Synthesis of naturally occurring pyridine alkaloids via palladium-catalyzed coupling/migration chemistry

Article abstract of DOI:10.1021/jo026716p

The palladium-catalyzed cross-coupling of 3-iodopyridine, long-chain terminal dienes, and benzylic amines or tosylamides provides a novel route to key intermediates for the synthesis of the naturally occurring, biologically active pyridine alkaloids theonelladins C and D, niphatesine C, and xestamine D. This process involves (1) oxidative addition of the heterocyclic iodide to Pd(0), (2) carbopalladation of the least hindered carbon-carbon double bond of the diene, (3) palladium migration, and (4) π-allylpalladium displacement by the nitrogen nucleophile with simultaneous regeneration of the Pd catalyst. Subsequent hydrogenation and deprotection affords good yields of the natural products. The Pd-catalyzed coupling of 3-iodopyridine and 2-methyl-11-dodecen-1-ol provides a convenient synthesis of a long-chain aldehyde by an analogous palladium migration process, which is easily converted to the pyridine alkaloid ikimine A.

Full text of DOI:10.1021/jo026716p

Syn th esis of Na tu r a lly Occu r r in g P yr id in e Alk a loid s via
P a lla d iu m -Ca ta lyzed Cou p lin g/Migr a tion Ch em istr y
Yao Wang, Xiaoyang Dong, and Richard C. Larock*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
larock@iastate.edu
Received November 14, 2002
The palladium-catalyzed cross-coupling of 3-iodopyridine, long-chain terminal dienes, and benzylic
amines or tosylamides provides a novel route to key intermediates for the synthesis of the naturally
occurring, biologically active pyridine alkaloids theonelladins C and D, niphatesine C, and xestamine
D. This process involves (1) oxidative addition of the heterocyclic iodide to Pd(0), (2) carbopalladation
of the least hindered carbon-carbon double bond of the diene, (3) palladium migration, and (4)
π-allylpalladium displacement by the nitrogen nucleophile with simultaneous regeneration of the
Pd catalyst. Subsequent hydrogenation and deprotection affords good yields of the natural products.
The Pd-catalyzed coupling of 3-iodopyridine and 2-methyl-11-dodecen-1-ol provides a convenient
synthesis of a long-chain aldehyde by an analogous palladium migration process, which is easily
converted to the pyridine alkaloid ikimine A.
In tr od u ction
several groups. More recently, nitro-12 and azomethine
N-oxide13 variants of these pyridine alkaloids have been
discovered. Some of the alkaloids containing a 3-pyridyl
group on one end of a saturated chain and simple amine
functionality on the other have been synthesized. Rao et
al. reported the first total synthesis of theonelladins A-D
using a Wittig reaction for construction of the carbon
skeleton.1b Six steps were required to complete the total
synthesis of theonelladins C and D. Sulfone alkylation
chemistry has also been utilized to prepare theonelladin
D.1d Grignard or alkyne alkylation chemistry have also
been employed to synthesize theonelladins A-D, as well
as niphatesine A1c and hachijodines F and G.10b Nipha-
tesines A-D have been prepared by Friedel-Crafts
acylation,Wittig,Heck,and alkyne alkylation chemistry.2c-e
The only prior synthesis of ikimine A also employed a
Friedel-Crafts acylation.3b There presently exist no
syntheses of any of the xestamines. To date, no general
synthetic strategy applicable to any chain length has
been employed to prepare a variety of these interesting
alkaloids in a minimum of steps.
Recently, many pyridine alkaloids have been isolated
from marine organisms and shown to exhibit interesting
biological activity. For example, the antileukemic and
antineoplastic theonelladins C (1) and D (2) have been
isolated from the Okinawan marine sponge Theonella
swinhoei.1 The antileukemic niphatesines C (3) and D (4)
and the cytotoxic and antimicrobial niphatesine G (5)
have been obtained from the Okinawan marine sponge
Niphates sp.1c,2 The cytotoxic ikimines A-C (6-8, re-
spectively) have been isolated from a Micronesian
sponge.2b,3 The antimicrobial xestamine C (9) comes from
a Caribbean sponge Xestospongia wiedenmayeri, while
the antimicrobial xestamines D-H (10-13, respectively)
have been extracted from a Bahamian sponge Calyx
podatypa.4 3-Pyridine alkaloids such as the navenones,5
halitoxins,6 niphatynes,7 niphatoxins,8 haminols,9 hachi-
jodines,10 and cribochalines11 have also been isolated by
(1) (a) Kobayashi, J .; Murayama, T.; Ohizumi, Y. Tetrahedron Lett.
1989, 30, 4833. (b) Rao, A. V.; Reddy, G. R.; Rao, B. V. J . Org. Chem.
1991, 56, 4545. (c) Teubner, A.; Gerlach, H. Liebigs Ann. Chem. 1993,
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Tetrahedron Lett. 1999, 40, 7359.
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M.; Kobayashi, H.; Ohizumi, Y.; Ohta, T.; Nozoe, S.; Sasaki, T. J . Chem.
Soc., Perkin Trans. 1 1990, 3301. (b) Kobayashi, J .; Zeng, C. M.;
Ishibashi, M.; Shigemori, H.; Sasaki, T.; Mikami, Y. J . Chem. Soc.,
Perkin Trans. 1 1992, 1291. (c) Rao, A. V. R.; Reddy, G. R. Tetrahedron
Lett. 1993, 34, 8329. (d) Bracher, F.; Papke, T. J . Chem. Soc., Perkin
Trans. 1 1995, 2323. (e) Bracher, F.; Papke, T. Monatsh. Chem. 1996,
127, 91.
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Bracher, F.; Papke, T. Nat. Prod. Lett. 1994, 4, 223. (c) Nicholas, G.
M.; Molinski, T. F. Tetrahedron 2000, 56, 2921.
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995. (b) Stierle, D. B.; Faulkner, D. J . J . Nat. Prod. 1991, 54, 1134.
(5) (a) Sleeper, H. L.; Fenical, W. J . Am. Chem. Soc. 1977, 99, 2367.
(b) Fenical, W.; Sleeper, H. L.; Paul, V. J .; Stallard, M. O.; Sun, H. H.
Pure Appl. Chem. 1979, 51, 1865. (c) Sleeper, H. L.; Paul, V. J .; Fenical,
W. J . Chem. Ecol. 1980, 6, 57.
(6) (a) Schmitz, F. J .; Hollenbeak, K. H.; Campbell, D. C. J . Org.
Chem. 1978, 43, 3916. (b) Scott, R. H.; Whyment, A. D.; Foster, A.;
Gordon, K. H.; Milne, B. F.; J aspars, M. J . Membr. Biol. 2000, 176,
119.
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(8) Talpir, R.; Rudi, A.; Ilan, M.; Kashman, Y. Tetrahedron Lett.
1992, 33, 3033.
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Tetrahedron 1993, 49, 1307. (b) Eila, P.; J orma, M.; Hannu, E. Z.
Naturforsch., Sec. C: Biosci. 2002, 57, 548.
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van Soest, R. W. M. J . Nat. Prod. 2000, 63, 682. (b) Goundry, W. R.
F.; Lee, V.; Baldwin, J . E. Tetrahedron Lett. 2002, 43, 2745.
(11) Nicholas, G. M.; Molinski, T. F. Tetrahedron 2000, 56, 2921.
(12) Wang, G.-Y.-S.; Kuramoto, M.; Uemura, D.; Yamada, A.;
Yamaguchi, K.; Yazawa, K. Tetrahedron Lett. 1996, 37, 1813.
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1993, 34, 5953.
