Angewandte
Chemie
141.0, 134.9, 132.8, 130.7, 130.0, 129.7, 127.1, 124.9, 69.5, 54.6, 54.1,
yield over two steps. Reductive alkylation of 19 with 2-(1H-
indol-3-yl)acetaldehydealdehyde (20) provided 21. Stau-
dinger reduction of the azide was followed by spontaneous
lactamization to furnish the g-lactam 22 in 78% yield.
Reduction of nitro group followed by the treatment of
resulting diamine 23 with trimethyl orthoformate (PPTS,
608C) yielded the spirocycle 24 without event.
~
32.3 ppm. ATR-IR n ¼3063 (w), 2958 (w), 2135 (m), 1748 (s), 1447
(m), 1254 (s), 1165 (w), 1065 (w), 941 (s), 886 (s), 731 (s), 697 (m), 687
(s); HRMS (ESI) calcd for C18H18NO4Se+ [M+H]+ 392.0396; found
392.0409.
Received: July 30, 2013
Published online: October 11, 2013
To complete the synthesis, the Bischler–Napieralski
reaction was envisioned to close the remaining seven-
membered ring.[26] To the best of our knowledge, there was
no example, prior to our work on the synthesis of trigonolii-
mine B, in the literature dealing with the formation of
a hexahydroazepino[4,5-b]indole skeleton with the concur-
rent formation of an exo-imine function.[23c] Application of
our previously developed conditions to 24 afforded the
desired product in only 20% yield, and was accompanied by
degradation. Therefore, the reaction conditions were reopti-
mized by varying the stoichiometry and concentration of the
reaction. Gratefully, under optimum reaction conditions
(sulfolane, c = 0.025m, POCl3 (40.0 equiv), 808C, 70 h), the
(+)-4a was isolated in 54% yield. All spectroscopic data for
our synthetic product are in perfect agreement with those
reported in the literature. The sign of specific rotation of our
synthetic sample ([a]D =+ 225 (c = 0.3, CHCl3, e.r. 92:8) is
opposite to that of Movassaghiꢁs synthetic compound ([a]D =
ꢀ294 (c = 0.24, CHCl3, e.r. 97:3), thus indicating the R confi-
guration at C20 for our synthetic sample. Following exactly
the same synthetic sequence using quinidine derivative 6 as
a bifunctional catalyst, (ꢀ)-trigonoliimine A [(+)-4a] ([a]D =
ꢀ189, c = 0.29, CHCl3, e.r. 86.5:13.5) was synthesized in 6.8%
overall yield.
In conclusion, a catalytic enantioselective cinchona-alka-
loid-catalyzed Michael addition between methyl a-aryl-a-
isocyanoacetates and vinyl phenylselenone has been devel-
oped. The resulting enantioenriched a-aryl-a-(2’-phenylsele-
nonylethyl)-a-isocyanoacetates 3 were subsequently con-
verted into a-aryl-a-(2’-FG-alkyl)-a-amino acids and medic-
inally important heterocycles such as oxindoles and pyrroli-
dinones. A concise total synthesis of (+)- and (ꢀ)-trigonoli-
imine A(nine steps, overall yield 7.5% and 6.8%,
respectively) was completed using the Michael adduct 3i as
a starting material.[27] The successful cyclization of 24 into the
natural product 4a further illustrates the power of the
Bischler–Napieralski reaction for the formation of a seven-
membered ring with concurrent creation of an exo-imine
function, a hitherto unknown transformation.
Keywords: asymmetric synthesis · heterocycles ·
natural products · organocatalysis · selenium
.
[2] Y. Ito, M. Sawamura, M. Matsuoka, Y. Matsumoto, T. Hayashi,
Xue, C. Guo, L.-Z. Gong, Synlett 2009, 2191 – 2197; e) H. Y. Kim,
1710 – 1713; g) M.-X. Zhao, H. Zhou, W.-H. Tang, W.-S. Qu, M.
[4] a) T. Hayashi, E. Kishi, V. A. Soloshonok, Y. Uozumi, Tetrahe-
M. Ohara, A. Yamamura, Y. Funahashi, N. Shibata, Org. Lett.
[5] D. Monge, K. L. Jensen, I. Marin, K. A. Jørgensen, Org. Lett.
[7] a) C. Arrꢂniz, A. Gil-Gonzꢃlez, V. Semak, C. Escolano, J. Bosch,
L.-N. Jia, Y.-L. Guo, X.-Y. Luo, X.-Y. Xu, L.-X. Wang, Chem.
[8] a) M.-X. Zhao, D.-K. Wei, F.-H. Ji, X.-L. Zhao, M. Shi, Chem.
[9] J.-F. Bai, L.-L. Wang, L. Peng, Y.-L. Guo, L.-N. Jia, F. Tian, G.-Y.
[10] Recent reviews on a,a-disubstituted amino acids: a) C. Cati-
[12] a) S. Sternativo, A. Calandriello, F. Costantino, L. Testaferri, M.
Walczak, B. Battistelli, L. Testaferri, F. Marini, Tetrahedron
[13] a) F. Marini, S. Sternativo, F. Del Verme, L. Testaferri, M.
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Experimental Section
Typical procedure: A solution of methyl a-phenyl-a-isocyanoacetate
(1a; 18.3 mg, 1.0 mmol) in toluene (0.2 mL) was added to a solution
of vinyl phenylselenone (2; 15.0 mg, 0.07 mmol),
5 (2.6 mg,
10 mol%), 4 ꢀ molecular sieves (8.0 mg) in toluene (0.1 mL) at
ꢀ408C . After being stirred at ꢀ408C for 20 h, the reaction mixture
was directly submitted to column chromatography (petroleum ether/
ethyl acetate 7:3 to 3:7) to afford 3a (26.1 mg, 96%, e.r. 97:3).
1H NMR (400.13 MHz, CDCl3): d = 7.99–7.92 (m, 2H), 7.79–7.72 (m,
1H), 7.70–7.63 (m, 2H), 7.50–7.39 (m, 5H), 3.79 (s, 3H), 3.51 (ddd,
J = 12.2, 11.9, 5.7 Hz, 1H), 3.30 (ddd, J = 12.2, 11.5, 5.4 Hz, 1H), 2.99–
2.83 ppm (m, 2H). 13C NMR (100.62 MHz, CDCl3): d = 166.9, 163.6,
Angew. Chem. Int. Ed. 2013, 52, 12714 –12718
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim