Abstract
A new versatile synthesis of N
6 -[endo -2′-(endo -5′-hydroxy)norbornyl]-8-(N -methylisopropylamino)-9-methyladenine (WRC-0571), a highly potent and selective antagonist for adenosine A1 receptor, is presented. The overall yield is 14%. The key step involved the stereoselective reduction of endo -2-(diphenylmethylamino)norbornan-5-one to generate the endo -5-hydroxy substituent using the Luche reagent (NaBH4 -CeCl3 ) at -40 °C.
Key words
WRC-0571 - Luche reduction - palladium-catalyzed amination
References
1 Adenosine and Adenosine Receptors
Williams M.
Humana Press;
Clifton NJ:
1990.
2 Jacobson KA.
van Galen PJM.
Williams M.
J. Med. Chem.
1992,
35:
407
3 Müller CE.
Expert Opin. Ther. Pat.
1997,
7:
419
4 Martin PL.
Wysocki RJ.
Barrett RJ.
May JM.
Linden J.
J. Pharmacol. Exp. Ther.
1996,
276:
490
5 Peck JV, Wysocki RJ, Uwaydah IM, and Cuscak NJ. inventors; US Patent 5670501.
; Chem. Abstr. 1996, 125, 58207
6 Ohkita M.
Nishizawa O.
Tsuji T.
Nishida S.
J. Org. Chem.
1993,
58:
5200
7 The endo stereochemistry at C-2 of 9 was confirmed by NMR studies of compound 11 .
8 Reduction of 10 to 11 using LiAlH4 or 9-BBN did not improve the stereoselectivity significantly. In the case of LiAlH4 , some side reactions occurred to give a mixture of crude products as detected by 1 H NMR spectroscopy.
9 Gemal AL.
Luche J.-L.
J. Am. Chem. Soc.
1981,
103:
5454
10 de Ligt RAF.
van der Klein PAM.
von Frijtag Drabbe Künzel JK.
Lorenzen A.
Maate FAE.
Fujikawa S.
van Westhoven R.
van de Hoven T.
Brussee J.
Ijzerman AP.
Bioorg. Med. Chem.
2004,
12:
139
11 Nolsøe JMJ.
Gundersen L.-L.
Rise F.
Acta Chem. Scand.
1999,
53:
366
12 Laufer SA.
Domeyer DMT.
Scior RF.
Albrecht W.
Hauser DRJ.
J. Med. Chem.
2005,
48:
710
13 Yang BH.
Buchwald SL.
J. Organomet. Chem.
1999,
576:
125
14 Wolfe JP.
Buchwald SL.
J. Org. Chem.
1997,
62:
6066
15 Meyers C.
Maes BUW.
Loones KTJ.
Bal G.
Lemière GLF.
Dommisse RA.
J. Org. Chem.
2004,
69:
6010
16 The coupling reaction was also tried with a similar outcome using (N -methylisopropylamino)tributyltin, generated from N -methylisopropylamine(5 ) and (N ,N -dimethylamino)tri-butyltin, and Pd[(2-furyl)3 P]4 in toluene at 80 °C.
17 Sutcliffe EY.
Robins RK.
J. Org. Chem.
1963,
28:
1662
18 Kelley JL.
McLean EW.
Linn JA.
Krochmal MP.
Ferris RM.
Howard JL.
J. Med. Chem.
1990,
33:
196
19 Moravec J.
Kryštof V.
Hanuš J.
Havlíček L.
Moravcová D.
Fuksová K.
Kuzma M.
Lenobel R.
Otyepka M.
Strnad M.
Bioorg. Med. Chem. Lett.
2003,
13:
2993
20 Roelen H.
Veldman N.
Spek AL.
Künzel JFD.
Mathôt RAA.
Ijzerman AP.
J. Med. Chem.
1996,
39:
1463
21 Hayakawa H.
Tanaka H.
Sasaki K.
Haraguchi K.
Saitoh T.
Takai F.
Miyasaka T.
J. Heterocycl. Chem.
1989,
26:
189
