The application of vinylogous iminium salt derivatives to the synthesis of Ningalin B hexamethyl ether

Article abstract of DOI:10.1016/S0040-4020(02)01475-8

A vinylogous iminium salt derivative has been used to prepare a 2,3,4-trisubstituted pyrrole synthon in a regioselective, efficient and convenient manner. This pyrrole synthon was subsequently converted to the multidrug-resistant (MDR) reversal agent, Ningalin B hexamethyl ether, via alkylation, hydrolysis and oxidative lactonization steps. This methodology provides an alternative pathway to this important class of pyrrole containing marine natural products.

Full text of DOI:10.1016/S0040-4020(02)01475-8

Tetrahedron 59 (2003) 207–215
The application of vinylogous iminium salt derivatives to the
synthesis of Ningalin B hexamethyl ether
a
a
a
a
John T. Gupton,a Stuart C. Clough, Robert B. Miller, John R. Lukens, Charlotte A. Henry,
,
*
a
Rene P. F. Kanters and James A. Sikorski
b
´
aDepartment of Chemistry, University of Richmond, Richmond, VA 23173, USA
bAtheroGenics Inc., 8995 Westside Parkway, Alpharetta, GA 30004, USA
Received 12 September 2002; accepted 8 November 2002
Abstract—A vinylogous iminium salt derivative has been used to prepare a 2,3,4-trisubstituted pyrrole synthon in a regioselective, efficient
and convenient manner. This pyrrole synthon was subsequently converted to the multidrug-resistant (MDR) reversal agent, Ningalin B
hexamethyl ether, via alkylation, hydrolysis and oxidative lactonization steps. This methodology provides an alternative pathway to this
important class of pyrrole containing marine natural products. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
has applied a very elegant biomimetic approach to the
synthesis of Lamellarin G trimethyl ether which creates the
key pyrrole synthon by reaction of a primary amine with a
symmetrical 1,4-diketone. Banwell has used several
approaches which involve both intermolecular and intra-
molecular cross-coupling reactions as well as the cycliza-
tion of azomethine ylids. Azomethine ylid cyclization has
also been employed by Ishibashi in his synthesis of
Lamellarin D and H.
The isolation1 and synthesis of pyrrole-containing marine
natural products and related derivatives continues to be a
very active area of research given the interesting bioactivity
exhibited by such compounds (Fig. 1).
The Boger research group has recently completed2 an
efficient and versatile total synthesis of Ningalin B and
related derivatives by application of the their well
established heterocyclic azadiene Diels–Alder/retrograde
Diels–Alder methodology which provides for the construc-
tion of a 4,5-diaryl-1,2-diazine-3,6-dicarboxylic acid ester.
This diazine is then subjected to a reductive ring contraction
to yield a 3,4-diarylpyrrole-2,5-dicarboxylic acid ester
which becomes the key synthon for the construction of
Ningalin B (Scheme 1).
Much of the interest in such alkaloids arises from their
observed cytotoxicity against various cancer cell lines and
more importantly from their ability to act as multidrug-
resistant (MDR) reversal agents2 at non-cytotoxic concen-
trations thereby allowing many standard chemotherapeutic
agents to be used in concert, and in potentially lower
concentrations. The MDR activity is thought to be due to the
action of such compounds on P-glycoprotein efflux pumps9
which function at the cellular level. As part of a QSAR
study2 undertaken by Boger and colleagues, Ningalin B
hexamethyl ether was found to have good MDR activity
when used in conjunction with vinblastine or doxorubicin as
compared to the use of verapamil, which is a standard MDR
reversal agent.
This same strategy has also been used by the Boger group3
for the efficient preparation of other members of this class of
alkaloids such as Ningalin A, Lamellarin O, Lukianol A and
Permethyl Storniamide. Alternative approaches to the
synthesis of Lamellarin and Lukianol alkaloids have been
developed by Furstner4 (Scheme 2), Banwell5 (Scheme 3),
Steglich,6 Ishibashi7 and Wong.8 Furstner has utilized a
titanium mediated, intramolecular cyclization of a 1,5-
dicarbonyl compound as a key step for pyrrole synthesis,
whereas Wong has utilized silylated pyrroles as building
blocks for subsequent cross-coupling chemistry. Steglich
For some years, our research group has been interested in
utilizing vinylogous iminium salt derivatives10 as key
intermediates for the regioselective synthesis of hetero-
cyclic compounds in general and highly functionalized
pyrroles in particular. We have also previously reported11 an
efficient, relay synthesis of Lukianol A and related
compounds by such methodology and now report extending
this methodology to a convenient and efficient synthesis of
Ningalin B hexamethyl ether.
Keywords: chloropropeniminium salt; b-chloroenal; trisubstituted pyrrole;
Ningalin B.
*
Corresponding author. Tel.: þ1-804-287-6498; fax: þ1-804-287-1897;
e-mail: jgupton@richmond.edu
0040–4020/03/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01475-8

