First Synthesis of Marine Sponge Alkaloid Niphatoxin B

Full text of DOI:10.1021/jo9825299

3778
J . Org. Chem. 1999, 64, 3778-3782
Sch em e 1
F ir st Syn th esis of Ma r in e Sp on ge Alk a loid
Nip h a toxin B
Alexander Kaiser,*,† Christian Marazano, and
Michael Maier
Institut fu¨r Pharmazie, Pharmazeutische Chemie I,
Universita¨t Regensburg, D-93040 Regensburg, Germany
Received December 30, 1998
In 1992, Talpir et al. reported the isolation and
structure elucidation of niphatoxins A (1) and B (2), two
ichthyo- and cytotoxic (IC50 ) 0.1 µg/mL, P388) tripyri-
dine alkaloids.1,2 These Red Sea sponge alkaloids, isolated
from a Niphates sp., belong to an emerging and intrigu-
ing class of marine secondary metabolites which are
related to each other by their apparent biogenetic origin
from 3-alkylpyridine or reduced 3-alkylpyridine units.3
Among them niphatoxins are unique in having three
pyridine units and a substructure in which two pyridine
rings are linked through their 3 positions to the same
alkyl chain. Whereas other members of this group have
become subjects of total syntheses or synthetic studies,4
no synthesis of niphatoxins has been reported up to now.
Herein we report the first total synthesis of niphatoxin
B (2) based on a novel approach to glutaconaldehyde
bisacetals.5 The retrosynthetic analysis for our approach
is outlined in Scheme 1. Disconnections of the two C-N
bonds in the pyridinium moiety lead to a 3-(ω-aminoalkyl)-
pyridine 4 and 2-substituted glutaconaldehyde 3 which
in turn could be divided via its bisacetal into two
commercially available three carbon fragments and a
3-alkylpyridine unit. Na+- and K+-salts of glutaconalde-
hyde enolates have been used as starting materials to
prepare pyridines by reaction with ammonium salts.5
These glutaconaldehyde salts, however, have been ob-
tained from pyridine by ring opening reactions, and not
from acyclic starting materials. In a new biogenetic
hypothesis, amino derivatives of glutaconaldehyde were
proposed as key intermediates in the biosynthesis of
manzamine alkaloids.6
Our efforts were first directed to exploring the feasibil-
ity of the envisioned key reactions with simple model
compounds. Phosphonium salt 5 was deprotonated with
n-BuLi in THF at -20 °C, and the resulting ylide was
reacted with 1,1-dimethoxy-2-propanone (6) to give ole-
fination product 7 in 54% yield as a 9:1 mixture of E/Z-
isomers. Bearing in mind the low stability of glutacon-
aldehyde in its free form,5 we planned to subject
intermediate 3 to the cyclocondensation with the amine
4 without prior isolation. Acid treatment of 7 until
disappearance of the starting material (TLC), addition
of cyclohexylamine and Et3N, and reflux in n-butanol
gave disappointing results, probably due to decomposition
of the resulting 2-methylglutaconaldehyde under the
conditions of acetal hydrolysis. Finally, short treatment
of 7 with FeCl3,7 adsorbed on silica gel, in CH2Cl2 prior
to addition of cyclohexylamine hydrochloride and Et3N,
removal of CH2Cl2, and reflux in n-butanol afforded
pyridinium salt 8 in 39% yield after column chromatog-
raphy.
† E-mail: alexander.kaiser@chemie.uni-regensburg.de.
(1) Talpir, R.; Rudi, A.; Ilan, M.; Kashman, Y. Tetrahedron Lett.
1992, 33, 3033-3034.
(2) The structural formula given in ref 1 on page 3034 appears to
be incorrect in respect to the molecular formulas in the text. Structural
formula given on page 3034 corresponds to molecular masses of 524
and 538 u, whereas molecular masses given in the text are 510 and
524 u. Comparison of the masses of pyridinealkyl fragments resulting
from cleavage of the C-N bond in the text (216 and 230) with the
masses of these units in the structural formula (230 and 244) shows
that one methylene unit in the N+-alkyl chain should be omitted. The
same incorrect structural formula appears also in ref 3.
(3) For an excellent recent review, see: Andersen, R. J .; Van Soest,
R. W. M.; Kong, F. Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Pergamon Press: Elsevier Science: Oxford, U.K.,
1996; Vol. 10, pp 301-355.
(4) Manzamines, ircinol A, and ircinal A: (a) Winkler, J . D.; Axten,
J . M. J . Am. Chem. Soc. 1998, 120, 6425-6426. (b) Magnier, E.;
Langlois, Y. Tetrahedron 1998, 54, 6201-6258 and references therein.
Xestospongines: (c) Baldwin, J . E.; Melman, A.; Lee, V.; Firkin, C. R.;
Whitehead, R. C. J . Am. Chem. Soc. 1998, 120, 8559-8560 and
references therein. Petrosines: (d) Heathcock, C. H.; Brown, R. C. D.;
Norman, T. C. J . Org. Chem. 1998, 63, 5013-5030 and references
therein. Sarains: (e) Downham, R.; Ng, F. W.; Overman, L. E. J . Org.
Chem. 1998, 63, 8096-8097 and references therein. Mandangamin:
(f) Matzanke, N.; Gregg, R. J .; Weinreb, S. M. J . Org. Chem. 1997, 62,
1920-1921. Cyclostellettamines: (g) Kaiser, A.; Billot, X.; Gateau-
Olesker, A.; Marazano, C.; Das, B. C. J . Am. Chem. Soc. 1998, 120,
8026-8034. (h) Baldwin, J . E.; Spring, D. R.; Atkinson, C. E.; Lee, V.
Tetrahedron 1998, 54, 13655-13680 and references therein. Hal-
iclamines: (i) Morimoto, Y.; Yokoe, C.; Kurihara, H.; Kinoshita, T.
Tetrahedron 1998, 54, 12197-12214 and references therein. Halicy-
clamine A and keramaphidine B: (j) Baldwin, J . E.; Claridge, T. D.