10.1021/jo026716p CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/20/2003
3090
J . Org. Chem. 2003, 68, 3090-3098

Synthesis of Naturally Occurring Pyridine Alkaloids
turns out to be critical to the success of this approach.
Unfortunately, ammonia and primary amines do not
usually work well in this three-component coupling
process. However, secondary amines generally afford high
yields of the desired long-chain amines.15 Since the benzyl
group (PhCH2) is often used as a protecting group for
amines and is easily removed by a variety of methods,18
benzylmethylamine and dibenzylamine were chosen as
the most appropriate nucleophiles for synthesis of the
theonelladins.
In our exploratory studies, 1,13-tetradecadiene was
used as a model for 1,12-tridecadiene, since it is com-
mercially available and 1,12-tridecadiene is not. Based
on our previous work, the coupling of 3-iodopyridine, 1,13-
tetradecadiene and benzylmethylamine was examined
(eq 3).
F IGURE 1. Some naturally occurring pyridine alkaloids.
We have recently reported several palladium-catalyzed
migration processes, which are extraordinarily efficient
for the construction of long-chain compounds with an
aromatic ring on one end of the chain and some kind of
functionality on the other end of the chain. For example,
the palladium-catalyzed cross-coupling of aryl halides,
1,ω-dienes, and carbanions14 or amines15 provides a
highly efficient route to long-chain carbonyl or amine
products (eq 1). In an analogous fashion, the palladium-
catalyzed cross-coupling of aryl halides and ω-alken-1-
ols provides long-chain carbonyl products quite efficiently
(eq 2).16
We have examined the effect on the yield and ratio of
14 and 15 of the solvent (DMSO and DMF), the stoichi-
ometry of the reactants in eq 3 (n1, n2, and n3), and the
number of equivalents of added LiCl. The best result was
obtained when the reaction was run in DMF in the
presence of 1 equiv of LiCl at 100 °C for 24 h with a
1:2.5:2 ratio of 3-iodopyridine, diene, and amine. The
isolated product 14 was examined by GC-MS and 1H
NMR spectroscopy and found to be a mixture of two
isomers in a ratio of 86:14.
The beauty of this methodology is that one can readily
employ a wide range of aromatic substrates, dienes and
alkenols of varying chain length, and various nucleo-
philes to prepare a tremendous range of products in one
easy step. This chemistry appeared to be ideal for the
synthesis of the pyridine alkaloids discussed above.
Indeed, we now report very efficient syntheses of theon-
elladins C and D, niphatesine C, xestamine D, and
ikimine A using this methodology.17
The minor isomer (14b) is formed by addition of the
pyridylpalladium intermediate to the more hindered
internal carbon of one of the double bonds of the diene.
Unfortunately, these two isomers are not easily sepa-
rated.
It appeared that a carbon analogue of theonelladin D
bearing one more methylene unit could be easily obtained
simply by hydrogenation of the double bond and deben-
zylation of compound 14a . The traditional procedure for
debenzylation of benzylamines is heterogeneous catalytic
hydrogenation.19 It was hoped that compound 14a would
undergo hydrogenation of the double bond and deben-
zylation simultaneously.
Resu lts a n d Discu ssion
Tota l Syn th esis of Th eon ella d in s C a n d D. To
prepare theonelladins C and D using the methodology
outlined in eq 1, we required three major components:
3-iodopyridine, 1,12-tridecadiene, and an appropriate
nitrogen nucleophile. The choice of nitrogen nucleophile
Pearlman’s catalyst,20 20% Pd(OH)2 on charcoal, has
proven to be an effective catalyst for debenzylation, even
when other palladium catalysts have failed.21 Thus, the
(14) Larock, R. C., Lu, Y.; Bain, A. C.; Russell, C. E. J . Org. Chem.
1991, 56, 4589.
(15) Larock, R. C.; Wang, Y.; Lu, Y.; Russell, C. E. J . Org. Chem.
1994, 59, 8107.
(16) Larock, R. C.; Leung, W.-Y.; Stolz-Dunn, S. Tetrahedron Lett.
1989, 30, 6629.
(17) For a preliminary communication, see: Larock, R. C.; Wang,
Y. Tetrahedron Lett. 2002, 43, 21.
(18) Greene, T. W. Protective Groups in Organic Synthesis; J .
Wiley: New York, 1991.
(19) (a) Rylander, P. N. Hydrogenation Methods; Academic Press:
London, 1985. (b) Velluz, L.; Amiard, G.; Heymes, R. Bull. Soc. Chim.
Fr. 1954, 1012. (c) Hartung, W. H.; Simonoff, R. Org. React. 1953, 7,
263.
(20) Pearlman, W. M. Tetrahedron Lett. 1967, 1663.
J . Org. Chem, Vol. 68, No. 8, 2003 3091

Wang et al.
mixture of compounds 14a and 14b was hydrogenated
using Pearlman’s catalyst (eq 4).
54 and 42%, respectively. On the other hand, 0.20, 0.35,
or 0.75 equiv of Pd as 20% Pd(OH)2/C gave 46, 76, and
75% yields, respectively. Thus, Pearlman’s catalyst gave
the best results, provided approximately 0.35 equiv of the
Pd catalyst was employed.
We have tried to simplify this procedure still further.
For example, a mixture of compounds 14a and 14b was
mixed with HCO2NH4 and 20% Pd(OH)2/C in methanol
and flushed with 1 atm of H2 at room temperature. This
approach afforded the anticipated mixture of 18a plus
18b in 53% yield. Alternatively, a mixture of 14a and
14b plus HCO2NH4 and 20% Pd(OH)2/C in methanol was
simply refluxed without flushing with H2. This provided
a 43% yield of a mixture of 18a plus 18b. Thus, unfor-
tunately, neither effort provided better results.
With proven procedures for the palladium-catalyzed
coupling, hydrogenation, and debenzylation in hand, we
were ready to synthesize the natural product theonella-
din D by substituting 1,12-tridecadiene for 1,13-tetra-
decadiene. Although the former diene is not commercially
available, it is easily made from 9-decen-1-ol in two steps.
Thus, 9-decen-1-ol was allowed to react with iodine in
the presence of PPh3 and imidazole25 to give 10-iodo-1-
decene (19) in 88% yield (eq 7). The copper-catalyzed
coupling of 10-iodo-1-decene with allylmagnesium bro-
mide26 afforded a 60% yield of 1,12-tridecadiene (20)
(eq 8).
Unfortunately, none of the desired theonelladin D ana-
logue was formed. 3-n-Tetradecylpyridine (16a ) and the
branched isomer 16b were isolated along with an un-
known product, which proved to be a major component.
Apparently, compounds 16a and 16b were formed by
cleavage of the allylic C-N bond. Allylic amines, like
benzylic amines, can be cleaved at the C-N bond by
catalytic hydrogenation.22 We, therefore, decided to satu-
rate the carbon-carbon double bond first and then
remove the benzyl group. Hydrogenation of the C-C
double bond in the mixture of compounds 14a and 14b
proceeded smoothly under mild conditions as shown in
eq 5.
Debenzylation is usually carried out by high-pressure
catalytic hydrogenation.19b,c,23 This was not particularly
attractive to us. Ram et al.24 have reported a more
convenient debenzylation procedure using ammonium
formate as a hydrogen source and 10% Pd/C as a catalyst.
We have successfully applied Ram’s procedure to the
conversion of compound 17a to the theonelladin D
analogue 18a . To simplify the procedure, the same
catalyst and solvent were used for sequential hydrogena-
tion of the carbon-carbon double bond and debenzylation
without purification or separation of the intermediates.
Thus, a mixture of compounds 14a and 14b was dissolved
in methanol and flushed with 1 atm of H2 gas in the
presence of 10% Pd/C at room temperature for 2 h. Then,
6 equiv of HCO2NH4 was added to the reaction mixture.
