Total synthesis of (±)-stemonamide and (±)-isostemonamide using a radical cascade

Article abstract of DOI:10.1021/ol702563p

(Chemical Equation Presented) Total synthesis of stemonamide and isostemonamide is described. The concise construction of the tricyclic core of these alkaloids was achieved by radical cascade involving 7-endo and 5-endo cyclizations.

Full text of DOI:10.1021/ol702563p

ORGANIC
LETTERS
2008
Vol. 10, No. 2
197-199
Total Synthesis of (
)-Isostemonamide Using a Radical
Cascade
±)-Stemonamide and
(±
Tsuyoshi Taniguchi,† Genzo Tanabe,‡ Osamu Muraoka,‡ and Hiroyuki Ishibashi*,†
DiVision of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan,
and Faculty of Pharmaceutical Sciences, Kinki UniVersity, Higashi-osaka,
Osaka 577-0818, Japan
isibasi@p.kanazawa-u.ac.jp
Received October 22, 2007
ABSTRACT
Total synthesis of stemonamide and isostemonamide is described. The concise construction of the tricyclic core of these alkaloids was
achieved by radical cascade involving 7-endo and 5-endo cyclizations.
Stemona alkaloids such as stemonamide (1), isostemonamide
(2), stemonamine (3), and isostemonamine (4) isolated from
the roots of Stemona japonica that are used in Chinese and
Japanese folk medicine as cough medicines and insecticides1,2
provide attractive target molecules for total synthesis (Figure
1). These alkaloids have a complex tetracyclic structure
containing two contiguous spirocyclic quaternary centers.
Only one example was reported for the synthesis of (()-1
and (()-2, which consisted of constuction of a seven-
membered ring as a final step.3 Herein, we describe a concise
total synthesis of (()-1 and (()-2 using a radical cascade
as a key step.4
Scheme 1 shows the retrosynthetic analysis of (()-
stemonamide (1). We envisioned that compound (()-1 could
be synthesized by chemical transformation of the carbonyl
group of cyclopentanone of the tricyclic skeleton 5. Com-
pound 5 may be obtained by a Bu3SnH-mediated radical
cascade of 7 that involves 7-endo-trig cyclization of alkyl
radical and a subsequent 5-endo-trig cyclization of the
resulting R-amidoyl radical 6.5
Synthesis of 7 was begun by condensation of 1,2-cyclo-
pentanedione6 and 4-(tert-butyldimethylsiloxy)butylamine7
† Kanazawa University.
‡ Kinki University.
(1) Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Rep. 2000, 17,
117.
(2) (a) Iizuka, H.; Irie, H.; Masaki, N.; Osaki, K.; Ueno, S. J. Chem.
Soc., Chem. Commun. 1973, 125. (b) Ye, Y.; Qin, G.-W.; Xu, R.-S. J. Nat.
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(3) (a) Kende, A. S.; Martin Hernando, J. I.; Milbank, J. B. J. Org. Lett.
2001, 3, 2505. (b) Kende, A. S.; Martin Hernando, J. I.; Milbank, J. B. J.
Tetrahedron 2002, 58, 61.
(4) For reviews on radical cascades, see: (a) McCarroll, A. J.; Walton,
J. C. Angew. Chem., Int. Ed. 2001, 40, 2224. (b) McCarroll, A. J.; Walton,
J. C. J. Chem. Soc., Perkin Trans. 1 2001, 3215.
Figure 1. Stemonamide and related alkaloids.
10.1021/ol702563p CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/20/2007