W.; Culshaw, A. J .; Heupel, F. A.; Lee, V.; Spring, D. R.; Whitehead,
R. C.; Boughtflower, R. J .; Mutton, I. M.; Upton, R. J . Angew. Chem.
1998, 110, 2806-2808 and references therein. Niphatesines and
theonelladins: (k) Bracher, F.; Papke, T. Monatsh. Chem. 1996, 127,
91-95 and references therein. (l) Teubner, A.; Gerlach, H. Liebigs Ann.
Chem. 1993, 161-165. Polymeric 3-alkylpyridinium alkaloids: (m) ref
4g and references therein.
We next turned our attention to the preparation of the
required glutaconaldehyde bisacetal. Known aldehyde8
10 was prepared in 38% and 90% yields by oxidation of
THP-protected bromo alcohol 9 using pyridine N-oxide
or trimethyamine N-oxide,9 respectively. (Z)-Selective
Wittig olefination of aldehyde 10 with phosphonium salt
(6) Reference 4g.
(7) Kim, K. S.; Song, Y. H.; Lee, B. H.; Hahn, C. S. J . Org. Chem.
1986, 51, 404-407.
(8) Mancini et al. prepared aldehyde 10 from bromide 9 using DMSO
as an oxidant: Mancini, I.; Guella, G.; Pietra, F. Helv. Chim. Acta 1991,
74, 941-950.
(5) For glutaconaldehyde and its derivatives, including glutaconal-
dehyde bisacetals, see: Becher, J . Synthesis 1980, 589-612.
10.1021/jo9825299 CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/24/1999

Notes
J . Org. Chem., Vol. 64, No. 10, 1999 3779
Sch em e 2
Sch em e 3
11,10 using potassium tert-butoxide in the presence of 18-
crown-6 as a base, afforded (Z)-alkene 12 nearly as a
single geometrical isomer (E-isomer < 2%). Deprotection
to alcohol 13 and subsequent treatment with TsCl/
pyridine led to tosylate 14 which was used immediately
without purification for the next step to prevent poly-
merization. Imine 1511 was deprotonated with LDA in
THF at -78 °C, and the resulting lithio enamine was
alkylated with tosylate 14. Hydrolysis of the imine
functionality upon aqueous workup provided ketone 16
in 70% yield. Wittig reaction of 16 with the ylide
generated from phosphonium salt 5 furnished glutacon-
aldehyde precursor 17 as a 9:1 mixture of E/Z-isomers
in 63% yield. In contrast to ketone 6 (Scheme 2), the use
of an excess (4.7 equiv) of ylide and a modified temper-
ature protocol were found essential to achieve this result.
In some experiments 17 was accompanied by minor
amounts (<15%) of aldehyde 18 arising from dimethyl
acetal hydrolysis which was of no consequence for the
subsequent reaction. This sequence allowed us to obtain
glutaconaldehyde precursor 17 in 27% overall yield in
six steps starting from 9 (Scheme 3).
For the construction of the amine component 4, propyn-
1-ol was deprotonated with n-BuLi, and the resulting
dianion was alkylated with THP-protected bromo alcohol
19, giving the known propargyl alcohol 2012 which was
treated with CBr4/PPh313 to provide bromide 21 (Scheme
4). Generation of the enolate14 from ester 22, followed
by addition of bromide 21, afforded alkylation product
23 which was reduced with LiAlH4 to alcohol 24. Partial
hydrogenation using Lindlar catalyst and subsequent
Swern oxidation gave glutaraldehyde monoacetal 26.
Glutaraldehyde-pyridine cyclization15 and THP depro-
tection to pyridine alcohol 27 were achieved in one
laboratory step by treatment with hydroxylammonium
chloride in refluxing ethanol. Tosylation, azide substitu-
tion, and reduction afforded amine 4 which was isolated
as its dihydrochloride salt 4a . The overall yield of this
10-step sequence starting from 19 was 4.3%.
With both components in hand, the stage was set for
the condensation of 17 and 4 to niphatoxin B. Glutacon-
aldehyde 3 (Scheme 1) was liberated by hydrolysis of the
acetal functionalities, applying the conditions found in
the model reaction with bisacetal 7, and cyclized in situ
with amine 4 to give niphatoxin B (2) in 45% yield after
column chromatography.
1H and 13C NMR data16 of synthetic niphatoxin B (2)
were identical with those reported for the natural prod-
uct.1 In the FAB-MS, synthetic 2 revealed a base peak
at m/z 524 and prominent peaks at m/z 295 and 230
which were assigned to [M+] and the fragments of C-N
cleavage, respectively. The dimethylation product of
1
synthetic niphatoxin B showed the same behavior in H
and 13C NMR experiments17 as that of natural niphatox-
in.1
In conclusion, the first synthesis of niphatoxin B has
been accomplished. We have shown that the reaction of
primary amines with 2-substituted glutaconaldehydes,
generated in situ from the corresponding bisacetals,
provides a practical entry to 3-substituted pyridinium
salts for which classical approaches, i.e., halide or sul-
fonate displacement by pyridines, are not considered
convenient. Our protocol allows the synthesis of pyri-
(9) For oxidation with pyridine N-oxide: (a) Waugh, K. M.; Berlin,
K. D. J . Org. Chem. 1984, 49, 873-878. With trimethylamine N-
oxide: (b) Godfrey, A. G.; Ganem, B. Tetrahedron Lett. 1990, 31, 4825-
4826.
(10) Prepared in one step from commercially available 3-(3-pyridyl)-
1-propanol in 80% yield: Staab, H. A.; Zipplies, M. F.; Mu¨ller, T.;
Storch, M.; Krieger, C. Chem. Ber. 1994, 127, 1667-1680.
(11) Cuvigny, T.; Normant, H. Synthesis 1977, 198-200.
(12) Vig et al. used LiNH2/liquid NH3 for this conversion: Vig, O.
P.; Sharma, M. L.; Kapur, J .; Thapar, S.; Gupta, R. Indian J . Chem.
Sect. B 1990, 29, 606-610.