The mixture was stirred at 70 °C for 10 min, and the
products 18a and 18b were obtained in 42% combined
yield (eq 6).
1,12-Tridecadiene was then employed in the palladium-
catalyzed coupling reaction under our “optimal” reaction
conditions. The desired coupling products (21a and 21b)
were isolated in a 68% combined yield in a ratio of 85:15
(eq 9). We have found that slightly increasing the amount
of LiCl afforded a still better 78% yield.
To obtain better yields of the products, several different
palladium catalysts were examined in this reaction.
Using 5% (0.10 equiv of Pd) or 10% Pd/C (0.35 equiv of
Pd) gave isolated yields of a mixture of 18a and 18b of
Finally, the hydrogenation and debenzylation of com-
pounds 21a and 21b afforded the natural product the-
onelladin D (2) and its isomer (22) in a 70% combined
yield (eq 10).
(21) Gold, E. H.; Chang, W.; Cohen, M.; Baum, T.; Ehrreich, S.;
J ohnson, G.; Prioli, N.; Sybertz, E. J . J . Med. Chem. 1982, 25, 1363.
(22) Weir, J . R.; Patel, B. A.; Heck, F. R. J . Org. Chem. 1980, 45,
4926.
(23) Bernotas, R. C.; Cube, R. V. Synth. Commun. 1990, 20, 1209.
(24) (a) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515. (b)
Ram, S.; Spicer, L. D. Synth. Commun. 1987, 17, 415.
(25) (a) Singh, A. K.; Bakshi, R. K.; Corey, E. J . J . Am. Chem. Soc.
1987, 109, 6187. (b) Millar, J . G.; Underhill, E. W. J . Org. Chem. 1986,
51, 4726.
(26) Derguini-Boumechal, F.; Lorne, R.; Linstrumelle, G. Tetrahe-
dron Lett. 1977, 1181.
3092 J . Org. Chem., Vol. 68, No. 8, 2003

Synthesis of Naturally Occurring Pyridine Alkaloids
TABLE 1. P a lla d iu m -Ca ta lyzed Cou p lin g of
3-Iod op yr id in e, 1,13-Tetr a d eca d ien e, a n d N-Ben zyl
Tosyla m id e (eq 11)a
% isolated
yield
n-Bu4NCl
(equiv)
Na2CO3
(equiv)
temp
(°C)
time
(h)
entry
23a
23b
1
2
3
4
5f
6
7
1
c
4
0
2
e
4
4
4
100
100
100
100
100
80
24
24
48
48
48
48
24
50b
d
Theonelladin C having an NH2 group at the end of the
carbon chain was our next synthetic target. As in the
synthesis of theonelladin D, the key issue here is the
choice of the nitrogen nucleophile for use in the palladium
reaction. On the basis of the success of our debenzylation
process, benzylamine and dibenzylamine were chosen as
nucleophiles. In our exploratory work with these nucleo-
philes, commercially available 1,13-tetradecadiene was
again used as a substitute for 1,12-tridecadiene.
When employed in the palladium-catalyzed coupling,
benzylamine failed to give the desired product. Our
previous work indicated that 1° amines were generally
not as good as 2° amines as nucleophiles.15 We, therefore,
anticipated that dibenzylamine would provide better
results. Surprisingly, dibenzylamine did not work well
in this coupling process either. We tried to improve this
reaction by changing the chloride reagent added, adding
a base, extending the reaction time and using a short-
chain diene. Unfortunately, the reactions employing 1,13-
tetradecadiene gave very low yields of the desired cou-
pling product and even 1,5-hexadiene gave yields no
higher than approximately 35%, and the products were
rather impure.
It appeared that another protecting group was neces-
sary. The protecting group had to facilitate the palladium
process itself and be easily removed after the palladium
reaction. The tosyl group is well-known as a useful
protecting group for amines,18 and tosylamides are
generally good nucleophiles in π-allylpalladium coupling
processes.27 N-Benzyl tosylamide was therefore examined
in our palladium-catalyzed three-component coupling.
The results from the coupling of 3-iodopyridine, 1,13-
tetradecadiene, and N-benzyl tosylamide are summarized
in eq 11 and Table 1.
1
1
1
1
2
46b
23
37
23
58
5
7
5
100
11
a
Reactions were run in the presence of 5 mol % Pd(dba)2 in
DMF using 2.5 equiv of 1,13-tetradecadiene and 2 equiv of
N-benzyl tosylamide. Combined yield of 23a and 23b. c Used 1
b
d
equiv of LiCl. Reaction was very slow, and the yield was not
determined. e Used 4 equiv of NaHCO3. f Ph3P (5 mol %) was
added.
ably. No improvement was observed by either adding
PPh3 or lowering the temperature.
There is an additional benefit to be gained by using
the tosylamide protecting group. Unlike the products of
the palladium reactions of benzylmethylamine, the cou-
pling products 23a and 23b could be readily separated
by flash chromatography. This permits the synthesis of
pure theonelladin C as a single isomer after deprotection
and hydrogenation. We first tried to apply our earlier
procedure for hydrogenation and debenzylation to com-
pound 23a . Unfortunately, debenzylation did not occur
and only the hydrogenation product 25 was formed in
78% yield (eq 12). This suggests that this debenzylation
procedure is only effective on N-benzylamines, not on
N-benzyl tosylamides. Therefore, the tosyl group must
be removed first.
J i et al. have reported a very efficient method for the
cleavage of sulfonamides.28 The N-S bond in sulfona-
mides is cleaved by the anion radical formed from Na
and naphthalene under very mild conditions. We applied
their procedure to our tosylamide coupling product.
Compound 23a was treated with 8 equiv of sodium
naphthalenide in dimethoxyethane at room temperature
for 10 min to give the detosylation product 26 in 77%
yield (eq 13). Compound 26, a benzylamine, was then
hydrogenated and debenzylated as before to give the
theonelladin C analogue 27 in 67% yield (eq 14).
From Table 1, one can see that N-benzyl tosylamide is
a relatively good nucleophile in this coupling reaction
once appropriate reaction conditions have been deter-
mined. The results indicate that an excess of base is
required to get a good yield and Na2CO3 is better than
NaHCO3. The use of LiCl slowed the reaction consider-
(27) (a) Larock, R. C.; Berr´ıos-Pen˜a, N. G.; Fried, C. A.; Yum, E. K.;
Tu, C. Leong, W. J . Org. Chem. 1993, 58, 4509. (b) Larock, R. C.; Yum,
E. K. Synlett 1990, 529. (c) Larock, R. C.; Berr´ıos-Pen˜a, N. G.; Fried,
C. A. J . Org. Chem. 1990, 55, 2615. (d) Larock, R. C.; Berr´ıos-Pen˜a, N.
G.; Narayanan, K. J . Org. Chem. 1990, 55, 3447. (e) Inoue, Y.; Taguchi,
M.; Hashimoto, H. Bull. Chem. Soc. J pn. 1985, 58, 2721. (f) Bystro¨m,
S. E.; Aslanian, R.; Ba¨ckvall, J .-E. Tetrahedron Lett. 1985, 26, 1749.
(g) Stolle, A.; Ollivier, J .; Piras, P. P.; Salau¨n, J .; de Meijere, A. J . Am.
Chem. Soc. 1992, 114, 4051. (h) Uozumi, Y.; Tanahashi, A.; Hayashi,
T. J . Org. Chem. 1993, 58, 6826.
J . Org. Chem, Vol. 68, No. 8, 2003 3093

Wang et al.
