10 (a) B. Bhat and D. M. Harrison, Tetrahedron Lett., 1986, 27, 5873–5874;
(b) B. Bhat and D. M. Harrison, Tetrahedron, 1993, 49, 10655–10662.
11 (a) K. Fuji, T. Kawabata, T. Ohmori and M. Node, Synlett, 1995,
367–368; (b) K. Fuji, T. Kawabata, T. Ohmori, M. Shang and M. Node,
Heterocycles, 1998, 47, 951–964.
12 (a) T. Hino, T. Tanaka, K. Matsuki and M. Nakagawa, Chem. Pharm.
Bull., 1983, 31, 1806–1808; (b) M. S. Morales-R´ıos, O. R. Sua´rez-
Castillo, J. J. Trujillo-Serrato and P. Joseph-Nathan, J. Org. Chem.,
2001, 66, 1186–1192; (c) M. S. Morales-R´ıos, O. R. Sua´rez-Castillo,
J. J. Trujillo-Serrato and P. Joseph-Nathan, Tetrahedron, 2002,
58, 1479–1484; (d) J. R. Fuchs and R. L. Funk, Org. Lett., 2005, 7,
677–680.
13 (a) P. Muthusubramanian, J. S. Carle´ and C. Christophersen, Acta
Chem. Scand., Ser. B, 1983, 37, 803–807; (b) S. Takase, I. Uchida,
H. Tanaka and H. Aoki, Heterocycles, 1984, 22, 2491–2494; (c)
S. Takase, I. Uchida, H. Tanaka and H. Aoki, Tetrahedron, 1986, 42,
5879–5886; (d) M. Bruncko, D. Crich and R. Samy, J. Org. Chem.,
1994, 59, 5543–5549; (e) M. Somei, F. Yamada, T. Izumi and
M. Nakajou, Heterocycles, 1997, 45, 2327–2330; (f) J. Jensen,
U. Anthoni, C. Christophersen and P. H. Nielsen, Acta Chem.
Scand., 1995, 49, 68–71; (g) M. S. Morales-R´ıos, O. R. Sua´rez-Castillo
and P. Joseph-Nathan, J. Org. Chem., 1999, 64, 1086–1087; (h)
A. S. Cardoso, N. Srinivasan, A. M. Lobo and S. Prabhakar,
Tetrahedron Lett., 2001, 42, 6663–6666; (i) G. H. Tan, X. Zhu and
A. Ganesan, Org. Lett., 2003, 5, 1801–1803.
aldehyde 20 underwent N-prenylation followed by Wittig olefina-
tion with 21 to give the desired reverse-prenyl product 22 in 63%
overall yield. After alkaline hydrolysis of the nitrile 22, condensa-
tion of the resulting acid 23 with methylamine through
pentafluorophenol activated ester using EDC afforded
N-methylamide 24, which was recrystallized with ethyl acetate–
hexane to give the optically pure product (99% ee, 67% overall
yield form 22). Reduction of 24 with the alane complex at 215 uC
took place smoothly with cyclization to form flustramide A (3)
18
[a]D 273.2 (c 1.09, EtOH) in 92% yield.23 Additional alane-
reduction of 3 at room temperature12b led to complete construction
22
of flustramine A (1, 90%) [a]D18 2139.4 (c 0.73, EtOH) (lit.3 [a]D
240.0 (c 0.1, EtOH)).23
In summary, we have completed the asymmetric total synthesis
of four marine indole alkaloids, flustramines A (1), B (2), and
flustramides A (3), B (4) in a concise fashion. The highlights of our
synthesis include the domino reactions (olefination/isomerization/
Claisen rearrangement) for highly enantioselective construction of
the asymmetric quaternary carbon center and the chemoselective
reduction–cyclization. Further application of this methodology to
asymmetric total synthesis of a variety of pyrrolo[2,3-b]indole
alkaloids is currently in progress in our laboratory.
14 J. F. Austin, S.-G. Kim, C. J. Sinz, W.-J. Xiao and D. W. C. MacMillan,
Proc. Natl. Acad. Sci. U. S. A. , 2004, 101, 5482–5487.
