Synthesis of the cytotoxic sponge metabolite haliclamine A

Article abstract of DOI:10.1021/jo025650v

A new convergent and unified synthesis of the marine natural alkaloid haliclamine A is described. The synthesis of 3-alkylpyridine monomers 8 and 9 was first achieved from a common thiophene intermediate 5. These syntheses make use of thiophene chemistry and the ability of cyclopropylcarbinols 20 and 21 to rearrange to the homoallylic bromides 22 and 23, respectively. The Zincke procedure for the synthesis of pyridinium salts was then applied to the corresponding amino derivatives 8 and 9 to give efficiently unsymmetrical bis-pyridinium macrocycle 1, whose reduction afforded haliclamine A.

Full text of DOI:10.1021/jo025650v

Syn th esis of th e Cytotoxic Sp on ge Meta bolite Ha licla m in e A
Sophie Michelliza, Ali Al-Mourabit,* Alice Gateau-Olesker, and Christian Marazano
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
ali.almourabit@icsn.cnrs-gif.fr
Received February 25, 2002
A new convergent and unified synthesis of the marine natural alkaloid haliclamine A is described.
The synthesis of 3-alkylpyridine monomers 8 and 9 was first achieved from a common thiophene
intermediate 5. These syntheses make use of thiophene chemistry and the ability of cyclopropyl-
carbinols 20 and 21 to rearrange to the homoallylic bromides 22 and 23, respectively. The Zincke
procedure for the synthesis of pyridinium salts was then applied to the corresponding amino
derivatives 8 and 9 to give efficiently unsymmetrical bis-pyridinium macrocycle 1, whose reduction
afforded haliclamine A.
In tr od u ction
SCHEME 1
The bis-tetrahydropyridine macrocycle haliclamine A1
(Scheme 1) was isolated from a sponge Haliclona sp. and
reported to inhibit cell division of fertilized sea urchin
eggs. It also possesses in vitro cytotoxicity against P388
leukemia cells with an IC50 value of 0.75 mg/mL. This
alkaloid belongs to an original class of natural products
produced by sponges in the order Haplosclerida (“man-
zamine family of alkaloids”).2 A likely precursor of
haliclamine A is the bis-pyridinium macrocycle 1, whose
analogues, cyclostelletamines A-F, have also been iso-
3
lated from sponges in the same order. After the first
biogenetic proposal published by Whitehead and Bald-
win,4a it was recently proposed that the biosynthesis of
mental support favoring this biogenetic proposal, a
synthetic approach to cyclostelletamines that partially
mimics this process and makes use of the Zincke syn-
thesis of pyridinium salts was reported.4b
Previous syntheses of haliclamine A involved access
to bis-pyridinium macrocycle 1 via a stepwise condensa-
tion involving formation of pyridinium salts from mesyl-
these pyridinium salts can be the result of the cyclization,
in acidic conditions, of aminopentadienal derivatives (e.g.,
5
intermediate 2 for haliclamine A). Macrocycles such as
2
can result from condensation of two long-chain amino-
aldehydes (3 and 4) with two three-carbon units possess-
ing the oxidation degree of malondialdehyde. For experi-
ate derivatives, in the presence of KI, of appropriate
6
3
-alkyl pyridines. In this case, temporary protection of
(
1) Fusetani, N.; Yasumuro, K.; Matsunaga, S. Tetrahedron Lett.
989, 30, 6891-6894.
2) For reviews on the manzamine family of alkaloids, see: (a)
Matzanke, N.; Gregg, R. J .; Weinreb, S. M. Org. Prep. Proc. Int. 1998,
one pyridine ring as an N-oxide was necessary. Syntheses
of bis-pyridinium macrocycles related to 1 have also been
1
(
4f,7
reported.
3
7
0, 3-51. (b) Tsuda, M.; Kobayashi, J . Heterocycles 1997, 46, 765-
94. (c) Andersen, R. J .; Van Soest, R. W. M.; Kong, F. In Alkaloids:
Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon
Press: Elmsford, NY, 1996; Vol. 10, pp 301-355. (d) Crews, P.; Cheng,
X.-C.; Adamczeski, M.; Rodriguez, J .; J aspar, M.; Schmitz, F. J .;
Traeger, S. C.; Pordesimo, E. O. Tetrahedron 1994, 50, 13567-13574.
(5) (a) Baldwin, J . E.; Whitehead, R. C. Tetrahedron Lett. 1992, 33,
2059-2062. (b) Kaiser, A.; Billot, X.; Gateau-Olesker, A.; Marazano,
C.; Das, B. C. J . Am. Chem. Soc. 1998, 120, 8026-8034. For extension
of this proposal to other related alkaloids, see: (c) Herdemann, M.;
Al-Mourabit, A.; Martin, M.-T.; Marazano, C. J . Org. Chem. 2002, 67,
1890-1897. (d) J akubowicz, K.; Ben Abdeljelil, K.; Herdemann, M.;
Martin, M.-T.; Gateau-Olesker, A.; Almourabit, A.; Marazano, C.; Das,
B. C. J . Org. Chem. 1999, 64, 7381-7387 and references therein. For
an alternate proposal, see: (e) Gomez, J .-M.; Gil, L.; Ferroud, C.;
Gateau-Olesker, A.; Martin, M.-T.; Marazano, C. J . Org. Chem. 2001,
66, 4898-4903. (f) Baldwin, J . E.; Claridge, T. D. W.; Culshaw, A. J .;
Heupel, F. A.; Lee, V.; Spring, D. R.; Whitehead, R. C. Chem. Eur. J .
