A short diastereoselective synthesis of the putative alkaloid jamtine, using a tandem Pummerer/Mannich cyclization sequence

Article abstract of DOI:10.1021/jo026471g

Treatment of 2-phenylhex-5-enal with benzylamine followed by sequential reaction with ethylthioacetyl chloride and sodium periodate oxidation afforded a E/Z mixture of α-sulfinylamides. As anticipated from a 4π-conrotatory mechanism, cyclization of each olefin afforded fused isoquinoline lactams as single diastereomers epimeric at the ethylthio position without any cross contamination. Some preliminary studies were directed toward the synthesis of mesembrine using a 3,4-dimethoxy aryl group. In this case, the Z-enamide prefers to undergo electrophilic aromatic substitution to give a substituted azepinone as the preferred product in 87% yield. In contrast, the E-enamide isomer provided the desired hydroindolone. The convergency and stereochemical control associated with the tandem Pummerer/Mannich cyclization make it particularly suited for the assembly of jamtine, a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties. The key step in the synthesis involves a domino thionium/N-acyliminium ion cyclization to provide the tricyclic ring skeleton 27a as the major diastereomer. Deprotonation of 27a with NaH gave 28a, which contains the fully assembled skeleton of jamtine. Completion of the synthesis entailed installation of the double bond and reduction of the lactam. Oxidation of a synthetic sample of jamtine with MCPBA afforded the corresponding N-oxide, which does not match the spectral data reported in the literature for this alkaloid. Our synthetic efforts raise the possibility of a revision of the earlier assignment.

Full text of DOI:10.1021/jo026471g

A Sh or t Dia ster eoselective Syn th esis of th e P u ta tive Alk a loid
J a m tin e, Usin g a Ta n d em P u m m er er /Ma n n ich Cycliza tion
Sequ en ce
Albert Padwa,* M. Diana Danca,† Kenneth I. Hardcastle,‡ and Michael S. McClure
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received September 24, 2002
Treatment of 2-phenylhex-5-enal with benzylamine followed by sequential reaction with ethyl-
thioacetyl chloride and sodium periodate oxidation afforded a E/Z mixture of R-sulfinylamides. As
anticipated from a 4π-conrotatory mechanism, cyclization of each olefin afforded fused isoquinoline
lactams as single diastereomers epimeric at the ethylthio position without any cross contamination.
Some preliminary studies were directed toward the synthesis of mesembrine using a 3,4-dimethoxy
aryl group. In this case, the Z-enamide prefers to undergo electrophilic aromatic substitution to
give a substituted azepinone as the preferred product in 87% yield. In contrast, the E-enamide
isomer provided the desired hydroindolone. The convergency and stereochemical control associated
with the tandem Pummerer /Mannich cyclization make it particularly suited for the assembly of
jamtine, a tetrahydroisoquinoline alkaloid reputed for its therapeutic properties. The key step in
the synthesis involves a domino thionium/N-acyliminium ion cyclization to provide the tricyclic
ring skeleton 27a as the major diastereomer. Deprotonation of 27a with NaH gave 28a , which
contains the fully assembled skeleton of jamtine. Completion of the synthesis entailed installation
of the double bond and reduction of the lactam. Oxidation of a synthetic sample of jamtine with
MCPBA afforded the corresponding N-oxide, which does not match the spectral data reported in
the literature for this alkaloid. Our synthetic efforts raise the possibility of a revision of the earlier
assignment.
Polyannular heterocyclic compounds have attracted
much interest and a variety of synthetic methodologies
have been developed over the years.1-8 The elaboration
of ring-fused heterocycles based upon cascade sequences
such as cationic cyclization,9 radical cyclization,10 and
tandem Heck processes11 allows for the rapid and stereo-
controlled synthesis of azapolycyclic skeletons. Domino
reactions are among the most powerful strategic tools
available to the synthetic organic chemist because they
rapidly increase the complexity of a substrate while at
the same time making economical use of available
functional groups.12-23 N-Acyliminium ion-mediated car-
bon-carbon bond-forming reactions have been utilized
† NIH Postdoctoral Fellow, grant GM20461-02.
‡ Emory University X-ray Crystallography Laboratory.
(1) Comprehensive Heterocyclic Chemistry; Katritzky, A., Rees, C.
W., Scriven, E. F. V., Eds.; Elsevier Science: Oxford, U.K., 1996.
(2) Rawal, V. H.; Michoud, C.; Monestel, R. F. J . Am. Chem. Soc.
1993, 46, 3030. Kuehne, M. E.; Matsko, T. H.; Bohnert, J . C.; Motyka,
L.; Oliver-Smith, D. J . Org. Chem. 1981, 46, 2002. Kuehne, M. E.;
Earley, W. G. Tetrahedron 1983, 39, 3707. Kuehne, M. E.; Brook, C.
S.; Xu, F.; Parsons, R. Pure Appl. Chem. 1994, 66, 2095. Nkiliza, J .;
Vercauteren, J . Tetrahedron Lett. 1991, 32, 1787.
(8) Mori, M.; Kuroda, S.; Zhang, C.; Sato, Y. J . Org. Chem. 1997,
62, 3263. Takano, S.; Inomata, K.; Ogasawara, K. Chem. Lett. 1992,
443. Uesaka, N.; Saitoh, F.; Mori, M.; Shibasaki, M.; Okamura, K.;
Date, T. J . Org. Chem. 1994, 59, 5633
(9) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
131. Tietze, L. F. Chem. Rev. 1996, 96, 115.
(10) Ho, T. L. Tandem Organic Reactions; Wiley: New York, 1992.
Bunce, R. A. Tetrahedron 1995, 51, 13103. Parsons, P. J .; Penkett, C.
S.; Shell, A. J . Chem. Rev. 1995, 95, 195.
(11) Grigg, R.; Sridharan, S.; York, M. Tetrahedron Lett. 1998, 39,
4139. de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2374.
(12) Waldmann, H. Domino Reaction in Organic Synthesis Highlight
II; Waldmann, H., Ed.; VCH: Weinheim, Germany, 1995; pp 193-
202.
(13) Curran, D. P. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4, p 779.
(14) Wender, P. A., Ed. Frontiers in Organic Synthesis. In Chem.
Rev. 1996, 96, 1-600.
(15) Grigg, R.; Kennewell, P.; Teasdale, A. J . Tetrahedron Lett. 1992,
33, 7789 and references therein. Snider, B. B.; Vo, N. H.; Foxman, B.
M. J . Org. Chem. 1993, 58, 7228 and references therein. Ali, A.;
Harrowven, D. C.; Pattenden, G. Tetrahedron Lett. 1992, 33, 2851.
Batty, D.; Crich, D. J . Chem. Soc., Perkin Trans. 1 1992, 3205 and
references therein.
(3) Overman, L. E.; Sworin, M.; Burk, R. M. J . Org. Chem. 1983,
48, 2685. Overman, L. E.; Sugai, S. Helv. Chim. Acta 1985, 68, 745.
Overman, L. E.; Robertson, G.; Robichaud, A. J . J . Org. Chem. 1989,
54, 1236.
(4) Sole, D.; Bonjoch, J . Tetrahedron Lett. 1991, 32, 5183. Bonjoch,
J .; Sole, D.; Bosch, J . J . Am. Chem. Soc. 1993, 115, 2064. Schultz, A.
G.; Holoboski, M. A.; Smyth, M. S. J . Am. Chem. Soc. 1993, 115, 7904.
Kraus, G. A.; Thomas, P. J .; Bougie, D.; Chen, L. J . Org. Chem. 1990,
55, 1624. Schultz, A. G.; Guzzo, P. R.; Nowak, D. M. J . Org. Chem.
1995, 60, 8044. Schultz, A. G.; Holoboski, M. A.; Smyth, M. S. J . Am.
Chem. Soc. 1996, 118, 6210.
(5) Rigby, J . H.; Laurent, S.; Cavezza, A.; Heeg, M. J . J . Org. Chem.
1998, 63, 5587. Rigby, J . H.; Qabar, M. H. J . Org. Chem. 1993, 58,
4473. Rigby, J . H.; Qabar, M.; Ahmed, G.; Hughes, R. C. Tetrahedron
1993, 49, 10219. Rigby, J . H.; Hughes, R. C.; Heeg, M. J . J . Am. Chem.
Soc. 1995, 117, 7834. Rigby, J . H.; Mateo, M. E. Tetrahedron 1996,
52, 10569.
(6) Pearson, W. H.; Postich, M. J . J . Org. Chem. 1994, 59, 5662.
Padwa, A.; Price, A. T. J . Org. Chem. 1995, 60, 6258.
(7) Gallagher, T.; Magnus, P.; Huffman, J . C. J . Am. Chem. Soc.
1983, 105, 4750. Magnus, P.; Gallagher, T.; Brown, P.; Pappalardo, P.
Acc. Chem. Res. 1984, 17, 35.
10.1021/jo026471g CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/01/2003
J . Org. Chem. 2003, 68, 929-941
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Padwa et al.
in an impressive number of synthetic applications.23-25
In recent years, the Pummerer reaction followed by a
π-cyclization has also been found to be a very effective
and general method for the preparation of many di-
verse azapolycyclic skeletons.26-28 The combination of a
Pummerer/Mannich cyclization sequence offers unique
opportunities for the assemblage of complex target
molecules.29,30
SCHEME 1
A strategy that we have found particularly effective
in the design of new processes for heterocyclic ring
construction is to employ ene-amides such as 1 which
contains a tethered sulfoxide.31 The cascade reaction can
be triggered by using a Pummerer promoter and, once
the thionium ion (i.e., 2) is generated, cyclization occurs
(16) Chamberlin, A. R.; Bloom, S. H.; Cervini, L. A.; Fotsch, C. H.
J . Am. Chem. Soc. 1988, 110, 4788. Canonne, P.; Boulanger, R.;
Bernatchez, M. Tetrahedron Lett. 1987, 28, 4997. Bailey, W. F.; Ovaska,
T. V. Tetrahedron Lett. 1990, 31, 627. Bunce, R. A.; Dowdy, E. D.;
J ones, P. B.; Holt, E. M. J . Org. Chem. 1993, 58, 7143 and references
therein.
(17) Curran, D. P. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 4,
Chapter 4.2. Motherwell, W. B.; Crich, D. Free Radical Reactions in
Organic Synthesis; Academic Press: London, 1991. Mowbray, C. E.;
Pattenden, G. Tetrahedron Lett. 1993, 34, 127 and references therein.
Hitchcock, S. A.; Pattenden, G. Tetrahedron Lett. 1992, 33, 4843.
Curran, D. P.; Sisko, J .; Yeske, P. E.; Liu, H. Pure Appl. Chem. 1993,
65, 1153. Curran, D. P.; Shen, W. Tetrahedron 1993, 49, 755. Parker,
K. A.; Fokas, D. J . Am. Chem. Soc. 1992, 114, 9688.
(18) Davies, H. M. L.; Clark, T. J .; Smith, H. D. J . Org. Chem. 1991,
56, 3817 and references therein. Padwa, A.; Fryxell, G. E.; Zhi, L. J .
Am. Chem. Soc. 1990, 112, 3100 and references therein. Kim, O. K.;
Wulff, W. D.; J iang, W.; Ball, R. G. J . Org. Chem. 1993, 58, 5571.
(19) Danheiser, R. L.; Gee, S. K.; Perez, J . J . J . Am. Chem. Soc.
1986, 108, 806. Nicolaou, K. C.; Petasis, N. A. In Strategies and Tactics
in Organic Synthesis; Lindberg, T., Ed.; Academic Press: New York,
1984; Vol. 1, pp 155-173. Denmark, S. E.; Thorarensen, A. Chem. Rev.
1996, 96, 137. Funk, R. L.; Vollhardt, K. P. C. Chem. Soc. Rev. 1980,
9, 41.
(20) Wender, P. A.; Sieburth, S. M.; Petraitis, J . J .; Singh, S. K.
Tetrahedron 1981, 37, 3967 and references therein. Marko´, I. E.; Seres,
P.; Swarbrick, T. M.; Staton, I.; Adams, H. Tetrahedron Lett. 1992,
33, 5649 and references therein. Guevel, R.; Paquette, L. A. J . Am.
Chem. Soc. 1994, 116, 1776 and references therein. J isheng, L.;
Gallardo, T.; White, J . B. J . Org. Chem. 1990, 55, 5426.
(21) Sutherland, J . K. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 3, p
341.
(22) Overman, L. E. Acc. Chem. Res. 1992, 25, 352. Overman, L.
E.; Ricca, D. J . In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 2, pp 1007-
1046.
(23) Blumenkopf, T A.; Overman, L. E. Chem. Rev. 1986, 86, 857.
(24) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.
Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991;
Vol. 2, pp 1047-1082.
(25) Hart, D. J . J . Org. Chem. 1981, 46, 367. Hart, D. J .; Kanai, K.
J . Org. Chem. 1982, 47, 1555. Hart, D. J .; Kanai, K. J . Am. Chem.
Soc. 1983, 105, 1255.
(26) Padwa, A.; Gunn, D. E.; Osterhout, M. H. Synthesis 1997, 1353.
(27) Grierson, D. S.; Husson, H. P. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
UK, 1991; Vol. 6, pp 909-947.
(28) Kennedy, M.; McKervey, M. A. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
UK, 1991; Vol. 7, pp 193-216.
(29) Ishibashi, H.; Sato, Takahashi, M.; Hayashi, M.; Ikeda, M.
Heterocycles 1988, 27, 2787. Tamura, Y.; Maeda, H.; Akai, S.; Ishibashi,
H. Tetrahedron Lett. 1982, 23, 2209. Ishibashi, H.; Sato, K.; Maruyama,
K.; Ikeda, M.; Tamura, Y. Chem. Pharm. Bull. 1985, 33, 4593.
Ishibashi, H.; Harada, S.; Sato, K.; Ikeda, M.; Akai, S.; Tamura, Y.
