molecules involving an Ugi-4CR and a subsequent PS
reaction. Significantly, aliphatic acyclic and cyclic as well as
aromatic oxo acids are substrates for this reaction sequence.
Scope and limitation of the sequence are described. Further
work is being performed in our laboratory to investigate the
intriguing biological activities of these molecules and will be
reported in due course.
Evaporation and purification by preparative TLC or column chromato-
graphy gave the corresponding polycyclic product.
Less polar product 16a, C20H21N3O2, Mw: 335.40 g molꢁ1; HRMS
(ESI-TOF) m/z (calc.): 335.1634, (found) [M]+
: 335.1598, m/z
[M + H]+: 336.2. 1H-NMR (CDCl3, 600 MHz): d = 1.62 (dt, J =
7.98, 5.63 Hz, 1 H), 1.91 (dd, J = 8.24, 14.42 Hz, 1 H), 1.95 (dd, J =
8.24, 11.20 Hz, 1 H), 2.22 (m, 1 H), 2.35 (m, 4 H), 2.59 (dd, J = 4.22,
14.29 Hz, 1 H), 2.75 (ddd, J = 3.81, 10.21, 22.61 Hz, 1 H), 2.80
(m, 1 H), 2.86 (ddt, J = 2.58, 5.85, 6.75 Hz, 1 H), 3.27 (dd, J = 11.31,
13.11 Hz, 1 H), 4.96 (dd, J = 5.94, 13.32 Hz, 1 H), 5.11 (dd, J = 4.42,
12.76 Hz, 1 H), 5.20 (dd, J = 5.92, 11.08 Hz, 1 H), 7.14 (t, J =
7.32 Hz, 1 H), 7.22 (t, J = 7.59 Hz, 1 H), 7.37 (d, J = 8.10 Hz, 1 H),
7.53 (d, J = 7.80 Hz, 1 H), 9.03 (s, 1 H). 13C-NMR (CDCl3, 150.92 MHz):
d = 21.2, 22.9, 26.4, 32.7, 34.9, 40.2, 43.2, 50.2, 51.3, 73.7, 110.1,
111.2, 118.4, 119.9, 122.4, 126.4, 130.5, 136.6, 169.7, 183.2.
Notes and references
z General procedure for Ugi reaction: 1 mmol of aldehyde or ketone
acid was dissolved in 1 mL MeOH, 1 mmol of isocyanide and 1mmol
amino acetal were added into the solution. The solution was stirred for
24 hours at rt. The solution was evaporated and purified by SiO2
column chromatography to give the Ugi product.Ugi product 21,
3-(2-{[1-(2,2-diethoxy-ethyl)-2-oxo-hexahydro-cyclopenta[b]pyrrole-6a-
carbonyl]-amino-ethyl)-indole-1-carboxylic acid tert-butyl ester,
C29H41N3O6, Mw: 527.65 g molꢁ1; HRMS (ESI-TOF) m/z (calc.):
527.2995, (found) [M]+
: 527.3001; HPLC-MS rt: 12.06, m/z
[M ꢁ Boc]+: 426.0. 1H-NMR (CDCl3, 600 MHz): d = 1.17 (t, J =
7.02 Hz, 3 H), 1.19 (t, J = 7.02 Hz, 3 H), 1.68 (s, 9 H), 1.80 (m, 1 H),
2.10 (m, 2 H), 2.22 (m, 2 H), 2.29 (dd, J = 6.17, 14.83 Hz, 1 H), 2.39
(t, J = 14.57 Hz, 1 H), 2.91 (dt, J = 1.56, 3.62 Hz, 1 H), 3.36 (q, J =
7.02 Hz, 1 H), 3.45 (dd, J = 7.10, 9.24 Hz, 1 H), 3.54 (m, J = 6.80 Hz,
1 H), 3.61 (m, 3 H), 3.72 (q, J = 5.47 Hz, 1 H), 4.61 (t, J = 4.72 Hz,
1 H), 6.69 (t, J = 5.48 Hz, 1 H), 7.26 (t, J = 7.74 Hz, 1 H), 7.33 (t, J =
7.50 Hz, 1 H), 7.41 (s, 1 H), 7.55 (d, J = 7.55 Hz, 2 H), 8.16 (s, 1 H).
13C-NMR (CDCl3, 150.92 MHz): d = 15.2, 15.3, 22.4, 25.0, 26.5, 28.2,
30.5, 33.8, 39.6, 44.8, 52.4, 62.8, 62.9, 100.1, 115.3, 117.5, 118.8, 122.6,
123.0, 124.5, 130.5, 172.0, 180.2.
More polar product 16b, C20H21N3O2, Mw: 335.40 g molꢁ1; HRMS
(ESI-TOF) m/z (calc.): 335.1634, (found) [M]+: 335.1598; HPLC-MS
rt: 10.05, m/z [M + H]+: 336.2. 1H-NMR (CDCl3, 600 MHz): d =
1.83–1.91 (m, 2 H), 2.01 (dd, J = 13.22, 7.93, 1 H), 2.03–2.16 (m, 3 H),
2.35 (t, J = 14.52 Hz, 1 H), 2.44 (dd, J = 6.00, 15.12 Hz, 1 H),
2.48–2.55 (m, 1 H), 2.78 (ddd, J = 1.67, 4.87, 15.63 Hz, 1 H),
2.84–2.86 (m, 1 H), 3.05 (ddd, J = 4.33, 12.84, 11.16 Hz, 1 H), 3.79
(dd, J = 6.06, 12.30 Hz, 1 H), 3.94 (dd, J = 10.06, 12.20 Hz, 1 H), 4.67
(ddd, J = 2.48, 5.09, 12.86 Hz, 1 H), 5.03 (dd, J = 6.18, 9.96 Hz, 1 H),
7.15 (t, J = 7.46 Hz, 1 H), 7.20 (t, J = 7.07 Hz, 1 H), 7.33 (d, J =
8.10 Hz, 1 H), 7.52 (d, J = 7.93 Hz, 1 H), 8.16 (s, 1 H). 13C-NMR
(CDCl3, 150.92 MHz): d = 20.2, 22.0, 25.2, 31.8, 33.9, 39.3, 46.6, 48.8,
49.5, 72.0, 110.2, 111.2, 118.5, 120.0, 122.6, 126.5, 129.4, 136.7, 171.4,
182.3.
