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D. Orain et al.
LETTER
Scheme 5 Functionalisation of the immobilised scaffold. Reagents and conditions: i) AcCl, Pyridine, CH2Cl2, 16 h, r.t. ii) BnBr, i-Pr2NEt,
DMF, 50 °C, 24 h. iii) NaOHaq 2N/H2O/THF (2/8/10), r.t., 2 h.
In conclusion, we have shown an efficient solution and
solid-phase synthesis of a novel diazabicyclo[3.3.1]non-
enone core which might serve as an attractive scaffold for
combinatorial libraries. The key step of this synthesis was
a sequential Dakin–West/Pictet–Spengler reaction. Cur-
rently, optimisation of the linker and the cleavage condi-
tions are under investigation as well as the diversification
of the scaffold.
Scheme 6 i) 20% TFA/CH2Cl2, 16 h, r.t.; ii) NaBH4, MeOH
Acknowledgement
NHCO), 6.60 (dd, 3J (H,H) = 8.60 Hz, 4J (H,H) = 2.15 Hz, 1
We thank the Chemistry Council of Novartis for funding DO, Mr.
F. Houdière for LC/MS and CCU staff for their support.
H, ArH), 6.71 (d, 4J (H,H) = 2.15 Hz, 1 H, ArH), 7.16 (d, 3J
(H,H) = 8.60 Hz, 1 H, ArH), 7.25 (t, 3J (H,H) = 6.98 Hz, 1
H, PhH), 7.28 (d, 3J (H,H) = 6.98 Hz, 2 H, PhH), 7.34 (t, 3J
(H,H) = 6.98 Hz, 2 H, PhH), 8.61 (s, 1 H, OH), 10.67 (s, 1
References
H, Indole NH). MS (negative electrospray): m/z (%) = 346
(100) [M – H]–.
(1) Dole, R. E. J. Comb. Chem. 2001, 3, 477.
For the cis diastereoisomer 1H NMR (400 MHz, [d6]DMSO,
(2) (a) Tan, D. S.; Foley, M. A.; Shair, M. D.; Schreiber, S. L. J.
26 °C): = 1.44 (s, 3 H, CH3), 2.67 (d, 2J (H,H) = 15.04 Hz,
Am. Chem. Soc. 1998, 120, 8568. (b) Spring, D. R.;
1 H, IndCHH-), 2.84 (dd, 2J (H,H) = 15.04 Hz, 3J
Krishnan, S.; Blackwell, H. E.; Schreiber, S. L. J. Am. Chem.
Soc. 2002, 124, 1354.
(3) Manzanares, I.; Cuevas, C.; Garcia-Nieto, R.; Marco, E.;
(H,H) = 4.30 Hz, 1 H, IndCHH-), 2.95 (dd, 2J (H,H) = 13.97
Hz, 3J (H,H) = 13.97 Hz, 1 H, CHHPh), 3.12 (dd, 2J
(H,H) = 13.97 Hz, 3J (H,H) = 4.83 Hz, 1 H, CHHPh), 3.58
Gago, F. Curr. Med. Chem. 2001, 1, 257.
(m, 1 H, CCHNHCO), 3.73 (m, 1 H, CHNH), 6.97 (m, 1 H,
NHCO), 6.55 (dd, 3J (H,H) = 8.60 Hz, 4J (H,H) = 2.14 Hz, 1
H, ArH), 6.66 (d, 4J (H,H) = 2.14 Hz, 1 H, ArH), 7.08 (d, 3J
(H,H) = 8.60 Hz, 1 H, ArH), 7.22 (t, 3J (H,H) = 7.52 Hz, 1
H, PhH), 7.24 (d, 3J (H,H) = 7.52 Hz, 2 H, PhH), 7.32 (t, 3J
(H,H) = 7.52 Hz, 2 H, PhH), 8.55 (s, 1 H, OH), 10.55 (s, 1
H, Indole NH). MS (negative electrospray): m/z (%) = 346
(100) [M – H]–, 460 (25) [M + CF3COO–], 693 (5) [2 M –
H]–.
(4) (a) Hamaguchi, F.; Nagasaka, T.; Ohki, S. Yakugaku Zasshi
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(6) The intramolecular formation of the intermediate imine is
based on the result obtained with the 3,4-dimethoxy-L-
DOPA amino acid. No Pictet–Spengler cyclisation was
observed when the methyl ketone derivative was treated
with TFA. Nevertheless, when the crude reaction mixture
was treated with sodium borohydride, the ketopiperazine
adduct was obtained indicating the presence of an imine
intermediate (Scheme 6).
(9) Dalvit, C.; Bovermann, G. Magn. Reson. Chem. 1995, 33,
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(10) (a) Chou, Y.-L.; Morrissey, M. M.; Mohan, R. Tetrahedron
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100, 2091.
(11) Alsina, J.; Rabanal, F.; Chiva, C.; Giralt, E.; Albericio, F.
Tetrahedron 1998, 54, 10125.
(12) Synphase D-series Lantern from Mimotopes,
aminomethylated, 36 mol/Lantern.
(13) General review for the protecting groups strategy on solid-
phase: Orain, D.; Ellard, J.; Bradley, M. J. Comb. Chem.
2002, 4, 1.
(7) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
(8) For the trans diastereoisomer 1H NMR (400 MHz,
[d6]DMSO, 26 °C): = 1.56 (s, 3 H, CH3), 2.07 (dd, 2J
(H,H) = 13.97 Hz, 3J (H,H) = 13.98 Hz, 1 H, CHHPh), 2.70
(d, 2J (H,H) = 15.58 Hz, 1 H, IndCHH-), 2.88 (dd, 2J
(H,H) = 15.58 Hz, 3J (H,H) = 6.44 Hz, 1 H, IndCHH-), 3.27
(dd, 2J (H,H) = 13.97 Hz, 3J (H,H) = 2.15 Hz, 1 H, CHHPh),
3.72–3.78 (m, 2 H, CHNH and CCHNHCO), 5.93 (m, 1 H,
Synlett 2002, No. 9, 1443–1446 ISSN 0936-5214 © Thieme Stuttgart · New York