Chem. Pharm. Bull. 1985, 33, 5278. Ishibashi, H.; Sato, K.; Ikeda, M.;
Maeda, H.; Akai, S.; Tamura, Y. J . Chem. Soc., Perkin Trans. 1 1985,
605.
onto the proximal enamide π-bond to furnish N-acyl-
iminium ion 3 (Scheme 1). Since a tethered nucleophile
is present in the starting material, a subsequent cycliza-
tion takes place resulting in the formation of the octa-
hydropyrrolo[2,1-a]-isoquinolinone 4. To showcase the
method, the above strategy was applied to the synthesis
of jamtine,32 a novel tetrahydroisoquinoline alkaloid that
was isolated from a climbing shrub in Pakistan.33 The
present paper documents the results of our studies.34
Resu lts a n d Discu ssion
The convergency and stereochemical control associated
with the Pummerer/Mannich ion cyclization sequence
make it particularly suited for the assembly of natural
product scaffolds. With this in mind, some preliminary
model studies were first directed toward the synthesis
of the cis-3a-aryloctahydroindole nucleus which corre-
sponds to a prominent substructural motif found in the
Amaryllidaceae and Sceletium alkaloids.35 This ring
system (i.e., 8) represents a considerable synthetic chal-
lenge as a result of the presence of a highly congested
quaternary center at C3a. In an earlier study we had
demonstrated that treatment of the model Z-enamido
sulfoxide 5 with p-TsOH afforded tosylate 6, which was
subsequently converted to the octahydro-indolone skel-
eton 7 (Scheme 2).31
The success we had with the cyclization of enamido
sulfoxide 5 suggested that the method might be ap-
plicable for the synthesis of mesembrine.36 Although
mesembrine is devoid of significant biological activity, it
has nevertheless attracted considerable interest over the
years as a favorite target in alkaloid synthesis.37 Beyond
the issue of testing new methodologies, the preparation
of this alkaloid provides access toward the more complex
Sceletium alkaloids of pharmacological interest, such as
tazettine, lycoramine, or galanthamine.38 Initial feasibil-
(32) Ahmad, V. U.; Rahman, A.; Rasheed, T.; Rehman, H. Hetero-
cycles 1987, 26, 1251.
(33) Ahmad, V. U.; Iqbal, S. Phytochemistry 1993, 3, 735.
(34) For a preliminary report, see: Padwa, A.; Danca, D. M. Org.
Lett. 2002, 4, 715.
(30) Padwa, A.; Hennig, R.; Kappe, C. O.; Rr, T. S. J . Org. Chem.
1998, 63, 32, 1144. Padwa, A.; Kappe, C. O.; Reger, T. S. J . Org. Chem.
1996, 61, 4888.
(31) Padwa, A.; Heidelbaugh, T. M.; Kuethe, J . T.; McClure, M. S.
J . Org. Chem. 1998, 63, 6778.
(35) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic Press
Inc.: New York, 1987; Vol. 30, pp 251-377. Lewis, J . R. Nat. Prod.
Rep. 1994, 11, 329. J effs, P. W. In The Alkaloids; Rodrigo, R. G. A.,
Ed.; Academic Press: New York, 1981; Vol. 19, pp 1-80.
(36) Bodendorf, K.; Krieger, W. Arch. Pharm. 1957, 290, 441.
930 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of the Alkaloid J amtine
SCHEME 2
SCHEME 3
SCHEME 4
ity studies were conducted with the simple phenyl-
substituted enamide 9. Treatment of benzylamine with
2-phenylhex-5-enal followed by sequential reaction with
ethylthioacetyl chloride and sodium periodate oxidation
ultimately afforded a 2:1-mixture of the E- and Z-
enamides 9 and 10 (Scheme 3). The olefin geometry was
assigned on the basis of an NOE between the vinylic and
allylic methylene hydrogens. Heating a sample of 9 with
p-TsOH in benzene at 80 °C afforded tosylate 11 as the
major diastereomer in 76% yield. As anticipated from a
4π-conrotatory mechanism,31 cyclization of each olefin
(i.e., 9 or 10) afforded single diastereomers epimeric at
the ethylthio position without any cross contamination.
A set of isomeric R-sulfinylenamides 13 and 14 con-
taining the ubiquitous 3,4-dimethoxyphenyl moiety was
also prepared by a related synthetic method. The
dimethoxy-substituted aryl group was required for the
synthesis of mesembrine. Surprisingly, when Z-enamide
13 was exposed to p-TsOH, the unexpected azepinone 15
was obtained in 78% isolated yield as the exclusive
product (Scheme 4). Treatment of 15 with Raney-Ni
resulted in reduction of the ethylthio group and gave rise
to 16 in 87% yield. The presence of the dimethoxy
substituents on the aromatic ring certainly enhances its
(37) For previous synthesis of mesembrine, see: Kamikubo, T.;
Ogasawara, K. J . Chem. Soc., Chem. Commun. 1998, 783. Yamada,
O.; Ogasawara, K. Tetrahedron Lett. 1998, 39, 7747. Dalko, P. I.; Brun,
V.; Langlois, T. Tetrahedron Lett. 1998, 39, 8979. Mori, M.; Kuroda,
S.; Zhang, C.-S.; Sato, Y. J . Org. Chem. 1997, 62, 3263. Denmark, S.
E.; Marcin, L. R. J . Org. Chem. 1997, 62, 1675. Rajagopalan, P.
Tetrahedron Lett. 1997, 38, 1893. Takano, S.; Samizu, K.; Ogasawara,
K. Chem. Lett. 1990, 1239. Winkler, J . D.; Muller, C. L.; Scott, R. D.
J . Am. Chem. Soc. 1988, 110, 4831. Hoshino, O.; Sanaki, S.; Shima-
mura, N.; Onodera, A.; Umezawa, B. Chem. Pharm. Bull. 1987, 35,
2734. Meyers, A. I.; Hanreich, R.; Wanner, K. T. J . Am. Chem. Soc.
1985, 107, 7776. Kochhar, K. S.; Pinnick, H. W. Tetrahedron Lett. 1983,
24, 4785. Sanchez, I. H.; Soria, J . J .; Larraza, M. I.; Flores, H. J .
Tetrahedron Lett. 1983, 24, 551. Keck, G. E.; Webb, R. R., II J . Org.
Chem. 1982, 47, 1302. Takano, S.; Imamura, Y.; Ogasawara, K.
Tetrahedron Lett. 1981, 22, 4479. Takano, S.; Imamura, Y.; Ogasawara,
K. Chem. Lett. 1981, 1385. Strauss, H. F.; Wiechers, A. Tetrahedron
Lett. 1979, 4495. Martin, S. F.; Puckette, T. A.; Colapret, J . A. J . Org.
Chem. 1979, 44, 3391. Stevens, R. V.; Wentland, M. P. J . Am. Chem.
Soc. 1968, 90, 5580. Keely, S. L., J r.; Tahk, F. C. J . Am. Chem. Soc.
1968, 90, 5584. Shamma, M.; Rodriguez, H. R. Tetrahedron 1968, 24,
6583. Curphey, T. J .; Kim, H. L. Tetrahedron Lett. 1968, 1441.
(38) Lewis, J . R. Nat. Prod. Rep. 1998, 15, 107.
electron density. This, coupled with its close proximity
to the incipient thionium ion, allowed the electrophilic
aromatic substitution process to become the preferred
reaction path with this stereoisomer. In mark contrast,
the reaction of R-sulfinyl enamide 14 with p-TsOH
provided the desired hydroindolone 17, but as a 3:1
mixture of tosylate isomers and in only 50% yield.
Attempts to isomerize the Z-enamide 13 to the E-isomer
14 failed to provide us with sufficient quantities of the
necessary stereoisomer and consequently we abandoned
this approach toward mesembrine.
To further elaborate the unique features exhibited by
olefin geometry on the course of the cyclization reaction,
we decided to examine the reactivity patterns of the
related R-sulfinyl enamides 18 and 19. Treatment of 18
with 2 equiv of p-TsOH in refluxing benzene afforded the
rearranged lactam 21 in 62% yield (Scheme 5). In this
J . Org. Chem, Vol. 68, No. 3, 2003 931

Padwa et al.
SCHEME 5
SCHEME 6
case, the initially formed thionium ion 20 undergoes a
1,2-aryl shift and is followed by deprotonation to furnish
the observed product. Following the trend observed in
the previous series, cyclization of the Z-enamide 19
provided azepinone 22 in 76% yield. Raney-Ni reduction
of 22 smoothly removed the ethylthio group furnishing
23 in excellent yield. With the Z-stereoisomer 19, attack
by the activated aromatic ring onto the initially formed
thionium ion is again much faster than the Nazarov-like
electrocyclization that can only occur with the E-stereo-
isomer 18.
formulated about their role in plant metabolism.41 In fact,
more than 200 individual alkaloid N-oxides have been
described in the literature, but it well may be that many
other N-oxides have gone undetected.41 Generally, the
N-oxides of aliphatic tertiary amines are very polar
substances not unlike the corresponding quaternary salts
in terms of solubility and chromatographic behavior.42
Alkaloid N-oxides such as 24 are easily obtained from
the amine and likewise are easily deoxygenated.43 Since
the nonbasic, water-soluble N-oxide of jamtine is quite
different from the corresponding amine in its properties,
we opted to first synthesize jamtine (25) and then carry
out a subsequent oxidation at the amino site. For our
purposes, a synthesis of (()-jamtine provided an op-
portunity to further develop the tandem Pummerer/
Mannich sequence and its application to tetrahydro-
isoquinoline alkaloids.
Our retrosynthetic analysis of this structure is outlined
in Scheme 6. The attractiveness of this strategem in-
volves the efficient use of the ethylthio group in each of
the critical stages of the synthesis. The first step in this
highly convergent synthesis involves the domino ring
closure of enamido sulfoxide 26 to provide the tricyclic
ring skeleton 27. Assembly of the D ring should proceed
uneventfully by a base-induced cyclization and furnish
the tetracyclic core of jamtine (25). Finally, standard
functional group manipulations and selective reduction
of the lactam would lead to the desired tetrahydroiso-
quinoline.
J a m tin e
To properly highlight the potential of the linked
thionium/N-acyliminium ion cascade, we opted to use the
method for the synthesis of the alkaloid jamtine N-oxide
(24). In 1987, Rahman and co-workers32 reported the
isolation of a novel N-oxide from the Cocculus hirsutus,39
which is commonly found as a shrub in Pakistan. Its
various parts are reputed to possess purgative, diuretic,
abortificient, and antituberculotic properties and the
shrub is used as a remedy for rheumatism and diarrhea.40
The compound was named jamtine N-oxide and assigned
the structure 24 on the basis of extensive NMR studies.
This alkaloid contains a tetrahydroisoquinoline skeleton,
a double bond in ring D, and two stereogenic centers in
a relatively compact molecule.
Our approach starts from commercially available ꢀ-
caprolactone which was transformed into the open chain
hydroxymethyl ester under acidic conditions.44 The pri-
mary alcohol was converted into a series of ethers (29-
31)45-47 as this would provide us with some flexibility in
generating the alcohol at some later point in the syn-
It should be noted that reports of the isolation of
alkaloid N-oxides have increased in number since 1970
and these compounds have become recognized as authen-
tic natural products, not artifacts. Hypotheses have been
(41) Albini, A. Heterocycles 1992, 34, 1973.
(42) Wagner, H.; Neidhart, U.; Tittel, G. Planta Med. 1981, 41, 232.
(43) Mattock, A. R. Anal. Chem. 1967, 39, 443.
(44) King, S. A. J . Org. Chem. 1994, 59, 2253.
(45) Hoye, T. R.; Kurth, M. J .; Lo, V. Tetrahedron Lett. 1981, 22,
815.
(46) Ahmar, M.; Bloch, R.; Bortolussi, M. Synth. Commun. 1991,
1071.
(47) Bookser, B. C.; Kasibhatla, S. R.; Applemann, J . R.; Erion, M.
D. J . Med. Chem. 2000, 43, 1495.
(39) Ahmad, V. U.; Iqbal, S. Phytochemistry 1993, 3, 735. Ahmad,
V. U.; Iqbal, S. Nat. Prod. Lett. 1993, 2, 105. Chopra, R. N.; Chopra, I.
C.; Handa, K. L.; Kapoor, L. D. Indigenous Drugs of India; U. N. Dhar
and Sons Pvt. Ltd.: Calcutta, India, 1958; p 501. Kirtikar, K. R.; Basu,
B. D. The Indian Medicinal Plants; L. M. Basu Allahabad, 1933; Vol.
1, p 86. Nadkarni, K. M. Indian Materia Medica; Popular Prakashan
Pvt. Ltd.: New Delhi, India, 1976; Vol. 1, 362.
(40) Rao, K. V. J .; Rao, L. R. C. J . Sci. Ind. Res. 1981, 20B, 125.
932 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of the Alkaloid J amtine
SCHEME 7a
SCHEME 8a
a
Reagents: (a) MsCl, Et3N; (b) CSA, benzene, reflux; (c) NaI,
acetone; (d) NaH, THF, reflux.
SCHEME 9a
a
Reagents: (a) H+, MeOH; (b) see refs 45-47; (c) LDA, HCO2Et;
(d) 3,4-dimethoxyphenethylamine, EtSCH2COCl; (e) NaIO4, MeOH/
H2O.
thesis. Each carbomethoxy ether was formylated by
treatment with LDA and ethyl formate to give the
aldehydic esters 32-34 in good yield (Scheme 7). Con-
densation with 3,4-dimethoxyphenethylamine led to the
expected enamines, which were in turn acylated with
ethyl sulfenylacetyl chloride48 to provide enamides 35-
37 in high yield as Z/ E-mixtures of isomers. Oxidation
to the corresponding sulfoxides 38-40 was easily achieved
by using NaIO4 in aqueous methanol in good overall
yield. In the case of 40, the tert-butyldimethyl silyl group
was removed under the oxidative conditions required for
the formation of the sulfoxide, thereby allowing for an
effortless purification of the highly polar alcohol 41.
a
Reagents: (a) MsCl, Et3N, 68%; (b) CSA, benzene, reflux, 75%;
NaI, acetone 93%; (d) NaH, THF, reflux, 72%.
isolated in 34% overall yield corresponded to the unusual
cyclic enol ether 42, whose structure was unequivocally
established by an X-ray crystallographic study.
