth-
ylsilyl-2,3-O-isopropylidene-â-D-ribofuranosyl)-6-(2,5-dimethylpyrrol-
1-yl)purine (2c). UV (MeOH) max 283 nm (ꢀ 11 700), min 245 nm (ꢀ
3400); 1H NMR (CDCl3) δ -0.02 (s, 3H), 0.00 (s, 3H), 0.81 (s, 9H), 1.42
(s, 3H), 1.66 (s, 3H), 2.18 (s, 6H), 3.81 (dd, J ) 3.7, 11.4 Hz, 1H), 3.91
(dd, J ) 3.3, 11.4 Hz, 1H), 4.50 (m, 1H), 4.96 (dd, J ) 2.2, 6.2 Hz, 1H),
5.28 (dd, J ) 2.7, 6.1 Hz, 1H), 5.96 (s, 2H), 6.28 (d, J ) 2.6 Hz, 1H), 8.34
(s, 1H), 8.94 (s, 1H); 13C NMR (CDCl3) δ -6.2, -6.1, 12.9, 17.6, 24.7,
25.2, 26.6, 63.0, 80.9, 84.4, 86.9, 91.3, 108.2, 113.3, 128.5, 129.0, 143.3,
149.4, 151.6, 152.3; EI-MS m/z 499 ([M+] 100%), 484, 442, 296, 212,
129; HRMS calcd for C25H37N5O4Si 499.2614, found 499.2621. (d) 9-(5-
O-Acetyl-2,3-O-isopropylidene-â-D-ribofuranosyl)-6-(2,5-dimethylpyr-
rol-1-yl)purine (2d). UV (MeOH) max 283 nm (ꢀ 12 100), min 247 nm (ꢀ
3900); 1H NMR (CDCl3) δ 1.39 (s, 3H), 1.63 (s, 3H), 1.98 (s, 3H), 2.18 (s,
6H), 4.27 (dd, J ) 5.9, 12.2 Hz, 1H), 4.38 (dd, J ) 4.4, 12.2 Hz, 1H),
4.49-4.53 (m, 1H), 5.05 (dd, J ) 3.9, 5.9 Hz, 1H), 5.47 (dd, J ) 2.0, 5.9
Hz, 1H), 5.95 (s, 2H), 6.21 (d, J ) 2.0 Hz, 1H), 8.18 (s, 1H), 8.92 (s, 1H);
13C NMR (CDCl3) δ 13.4, 20.5, 25.2, 27.0, 63.8, 81.2, 84.0, 84.6, 90.9,
109.0, 114.8, 129.2, 129.6, 143.7, 150.3, 152.3, 152.5, 170.2; FAB-MS
(thioglycerol) m/z 427 ([M+] 100%), 411, 367; HRMS calcd for C21H25N5O5
427.1855, found 427.1866. (e) 9-(2,3,5-Tri-O-acetyl-â-D-erythro-pento-
furanosyl)-6-(2,5-dimethylpyrrol-1-yl)purine (2e). UV (MeOH) max 283
nm (ꢀ 6200), 267 nm (ꢀ 8300); H NMR (CDCl3) δ 1.38 (s, 3H), 1.63 (s,
3H), 2.27 (s, 6H), 3.73 (d, J ) 12.2 Hz, 1H), 3.92 (d, J ) 12.2 Hz, 1H),
4.46 (s, 1H), 5.02 (d, J ) 5.9 Hz, 1H), 5.09 (dd, J ) 3.9, 5.9 Hz, 1H), 5.82
(s, 1H), 5.86 (s, 2H), 6.03 (d, J ) 3.9 Hz, 1H), 8.26 (br s, 1H), 11.30 (br
s, 1H); 13C NMR (DMSO-d6) δ 12.7, 25.1, 27.0, 61.5, 81.2, 84.1, 86.8,
89.9, 108.1, 113.1, 123.0, 129.0, 139.2, 145.4, 147.5, 157.0; EI-MS m/z
401 ([M+] 75%), 386, 268, 229 (100%), 212; HRMS calcd for C19H23O5N5
401.1699, found 401.1707. (j) 9-(5-O-tert-Butyldimethylsilyl-2,3-O-iso-
propylidene-â-D-ribofuranosyl)-2-(2,5-dimethylpyrrol-1-yl)purin-6-
one (2j). UV (MeOH) max 254 nm (ꢀ 12 800), 277 nm (ꢀ 11 000), min
1