(13) Harnden, M. R.; J arvest, R. L. J . Chem. Soc., Perkin Trans. 1
1988, 2777-2784
(14) Cooke, M. P., J r.; Gopal, D. J . Org. Chem. 1994, 59, 260-263.
(15) Spitzner, D. In Houben-Weyl-Methoden der Organischen Che-
mie, 4th ed.; Kreher, R. P., Ed.; Thieme: Stuttgart, 1992; Vol. E7b, pp
301-304.
(16) Since our 1H and 13C NMR data of synthetic 2 matched exactly
those reported for the natural product when recorded in CD3OD, we
assume that also Talpir et al. used CD3OD as the solvent for their
NMR experiments and not CDCl3 as stated in ref 1. Especially the 1H
NMR chemical shifts of the pyridinium protons show strong solvent
dependence. For details, see the Experimental Section.
(17) See the Supporting Information.

3780 J . Org. Chem., Vol. 64, No. 10, 1999
Notes
by using Merck Kieselgel 60 and Merck aluminum oxide 90 (70-
230 mesh, activity II-III). Spots were visualized with ultraviolet
light (254 nm) or detected by exposure to iodine fumes. Infrared
Sch em e 4
1
spectra were recorded with an FT-IR spectrometer. H and 13C
NMR spectra were obtained at 250 and 62 MHz, respectively.
Compounds which were not submitted for or did not pass
elemental analysis were judged to be of >95% purity on the basis
of TLC homogenity and 1H NMR analyses (see Supporting
Information).
1,1-Dim eth oxy-4-(1,3-dioxolan -2-yl)-2-m eth ylbu t-2-en e (7)
(E/Z-m ixtu r e). Phosphonium salt 5 (8.87 g, 20 mmol) was
suspended in THF (60 mL) and cooled to -20 °C. n-BuLi (12.5
mL, 20 mmol, 1.6 M in hexane) was added dropwise under a
nitrogen atmosphere. After 1 h at this temperature, ketone 6
(2.48 g, 21 mmol) in THF (10 mL) was added. The cooling bath
was removed, and stirring was continued for 16 h. Water (300
mL) was added, the layers were separated, and the aqueous
phase was extracted with ether. The combined organic layers
were washed with water and brine, dried, and concentrated in
vacuo. The residue was purified by bulb-to-bulb distillation (0.05
Torr, ot 50 °C) to afford 7 (2.2 g, 54%, 9:1 mixture of E/Z-isomers)
as colorless oil. IR (film): 2890, 2830 cm-1. 1H NMR (CDCl3): δ
5.64 (m, 0.1 H) and 5.52 (m, 0.9 H), 4.93 (d, J ) 0.9 Hz, 1 H),
4.89 (t, J ) 4.8 Hz, 1 H), 3.80-4.05 (m, 4 H), 3.34 (s, 5.4 H) and
3.29 (s, 0.6 H), 2.49-2.57 (m, 2 H), 1.70-1.75 (m, 2.7 H), and
1.62-1.65 (m, 0.3 H). 13C NMR (CDCl3): δ 135.6 (major), 134.9
(minor), 123.5 (major), 122.5 (minor), 103.9, 102.4, 64.9 (2C), 54.0
(minor, 2C), 53.5 (major, 2C), 32.55 (minor), 32.38 (major), 17.9.
N-Cycloh exyl-3-m eth ylp yr id in iu m Ch lor id e (8). 7 (440
mg, 2.2 mmol) was dissolved in CH2Cl2 (4 mL), FeCl3/SiO2
catalyst7 (100 mg) was added, and the mixture was stirred for 5
min. Then cyclohexylamine hydrochloride (400 mg, 2.9 mmol)
in methanol (0.5 mL) was added. After 1 h n-butanol (5 mL)
and Et3N (300 mg, 3.0 mmol) were added and CH2Cl2 was
removed in vacuo. The solution was refluxed for 16 h. Then the
solvent was removed in vacuo, and water (5 mL), a concentrated
Na2CO3 solution (5 mL), and ether (5 mL) were added. The layers
were separated, and the aqueous layer was extracted with ether.
The aqueous phase was concentrated in vacuo to dryness, and
8 was extracted from the residue with CH2Cl2. The crude product
was further purified by column chromatography (SiO2, gradient
CH2Cl2/methanol: 0-15% methanol) to afford 8 (180 mg, 39%)
as a light brown oil. IR (film): 3039, 1630 cm-1 1H NMR
.
(CDCl3): δ 9.71 (br s, 1 H), 9.52 (d, J ) 6.1 Hz, 1 H), 8.27 (br d,
J ) 7.8 Hz, 1 H), 8.12 (dd, J ) 7.8, 6.1 Hz, 1 H), 5.19 (tt, J )
12.0, 4.0 Hz, 1 H), 2.70 (s, 3 H), 1.90-2.31 (m, 6 H), 1.31-1.83
(m, 4 H). 1H NMR (CD3OD): δ 9.00 (s, 1 H), 8.92 (d, J ) 5.9 Hz,
1 H), 8.42 (d, J ) 7.9 Hz, 1 H), 7.93-8.06 (m, 1 H), 4.57-4.79
(m, 1 H), 2.60 (s, 3 H), 1.26-2.28 (m, 10 H). 13C NMR (CD3OD):
δ 147.4, 144.1, 141.6, 141.5, 128.9, 73.3, 34.5 (2C), 26.5 (2C),
25.7, 18.5.
dinium salts in only three steps from acyclic starting
materials18 by the sequence of (a) alkylation of 1,1-
dimethoxy-2-propanone via its azaenolate, (b) Wittig
olefination with 2-(1,3-dioxolan-2-yl)ethyltriphenylphos-
phonium bromide, and (c) cyclization with a primary
amine. It should be equally useful for making a range of
analogues for biological investigations.
6-(Tetr a h yd r o-2-p yr a n yloxy)h exa n a l (10). With P yr i-
d in e N-Oxid e. A mixture of 1-bromo-6-(tetrahydro-2-pyranyl-
oxy)hexane (9) (16.3 g, 90 mmol), NaHCO3 (16.8 g, 200 mmol),
and pyridine N-oxide (19.0 g, 200 mmol) in toluene (150 mL)
was refluxed for 4 h, using a Dean-Stark water trap, to remove
the water formed in the reaction. After cooling, the mixture was
filtered and the solution was concentrated in vacuo. The crude
product was purified by column chromatography (SiO2, EtOAc/
petroleum ether 8/2) to afford 10 (6.88 g, 38%) as a colorless oil.