Scheme 9 outlines a working mechanistic hypothesis
to rationalize the formation of 42. Under the conditions
used to convert the hydroxyl functionality to the corre-
sponding mesylate, reduction of the sulfoxide to the
corresponding sulfide 43 also occurred, an event not
unprecedented in the literature.49 In fact, we have been
able to isolate sulfide 43 in 68% yield from this reaction.
When treated with camphorsulfonic acid, 43 underwent
Pictet-Spengler cyclization to give the tetrahydroiso-
quinoline substructure 44 in 75% yield. After conversion
of 44 to iodide 45, treatment with NaH resulted in a
Dieckman condensation to first give 46 as a transient
intermediate that underwent further O-alkylation under
the basic conditions to furnish the observed product.
Because the attempted thionium ion cascade of alcohol
41 failed due to the ease with which the sulfoxide group
was reduced, we decided to proceed in a stepwise manner.
Subjection of enamides 38-41 to camphorsulfonic acid
gave rise to the expected fused isoquinoline lactams 47-
50 in high yield but as a mixture of diastereomers. In all
cases the major diastereomer (ca. 60%) was derived from
a Nazarov type 4π-electrocyclic reaction followed by
π-cyclization onto the least hindered side of the N-
acyliminium ion (Scheme 10). The tert-butyldimethylsilyl
protecting group present in lactam 49 was easily hydro-
Studies dealing with the conversion of the hydroxyl
functionality into an appropriate leaving group were
carried out at this junction. Our intention was to first
prepare an appropriate alcohol derivative that would be
carried through the Pummerer/Pictet-Spengler cascade
and then perform an anionic intramolecular cyclization
(i.e., 27 f 28) so as to install the D ring of jamtine. Most
surprisingly, an intriguing and totally unexpected prod-
uct was obtained when the following reaction sequence
was executed (Scheme 8). Treatment of alcohol 41 with
methanesulfonyl chloride and Et3N was expected to
furnish a mesylate, which we intended to subject to
camphorsulfonic acid in refluxing benzene to induce the
desired tandem thionium/N-acyliminium ion cascade
(vide infra). Without isolation, the crude reaction mixture
was treated with NaI in acetone so as to replace the
mesylate with an iodo group, and this was followed by
treatment with NaH. Surprisingly, the only product
(48) Mooradian, A.; Cavallito, C. J .; Bergman, A. J .; Lawson, E. J .;
Suter, C. M. J . Am. Chem. Soc. 1949, 71, 3372.
(49) Madesclaire, M. Tetrahedron 1988, 44, 6537.
J . Org. Chem, Vol. 68, No. 3, 2003 933

Padwa et al.
SCHEME 10
F IGURE 1. A representative low-energy conformer of 50.
lyzed to afford the corresponding alcohol 50 in excellent
yield. Surprisingly, conversion of the hydroxyl group
present in 50 to a suitably activated derivative (i.e.,
bromo, iodo, mesylate, tosylate, triflate, etc.) only pro-
ceeded in low yield (<20%). Either the starting alcohol
was recovered unchanged or decomposition occurred at
the elevated temperatures employed. This lack of reactiv-
ity at the hydroxylic functionality was unanticipated
since the primary alcohol seemed devoid of any steric
hindrance. Removal of the ethylthio group from 50 was
easily accomplished using Raney-Ni but our efforts to
replace the OH group in 50 with an appropriate leaving
group for eventual SN2 displacement were also unsuc-
cessful.
SCHEME 11a
To gain some insight into the resilience of the C(4′)
hydroxyl toward functionalization, we performed a simple
conformational search of lactam 50 using the Monte-
Carlo Multiple Minimum (MCMM) protocol.50-52 Low-
energy conformations, a representative example of which
appears in Figure 1, were identified with the MM2* force
field and CHCl3 GB/SA solvation model.53 Based upon
the examination of several low-energy conformations, it
would appear that a combination of the aromatic ring
and the thioethyl and carbomethoxy groups shields the
C(4′) hydroxyl from potential electrophiles. Although
conformations which allow free access to the C(4′) hy-
droxyl were identified, the higher temperatures required
to sufficiently populate these conformations led to ex-
tensive decomposition.
Our Pummerer/Mannich ion approach toward jamtine
was reduced to practice in the following manner. The
hydroxyl present in the acyclic enamide 41 was first
converted to the corresponding bromide,54 which also
resulted in the simultaneous reduction of the sulfoxide
functionality. Subsequent reoxidation with NaIO4 deliv-
ered the required bromo-enamide 52 as a 4:1 (Z/ E)
mixture of isomers in high yield. Heating a sample of 52
with camphorsulfonic acid afforded the expected tetra-
hydroisoquinoline 27 in excellent yield (88%) but as a
5:2:1:1 mixture of diastereomers (Scheme 11). The major
a
Reagents: (a) CBr4, PPh3, 83%; (b) NaIO4, MeOH/H2O, 99%;
(c) CSA, toluene, reflux, 88%; (d) NaH, THF, reflux, 99%.
product obtained corresponded to the desired diastere-
omer 27a . The preferential formation of 27a is consistent
with our earlier stereochemical observations,31 suggesting
that a 4π-Nazarov-type electrocyclization55 controls the
direction of closure from the R-acylthionium ion inter-
mediate. The subsequent Pictet-Spengler step involves
attack of the proximal aromatic ring from the less
hindered side of the iminium ion. Deprotonation of 27a
with NaH resulted in quantitative cyclization to give 28a ,
which contains the fully assembled skeleton of jamtine
and whose structure was verified by X-ray analysis. It
should be noted that treating the crude mixture of
diastereomers 27 obtained from 52 with NaH not only
afforded 28a (67%) but also gave some of the correspond-
ing cis-(a,b)-isomer 28b (25%).
Completion of the synthesis entailed installation of the
double bond and reduction of the lactam. This was
accomplished by oxidation of the sulfide to the sulfoxide
followed by thermal elimination to furnish the unsatu-
rated lactam 53 in 89% overall yield (Scheme 12).
Conversion of 53 to thioamide 54 with Lawesson’s
reagent was followed by reduction to jamtine (25) with
Meerwein’s salt and NaBH456 in a respectable 61% yield.
(50) MCMM as implemented by MacroModel v.7.0. See: Mohamadi,
F.; Richards, N. G. J .; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield,
C.; Chang, G.; Hendrickson, T.; Still, W. C. J . Comput. Chem. 1990,
11, 440.
(51) Chang, G.; Guida, W. C.; Still, W. C. J . Am. Chem. Soc. 1990,
112, 1419.
(52) Chang, G.; Guida, W. C.; Still, W. C. J . Am. Chem. Soc. 1989,
111, 4379.
(53) Still, W. C.; Tempczyk, A.; Hawley, R. C.; Hendrickson, T. J .
Am. Chem. Soc. 1990, 112, 6127.
(54) Nakano, H.; Inoue, T.; Kawasaki, N.; Miyataka, H.; Matsumoto,
H.; Taguchi, T.; Inagaki, N.; Nagai, H.; Satoh, T. Bioorg. Med. Chem.
2000, 8, 373.
(55) Denmark, S. E. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 5, p
751.
(56) Raucher, S.; Klein, P. Tetrahedron Lett. 1980, 21, 4062.
934 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of the Alkaloid J amtine
SCHEME 12a
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry nitrogen. Solutions were evaporated
under reduced pressure with a rotary evaporator and the
residue was chromatographed on a silica gel column with an
ethyl acetate-hexane mixture as the eluent unless specified
otherwise.
N-Ben zyl-2-eth ylsu lfa n yl-N-(2-p h en ylh exa -1,5-d ien yl)-
a ceta m id e. To a stirred solution containing 3.5 g (20 mmol)
of 2-phenyl-hex-5-enal58 in 150 mL of benzene was added 2.2
g (20 mmol) of benzylamine and the resulting mixture was
heated at reflux for 16 h in a flask equipped with a Dean-
Stark trap. The solvent was removed under reduced pressure
and the crude imine was taken up in 150 mL of CH2Cl2 and
to this solution was added 4.7 g (60 mmol) of pyridine followed
by 2.8 g (20 mmol) of ethylthioacetyl chloride. The mixture
was stirred for 2 h at 25 °C, washed with a saturated NaHCO3
solution, and dried over MgSO4. Removal of the solvent under
reduced pressure followed by silica gel chromatography af-
forded 4.2 g (58%) of N-benzyl-2-ethylsulfanyl-N-(2-phenyl-
hexa-1,5-dienyl)acetamide as a yellow oil that consisted of a
2:1 mixture of stereomers that could be separated by silica
gel chromatography. The major E-isomer showed the following
a
Reagents: (a) NaIO4, MeOH/H2O; (b) heat, 90%; (c) Lawes-
son’s reagent, 99%; (d) Meerwein’s salt, NaBH4, MeOH, 61%; (e)
MCPBA, CH2Cl2, 95%; (f) PCl3, CH2Cl2, 78%.
properties: IR (neat) 1656, 1405, and 1256 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.29 (t, 3H, J ) 7.2 Hz), 1.86 (dt, 2H, J )
8.4 and 6.6 Hz), 2.44-2.49 (m, 2H), 2.69 (q, 2H, J ) 7.2 Hz),
3.35 (s, 2H), 4.76 (s, 2H), 4.85-4.95 (m, 2H), 5.64 (ddt, 1H, J
) 17.1, 10.5, and 6.6 Hz), 6.29 (s, 1H), and 7.24-7.37 (m, 10H);
13C NMR (CDCl3, 75 MHz) δ 14.7, 26.5, 28.8, 31.4, 33.8, 56.7,
115.5, 126.2, 127.0, 127.6, 128.2, 128.6, 128.7, 128.8, 137.0,
137.5, 138.5, 143.8, and 169.7. Anal. Calcd for C23H27NOS: C,
75.58; H, 7.45; N, 3.83. Found: C, 75.42; H, 7.48; N, 3.76.
The minor Z-isomer exhibited the following spectral proper-
The structure of 25 was unequivocally verified by X-ray
analysis. Oxidation of 25 with MCPBA led to the corre-
sponding N-oxide 55 as a single isomer in 95% yield. We
were surprised to find, however, that the 1H and 13C NMR
data of synthetic N-oxide 55 did not match the corre-
sponding data reported by Rahman for jamtine N-oxide
(24).32 N-Oxide 55 was subsequently reduced with PCl3
to give 25 in 78% yield thereby establishing that a
structural reorganization did not occur during the oxida-
tion step. The nonplanarity of the NfO group potentially
gives rise to the issue of stereoisomerism. In most cases,
a single N-oxide isomer is generally isolated from natural
sources, though only in a few instances has the stereo-
chemistry actually been determined.41 Chemical oxida-
tion of the corresponding tertiary base often produces a
mixture of stereoisomers. In our case, however, only a
single diastereomer was formed from the MCPBA oxida-
tion. Thus, one explanation to account for the fact that
synthetic N-oxide 55 does not correspond to the isolated
alkaloid is that we have simply prepared the other
diastereomer.57 Of course, an alternate possibility is that
a structure reassignment is in order for the natural
product isolated from the Cocculus hirsutus shrub.
Further work is necessary to sort out these possibilities.
ties: IR (neat) 1657, 1631, 1491, and 1154 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 1.23 (t, 3H, J ) 7.6 Hz), 2.02 (dt, 2H, J )
7.6 and 6.8 Hz), 2.42-2.46 (m, 2H), 2.62 (q, 2H, J ) 7.6 Hz),
3.27 (s, 2H), 4.32 (s, 2H), 4.89-4.96 (m, 2H), 5.69 (ddt, 1H, J
) 16.8, 10.4, and 6.4 Hz), 6.24 (s, 1H), 7.11-7.15 (m, 4H), and
7.21-7.34 (m, 6H); 13C NMR (CDCl3, 100 MHz) δ 14.5, 26.3,
32.2, 33.7, 35.2, 50.2, 115.7, 124.9, 127.4, 127.6, 128.2, 128.3,
128.6, 129.0, 137.4, 137.5, 137.6, 139.2, and 169.5. Anal. Calcd
for C23H27NOS: C, 75.58; H, 7.45; N, 3.83. Found: C, 75.55;
H, 7.41; N, 3.67.
(E)-N-Ben zyl-2-et h ylsu lfin yl-N-(2-p h en ylh exa -1,5-d i-
en yl)a ceta m id e (9). To a stirred solution containing 0.8 g
(3.8 mmol) of sodium periodate in 15 mL of H2O was added
0.6 g (1.5 mmol) of the above E-isomer in 15 mL of methanol.
The resulting mixture was stirred for 3 h at 25 °C, extracted
with chloroform, and dried over MgSO4. The solvent was
removed under reduced pressure and the residue was sub-
jected to silica gel chromatography to give 0.49 g (86%) of
R-sulfinyl enamide 9 as a yellow oil: IR (neat) 1656, 1399, and
1
1055 cm-1; H NMR (CDCl3, 300 MHz) δ 1.39 (t, 3H, J ) 7.5
In conclusion, we have accomplished the total synthesis
of the putative alkaloid jamtine (25) and our synthetic
efforts raise the possibility of a revision of the earlier
assignment. This approach to jamtine demonstrates the
utility of the domino Pummerer/Mannich ion cyclization
for preparing stereochemically complex azapolycyclic ring
systems. Further studies on the synthesis of related
alkaloids using this methodology are in progress and will
be reported in due course.