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J. T. Gupton et al. / Tetrahedron 59 (2003) 207–215
Figure 1.
Scheme 1.

J. T. Gupton et al. / Tetrahedron 59 (2003) 207–215
209
Scheme 2.
Scheme 3.

210
J. T. Gupton et al. / Tetrahedron 59 (2003) 207–215
Scheme 4.
2. Results and discussion
Scheme 4. The starting ketone (desoxyveratroin, 18) has
been previously prepared,12 used in a variety of appli-
cations, and is readily available by reaction of 1,2-
dimethoxybenzene (veratrole) with 3,4-dimethoxyphenyl-
acetyl chloride under Friedel–Crafts conditions.
Our strategy for the synthesis of Ningalin B hexamethyl
ether (32) relies on the regioselective preparation of
2-carbomethoxy-3,4-diarylpyrroles (22) as outlined in
Figure 2.

J. T. Gupton et al. / Tetrahedron 59 (2003) 207–215
211
Scheme 5.
Desoxyveratroin (18) is then refluxed with N,N-dimethyl-
formamide dimethyl acetal in dimethylformamide
to produce the corresponding vinylogous amide (19)
very cleanly in 78% isolated yield. This compound
has been previously prepared by Dominguez and
co-workers13 in a similar fashion. The vinylogous
amide was subsequently treated with phosphorous
oxychloride in refluxing methylene chloride followed
by water/THF in which case an initial crop of
analytically pure E-b-chloroenal (21a) was obtained in
41% yield after dilution of the reaction mixture with
additional water. Subsequent crystallization from the
mother liquor produced a 14% yield of the Z-b-chloroenal
(21b), Fig. 2.
Scheme 6.

212
J. T. Gupton et al. / Tetrahedron 59 (2003) 207–215
Scheme 7.
The E and Z b-chloroenals (21a and 21b, respectively) are
easily differentiated from each other in the proton NMR
spectrum by virtue of a larger downfield shift (,1 ppm) of
the aldehyde proton when it is cis to the chloro group as in
21b as opposed to being cis to the aromatic ring as in 21a.
Alternatively, if the crude aqueous reaction mixture is
subjected to an extractive workup with ethyl acetate, a
quantitative yield of E- and Z-b-chloroenals is obtained with
a 4:1 ratio of E/Z isomers. Elliot and co-workers14 have
reported the preparation of the E-b-chloroenal (21a) (59%
yield) directly from desoxyveratroin by reaction under
Vilsmeier conditions (DMF/phosphorous oxychloride).
This transformation is reported to be very temperature
sensitive and can give several different products depending
on the reaction conditions (Scheme 5). The E-b-chloroenal
(21a) represents an interesting substrate and we have treated
this compound with trifluoroacetic acid at room temperature
for 3 h in methylene chloride in which case an 86% yield of
analytically pure indenol (24) was obtained. This reaction
further confirms the stereochemical assignment of the E-b-
chloroenal (21a) and suggests that this substance may well
be a useful synthon for a variety of indene targets as has
been suggested by Elliot and co-workers.14 In addition, the
E-b-chloroenal (21a) has been the subject of a patent for use
as an antiviral agent.15
In previous work10 we have reacted glycinate ester
hydrochlorides with analogous b-chloroenals in refluxing
DMF with and without bases (sodium hydride being the
base of choice). The reaction is thought to proceed in the
manner depicted in Scheme 6.
Refluxing a mixture of E-b-chloroenal (21a) with glycine
methyl ester hydrochloride in DMF produced the expected
2,3,4-trisubstituted pyrrole (22) (Scheme 4) but after
evaluating a variety of solvents with and without bases,
the combination of toluene and DABCO was found to give
the best yields (.90%) and purity of the desired material. In
the past10 we have used mixtures of E- and Z-b-chloroenals
for such pyrrole-forming reactions in which case somewhat