Analytical data were in agreement with those in the literature.8
With Tr im eth yla m in e N-Oxid e (TMANO). 1-Bromo-6-
(tetrahydro-2-pyranyloxy)hexane (9) (0.53 g, 2 mmol) was dis-
solved in DMSO (4 mL). TMANO (0.60 g, 8 mmol) was added,
and the mixture was stirred for 5 h. The mixture was poured
into a half-saturated NaCl solution and extracted with ether.
The combined organic layers were washed with water and brine,
dried, and concentrated in vacuo. The residue was purified as
indicated above to give 10 (0.36 g, 90%) as a colorless oil.
(Z)-3-[9-(Tet r a h yd r o-2-p yr a n yloxy)n on -3-en -1-yl]p yr i-
d in e (12). To a stirred suspension of phosphonium salt10 11 (23.4
g, 50.5 mmol) and 18-crown-6 (0.9 g, 3.4 mmol) in THF (60 mL)
was added a solution of potassium tert-butylate (8.5 g, 75.8
mmol) in THF (60 mL) dropwise under a nitrogen atmosphere
at 0 °C. After 30 min at 0 °C, the solution was cooled to -78 °C
and aldehyde 10 (6.75 g, 33.7 mmol) in THF (30 mL) was added
over a period of 30 min. After 30 min, the cooling bath was
Exp er im en ta l Section
Gen er a l. Compounds 9 and 19 were prepared according to
literature procedures8,19,20 from the corresponding diols. Com-
mercial reagent grade solvents and chemicals were used as
obtained except as indicated below. DMPU (absolute, puriss. over
molecular sieve) was purchased from Fluka and DMSO (dried)
from Merck. THF was distilled from sodium benzophenone ketyl.
Pyridine and Et3N were stored over KOH pellets. Prior to use
in Swern oxidation, CH2Cl2 was distilled from P2O5. Petroleum
ether refers to the 40-60 °C boiling fraction. Solvents used for
column chromatography were distilled prior to use. All metal-
lorganic reactions were run in flame-dried glassware under
nitrogen. Organic extracts were dried over anhydrous Na2SO4.
For thin-layer chromatography (TLC) analysis, precoated TLC
plates (Merck Kieselgel 60 F254 and Merck aluminum oxide 60
F254 neutral) were used, and column chromatography was done
(18) For a recent example and references for the preparation of
pyridinium salts from acyclic starting materials, see: Yu, L.-B.; Chen,
D.; Li, J .; Ramirez, J .; Wang, P. G. J . Org. Chem. 1997, 62, 208-211.
(19) Kang, S.-K.; Kim, W.-S.; Moon, B.-H. Synthesis 1985, 1161-
1162.
(20) Chapman, O. L.; Mattes, K. C.; Sheridan, R. S.; Klun, J . A. J .
Am. Chem. Soc. 1978, 100, 4878-4884.

Notes
J . Org. Chem., Vol. 64, No. 10, 1999 3781
removed and the mixture was stirred for additional 2 h. The
reaction was quenched with water (100 mL), the layers were
separated, and the aqueous phase was extracted with EtOAc.
The combined organic layers were washed with water and brine,
dried, and concentrated in vacuo. The residue was purified by
column chromatography (SiO2, ether) to afford 12 (7.3 g, 81%)
J ) 7.8, 2.2, 1.7 Hz, 1 H), 7.20 (ddd, J ) 7.8, 4.8, 0.8 Hz, 1 H),
5.67 (t, J ) 7.1 Hz, 0.1 H), 5.48 (t, J ) 7.1 Hz, 0.9 H), 5.37 (m,
2 H), 4.92 (s, 1 H), 5.03 (t, J ) 4.4 Hz, 0.9 H), 4.89 (t, J ) 4.4
Hz, 0.1 H), 3.81-4.04 (m, 4 H), 3.33 (s, 5.4 H), 3.27 (s, 0.6 H),
2.66 (t, J ) 7.8 Hz, 2 H), 2.54 (m, 2 H), 2.35 (m, 2 H), 1.84-2.09
(m, 4 H), 1.19-1.49 (m, 7 H). 13C NMR (CDCl3): δ 149.6, 146.8,
139.5, 137.5, 136.3, 131.5, 127.6, 123.2, 122.7, 104.0, 103.2, 64.9
(2C), 54.2 (2C), 33.1, 32.5, 31.3, 29.5, 29.2, 29.0, 28.7 (2C), 27.3.
11-(Tetr a h yd r o-2-p yr a n yloxy)u n d ec-2-yn -1-ol (20). In a
three-necked flask with a mechanical stirrer, a solution of
2-propyn-1-ol (1.12 g, 20 mmol) in THF (75 mL) was cooled to
-78 °C under a nitrogen atmosphere. n-BuLi (25 mL, 40 mmol,
1.6 M in hexane) was slowly added. After addition was complete,
the temperature was allowed to rise to -30 °C. After 45 min at
this temperature, a solution of 19 (2.93 g, 10 mmol) in DMPU
(40 mL) and THF (30 mL) was added. The cooling bath was
removed, and stirring was continued for an additional 16 h.
Water (100 mL) was added, the layers were separated, and the
aqueous layer was extracted with EtOAc. The combined organic
layers were washed with water and brine, dried, and concen-
trated in vacuo. The residue was purified by column chroma-
tography (SiO2, petroleum ether/EtOAc 7/3) to give 20 (1.35 g,
47%) as a colorless oil. Analytical data were in agreement with
the reported data.21
as pale yellow oil. IR (film): 3006, 2938, 2860 cm-1 1H NMR
.