TABLE 2. P a lla d iu m -Ca ta lyzed Cou p lin g of
SCHEME 1
3-Iod op yr id in e, Non con ju ga ted Dien es, a n d N-Meth yl
Tosyla m id e (eq 15)a
entry
n
base (equiv)
time (d)
product, % yield
b
1
2
10
10
9
9
9
Na2CO3 (4)
Na2CO3 (4)
Na2CO3 (4)
Na2CO3 (4)
NaH (2)
1
2
4
4
4
30a , 28
30a , 42
31a , 50
31a , 59
31a , 40
30b,
30b,
31b,
b
b
3c
4d
5
31b, 11
31b, 8
a
Reactions were run in DMF in the presence of 5 mol %
Pd(dba)2 and 2 equiv of n-Bu4NCl using 2.5 equiv of diene and
b
2.0 equiv of N-methyl tosylamide at 100 °C. Not determined.
c Crude products treated with NaH to remove excess CH3NHTs.
d
Crude products treated with NaOH to remove excess CH3NHTs.
SCHEME 2
With successful procedures in hand for the preparation
of the theonelladin analogue 27, synthesis of the natural
product theonelladin C (1) was tackled using 1,12-
tridecadiene instead of 1,13-tetradecadiene in the pal-
ladium-catalyzed cross-coupling, followed by deprotection
and hydrogenation (Scheme 1). The coupling of 3-iodo-
pyridine, 1,12-tridecadiene, and N-benzyl tosylamide
afforded the desired product 28a and its isomer 28b in
62 and 13% yields, respectively. Compound 28a was
converted into benzylamine 29 in 95% yield upon treat-
ment with sodium naphthalenide. Finally, theonelladin
C was obtained in 68% yield from the hydrogenation and
debenzylation of 29.
The successful synthesis of theonelladin C using a
tosylamide as a nucleophile in the palladium-catalyzed
cross-coupling encouraged us to attempt the synthesis
of theonelladin D by a similar process. Commercially
available N-methyl tosylamide was therefore chosen as
the nucleophile for the coupling reaction. It was antici-
pated that N-methyl tosylamide would be a good nucleo-
phile and the desired coupling product should be easily
separated from its isomer.
Table 2. First, 1,13-tetradecadiene was again used as a
substitute for 1,12-tridecadiene (entries 1 and 2). Com-
pared with N-benzyl tosylamide (Table 1), N-methyl
tosylamide underwent a slower coupling reaction, and 4
days were required to get good results. The desired
product 31a was obtained in 59% isolated yield as a
single isomer from the coupling of 3-iodopyridine, 1,12-
tridecadiene, and N-methyl tosylamide (entry 4).
Theonelladin D was finally obtained through the
hydrogenation and subsequent detosylation of compound
31a . As shown in Scheme 2, the C-C double bond of
compound 31a was saturated by H2 using 5% Pd/C as a
catalyst to give a 92% yield of compound 32, which, in
turn, was treated with fresh radical anion formed from
Na and naphthalene to afford theonelladin D in 90%
yield.
Tota l Syn th esis of Nip h a tesin e C. Niphatesine C
has a structure very similar to theonelladin C. They both
have amino and 3-pyridyl groups at the ends of a long
carbon chain. Niphatesine C contains a saturated 12-
carbon chain with a methyl group on the second carbon
from the amine, while theonelladin C contains a straight,
saturated 13-carbon chain. Therefore, all of the proce-
dures used to prepare theonelladin C should be applicable
to the synthesis of niphatesine C. One should only need
to replace the 1,12-tridecadiene with 2-methyl-1,11-
dodecadiene (33).
Diene 33 was easily prepared in an excellent yield by
the copper-catalyzed reaction of 10-iodo-1-decene and
isopropenylmagnesium bromide (eq 16).
Some results from the palladium-catalyzed coupling of
3-iodopyridine, 1,12-tridecadiene or 1,13-tetradecadiene,
and N-methyl tosylamide are summarized in eq 15 and
(28) J i, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson,
W. D.; Wriede, P. J . Am. Chem. Soc. 1967, 89, 5311.
3094 J . Org. Chem., Vol. 68, No. 8, 2003

Synthesis of Naturally Occurring Pyridine Alkaloids
TABLE 3. P a lla d iu m -Ca ta lyzed Cou p lin g of Ar yl
Iod id es, 1,5-Hexa d ien e, a n d N,O-Dim eth ylh yd r oxyla m in e
(eq 18)a
Diene 33 was then employed in the palladium-catalyzed
coupling with 3-iodopyridine and N-benzyl tosylamide (eq
17). The reaction was very slow, and only after 5 days
was a satisfactory yield of 61% of the desired tosylamide
34a obtained, along with 13% of the isomer 34b.
base
(equiv)
temp time % yield
(°C) (days) (ratio)
entry ArI n1/n2/n3 solvent
1
2
3
4
5
6
7
8
9d
PhI
1/5/2 DMF
Na2CO3 (2) 100
2
1
2
4
2
2
2
2
1
trace
14b
1/5/5 DMSO Na2CO3 (5) 100
1/5/5 DMSO Na2CO3 (5) 60
1/5/5 DMSO Na2CO3 (5) rt
1/5/5 DMF
1/5/5 DMA Na2CO3 (5) 60
39b
<20b
trace
trace
46 (95:5)
45b
Na2CO3 (5) 60
PyIc 1/5/5 DMSO Na2CO3 (5) 60
1/5/2 DMSO Na2CO3 (2) 60
1/5/5 DMSO Li2CO3 (5) 60
43 (97:3)
a
Reactions were run in the presence of 5 mol % Pd(dba)2 and
2 equiv of n-Bu4NCl. Ratios were not determined. c 3-Iodopyri-
dine. n-Bu4NCl was not added.
b
With the coupling product 34a readily separable from
34b, it would appear that niphatesine C could be readily
prepared by detosylation, hydrogenation, and deben-
zylation (Scheme 3). Indeed, compound 34a was treated
d
SCHEME 4
SCHEME 3
with the radical anion formed from Na and naphthalene
to give the detosylated product 35 in 91% yield. Then,
compound 35 underwent hydrogenation and debenzyla-
tion catalyzed by 20% Pd(OH)2 in MeOH to afford the
natural product niphatesine C (3) in 70% yield.
Tota l Syn th esis of Xesta m in e D. The interesting
alkaloid xestamine D (10) contains a 14-carbon chain
with a simple 3-pyridyl group on one end and an
N-(methoxyl)methylamine on the other end. It appeared
that this natural product might be easily synthesized
using our palladium chemistry and N,O-dimethylhy-
droxylamine, 1,13-tetradecadiene, and 3-iodopyridine, all
of which are readily available. The critical question is
whether N,O-dimethylhydroxylamine will successfully
undergo the palladium coupling.
is needed in the reaction system to release the hydrox-
ylamine. From Table 3, one can see that DMSO is a
suitable solvent for this coupling reaction, and the
temperature is crucial. The reaction was very slow at
room temperature (entry 4), but a temperature of 100
°C also gave only a very low yield of the desired product
(entry 2). The same reaction run at 60 °C, however, gave
a better yield, although it was still not very satisfactory
(entry 3). Fortunately, 3-iodopyridine gave somewhat
better results than iodobenzene in this coupling process
and generally afforded a modest yield of the desired
product (entries 7-9). It was observed that Na2CO3 did
not completely dissolve in the solvent (DMSO) during the
reaction. Li2CO3 was therefore used, because (1) it is more
soluble in most organic solvents and (2) neutralizing HCl
would generate LiCl, which might substitute for n-Bu4-
NCl, which has proven to be useful in many of these
coupling reactions. The reaction run with Li2CO3 (entry
9) was faster than that of Na2CO3 and gave about the
same yield. Remarkably, the use of N,O-dimethylhy-
droxylamine provided much better regioselectivity than
alkylamines or tosylamides in the arylpalladation step
of the coupling process.