J. T. Gupton et al. / Tetrahedron 59 (2003) 207–215
213
lower yields of the desired 2,3,4-trisubstituted pyrroles were
always obtained. Reaction of the pure Z-b-chloroenal (21b)
with glycine methyl ester hydrochloride under similar
conditions produced a gross mixture of products suggesting
that for the disubstituted b-chloroenals (25), the E isomer is
uniquely preferred for pyrrole formation. In should also be
noted that previous work10 in our laboratory had established
the regioselective nature of such pyrrole-forming reactions
and that the 2,3,4-trisubstituted pyrrole was always
produced as the major regioisomer. The overall efficiency
of the reaction sequence illustrated in Scheme 4 allowed for
the preparation of multigram quantities of the key pyrrole
synthon (22). With the requisite 2,3,4-trisubstituted pyrrole
(22) in hand, the following reaction sequence (Scheme 7)
was carried out to complete the synthesis of Ningalin B
hexamethyl ether.
employed in this methodology are very amenable to scale up
so that multigram quantities of analogs could be efficiently
obtained. Given that such substances exhibit the ability to
act as MDR reversal agents at non-cytotoxic concentrations,
our synthetic approach should complement those currently
available for the synthesis of this important class of
bioactive agents.
4. Experimental
4.1. General18
All chemicals were used as received from the manufacturer
(Aldrich Chemicals and Fisher Scientific) and all reactions
were carried out under a nitrogen atmosphere. All solvents
˚
were dried over 4 A molecular sieves prior to their use.
The pyrrole synthon (22) was alkylated by a procedure
similar to that developed by Boger and co-workers2 with the
exception that sodium hydride/DMF was used along with
the mesylate ester of 20-(3,4-dimethoxyphenyl)ethanol. A
71% yield of the N-phenethylpyrrole (30) was obtained after
chromatographic purification. An excess of the mesylate
ester was used in this reaction to minimize the competing
elimination to the corresponding styrene. The N-phenethyl-
pyrrole (30) was then subjected to basic hydrolysis with
sodium hydroxide in aqueous ethanol producing the
respective carboxylic acid (31) in 90% yield and in an
analytically pure form. It was anticipated that the last step in
the sequence could be accomplished by using lead
tetraacetate (LTA) oxidation conditions, which had been
developed by Steglich and co-workers6 for a similar
transformation in the preparation of Lamellarin G trimethyl
ether. When the pyrrole carboxylic acid was heated with
LTA in refluxing ethyl acetate, a 52% yield of Ningalin B
hexamethyl ether (32) was obtained.16 The Ningalin B
hexamethyl ether prepared by our methodology was
identical by proton and carbon NMR spectra and also IR
spectra to Ningalin B hexamethyl ether prepared by Boger
and co-workers.17 The oxidative lactonization appeared to
be highly regioselective but small amounts of an impurity
were detected in the crude product prior to chromatography.
This side product may be attributed to competing oxidation
at the alternative ortho position of the aromatic ring at the
3-position of the pyrrole.
NMR spectra were obtained on either a GE Omega
300 MHz spectrometer or a Bruker 500 MHz spectrometer