1999, 5, 3154-3161 and references therein.
(
3) Fusetani, N.; Asai, N.; Matsunaga, S.; Honda, K.; Yasumuro, K.
Tetrahedron Lett. 1994, 35, 3967-3970.
4) (a) Baldwin, J . E.; Whitehead, R. C. Tetrahedron Lett. 1992, 33,
(
2
059-2062. (b) Kaiser, A.; Billot, X.; Gateau-Olesker, A.; Marazano,
C.; Das, B. C. J . Am. Chem. Soc. 1998, 120, 8026-8034. For extension
of this proposal to other related alkaloids, see: (c) Herdemann, M.;
Al-Mourabit, A.; Martin, M.-T.; Marazano, C. J . Org. Chem., 2002, 67,
1
890-1897. (d) J akubowicz, K.; Ben Abdeljelil, K.; Herdemann, M.;
Martin, M.-T.; Gateau-Olesker, A.; Almourabit, A.; Marazano, C.; Das,
B. C. J . Org. Chem. 1999, 64, 7381-7387 and references therein. For
an alternate proposal, see: (e) Gomez, J .-M.; Gil, L.; Ferroud, C.;
Gateau-Olesker, A.; Martin, M.-T.; Marazano, C. J . Org. Chem. 2001,
(6) (a) Morimoto, Y.; Yokoe, C.; Kurihara, H.; Kinoshita, T. Tetra-
hedron 1998, 54, 12197-12214. (b) Baldwin, J . E.; J ames, D. A.; Lee,
V. Tetrahedron Lett. 2000, 41, 733-736.
6
6, 4898-4903. (f) Baldwin, J . E.; Claridge, T. D. W.; Culshaw, A. J .;
(7) (a) Wanner, M. J .; Koomen, G.-J . Eur. J . Org. Chem. 1998, 889-
895. (b) Anan, H.; Seki, N.; Noshiro, O.; Honda, K.; Yasumuro, K.;
Ozasa, T.; Fusetani, N. Tetrahedron 1996, 52, 10849-10860.
Heupel, F. A.; Lee, V.; Spring, D. R.; Whitehead, R. C. Chem. Eur. J .
1
999, 5, 3154-3161 and references therein.
1
0.1021/jo025650v CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/15/2002
6
474
J . Org. Chem. 2002, 67, 6474-6478

Synthesis of Haliclamine A
SCHEME 2
SCHEME 4a
SCHEME 3a
a
Reagents and conditions: (a) Na2CO3, Ni (Raney), EtOH, ∆.
establish the stereoselectivity inferred for the reaction.
Reaction of thiophene 11, in the same conditions but
using N-formylpiperidine instead of nicotinaldehyde,
provided the aldehyde 13 in 95% yield. Wittig condensa-
1
0
tion of this last aldehyde with phosphonium salt 14 led
to the 3-alkylpyridine derivative 15 (12-carbon side chain)
in 55% yield.
With pyridines 12 and 15 in hand, we next explored
their reduction to give cyclopropyl derivatives 16 and 17,
respectively (Scheme 4). This task proved to be nontrivial.
Among the catalysts and reaction conditions used so far,
reflux in ethanol with a large excess of Raney nickel and
sodium bicarbonate was found to give the best results.
Thus, treatment of pyridine 12 in the later conditions
gave the desired reduced compound 16 but only in 30%
yield due to the unavoidable formation of partially
reduced species 18 and 19. These compounds were easily
separated by flash chromatography. While 18 was re-
cycled into 16 by reduction under the same conditions,
resulting in a 43% combined yield for 16, alcohol 19
remained resistant to further reduction. This can be
rationalized if one considers the bis-benzylic position of
the alcohol position in 12 compared to the monobenzylic
position of the corresponding alcohol in 19. Removal of a
a
Reagents and conditions: (a) NaBH4, MeOH, rt (100% yield);
(
-
b) TBDMSCl, imidazole, DMF, rt (95% yield); (c) n-BuLi, THF,
78 °C, and then addition of nicotin aldehyde 6 (70% yield); (d)
n-BuLi, THF, -78 °C, then formylpiperidine, 2.5 equiv (73% yield);
e) 14, NaH, THF, 0 °C, then addition of 13 at -78 °C (55% yield).
(
In this paper, we describe a new synthesis of hal-
iclamine A displaying two essential features (Scheme 2).