(CDCl3): δ 8.44 (br s, 1H), 8.42 (dd, J ) 4.9, 1.7 Hz, 1 H), 7.48
(ddd, J ) 7.7, 2.2, 1.7 Hz, 1 H), 7.18 (ddd, J ) 7.7, 4.8, 0.8 Hz,
1 H), 5.38 (m, 2 H), 4.57 (m, 1 H), 3.80-3.92 (m, 1 H), 3.65-
3.78 (m, 1 H), 3.43-3.55 (m, 1 H), 3.30-3.42 (m, 1 H), 2.66 (t, J
) 7.6 Hz, 2 H), 2.35 (dt, J ) 7.1, 7.0 Hz, 2 H), 1.20-2.02 (m, 14
H). 13C NMR (CDCl3): δ 150.1, 147.3, 137.2, 135.8, 131.2, 127.9,
123.1, 98.9, 67.5, 62.3, 33.0, 30.8, 29.6, 29.4, 28.7, 27.2, 25.9,
25.5, 19.7.
(Z)-9-(3-P yr id yl)n on -6-en -1-ol (13). To a stirred solution of
12 (1.9 g, 6.3 mmol) in methanol (35 mL) was added TsOH (1.24
g, 6.5 mmol). Stirring was continued for 4 h. A saturated
NaHCO3 solution (45 mL) and water (90 mL) were added, and
the mixture was extracted with EtOAc. The combined organic
phases were washed with a saturated NaHCO3 solution and
brine, dried, and concentrated in vacuo. The residue was purified
by column chromatography (SiO2, CH2Cl2/methanol 9/1) to afford
13 (1.16 g, 84%) as pale yellow oil. IR (film): 3315 cm-1. 1H NMR
(CDCl3): δ 8.44 (d, J ) 2.2 Hz, 1 H), 8.42 (dd, J ) 4.8, 1.7 Hz,
1 H), 7.49 (ddd, J ) 7.7, 2.2, 1.7 Hz, 1 H), 7.19 (ddd, J ) 7.7,
4.8, 0.8 Hz, 1 H), 5.29-5.47 (m, 2 H), 3.61 (t, J ) 6.6 Hz, 2 H),
2.67 (t, J ) 7.5 Hz, 2 H), 2.36 (dt, J ) 7.5. 6.7 Hz, 2 H), 1.83-
2.13 (m, 3 H), 1.44-1.62 (m, 2 H), 1.17-1.37 (m, 4 H). 13C NMR
(CDCl3): δ 149.9, 147.2, 137.2, 136.1, 131.2, 127.9, 123.2, 62.6,
33.0, 32.7, 29.3, 28.6, 27.1, 25.4. Anal. Calcd for C14H21NO: C,
76.67; H, 9.65; N, 6.39. Found: C, 76.23; H, 9.65; N, 6.39.
(Z)-1,1-Dim eth oxy-12-(3-p yr id yl)d od ec-9-en -2-on e (16).
Alcohol 13 (1.06 g, 5.0 mmol) was dissolved in pyridine (15 mL)
and cooled to -10 °C, and p-toluenesulfonyl chloride (1.05 g, 5.5
mmol) was added. After 15 min, the cooling bath was removed
and the mixture stirred for 2 h at room temperature. Water (20
mL) and a saturated NaHCO3 solution (2 mL) were added, and
the solution was extracted with ether. The combined organic
layers were washed with water and brine, dried, and concen-
trated in vacuo. The unstable product 14 was used immediately
for the following reaction without further purification.
1-Br om o-11-(tetr a h yd r o-2-p yr a n yloxy)u n d ec-2-yn e (21).
A stirred solution of 20 (7.0 g, 26.1 mmol) and CBr4 (13.0 g, 39.1
mmol) in DMF (90 mL) was cooled to 0 °C. PPh3 (10.3 g, 39.1
mmol) was added in one portion, and the mixture was stirred
for 25 min at 0 °C. A half-saturated NaHCO3 solution (80 mL)
was added, and the mixture was extracted with petroleum ether.
The combined organic layers were washed with water and brine,
dried, and concentrated in vacuo. The residue was purified by
column chromatography (SiO2, petroleum ether/EtOAc 9/1) to
give 21 (7.90 g, 91%) as a colorless oil. IR (film): 2312, 2234
cm-1 1H NMR (CDCl3): δ 4.53-4.62 (m, 1 H), 3.93 (t, J ) 2.4
.
Hz, 2 H), 3.81-3.98 (m, 1 H), 3.67-3.79 (m, 1 H), 3.44-3.56
(m, 1 H), 3.32-3.44 (m, 1 H), 2.16-2.29 (m, 2 H), 1.20-1.93 (m,
18 H). 13C NMR (CDCl3): δ 98.8, 88.3, 75.3, 67.6, 62.3, 30.8,
29.7, 29.3, 29.0, 28.7, 28.3, 26.2, 25.5, 19.7, 18.9, 15.6.
Meth yl 2-(3,3-Dim eth oxyp r op yl)-13-(tetr a h yd r o-2-p yr a -
n yloxy)tr id ec-4-yn oa te (23). A solution of diisopropylamine
(4.8 g, 47.0 mmol) in THF (100 mL) was cooled to -78 °C, and
n-BuLi (25 mL, 40 mmol, 1.6 M in hexane) was added slowly.