Hz), 1.79 (dt, 2H, J ) 8.1 and 6.9 Hz), 2.38-2.43 (m, 2H),
2.79-2.91 (m, 1H), 3.03-3.15 (m, 1H), 3.78 (d, 1H, J ) 14.1
Hz), 3.91 (d, 1H, J ) 13.8 Hz), 4.71 (d, 1H, J ) 14.1 Hz), 4.79
(d, 1H, J ) 14.1 Hz), 4.82-4.94 (m, 2H), 5.58 (ddt, 1H, J )
17.1, 10.2, and 6.6 Hz), 6.20 (s, 1H), and 7.22-7.36 (m, 10H);
13C NMR (CDCl3, 75 MHz) δ 6.8, 28.8, 31.2, 46.7, 51.7, 55.8,
115.7, 125.1, 126.8, 127.9, 128.5, 128.7, 129.0, 136.1, 137.1,
137.7, 145.6, and 164.7. Anal. Calcd for C23H27NO2S: C, 72.41;
H, 7.14; N, 3.67. Found: C, 72.33; H, 7.08; N, 3.56.
(Z)-N-Ben zyl-2-et h ylsu lfin yl-N-(2-p h en ylh exa -1,5-d i-
en yl)a ceta m id e (10). To a stirred solution containing 0.6 g
(2.8 mmol) of sodium periodate in 15 mL of H2O was added
0.4 g (1.1 mmol) of the above Z-isomer in 15 mL of methanol.
The resulting mixture was stirred for 3 h at 25 °C, extracted
with chloroform, and dried over MgSO4. The solvent was
removed under reduced pressure and the residue was sub-
jected to silica gel chromatography to give 0.38 g (91%) of
(57) Note Ad d ed in P r oof: Recent work by Professor Nigel S.
Simpkins and C. D. Gill has resulted in an independent synthesis of
jamtine 25. These workers have also concluded that the original
structure assignment32 of jamtine N-oxide (24) is incorrect. The spectral
data obtained by us for compound 24 are virtually identical with those
forwarded to us by Professor Simpkins (private communication).
J . Org. Chem, Vol. 68, No. 3, 2003 935

Padwa et al.
R-sulfinyl enamide 10 as a yellow oil: IR (neat) 1636, 1439,
and 1045 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.27 (t, 3H, J )
7.5 Hz), 2.01-2.08 (m, 2H), 2.42-2.56 (m, 2H), 2.59-2.71 (m,
1H), 2.85-2.97 (m, 1H), 3.47 (d, 1H, J ) 14.1 Hz), 3.75 (d,
1H, J ) 14.1 Hz), 4.49 (s, 2H), 4.91-5.01 (m, 2H), 5.71 (ddt,
1H, J ) 17.1, 10.2, and 6.6 Hz), 6.11 (s, 1H), 6.99-7.02 (m,
4H), and 7.23-7.36 (m, 6H); 13C NMR (CDCl3, 75 MHz) δ 6.7,
32.1, 35.4, 46.5, 51.2, 55.9, 115.9, 124.0, 127.4, 127.9, 128.4,
128.7, 128.8, 129.1, 136.0, 136.9, 137.2, 141.4, and 164.3. Anal.
Calcd for C23H27NO2S: C, 72.41; H, 7.14; N, 3.67. Found: C,
72.16; H, 6.95; N, 3.44.
121.3, 137.8, 148.7, 149.6, and 200.8. Anal. Calcd for
C14H18O3: C, 71.76; H, 7.75. Found: C, 71.59; H, 7.78.
N-Ben zyl-N-[2-(3,4-d im eth oxyp h en yl)h exa -1,5-d ien yl]-
2-eth ylsu lfa n yla ceta m id e. To a stirred solution containing
2.0 g (8.6 mmol) of 2-(3,4-dimethoxyphenyl)hex-5-enal in 60
mL of benzene was added 0.9 g (8.6 mmol) of benzylamine and
the resulting mixture was heated at reflux for 16 h in a flask
equipped with a Dean-Stark trap. The solvent was removed
under reduced pressure and the crude imine was taken up in
60 mL of CH2Cl2 and to this solution was added 2.0 g (26 mmol)
of pyridine followed by 1.2 g (8.6 mmol) of ethylthioacetyl
chloride. The mixture was stirred for 2 h at 25 °C, washed
with a saturated NaHCO3 solution, and dried over MgSO4.
Removal of the solvent under reduced pressure followed by
silica gel chromatography afforded 0.8 g (37%) of N-benzyl
N-[2-(3,4-methoxyphenyl)hexa-1,5-dienyl]-2-ethylsulfanylacet-
amide as a yellow oil. Silica gel chromatography of the 1.4:1
mixture of stereoisomers afforded the Z-isomer as a clear oil:
IR (neat) 1652, 1510, 1254, and 1140 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.27 (t, 3H, J ) 7.3 Hz), 2.09 (q, 2H, J ) 7.0 Hz),
2.47 (t, 2H, J ) 7.0 Hz), 2.66 (q, 2H, J ) 7.3 Hz), 3.30 (s, 2H),
3.80 (s, 3H), 3.91 (s, 3H), 4.39 (s, 2H), 4.98 (m, 2H), 5.75 (ddt,
1H, J ) 17.0, 10.3, and 6.6 Hz), 6.24 (s, 1H), 6.75 (m, 2H),
6.85 (d, 1H, J ) 7.9 Hz), 7.19 (m, 2H), and 7.28 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 14.3, 26.2, 32.1, 33.3, 35.0, 49.9,
55.8, 55.9, 110.6, 111.2, 115.5, 119.9, 124.1, 127.2, 128.1, 128.3,
129.6, 137.3, 137.4, 138.0, 148.7, 149.0, and 169.5; Anal. Calcd
for C25H31NO3S: C, 70.55; H, 7.35; N, 3.29. Found: C, 70.46;
H, 7.35; N, 3.21.
p-Tolu en e-4-su lfon ic Acid 1-Ben zyl-3-eth ylsu lfa n yl-2-
oxo-3a -p h en ylocta h yd r oin d ol-6-yl Ester (11). To a solu-
tion containing 0.7 g (3.9 mmol) of p-TsOH in 50 mL of benzene
at 80 °C was added 0.5 g (1.3 mmol) of E-enamide 9 in 2 mL
of benzene. After being heated at reflux for 20 min, the reaction
mixture was cooled to room temperature, washed with a
saturated NaHCO3 solution and brine, and dried over MgSO4.
Removal of the solvent under reduced pressure followed by
silica gel chromatography afforded 0.52 g (76%) of the title
compound as a 5:1 mixture of diastereomers. The major
diastereomer exhibited the following spectral data, mp 181-
183 °C: IR (neat) 1691, 1362, and 1171 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.01 (t, 3H, J ) 7.6 Hz), 1.45-1.66 (m, 3H), 1.75-
1.79 (m, 1H), 2.32-2.55 (m, 4H), 2.47 (s, 3H), 3.51 (s, 1H), 3.76
(d, 1H, J ) 15.2 Hz), 4.04 (s, 1H), 4.28-4.36 (m, 1H), 5.28 (d,
1H, J ) 14.8 Hz), 7.20-7.43 (m, 12H), and 7.77 (d, 2H, J )
8.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 14.7, 21.9, 27.2, 27.4,
28.2, 29.6, 29.9, 44.4, 46.5, 59.7, 61.7, 126.7, 127.7, 128.0, 128.1,
128.3, 129.1, 129.2, 130.2, 134.1, 135.9, 139.5, 145.2, 172.8.
Anal. Calcd for C30H33NO4S2: C, 67.27; H, 6.21; N, 2.62.
Found: C, 67.21; H, 6.25; N, 2.57.
The minor E-stereoisomer exhibited the following spectral
properties: IR (neat) 1652, 1510, 1410, 1254, and 1019 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H, J ) 7.3 Hz), 1.87 (q,
2H, J ) 7.0 Hz), 2.43 (m, 2H), 2.67 (q, 2H, J ) 7.5 Hz), 3.32
(s, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 4.74 (s, 2H), 4.90 (m, 2H),
5.64 (ddt, 1H, J ) 17.0, 10.3, and 6.6 Hz), 6.22 (s, 1H), 6.70
(d, 1H, J ) 1.8 Hz), 6.82 (m, 2H), and 7.32 (m, 5H); 13C NMR
(100 MHz, CDCl3) δ 14.3, 26.1, 28.5, 31.2, 33.4, 51.4, 55.8 (2),
109.9, 111.0, 115.3, 119.3, 125.1, 127.4, 128.4, 128.6, 131.0,
136.9, 137.4, 143.2, 148.8, 149.0, and 169.7. Anal. Calcd for
p-Tolu en e-4-su lfon ic Acid 1-Ben zyl-3-eth ylsu lfa n yl-2-
oxo-3a -p h en ylocta h yd r oin d ol-6-yl Ester (12). To a solu-
tion containing 0.5 g (2.5 mmol) of p-TsOH in 50 mL of benzene
at 80 °C was added 0.4 g (0.8 mmol) of Z-enamide 10 in 2 mL
of benzene. After being heated at reflux for 20 min, the reaction
mixture was cooled to room temperature, washed with a
saturated NaHCO3 solution, washed with brine, and dried over
MgSO4. Removal of the solvent under reduced pressure
followed by silica gel chromatography afforded 0.3 g (70%) of
the title compound as a white solid, mp 124-125 °C: IR (neat)
1688, 1592, 1354, and 1163 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.19 (t, 3H, J ) 7.5 Hz), 1.56-1.67 (m, 2H), 1.82-1.94 (m,
2H), 2.17-2.28 (m, 2H), 2.46 (s, 3H), 2.57-2.81 (m, 2H), 3.47
(s, 1H), 3.99 (d, 1H, J ) 15.6 Hz), 4.23 (d, 1H, J ) 3.3 Hz),
4.81 (s, 1H), 5.38 (d, 1H, J ) 15.6 Hz), 7.14 (m, 12H), and 7.83
(d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.5, 22.0,
25.2, 26.6, 27.3, 29.3, 43.3, 47.7, 53.0, 54.6, 76.4, 127.3, 127.4,
127.5, 127.7, 127.9, 128.5, 128.8, 130.1, 134.2, 135.8, 138.5,
145.0, and 172.2. Anal. Calcd for C30H33NO4S2: C, 67.27; H,
6.21; N, 2.62. Found: C, 67.04; H, 6.15; N, 2.66.
C
23H27NOS: C, 70.55; H, 7.35; N, 3.29. Found: C, 75.40; H,
7.28; N, 3.15.
(Z)-N-Ben zyl-N-[2-(3,4-d im et h oxyp h en yl)h exa -1,5-d i-
en yl]-2-eth ylsu lfin yla ceta m id e (13). To a solution contain-
ing 0.7 g (3.1 mmol) of NaIO4 in 20 mL of water was added
0.7 g (1.6 mmol) of the above Z-sulfide in 20 mL of methanol.
The reaction mixture was stirred at 25 °C for 2.5 h and then
poured into water and extracted with CHCl3. The combined
extracts were dried over anhydrous MgSO4. Silica gel chro-
matography provided 0.64 g (93%) of the title compound as a
1
colorless oil: IR (neat) 1631, 1510, 1254, and 1019 cm-1; H
NMR (400 MHz, CDCl3) δ 1.24 (t, 3H, J ) 7.3 Hz), 2.01 (m,
2H), 2.46 (m, 2H), 2.65 (m, 1H), 2.88 (m, 1H), 3.42 (d, 1H, J )
14.3 Hz), 3.66 (s, 3H), 3.72 (d, 1H, J ) 14.3 Hz), 3.85 (s, 3H),
4.42 (d, 1H, J ) 14.3 Hz), 4.54 (d, 1H, J ) 14.3 Hz), 4.93 (dd,
1H, J ) 15.6 and 1.6 Hz), 4.98 (d, 1H, J ) 9.2 Hz), 5.71 (ddt,
1H, J ) 16.8, 10.3, and 6.6 Hz), 6.07 (s, 1H), 6.53 (d, 1H, J )
1.8 Hz), 6.63 (dd, 1H, J ) 8.2 and 1.8 Hz), 6.80 (d, 1H, J ) 8.2
Hz), and 7.27 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 6.2, 31.9,
34.9, 46.1, 50.9, 55.5, 55.6, 55.7, 110.1, 111.3, 115.6, 119.7,
123.3, 127.6, 128.5, 128.7, 128.8, 135.9, 137.1, 139.9, 148.8,
149.0, and 164.3. Anal. Calcd for C25H31NO4S: C, 68.00; H,
7.08; N, 3.17. Found: C, 67.79; H, 7.02; N, 3.11.
2-(3,4-Dim eth oxyp h en yl)h ex-5-en a l. To a stirred solution
containing 2.7 g (12 mmol) of 2-(3,4-dimethoxyphenyl)hex-5-
ene nitrile in 110 mL of dry toluene at 0 °C was added 18 mL
of a 1.0 M solution of diisobutylalumminum hydride in toluene
and the resulting mixture was stirred at 25 °C for 1.5 h. To
this solution was added 65 mL of a 1.0 M solution of tartaric
acid in ether and the reaction mixture was diluted with 300
mL of ether. The mixture was washed with 10% Rochelle’s salt,
the two layers were separated, and the aqueous layer was
extracted with ether. The organic layer was washed with brine
and dried over MgSO4. The solvent was removed under
reduced pressure, and the residue was subjected to silica gel
chromatography to give 2.0 g (72%) of the titled aldehyde as a
(E)-N-Ben zyl-N-[2-(3,4-d im et h oxyp h en yl)h exa -1,5-d i-
en yl]-2-eth ylsu lfin yla ceta m id e (14). To a solution contain-
ing 0.9 g (4.2 mmol) of NaIO4 in 25 mL of water was added
0.9 g (2.1 mmol) of the above E-sulfide in 25 mL of methanol.