231 nm (ꢀ 8800), 267 nm (ꢀ 10 300); H NMR (CDCl3) δ 0.057 (s, 3H),
0.063 (s, 3H), 0.87 (s, 9H), 1.37 (s, 3H), 1.61 (s, 3H), 2.31 (s, 6H), 3.80
(dd, J ) 3.4, 11.4 Hz, 1H), 3.88 (dd, J ) 2.9, 11.2 Hz, 1H), 4.40-4.43 (m,
1H), 4.86 (dd, J ) 2.4, 5.9 Hz, 1H), 5.03 (dd, J ) 2.9, 5.9 Hz, 1H), 5.91
(s, 2H), 6.12 (d, J ) 2.9 Hz, 1H), 8.08 (s, 1H), 11.90 (br s, 1H); 13C NMR
(CDCl3) δ -6.0, -5.9, 12.7, 17.9, 24.9, 25.5, 26.8, 63.2, 80.8, 84.8, 86.3,
90.6, 108.8, 113.7, 122.4, 128.8, 138.3, 145.2, 147.7, 158.1; EI-MS m/z
515 ([M+] 65%), 500, 458, 440, 400, 312 (100%), 83; HRMS calcd for
C25H37O5N5Si: 515.2564, found: 515.2569. (k) 5′-O-Acetyl-2′,3′-O-
isopropylideneguanosine (1k). Ac2O (7 mL) was added to a suspension
of 2′,3′-O-isopropylideneguanosine (3.0 g, 9.3 mmol) in dried pyridine (20
mL). The mixture was stirred at ambient temperature overnight and then
concentrated in vacuo. The residue was suspended in MeOH and deposited
on a silica gel column. Elution (EtOAc/MeOH, 10:1 f 1:1) gave material
that was recrystallized (MeOH) to give 1k (1.46 g, 43%) as a white
powder: mp > 250 °C; UV (MeOH) max 255 nm (ꢀ 14 500), min 222 nm
1
(ꢀ 2800); H NMR (DMSO-d6) δ 1.33 (s, 3H), 1.53 (s, 3H), 2.02 (s, 3H),
4.04-4.32 (m, 3H), 5.17 (dd, J ) 3.4, 6.3 Hz, 1H), 5.30 (dd, J ) 1.7, 6.1
Hz, 1H), 6.06 (d, J ) 1.8 Hz, 1H), 6.34 (br s, 2H), 7.91 (s, 1H), 10.87 (s,
1H); 13C NMR (DMSO-d6) δ 20.6, 25.3, 27.0, 64.2, 81.2, 83.7, 84.3, 88.4,
113.4, 117.0, 136.4, 150.6, 153.8, 156.9, 170.2; FAB-MS (glycerol) m/z
366 ([M + H+] 100%); HRMS calcd for C15H20O6N5 366.1413, found
366.1408. (l) 9-(5-O-Acetyl-2,3-O-isopropylidene-â-D-ribofuranosyl)-2-
(2,5-dimethylpyrrol-1-yl)purin-6-one (2k). UV (MeOH) max 254 nm (ꢀ
11 700), 277 nm (ꢀ 9900), min 232 nm (ꢀ 8600), 267 nm (ꢀ 9400); 1H
NMR (CDCl3) δ 1.37 (s, 3H), 1.61 (s, 3H), 2.00 (s, 3H), 2.30 (s, 6H), 4.22
(dd, J ) 5.4, 12.1 Hz, 1H), 4.27 (dd, J ) 3.7, 11.9 Hz, 1H), 4.87 (dd, J )
3.4, 6.3 Hz, 1H), 5.23 (dd, J ) 2.9, 6.3 Hz, 1H), 5.90 (s, 2H), 6.09 (d, J )
2.9 Hz, 1H), 7.92 (s, 1H), 11.87 (br s, 1H); 13C NMR (CDCl3) δ 12.9,
20.4, 25.9, 26.9, 63.5, 80.7, 83.8, 84.2, 90.0, 109.0, 114.8, 123.1, 129.0,
138.8, 145.5, 147.9, 158.1, 170.2; FAB-MS (glycerol) m/z 444 ([M + H+]
100%), 443 ([M+] 50%); HRMS calcd for C21H26O6N5 444.1882, found
444.1886.