After 30 min at -78 °C, 22 (4.46 g, 25.3 mmol) in THF (20 mL)
was added dropwise and the solution was stirred for additional
30 min. 21 in DMPU (50 mL) was added, and after 1 h the
cooling bath was removed. After 16 h water (100 mL) was added,
the layers were separated, and the aqueous layer was extracted
with EtOAc. The combined organic layers were washed with
water and brine, dried, and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, petroleum ether/
EtOAc 8/2) to give 23 (5.14 g, 47%) as a colorless oil. IR (film):
A solution of diisopropylamine (3.04 g, 30 mmol) in THF (50
mL) was cooled to -78 °C, and n-BuLi (15.6 mL, 25 mmol, 1.6
M in hexane) was added dropwise. After 30 min at -78 °C,
imine11 15 (4.98 g, 25 mmol) in DMPU (5 mL) was added, and
the solution was stirred for 1 h at -78 °C. Then tosylate 14 (5.0
mmol, crude) in THF (15 mL) was added. After 2 h, the cooling
bath was removed and stirring was continued for 16 h at room
temperature. The reaction was quenched with water (50 mL),
the layers were separated, and the aqueous phase was extracted
with EtOAc. The combined organic phases were washed with
water and brine, dried, and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, EtOAc) to afford
16 (1.12 g, 70% from 13) as a pale yellow oil. IR (film): 1728
cm-1. 1H NMR (CDCl3): δ 8.44 (br d, J ) 2.2 Hz, 1 H), 8.42 (dd,
J ) 4.8, 1.7 Hz, 1 H), 7.49 (ddd, J ) 7.8, 2.2, 1.7 Hz, 1 H), 7.19
(ddd, J ) 7.8, 4.8, 0.8 Hz, 1 H), 5.37 (m, 2 H), 4.45 (s, 1 H), 3.40
(s, 6 H), 2.65 (t, J ) 7.6 Hz, 2 H), 2.53 (t, J ) 7.3 Hz, 2 H), 2.34
(m, 2 H), 1.91 (m, 2 H), 1.55 (m, 2 H), 1.24 (br s, 6 H).13C NMR
(CDCl3): δ 205.6, 150.1, 147.3, 137.2, 135.8, 131.2, 127.8, 123.1,
104.3, 54.7 (2 C), 37.2, 33.0, 29.3, 29.0, 28.9, 28.7, 27.1, 22.9.
(3Z)-3-[11-Dim eth oxym eth yl-13-(1,3-dioxolan -2-yl)tr idec-
3,11-d ien -1-yl]p yr id in e (17). Phosphonium salt 5 (7.27 g, 16.4
mmol) was suspended in THF (100 mL) and cooled to -20 °C.
n-BuLi (11.0 mL, 17.6 mmol, 1.6 M in hexane) was added
dropwise, and the solution was stirred for 1 h at -20 °C. Then
the reaction was cooled to -78 °C and ketone 16 (1.12 g, 3.51
mmol) in THF (15 mL) was added dropwise. The solution was
allowed to reach room temperature over a period of 16 h. Water
(150 mL) was added, the layers were separated, and the aqueous
phase was extracted with EtOAc. The combined organic layers
were washed with water and brine, dried, and concentrated in
vacuo. The residue was purified by column chromatography
(SiO2, ether) to afford 17 (0.88 g, 63%, E/Z-mixture 9:1) as pale
1
1740 cm-1. H NMR (CDCl3): δ 4.53-4.62 (m, 1 H), 4.32-4.41
(m, 1 H), 3.81-3.94 (m, 1 H), 3.65-3.79 (m, 1 H), 3.69 (s, 2.7 H,
major diastereomer) and 3.67 (s, 0.3 H, minor diastereomer),
3.44-3.56 (m, 1 H), 3.26-3.44 (m, 1 H), 3.32 (minor diastere-
omer, s, 0.6 H) and 3.30 (major diastereomer, d, J ) 2.0 Hz, 5.4
H), 2.49-2.61 (m, 1 H), 2.29-2.47 (m, 2 H), 2.07-2.16 (m, 2 H),
1.22-1.89 (m, 22 H). 13C NMR (CDCl3): δ 174.9, 104.2, 98.8,
67.6, 62.3, 52.8, 52.5, 51.6, 44.7, 33.7, 31.9, 30.8, 30.0, 29.7, 29.3,
29.1, 28.9, 28.7, 26.2 (2C), 25.5, 21.7, 19.7, 18.7.
2-(3,3-Dim eth oxyp r op yl)-13-(tetr a h yd r o-2-p yr a n yloxy)-
tr id ec-4-yn -1-ol (24). A stirred suspension of LiAlH4 (0.89 g,
23.4 mmol) in THF (65 mL) was cooled to 0 °C. Ester 23 (5.01 g,
11.74 mmol) in THF (30 mL) was added slowly at this temper-
ature, and the mixture was stirred for an additional 3 h at room
temperature. Then water (32.5 mL) was added dropwise to
quench the reaction upon which a white solid precipitated. The
solution was decanted, and the solid was extracted with ether
(3 × 100 mL). The combined organic phases were washed with
water and brine, dried, and concentrated in vacuo. The residue
was purified by column chromatography (SiO2, petroleum ether/
EtOAc 1/1) to afford 24 (3.42 g, 73%) as pale yellow oil. IR
1
yellow oil. IR (film): 2929, 2857 cm-1. H NMR (CDCl3): δ 8.44
(21) Poulain, S.; Noiret, N.; Nugier-Chauvin, C.; Patin, H. Liebigs
Ann./ Recl. 1997, 35-40.
(br d, J ) 2.2 Hz, 1 H), 8.43 (dd, J ) 4.8, 1.7 Hz, 1 H), 7.50 (ddd,

3782 J . Org. Chem., Vol. 64, No. 10, 1999
(film): 3450, 2362 cm-1 1H NMR (CDCl3): δ 4.54-4.60 (m, 1
H), 4.35 (t, J ) 5.1 Hz, 1 H), 3.81-3.93 (m, 1 H), 3.58-3.79 (m,
1 H), 3.64 (d, 2 H), 3.26-3.56 (m, 2 H), 3.32 (s, 6 H), 2.20-2.31
(m, 2 H), 2.07-2.20 (m, 2 H), 1.20-1.91 (m, 23 H). 13C NMR
(CDCl3): δ 104.7, 98.8, 67.6, 62.3, 55.5, 54.5, 35.1, 34.3, 30.8,
29.7, 29.6, 29.3, 29.1, 29.0 (2C), 28.8, 26.2, 26.1, 25.5, 24.2, 22.1,
19.7, 18.7. Anal. Calcd for C23H42O5: C, 69.31; H, 10.62. Found:
C, 69.31; H, 10.51.
Notes
.