The reaction mixture was stirred at 25 °C for 2.5 h and then
poured into water and extracted with CHCl3. The combined
extracts were dried over anhydrous MgSO4. Silica gel chro-
matography provided 0.55 g (60%) of the title compound as a
1
colorless oil: IR (neat) 1727, 1517, and 1268 cm-1; H NMR
(CDCl3, 400 MHz) δ 1.75-1.84 (m, 1H), 1.98-2.20 (m, 3H),
3.47-3.51 (m, 1H), 3.88 (s, 6H), 4.99-5.03 (m, 2H), 5.73-5.83
(m, 1H), 6.67 (d, 1H, J ) 2.0 Hz), 6.75 (dd, 1H, J ) 8.0 and
2.0 Hz), 6.88 (d, 1H, J ) 8.0 Hz), and 9.66 (m, 1H); 13C NMR
(CDCl3, 100 MHz) δ 28.8, 31.1, 56.0, 57.9, 111.7, 111.8, 115.7,
1
colorless oil: IR (neat) 1652, 1510, 1247, and 1012 cm-1; H
NMR (400 MHz, CDCl3) δ 1.29 (t, 3H, J ) 7.5 Hz), 1.76 (m,
936 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of the Alkaloid J amtine
2H), 2.31 (t, 2H, J ) 7.7 Hz), 2.78 (m, 1H), 3.04 (m, 1H), 3.70
(d, 1H, J ) 14.1 Hz), 3.79 (s, 3H), 3.81 (s, 3H), 3.84 (d, 1H, J
) 14.1 Hz), 4.62 (d, 1H, J ) 13.9 Hz), 4.70 (d, 1H, J ) 13.9
Hz), 4.79 (dd, 1H, J ) 17.0 and 1.6 Hz), 4.85 (dd, 1H, J ) 10.3
and 1.5 Hz), 5.53 (ddt, 1 H, J ) 16.8, 10.3, and 6.6 Hz), 6.07
(s, 1H), 6.63 (d, 1H, J ) 1.8 Hz), 6.73 (dd, 1H, J ) 8.2 and 1.8
Hz), 6.76 (d, 1H, J ) 8.2 Hz), and 7.26 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 6.4, 28.5, 31.0, 46.4, 51.4, 55.5, 55.8, 55.9, 109.8,
111.0, 115.5, 119.3, 124.0, 127.7, 128.6, 128.9, 130.2, 136.0,
118.6, 127.7, 127.8, 128.0, 128.9, 129.9, 131.9, 133.8, 135.6,
144.9, 148.2, 148.9, 172.7. Anal. Calcd for C32H37NO6S2: C,
64.51; H, 6.26; N, 2.35. Found: C, 64.65; H, 6.17; N, 2.33.
2-(3,4-Dim eth oxyp h en yl)p r op ion a ld eh yd e. To a stirred
solution containing 2.5 g (13 mmol) of 2-(3,4-dimethoxyphenyl)-
propionitrile in 100 mL of dry toluene at 0 °C was added 20
mL (20 mmol) of a 1.0 M solution of diisobutylalumminum
hydride in toluene and the resulting mixture was stirred for
1.5 h. To this mixture was added 60 mL of a 1.0 M tartaric
acid solution in ether and the mixture was diluted with 300
mL of ether. The solution was washed with a 10% solution of
Rochelle’s salt, the two layers were separated, and the aqueous
layer was extracted with ether. The organic portion was
washed with brine and dried over MgSO4. The solvent was
removed under reduced pressure and the residue was sub-
jected to silica gel chromatography to give 2.4 g (95%) of the
137.1, 145.1, 148.8, 149.2, and 164.7. Anal. Calcd for C25H31
-
NO4S: C, 68.00; H, 7.08; N, 3.17. Found: C, 68.14; H, 6.83;
N, 3.06.
3-Ben zyl-5-b u t -3-en yl-1-et h ylsu lfa n yl-7,8-d im et h oxy-
1,3-d ih yd r oben zo[d ]a zep in -2-on e (15). To a refluxing solu-
tion containing 0.8 g (4.3 mmol) of p-TsOH in 45 mL of benzene
was added dropwise 0.6 g (1.4 mmol) of Z-sulfoxide 13
dissolved in 30 mL of benzene. After the addition was complete,
the reaction mixture was stirred for an additional 1 h before
cooling to rt and pouring into a saturated solution of NaHCO3.
The organic layer was dried over anhydrous MgSO4 and
further purified by silica gel chromatography to give 0.48 g
(78%) of the title compound as a mixture of atropoisomers: IR
(neat) 1652, 1510, 1446, 1261, and 1175 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.17 (t, 3H, J ) 7.5 Hz), 2.16 (m, 2H), 2.42 (m,
2H), 2.63 (dt, 1H, J ) 14.7 and 7.3 Hz), 2.89 (m, 1H), 3.85 (s,
3H), 3.91 (s, 3H), 4.37 (s, 1H), 4.56-5.00 (m, 4H), 5.60 (ddt,
1H, J ) 17.2, 10.0, and 6.0 Hz), 6.11 (s, 1H), 6.80 (s, 1H), 6.96
(m, 2H), 7.24 (m, 3H), and 7.44 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 14.4, 24.8, 33.1, 33.9, 50.2, 52.3, 55.8, 56.0, 107.5,
108.1, 115.5, 125.1, 125.5, 127.1, 127.2, 127.4, 128.4, 128.5,
137.4, 138.1, 148.0, 150.3, 166.4. Anal. Calcd for C25H29NO3S:
C, 70.89; H, 6.91; N, 3.31. Found: C, 70.74; H, 7.04; N, 3.15.
titled aldehyde as a colorless oil: IR (neat) 1723 and 1506 cm-1
;
1H NMR (CDCl3, 40.0 MHz) δ 1.41 (d, 3H, J ) 6.8 Hz), 3.55-
3.60 (s, 6H), 6.68 (d, 1H, J ) 2.0 Hz), 6.76 (dd, 1H, J ) 8.0
and 2.0 Hz), 6.87 (d, 1H, J ) 8.4 Hz), and 9.62 (s, 1H); 13C
NMR CDCl3, 100 MHz) δ 14.8, 52.7, 56.1, 111.4, 111.7, 120.6,
130.1, 148.6, 149.5, and 201.2. Anal. Calcd for C11H14O3: C,
68.01; H, 7.27. Found: C, 68.12; H, 7.09.
N-Ben zyl-N-[2-(3,4-dim eth oxyph en yl)pr open yl-2-eth yl-
su lfa n yla ceta m id e. To a stirred solution containing 2.4 g (12
mmol) of 2-(3,4-dimethoxyphenyl)propionaldehyde in 90 mL
of benzene was added 1.3 g (12 mmol) of benzylamine and the
resulting mixture was heated at reflux for 24 h in a flask
equipped with a Dean-Stark trap. The solvent was removed
under reduced pressure and the crude imine was taken up in
90 mL of CH2Cl2 and to this solution was added 2.9 g (37 mmol)
of pyridine followed by 1.7 g (12 mmol) of ethylthioacetyl
chloride. The mixture was stirred for 2 h at 25 °C, washed
with a saturated NaHCO3 solution, and dried over MgSO4.
Removal of the solvent under reduced pressure followed by
silica gel chromatography afforded 2.0 g (42%) of N-benzyl-
N-[2-(3,4-dimethoxyphenyl)propenyl]-2-ethylsulfinylacet-
amide as a yellow oil, which contained a 1:1 mixture of E/Z
isomers. The E-isomer exhibited the following spectral proper-
3-Ben zyl-5-bu tyl-7,8-d im eth oxy-1,3-d ih yd r oben zo[d ]-
a zep in -2-on e (16). To a solution containing 0.07 g (0.2 mmol)
of azepinone 15 in 30 mL of a 1:1-THF/EtOH mixture was
added an excess of Raney nickel. The reaction mixture was
stirred at 25 °C for 30 min and then filtered through Celite.
The solvent was removed under reduced pressure and the
residue was chromatographed on silica gel to give 0.05 g (87%)
of the title compound as a colorless oil: IR (neat) 1659, 1510,
1
ties: IR (neat) 1652, 1517, and 1138 cm-1; H NMR (CDCl3,
1261, and 1140 cm-1 1H NMR (CDCl3, 300 MHz) δ 0.85 (t,
;
400 MHz) δ 1.28 (t, 3H, J ) 7.4 Hz), 1.86 (d, 3H, J ) 1.2 Hz),
2.69 (q, 2H, J ) 7.4 Hz), 3.29 (s, 2H), 3.87 (s, 1H), 3.88 (s,
1H), 4.72 (s, 2H), 6.35 (d, 1H, J ) 1.2 Hz), 6.82 (s, 1H), 6.83
(d, 1H, J ) 8.0 Hz), 6.90 (dd, 1H, J ) 8.4 and 2.0 Hz), and
7.27-7.32 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 14.6, 16.0,
26.5, 33.8, 51.2, 56.1, 109.5, 111.2, 118.9, 124.8, 127.6, 128.6,
129.0, 132.5, 137.1, 138.6, 149.0, 149.4, and 170.0. Anal. Calcd
for C22H27NO3S: C, 68.54; H, 7.06; N, 3.64. Found: C, 68.43;
H, 7.02; N, 3.44.
3H, J ) 7.1 Hz), 1.17-1.40 (m, 4H), 2.20-2.82 (m, 2H), 3.48
(s, 2H), 3.90 (s, 3H), 3.93 (s, 3H), 4.70 (s, 2H), 6.12 (s, 1H),
6.85 (s, 1H), 6.86 (s, 1H), 7.07 (m, 2H), and 7.24 (m, 3H); 13C
NMR (CDCl3, 75 MHz) δ 13.9, 22.3, 31.5, 34.5, 42.9, 50.0, 55.9,
56.1, 107.9, 110.8, 125.1, 126.5, 127.1, 127.2, 127.3, 128.4,
130.5, 136.9, 147.8, 149.6, and 168.6. Anal. Calcd for C23H27
-
NO3: C, 75.58; H, 7.45; N, 3.83. Found: C, 75.41; H, 7.26; N,
3.50.
The Z-isomer exhibited the following spectral properties: IR
(neat) 1655, 1509, and 1262 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.25 (t, 3H, J ) 7.2 Hz), 2.04 (d, 3H, J ) 1.2 Hz), 2.64 (q,
2H, J ) 7.2 Hz), 3.25 (s, 2H), 3.79 (s, 3H), 3.89 (s, 3H), 4.46 (s,
2H), 6.23 (d, 1H, J ) 1.2 Hz), 6.84 (br s, 3H), and 7.20-7.31
(m, 5H); 13C NMR (CDCl3, 100 MHz) δ 14.5, 22.1, 26.4, 33.6,
50.3, 56.0, 56.1, 110.3, 111.3, 119.9, 123.7, 127.5, 128.4, 128.6,
129.0, 131.0, 134.1, 137.5, 149.0, and 169.8. Anal. Calcd for
p-Tolu en e-4-su lfon ic Acid 1-Ben zyl-3a -(3,4-d im eth oxy-
p h en yl)-3-eth ylsu lfa n yl-2-oxoocta h yd r oin d ol-6-yl Ester
(17). To a refluxing solution containing 0.7 g (3.6 mmol) of
p-TsOH in 35 mL of benzene was added dropwise a solution
containing 0.5 g (1.2 mmol) of E-enamido sulfoxide 14 in 25
mL of benzene. After the addition was complete, the reaction
mixture was heated for 1 h at reflux before being cooled to
room temperature. The mixture was poured into a saturated
solution of NaHCO3. The organic phase was separated, washed
with brine, and dried over anhydrous MgSO4. The solvent was
removed under reduced pressure and the residue was purified
by silica gel chromatography to give 0.3 g (50%) of the title
compound as a 3:1 mixture of diastereomers. The major
diastereomer was a crystalline solid, mp 183-184 °C: IR (neat)
1695, 1510, 1168, and 934 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.06 (t, 3H, J ) 7.3 Hz), 1.41-1.50 (m, 1H), 1.57-1.75 (m, 3H),
2.30-2.44 (m, 2H), 2.46 (s, 3H), 2.35-2.62 (m, 2H), 3.44 (s,
1H), 3.77 (d, 1H, J ) 15.0 Hz), 3.84 (s, 3H), 3.85 (s, 3H), 3.99
(br s, 1H), 4.29 (m, 1H), 5.23 (d, 1H, J ) 15.0 Hz), 6.77 (d, 1H,
J ) 8.6 Hz), 6.84 (dd, 1H, J ) 8.6 and 2.4 Hz), 7.10 (d, 1H, J
) 2.2 Hz), 7.19 (d, 1H, J ) 2.2 Hz), 7.35 (m, 5H), and 7.75 (d,
2H, J ) 8.4 Hz); 13C NMR (100 MHz) δ 14.5, 21.6, 27.3, 27.7,
27.8, 29.3, 44.2, 45.8, 55.8, 56.0, 59.1, 61.2, 77.2, 110.2, 110.8,
C
22H27NO3S: C, 68.54; H, 7.06; N, 3.64. Found: C, 68.66; H,
7.15; N, 3.58.
(E)-N-Ben zyl-N-[2-(3,4-d im et h oxyp h en yl)p r op en yl-2-
eth ylsu lfin yla ceta m id e (18). To a stirred solution containing
0.4 g (2.0 mmol) of sodium periodate in 7 mL of H2O was added
0.4 g (0.1 mmol) of the above E-sulfide in 7 mL of methanol.
The resulting mixture was stirred for 2 h at 25 °C, extracted
with chloroform, and dried over MgSO4. The solvent was
removed under reduced pressure and the residue was sub-
jected to silica gel chromatography to give 0.3 g (74%) of
R-sulfinyl enamide 18 as a yellow oil: IR (neat) 1514 and 1260
1
cm-1; H NMR (CDCl3, 300 MHz) δ 1.37 (t, 3H, J ) 7.5 Hz),
1.82 (br s, 3H), 2.78-2.90 (m, 1H), 3.01-3.13 (m, 1H), 3.76 (d,
1H, J ) 13.8 Hz), 3.87 (s, 6H), 3.88 (d, 1H, J ) 13.8 Hz), 4.68
(d, 1H, J ) 13.8 Hz), 4.76 (d, 1H, J ) 14.1 Hz), 6.93 (d, 1H, J
J . Org. Chem, Vol. 68, No. 3, 2003 937

Padwa et al.
) 1.2 Hz), 6.82 (s, 1H), 6.83 (d, 1H, J ) 8.4 Hz), and 6.91 (dd,
1H, J ) 8.4 and 1.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 6.7,
16.0, 46.5, 51.2, 55.6, 56.0, 109.2, 110.0, 118.7, 123.4, 127.7,
128.5, 128.9, 131.5, 135.9, 140.2, 148.7, 149.4, and 164.5. Anal.