Ugi product 22, 3-(2-{[1-(2,2-diethoxy-ethyl)-2-oxo-hexahydro-
cyclopenta[b]pyrrole-6a-carbonyl]-amino}-ethyl)-indole-1-carboxylic
acid tert-butyl ester, C29H41N3O6, Mw: 527.65 g molꢁ1; HRMS (ESI-TOF)
m/z (calc.): 527.2995, (found) [M]+: 527.3001; HPLC-MS rt: 12.04,
m/z [M + H]+: 426.2. 1H-NMR (CDCl3, 600 MHz): d = 1.05 (t, J =
7.08 Hz, 3 H), 1.17 (t, J = 7.02 Hz, 3 H), 1.43 (m, 1 H), 1.59 (m, 1 H),
1.65 (m, 1 H), 1.77 (m, 1 H), 1.87 (m, 1 H), 2.02 (dd, J = 1.77,
17.43 Hz, 1 H), 2.08 (m, 1 H), 2.34–2.38 (m, 2 H), 2.60 (dd, J = 17.4,
9.78 Hz, 1 H), 2.72 (w, 1 H), 2.79 (dd, J = 7.41, 14.01 Hz, 1 H), 2.93
(t, J = 7.29 Hz, 2 H), 3.39 (dd, J = 4.21, 13.92 Hz, 1 H), 3.47 (m, 2 H),
3.52 (m, 1 H), 3.57 (dt, J = 7.02, 6.57 Hz, 1 H), 3.66 (dt, J = 7.16,
7.96 Hz, 1 H), 3.68 (dd, J = 5.48, 16.05 Hz, 1 H), 5.33 (dd, J = 4.32,
7.32 Hz, 1 H), 7.22 (t, J = 7.44 Hz, 1 H), 7.29 (dd, J = 6.69, 14.25 Hz,
1 H), 7.37 (s, 1 H), 7.55 (d, J = 7.93 Hz, 2 H), 7.98 (t, J = 5.67 Hz,
1 H), 8.12 (s, 1 H). 13C-NMR (CDCl3, 150.92 MHz): d = 15.2, 15.5,
24.8, 25.5, 28.2, 34.1, 35.0, 37.0, 39.7, 43.7, 46.2, 63.8, 64.9, 78.6, 83.4
(rotamer), 99.4, 115.3, 117.8, 118.8, 122.4, 123.0, 124.4, 130.5, 135.5
(rotamer), 149.6 (rotamer), 174.0, 177.1.
X-Ray single crystal structure analysis of compound 16b:
C20H21N3O2, Mr = 335.40, colorless fragment, monoclinic, P21/c
(no.: 14), a = 11.3899(5), b = 8.9061(4), c = 16.9450(7) A, b =
94.3181(18)1, V = 1714.02(13) A3, Z = 4, dcalc = 1.300 g cmꢁ3
,
F000 = 712, m = 0.686 mmꢁ1, 11 088 reflections, Rint = 0.023, 2862
independent data [2665: Io 4 2s(Io)], R1 = 0.0329 [Io 4 2s(Io)],
wR2 = 0.0817 [all data]. For more detailed information see the ESI.w
1 (a) A. Pictet and T. Spengler, Chem. Ber., 1911, 44, 2030–2036;
(b) W. M. Whaley and T. R. Govindachari, in Organic Reactions,
ed. R. Adams, John Wiley & Sons, New York, 1951, pp. 151–190.
2 A. Domling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39,
¨
3169–3210.
3 (a) H. U. Kaniskan and P. Garner, J. Am. Chem. Soc., 2007, 129,
15460–15461; (b) L. El Kaim, M. Gageat, L. Gaultier and
L. Grimaud, Synlett, 2007, 500–502; (c) A. S. Karpov, T. Oeser
and T. J. J. Muller, Chem. Commun., 2004, 1502–1503; (d) S. Brase,
¨
C. Gil and K. Knepper, Bioorg. Med. Chem., 2002, 10, 2415–2437;
for a recent review on MCRs involving PS see: (e) J. Sapi and
J.-Y. Laronze, ARKIVOC, 2004, 208–222.
4 (a) C. Boss, C. Brisbare-Roch and F. Jenck, J. Med. Chem., 2009,
52, 891–903; (b) H. Aissaoui, M. Cappi, M. Clozel, W. Fischli and
R. Koberstein (Actelion Pharmaceuticals Ltd., Switz.), WO
2 001 068 609, 2001, p. 158.
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¨
(b) B. Beck, S. Hess and A. Domling, Bioorg. Med. Chem. Lett.,
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General procedure for Pictet–Spengler reaction: 0.1 mmol of Ugi
product was dissolved in 0.5 ml of HCOOH and stirred for 4 h at rt.
N. E. Shevchenko, E. S. Balenkova, G.-V. Roschenthaler and
¨
V. G. Nenajdenko, Tetrahedron, 2008, 64, 11706–11712.
ꢀc
This journal is The Royal Society of Chemistry 2010
772 | Chem. Commun., 2010, 46, 770–772