(200 mL) and extracted with ether. The combined organic phases
were washed with water and brine, dried, and evaporated in
vacuo. The residue was immediately dissolved in DMF (20 mL),
NaN3 (1.5 g, 23.1 mmol) was added, and the solution was stirred
for 16 h at 70 °C. Then water (200 mL) was added, and the
solution was extracted with petroleum ether. The combined
organic layers were washed with water and brine, dried, and
concentrated in vacuo. The residue was purified by column
chromatography (SiO2, EtOAc) to afford 29 (470 mg, 73%) as a
colorless oil. IR (film): 2095 cm-1. 1H NMR (CDCl3): δ 8.40 (dd,
J ) 2.3, 0.7 Hz, 1 H), 8.37 (dd, J ) 4.8, 1.7 Hz, 1 H), 7.42 (ddd,
J ) 7.8, 2.3, 1.7 Hz, 1 H), 7.13 (ddd, J ) 7.8, 4.8, 0.7 Hz, 1 H),
5.37-5.58 (m, 2 H), 3.19 (d, J ) 5.9 Hz, 2 H), 3.33 (t, J ) 6.9
Hz, 2 H), 2.01-2.15 (m, 2 H), 1.42-1.61 (m, 2 H), 1.17-1.42
(m, 10 H). 13C NMR (CDCl3): δ 149.9, 147.3, 136.4, 135.6, 131.9,
126.6, 123.2, 51.4, 30.7, 29.4, 29.3, 29.1, 29.0, 28.8, 27.2, 26.6.
(Z)-2-(3,3-Dim et h oxyp r op yl)-13-(t et r a h yd r o-2-p yr a n yl-
oxy)tr id ec-4-en -1-ol (25). Methanol (50 mL), quinoline (200
µL), Lindlar catalyst (250 mg, Fluka), and 24 (500 mg, 1.25
mmol) were placed in a hydrogenation flask and hydrogenated
for 15 min at atmospheric pressure. The mixture was filtered,
and the filtrate was concentrated in vacuo to afford 25 as a pale
yellow oil in quantitative yield. The crude product was used for
the subsequent reaction without further purification. An ana-
lytical sample was prepared by column chromatography (Al2O3,
petroleum ether/ether gradient (0% ether-100% ether). IR
(film): 3454 cm-1. 1H NMR (CDCl3): δ 5.29-5.53 (m, 2 H), 4.53-
4.63 (m, 1 H), 4.33 (t, J ) 5.1 Hz, 1 H), 3.81-3.94 (m, 1 H),
3.65-3.79 (m, 1 H), 3.22-3.63 (m, 4 H), 3.30 (s, 6 H), 1.20-2.24
(m, 27 H). 13C NMR (CDCl3): δ 131.6, 126.5, 105.0, 98.9, 67.7,
65.4, 62.4, 52.8, 41.0, 32.6, 30.8, 30.0, 29.8, 29.6, 29.43, 29.41,
29.2, 29.0, 27.3, 26.2, 25.7, 25.5, 19.7. Anal. Calcd for C23H44O5:
C, 68.96; H, 11.07. Found: C, 68.83; H, 11.09.
(Z)-2-(3,3-Dim et h oxyp r op yl)-13-(t et r a h yd r o-2-p yr a n yl-
oxy)tr id ec-4-en -1-a l (26). A solution of oxalyl chloride (228 mg,
1.8 mmol) in dry CH2Cl2 (2 mL) was cooled to -78 °C, and a
solution of DMSO (281 mg, 3.6 mmol) in dry CH2Cl2 (0.5 mL)
was added dropwise under a nitrogen atmosphere. After 30 min
alcohol 25 (600 mg, 1.5 mmol) in dry CH2Cl2 (0.5 mL) was added
slowly and the mixture was stirred for an additional 30 min.
Et3N (1.05 mL) was added, and the cooling bath was removed.
After the reaction mixture reached room temperature, water (3
mL) was added and the solution was extracted with CH2Cl2. The
combined organic layers were washed with water and brine,
dried, and concentrated in vacuo. The residue was purified by
column chromatography (SiO2, petroleum ether/EtOAc 7/3) to
give 26 (480 mg, 80% from 24) as a pale yellow oil. IR (film):
1726 cm-1. 1H NMR (CDCl3): δ 9.61 (d, J ) 2.0 Hz, 1 H), 5.39-
5.55 (m, 1 H), 5.23-5.37 (m, 1 H), 4.53-4.62 (m, 1 H), 4.34 (t, J
) 5.3 Hz, 1 H), 3.81-3.94 (m, 1 H), 3.66-3.79 (m, 1 H), 3.44-
3.56 (m, 1 H), 3.33-3.44 (m, 1 H), 3.31 (s, 6 H), 2.15-2.46 (m,
3 H), 1.93-2.09 (m, 2 H), 1.21-1.87 (m, 22 H).13C NMR
(CDCl3): δ 204.3, 132.6, 125.2, 104.4, 98.8, 67.6, 62.3, 52.9, 52.8,
51.6, 30.8, 30.0, 29.9, 29.5, 29.42, 29.39, 29.2, 27.3, 26.7, 26.2,
25.5, 23.3, 19.7. Anal. Calcd for C23H42O5: C, 69.31; H, 10.62.
Found: C, 69.06; H, 10.61.
(Z)-11-(3-P yr id yl)u n d ec-9-en -1-ol (27). NH2OH‚HCl (770
mg, 11.0 mmol) was added to a solution of aldehyde 26 (880 mg,
2.21 mmol) in 99% EtOH (20 mL), and the mixture was refluxed
for 60 min. After the red solution reached room temperature,
water (70 mL) and ether (70 mL) were added and the solution
was basified with 2 N NaOH. The layers were separated, and
the aqueous layer was extracted with ether. The combined
organic layers were washed with water and brine, dried, and
concentrated in vacuo. The residue was purified by column
chromatography (SiO2, EtOAc) to afford 27 (290 mg, 54%) as a
colorless oil. IR (film): 3331 cm-1. 1H NMR (CDCl3): δ 8.42 (dd,
J ) 2.3, 0.8 Hz, 1 H), 8.40 (dd, J ) 4.8, 1.7 Hz, 1 H), 7.48 (ddd,
J ) 7.8, 2.3, 1.7 Hz, 1 H), 7.19 (ddd, J ) 7.8, 4.8, 0.8 Hz, 1 H),
5.44-5.64 (m, 2 H), 3.61 (t, J ) 6.6 Hz, 2 H), 3.37 (d, J ) 6.1
Hz, 2 H), 2.49 (br s, 1 H), 2.06-2.21 (m, 2 H), 1.16-1.63 (m, 12
H). 13C NMR (CDCl3): δ 149.7, 147.2, 136.6, 135.8, 132.1, 126.5,
123.3, 62.8, 32.8, 30.7, 29.5, 29.4, 29.3, 29.1, 27.2, 25.7.
