ORGANIC
LETTERS
2011
Vol. 13, No. 7
1778–1780
Total Synthesis of (()-Meloscine
Yujiro Hayashi, Fuyuhiko Inagaki, and Chisato Mukai*
Division of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
Received February 1, 2011
ABSTRACT
The total synthesis of (()-meloscine was completed in a highly stereoselective manner starting from the known 4-(2-aminophenyl)-2,3-dihydro-
N-methoxycarbonylpyrrole. The crucial step in this total synthesis involves the efficient construction of the tetracyclic framework of the target
natural product by the intramolecular Pauson-Khand reaction.
Meloscine (1) is a representative of the Melodinus alka-
loids, which have been isolated from Apocynacea species,
such as Melodinus scandens Forst.1 The Melodinus alka-
loids, otherwise known as meloquinolines, having a
unique pentacyclic carbon framework, represent a group of
monoterpenoid indole alkaloids and are believed to bio-
synthetically arise from the Aspidosperma alkaloid,2 18,19-
dehydrotabersonine, through its oxidative skeletal rearrange-
ment (Figure 1). The structural elucidation of meloscine
was completed by the end of the 1960s.3 The first total
Figure 1. Meloscine and dehydrotabersonine.
synthesis of melocine was completed in a racemic form
by Overman4 using the Aza-Cope rearrangement-Mannich
We now report the short total synthesis of (()-meloscine
cyclization reaction, and recently, Bach5 reported the first
by taking advantage of the intramolecular carbonylative
[2 þ 2 þ 1] cycloaddition reaction.6,7 As described in
enantioselctive total synthesis of (þ)-meloscine based on a
Scheme 1, our simple retrosynthetic analysis of the target
natural product revealed that the dihydropyrrole-propio-
template-controlled [2 þ 2] photocycloaddition reaction.
lamide derivative 3 must be the proper substrate for the
Pauson-Khand reaction,6,7 which would result in the
(1) (a) Bernauer, K.; Englert, G.; Vetter, W. Experientia 1965, 21,
374–375. (b) Plat, M.; Hachem-Mehri, M.; Koch, M.; Scheidegger, U.;
Potier, P. Tetrahedron Lett. 1970, 11, 3395–3398. (c) Daudon, M.;
Mehri, M. H.; Plat, M. M.; Hagaman, E. W.; Wenkert, E. J. Org. Chem.
1976, 41, 3275–3278. (d) Mehri, H.; Diallo, A. O.; Plat, M. Phytochem-
istry 1995, 40, 1005–1006.
(6) For recent reviews, see: (a) Brummond, K. M.; Kent, J. L.
Tetrahedron 2000, 56, 3263–3283. (b) Sugihara, T.; Yamaguchi, M.;
Nishizawa, M. Chem.;Eur. J. 2001, 7, 1589–1595. (c) Blanco-Urgoiti,
ꢀ
(2) (a) Hugel, G.; Levy, J. J. Org. Chem. 1984, 49, 3275–3277. (b)
Palmisano, G.; Danieli, B.; Lesma, G.; Riva, R.; Riva, S.; Demartin, F.;
~
ꢀ
ꢀ
J.; Anorbe, L.; Perez-Serrano, L.; Domınguez, G.; Perez-Castells, J.
´
ꢀ
Masciocchi, N. J. Org. Chem. 1984, 49, 4138–4143. (c) Hugel, G.; Levy,
Chem. Soc. Rev. 2004, 33, 32–42. (d) Lee, H.-W.; Kwong, F.-Y. Eur.
J. Org. Chem. 2010, 789–811.
J. J. Org. Chem. 1986, 51, 1594–1595.
(3) (a) Bernauer, K.; Englert, G.; Vetter, W.; Weiss, E. Helv. Chim.
(7) For total syntheses of natural products based on a Pauson-
Khand reaction of enynes from our laboratory, see: (a) Mukai, C.;
Kobayashi, M.; Kim., I. J.; Hanaoka, M. Tetrahedron 2002, 58, 5225–
5230. (b) Nomura, I.; Mukai, C. Org. Lett. 2002, 4, 4301–4304. (c)
Nomura, I.; Mukai, C. J. Org. Chem. 2004, 69, 1803–1812. (d) Kozaka,
T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72, 10147–10154. (e)
Inagaki, F.; Kinebuchi, M.; Miyakoshi, N.; Mukai, C. Org. Lett. 2010,
12, 1800–1803. (f) Otsuka, Y.; Inagaki, F.; Mukai, C. J. Org. Chem.
2010, 75, 3420–3426.
€
Acta 1969, 52, 1886–1905. (b) Oberhansli, W. E. Helv. Chim. Acta 1969,
52, 1905–1911.
(4) (a) Overman, L. E.; Rovertson, G. M.; Robichaud, A. J. J. Org.
Chem. 1989, 54, 1236–1238. (b) Overman, L. E.; Rovertson, G. M.;
Robichaud, A. J. J. Am. Chem. Soc. 1991, 113, 2598–2610.
(5) (a) Selig, P.; Bach, T. Angew. Chem., Int. Ed. 2008, 47, 5082–5084.
(b) Selig, P.; Herdtweck, E.; Bach, T. Chem.;Eur. J. 2009, 15, 3509–
3525.
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10.1021/ol200311y
Published on Web 03/07/2011
2011 American Chemical Society