The first is the synthesis, from a common and com-
mercially available thiophene 5 and pyridines 6 or 7, of
-alkylpyridine derivatives 8 or 9, respectively. The
thiophene derivative 5 offered the advantages of being a
3
1
1
similar hydroxyl group was achieved by Tanouchi et Al.
after acetylation or chlorination followed by reduction
with ZnCl in acetic acid, but the use of this procedure
four-carbon precursor of the alkyl side chain (reductive
desulfurization of the thiophene ring), as well as permit-
8
2
ting access to the homoallylic primary amine moiety via
opening of the cyclopropane ring according to a method
originally described by J ulia. The second future is the
was also found to be unsuccessful for reduction of alcohol
19. Reduction of this thiophen derivative 15 gave the
desired product 17 in 85% yield.
9
easy construction from primary amines 8 and 9 of the
bis-pyridinium macrocycle 1 by using our reported Zincke
procedure.4b
4
Desilylation of pyridines 16 and 17, using BuNF , gave
alcohols 20 and 21 in 95 and 78% yields, respectively
(Scheme 5). Homoallylic rearrangement of the obtained
alcohols into the corresponding bromides is usually
9
carried out by the J ulia (HBr) or Barton conditions
Resu lts a n d Discu ssion
1
2
(
2
MgBr ). In our hands, the isomerization of cyclopropyl
Commercial cyclopropyl 2-thienyl ketone 5 (Scheme 3)
was first reduced to alcohol 10 and then silylated to give
protected derivative 11 in 95% overall yield. This
thiophene derivative was deprotonated with n-BuLi in
THF at -78 °C and allowed to react with nicotinaldehyde
derivatives 20 and 21 was found to proceed better under
the mild conditions described by Nefedov and co-work-
13
ers. Thus, treatment of 20 and 21 with Me
3
SiBr in the
presence of ZnBr
2
at -20 °C gave the rather unstable
homoallylic bromides 22 and 23, which reacted with
sodium azide to produce the azido derivatives 24 and 25,
(
6) to furnish the 3-alkylpyridine 12 (pyridine substituted
by a nine-carbon side chain) in 70% yield. In principle,
two diastereoisomeric derivatives were expected, but on
the basis of the results of chromatography and NMR
studies showing a single product, we could not firmly
(
10) Staab, H. A.; Zipplies, M. F.; M u¨ ller, T.; Storch, M.; Krieger,
C. Chem. Ber. 1994, 127, 1667-1680.
11) (a) Tanouchi, T.; Kawamura, M.; Ohyama, I.; Igushi, Y.; Okada,
T.; Miyamoto, T.; Tangushi, K.; Hayashi. M. J . Med. Chem. 1981, 24,
(
1
149-1155. (b) Noe, C. R.; Knomuller, M.; Dungler, C.; Miculka, C.;
(
8) (a) Badger, G. M.; Rodda, H. J .; Sasse, W. H. F. J . Chem. Soc.
954, 4162-4167. (b) Gol’Dfarb, Y. L.; Fabrichnyi, B. P.; Shalavina, I.
F. Tetrahedron 1961, 18, 21-36.
9) J ulia, M.; J ulia, S.; Tchen, S. Y. Bull. Soc. Chim. Fr. 1661, 1849-
853.
G a¨ rtner, P. Monat. Chem. 1991, 122, 705-718.
(12) McCormick, J . P.; Barton D. L. J . Org. Chem. 1980, 25, 2566-
2570.
(13) Moiseenkov, A. M.; Czeskis, B. A.; Ivanova, N. M.; Nefedov, O.
M. Org. Prep. Proc. Int. 1990, 22, 215-227.
1
(
1
J . Org. Chem, Vol. 67, No. 18, 2002 6475

Michelliza et al.
SCHEME 5a
14
the synthetic product were shown to be identical in all
respects to the data reported for haliclamine A.
1
Con clu sion
In conclusion, we have developed an efficient and
convergent synthesis of haliclamine A 1. Our new syn-
thetic route employed a combination of thiophen and
cyclopropyl chemistry. We have exploited simple and
convenient synthetic methods for the convergent prepa-
ration of functionalized 3-alkylpyridines. This strategy
offers some advantages over the existing methods, in
particular easy purification and characterization of syn-
thetic intermediates as well as the possibility of modulat-
ing the length of the side chains through the thiophen
reactivity and the choice of the pyridine moiety. The
Zincke procedure appears as a practical and selective
approach to unsymmetrical bis-pyridinium macrocycles.
a
Reagents and conditions: (a) Bu4NF, 6 equiv, THF, rt; (b)
ZnBr2, 0.5 equiv, TMSBr, 2.5 equiv, CH2Cl2, -20 °C; (c) NaN3, 5
equiv, DMF, 60 °C; (d) PPh3, 1.7 equiv, 0 °C, rt, overnight, then
NH2OH at 0 °C.