15 T. Kawasaki, A. Ogawa, R. Terashima, T. Saheki, N. Ban, H. Sekiguchi,
K. Sakaguchi and M. Sakamoto, J. Org. Chem., 2005, 70,
2957–2966.
16 T. Kawasaki, R. Terashima, K. Sakaguchi, H. Sekiguchi and
M. Sakamoto, Tetrahedron Lett., 1996, 37, 7525–7528.
17 T. Kawasaki, A. Ogawa, Y. Takashima and M. Sakamoto, Tetrahedron
Lett., 2003, 44, 1591–1593.
Notes and references
1 (a) J. S. Carle´ and C. Christophersen, J. Am. Chem. Soc., 1979, 101,
4012–4013; (b) J. S. Carle´ and C. Christophersen, J. Org. Chem., 1980,
45, 1586–1589; (c) P. B. Holst, U. Anthoni, C. Christophersen and
P. H. Nielsen, J. Nat. Prod., 1994, 57, 997–1000.
2 P. Wulff, J. S. Carle´ and C. Christophersen, Comp. Biochem. Physiol. B,
1982, 71, 523–524.
3 P. Keil, E. G. Nielsen, U. Anthoni and C. Christophersen, Acta Chem.
Scand., Ser. B, 1986, 40, 555–558.
4 T. Sjoeblom, L. Bohlin and C. Christophersen, Acta Pharm. Suec., 1983,
20, 415–418.
18 T. Kawasaki, Y. Nonaka, K. Matsumura, M. Monai and M. Sakamoto,
Synth. Commun., 1999, 29, 3251–3261.
19 Y. Gao, R. M. Hanson, J. M. Klunde, S. Y. Ko, H. Masamune and
K. B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765–5780.
20 The stereochemistry can be tentatively assigned by our previous results
of an analogous debromo version17 and confirmed by completion of the
total synthesis of 2.
5 L. Peters, G. M. Ko¨nig, H. Terlau and A. D. Wright, J. Nat. Prod.,
2002, 65, 1633–1637.
21 Oxidative fission produced an unstable aldehyde, which was used
without further purification in the next reaction.
6 For reviews: U. Anthoni, C. Christophersen and P. H. Nielsen, in
Alkaloids: Chemical and Biological Perspectives, ed. S. W. Pelletiesr,
Pergamon Press, New York, 1999, vol. 13, pp. 163–236.
7 (a) S. Takase, Y. Itoh, I. Uchida, H. Tanaka and H. Aoki, Tetrahedron
Lett., 1985, 26, 847–850; (b) S. Takase, Y. Itoh, I. Uchida, H. Tanaka
and H. Aoki, Tetrahedron, 1986, 42, 5887–5894.
8 (a) S. P. Marsden, K. M. Depew and S. J. Danishefsky, J. Am. Chem.
Soc., 1994, 116, 11143–11144; (b) K. M. Depew, S. P. Marsden,
D. Zatorska, A. Zatorski, W. G. Bornmann and S. J. Danishefsky,
J. Am. Chem. Soc., 1999, 121, 11953–11963.
22 When alane-reduction of 15 at room temperature was carried out,
flustramine B (2) was directly obtained, but the yield was low (34%).
23 All spectra of the synthetic products 1–4 agreed with those of isolated
products1–3 and synthetic materials in racemic form,12 respectively.
24 K. Tani, Y. Sato, S. Okamoto and F. Sato, Tetrahedron Lett., 1993, 34,
4975–4978.
25 Racemic 17: S. R. Wilson, A. E. Davey and M. E. Guazzaroni, J. Org.
Chem., 1992, 57, 2007–2012.
26 The tentative assignment of the stereochemistry was based on
consideration of transition state in Claisen rearrangement, and
comparison of the specific rotations of the reverse-prenyl series with
that of the prenyl version.
9 (a) W.-C. Chen and M. M. Joullie´, Tetrahedron Lett., 1998, 39,
8401–8404; (b) B. M. Schiavi, D. J. Richard and M. M. Joullie´, J. Org.
Chem., 2002, 67, 620–624.
422 | Chem. Commun., 2006, 420–422
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