In our initial investigation of this question, a short-
chain diene was used in order to simplify the reaction.
In addition to 3-iodopyridine, iodobenzene was also
examined. The results are summarized in eq 18 and
Table 3.
The reaction conditions described in entry 9 of Table
3 were then applied to the coupling of 3-iodopyridine,
1,13-tetradecadiene, and N,O-dimethylhydroxylamine,
and the desired product 36a was obtained in 45% yield,
along with a small amount of an isomer 36b (Scheme 4).
Interestingly, the reaction with the long chain diene was
Since N,O-dimethylhydroxylamine is only commer-
cially available as the hydrochloride salt, another base
J . Org. Chem, Vol. 68, No. 8, 2003 3095

Wang et al.
much slower than that of 1,5-hexadiene. The efficient
catalytic hydrogenation of 36a afforded xestamine D in
94% yield.
Syn th esis of Ik im in e A. Our previous work on the
synthesis of long-chain aromatic aldehydes and ketones
by the palladium-catalyzed cross-coupling of aryl halides
and ω-alken-1-ols (eq 2)16 suggested a very efficient route
to ikimine A by the reaction of 3-iodopyridine and
2-methyl-11-dodecen-1-ol and subsequent oxime forma-
tion.
The reaction of 3-iodopyridine and 10-undecen-1-ol was
chosen as a model system to optimize the palladium-
catalyzed cross-coupling procedure, since this alcohol is
commercially available (eq 19).
and syn isomers in a ratio of 66:34. Thus, ikimine A has
been synthesized in five steps from readily available
starting materials and in 19% overall yield.
After studying the effect on the yield of 38a and 38b of
the stoichiometry (n1 and n2), the percent of palladium
catalyst, and the temperature and the reaction time, we
found that the optimal procedure for the coupling reac-
tion utilizes 0.5 mmol of 3-iodopyridine, 1.0 mmol of 10-
undecen-1-ol, 5 mol % Pd(OAc)2, 2 equiv of n-Bu4NCl, 2.5
equiv of LiOAc, and 1 equiv of LiCl at 65 °C in 1 mL of
DMF. An 86:14 mixture of the desired product 38a and
its regioisomer 38b was obtained in 80% combined yield.
With this method in hand, we reasoned that we should
be able to easily synthesize ikimine A by simply changing
the alcohol from 10-undecen-1-ol to 2-methyl-11-dodecen-
1-ol.
The required starting material 2-methyl-11-dodecen-
1-ol was easily synthesized in two simple steps. The ester
enolate of ethyl propionate was alkylated by 10-iodo-1-
decene (19) prepared previously in 88% yield (eq 7) to
form ethyl 2-methyl-11-dodecenoate (39), which was
subsequently reduced by LiAlH4 to afford an 86% yield
of 2-methyl-11-dodecen-1-ol (40) (Scheme 5).
Con clu sion
The palladium-catalyzed coupling of 3-iodopyridine,
long-chain nonconjugated dienes and appropriate nitro-
gen nucleophiles has been successfully applied to the
synthesis of the naturally occurring alkaloids theonella-
dins C and D, niphatesine C, and xestamine D. Only two
to three steps were needed to accomplish the total
synthesis of these natural products from readily available
starting materials. Benzyl and tosyl groups were chosen
as suitable protecting groups for the nitrogen nucleo-
philes, because they afforded good yields of coupling
products and could be easily removed by convenient
procedures.
The palladium-catalyzed coupling of 3-iodopyridine and
2-methyl-11-dodecen-1-ol has been successfully applied
to the synthesis of the naturally occurring pyridine
alkaloid ikimine A in five steps and 19% overall yield.
These palladium-catalyzed coupling/migration pro-
cesses provide convenient approaches to the synthesis of
the pyridine alkaloids and other natural products con-
taining a long chain with an aromatic or heteroaryl group
on one end of the chain and various functionality on the
other end.
SCHEME 5
The “optimal” palladium coupling procedure was next
employed to give a mixture of compounds 41a and 41b
in a 64% combined yield (eq 20). The yield is somewhat
lower than that of the model reaction, and a 16% yield
of the Heck product 2-methyl-12-(3-pyridyl)-11-dodecen-
1-ol (42) was also isolated from the reaction.
The mixture of 41a and 41b was subsequently reacted
with methoxylamine to provide ikimine A (6) and its
regioisomer 43 (eq 21). Ikimine A was isolated by
preparative TLC. This compound consists of both anti
Exp er im en ta l Section
Equ ip m en t. All proton and carbon nuclear magnetic reso-
nance spectra were recorded at 300 and 75.5 MHz, respec-
tively, or 400 and 100 MHz, respectively. Flash chromatogra-
phy was carried out on 230-400 mesh silica gel. Thin-layer
chromatography was performed using commercially prepared
60 mesh silica gel plates. Visualization was effected with short
wavelength UV light (254 nm) or a basic KMnO4 solution (3 g
of KMnO4 + 20 g of K2CO3 + 5 mL of 5% NaOH + 300 mL of
H2O). Melting points are uncorrected.
3096 J . Org. Chem., Vol. 68, No. 8, 2003

Synthesis of Naturally Occurring Pyridine Alkaloids
Rea gen ts. Most reagents were commercially available.
3-Iodopyridine was prepared using a literature procedure.29
Gen er a l P r oced u r e for th e P a lla d iu m -Ca ta lyzed Cou -
plin g of Ar yl Iodides, Non con ju gated Dien es, an d Am in es.
To a 2 dram vial with a stirring bar were added 0.25 or 0.5
mmol of aryl iodide, 0.625 or 1.25 mmol of nonconjugated
diene, 0.5 or 1.0 mmol of nucleophile, 5 mol % of bis-
(dibenzylideneacetone)palladium, 0.5 or 1.0 mmol of n-Bu4NCl
(only for reactions with tosylamides), 1.0 or 2.0 mmol of Na2-
CO3 (only for reactions with tosylamides), and 1 or 2 mL of
DMF, respectively, unless indicated otherwise. The vial was
capped with a Teflon-lined screw-cap. The resulting mixture
was stirred at 100 or 60 °C for the required period of time.
The mixture was then allowed to cool to room temperature,
diluted with saturated NaCl solution, and extracted with
diethyl ether. The ether layer was dried over anhydrous Na2-
SO4 and then evaporated under reduced pressure to remove
the solvent. The crude products were isolated by flash chro-
matography on a silica gel column.
procedure above at 100 °C for 5 days: 1H NMR (CDCl3) δ 1.15-
1.32 (br m, 12 H), 1.36 (s, 3 H), 1.60 (quintet, J ) 7.5 Hz, 2
H), 1.84 (m, 2 H), 2.42 (s, 3 H), 2.59 (t, J ) 7.5 Hz, 2 H), 3.65
(s, 2 H), 4.26 (s, 2 H), 5.10 (t, J ) 6.9 Hz, 1 H), 7.15-7.24 (m,
6 H), 7.28 (d, J ) 8.1 Hz, 2 H), 7.47 (d, J ) 7.5 Hz, 1 H), 7.69
(d, J ) 8.1 Hz, 2 H), 8.42 (m, 2 H); 13C NMR (CDCl3) δ 14.0,
21.5, 27.8, 29.1, 29.2, 29.3, 29.4, 29.5, 31.1, 33.0, 50.8, 56.1,
123.2, 127.2, 127.3, 128.1, 128.5, 129.5, 130.6, 135.7, 136.5,
137.4, 137.9, 143.0, 147.1, 149.9 (two peaks missing due to
overlap); IR (neat) 3087, 3031, 2921, 2853, 1599, 1455, 1338,
1160 cm-1; HRMS for C32H42N2O2S calcd 518.2967, found
518.2960.