in either CDCl3 or d6-DMSO solutions. IR spectra were
recorded on a Nicolet Avatar 320 FTIR spectrometer with
an HATR attachment. High-resolution mass spectra were
provided by the Midwest Center for Mass Spectrometry at
the University of Nebraska at Lincoln. Melting points and
boiling points are uncorrected. Radial chromatographic
separations were carried out on a Harrison Chromatotron
using silica gel plates of 2 mm thickness with a fluorescent
backing. Flash chromatographic separations were carried
out on a Biotage Horizon HFC instrument, which had been
equipped with a #1542-2 silica cartridge.
4.1.1. 30-Chloro-20,30-bis-(3,4-dimethoxypheny)-2-pro-
penal (21a and 21b). Into a 250 mL flask which had been
equipped with a condenser and magnetic stirring bar and
had been placed under a nitrogen atmosphere was added
2.50 g (6.74 mmol) of 30-(N,N-dimethylamino)-10,20-bis-
(3,4-dimethoxyphenyl)-2-propen-1-one13 (19) and 100 mL
of dry methylene chloride. To the stirring solution was
added dropwise 2.58 g (16.8 mmol) of phosphorous oxy-
chloride and the mixture was heated at reflux for 3 h. The
reaction mixture was cooled to room temperature and the
solvent was removed in vacuo yielding a dark solid. To the
solid was added 80 mL of a 1:1 solution of THF/water and
this mixture was allowed to stir at room temperature for 1 h.
An additional 50 mL of water was added and the solution
was allowed to stir for another 30 min. The resulting solid
(21a) (E-isomer, 1.00 g, 41% yield) was collected by
vacuum filtration and exhibited the following properties: mp
181–1828C (lit.14 183–1848C); 1H NMR (CDCl3) d 3.90 (s,
3H), 3.92 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 6.81–6.96 (m,
4H), 7.10–7.13 (m, 2H) and 9.66 (s, 1H); 13C NMR
(CDCl3) d 55.8, 55.9, 56.1, 110.3, 110.9, 112.5, 113.1,
122.7, 124.5, 126.6, 128.3, 139.9, 148.6, 149.0, 149.1,
3. Conclusions
We have demonstrated that b-chloroenals, which are
formally derived from chloropropeniminium salts, are
convenient and efficient precursors to regioselectively
functionalized pyrroles which are in turn precursors to
marine natural product derivatives such as Ningalin B
hexamethyl ether. In addition, the E-b-chloroenal isomer
exhibited unique selectivity for the formation of the desired
trisubstituted pyrrole synthon. The overall yield for the five-
step, chloroenal-based synthesis (assuming the use of the
Elliot procedure for the preparation of 21a) is 18%. Since
chloroenal intermediates can be easily assembled from
a-substituted ketones,10 this methodology should provide
substantial flexibility for the rapid preparation of a diverse
group of Ningalin B analogs. The reaction conditions
151.6, 154.8 and 190.3; FTIR (neat) 1662 and 1572 cm21
;
HRMS calcd for C19H19ClO5 (Mþ) m/z 362.0921 found
362.0918. The remaining filtrate was allowed to stir in an
ice bath for an additional hour and the resulting solid (21b)
(Z-isomer, 0.343 g, 14% yield) was collected by vacuum
filtration and exhibited the following properties: mp 136–
1388C; 1H NMR (CDCl3) d 3.53 (s, 3H), 3.64 (s, 3H), 3.79
(s, 3H), 3.81 (s, 3H), 6.49 (s, 1H), 6.56 (d, J¼9 Hz, 1H),
6.67–6.77 (m, 3H), 7. 00 (d, J¼9 Hz, 1H) and 10.52 (s, 1H);
13C NMR (CDCl3) d 55.6, 55.9, 56.1, 56.2, 110.3, 111.1,