Calcd for C22H27NO4S: C, 65.81; H, 6.78; N, 3.49. Found: C,
65.77; H, 6.53; N, 3.59.
23 as a clear oil: IR (neat) 1659, 1510, 1356, 1261, and 1140
1
cm-1; H NMR (CDCl3, 400 MHz) δ 2.14 (d, 2H, J ) 1.2 Hz),
3.50 (s, 2H), 3.90 (s, 3H), 3.92 (s, 3H), 4.70 (s, 2H), 6.12 (d,
1H, J ) 1.2 Hz), 6.83 (s, 1H), 6.86 (s, 1H), 7.06-7.09 (m, 2H),
and 7.21-7.28 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ 20.8,
42.9, 50.0, 55.9, 56.0, 108.0, 110.9, 125.2, 125.5, 125.8, 127.2,
127.3, 128.5, 128.7, 137.0, 147.9, 149.8, and 168.7. Anal. Calcd
for C20H21NO3: C, 74.27; H, 6.55; N, 4.33. Found: C, 74.20;
H, 6.43; N, 4.22.
(Z)-N-Ben zyl-N-[2-(3,4-d im et h oxyp h en yl)p r op en yl-2-
eth ylsu lfin yl-a ceta m id e (19). To a stirred solution contain-
ing 0.24 g (1.1 mmol) of sodium periodate in 7 mL of H2O was
added 0.18 g (0.5 mmol) of the above Z-sulfide in 7 mL of
methanol. The resulting mixture was stirred for 4 h at room
temperature, extracted with chloroform, and dried over Mg-
SO4. The solvent was removed under reduced pressure and
the residue was subjected to silica gel chromatography to give
0.16 g (92%) of R-sulfinyl enamide 19 as a yellow oil: IR (neat)
1642, 1509, 1414, and 1263 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.22 (t, 3H, J ) 7.4 Hz), 2.04 (d, 3H, J ) 1.2 Hz), 2.57-2.65
(m, 1H), 2.84-2.93 (m, 1H), 3.40 (d, 1H, J ) 13.6 Hz), 3.66 (s,
3H), 3.70 (d, 1H, J ) 14.4 Hz), 3.84 (s, 3H), 4.49 (d, 1H, J )
14.4 Hz), 4.57 (d, 1H, J ) 14.0 Hz), 6.06 (d, 1H, J ) 0.8 Hz),
6.62 (d, 1H, J ) 1.6 Hz), 6.71 (dd, 1H, J ) 8.0 and 2.0 Hz),
6.79 (d, 1H, J ) 8.0 Hz). and 7.23-7.31 (m, 5H); 13C NMR
(CDCl3, 75 MHz) δ 6.6, 22.3, 46.6, 51.2, 56.0, 56.1, 109.9, 111.4,
119.7, 122.8, 127.9, 128.8, 128.9, 130.3, 136.0, 136.1, 149.1,
and 164.6. Anal. Calcd for C22H27NO4S: C, 65.81; H, 6.78; N,
3.49. Found: C, 65.64; H, 6.82; N, 3.61.
2-[4-(ter t-Bu t yld im et h ylsila n yloxy)b u t yl]-3-h yd r oxy-
a cr ylic Acid Meth yl Ester (34). A solution containing 9.6 g
(37 mmol) of 6-(tert-butyldimethylsilanoxy)hexanoic acid meth-
yl ester59 in 30 mL of THF was added dropwise to a solution
of LDA prepared from 19 mL (48 mmol) of 2.5 M n-BuLi in
hexane and 6.2 mL (44 mmol) of diisopropylamine in 130 mL
of THF at -78 °C. The reaction mixture was stirred for 1 h
then treated with 3.9 mL (48 mmol) of ethyl formate. The
solution was stirred for an additional 2 h while warming to
room temperature, quenched with H2O, and extracted with
hexane to remove any impurities. The aqueous layer was
acidified with 10% HCl and extracted with CH2Cl2, and the
combined organic layer was dried over Na2SO4. The solvent
was removed under reduced pressure and the residue was
subjected to flash silica gel chromatography to afford 10.1 g
(95% yield) of aldehydic ester 34 as a pale yellow oil: IR (neat)
1723, 1670, 1444, and 1185 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.01 (s, 6H), 0.09 (s, 6H, enol), 0.85 (s, 9H), 0.9 (s, 9H, enol),
1.33-1.55 (m, 4H), 1.84-1.88 (m, 2H, enol), 2.04-2.06 (t, 2H,
J ) 7.5 Hz), 2.39-2.41 (m, 1H, enol), 3.23-3.27 (td, 1H, J )
7.6 and 2.4 Hz, enol), 3.57-3.59 (t, 2H, J ) 7.5 Hz), 3.66 (s,
3H, enol), 3.74 (s, 3H), 6.95-6.98 (d, 1H, J ) 12.6 Hz, enol),
9.66 (s, 1H), 11.33-11.36 (d, 1H, J ) 12.6 Hz, enol); 13C NMR
(CDCl3, 75 MHz) δ -5.0, 18.6, 26.2, 26.3, 27.4, 32.5, 51.5, 63.1,
104.7, 160.9, and 172.8; HRMS calcd for C14H28O4Si 288.1757,
found 288.1757.
1-Ben zyl-5-(3,4-d im et h oxyp h en yl)-3-et h ylsu lfa n yl-4-
m eth yl-1,5-d ih yd r op yr r ol-2-on e (21). To a solution contain-
ing 0.4 g (2.0 mmol) of p-TsOH in 35 mL of benzene at 80 °C
was added 0.3 g (0.67 mmol) of E-enamide in 1 mL of benzene.
After being heated at reflux for 20 min, the reaction mixture
was cooled to room temperature, washed with a saturated
NaHCO3 solution, washed with brine, and dried over MgSO4.
Removal of the solvent under reduced pressure followed by
silica gel chromatography afforded 0.16 g (62%) of lactam 21
2-[4-(t er t -Bu t yld im e t h ysila n yloxy)b u t yl]-3-[[2-(3,4-
d im et h oxyp h en yl)et h yl](2-et h ylsu lfa n yla cet yl)a m in o]-
a cr ylic Acid Meth yl Ester (37). A solution of 8.9 g (31 mmol)
of aldehyde 34 and 6.2 g (34 mmol) of 3,4-dimethoxyphen-
ethylamine in 125 mL of benzene was heated at reflux
overnight using a Dean-Stark water trap. The reaction
mixture was cooled to room temperature and the solvent was
removed under reduced pressure. The crude enamine was
taken up in 100 mL of CH2Cl2 and treated with 3.2 g (40 mmol)
of pyridine. To the resulting solution was added 40 mmol of
ethylsulfanyl acetyl chloride48 in 25 mL of CH2Cl2 and the
solution was stirred at room temperature for an additional 2
h. The reaction mixture was quenched with a saturated
NaHCO3 solution and extracted with CH2Cl2. The combined
organic layer was washed with NH4Cl and dried over MgSO4.
The solvent was removed under reduced pressure and the
residue was subjected to flash silica gel chromatography to
give 15.9 g (92% yield) of 37 as a 1:4 E/ Z mixture of isomers:
1
as a clear oil: IR (neat) 1680, 1512, 1396, and 1260 cm-1; H
NMR (CDCl3, 400 MHz) δ 1.27 (t, 3H, J ) 7.2 Hz), 1.82 (s,
1H), 2.96-3.05 (m, 1H), 3.11-3.20 (m, 1H), 3.64 (d, 1H, J )
14.8 Hz), 3.79 (s, 3H), 3.91 (s, 3H), 4.55 (s, 1H), 5.16 (d, 1H, J
) 14.8 Hz), 6.40 (d, 1H, J ) 2.4 Hz), 6.66 (dd, 1H, J ) 10.8
and 2.8 Hz), 6.87 (d, 1H, J ) 10.8 Hz), 7.12-7.15 (m, 2H),
and 7.27-7.35 (m, 3H); 13C NMR (CDCl3, 75 MHz) δ 13.9, 15.8,
26.5, 44.4, 56.1, 67.4, 111.4, 121.0, 125.7, 127.2, 127.6, 128.5,
128.7, 129.5, 137.5, 149.4, 149.8, 158.8, and 169.4. Anal. Calcd
for C22H25NO3S: C, 68.90; H, 6.58; N, 3.65. Found: C, 68.83;
H, 6.62; N, 3.49.
3-Ben zyl-1-eth ylsu lfa n yl-7,8-d im eth oxy-5-m eth yl-1,3-
d ih yd r oben zo[d ]a zep in -2-on e (22). To a solution containing
0.23 g (1.2 mmol) of p-TsOH in 40 mL of benzene at 80 °C
was added 0.17 g (0.4 mmol) of enamide 19 in 1 mL of benzene.
After being heated at reflux for 20 min, the reaction mixture
was cooled to room temperature, washed with a saturated
NaHCO3 solution, then with brine, and dried over MgSO4.
Removal of the solvent under reduced pressure followed by
silica gel chromatography afforded 0.12 g (76%) of the title
compound as a colorless oil as a mixture of atropoisomers. IR
1
IR (film) 1716, 1669, 1511, and 1255 cm-1; H NMR (CDCl3,
400 MHz) E-isomer δ 0.03 (s, 6H), 0.87 (s, 9H), 1.21 (t, 3H, J
) 7.4 Hz), 1.45-1.49 (m, 4H), 2.25-2.28 (t, 2H, J ) 6.8 Hz),
2.55-2.60 (q, 2H, J ) 7.4 Hz), 2.73-2.76 (t, 2H, J ) 7.5 Hz),
3.25 (s, 2H), 3.57-3.60 (t, 2H, J ) 6.0 Hz), 3.64-3.68 (t, 2H,
J ) 7.5 Hz), 3.70 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 6.36 (s,
1H), and 6.69-6.77 (m, 3H); 13C NMR (CDCl3, 100 MHz)
E-isomer, δ -5.0, 14.5, 18.5, 25.2, 26.1, 26.3, 32.0, 32.4, 33.7,
50.3, 52.2, 56.0, 62.8, 111.3, 112.1, 120.9, 131.5, 134.1, 147.7,
149.0, 160.0, and 169.3; 1H NMR (CDCl3, 400 MHz) Z-
diastereomer, δ 0.01 (s, 6H), 0.85 (s, 9H), 1.22-1.26 (m, 5H),
1.48-1.49 (m, 4H), 2.27-2.30 (t, 2H, J ) 7.0 Hz), 2.55-2.61
(q, 2H, J ) 7.4 Hz), 2.76-2.80 (t, 2H, J ) 7.6 Hz), 3.21 (s,
2H), 3.54-3.57 (t, 2H, J ) 5.6 Hz), 3.76 (s, 3H), 3.84 (s, 3H),
3.86 (s, 3H), 6.71-6.78 (m, 3H), and 7.37 (s, 1H); 13C NMR
(CDCl3, 100 MHz) Z-isomer, δ -5.1, 14.4, 14.8, 18.4, 21.0, 24.7,
1
(neat) 1648, 1512, 1400, and 1258 cm-1; H NMR (400 MHz,
CDCl3) δ 1.30 (t, 3H, J ) 7.2 Hz), 2.17 (d, 3H, J ) 1.6 Hz),
2.52 (dt, 2H, J ) 7.6 and 7.2 Hz), 3.90 (s, 3H), 3.92 (s, 3H),
4.62 (d, 1H, J ) 15.2 Hz), 4.70 (s, 1H), 4.89 (d, 1H, J ) 15.2
Hz), 6.05 (s, 1H), 6.78 (s, 1H), 6.87 (s, 1H), 7.16-7.18 (m, 2H),
and 7.22-7.29 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 15.1,
21.4, 25.3, 28.3, 51.2, 56.2, 56.3, 107.8, 111.5, 125.4, 125.5,
127.4, 127.5, 127.7, 128.7, 128.8, 137.0, 148.9, 149.6, and 168.9.
Anal. Calcd for C22H25NO3S: C, 68.90; H, 6.58; N, 3.65.
Found: C, 68.75; H, 6.50; N, 3.58.
3-Ben zyl-7,8-d im eth oxy-5-m eth yl-1,3-d ih yd r oben zo[d ]-
a zep in -2-on e (23). To a solution containing 0.05 g (0.12 mmol)
of 22 in 20 mL of a 1:1 mixture of THF/EtOH was added an
excess of Raney Nickel. The reaction mixture was stirred at
25 °C for 30 min and then filtered through Celite. The solvent
was removed under reduced pressure to give 0.04 g (90%) of
(58) J ung, M. E.; Vu, B. T. J . Org. Chem. 1996, 61, 4427.
(59) Bookser, B. C.; Kasibhatta, S. R.; Applemann, J . R.; Erion, M.
D. J . Med. Chem. 2000, 43, 1495.
938 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of the Alkaloid J amtine
25.7, 26.3, 26.6, 33.0, 33.8, 34.2, 44.9, 52.2, 52.3, 56.0, 62.4,
62.7, 71.8, 111.3, 112.1, 120.7, 120.9, 131.3, 137.7, 145.4, 149.0,
165.4, and 171.0. Anal. Calcd for C28H47NO6SSi: C, 60.73; H,
8.56; N, 2.53. Found: C, 60.59; H, 8.41; N, 2.54.
2-(4-Br om obu tyl)-3-[[2-(3,4-d im eth oxyp h en yl)eth yl](2-
eth a n esu lfin yla cetyl)a m in o]a cr ylic Acid Meth yl Ester
(52). To a solution of 1.4 g of the above sulfide in 50 mL of a
4:1 mixture of MeOH/H2O was added 0.9 g of NaIO4 and the
resulting solution was stirred at room temperature for 16 h.