SCHEME 6a
Exp er im en ta l Section
{5-[(ter t-Bu tyl-d im eth yl-sila n yloxy)-cyclop r op yl-m eth -
yl]-th iop h en -2-yl}-p yr id in e-3-yl Meth a n ol (12). To a solu-
tion of silyl derivative 11 (20.14 g, 75.1 mmol) in THF (50 mL)
was added dropwise, at -78 °C under N , n-BuLi (1.6 M in
2
hexane, 50.1 mL, 75.1 mmol). The resulting mixture was
stirred for 30 min at the same temperature, and 3-pyridin-
ecarboxaldehyde (6.44 mL, 68.2 mmol) in THF (20 mL) was
added dropwise. After the mixture was stirred for 1.5 h, the
reaction was quenched with a saturated aqueous solution of
NH
layer was washed with H
anhydrous MgSO , and concentrated in vacuo. The residue was
4
Cl and extracted with AcOEt (4 × 100 mL). The organic
2
O (100 mL) and brine, dried over
4
subjected to column chromatography (70/30 heptane/AcOEt)
on silica gel to furnish the pyridine derivative 12 (17.81 g, 70%
1
yield) as a yellow oil: H NMR (300 MHz, CDCl
3
9
(
7
3
) δ -0.05 (s,
H), -0,03 (s, 3H), 0.07 (s, 3H), 0.32-0.57 (m, 4H), 0.89 (s,
H), 1.15 (m, 1H), 3.86 (s, 1H), 4.47 (dd, J ) 2, 7 Hz, 1H), 6.13
s, 1H), 6.78 (dd, J ) 1, 4 Hz, 1H), 6.86 (dd, J ) 1, 4 Hz, 1H),
a
Reagent and conditions: (a) Boc2O (93% yield); (b) 2,4-DNBCl,
.39 (m, 1H), 7.93 (m, 1H), 8.57 (m, 1H), 8.69 (d, J ) 2 Hz);
3
-equiv, MeOH, ∆, 48 h (80% yield); (c) n-BuOH, ∆, 15 min (88%
1
3
C NMR (75.47 MHz, CDCl
3
) δ -4.8, -4.6, 2.7, 3.2, 18.2, 20.0,
yield); (d) 2,4-DNBCl, 3 equiv, MeOH, ∆, 48 h (74% yield); (e)
CF3CO2H, 1 equiv, CH2Cl2, 1 h (100% yield); (f) Et3N, n-BuOH, ∆
2
1
5.8, 70.2, 73.5, 122.2, 123.3, 124.3, 134.1, 138.8, 145.4, 148.0,
48.8, 150.9; IR (neat) 3179, 2929, 2857, 1472, 1055, 939 cm
MS (IC) m/z 376 (MH ), 358 (C20
NOS ); HRMS (IC) calcd for C20
found 376.1771.
-1
;
(71% yield); (g) NaBH4, MeOH‚H2O (68% yield).
+
+
H
28NOSSi ), 244 (C14
H
14
-
+
+
respectively, in good yield. Finally, reduction of these
derivatives, using triphenylphosphine at 0 °C, followed
by treatment with ammonia, afforded primary amines 8
and 9, respectively.
The next step was the synthesis, from these 3-alkyl-
amino pyridine derivatives, of the bis-pyridinium mac-
rocycle 1 (Scheme 6) using our reported methodology.4b
The Boc-protected derivative 26 was first reacted with
H
30NO
2
SSi (MH ) 376.1767,
5
-[(ter t-Bu tyl-d im eth yl-sila n yloxy)-cyclop r op yl-m eth -
yl]-th ioph en -2-car baldeh yde (13). To a solution of thiophene
1 (17.7 g, 66 mmol) in THF (100 mL) at 0 °C under N was
1
2
added dropwise n-BuLi (1.5 M in hexane, 46.2 mL, 69.3 mmol).
The mixture was stirred for 30 min at the same temperature,
and N-formylpiperidine (18.3 mL, 160 mmol) was added
dropwise. After stirring at room temperature for 5 h, the
reaction mixture was poured into a saturated aqueous solution
of NH
The organic layer was washed with water (100 mL) and brine
100 mL), dried over anhydrous MgSO , and concentrated in
vacuo. The residue was purified by column chromatography
98/2 heptane/AcOEt) on silica gel to afford aldehyde 13 (14.32
1
-chloro-2,4-dinitrobenzene to give the Zincke salt 27.
4
Cl (250 mL) and extracted with AcOEt (3 × 250 mL).
This salt, when treated with amine 8 in refluxing
n-butanol, easily afforded the pyridinium salt 28 in 88%
yield. After new activation of the pyridine ring of 28 as
the Zincke salt 29, deprotection of the primary amino
group in acidic medium furnished the ammonium salt
(
4
(
1
g, 73% yield) as a yellow paste: H NMR (300 MHz, CDCl ) δ
3
3
0. This salt was stable, but liberation of the amino group
0.00 (s, 3H), 0.10 (s, 3H), 0.44-0.54 (m, 4H), 0.9 (s, 9H), 1.17
with triethylamine resulted in formation of a deep red
color, indicating an attack of the Zincke salt by the
primary amine function to give open chain intermediates.
These intermediates were not isolated, but reflux of the
crude mixture in n-butanol over 45 min gave, as expected,
bis-pyridinium macrocycle 1 in 71% yield.
