P. G. Jagtap et al. / Tetrahedron Letters 50 (2009) 2693–2696
2695
a
b
+
O
O
O
O
OH
OAc
e
OAc
d
OH
(
+)-6
(+)-5
(R)-5
(S)-6
c
NH2
N
N
N
N
O
N
N
H
O
O
O
H
H
OH
O
OH
(R)-7
(R)-6
O
OH
NHEt
3
Scheme 2. (a) Ac
2
O, pyridine, rt, 8 h, 75%; (b) 0.01 M phosphate buffer, acetone, NaOH, PPL, 4 days, R-(ꢀ)-acetate 31%; (c) MeOH, KOH (1 N, 0.3 equiv), 0 °C–rt, 1 h, 82%; (d)
BAIB, TEMPO, CH
2
Cl
2
, 5 h, 54%; (e) 1, MeOH, rt, 3 h, 93%.
Table 2
Oxidation of alcohol 6
Acknowledgments
This work was supported by a grant from the National Institutes
of Health (R44AR046167-03). We thank Sonja Kachler for her ex-
pert technical assistance.
Entry
Conditions
Yield (%)
1
2
3
4
5
6
7
DMSO, (COCl)
DMSO, SO –pyridine, Et
TPAP, NMO, CH Cl
MnO , acetone
PCC, ether or PCC, CH
Dess–Martin periodinane, CH
BAIB, TEMPO, CH Cl
2
, Et
3
N, CH
2
Cl
2
30
22
0
0
0
3
3
N, CH Cl
2 2
2
2
2
References and notes
2
Cl
2
2
Cl
2
25
54
1
.
.
Fredholm, B. B.; IJzerman, A. P.; Jacobson, K. A.; Klotz, K.-N.; Linden, J.
Pharmacol. Rev. 2001, 53, 1–26.
2
2
2
For adenosine receptor agonists and antagonists reviews see: (a) Jacobson, K.
A.; Gao, Z. G. Nat. Rev. Drug Disc. 2006, 5, 247–264; (b) Jacobson, K. A.; van
Galen, P. J. M.; Williams, M. J. Med. Chem. 1992, 35, 407–422; (c) DeNinno, M. P.
Annu. Rep. Med. Chem. 1998, 33, 111–120; (d) Poulsen, S. A.; Quinn, R. J. Bioorg.
Med. Chem. 1998, 6, 619–641; (e) Appleman, J. R.; Erion, M. D. Exp. Opin. Invest.
Drugs 1998, 7, 225–243; (f) Cristalli, G.; Lambertucci, C.; Taffi, S.; Vittori, S.;
Volpini, R. Curr. Top. Med. Chem. 2003, 3, 387–401; (g) Baraldi, P. G.; Cacciari, B.;
Romagnoli, R.; Merighi, S.; Varani, K.; Borea, P. A.; Spalluto, G. Med. Res. Rev.
um chlorochromate (PCC), ether; (4) Pyridinium dichromate
PDC), CH Cl
The reaction of (±)-6 in the presence of Dess–Martin period-
(
2
2
.
inane1 in CH
6
Cl provided aldehyde 7 as the major product but
2 2
the separation of 7 from impurities was complicated. Further at-
tempts to oxidize (±)-6 using iodobenzene diacetate (BAIB) and
2000, 20, 103–128; (h) Akkari, R.; Burbiel, J. C.; Hockemeyer, J.; Müller, C. E.
Curr. Top. Med. Chem. 2006, 6, 1375–1399.
2
,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) in CH
2
Cl
2
provided
3. (a) Niiya, K.; Olsson, R. A.; Thompson, R. D.; Silvia, S. K.; Ueeda, M. J. Med. Chem.
1992, 35, 4557–4561; (b) Niiya, K.; Thompson, R. D.; Silvia, S. K.; Olsson, R. A. J.
Med. Chem. 1992, 35, 4562–4566; (c) Viziano, M.; Ongini, E.; Conti, A.; Zocchi,
C.; Seminati, M.; Pocar, D. J. Med. Chem. 1995, 38, 3581–3585; (d) van Tilburg, E.
W.; von Frijtag Drabbe Kunzel, J.; de Groote, M.; IJzerman, A. P. J. Med. Chem.
1
7
(
(
±)-7 in better yield. Under similar conditions, the enantiomer
R)-7 was then prepared from (R)-6.18 (R)-Aldehyde was separated
from the crude reaction mixture by column chromatography. Of
the various oxidizing reagents studied, the method with BAIB
and TEMPO was found to be efficient and clean.
2002, 45, 420–429.
4.