214
J. T. Gupton et al. / Tetrahedron 59 (2003) 207–215
112.9, 113.8, 123.3, 123.5, 126.9, 129.4, 136.0, 147.9,
148.8, 148.8, 150.1, 150.5, and 191.6; FTIR (neat) 1660 and
1592 cm21; HRMS calcd for C19H19ClO5 (Mþ) m/z
362.0921 found 362.0909.
10% aqueous hydrochloric acid, once with 20 mL of water,
once with 20 mL of brine and subsequently dried over
anhydrous sodium sulfate. After filtration, and concen-
tration in vacuo, 0.70 g (89% yield) of an oil (29) was
obtained which was used without further purification. This
compound exhibited the following physical properties: bp
4.1.2. 3-Chloro-20-(3,4-dimethoxyphenyl)-50,60-
dimethoxy-1H-inden-1-ol (24). A round bottom flask was
equipped with magnetic stirring and 0.22 g (0.61 mmol) of
the E-b-chloroenal (21a) along with 30 mL of dry
methylene chloride was placed in the flask. The mixture
was cooled in an ice bath and 5 drops of trifluoroacetic acid
were added and the mixture was stirred for 3 h at room
temperature. The reaction mixture was extracted with
saturated aqueous bicarbonate and dried over anhydrous
sodium sulfate. After filtering off the drying agent and
removing the solvent in vacuo, a solid (24) (0.19 g, 86%
yield) was obtained. An analytical sample was prepared by
recrystallization of a small amount of 24 from methanol and
the resulting solid exhibited the following properties: mp
186–1898C (lit.14 189–1908C); 1H NMR (CDCl3) d 1.79 (d,
J¼9 Hz, 1H), 3.92 (s, 3H), 3.94 (s, 3H), 3.95 (s, 3H), 3.97 (s,
3H), 5.50 (d, J¼9 Hz, 1H), 6.95–6.98 (m, 2H), 7.17 (s, 1H),
7.42 (dd, J¼2, 9 Hz, 1H) and 7.55 (d, J¼2 Hz, 1H); 13C
NMR (CDCl3) d 55.8, 55.9, 56.2, 56.3, 75.8, 102.8, 107.5,
111.1, 111.4, 121.4, 125.5, 133.6, 134.6, 138.9, 148.71,
148.76, 148.82 and 149.9; FTIR (neat) 3266 cm21; HRMS
calcd for C19H19ClO5 (Mþ) m/z 364.0921 found 364.0922.
1
168–1698C at 0.2 mm; H NMR (CDCl3) d 2.87 (s, 3H),
3.00 (t, J¼7 Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 4.39 (t,
J¼7 Hz, 2H) and 6.74–6.83 (m, 3H); 13C NMR (CDCl3) d
35.0, 37.0, 55.8, 70.6, 111.5, 112.3, 121.0, 128.9, 148.0 and
149.0; FTIR (neat) 1348 and 1169 cm21; HRMS calcd for
C11H16SO5 (Mþ) m/z 260.0718 found 260.0708.
4.1.5. Methyl N-3,4-dimethoxyphenethyl-30,40-bis-(3,4-
dimethoxyphenyl)pyrrole-2-carboxylate (30). Into
a
250 mL flask, which had been placed under a nitrogen
atmosphere was added 0.25 g (7.55 mmol) of sodium
hydride (60% dispersion in mineral oil). The sodium
hydride was washed with hexane and 50 mL of dry DMF
was added. A solution consisting of 1.20 g (3.02 mmol) of
methyl 3,4-bis-(3,4-dimethoxyphenyl)pyrrole-2-carboxyl-
ate (22) in 50 mL of DMF was added dropwise to the
stirred suspension. The reaction mixture was allowed to stir
at room temperature for 35 min and this was followed by the
addition of 1.58 g (6.04 mmol) of 3,4-dimethoxyphenethyl
methanesulfonate in 10 mL of DMF. The reaction mixture
was heated at 708C for 12 h, cooled to room temperature and
quenched with 2 mL of methanol. The solution was poured
into 100 mL of water and extracted with ethyl acetate
(3£50 mL). The organic extracts were combined and
washed once with brine, dried over anhydrous sodium
sulfate, filtered and concentrated in vacuo. The crude
material was subjected to chromatography on silica gel
(50:50 ethyl acetate/hexanes as the eluant) to give 1.20 g
(70.5% yield) of a yellow solid (30) which exhibited the
4.1.3. Methyl 30,40-bis-(3,4-dimethoxyphenyl)pyrrole-2-
carboxylate (22). Into a 0250 mL flask was placed 1.40 g
(3.86 mmol) of E-3 -chloro-20,30-bis-(3,4-dimethoxy-
phenyl)-2-propenal (21a), 1.45 g (11.6 mmol) of glycine
methyl ester hydrochloride and 100 mL of toluene. To the
stirred suspension was added 0.66 g (5.79 mmol) of
