2950
S. Fletcher / Tetrahedron Letters 51 (2010) 2948–2950
NH2
N
N(Boc)2
N(Boc)2
Acknowledgement
N
N
N
N
a
b
N
N
N
N
The author gratefully acknowledges financial support for this
work from the University of Maryland School of Pharmacy.
N
H
N
H
N
References and notes
4
9
10
1. Yan, L.; Burbiel, J. C.; Maaß, A.; Müller, C. E. Expert Opin. Emerg. Drugs 2003, 8,
537–576.
2. Moos, W. H.; Szotek, D. S.; Bruns, R. F. J. Med. Chen. 1985, 28, 1383–1384.
3. Thompson, R. D.; Secunda, S.; Daly, J. W.; Olsson, R. A. J. Med. Chem. 1991, 34,
2877–2882.
c - e
e
4. Gasque, C. E. Phytochemistry 1981, 21, 1501–1507.
5. Tunçbilek, M.; Ateßs-Alagöz, Z.; Altanlar, N.; Karayel, A.; Özbey, S. Bioorg. Med.
Chem. 2009, 17, 1693–1700.
6. (a) Legraverend, M. Tetrahedron 2008, 64, 8585–8603; (b) Borrmann, T.;
Abdelrahman, A.; Volpini, R.; Lambertucci, C.; Alksnis, E.; Gorzalka, S.; Knospe,
M.; Schiedel, A. C.; Cristalli, G.; Mueller, C. E. J. Med. Chem. 2009, 52, 5974–
5989; (c) Fiol, J. J.; Garcia-Raso, A.; Alberti, F. M.; Tasada, A.; Barcelo-Oliver, M.;
Terron, A.; Prieto, M. J.; Moreno, V.; Molins, E. Polyhedron 2008, 27, 2851–2858;
(d) Tuncbilek, M.; Ates-Alagoez, Z.; Altanlar, N.; Karayel, A.; Oezbey, S. Bioorg.
Med. Chem. 2009, 17, 1693–1700.
HN
N
NH2
N
N
N
N
N
N
N
7. Singer, B.; Sun, L.; Fraenkel-Conrat, H. Biochemistry 1973, 13, 1913–1920.
8. Robins, M. J.; Trip, E. M. Biochemistry 1973, 12, 2179–2187.
9. El-Kafrawy, S. A.; Zahran, M. A.; Pedersen, E. B. Acta Chem. Scand. 1999, 53, 280–
283.
11
12
10. Mitsuoka, Y.; Kodama, T.; Ohnishi, R.; Hari, Y.; Imanishi, T.; Obika, S. Nucleic
Acids Res. 2009, 37, 1225–1238.
11. Zhang, H.; Guibe, F.; Balavoine, G. Youji Huaxue 1989, 9, 445–458.
12. (a) Fletcher, S.; Shahani, V. M.; Gunning, P. T. Tetrahedron Lett. 2009, 50, 4258–
4261; (b) Fletcher, S.; Shahani, V. M.; Lough, A. J.; Gunning, P. T., Tetrahedron,
13. Hakimelahi, G. H.; Ly, T. W.; Moosavi-Movahedi, A. A.; Jain, M. L.; Zakerinia, M.;
Davari, H.; Mei, H.-C.; Sambaiah, T.; Moshfegh, A. A.; Hakimelahi, S. J. Med.
Chem. 2001, 44, 3710–3720.
Scheme 2. Reagents and conditions: (a) (1) Boc2O, cat. DMAP, THF, rt, 16 h, (2)
saturated NaHCO3, MeOH, 50 °C, 1 h, 92%; (b) (1) cyclopentanol, PPh3, THF, rt, 2 min,
(2) DIAD, rt, 30 min, 94%; (c) K2CO3, MeOH, reflux, 45 min, 90%; (d) (1) 1-butanol,
PPh3, THF, 45 °C, 2 min, (2) DIAD, 45 °C, 30 min, 92%; (e) TFA/CH2Cl2, 1:1, rt, 1 h, 98%
(for 11), 99% (for 12).
14. Darnbrough, S.; Mervic, M.; Condon, S. M.; Burns, C. J. Synth. Commun. 2001, 31,
3273–3280.
NH2
N
NHBoc
N
N
N
N
15. Typical procedure for Mitsunobu reaction:
0.5 mmol, 1 equiv), 1-butanol (69 l, 0.75 mmol, 1.5 equiv) and PPh3 (197 mg,
0.75 mmol, 1.5 equiv) in anhydrous THF (7 mL) was stirred at 45 °C for 2 min.
