Total synthesis of (+/-)-stenine using the IMDAF cycloaddition of a 2-methylthio-5-amido-substituted furan.

Article abstract of DOI:10.1021/ol025746b

[reaction: see text]. The intramolecular [4 + 2]-cycloaddition of a 2-methylthio-5-amidofuran was used to create the azepinoindole skeleton present in the Stemona alkaloid stenine. The rearranged cycloadduct was converted to stenine (1) in 11 additional steps via a sequence that features a Crabtree catalyst directed hydrogenation (9-->10), iodolactonization (2-->11), and a Keck allylation (11-->12).

Full text of DOI:10.1021/ol025746b

ORGANIC
LETTERS
2002
Vol. 4, No. 9
1515-1517
Total Synthesis of (±)-Stenine Using the
IMDAF Cycloaddition of a
2-Methylthio-5-amido-substituted Furan
John D. Ginn and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received February 19, 2002
ABSTRACT
The intramolecular [4 + 2]-cycloaddition of a 2-methylthio-5-amidofuran was used to create the azepinoindole skeleton present in the Stemona
alkaloid stenine. The rearranged cycloadduct was converted to stenine (1) in 11 additional steps via a sequence that features a Crabtree
catalyst directed hydrogenation (9f10), iodolactonization (2f11), and a Keck allylation (11f12).
The pyrrolo[1,2-a]azepine nucleus is a common structural
motif shared by several of the stemona alkaloids, including
stenine (1), whose hydroindole core skeleton contains six
contiguous stereocenters.1 Members of the stemona family
are generally classified into six groups according to their
structural features.2 Many of these alkaloids possess diverse
physiological properties3 as well as structural complexity and,
therefore, have attracted the interest of synthetic chemists.4
Previous syntheses of stenine have focused on the initial
construction of the hydroindole portion (BD rings), with
closure to the seven-membered azepine ring being postponed
until the end of the synthesis.5 We envisioned an alternative
approach, in which the azepine ring would be incorporated
at any early point in the synthetic sequence and then used
as a template for setting the required stereochemistry. Scheme
1 depicts the basic features of our strategy directed toward
stenine. Our synthesis relies on an intramolecular Diels-
Alder reaction of a 2-amido-5-alkylthio-substituted furan
(IMDAF) to create the azepinoindole skeleton.6 This is
followed by a series of reductions to set the syn-anti
stereochemical relationship at the incipient ring fusion sites
present in stenine. In this letter, we describe a highly efficient
synthesis of (()-stenine using this cycloaddition strategy that
we hope to extend to other members of the stemona family.
The required 2-methylthio-5-amidofuran (4) necessary for
the intramolecular [4 + 2]-cycloaddition reaction was
(1) Pilli, R. A.; Ferreira de Oliveira, M. C. Nat. Prod. Rep. 2000, 17,
117.
(2) Kende, A. S.; Hernando, J. I. M.; Milbank, J. B. Tetrahedron 2002,
58, 61.
(3) Sakata, K.; Aoki, K.; Chang, C. F.; Sakurai, A.; Tamura, S.;
Murakoshi, S. Agric. Biol. Chem. 1978, 42, 457. Tereda, M.; Sano, M.;
Ishii, A. I.; Kino, H.; Fukushima, S.; Noro, T. J. Pharm. Soc. Jpn. 1982,
79, 93. Shinozaki, H.; Ishida, M. Brain Res. 1985, 334, 33.
(4) For approaches to some of the Stemona alkaloids, see: Williams, D.
R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc. 1989, 111, 1923.
Williams, D. R.; Reddy, J. P.; Amato, G. S. Tetrahedron Lett. 1994, 35,
6417. Jacobi, P. A.; Lee, K. J. Am. Chem. Soc. 2000, 122, 4295. Martin, S.
F.; Barr, K. J.; Smith, D. W.; Bur, S. K. J. Am. Chem. Soc. 1999, 121,
6990. Kende, A. S.; Smalley, T. L.; Huang, H. J. Am. Chem. Soc. 1999,
121, 7431. Kende, A. S.; Martin Hernando, J. I.; Milbank, J. B. J. Org.
Lett. 2001, 3, 2505.
(5) For total syntheses of stenine, see: Chen, C. Y.; Hart, D. J. J. Org.
Chem. 1990, 55, 6236. Chen, C. Y.; Hart, D. J. J. Org. Chem. 1993, 58,
3840. Wipf, P.; Kim, Y.; Goldstein, D. M. J. Am. Chem. Soc. 1995, 117,
11106. Morimoto, Y.; Iwahashi, M.; Nishida, K.; Hayashi, Y.; Shirahama,
H. Angew. Chem., Int. Ed. Engl. 1996, 35, 904.
(6) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org. Chem.
1998, 63, 3986. Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem.
1998, 63, 5304. Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu, T. J.
Org. Chem. 1999, 64, 3595. Padwa, A.; Brodney, M. A.; Lynch, S. M. J.
Org. Chem. 2001, 66, 1716.
10.1021/ol025746b CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/28/2002