(m, 1H), 4.51 (d, J ) 7 Hz, 1H), 7.08 (d, J ) 4 Hz, 1H), 7.68,
(
d, J ) 4 Hz, 1H), 9.9 (s, 1H); 13C NMR (75.47 MHz, CDCl
) δ
3
-
1
4.7, -4.4, 3.0, 3.5, 18.3, 20.3, 25.8, 73.7, 123.7, 136.5, 142.0,
-
1
62., 183.2; IR (neat) 2930, 2857, 1671, 1459 cm ; MS (IC)
+
+
+
+
m/z 297 (MH ), 183 (C
9 2 9 9 8 9
H11SO ), 165 (C H SO ), 137 (C H S ).
(14) All complex structures were resolved by intensive NMR spec-
5
Finally, sodium borohydride reduction of salt 1 gave
troscopy studies, including one- and two-dimensional NMR experi-
ments (COSY 90, HMQC, HMBC).
haliclamine A in 68% yield. The spectroscopic data for
6
476 J . Org. Chem., Vol. 67, No. 18, 2002

Synthesis of Haliclamine A
3
-[6-(ter t-Bu t yl-d im et h yl-sila n yloxy)-6-cyclop r op yl-
h exyl]-p yr id in e (16). To a solution of pyridine derivative 12
17.8 g, 47.4 mmol) in EtOH (500 mL) was added Na CO (9
g) and a large excess of freshly prepared Raney nickel. After
h at reflux, another excess of Raney nickel was added and
dinitrobenzene (478 mg, 2.4 mmol) in MeOH (5 mL) was
refluxed over 48 h. The solvent was evaporated, and the
(
2
3
residue was purified by column chromatography (CH
90/10 CH Cl /MeOH) on silica gel to afford the Zincke salt 27
(537 mg, 80% yield) as an orange powder: H NMR (250 MHz,
CDCl ) δ 1.17-1.38 (m, 10H), 1.41 (s, 9H), 1.76 (m, 2H), 1.98
2 2
Cl then
2
2
1
2
the mixture was refluxed for 2 days. The resulting mixture
was decanted; the EtOH was collected and the catalyst washed
with petroleum ether (2 × 100 mL), diisopropyl ether (3 × 100
3
(m, 2H), 2.17 (m, 2H), 2.81 (t, J ) 6 Hz, 2H), 3,12 (m, 2H),
4.62 (s, 1H), 5.38 (dt, J ) 5, 18 Hz, 1H), 5.51 (dt, J ) 5, 18 Hz,
1H), 8.29 (t, J ) 5 Hz, 1H), 8.60 (m, 2H), 8.82 (d, J ) 6 Hz,
mL), and CH
2
Cl
2
(3 × 100 mL). The combined organic phases
3
1
3
were washed with a saturated aqueous solution of NaHCO
The combined organic layers were dried over anhydrous
MgSO and concentrated in vacuo. Purification of the residue
.
1H), 9.10 (s, 1H), 9.67 (m, 1H), 9.83 (d, J ) 4 Hz, 1H);
NMR (69.82 MHz, CDCl
C
3
) δ 28.4, 29.0, 29.3, 30.3, 32.5, 32.8,
33.1, 40.3, 121.9, 126.5, 128.0, 130.4, 132.6, 133.3, 138.5, 143.2,
4
by column chromatography (85/15 heptane/AcOEt) on silica
gel afforded pure derivative 16 (4.8 g, 30% yield) as a colorless
oil, thiophene 18 (20% yield), and alcohol 19 (24% yield).
144.0, 144.4, 145.0, 147.7, 149.2, 156.0; MS (ESI) m/z 527 (M
- Cl) .
+
3
-(12-ter t-Bu toxyca r bon yla m in o-d od ec-9-en yl)-1-(9-p y-
1
Pyridine 16: H NMR (250 MHz, CDCl
(
2
1
3
) δ 0.03 (s, 3H), 0.09
r idin -3-yl-n on -3-en yl)-pyr idin iu m Ch lor ide (28). To Zincke
salt 27 (522 mg, 0.93 mmol) in n-BuOH was added dropwise,
at 80 °C, the amine 8 (223 mg, 1.02 mmol). The resulting deep
