rolo[2,3-b]indoles 6a and 6b. We were delighted to find that
the conditions used have only a small effect on our system
since 6a and 6b could be isolated with 96% ee.
The scope of the reaction was next investigated with
various 2-iodo-tryptophan derivatives using the optimized
conditions: results are summarized in Table 1. In most cases,
polycyclic products were obtained in good to excellent yields.
Moreover, protecting groups on the nitrogen atoms have little
influence as complete conversion was observed in all cases,
and even substrate 7d possessing two bulky carbamates
cyclized smoothly (entry 4). However, the presence of two
Boc groups (entry 5) or smaller substituents (tryptophanol,
entries 6 and 7, or tryptamine derivatives, entry 8) did result
in a more sluggish cyclization. Interestingly, yields did not
significantly vary upon scaling up the reactions since
substrates 6a, 6b, and 6d were obtained in similar yields
when the reaction was performed on milligram or multigram
scales. It is noteworthy that the absence of a carbamate or
an amide on the indole nitrogen has a dramatic impact on
the reaction, since cyclization is completely inhibited with
such substrates, and reduction is the preferred pathway (entry
9). This indicates that either a deprotonation of the indole
inhibits the cyclization or that a strong ortho effect is
operating.15 The presence of a chelating group close to the
iodide might stabilize the intermediate copper complex,
therefore facilitating the overall cyclization process.
Table 1. Scope and Limitations
The hexahydropyrrolo[2,3-b]indole core being an impor-
tant constituent of various biologically active peptides, the
ability to form the pyrroloindole skeleton within peptides is
very attractive since it offers an interesting alternative to
classical routes that involve its formation prior to peptide
bond formation. The cyclization of iodinated dipeptides 12
and 14 was therefore considered (Scheme 3). Using trans-
cyclohexane-1,2-diamine as ligand, the desired TPI-isoleu-
cine 13 and TPI-phenylalanine 15 cyclized products were
obtained in good yields and without noticeable epimeriza-
tion.16 These results demonstrate the possibility of a late stage
cyclization and should pave the way for its use on more
complex peptidic or cyclopeptidic systems.
(7) For selected syntheses, see: (a) Depew, K. M.; Marsden, S. P.;
Zatorska, D.; Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J. J. Am.
Chem. Soc. 1999, 121, 11953. (b) Roe, J. M.; Webster, R. A. B.; Ganesan,
A. Org. Lett. 2003, 5, 2825. (c) Baran, P. S.; Guerrero, C. A.; Corey, E. J.
J. Am. Chem. Soc. 2003, 125, 5628. (d) Hewitt, P. R.; Cleator, E.; Ley,
S. V. Org. Biomol. Chem. 2004, 2, 2415. (e) Lindel, T.; Bra¨uchle, L.; Golz,
G.; Bo¨hrer, P. Org. Lett. 2007, 9, 283. (f) Movassaghi, M.; Schmidt, M. A.;
Ashenhurst, J. A. Angew. Chem., Int. Ed. 2008, 47, 1485. (g) Shangguan,
N.; Hehre, W. J.; Ohlinger, W. S.; Beavers, M. P.; Joullie´, M. J. Am. Chem.
Soc. 2008, 130, 6281. (h) Dounay, A. B.; Humphreys, P. G.; Overman,
L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2008, 130, 5368. (i) Matsuda,
Y.; Kitajima, M.; Takayama, H. Org. Lett. 2008, 10, 125.
(8) For examples, see: (a) Ohno, M.; Tanaka, S.; Shieh, T.-C.; Spande,
T. F. J. Org. Chem. 1984, 49, 5069. (b) Kamenecka, T. M.; Danishefsky,
S. J. Chem. Eur. J. 2001, 7, 41. (c) Okada, M.; Sato, I.; Cho, S. J.; Dubnau,
D.; Sakagami, Y. Tetrahedron 2006, 62, 8907. (d) Cardoso, A. S.; Marques,
M. M. B.; Srinivasan, N.; Prabhakar, S.; Lobo, A. M. Tetrahedron 2007,
63, 10211.
(9) (a) Ohno, M.; Spande, T. F.; Witkop, B. J. Am. Chem. Soc. 1968,
90, 6521. (b) Ohno, M.; Spande, T. F.; Witkop, B. J. Am. Chem. Soc. 1970,
92, 343.
(10) Bailey, P. D.; Cochrane, P. J.; Irvine, F.; Morgan, K. M.; Pearson,
D. P. J.; Veal, K. T. Tetrahedron Lett. 1999, 40, 4593.
(11) (a) Toumi, M.; Couty, F.; Evano, G. Angew. Chem., Int. Ed. 2007,
46, 572. (b) Toumi, M.; Couty, F.; Evano, G. J. Org. Chem. 2007, 72,
9003. (c) Toumi, M.; Couty, F.; Evano, G. Synlett 2008, 29.
(12) (a) Mingoia, Q. Gazz. Chim. Ital. 1930, 60, 509. (b) Snider, B. B.;
Zeng, H. J. Org. Chem. 2003, 68, 545.
(13) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727. (b) Klapars, A.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2002, 124, 7421.
(14) Yuen, J.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 653.
(15) For an ortho effect with trifluoroacetamides, see: (a) Cai, Q.; Zou,
B.; Ma, D. Angew. Chem., Int. Ed. 2006, 45, 1276. (b) Xie, X.; Chen, Y.;
Ma, D. J. Am. Chem. Soc. 2006, 128, 16050. (c) Zou, B.; Yuan, Q.; Ma, D.
Angew. Chem., Int. Ed. 2007, 46, 2598. (d) Liu, F.; Ma, D. J. Org. Chem.
2007, 72, 4844.
a Conditions A: CuI (10 mol %), N,N′-dimethylethylenediamine (20
mol %), K3PO4 (2 equiv), toluene (0.1 mol·L-1), 110 °C, 12-16 h.
Conditions B: CuI (10 mol %), trans-cyclohexane-1,2-diamine (20 mol %),
K3PO4 (2 equiv), toluene (0.1 mol·L-1), 110 °C, 12-16 h. b Yield of pure,
isolated product. c Reaction performed on gram scale. d Reaction performed
on a 13 g scale.
(16) Compounds obtained as single diastereoisomers by 1H NMR
analysis of crude reaction mixtures.
Org. Lett., Vol. 10, No. 17, 2008
3843