Scheme 1. Synthetic Strategy
Scheme 3
dehyde (Scheme 3). A subsequent addition reaction of 12
with lithium ethyl propiolate afforded the adducts 13 and
14 in 50% and 48% yields, respectively. X-ray crystal-
lographic analysis of 13 and 14 confirmed their structures,
indicating that the phenyl groups of the mixture 12 have
stereochemistries as depicted in Scheme 3. Treatment of the
adducts 13 and 14 with magnesium methoxide in boiling
MeOH8 afforded methyl tetronates 15 and 18 in 85% and
75% yields, respectively (Scheme 4). Several attempts to
introduce the methyl group to compound 15 (e.g., LDA then
MeI) failed, but iodination compound 16 afforded methyl
tetronate derivative 17 in high yield (Scheme 4).9
followed by acylation of the resulting imine with acryloyl
chloride in the presence of N,N-diethylaniline to give
enamide 8. After removal of the TBS group of 8, mesylation
of alcohol 9, followed by bromination with lithium bromide,
afforded the radical precursor 7.
When a boiling solution of enamide 7 in toluene was
treated with Bu3SnH in the presence of 1,1′-azobis-cyclo-
hexanecarbonitrile (ACN), a mixture of almost equal amounts
of tricyclic compound 10 and its stereoisomer 11, was
obtained in 55% total yield (Scheme 2). The mixture of
Similar iodination of compound 18 with bis(trimethylpy-
ridine)iodonium hexafluorophosphate/TfOH10 followed by
Suzuki-Miyaura coupling of the resulting compound 19
afforded compound 20 (Scheme 4).
Scheme 2
Oxidative cleavage of alkenes 17 and 20 with OsO4-
NaIO4 afforded ketones 21 and 23 in 88% and 62% yields,
respectively (Scheme 5). R-Methylenation of ketone 21 with
Eschenmoser’s salt11 in the presence of the various bases
afforded the unsaturated ketone 22 in poor yield. Similar
R-methylenation using paraformaldehyde/N-methylanilinium
trifluoroacetate12 also gave an unsatisfactory result. Fortu-
nately, treatment of ketone 21 with tert-butoxybis(dimethy-
lamino)methane (Bredereck’s reagent)13 followed by reduc-
tion of the resulting enaminone with DIBAL14 and alkylation
by MeI afforded R-methylenation ketones 22 in 67% yield.
Similarly, compound 23 was converted to 24 in 74% yield.
Finally, RhCl3-mediated isomerization of the double bond15
of exo-methylene ketone 22 furnished (()-stemonamide (1)
(7) Ferraz, H. M. C.; Sasahara, R. M.; Losco, P. Tetrahedron Lett. 1992,
33, 8131.
(8) Witiak, D. T.; Tehim, A. K. J. Org. Chem. 1987, 52, 2324.
(9) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(10) Campos, P. J.; Tan, C.-Q.; Rodriguez, M. A. Tetrahedron Lett. 1995,
36, 5257.
compounds 10 and 11 was converted to the mixture of R,â-
unsaturated ketones 12 by aldol condensation with benzal-
(5) We previously reported the synthesis of a cephalotaxine skeleton by
7-endo-selective cyclization of aryl radical onto enamides followed by
5-endo cyclization of the resulting R-amidoyl radical, see: Taniguchi, T.;
Ishita, A.; Uchiyama, M.; Tamura, O.; Muraoka, O.; Tanabe, G.; Ishibashi,
H. J. Org. Chem. 2005, 70, 1922. See also references cited therein.
(6) Tomari, K.; Machiya, K.; Ichimoto, I.; Ueda, H. Agric. Biol. Chem.
1980, 44, 2135.
(11) For a recent review of the Mannich reaction, see: Arend, M.;
Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044.
(12) Gras, J. L. Tetrahedron Lett. 1978, 19, 2111.
(13) Bredereck, H.; Simchen, G.; Rebsdat, S.; Kantlehner, W.; Horn,
P.; Wahl, R.; Hoffman, H.; Grieshaber, P. Ber. 1968, 101, 41.
(14) Murai, A.; Tanimoto, N.; Sakamoto, N.; Masamune, T. J. Am. Chem.
Soc. 1988, 110, 1985.
198
Org. Lett., Vol. 10, No. 2, 2008

Scheme 4
Scheme 5
cascade process for synthesis of nitrogen-containing poly-
cyclic compounds.
(mp 232-233 °C, lit.3 mp 240-241 °C) in 31% yield.
Similar isomerization of 24 occurred smoothly to afford (()-
isostemonamide (2) (mp 223-224 °C, lit.3 mp 225-227 °C)
quantitatively (Scheme 5). Our spectral data were in accord
with the literature values.2,3
In summary, we achieved an efficient total synthesis of
(()-stemonamide (1) and (()-isostemonamide (2). The use
of a radical cascade involving two endo-selective cyclizations
allowed us to create the tricyclic core in one step. The present
synthesis clearly demonstrates the usefulness of the radical
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Sciences and Technology of Japan. We
are grateful to Professor Yang Ye (Shanghai Institute of
Materia Medica) for giving us the 1H and 13C NMR spectra
of natural 1 and 2.
Supporting Information Available: Expermental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) (a) Grieco, P.; Nishizawa, M.; Marinovic, N.; Ehmann, W. J. J.
Am. Chem. Soc. 1976, 98, 7102. (b) Andrieux, J.; Barton, D. H. R.; Patin,
H. J. Chem. Soc., Perkin Trans. 1 1977, 359.
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