(Z)-3-(11-Azid ou n d ec-2-en -1-yl)p yr id in e (29). A solution
of p-toluenesulfonyl chloride (2.0 g, 10.4 mmol) in pyridine (10
mL) was cooled to 0 °C, and alcohol 27 (580 mg, 2.36 mmol) in
pyridine (3.4 mL) was added dropwise. The solution was stirred
for 1 h at room temperature and cooled to 0 °C, and water (2
mL) was added. After 5 min the solution was diluted with water
(Z)-11-(3-P yr id yl)u n d ec-9-en -1-a m in e Dih yd r och lor id e
(4a ). PPh3 (670 mg, 2.54 mmol) was added to a solution of azide
29 (470 mg, 1.72 mmol) in pyridine (1.6 mL) at 0 °C and was
stirred for 24 h at room temperature. The solution was then
cooled to 0 °C, concentrated NH3 (430 µL) was added, and the
solution was stirred for another 24 h at room temperature.
Pyridine was evaporated and the residue mixed with 2 N HCl
(10.2 mL). The mixture was extracted with ether (4 × 15 mL).
The aqueous phase was concentrated in vacuo to afford 4a (517
mg, 94%) as a pale yellow oil. IR (film): 3384 cm-1 1H NMR
.
(CD3OD): δ 8.73 (br s, 2 H), 8.52 (br d, J ) 8.3 Hz, 1 H), 8.05
(dd, J ) 8.3, 6.1 Hz, 1 H), 5.54-5.78 (m, 2 H), 3.70 (br d, J )
7.1 Hz, 2 H), 2.91 (t, J ) 7.6 Hz, 2 H), 2.12-2.25 (m, 2 H), 1.60-
1.69 (m, 2 H), 1.29-1.37 (m, 10 H). 13C NMR (CD3OD): δ 148.2,
142.8, 141.9, 140.4, 135.4, 128.5, 125.4, 40.9, 31.1, 30.5, 30.3,
30.2, 30.1, 28.5, 28.3, 27.5.
Nip h a toxin B (2). 17 (72 mg, 0.18 mmol) was dissolved in
CH2Cl2 (2 mL), FeCl3/SiO2 catalyst (30 mg) was added, and the
mixture was stirred for 5 min. Dihydrochloride 4a (83 mg, 0.26
mmol) in methanol (0.6 mL) was added, and stirring was
continued for 30 min. n-BuOH (3 mL) was added, and CH2Cl2
was removed in vacuo. Et3N (100 µL) was added, and the
solution was refluxed for 16 h. The solvents were evaporated in
vacuo, and the residue was purified by column chromatography
(SiO2, gradient CH2Cl2/methanol: 0-10% methanol) to afford
2 (45 mg, 45%) as a light brown oil. IR (film): 3010, 2929, 2856,
1632, 1592, 1576, 1507, 1478, 1466, 1424, 1328, 1241, 1192,
1160, 1104, 1044, 1028, 834, 799, 718, 695, 523 cm-1.1H NMR
(CD3OD): δ 8.94 (br s, 1 H), 8.85 (br d, J ) 6.0 Hz, 1 H), 8.46
(br d, J ) 8.2 Hz, 1 H), 8.30-8.41 (m, 4 H), 8.02 (dd, J ) 7.9,
6.1 Hz, 1 H), 7.63-7.73 (m, 2 H), 7.31-7.39 (m, 2 H), 5.47-5.63
(m, 2 H), 5.30-5.44 (m, 2 H), 4.61 (t, J ) 7.5 Hz, 2 H), 3.40-
3.47 (m, 2 H), 2.87 (t, J ) 7.8 Hz, 2 H), 2.70 (t, J ) 7.2 Hz, 2 H),
2.31-2.43 (m, 2 H), 2.12-2.23 (m, 2 H), 1.84-2.08 (m, 4 H),
1.61-1.77 (m, 2 H), 1.13-1.48 (m, 16 H). 1H NMR (CDCl3): δ
9.43 (d, J ) 5.7 Hz, 1 H), 9.23 (s, 1 H), 8.43 (br s, 4 H), 8.21 (d,
J ) 7.8 Hz, 1 H), 7.97-8.10 (m, 1 H), 7.46-7.55 (m, 2 H), 7.16-
7.27 (m, 2 H), 5.45-5.61 (m, 2 H), 5.27-5.45 (m, 2 H), 5.00 (t, J
) 7.1 Hz, 2 H), 3.39 (d, J ) 6.0 Hz, 2 H), 2.87 (t, J ) 7.2 Hz, 2
H), 2.67 (t, J ) 7.2 Hz, 2 H), 1.11-2.53 (m, 26 H). 13C NMR
(CD3OD): δ 150.26, 149.97, 147.65, 147.56, 146.67, 145.83,
145.25, 143.37, 139.57, 138.97, 138.48, 138.13, 133.10, 132.20,
129.05 (2 C), 127.81, 125.20, 125.05, 63.02, 33.79, 33.55, 32.47,
31.46, 31.45, 30.57, 30.49, 30.33, 30.17, 30.03, 29.99, 29.94, 29.74,
28.17, 28.07, 27.17. FAB MS, m/z (%): 524 (100) [M+], 431 (9),
391 (7), 349 (7), 335 (15), 295 (15), 230 (15), 160 (8), 146 (13),
132 (20), 106 (28).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra for
compounds 2, 4a , 7, 8, 12, 16, 17, 21, 23, 27, and 29 and for
the dimethylation product of 2. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O9825299