1
nm (ꢀ 12 200), min 247 nm (ꢀ 4900); H NMR (CDCl3) δ 2.129 (s, 3H),
2.131 (s, 3H), 2.17 (s, 3H), 2.22 (s, 6H), 4.41 (dd, J ) 5.4, 12.2 Hz, 1H),
4.48-4.52 (m, 2H), 5.73 (t, J ) 5.1 Hz, 1H), 5.99 (s, 2H), 6.01 (d, J ) 5.2
Hz, 1H), 6.27 (d, J ) 4.9 Hz, 1H), 8.23 (s, 1H), 8.95 (s, 1H); 13C NMR
Org. Lett., Vol. 5, No. 18, 2003
3347

cytidine adducts was suggested by darkening of the color of
the reaction mixtures and formation of insoluble resins on
the surface of the flask. Analogous darkening and resin
formation was observed with reactions of 3′,5′-bis-O-(tert-
butyldimethylsilyl)-2′-deoxyadenosine (1f) (entry 6), as was
anticipated for a more thermally labile deoxynucleoside.
However, in this case the pyrrole adduct 2f was obtained in
15% yield (along with 28% of recovered starting material)
when the reaction was conducted at 130 °C for 2 days.
Protection of the sugar hydroxyl groups as acetyl esters
rather than as silyl ethers resulted in slightly higher yields
when the temperature was controlled at e150 °C (entry 7).
Although the TBS protecting group improves solubility, its
hydrolytic stability under prolonged heating is limited. This
condensation of a diketone with the amino function results
in release of two molecules of superheated water into the
reaction medium. Sublimation of TBSOH (entries 3, 6, 8,
and 10) and formation of deprotected nucleoside 2b (entry
3) was observed in some cases. In addition to its hydrolytic
lability, migration of the TBS protecting group between O2′
and O3′ on the sugar moiety complicates some reactions, as
observed with 1h (entry 8). The combined yield (69%) of
the 2′,5′- (2h) and 3′,5′-bis-O-TBS (2h′) isomers (1:1 ratio)
is quite good, even though migration and hydrolysis of the
silyl groups occurred.
It is noteworthy that 2′,3′-O-isopropylideneguanosine (1i)
afforded the soluble 2,5-dimethylpyrrole adduct 2i in 47%
yield (entry 9). Addition of a 5′-O-TBS group did not
improve the yield of condensation product (entry 10) and
instead resulted in formation of a complex reaction mixture
from which 2j was isolated in 23% yield. The acetyl-
protected derivatives 1d,g,k (entries 4, 7, and 11) were more
stable than the corresponding TBS ethers 1c,f,j (entries 3,
6, and 10) under the reaction conditions, which resulted in
higher condensation yields with the acetate esters. As
expected, nucleosides with lower thermal stability such as
analogues with double bonds, oxirane rings, or carbonyl
substituents in the sugar moiety underwent decomposition
and failed to give pyrrole-adduct products. No improvements
in yields or reaction times were observed upon addition of
molecular sieves to certain reaction mixtures, but no serious
attempt has been made to optimize the procedure or yields.
1H and 13C NMR spectra of our adducts have only one
set of pyrrole methyl signals.15 This suggests that either the
barrier to rotation around the C-N bond in these 2- or
6-purinyl derivatives of 2,5-dimethylpyrrole is too low to
give rise to rotational isomers16 with significant lifetimes or
anisotropic effects of the sugar moiety are similar on the
opposite faces of the purine ring (see ref 15 for selected data
for 1k and 2a-k).
Cleavage of the pyrrole ring (deprotection of the amino
function) was complete within 3 h at ambient temperature
with TFA/H2O (9:1). Acetyl esters were stable under these
conditions, but TBS and isopropylidene groups were removed
concomitantly.
In summary, condensation of adenine and guanine nucleo-
sides with 2,5-hexanedione provides convenient protection
of the heterocyclic amino group. This represents valuable
methodology for generation of the more soluble 2,5-
dimethylpyrrole derivatives of these purine compounds,
which are stable in the presence of basic reagents but are
cleaved readily with TFA/H2O. Addition of carbene species
to unsaturated-sugar nucleoside analogues protected as 2,5-
dimethylpyrrole adducts and chemistry of the resulting
spirocyclopropane compounds will be reported.
Acknowledgment. We are grateful for pharmaceutical
company gift funds in support of this work.
OL035264F
(16) Vorkapic-Furac, J.; Mintas, M.; Kastner, F.; Mannschreck, A. J.
Heterocycl. Chem. 1992, 29, 327-333.
3348
Org. Lett., Vol. 5, No. 18, 2003