Com p ou n d s 36a a n d 36b. Compounds 36a and 36b were
obtained as an inseparable mixture of isomers (91:9) in 45%
combined yield from the coupling of 3-iodopyridine, 5 equiv of
1,13-tetradecadiene, and 5 equiv of N,O-dimethylhydroxyl-
amine hydrochloride in the presence of 5 equiv of Li2CO3 in
DMSO at 60 °C for 7 days: 1H NMR (CDCl3) δ 1.20 (d, J )
7.2 Hz, 3 H, PyCCH3 in 36b), 1.24-1.31 (br m, 16 H), 1.61
(quintet, J ) 7.2 Hz, 2 H), 2.02 (q, J ) 7.2 Hz, 2 H), 2.55 (s, 3
H), 2.60 (t, J ) 7.2 Hz, 2 H), 3.24 (m, 2 H), 3.51 (s, 3 H), 3.52
(s, 3 H, OCH3 in 36b), 5.51 (dt, J ) 15.3, 6.3 Hz, 1 H), 5.63
(dt, J ) 15.3, 6.3 Hz, 1 H), 7.19 (dd, J ) 7.8, 5.1 Hz, 1 H), 7.47
(d, J ) 7.8 Hz, 1 H), 8.43 (m, 2 H); 13C NMR (CDCl3) δ 29.1,
29.4, 29.5, 29.6, 31.1, 32.4, 33.0, 44.5, 59.8, 62.5, 123.1, 125.1,
135.1, 135.7, 137.9, 147.1, 149.9 (four peaks missing due to
overlap); IR (neat) 3083, 3026, 2924, 2853, 1574, 1460, 1361,
1049 cm-1; HRMS for C21H36N2O calcd 332.2828, found
332.2834.
Com p ou n d 32. To 115 mg of compound 31a in 3 mL of 95%
EtOH was added 11.5 mg (10 wt %) of 5% Pd/C. The resulting
mixture was stirred and flushed with H2 (1 atm) at room
temperature for 4 h. After filtration and removal of the solvent,
compound 32 was obtained in 92% yield: 1H NMR (CDCl3) δ
1.22-1.32 (br m, 18 H), 1.50 (m, 2 H), 1.61 (m, 2 H), 2.42 (s,
3 H), 2.60 (t, J ) 7.2 Hz, 2 H), 2.69 (s, 3 H), 2.96 (t, J ) 7.2
Hz, 2 H), 7.19 (dd, J ) 7.5, 4.2 Hz, 1 H), 7.30 (d, J ) 7.8 Hz,
2 H), 7.48 (d, J ) 7.5 Hz, 1 H), 7.66 (d, J ) 7.8 Hz, 2 H), 8.43
(m, 2 H); 13C NMR (CDCl3) δ 21.5, 26.5, 27.6, 29.1, 29.2, 29.4,
29.5, 31.1, 33.0, 34.5, 50.1, 59.1, 123.2, 127.3, 129.5, 134.5,
135.7, 137.9, 143.1, 147.0, 149.8 (three peaks missing due to
overlap); IR (neat) 3082, 3027, 2920, 2851, 1598, 1462, 1342,
1161 cm-1; HRMS for C26H39N2O2S (M+ - H) calcd 443.2732,
found 443.2733.
Gen er a l P r oced u r es for th e Dep r otection of Tosyla -
m id es: P r oced u r e A. To a 0.5 M solution of naphthalene in
1,2-dimethoxyethane (DME) was added 3 equiv of Na. The
resulting mixture was stirred under N2 at 25 °C for ap-
proximately 1 to 2 h. After turning dark, the mixture was
stirred for an additional 2 h at this temperature. The resulting
radical anion solution was added dropwise to the tosylamide
in DME until a brown color lasted over 10 s. The reaction
mixture was immediately poured into a saturated NaHCO3
solution and extracted with methylene chloride or ether. The
organic layer was dried over anhydrous Na2SO4; the solvent
was removed and the product purified on a silica gel column.
P r oced u r e B. The fresh radical anion was prepared as in
procedure A. The tosylamide in DME was added to this radical
anion solution. The resulting mixture was stirred under N2
at room temperature for about 10 min and then poured into a
saturated NaCl solution and extracted with ether. The organic
layer was dried over anhydrous Na2SO4; the solvent was
removed and the product purified on a silica gel column.
Com p ou n d s 21a a n d 21b. Compounds 21a and 21b were
obtained as an inseparable 85:15 mixture of isomers in 78%
combined yield from the coupling of 3-iodopyridine, 2.5 equiv
of 1,12-tridecadiene, and 2 equiv of benzylmethylamine in the
presence of 1.3 equiv of LiCl at 100 °C for 24 h: 1H NMR
(CDCl3) δ 1.23-1.35 (br m, 14 H), 1.60 (quintet, J ) 7.2 Hz, 2
H), 2.03 (q, J ) 6.0 Hz, 2 H), 2.16 (s, 3 H), 2.58 (t, J ) 7.2 Hz,
2 H), 2.67 (sextet, J ) 7.2 Hz, 1 H, PyCH in 21b), 2.96 (d, J )
6.0 Hz, 2 H), 3.47 (s, 2 H), 5.51 (dt, J ) 15.3, 6.0 Hz, 1 H),
5.59 (dt, J ) 15.3, 6.0 Hz, 1 H), 7.18 (dd, J ) 7.8, 5.1 Hz, 1 H),
7.22-7.34 (m, 5 H), 7.47 (d, J ) 7.8 Hz, 1 H), 8.43 (s, 2 H); 13
C
NMR (CDCl3) δ 29.2, 29.2, 29.3, 29.4, 29.5, 29.6, 31.1, 32.4,
33.0, 37.4, 42.0, 59.7, 61.6, 123.2, 126.8, 127.0, 128.1, 129.1,
134.3, 135.7, 137.9, 139.1, 147.2, 149.9; IR (neat) 3083, 3024,
2924, 2852, 1681, 1454, 1024 cm-1; HRMS for C26H37N2
(M+ - H) calcd 377.2957, found 377.2955.
Com p ou n d 28a . Compound 28a was obtained in 62% yield
from the coupling of 3-iodopyridine, 2.5 equiv of 1,12-trideca-
diene, and 2 equiv of N-benzyl tosylamide using the procedure
above at 100 °C for 4 days: 1H NMR (CDCl3) δ 1.20-1.31 (br
m, 14 H), 1.61 (quintet, J ) 6.9 Hz, 2 H), 1.86 (q, J ) 6.0 Hz,
2 H), 2.43 (s, 3 H), 2.59 (t, J ) 7.5 Hz, 2 H), 3.69 (d, J ) 6.9
Hz, 2 H), 4.32 (s, 2 H), 5.07 (dt, J ) 15.3, 6.9 Hz, 1 H), 5.37
(dt, J ) 15.3, 6.9 Hz, 1 H), 7.19 (dd, J ) 7.8, 4.8 Hz, 1 H),
7.23-7.35 (m, 5 H), 7.47 (d, J ) 7.8 Hz, 1 H), 7.73 (d, J ) 8.1
Hz, 2 H), 8.43 (m, 2 H); 13C NMR (CDCl3) δ 21.6, 28.9, 29.2,
29.5, 29.6, 31.2, 32.1, 33.0, 49.0, 50.0, 123.2, 123.3, 127.2, 127.6,
128.4, 129.6, 135.8, 136.3, 136.4, 137.7, 138.0, 143.1, 147.2,
150.0 (four peaks missing due to overlap); IR (neat) 3083, 3027,
2925, 2853, 1597, 1455, 1340, 1160 cm-1; HRMS for C32H42
-
N2O2S (M+ - H) calcd 518.2967, found 518.2960.