A white precipitate appeared after several hours. The mixture
was stirred for an additional 14 h to ensure full consumption
of the starting material. The reaction mixture was diluted with
water and extracted with CH2Cl2. The combined organic layer
was dried over MgSO4 and the solvent was removed under
reduced pressure. Flash silica gel chromatography afforded 1.2
g (88%) of bromosulfoxide 52 as a 1:4 mixture of E/ Z-isomers
as a light-yellow oil: IR (neat) 1711, 1660, 1629, 1511, 1261,
2-[4-(ter t-Bu t yld im et h ylsila n yloxy)b u t yl]-3-[[2-(3,4-
d im eth oxyp h en yl)eth yl](2-eth a n esu lfin yla cetyl)a m in o]-
a cr ylic Acid Meth yl Ester (40). To a solution of 6.7 g (12
mmol) of 37 in 100 mL of a 4:1 mixture of MeOH/H2O was
added 3.9 g (18 mmol) of NaIO4 and the resulting solution was
stirred at room temperature for 2 h. A white precipitate
appeared after 30 min. The reaction mixture was diluted with
water and extracted with CH2Cl2. The combined organic layer
was dried over MgSO4 and the solvent was removed under
reduced pressure. Flash silica gel chromatography afforded 4.8
g (68% yield) of a 1:3 mixture of E/ Z isomers of sulfoxide 40
and 1245 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.32-1.36 (t,
;
3H, J ) 7.4 Hz), 1.53-1.61 (m, 4H), 1.82-1.89 (m, 2H), 2.28-
2.32 (m, 2H), 2.74-2.83 (m, 3H), 2.93-3.00 (m, 1H), 3.39-
3.42 (t, 2H, J ) 6.6 Hz), 3.68 (s, 2H), 3.73 (s, 3H), 3.79 (s, 3H,
minor isomer) 3.84 (s, 3H), 3.85 (s, 3H), 6.27 (s, 1H), 6.70-
6.79 (m, 3H), and 7.22 (s, 1H, minor isomer); 13C NMR (CDCl3,
100 MHz) δ 6.7, 26.4, 26.7, 27.4, 31.2, 31.3, 32.3, 32.7, 33.3,
33.6, 33.8, 46.6, 49.7, 50.4, 52.5, 55.7, 56.1, 111.4, 112.1, 120.9,
130.5, 131.1, 133.1, 134.5, 137.4, 147.9, 149.2, and 164.5. Anal.
Calcd for C22H32BrNO6S: C, 51.05; H, 6.24; N, 2.71. Found:
C, 50.92; H, 6.09; N, 2.55.
as a colorless oil: IR (film) 1716, 1664, 1511, and 1260 cm-1
;
1H NMR (CDCl3, 400 MHz) δ -0.05 (s, 6H, minor isomer),
-0.02 (s, 6H, major isomer), 0.79 (s, 9H, minor isomer), 0.82
(s, 9H, major isomer), 1.26-1.30 (t, 2H, J ) 7.6 Hz), 1.41-
1.48 (m, 5H), 2.22-2.27 (m, 2H), 2.68-2.76 (m, 4H), 2.85-
2.96 (m, 1H), 3.51-3.78 (m, 7H), 3.66 (s, 3H), 3.70 (s, 2H), 3.78
(s, 3H), 3.80 (s, 3H), 6.20 (s, 1H, major isomer), 6.64-6.74 (m,
3H), and 7.13 (s, 1H, minor isomer); 13C NMR (CDCl3, 100
MHz) δ -5.1, 6.7, 18.5, 24.7, 25.2, 26.1, 27.1, 31.9, 32.4, 33.1,
33.5, 33.7, 46.5, 49.6, 50.1, 52.4, 55.7, 55.8, 56.0, 62.6, 62.7,
111.3, 112.0, 120.9, 130.5, 131.0, 132.1, 133.5, 134.4, 136.8,
147.8, 147.9, 149.1, 164.4, 166.5, and 167.1; HRMS calcd for
1-(4-Br om obu tyl)-2-eth ylsu lfa n yl-8,9-d im eth oxy-3-oxo-
1,2,3,5,6,10b-h exa h yd r op yr r olo[2,1-a ]isoqu in olin e-1-ca r -
boxylic Acid Meth yl Ester (27). To a refluxing solution
containing 3.1 g (13 mmol) of camphorsulfonic acid in 100 mL
of benzene was added 1.7 g (3.3 mmol) of sulfoxide 52 in 30
mL of benzene. The reaction mixture was heated at reflux for
30 min, cooled to room temperature, and quenched with a
saturated NaHCO3 solution. The aqueous solution was ex-
tracted with CH2Cl2 and dried over MgSO4. The solvent was
removed under reduced pressure followed by silica gel chro-
matography to give the tricyclic ring system as a 5:2:1:1
mixture of four diastereomers. One of the minor diastereomers
(27b) was obtained (0.1 g, 8% yield) as a pale-yellow solid: mp
C
28H47NO7SSi 569.2843, found 569.2849.
3-[[2-(3,4-Dim et h oxyp h en yl)et h yl](2-et h a n esu lfin yl-
a cetyl)a m in o]-2-(4-h yd r oxybu tyl)a cr ylic Acid Meth yl Es-
ter (41). To a solution of 30.1 g (54 mmol) of 37 in 1 L of MeOH
was added 58.2 g (272 mmol) of NaIO4 in 200 mL of H2O. The
resulting mixture was stirred at room temperature for 16 h
and then diluted with H2O. The mixture was extracted with
CH2Cl2 and the organic layers were combined and dried over
MgSO4. Removal of the solvent under reduced pressure
followed by silica gel flash chromatography afforded 18.7 g
(75% yield) of the 1:4 mixture E/ Z-sulfoxide 41 as a pale-
yellow oil: IR (film) 3411, 1716, 1654, 1623, 1516, and 1255
111-114 °C; IR (film) 1726, 1690, 1516, and 1260 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 0.95-1.07 (m, 2H), 0.87-1.22 (m,
1H), 1.22-1.26 (t, 3H, J ) 7.4 Hz), 1.33-1.48 (m, 3H), 1.53-
1.60 (m, 1H), 2.59-2.63 (m, 1H), 2.73-2.85 (m, 3H), 3.05-
3.10 (m, 2H), 3.26 (s, 1H), 3.77 (s, 3H), 3.80 (s, 3H), 3.81 (s,
3H), 4.34-4.38 (m, 1H), 5.47 (s, 1H), 6.55 (s, 1H), and 7.10 (s,
1H); 13C NMR (CDCl3, 100 MHz) δ 14.5, 23.3, 26.7, 28.9, 33.0,
33.1, 33.3, 37.3, 52.5, 53.1, 56.0, 56.1, 59.2, 59.4, 110.8, 111.9,
123.6, 127.6, 147.9, 148.3, 169.7, and 172.7. Anal. Calcd for
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.27-1.31 (t, 3H, J ) 7.2
Hz), 1.49-1.50 (m, 5H), 2.36-2.45 (m, 2H), 2.74-2.78 (t, 2H,
J ) 7.6 Hz), 2.82-3.00 (m, 1H), 3.53-3.56 (m, 2H), 3.64-3.77
(m, 4H), 3.72 (s, 3H), 3.77 (s, 2H), 3.83 (s, 3H), 3.85 (s, 3H),
6.26 (s, 1H), and 6.68-6.78 (m, 3H); 13C NMR (CDCl3, 100
MHz) δ 24.2, 26.8, 32.5, 33.6, 46.4, 49.7, 52.5, 53.6, 55.6, 56.0,
61.9, 111.4, 112.0, 120.9, 130.5, 132.3, 136.9, 148.0, 149.1,
164.4, and 167.1. Anal. Calcd for C22H33NO7S: C, 58.00; H,
7.31; N, 3.08. Found: C, 57.91; H, 7.23; N, 2.84.
C
22H30BrNO5S: C, 52.80; H, 6.04; N, 2.80. Found: C, 52.60;
H, 6.07; N, 2.75.
Diastereomers 27d and 27c (0.4 g, 22% yield) could not be
fully separated and the 2:1 mixture showed the following
spectral properties: IR (film) 2934, 2858, 1716, 1705, 1511,
2-(4-Br om obu tyl)-3-[[2-(3,4-d im eth oxyp h en yl)eth yl](2-
eth ylsu lfa n yla cetyl)a m in o]a cr ylic Acid Meth yl Ester . To
a solution of 1.8 g (4.0 mmol) of alcohol 41 in CH2Cl2 at room
temperature was added 4.0 g (12 mmol) of carbon tetra-
bromide. The resulting solution was stirred at room temper-
ature for 10 min followed by the addition of 3.1 g (12 mmol) of
triphenyl phosphine in several portions. The resulting mixture
was stirred at room temperature for 1 h followed by quenching
with water and extraction with CH2Cl2. The combined organic
layer was dried over MgSO4, the solvent was removed under
reduced pressure and the residue was subjected to silica gel
chromatography to provide 1.6 g (83% yield) of the titled
compound as a 1:4 mixture of E/Z isomers: IR (neat) 1706,
1655, 1629, 1511, 1440, and 1255 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.22-1.27 (t, 3H, J ) 7.3 Hz), 1.55-1.62 (m, 2H),
1.79-1.85 (m, 2H), 2.26-2.30 (m, 2H), 2.56-2.61 (q, 2H, J )
7.3 Hz), 2.77-2.81 (t, 2H, J ) 7.4 Hz), 3.21 (br s, 2H), 3.34-
3.40 (m, 3H), 3.76 (s, 3H), 3.77-3.79 (m, 1H), 3.83 (s, 3H), 3.85
(s, 3H), 6.70-6.78 (m, 3H), and 7.25 (s, 1H); 13C NMR (CDCl3,
100 MHz) δ 14.5, 26.3, 26.4, 26.8, 32.6, 32.8, 33.3, 33.6, 33.8,
43.8, 52.4, 56.1, 111.5, 112.1, 120.9, 127.6, 130.8, 138.2, 147.9,
and 1265 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.18-1.22 (t,
;
3H, J ) 7.6 Hz), 1.23-1.27 (t, 3H, J ) 7.2 Hz), 1.28-1.35 (m,
2H), 1.53-2.03 (m, 6H), 2.27-2.41 (m, 1H), 2.45-2.54 (m, 1H),
2.55-2.80 (m, 4H), 2.86-2.95 (m, 2H), 3.00-3.07 (m, 1H), 3.15
(s, 3H), 3.34-3.38 (t, 2H, J ) 6.8 Hz), 3.53 (s, 1H), 3.73 (s,
3H), 3.78 (s, 3H), 3.80 (s, 3H), 3.83 (s, 3H), 4.22 (s, 1H), 4.25-
4.29 (m, 1H), 4.34-4.36 (m, 1H), 4.73 (s, 1H), 5.09 (s, 1H), 6.46
(s, 1H), 6.49 (s, 1H), 6.53 (s, 1H), and 6.59 (s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 14.5, 14.9, 22.5, 24.1, 25.6, 27.6, 27.9, 28.6,
28.8, 31.1, 33.3, 33.4, 33.5, 37.5, 37.8, 48.9, 52.1, 53.2, 55.3,
55.9, 56.0, 56.3, 59.6, 60.9, 64.0, 108.7, 110.2, 111.8, 112.2,
123.0, 123.2, 126.9, 127.9, 147.6, 147.8, 148.3, 148.4, 169.6,
171.5, 172.5, and 175.3.
The major diastereomer 27a was isolated (0.8 g, 58% yield)
as a white solid, mp 49-51 °C; IR (film) 1713, 1695, 1512, and
1
1263 cm-1; H NMR (CDCl3, 400 MHz) δ 1.23-1.27 (t, 3H, J
) 7.4 Hz), 1.67-1.71 (m, 1H), 1.84-2.06 (m, 3H), 2.17-2.22
(m, 2H), 2.48-2.52 (m, 1H), 2.67-2.85 (m, 4H), 3.14 (s, 3H),
3.48-3.53 (m, 2H), 3.54 (s, 1H), 3.77 (s, 3H), 3.79 (s, 3H), 4.36-
4.04 (dd, 1H, J ) 13 and 4.0 Hz), 4.77 (s, 1H), 6.51 (s, 1H),
and 6.52 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 15.2, 23.1, 28.2,
149.2, 167.7, and 169.4; HRMS calcd for
501.1185, found 501.1184.
C22H32BrNO5S
J . Org. Chem, Vol. 68, No. 3, 2003 939

Padwa et al.
28.7, 32.1, 32.8, 33.6, 38.1, 51.3, 53.0, 55.9, 56.3, 59.8, 60.0,
108.8, 111.8, 123.9, 127.8, 128.6, 128.7, 132.1, 132.3, 147.7,
148.2, 170.7, and 170.8. Anal. Calcd for C22H30BrNO5S: C,
52.80; H, 6.04; N, 2.80. Found: C, 52.82; H, 6.09; N, 2.74.
