CLUSTER
Tandem Biginelli–Ugi
2337
2 M
NaOH
O
COOMe
O
O
COOH
COOMe
O
COOH
BnO
NH
NH
BnO
NH
NH
MeOH–THF
72%
N
O
O
N
O
O
N
N
O
O
1{1,1,1}
11{1,1,1}
Scheme 2 Synthesis of the free acid 11{1,1,1} via hydrolysis of 1{1,1,1}.
Walczak, M. A. A.; Coleman, C. M.; Twining, L. A.
In order to investigate if the diester 1{1,1,1} is the active
component in the biological assay for Hsp70 chaperone
function or if it is hydrolyzed to the diacid 11{1,1,1} un-
der the aqueous assay conditions, 11{1,1,1} was also syn-
thesized by hydrolysis of 1{1,1,1} (Scheme 2).
Tetrahedron 2005, 61, 11488. (d) Wipf, P.; Stephenson, C.
R. J. Org. Lett. 2005, 7, 1137. (e) Wipf, P.; Fletcher, J. M.;
Scarone, L. Tetrahedron Lett. 2005, 46, 5463. (f) Wipf, P.;
Coleman, C. M.; Janjic, J. M.; Iyer, P. S.; Fodor, M. D.;
Shafer, Y. A.; Stephenson, C. R. J.; Kendall, C.; Day, B. W.
J. Comb. Chem. 2005, 7, 322. (g) Wipf, P.; Stephenson, C.
R. J.; Okumura, K. J. Am. Chem. Soc. 2003, 125, 14694.
(4) (a) Kappe, C. O. Tetrahedron 1993, 49, 6937. (b)Kappe, C.
O. Acc. Chem. Res. 2000, 33, 879. (c) Kappe, C. O. Eur. J.
Med. Chem. 2000, 35, 1043. (d) Kappe, C. O.; Stadler, A.
Org. React. (N.Y.) 2004, 63, 1.
(5) (a) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36,
7819. (b) Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J.
Org. Chem. 1997, 62, 2917.
(6) Khanetskyy, B.; Dallinger, D.; Kappe, C. O. J. Comb. Chem.
2004, 6, 884.
(7) (a) Paulvannan, K. Tetrahedron Lett. 1999, 40, 1851.
(b) Lu, K.; Luo, T.; Xiang, Z.; You, Z.; Fathi, R.; Chen, J.;
Yang, Z. J. Comb. Chem. 2005, 7, 958.
(8) Timmer, M. S. M.; Risseeuw, M. D. P.; Verdoes, M.;
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2005, 16, 177.
In summary, we have synthesized a second generation fo-
cused library of 30 tetrahydropyrimidinone amides 1{1–
12,1–10,1–8} based on the structure of MAL3-101 that
was previously found to block the ability of Hsp70 co-
chaperones to enhance Hsp70 ATPase activity without af-
fecting the KCAT for ATP hydrolysis. This library demon-
strates the utility of TMCRs in SAR studies of biological
lead molecules. The tandem Biginelli–Ugi MCR facilitat-
ed the effective variation of four different substituents and
allowed the synthesis of the library members in a se-
quence of only two one-pot reactions. Detailed studies on
the ability of the tetrahydropyrimidinone amides 1{1–
12,1–10,1–8} to modulate Hsp70 ATPase activity are on-
going and will be reported in due course.
Acknowledgment
(9) (a) Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R.
Heterocycles 1997, 45, 1589. (b) Biennymé, H.; Bouzid, K.
Tetrahedron Lett. 1998, 39, 2735. (c) Lee, D.; Sello, J. K.;
Schreiber, S. L. Org. Lett. 2000, 2, 709. (d) Tempest, P.;
Ma, V.; Thomas, S.; Hua, Z.; Kelly, M. G.; Hulme, C.
Tetrahedron Lett. 2001, 42, 4959. (e) Tempest, P.; Ma, V.;
Kelly, M. G.; Jones, W.; Hulme, C. Tetrahedron Lett. 2001,
42, 4963. (f) Tempest, P.; Pettus, L.; Gore, V.; Hulme, C.
Tetrahedron Lett. 2003, 44, 1947. (g) Banfi, L.; Basso, A.;
Guanti, G.; Riva, R. Tetrahedron Lett. 2003, 44, 7655.
(h) Zhang, W.; Tempest, P. Tetrahedron Lett. 2004, 45,
6757.
(10) (a) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem.
Commun. 2003, 551. (b) Neuschütz, K.; Velker, J.; Neier, R.
Synthesis 1998, 227. (c) Bunce, R. A. Tetrahedron 1995, 51,
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(11) (a) Padwa, A. Pure Appl. Chem. 2003, 75, 47. (b) de
Meijere, A.; von Zezschwitz, P.; Nuske, H.; Stulgies, B. J.
Organomet. Chem. 2002, 653, 129.
We gratefully acknowledge financial support provided by NIGMS
(P50-GM067082). The authors also thank Dr. Claire M. Coleman
and Ms. Leslie A. Twining for LC-MS/UV/ELSD analyses, and
Prof. Jeff Brodsky for biological assays and stimulating discussi-
ons.
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