red solution was refluxed for 15 min. After removal of solvent,
s, 3H), 0.15-0.46 (m, 4H), 0.92 (s, 9H), 1.27-1.72 (m, 4H),
.59 (t, J ) 8 Hz, 2H), 3.04 (m, 1H), 7.24 (dd, J ) 5, 8 Hz,
H), 7.52 (dt, J ) 2, 8 Hz, 1H), 8.44 (m, 2H); 13C NMR (62.89
MHz, CDCl
3
) δ -4.4, -3.8, 2.3, 3.5, 17.5, 18.2, 25.3, 26.0, 29.4,
the residue was filtered over silica gel using a gradient of CH
Cl /MeOH (from 100/0 to 85/15) to give salt 28 (488 mg, 88%
yield) as a brown oil: H NMR (250 MHz, CDCl
2
-
3
2
1.3, 33.1, 38.2, 76.2, 123.3, 135.8, 138.0, 147.3, 150.1; IR (neat)
2
-1
+
928, 2853, 1249, 1051, 834 cm ; MS (IC) m/z 334 (MH ), 202
1
3
) δ 1.12-1.37
m, 14H), 1.44 (s, 9H), 1.52 (m, 2H), 1.67 (m, 2H), 1.86 (m,
+
1
(C
14
H
20N ). Thiophene derivative 18: H NMR (300 MHz,
) δ -0.05 (s, 3H), 0.06 (s, 3H), 0.32-0.59 (m, 4H), 0.88
s, 9H), 1.05-1.32 (m, 1H), 4.13 (s, 2H), 4.43 (d, J ) 7 Hz,
(
CDCl
3
2
H), 1.96 (m, 2H), 2.15 (m, 2H), 2.56 (t, J ) 6 Hz, 2H), 2.71
(
1
(
(
(
m, 2H), 2.86 (t, J ) 6 Hz, 2H), 3.12 (m, 2H), 4.61 (s, 1H), 5.06
t, J ) 5 Hz, 2H), 5.15-5.35 (m, 2H), 5.38-5.54 (m, 2H), 7.22
dd, J ) 3, 5 Hz, 1H), 7.45 (d, J ) 5 Hz, 1H), 7.93 (t, J ) 5 Hz,
H), 6.64 (dt, J ) 1, 7 Hz, 1H), 6.84 (d, J ) 5 Hz, 1H), 7.29
(
dd, J ) 1, 8 Hz, 1H), 7.64 (dt, J ) 3, 14 Hz, 1H), 8.58 (m,
13
2
2
1
3
H); C NMR (75.47 MHz, CDCl ) δ -4.7, -4.5, 2.8, 3.2, 18.3,
1
H), 8.13 (d, J ) 5 Hz, 1H), 8.34 (m, 2H), 9.18 (s, 1H), 9.33 (d,
0.1, 25.8, 60.4, 73.5, 122.5, 123.5, 124.6, 136.0, 136.1, 140.8,
13
J ) 5 Hz, 1H); C NMR (69.82 MHz, CDCl
3
) δ 28.5, 29.1, 29.4,
+
+
47.9, 149.3, 149.9; MS (IC) m/z 360 (MH ), 228 (C14
Alcohol 19: H NMR (200 MHz, CDCl
H
14NS ).
3
1
1
1
0.6, 30.9, 32.3, 32.6, 32.9, 33.1, 35.0, 40.2, 61.0, 123.4, 126.6,
1
3
) δ -0.06 (s, 3H), 0.00
27.6, 133.2, 135.9, 136.3, 136.9, 143.1, 143.9, 144.0, 144.4,
47.3, 149.9, 156.0; IR (neat) 3369, 2928, 2855, 1698, 1365,
(
2
8
s, 3H), 0.05-0.44 (m, 4H), 0.83 (s, 9H), 0.97-1.81 (m, 9H),
.90 (q, J ) 6 Hz, 1H), 4.57 (t, J ) 7 Hz, 1H), 7.11 (dd, J ) 5,
-1
+
174, 971 cm ; MS(ESI) m/z 562 [(M - Cl) ], 253.5 [(M -
Hz, 1H), 7.57 (dt, J ) 2, 8 Hz, 1H), 8.58 (m, 2H); 13C NMR
- ClH)2+].
4 8
C H
(
3
75.47 MHz, CDCl ) δ -4.5, -4.0, 2.2, 3.4, 17.2, 18.1, 25.3, 25.9,
Zin ck e Sa lt 29. The salt 28 (445 mg, 0.74 mmol) and
-chloro-2,4-dinitrobenzene (453 mg, 2.2 mmol) in MeOH (5
3
3
9.2, 71.7, 76.1, 123.5, 134.0, 141.0, 147.4, 147.9; IR (neat)
1
-
1
+
350, 2931, 1254, 1057, 836 cm ; MS (IC) m/z 350 (MH ), 292
mL) were heated under reflux for 48 h. The solvent was
evaporated. Filtration of the residue by column chromatogra-
+
+
+
(C
17
+
H
30NOSi ), 218 (C14
H
20NO ), 200 (C14
H
18N ), 185 (C11
H
16
-
+
NO ). HRMS (MALDI) calcd for C20
found 334.25662.
