Scheme 1. Retrosynthetic Analysis of Trigonoliimine Core
Figure 2. X-ray structure of compound 4b.
81% yield.8 Protection of 12 with PhSO2Cl provided our
key intermediate 6 in 96% yield on a multigram scale.
The synthesis of trigonoliimine hexacyclic skeletons is
shown in Schemes 3 and 4. Compound 13 was formed in
30% yield in one pot from compound 6 via bromideÀ
lithium exchange, intramolecular nucleophilic acyl substitu-
tion to form the seven-membered ring,9 and subsequent six-
membered ring formation with paraformaldehyde.10 Com-
pound 13 was converted to azide 5 via oxidative cleavage of
the vinyl group with OsO4/NaIO4 (85% yield),11,12 reduc-
tion with NaBH3CN12 (78% yield), mesylation with MsCl,
and azidation with NaN313 (71% yield). Compound 4a was
readily formed from 5 in 88% yield via aza-Wittig reaction
by refluxing with PPh3 in toluene.14 The hexacyclic skeleton
was confirmed by the X-ray structure of its tosyl analogue
4b (Figure 2).
Scheme 2. Synthesis of Compound 6
The nitrogen-protecting group was found to be impor-
tant for the key step (6 to 13, Scheme 3). For example,
when the amide and the secondary amine were protected
with the PMB or Boc group, no cyclization was observed.
(9) (a) Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2007, 46, 1444. (b) Li, C.; Chan, C.; Heimann, A. C.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 1448. (c) Simone,
D. F.; Gertsch, J.; Waser, J. Angew. Chem., Int. Ed. 2010, 49, 5767.
(10) (a) Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am.
Chem. Soc. 1991, 113, 2598. (b) Meyer, M. D.; Altenbach, R. J.; Bai, H.;
Basha, F. Z.; Carroll, W. A.; Kerwin, J. F., Jr.; Labold, S. A.; Lee, E.;
Pratt, J. K.; Sippy, K. B.; Tietje, K.; Wendt, M. D.; Brune, M. E.;
Buckner, S. A.; Hancock, A. A.; Drizin, I. J. Med. Chem. 2001, 44, 1971.
(11) (a) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett.
1976, 17, 1973. (b) Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005,
127, 11505.
(12) Chiba, S.; Kitamura, M.; Narasaka, K. J. Am. Chem. Soc. 2006,
128, 6931.
(13) (a) Chen, Z.-H.; Tu, Y.-Q.; Zhang, S.-Y.; Zhang, F.-M. Org.
Lett. 2011, 13, 724. (b) Yao, Y.; Fan, W.; Ma, X.; Zhu, L.; Xie, X.;
Zhang, Z. J. Org. Chem. 2011, 76, 2807. (c) Reddy, K. S.; Rao, B. V.
Tetrahedron: Asymmetry 2011, 22, 190.
was protected with PMB6 to give compound 11 in 65%
yield. Refluxing 11 with N2H4•H2O in EtOH afforded
amine 8 in 99% yield. Coupling 8 with isatin (9) in CH3OH
atroom temperatureprovidedimine 7 in 92% yield.7 Imine
7 was subsequently allylated with allyl magnesium chloride
in the presence of boron trifluoride to give compound 12 in
(6) Jones, S. B.; Simmons, B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2009, 131, 13606.
(7) For synthesis of a similar imine, see: Popp, F. D. J. Med. Chem.
(14) Williams, D. R.; Fromhold, M. G.; Earley, J. D. Org. Lett. 2001,
3, 2721.
(15) Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem. Soc.
1987, 109, 6493.
(16) Higuchi, K.; Sato, Y.; Tsuchimochi, M.; Sugiura, K.; Hatori,
1970, 13, 1017.
(8) Lesma, G.; Landoni, N.; Pilati, T.; Sacchetti, A.; Silvani, A.
J. Org. Chem. 2009, 74, 4537.
M.; Kawasaki, T. Org. Lett. 2009, 11, 197.
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