Ester (53). A solution of 1.2 g (2.8 mmol) of the above sulfoxide
in 100 mL of toluene was heated at reflux for 16 h and then
cooled to room temperature. The solvent was removed under
reduced pressure and the crude product was purified by flash
silica gel chromatography to give 1.0 g (98% yield) of 53 as a
white solid: mp 155-157 °C; IR (film) 1731, 1685, 1516, 1429,
8a -E t h ylsu lfa n yl-2,3-d im et h oxy-8-oxo-5,8,8a ,9,10,11,
12,12b-oct a h yd r o-6H -isoin d olo[1,2-a ]isoq u in olin e-12a -
ca r boxylic Acid Meth yl Ester (28a ). To a solution of 0.63
g (1.3 mmol) of bromide 27a in 40 mL of THF was added 0.13
g (3.1 mmol) of NaH (60% in oil) and the resulting mixture
was heated at reflux for 4 h. The mixture was cooled to room
temperature and quenched with water. The aqueous layer was
extracted with CH2Cl2 and dried over MgSO4. Flash silica gel
chromatography provided 0.5 g (99% yield) of the titled
compound as a white solid: mp 153-156 °C; IR (film) 1726,
1705, 1516, 1429, and 1296 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.22-1.25 (t, 3H, J ) 7.6 Hz), 1.66-1.68 (m, 3H), 1.75-1.79
(m, 2H), 1.95-1.98 (m, 1H), 2.21-2.30 (m, 2H), 2.54-2.57 (m,
1H), 2.81-2.88 (m, 3H), 3.06-3.11 (dd, 1H, J ) 11 and 7.6
Hz), 3.22 (s, 3H), 3.83 (s, 3H), 3.84 (s, 3H), 4.39-4.41 (m, 1H),
5.02 (s, 1H), and 6.58 (s, 2H); 13C NMR (CDCl3, 100 MHz) δ
14.5, 19.9, 21.9, 22.8, 26.0, 28.3, 32.1, 37.5, 51.3, 56.0, 56.3,
56.5, 56.9, 58.7, 108.8, 111.9, 124.4, 128.4, 147.7, 148.1, 171.7,
and 175.6. Anal. Calcd for C22H29NO5S: C, 62.98; H, 6.97; N,
3.34. Found: C, 62.81; H, 6.73; N, 3.27.
8a -E t h ylsu lfa n yl-2,3-d im et h oxy-8-oxo-5,8,8a ,9,10,11,
12,12b-oct a h yd r o-6H -isoin d olo[1,2-a ]isoq u in olin e-12a -
ca r boxylic Acid Meth yl Ester (28b). A solution of 0.1 g (0.2
mmol) of bromide 27d in 2 mL of anhydrous THF was treated
with 0.02 g (0.4 mmol) of NaH (60% in oil). The resulting
mixture was heated at reflux for 2 h, cooled to room temper-
ature, and quenched with water. The aqueous layer was
extracted with CH2Cl2 and dried over MgSO4. The solvent was
removed under reduced pressure. Flash silica gel chromatog-
raphy of the residue afforded 0.02 g (21% yield) of the titled
compound as a white solid: mp 144-146 °C; IR (film) 1726,
1690, 1516, 1424, and 1229 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 0.77-0.85 (td, 1H, J ) 14 and 5.0 Hz), 1.06-1.11 (m, 1H),
1.13-1.18 (t, 3H, J ) 7.6 Hz), 1.23-1.25 (m, 1H), 1.34-1.37
(m, 1H), 1.64-1.75 (m, 2H), 1.76-1.84 (td, 1H, J ) 14 and 5.0
Hz), 2.46-2.49 (m, 1H), 2.63-2.66 (m, 1H), 2.67-2.73 (q, 2H,
J ) 7.6 Hz), 2.78-2.85 (td, 1H, J ) 12 and 4.5 Hz), 2.89-2.96
(td, 1H, J ) 12 and 4.5 Hz), 3.79 (s, 3H), 3.83 (s, 3H), 3.85 (s,
3H), 4.39-4.44 (dd, 1H, J ) 14 and 4 Hz), 5.54 (s, 1H), 6.56
(s, 1H), and 7.13 (s, 1H);13C NMR (CDCl3, 100 MHz) δ 14.2,
21.1, 23.0, 23.3, 29.2, 29.9, 37.3, 52.3, 55.6, 55.9, 56.0, 57.1,
59.3, 110.4, 111.6, 124.1, 128.0, 147.9, 169.4, and 173.4. Anal.
Calcd for C22H29NO5S: C, 62.98; H, 6.97; N, 3.34. Found: C,
62.67; H, 6.84; N, 3.24.
8a -E t h a n e su lfin yl-2,3-d im e t h oxy-8-oxo-5,8,8a ,9,10,
11,12,12b-octah ydr o-6H-isoin dolo[1,2-a ]isoqu in olin e-12a -
ca r boxylic Acid Meth yl Ester . A solution containing 0.7 g
(1.7 mmol) of sulfide 28a in 25 mL of a 4:1 mixture of MeOH/
H2O was treated with 1.1 g (5.0 mmol) of NaIO4 at room
temperature. The mixture was stirred at 25 °C for 16 h, diluted
with H2O, and extracted with CH2Cl2. The combined organic
layer was dried over MgSO4, the solvent was removed under
reduced pressure, and the residue was subjected to flash silica
gel chromatography to give 0.65 g (90% yield) of the titled
compound as a white solid: mp 131-132 °C; IR (film) 1720,
1691, 1513, 1453, 1296, and 1208 cm-1; 1H NMR (CDCl3, 400
MHz) δ 1.42-1.46 (t, 3H, J ) 7.6 Hz), 1.68-1.72 (m, 2H),
1.85-1.90 (m, 2H), 1.99-2.10 (m, 1H), 2.40-2.44 (m, 2H),
2.52-2.55 (m, 1H), 2.77-2.84 (m, 3H), 3.01-3.06 (dd, 1H, J
) 13 and 7.6 Hz), 3.22 (s, 3H), 3.29-3.35 (dd, 1H, J ) 13 and
7.6 Hz), 3.84 (s, 3H), 3.86 (s, 3H), 4.32-4.34 (m, 1H), 5.08 (s,
1H), 6.58 (s, 1H), and 6.64 (s, 1H); 13C NMR (CDCl3, 100 MHz)
δ 8.6, 20.6, 21.2, 26.6, 28.4, 28.5, 37.7, 43.9, 51.7, 56.0, 56.4,
57.9, 58.4, 66.1, 109.4, 111.9, 123.3, 128.5, 147.8, 148.5, 171.3,
and 171.6. Anal. Calcd for C22H29NO6S: C, 60.67; H, 6.71; N,
3.22. Found: C, 60.64; H, 6.52; N, 3.12.
1
and 1224 cm-1; H NMR (CDCl3, 400 MHz) δ 1.52-1.69 (m,
2H), 1.87-1.92 (m, 1H), 2.13-2.29 (m, 2H), 2.55-2.59 (m, 1H),
2.72-2.80 (m, 1H), 2.83-2.89 (m, 2H), 3.13 (s, 3H), 3.79 (s,
3H), 3.82 (3H), 4.41-4.45 (dd, 1H, J ) 12 and 4.4 Hz), 4.58 (s,
1H), 6.54 (s, 1H), 6.57 (s, 1H), and 6.59-6.61 (t, 1H, J ) 3.4
Hz); 13C NMR (CDCl3, 100 MHz) δ 19.5, 24.4, 28.3, 30.1, 37.2,
51.6, 53.9, 55.9, 56.1, 65.1, 109.2, 111.5, 123.7, 127.4, 130.5,
134.6, 147.7, 148.2, 167.0, and 171.1; HRMS calcd for C20H23
-
NO5 357.1576, found 357.1578. Anal. Calcd for C20H23NO5: C,
67.21; H, 6.49; N, 3.92. Found: C, 67.08; H, 6.50; N, 3.84.
2,3-Dim et h oxy-8-t h ioxo-5,8,10,11,12,12b-h exa h yd r o-
6H -isoin d olo[1,2-a ]isoq u in olin e-12a -ca r b oxylic
Acid
Meth yl Ester (54). To a solution of 0.4 g of lactam 53 in 4
mL of THF was added 1.0 g of Lawesson’s reagent at room
temperature and the resulting yellow solution was stirred at
25 °C for 18 h. The solution was taken up in ether resulting
in the formation of yellow precipitate, which was subsequently
filtered. Concentration of the filtrate under reduced pressure
followed by flash silica gel chromatography provided 0.2 g (61%
yield) of thiolactam 54 as a yellow solid: mp 185-186 °C; IR
1
(film) 1726, 1669, 1603, 1511, 1465, and 1260 cm-1; H NMR
(CDCl3, 400 MHz) δ 1.57-1.65 (m, 1H), 1.66-1.75 (m, 1H),
1.93-1.98 (m, 1H), 2.18-2.27 (m, 1H), 2.28-2.38 (m, 1H),
2.69-2.74 (m, 1H), 2.85-2.96 (m, 2H), 3.14-3.21 (m, 1H), 3.17
(s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 4.80 (s, 1H), 5.23-5.28 (ddd,
1H, J ) 13.0, 4.4, and 1.6 Hz), 6.60-6.61 (d, 2H, J ) 2.8 Hz),
and 6.98-6.99 (t, 1H, J ) 3.6 Hz); 13C NMR (CDCl3, 100 MHz)
δ 19.4, 24.9, 28.0, 30.2, 42.6, 51.8, 55.6, 56.0, 56.2, 71.2, 108.9,
111.4, 122.1, 127.1, 134.2, 141.3, 148.0, 148.6, 170.6, and 192.7.
Anal. Calcd for C20H23NO4S: C, 64.32; H, 6.21; N, 3.75.
Found: C, 64.23; H, 6.14; N, 3.82.
(()-J a m tin e (25). A solution containing 0.2 g (0.4 mmol)
of thiolactam 54 in 2 mL of THF was treated with 0.1 g (0.4
mmol) of Meerwein’s salt at 0 °C. The resulting yellow-orange
solution was stirred at 0 °C for 5 min and then at room
temperature for an additional 1 h. The solvent was removed
under reduced pressure and the residue was taken up in
MeOH and cooled to 0 °C. To this solution was added 0.04 g
(1.2 mmol) of NaBH4 and the resulting mixture was warmed
to room temperature over a 2-h period. The solution was
quenched with 10% HCl, stirred for 5 min at room tempera-
ture, and then neutralized with a 10% NaOH solution. The
crude mixture was extracted with CH2Cl2 and dried over
MgSO4. Silica gel chromatography afforded 0.1 g (61% yield)
of (()-jamtine 25 as a pale yellow solid: mp 102-104 °C; IR
(film) 1726, 1613, 1521, and 1260; 1H NMR (CDCl3, 400 MHz)
δ 1.51-1.54 (m, 2H), 1.83-1.85 (m, 1H), 2.09-2.10 (m, 2H),
2.47-2.49 (dt, 1H, J ) 15.6 and 3.2 Hz), 2.51-2.53 (t, 1H, J
) 3.2 Hz), 2.69-2.91 (m, 2H), 3.06-3.11 (m, 1H), 3.27 (s, 3H),
3.38-3.41 (dd, 1H, J ) 12 and 1.8 Hz), 3.82 (s, 3H), 3.83 (s,
1H), 3.85 (s, 3H), 3.95-3.98 (dd, 1H, J ) 12 and 1.8 Hz), 5.69
(br s, 1H), 6.55 (s, 1H), and 6.77 (s, 1H); 13C NMR (CDCl3, 100
MHz) δ 20.0, 24.5, 27.4, 32.1, 48.0, 51.6, 55.9, 56.1, 57.0, 57.2,
71.4, 110.2, 111.2, 121.3, 127.1, 128.6, 138.0, 146.8, 147.5, and
173.6. Anal. Calcd for C20H25NO4: C, 69.95; H, 7.34; N, 4.08.
Found: C, 69.76; H, 7.22; N, 3.97.
(()-J a m tin e-N-oxid e (55). To a solution containing 0.1 g
(0.3 mol) of jamtine (25) in 1.5 mL of CH2Cl2 at 0 °C was added
0.06 g (0.4 mmol) of MCPBA. The reaction mixture was stirred
at room temperature for 2 h and then quenched with water.
The organic layer was extracted with CHCl3 and dried over
MgSO4, and the solvent was removed under reduced pressure.
Silica gel chromatography afforded 0.09 g (95% yield) of 55 as
a pale yellow oil: IR (film) 1726, 1234, and 1122 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.49-1.54 (m, 1H), 1.77-1.84 (t, 1H, J )
14 Hz), 1.91-1.94 (m, 1H), 2.15-2.24 (m, 2H), 2.76-2.85 (m,
2,3-Dim et h oxy-8-oxo-5,8,10,11,12,12b-h exa h yd r o-6H -
isoin d olo[1,2-a ]isoqu in olin e-12a -ca r boxylic Acid Meth yl
940 J . Org. Chem., Vol. 68, No. 3, 2003

Synthesis of the Alkaloid J amtine
2H), 3.20-3.25 (m, 1H), 3.28 (s, 3H), 3.80-3.81 (m, 2H), 3.83
(s, 3H), 3.84 (s, 3H), 4.43-4.46 (d, 1H, J ) 13.6 Hz), 4.82 (s,
1H), 4.88-4.91 (d, 1H, J ) 13.6 Hz), 6.00 (s, 1H), 6.59 (s, 1H),
and 6.62 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 19.5, 24.3, 25.8,
33.0, 52.2, 56.2, 56.3, 58.0, 64.1, 76.5, 90.3, 110.2, 111.6, 121.9,
125.1, 127.7, 131.1, 148.0, 148.7, and 172.1. Anal. Calcd for
experimental assistance and Dr. Scott K. Bur for the
molecular modeling calculations. We wish to acknowl-
edge the NSF (CHE 9974864) and the NIH (S10-
RR13673) for shared instrumentation grants which
were awarded for the purchase of the two D8 X-ray
instruments. We also thank Professor Nigel S. Simp-
kins, University of Nottingham, for helpful exchange of
information.
C
20H25NO5: C, 66.84; H, 7.01; N, 3.90. Found: C, 66.72; H,
6.94; N, 3.87.
To a solution containing 0.03 g (0.09 mmol) of 55 in 8 mL of
CH2Cl2 was added 1.6 mL (18 mmol) of PCl3. The resulting
yellow reaction mixture was heated at reflux for 15 min, cooled
to 0 °C, and quenched with a dilute NH4OH solution. The
organic layer was extracted with CHCl3 and dried over MgSO4,
and the solvent was removed under reduced pressure. Silica
gel chromatography afforded 0.03 g (78% yield) of pure jamtine
(25).
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic and
experimental procedures for compounds 30, 32, 33, 35, 36, 38,
39, 42-45, 47, 48, 50, and 51 and 1H and 13C NMR spectra
for new compounds lacking elemental analyses together with
ORTEP drawings for structures 25, 28a , 28b, 42, and 54. This
material is available free of charge via the Internet at http://
pubs.acs.org. The authors have deposited atomic coordinates
for these structures with the Cambridge Crystallographic Data
Centre.
Ack n ow led gm en t. This research was supported by
the National Science Foundation (CHE-0132651). We
thank Dr. Todd Heidelbaugh and Bethy J askal for some
J O026471G
J . Org. Chem, Vol. 68, No. 3, 2003 941