H
35NOSi (MH ) 334.25662,
phy on silica gel using a gradient of CH
2 2
Cl /MeOH (from 100/0
to 80/20) afforded the corresponding Zincke salt 29 (439 mg,
1
-Cyclop r op yl-9-p yr id in -3-yl-n on a n -1-ol (21). Treat-
1
7
4% yield) as an orange powder: H NMR (300 MHz, CDCl
δ 1.12-1.37 (m, 14H), 1.42 (s, 9H), 1.59-1.79 (m, 4H), 1.89
m, 2H), 1.95 (m, 2H), 2.15 (m, 2H), 2.66 (m, 2H), 2.84 (m,
3
)
ment of silyl derivative 17 under the conditions used for
deprotection of 16 to 20 gave alcohol 21 (2.16 g, 78% yield) as
(
1
a pale yellow oil: H NMR (300 MHz, CDCl
4
)
3
) δ 0.13-0.53 (m,
2
5
8
H), 2.96 (m, 2H), 3.08 (m, 2H), 4.63 (s, 1H), 4.89 (m, 2H),
.23-5.37 (m, 2H), 5.40-5.52 (m, 2H), 8.06 (t, J ) 4 Hz, 1H),
.25 (d, J ) 8 Hz, 1H), 8.34 (t, J ) 4 Hz, 1H), 8.57 (d, J ) 8
H), 0.89 (m, 1H), 1.29-1.53 (m, 10H), 1.58 (m, 4H), 2.57 (t, J
8 Hz, 2H), 2.86 (dt, J ) 2, 8 Hz, 1H), 3.52 (s, 1H), 7.20 (dd,
13
J ) 5, 8 Hz, 1H), 7.51 (dt, J ) 2,10 Hz, 1H), 8.42 (m, 2H);
C
Hz, 1H), 8.64 (d, J ) 8 Hz, 1H), 8.78 (d, J ) 8 Hz, 1H), 9.08
m, 1H), 9.23 (m, 1H), 9.35 (d, J ) 4 Hz, 1H), 9.69 (m, 1H),
NMR (75.47 MHz, CDCl ) δ 2.1, 17.4, 25.4, 28.6, 28.9, 29.1,
3
(
2
9.3, 30.6, 32.5, 37.1, 75.3, 122.8, 135.4, 137.5, 146.3, 149.0;
13
1
2
1
1
3
0.15 (m, 1H); C NMR (75.47 MHz, CDCl ) δ 27.6, 28.0, 28.5,
-
1
IR (neat) 3350, 2928, 2855, 1423, 1028, 713 cm ; MS (IC) m/z
62 (MH ), 244 (C17
MH ) 262.2171, found 262,2200.
9.1, 29.4, 29.7, 30.6, 31.6, 32.6, 32.7, 33.1, 35.1, 40.3, 61.0,
22.0, 123.8, 126.5, 127.9, 128.0, 130.4, 132.6, 133.3, 135.6,
38.7, 143.1, 143.4, 143.9, 144.8, 145.6, 148.1, 149.2; IR (neat)
+
+
2
(
H
26N ); HRMS (IC) calcd for C17
H
28NO
+
-1
3
-(9-Br om o-n on -6-en yl)-p yr id in e (22). To a vigorously
stirred suspension of alcohol 20 (2.66 g, 12 mmol) and ZnBr
1.65 g, 6 mmol) in CH Cl (10 mL) was added dropwise, at
20 °C under N , a solution of Me SiBr (4 mL, 30 mmol) in
CH Cl (5 mL). The reaction mixture was kept at the same
temperature for 15 min, treated at -10 °C with a saturated
aqueous solution of NaHCO (100 mL), and extracted with
CH Cl
(3 × 100 mL). The organic layer was washed with
brine, dried over anhydrous MgSO and concentrated in vacuo
to yield the bromo-alkyl pyridine 22 (3.28 g, 96% yield) as a
3382, 2928, 2855, 1694, 1345, 972, 733 cm ; MS(ESI) m/z 764
[(M - Cl) ], 364.5 [(M - 2Cl) ].
+
2+
2
(
2
2
Dep r otected Zin ck e Sa lt 30. To Zincke salt 29 (245 mg,
-
2
3
0
2 2
.31 mmol) dissolved in CH Cl (5 mL) was added dropwise,
2
2
at 0 °C, trifluoroacetic acid (24 mL, 0.31 mmol). After the
mixture was stirred for 3 h at 0 °C, the solvent was evaporated
to yield ammonium salt 30 (250 mg, quantitative yield) as a
3
1
2
2
brown paste: H NMR (300 MHz, CDCl
) δ 1.12-1.39 (m, 14H),
3
4
1
2
6
6
8
.50-1.69 (m,4H), 1.74-1.95 (m, 4H), 2.23 (q, J ) 6 Hz, 2H),
.57 (m, 2H), 2.76 (t, J ) 6 Hz, 2H), 2.83 (m, 4H), 4.57 (t, J )
Hz, 2H), 5.2-5.41 (m, 3H), 5.49-5.61 (m, 1H), 7.91 (t, J )
Hz, 1H), 8.18 (m, 2H), 8.34 (d, J ) 6 Hz, 1H), 8.71 (m, 2H),
1
brown oil: H NMR (200 MHz, CDCl ) δ 1.38 (m, 4H), 1.64 (q,
3
J ) 2 Hz, 2H), 2.07 (m, 2H), 2.62 (m, 4H), 3.41 (t, J ) 5 Hz,
2
7
2
3
2
H), 5,42 (dt, J ) 4, 14 Hz, 1H), 5.56 (dt, J ) 4, 14 Hz, 1H),
.27 (dd, J ) 3, 5 Hz, 1H), 7.56 (dt, J ) 2, 8 Hz, 1H), 8.54 (m,
13
.78 (m, 2H), 9.08 (d, J ) 6 Hz, 1H), 9.17 (s, 2H); C NMR
) δ 27.4, 27.9, 28.1, 28.2, 28.3, 28.4, 29.2,
(
75.47 MHz, CDCl
3
1
3
H); C NMR (75.47 MHz, CDCl ) δ 28.6, 29.0, 31.0, 32.4, 33.0,
3
2
1
1
9.6, 31.2, 31.6, 33.5, 38.5, 60.4, 121.1, 122.7, 123.1, 126.8,
27.1, 129.1, 130.6, 134.3, 135.1, 138.1, 141.3, 142.6, 143.1,
43.6, 143.8, 144.4, 144.6, 147.9, 149.0, 158.3, 158.8, 159.3,
6.0, 123.3, 126.8, 133.7, 135.8, 137.9, 147.3, 150.0; IR (neat)
929, 2855, 1435, 1061, 970 cm-1; MS (ESI) m/z 282 (MH ).