Com p ou n d 31a . Compound 31a was obtained in 59% yield
from the coupling of 3-iodopyridine, 2.5 equiv of 1,12-trideca-
diene, and 2 equiv of N-methyl tosylamide using the procedure
above at 100 °C for 4 days: 1H NMR (CDCl3) δ 1.20-1.30 (br
m, 14 H), 1.61 (m, 2 H), 1.97 (q, J ) 6.6 Hz, 2 H), 2.42 (s, 3 H),
2.60 (t, J ) 7.5 Hz, 2 H), 2.63 (s, 3 H), 3.55 (d, J ) 6.6 Hz, 2
H), 5.31 (dt, J ) 15.3, 6.6 Hz, 1 H), 5.56 (dt, J ) 15.3, 6.6 Hz,
1 H), 7.20 (dd, J ) 7.8, 4.8 Hz, 1 H), 7.31 (d, J ) 8.1 Hz, 2 H),
7.48 (d, J ) 7.8 Hz, 1 H), 7.66 (d, J ) 8.1 Hz, 2 H), 8.43 (m, 2
H); 13C NMR (CDCl3) δ 21.5, 29.0, 29.1, 29.2, 29.4, 29.5, 31.1,
32.1, 33.0, 33.9, 52.4, 58.8, 123.2, 123.8, 127.4, 129.5, 134.5,
135.7, 136.2, 137.9, 143.1, 147.0, 149.8 (one peak missing due
to overlap); IR (neat) 3083, 3027, 2923, 2853, 1598, 1455, 1343,
1163 cm-1; HRMS for C26H38N2O2S calcd 442.2654, found
442.2655.
Com p ou n d 29. Compound 29 was obtained in 95% yield
from the detosylation of compound 28a using procedure B: 1H
NMR (CDCl3) δ 1.21-1.30 (br m, 14 H), 1.60 (m, 2 H), 2.01 (q,
J ) 6.6 Hz, 2 H), 2.59 (t, J ) 7.5 Hz, 2 H), 3.23 (d, J ) 6.0 Hz,
2 H), 3.81(s, 2 H), 3.90-4.05 (br m, 1 H), 5.52 (dt, J ) 15.6,
6.0 Hz, 1 H), 5.62 (dt, J ) 15.6, 6.0 Hz, 1 H), 7.19 (dd, J ) 7.8,
4.8 Hz, 1 H), 7.24-7.36 (m, 5 H), 7.47 (dt, J ) 7.8, 1.8 Hz, 1
H), 8.41 (m, 2 H); 13C NMR (CDCl3) δ 29.2, 29.3, 29.6, 29.8,
31.2, 32.4, 33.1, 51.0, 53.1, 123.2, 127.0, 127.7, 128.3, 128.4,
Com p ou n d 34a . Compound 34a was obtained in 61% yield
from the coupling of 3-iodopyridine, 2.5 equiv of 2-methyl-1,11-
dodecadiene, and 2 equiv of N-benzyl tosylamide using the
(29) Shnaidman, L. O.; Siling, M. I.; Kushebinskaya, I. N.; Eremina,
T. N. Tr. Inst. Eksp. Klin. Med., Akad. Nauk Latv. SSR 1962, 27, 1;
Chem. Abstr. 1963, 58, 4508a.
J . Org. Chem, Vol. 68, No. 8, 2003 3097

Wang et al.
133.4, 135.8, 138.0, 140.0, 147.1, 149.9 (three peaks missing
due to overlap); IR (neat) 3288 (N-H), 3083, 3027, 2922, 2852,
1681, 1454, 1360, 1114 cm-1; HRMS for C25H35N2(M+ - H)
calcd 363.2800, found 363.2797.
2.60 (m, 4 H), 3.51 (s, 3 H), 7.19 (dd, J ) 7.5, 4.8 Hz, 1 H),
7.48 (d, J ) 7.5 Hz, 1 H), 8.43 (m, 2 H); 13C NMR (CDCl3) δ
27.3, 27.4, 29.1, 29.4, 29.6, 31.1, 33.0, 45.2, 60.0, 61.0, 123.1,
135.7, 137.9, 147.0, 149.9 (six peaks missing due to overlap);
Com p ou n d 35. Compound 35 was obtained in 91% yield
from the detosylation of compound 34a using procedure A: 1H
NMR (CDCl3) δ 1.27 (br s, 12 H), 1.60 (quintet, J ) 7.5 Hz, 2
H), 1.65 (s, 3 H), 2.01 (m, 2 H), 2.58 (t, J ) 7.5 Hz, 2 H), 3.16
(s, 2 H), 3.72 (s, 2 H), 5.31 (t, J ) 7.5 Hz, 1 H), 7.18 (dd, J )
7.5, 4.8 Hz, 1 H), 7.22-7.32 (m, 5 H), 7.47 (d, J ) 7.5 Hz, 1
H), 8.42 (s, 2 H); 13C NMR (CDCl3) δ 14.8, 27.8, 29.2, 29.3,
29.4, 29.5, 29.7, 31.2, 33.0, 52.8, 57.0, 123.2, 126.8, 128.2, 128.3,
132.9, 135.7, 137.9, 140.4, 147.1, 149.9 (two peaks missing due
to overlap); IR (neat) 3304 (N-H), 3084, 3027, 2921, 2852,
1682, 1454, 1359, 1106 cm-1; HRMS for C25H36N2 calcd
364.2879, found 364.2873.
IR (neat) 3082, 3026, 2923, 2853, 1576, 1461, 1048 cm-1
HRMS for C21H38N2O calcd 334.2984, found 334.2992.
;
Com p ou n d s 41a a n d 41b. To a 1 dram vial with a stirring
bar were added 0.5 mmol of 3-iodopyridine, 1.0 mmol of
2-methyl-11-dodecen-1-ol, 5 mol % of Pd(OAc)2, 1.0 mmol of
n-Bu4NCl, 0.5 or 1.0 mmol of LiCl, 1.25 mmol of LiOAc, and 1
mL of DMF. The vial was capped with a screw-cap containing
a Teflon liner. The resulting mixture was stirred at 65 °C for
5 days. The mixture was then allowed to cool to room
temperature. After removal of the solvent, the residue was
purified by flash chromatography on a silica gel column and
compounds 41a and 41b were obtained as an inseparable 86:
14 mixture of isomers in 64% yield: 1H NMR (CDCl3) δ 1.08
(d, J ) 6.9 Hz, 3 H), 1.09 (d, J ) 6.9 Hz, 3 H, 41b), 1.19-1.41
(m, 14 H), 1.56-1.74 (m, 4 H), 2.35 (m, 1 H), 2.63 (t, J ) 6.9
Hz, 2 H), 7.20 (dd, J ) 7.5, 5.1 Hz, 1 H), 7.49 (dt, J ) 7.5, 1.8
Hz, 1 H), 8,44 (s, 2 H); IR (neat) 3120, 2933, 2512, 1735, 1476,
Th eon ella d in D (2). Theonelladin D (2) was obtained in
90% yield from the detosylation of compound 32 using proce-
dure A: 1H NMR (CDCl3) δ 1.25 (br s, 18 H), 1.47 (m, 2 H),
1.60 (m, 2 H), 2.43 (s, 3 H), 2.56 (t, J ) 7.5 Hz, 2 H), 2.59 (t,
J ) 7.5 Hz, 2 H), 7.19 (dd, J ) 7.5, 4.8 Hz, 1 H), 7.48 (d, J )
7.8 Hz, 1 H), 8.43 (s, 2 H); 13C NMR (CDCl3) δ 27.3, 29.1, 29.4,
29.6, 29.8, 29.9, 31.1, 33.0, 36.5, 52.2, 123.1, 135.7, 137.9, 147.1,
149.9 (four peaks missing due to overlap); IR (neat) 3301 (N-
1120, 954 cm-1 13C NMR (CDCl3) δ 15.4, 18.3 (overlap), 22.0,
;
29.1, 29.3, 29.4, 31.1, 33.0, 43.9, 76.4, 123.2, 135.8, 138.0, 147.1,
149.9, 203.1. HRMS for C18H29NO calcd 275.2034, found
275.2033.