molecular sieves as a neutral scavenger to furnish imide 7
in 85% yield as a 4:1 mixture of diastereomers. Methyl-
sulfenylation of one of the methylthio groups of 7 with
DMTSF induces a thionium-promoted cyclization, and the
resulting dihydrofuran readily loses acetic acid to furnish
the desired furan.11 Interestingly, amidofuran 4 could not be
isolated under the conditions of its formation, as it rapidly
rearranged at room temperature to afford azepinoindole 3 in
80% yield as a 1:1 mixture of diastereomers. Conformational
effects imposed by the placement of a carbonyl group within
the tether, combined with a rotational bias about the C(2)-N
bond, apparently enhances the rate of the IMDAF reaction
of 4 so that it occurs readily at 25 °C.12
Scheme 1
Removal of the methylthio group was easily accomplished
by treating 3 with Raney Ni in ethanol, which afforded
azepinoindole 8 as a single diastereomer in 92% isolated
yield. Subsequent reduction of the keto group under Luche
conditions13 provided alcohol 9 in 77% isolated yield as a
single diastereomer (Scheme 3). The next step involved a
prepared by a dimethyl(methylthio)sulfonium tetrafluoro-
borate (DMTSF)7 induced cyclization of imido dithioacetal
7 (Scheme 2).8 The synthesis of 7 involved a mixed aldol
Scheme 3a
Scheme 2a
a Reagents: (a) Raney-Ni, EtOH; (b) NaBH4, CeCl3, MeOH; (c)
Crabtree’s catalyst, H2, CH2Cl2; (d) MsCl, NEt3, DBU, D.
controlled hydrogenation of the enamide π-bond. Hindered,
substituted double-bonds are often difficult to hydrogenate,
requiring forcing conditions, and frequently lead to a mixture
of isomers.14 Indeed, the hydrogenation of 9 under hetero-
geneous conditions using several palladium or rhodium
catalysts resulted in a mixture of products. Excellent stereo-
chemical control could be obtained, however, by hydrogena-
tion of 9 with the catalyst system [Ir(cod)pyr(PCy3)]PF6/
CH2Cl2 described by Crabtree and co-workers.15 The addition
of hydrogen is directed by the presence of the C10 hydroxyl
a Reagents: (a) LDA; (b) (MeS)2CHCHO; (c) Ac2O; (d)
MeO2CCH2CHdCHCH2COCl; (e) DMTSF, NEt3.
reaction of N-trimethylsilyl ꢀ-caprolactam (5) with bis-
(methylsulfanylacetaldehyde)9 followed by quenching with
acetic anhydride to give amide 6 in 80% yield. The resulting
lactam was acylated with trans-5-chlorocarbonyl-pent-3-
enoic acid methyl ester10 in the presence of 4 Å powdered
(11) For a related furan synthesis utilizing cuprous ions to remove the
sulfide group of a thioacetal, see: Cohen, T.; Herman, G.; Falck, J. R.;
Mura, A. J., Jr. J. Org. Chem. 1975, 40, 812.
(12) Bur, S. K.; Lynch, S. M.; Padwa, A. Org. Lett. 2002, 4, 473.
(13) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454.
(14) Nell, P. G. Synlett 2001, 160.
(7) Kim, J.; Pau, J.; Caserio, M. J. Org. Chem. 1979, 44, 1544. Trost,
B.; Murayama, E. J. Am. Chem. Soc. 1981, 103, 6529. Trost, B.; Sato, T.
J. Am. Chem. Soc. 1985, 107, 719.
(8) Padwa, A.; Ginn, J. D.; McClure, M. S. Org. Lett. 1999, 1, 1559.
(9) Nakane, M.; Hutchinson, C. J. Org. Chem. 1978, 43, 3922.
(10) DiMaio, J.; Gibbs, B.; Lefebvre, J.; Konishi, Y.; Munn, D.; Yue,
S. J. Med. Chem. 1992, 35, 3331.
(15) Crabtree, R. H.; Felkin, H.; Fellebeen-Khan, T.; Morris, G. E. J.
Organomet. Chem. 1979, 168, 183.
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Org. Lett., Vol. 4, No. 9, 2002