+
-
1
3
-(12-ter t-Bu toxyca r bon yla m in o-d od ec-9-en yl)-1-(2,4-
159.8; IR (neat) 3071, 2933, 2860, 1782, 1349, 813, 705 cm
MS (ESI) m/z 742 [(M - HCl - Cl) ], 315 [(M - HCl - Cl -
CF
;
+
d in itr op h en yl)-p yr id in iu m Ch lor id e (27). A mixture of the
protected amine 26 (425 mg, 1.2 mmol) and 1-chloro-2,4-
2
+
3+
3
CO
2
)
], 210 [(M - 2Cl - CF
3
COO) ].
J . Org. Chem, Vol. 67, No. 18, 2002 6477

Michelliza et al.
Bis-p yr id in iu m Ma cr ocycle 1. To refluxing n-BuOH (30
mL) were added, dropwise and simultaneously over a period
of 0.5 h, a solution of salt 30 (250 mg, 0.31 mmol) in n-BuOH
trated in vaccuo. The residue was hydrolyzed with 1 M
aqueous NaOH (50 mL) and extracted with CH
2
Cl
2
(5 × 50
mL). After removal of the solvent, the crude product was
purified by column chromatography over alumina using a
gradient of heptane/AcOEt (from 100/0 to 80/20) to afford
(
(
3 mL) and a solution of Et
3 mL). After the addition was complete, additional Et
3
N (0.2 mL, 1.5 mmol) in n-BuOH
N (0.3
3
1
mL) was added and the mixture was further refluxed during
5 min. After removal of the solvent, the residue was purified
by column chromatography over alumina (6 g) using a gradient
of CH Cl /MeOH (from 100/0 to 90/10) to afford macrocycle 1
112 mg, 71% yield) as a brown paste: H NMR (300 MHz, CD
OD) δ 0.92-1.38 (m, 14H), 1.52-1.72 (m, 4H), 1.77-1.94 (m,
haliclamine A (33 mg, 68% yield) as a colorless oil: H NMR
1
(300 MHz, CDCl
(m, 4H), 2.25 (m, 4H), 2.51 (m, 8H), 2.91 (m, 4H), 5.49 (m,
6H); 13C NMR (75.47 MHz, CDCl
) δ 25.8, 25.8, 26.4, 27.5, 27.8,
3
) δ 1.13-1.44 (m, 12H), 1.95 (m, 4H), 2.13
2
2
3
1
(
3
-
28.1, 28.3, 28.9, 29.0, 29.2, 29.8, 30.7, 32.0, 32.2 (15C), 35.5
(2C), 50.2 (2C), 55.6, 55.8 (2C), 58.6 (2C), 119.0 (2C), 128.5,
4
5
8
H), 2.65 (m, 4H), 2.72-2.87 (t, J ) 8 Hz, 4H), 4.60 (m, 4H),
.03-5.16 (m, 2H), 5.23-5.42 (m, 2H), 7.92 (t, J ) 7 Hz, 2H),
.35 (t, J ) 7 Hz, 2H), 8.67 (m, 4H); 13C NMR (75.47 MHz,
128.6 (2C), 131.6, 131.7, 136.3, 136.4 (2C); HRMS (IC) calcd
+
for C31
H
53
N
2
(MH ) 453.4208, found 453.4176.
CD OD) δ 29.8, 30.2, 30.4, 31.4, 31.7, 33.4, 35.1, 35.2, 62.1,
1
1
3
Su p p or tin g In for m a tion Ava ila ble: Experimental condi-
tions for the preparation of compounds 8-11, 15, 17, 20, and
24.5, 124.7, 128.9, 137.3, 137.7, 143.2, 143.4, 144.9, 145.2,
+
45.3, 145.5, 146.4, 146.7; MS (ESI) m/z 481 [(M - Cl) ], 223
1
13
2
8
3-26 and copies of H and C NMR spectra of derivatives 1,
-13, 15-30, and haliclamine A with attribution of signals.
2
+
[(M - 2Cl) ].
Ha licla m in e A. To a solution of bis-pyridinium salt 1 (56
This material is available free of charge via the Internet at
http://pubs.acs.org.
mg, 0.11 mmol) in MeOH (35 mL) and H
at 0 °C, an excess of NaBH . After stirring at 0 °C for 1 h and
then at room temperature for 3 h, the mixture was concen-
2
O (25 mL) was added,
4
J O025650V
6
478 J . Org. Chem., Vol. 67, No. 18, 2002