Then, DIAD (148 l, 0.75 mmol, 1.5 equiv) was added over about 30 s. The
A solution of purine 6 (239 mg,
N
N
l
N
a, b
c
HO
TrO
l
O
O
reaction mixture was stirred at 45 °C for 30 min under an N2 atmosphere, after
which time TLC analysis confirmed that the reaction was complete. The solvent
was concentrated under reduced pressure. The residue was adsorbed onto
silica gel from CH2Cl2, in the cold (<25 °C) to avert any Tr cleavage, and purified
by flash column chromatography (eluent: CH2Cl2/Hex/EtOAc, 3:6:1) to give
O
O
O
O
purine 7a as
a white foam (251 mg, 94%): dH (CDCl3, 500 MHz) 0.90 (t,
13
14
J = 7.4 Hz, 3H, CH3), 1.34 (app sextet, J = 7.4 Hz, 2H, CH2CH3), 1.49 (s, 9H,
C(CH3)), 1.70 (app quintet, J = 7.4 Hz, 2H, CH2CH2CH3), 3.98 (t, J = 7.4 Hz, 2H,
N6–CH2), 7.15–7.20 (m, 6H, Tr), 7.28–7.34 (m, 9H, Tr), 7.98 (s, 1H, H8), 8.45 (s,
1H, H2); LRMS (ESI) m/z 533.9 (M+H).
BocN
HN
N
16. Typical procedure for Boc and Tr deprotections: Purine 7a (133 mg, 0.25 mmol)
was dissolved in CH2Cl2 (2.5 mL), and then TFA (2.5 mL) was added. The
reaction mixture was stirred for 3 h, by which time TLC showed that the
deprotections were complete. All solvents were removed in vacuo, with
residual TFA removed by co-evaporation with CHCl3. The residue was adsorbed
onto silica gel from CH2Cl2, then passed through a short pad of silica gel
(eluent: CH2Cl2/MeOH/NH4OH, 92:7:1) to furnish purine 8a (46 mg, 97%) as its
free base and as a white solid: dH (DMSO-d6, 500 MHz) 0.90 (t, J = 7.4 Hz, 3H,
CH3), 1.32 (app sextet, J = 7.4 Hz, 2H, CH2CH3), 1.58 (app quintet, J = 7.4 Hz, 2H,
CH2CH2CH3), 3.47 (m, 1H, N6–CH2), 7.58 (br m, 1H, N6–NH), 8.07 (s, 1H, H8)
8.17 (s, 1H, H2), 12.85 (br s, 1H, N9–NH); LRMS (ESI) m/z 192.3 (M+H).
17. Purification of intermediate purines 7 was achieved by silica gel flash column
chromatography, eluting with Hex/EtOAc, 2:1 or CH2Cl2/Hex/EtOAc, 3:6:1.
Intermediate purines 7d, 7f and 7h could not be completely purified by this
method, being contaminated with varying amounts of DIAD-related by-
products. Nevertheless, complete purification of the target purines 8d, 8f and
8h was achieved after Boc and Tr removal in the overall yields shown (two
steps) in Table 1.
N
N
N
N
N
N
N
d
TrO
HO
O
O
OH OH
O
O
15
1
Scheme 3. Reagents and conditions: (a) TrCl, pyridine, 60 °C, 12 h, 87%; (b) (1)
Boc2O, cat. DMAP, THF, rt, 16 h, (2) K2CO3, MeOH, reflux, 45 min, 88%; (c) (1)
cyclopentanol, PPh3, THF, 45 °C, 2 min, (2) DIAD, 45 °C, 30 min, 93%; (d) 20% aq
AcOH/THF, 5:1, 55 °C, 3 d, 85%.
18. Dey, S.; Garner, P. J. Org. Chem. 2000, 65, 7697–7699.
19. Yin, X.; Li, W.; Schneller, S. W. Tetrahedron Lett. 2006, 47, 9187–9189.
20. Physical characterization data consistent with proposed structure of 1: dH (DMSO-
d6, 500 MHz) 1.50–1.64 (m, 4H, 4CH (cyclopentyl)), 1.67 – 1.74 (m, 2H, 2 CH
(cyclopentyl)), 1.90–1.98 (m, 2H, 2CH (cyclopentyl)), 3.52–3.58 (m, 1H, H50),
3.64–3.70 (m, 1H, H50), 3.96 (dd, J = 8, 5 Hz, 1H, H40), 4.14 (dd, J = 8, 5 Hz, 1H,
H3’), 4.52 (m, 1H, CH(CH2)2 (cyclopentyl)), 4.60 (dd, J = 11, 6 Hz, 1H, H20), 5.17
(d, J = 5 Hz, 1H, OH), 5.39–5.44 (m, 2H, 2 OH), 5.88 (d, J = 6 Hz, 1H, H10), 7.76 (br
m, 1H, NH), 8.19 (s, 1H, H8), 8.34 (s, 1H, H2); LRMS (ESI) m/z 336.2 (M+H).
alcohols were surveyed, and it was discovered that primary and
secondary aliphatic alcohols coupled in excellent yields, slightly
better than the more reactive benzylic, allylic and propargylic alco-
hols. Finally, the utility of this chemistry was further demonstrated
by facilitating the rapid access to both N9-mono- and N6,N9-di-
substituted adenines from a common intermediate, as well as by
the synthesis of the potent and selective A1 adenosine receptor
agonist N6-cyclopentyladenosine (1).