group delivering the desired syn-anti stereochemistry at the
ring fusion sites.16 The relevant coupling constants in the
NMR spectrum of 10 (J12 ) 10.2 Hz, J13 ) 5.5 Hz) were
fully consistent with its assignment and comparable in value
to those found in related ring systems.17 Final confirmation
of the stereochemistry comes from a single-crystal X-ray
analysis of 10. This result demonstrates that rapid access to
the stereochemically correct azepinoindole moiety of stenine
(and related stemona alkaloids) can be achieved via a
Crabtree catalyst directed hydrogenation reaction. Regio-
controlled dehydration of alcohol 10 to alkene 2 sets the stage
for the formation of the butyrolactone ring. Before the
planned iodolactonization of the γ,δ-unsaturated ester,5
alcohol 10 was converted to the corresponding mesylate and
this was followed by treatment with DBU in refluxing
toluene to effect elimination providing 2 in 64% yield. The
requirement of forcing conditions for elimination is undoubt-
edly related to the need of the system to adopt an antiperipla-
nar relationship of the mesylate and H4 proton (see 10). This
can only be achieved by populating the more strained boat
conformation, thereby diminishing the rate of elimination.
Scheme 4a
a Reagents: (a)LiOH,H2O;(b)I2,MeCN;(c)CH2dCHCH2SnBu3,
AlBN; (d) OsO4, NaIO4; (e) HSCH2CH2SH, BF3‚Et2O; (f) Lawes-
son’s reagent; (g) Raney-Ni (h) LDA, HMPA, MeI.
The conversion of 2 to stenine (1) was accomplished using
the sequence of reactions outlined in Scheme 4. Thus,
hydrolysis of the methyl ester with LiOH followed by
treatment with iodine gave iodolactone 11 in 60% yield.5
Subsequent Keck allylation with allyltributyl-stannane18 using
the Hart/Wipf protocol5 furnished 12 in 62% yield and with
excellent diastereoselectivity. Johnson-Lemieux oxidation19
of the allyl group afforded the expected aldehyde 13, which
was treated with 1,2-ethanedithiol and BF3‚Et2O to give 14
in 48% yield for both steps. Conversion of the amide to the
corresponding thioamide with Lawesson’s reagent20 provided
15 in 73% yield. Desulfurization with Raney nickel furnished
16 in 93% yield. Methylation of the lactone enolate derived
by treating 16 with LDA followed by reaction with methyl
iodide afforded racemic stenine (1) in an overall yield of
2.1% for the 16-step sequence starting from ꢀ-caprolactam.
Confirmation of the structure was obtained by comparison
of the spectral data with an authentic sample provided by
Professor Wipf.
In summary, this approach to stenine demonstrates the
utility of the intramolecular [4 + 2]-cycloaddition of 2-alkyl-
thio-5-amidofurans for preparing stereochemically complex
perhydroindole ring systems. All six stereocenters at the
azepinoindole core can be derived in high stereoselectivity
from the functionality present in the rearranged cycloadduct
3. Further application of this methodology toward the
construction of more complex stemona alkaloids is currently
in progress in our laboratory and will be reported at a later
date.
Acknowledgment. This research was supported by the
National Institutes of Health (GM59384 and GM60003). We
thank our colleague, Dr. Kenneth Hardcastle, for his as-
sistance with the X-ray crystallographic studies together with
Grants NSF CHE-9974864 and NIH S10-RR13673. We
thank Professors David Hart and Peter Wipf for providing
spectral data for stenine as well as an authentic sample.
(16) For the preferred addition of hydrogen from one face of a
homoallylic alcohol, see: Crabtree, R. H.; Davis, M. W. Organometallics
1983, 2, 681. Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072.
(17) Rigby, J. H.; Laurent, S.; Cavezza, A.; Heeg, M. J. J. Org. Chem.
1998, 63, 5587.
(18) Keck, G. E.; Yates, J. B. J. Am. Chem. Soc. 1982, 104, 5829.
(19) Pappo, R.; Allen, D. S.; Lemieux, R. U.; Johnson, W. S. J. Org.
Chem. 1956, 21, 478.
Supporting Information Available: Complete descrip-
tion of the synthesis and characterization of all compounds
prepared in this study together with an Ortep drawing for
compound 10. This material is available free of charge via
the Internet at http://pubs.acs.org.
(20) Scheibye, S.; Pedersen, B. S.; Lawesson, S. O. Bull. Soc. Chim.
Belg. 1978, 87, 229.
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