3150
B. Ludolph, H. Waldmann / Tetrahedron Letters 50 (2009) 3148–3150
Table 1
Trity l
HN
Selected results of the synthesis of the benzodiazepinedione collection
O
No.
R1
R2
Yield (%)
N
O
17/12
17/19
17/25
17/31
D
A
A
C
–Ala-OMe
63
50
59
43
OAll
–NH-n-C6H13
–Cys(Far)-Ome
–Cys(C16H33)-Ome
N
N3
O
14
H
1) SnCl2, Ph-SH,
Et3N, THF
2) DMAP, NMM, CH2Cl2,
O
N NH
17/35
17/38
A
B
16
35
(A - C) or R-COOH (D)
Cl
R
S
O
H
N
Trityl
HN
N
O
N
O
N
H
N
O
O
N
17/42
D
60
HN
O
R1
15
A
B
C
SO2
SO2
SO2
R1:
3. Conclusion
CO
We have shown that differently functionalized benzodiazepin-
ediones mimicking the lipidated C-terminus of the H-Ras protein
are accessible by means of a combination of solution and solid-
phase methods including six steps on the solid support. A total of
42 target molecules were synthesized with overall yields of 16–
59% for the last seven steps of 16–59%. The obtained lipidated pep-
tide mimetics will be subjected to chemical–biological investiga-
tions of Ras function.
D
2) H2N-R´, PyBOP,
NMM, DMF
1) Pd(PPh3)4,
PhSiH3, DMF
Trityl
HN
O
N
Acknowledgments
R2
N
HN
R1
This research was supported by the Deutsche Forschungsgeme-
inschaft, the Max Planck Gesellschaft, and the Fonds der Chemis-
chen Industrie.
O
O
16
Supplementary data
TFA, CH2Cl2 or
acetic acid, TFE, CH2Cl2 or
HFIP, CH2Cl2
Supplementary data associated with this article can be found, in
NH2
References and notes
O
N
1. Waldmann, H.; Wittinghofer, A. Angew. Chem., Int. Ed. 2000, 39, 4192–4214.
2. (a) Gelb, M. H.; Brunsveld, L.; Hrycyna, C. A.; Michaelis, S.; Tamanoi, F.; Van
Voorhis, W. C.; Waldmann, H. Nat. Chem. Biol. 2006, 2, 518–528; (b) Brunsveld,
L.; Kuhlmann, J.; Alexandrov, K.; Wittinghofer, A.; Goody, R. S.; Waldmann, H.
Angew. Chem., Int. Ed. 2006, 45, 6622–6646.
R2
N
HN
R1
O
O
3. (a) Deck, P.; Pendzialek, D.; Biel, M.; Wagner, M.; Popkirova, B.; Ludolph, B.;
Kragol, G.; Kuhlmann, J.; Giannis, A.; Waldmann, H. Angew. Chem., Int. Ed. 2005,
44, 4975–4980; (b) Biel, M.; Deck, P.; Giannis, A.; Waldmann, H. Chem. Eur. J.
2006, 12, 4121–4143.
17
Scheme 2.
4. Nägele, E.; Schelhaas, M.; Kuder, N.; Waldmann, H. J. Am. Chem. Soc. 1998, 120,
6889–6902.
5. Cini, E.; Lampariello, R.; Rodriguez, M.; Taddei, M. Tetrahedron 2009, 50, 448–
molecules such as phenylalanine methyl ester, benzyl amine, or
phenylhydrazide as well as basic functionalities (Table 1).
Release of the products 17 from the resin was achieved by treat-
ment with 2% TFA in dichloromethane (five times, 5 min each).
After purification, the desired products were obtained in 16–59%
yield for six steps on the polymeric support. For compounds incor-
porating cysteine building blocks, the use of acetic acid and trieth-
ylsilane (TES) or hexafluoro-2-propanol (HFIP) in dichloromethane
gave superior results. Selected examples are shown in Table 1, for
all synthesized compounds see Supplementary data.
6. Ettmayer, P.; Chloupek, S.; Weigand, K. J. Comb. Chem. 2003, 5, 253–259.
7. For previous syntheses of benzodiazepinodiones on the solid phase and on
fluorous tagged linkers see: (a) Zhang, W.; Lu, Y.; Hiu-Tung Chen, C.; Zeng, L.;
Kassel, D. B. J. Comb. Chem. 2006, 8, 687–695; (b) Zhang, W.; Lu, Y.; Hiu-Tung
Chen, C.; Curran, D. P.; Geib, S. Eur. J. Org. Chem. 2006, 2055–2059.
8. Kadereit, D.; Deck, P.; Heinemann, I.; Waldmann, H. Chem. Eur. J. 2001, 7, 1184–
1193.
9. Ludolph, B.; Eisele, F.; Waldmann, H. ChemBiochem 2002, 3, 901–904.
10. Addicks, E.; Mazitschek, R.; Giannis, A. ChemBioChem 2002, 3, 1078–1088.
11. Gennari, C.; Longari, C.; Ressel, S.; Salom, B.; Piarulli, U.; Ceccarelli, S.; Mielgo,
A. Eur. J. Org. Chem. 1998, 2437–2449.