H), 3081, 3025, 2924, 2852, 1574, 1465, 1369, 1126 cm-1
;
HRMS for C19H33N2(M+ - H) calcd 289.2644, found 289.2642.
Gen er a l P r oced u r e for th e Hyd r ogen a tion a n d De-
ben zyla tion of Allylic Ben zyla m in es. To 1.0 equiv of an
allylic benzylamine in MeOH (0.05-0.1 M solution) was added
0.35 equiv of Pearlman’s catalyst (20% Pd(OH)2/C). The
resulting mixture was flushed with H2 (1 atm) at room
temperature for 2-4 h. To the mixture was added 5.0 equiv
of NH4O2CH. The mixture was heated at 65-70 °C for 10-20
min. After filtration and removal of the solvent, the product
was purified on a silica gel column.
Th eon ella d in C (1). Theonelladin C (1) was obtained in
68% yield from the hydrogenation and debenzylation of
compound 29 using the above procedure: 1H NMR (CDCl3) δ
1.23-1.30 (br m, 18 H), 1.43 (m, 2 H), 1.61 (quintet, J ) 7.5
Hz, 2 H), 2.60 (t, J ) 7.5 Hz, 2 H), 2.67 (t, J ) 7.5 Hz, 2 H),
7.19 (dd, J ) 7.5, 4.8 Hz, 1 H), 7.47 (d, J ) 7.5 Hz, 1 H), 8.42
(m, 2 H) (NH2 peak overlapped); 13C NMR (CDCl3) δ 26.9, 29.1,
29.4, 29.5, 29.6, 31.1, 33.0, 33.8, 42.2, 123.1, 135.8, 138.0, 147.1,
149.9 (four peaks missing due to overlap); IR (neat) 3363 (N-
H), 3290 (N-H), 3028, 2927, 2854, 1575, 1466, 1309, 1026
cm-1; HRMS for C18H32N2 calcd 276.2566, found 276.2559.
Nip h a tesin e C (3). Niphatesine C (3) was obtained in 70%
yield from the hydrogenation and debenzylation of compound
35 using the above procedure: 1H NMR (CD3OD) δ 0.93 (d,
J ) 6.6 Hz, 3 H), 1.30-1.40 (br m, 16 H), 1.50 (m, 1 H), 1.66
(m, 2 H), 2.43 (dd, J ) 12.3, 7.2 Hz, 1 H), 2.60 (dd, J ) 12.3,
5.7 Hz, 1 H), 2.68 (t, J ) 7.2 Hz, 2 H), 7.37 (dd, J ) 7.8, 4.8
Hz, 1 H), 7.71 (d, J ) 7.8 Hz, 1 H), 8.37 (dd, J ) 4.8, 1.2 Hz,
1 H), 8.39 (d, J ) 1.2 Hz, 1 H); 13C NMR (CDCl3) δ 17.4, 27.0,
29.1, 29.4, 29.5, 29.6, 29.9, 31.1, 33.0, 34.3, 36.2, 48.3, 123.1,
135.7, 137.9, 147.1, 149.9 (one peak missing due to overlap);
IR (neat) 3365 (N-H), 3300 (N-H), 3025, 2925, 2853, 1574,
1464, 1026 cm-1; HRMS for C18H31N2 (M+ - H) calcd 275.2487,
found 275.2480.
Ik im in e A (6). To an aqueous solution of 93.5 mg (0.25
mmol) of 41a and 41b were added 23.0 mg (0.28 mmol) of
methoxylamine hydrochloride and 37.4 mg (0.28 mmol) of
NaOAc‚3H2O until the solution cleared. After 20 h of reflux,
the solution was extracted three times with ether. The ether
layer was washed three times with 5% aqueous NaHCO3 and
once with water and dried over MgSO4. After removal of the
solvent, the residue was purified by flash chromatography on
a silica gel column. A mixture of (E)- and (Z)-isomers was
obtained as a liquid in 79% yield. (E)-Isomer: 1H NMR (CDCl3)
δ 1.05 (d, J ) 7.5 Hz, 3 H), 1.26 (m, 16 H), 1.62 (m, 2 H), 2.33
(ddq, J ) 7.5, 7.5 Hz, 6.8 Hz, 1 H), 2.60 (t, J ) 7.5 Hz, 2 H),
3.81 (s, 3 H), 7.18-7.22 (m, 2 H), 7.49 (br d, J ) 7.8 Hz, 1 H),
8.44 (br s, 2 H); 13C NMR (CDCl3) δ 18.3, 27.1, 29.2, 29.4, 29.5
(three carbon peaks), 29.6, 31.2, 33.0, 34.4, 34.8, 61.2, 123.3,
135.8, 138.0, 147.2, 149.9, 156.8. (Z)-Isomer: 1H NMR (CDCl3)
δ 0.99 (d, J ) 7.5 Hz, 3 H), 1.26 (m, 16 H), 1.62 (m, 2 H), 2.60
(t, J ) 7.5 Hz, 2 H), 2.97 (ddq, J ) 7.5, 7.5, 6.8 Hz, 1H), 3.84
(s, 3 H), 6.38 (d, J ) 7.5 Hz, 1 H), 7.21 (m, 1 H), 7.49 (br d,
J ) 7.8 Hz, 1 H), 8.44 (br s, 2 H); IR (neat) 3021, 2976, 2431,
1630, 1105, 1066, 967 cm-1; HRMS for C19H32N2O calcd
304.2515, found 304.2507.
Ack n ow led gm en t. We gratefully acknowledge the
donors of the Petroleum Research Fund, administered
by the American Chemical Society, for partial support
of this research, Kawaken Fine Chemicals Co., Ltd., for
donation of the palladium acetate, and Merck and Co.,
Inc., for two Academic Development Awards in Chem-
istry.
Su p p or tin g In for m a tion Ava ila ble: Preparation and
characterization of starting materials 19, 20, 32, 38, and 39;
characterization data for compounds 14a /b, 17a /b, 18a /b, 23a ,
Com p ou n d s 10 (Xesta m in e D) a n d 37. To 39 mg of a
mixture of compounds 36a and 36b (91:9) in 3 mL of 95%
EtOH was added 7.7 mg of 5% Pd/C. The resulting mixture
was stirred and flushed with H2 (1 atm) at room temperature
for 6 h. After filtration and removal of the solvent, compounds
10 and 37 were obtained in 92% combined yield: 1H NMR
(CDCl3) δ 1.25-1.30 (br m, 20 H), 1.58 (m, 4 H), 2.56 (s, 3 H),
1
26, and 27; and copies of H NMR and 13C NMR spectra for
compounds 1-3, 10, 14a /b, 17a /b, 18a /b, 21a /b, 23a , 26, 27,
28a , 29, 31a , 32, 34a , 35, 36a /b, and 37. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O026716P
3098 J . Org. Chem., Vol. 68, No. 8, 2003