(a) Salvatore, C. A.; Tilley, S. L.; Latour, A. M.; Fletcher, D. S.; Koller, B. H.;
Jacobson, M. A. J. Biol. Chem. 2000, 275, 4429–4434; (b) Sitkovsky, M. V.;
Lukashev, D.; Apasov, S.; Kojima, H.; Koshiba, M.; Caldwell, C.; Ohta, A.; Thiel,
M. Annu Rev. Immunol. 2004, 22, 657–682.
Treatment of (R)-7 with 2-hydrazino-NECA (1) produced the
diastereoisomer
3
enriched with (R)-3,4-dihydro-2H-pyranyl
DHP) side chain. The (R)-DHP analogue 3 showed highest affin-
ity for both 2A and receptors [K (A2A) = 3.76 and
(A ) = 4.51 nM]. Compound 3 is sevenfold better than reference
compound CGS 21680, binds with a K (A2A) value of 3.76 nM, and
is 12-fold selective versus A . Compound 3 also showed 10-fold
selectivity versus the A subtype, which is slightly better than
the selectivity of CGS21680 as one of the most potent and selective
2A agonists known (Table 1). The adenylyl cyclase functional as-
1
9
5. Jagtap, P. G.; Salzman, A. L.; Szabo, C. WO 2006034190.
(
6.
(a) Powell, J. E., Barker, M. D. US patent 4,388,104.; (b) Etzkorn, W. G.; Galley, R.
A.; Snead, T. E.; Brockwell, J. L.; Young, M. A.; Maher, J. M.; Knight, B. US patent
6,187,793 B1.
A
A
3
i
K
i
3
7
8
.
.
Hsieh, H.-P.; Chen, S.-T.; Wang, K.-T. J. Chinese Chem. Soc. 1997, 44, 597–600.
Pedersen, T. M.; Jensen, J. F.; Humble, R. E.; Rein, T.; Tanner, D.; Boddman, K.;
Reiser, O. Org. Lett. 2000, 2, 535–538.
i
1
A
3
1
9. (a) Buffet, M. F.; Dixon, D. J.; Edwards, G. L.; Ley, S. V.; Tate, E. W. J. Chem. Soc.
Perkin Trans. 1 2000, 1815–1827; (b) Fehr, C.; Galindo, J.; Ohloff, G. Helv. Chim.
Acta 1981, 1247–1256; (c) Ibrahim, N.; Eggimann, T.; Dixon, E. A.; Wieser, H.
Tetrahedron 1990, 46, 1503–1514; (d) Brimacombe, J. S.; Hunedy, F.; Mather, A.
M.; Tucker, L. C. N. Carbohydr. Res. 1979, 68, 231–238; (e) Komada, H.; Okada,
M.; Sumitomo, H. Macromolecules 1979, 12, 5–9.
A
1
say has shown that it is a full agonist at A2A and A
not shown).
In summary, a synthesis of potent and selective adenosine A2A
and A receptor agonist 3 has been accomplished from the coupling
reaction of (R)-3,4-dihydro-2H-pyran-2-carboxaldehyde (7) and 2-
hydrazino-NECA (1). The enantiopure (R)-2-acetoxymethyl-3,4-
dihydro-2H-pyran (5) was prepared on multi-gram scale by modi-
3
receptors (data
10. (a) Thompson, L. A.; Ellman, J. A. Tetrahedron Lett. 1994, 35, 9333–9936; (b)
Kick, E. K.; Ellman, J. A. J. Med. Chem. 1995, 38, 1427–1430.
11. (a) Ley, S. V.; Mio, S.; Mesenguer, B. Synlett 1996, 787–788; (b) Lainé, D.; Fujita,
M.; Ley, S. V. J. Chem. Soc. Perkin Trans. 1 1999, 1639–1646.
3
12. Kang, S.-K.; Jeon, J.-H.; Yamaguchi, T.; Hong, R.-K.; Ko, B.-S. Tetrahedron:
Asymmetry 1995, 6, 97–100.
13. Typical procedure for the enzymatic hydrolysis of 2-acetoxymethyl-3,4-dihydro-
2H-pyran (5): To the mixture of phosphate buffer (4.2 l, 0.01 M, pH 7.6) was
added (±)-5 (29.5 g, 189.1 mmol) in acetone (145 ml) at rt and stirred for
11a,12
fying the earlier PPL catalyzed resolution methods.
A method
for the synthesis of aldehyde (R)-7 from alcohol (R)-6 has been dis-
cussed. The results from in vivo studies will be published
elsewhere.
5
min. Then it was treated with PPL (Sigma, 2.8 g) and the reaction mixture was
stirred at rt. During the reaction pH was constantly adjusted to 7.6 with NaOH
(3 N). Additional PPL (0.7 g) was added after 24 h. Progress of the reaction was