DABCO (1,4-diazbicyclo[2.2.2]octane) and the resulting
mixture was heated at reflux for 24 h. The reaction mixture
was allowed to cool to room temperature and was washed
water (3£30 mL), with brine (30 mL), dried over anhydrous
magnesium sulfate, filtered and concentrated in vacuo to
give 1.40 g (92% yield) of a yellow-brown solid (22) which
was sufficiently pure for use in subsequent reactions. An
analytical sample was prepared by subjecting a portion of
the solid (22) to chromatography on silica gel (50:50 ethyl
acetate/hexanes as the eluant). The material resulting from
chromatographic purification exhibited the following prop-
erties: mp 66–688C; 1H NMR (CDCl3) d 3.58 (s, 3H), 3.73
(s, 3H), 3.75 (s, 3H), 3.84 (s, 3H), 3.89 (s, 3H), 6.57 (broad s,
1H), 6.74 (broad s, 2H), 6.83 (broad s, 3H), 7.08 (d, J¼3 Hz,
1H) and 9.16 (broad s, 1H); 13C NMR (CDCl3) d 51.3, 55.5,
55.8, 55.9, 56.0, 110.6, 111.1, 111.9, 114.4, 119.4, 120.0,
120.3, 123.3, 126.5, 126.9, 127.3, 129.0, 147.4, 148.0,
1
following properties: mp 51–528C; H NMR (CDCl3) d
3.05 (t, J¼7 Hz, 2H), 3.55 (s, 3H), 3.62 (s, 3H), 3.75 (s, 3H),
3.81 (s, 3H), 3.82 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 4.54 (t,
J¼7 Hz, 2H), 6.44 (d, J¼2 Hz, 1H), 6.59 (d of d, J¼2, 6 Hz,
1H), 6.69 (d, J¼8 Hz, 1H) and 6.72–6.84 (m, 7H); 13C
NMR (CDCl3) d 37.9, 50.8, 51.7, 55.4, 55.73, 55.76, 55.81,
55.85, 55.91, 110.5, 111.0, 111.4, 111.6, 112.2, 114.3,
119.1, 120.0, 120.9, 123.0, 123.8, 126.2, 127.3, 128.6,
130.0, 131.0, 147.2, 147.7, 148.1, 148.3, 148.8 and 162.1;
FTIR (neat) 1685 cm21; HRMS calcd for C32H35NO8 (Mþ)
m/z 561.2363 found 561. 2347.
4.1.6. N-3,4-Dimethoxyphenethyl-30,40-bis-(3,4-
dimethoxyphenyl)pyrrole-2-carboxylic acid (31). Into a
250 mL flask was placed 1.03 g (1.85 mmol) of methyl
N-3,4-dimethoxyphenethyl-30,40-bis(3,4-dimethoxyphenyl)-
pyrrole-2-carboxylate (30) and 125 mL of ethanol. After
stirring for several minutes, the mixture became homo-
geneous and 0.29 g (7.34 mmol) of sodium hydroxide in
125 mL of water was added. The resulting reaction mixture
was heated at reflux for 16 h, cooled to room temperature
and made acidic with 6 M hydrochloric acid. The mixture
was stirred in an ice/water bath followed by the slow
addition of 200 mL of water. A yellow solid crystallized,
which was vacuum filtered and air dried, to yield 0.90 g
(90% yield) of an orange solid (31) which was sufficiently
pure for use in subsequent reactions. An analytical sample
was prepared by subjecting a portion of the solid (31) to
148.1, 148.4 and 161.6; FTIR (neat) 3320 and 1685 cm21
;
HRMS calcd for C22H23NO6 (Mþ) m/z 397.1525 found
397.1514.
4.1.4. 3,4-Dimethoxyphenethyl methanesulfonate (29).
Into a 100 mL flask was placed 0.51 g (2.74 mmol) of 3,4-
dimethoxyphenethyl alcohol, 40 mL of dry methylene
chloride, and 0.42 g (4.11 mmol) of dry triethylamine. The
reaction mixture was cooled to 08C and 0.38 g (3.30 mmol)
of methanesulfonyl chloride was added. After stirring for
5 min. at 08C and at room temperature for 30 min, the
reaction mixture was extracted three times with 20 mL of

J. T. Gupton et al. / Tetrahedron 59 (2003) 207–215
215
recrystallization from methanol in which case the resulting
References
material exhibited the following properties: mp 79–808C;
1H NMR (CDCl3) d 3.06 (t, J¼8 Hz, 2H), 3.57 (s, 3H), 3.76
(s, 3H), 3.81 (s, 3H), 3.82 (s, 3H), 3.86 (s, 3H), 3.89 (s, 3H),
4.56 (t, J¼8 Hz, 2H), 6.42 (d, J¼2 Hz, 1H), 6.56 (d of d,
J¼2.5, 9 Hz, 1H), 6.60 (d, J¼2 Hz, 1H), 6.69 (d, J¼9 Hz,
1H), 6.75 (d of d, J¼2, 9 Hz, 1H) and 6.79–6.89 (m, 5H);
13C NMR (CDCl3) d 37.8, 52.2, 55.4, 55.6, 55.7, 55.8, 55.9,
110.8, 111.0, 111.4, 111.5, 112.1, 114.3, 117.9, 120.0,
120.9, 123.1, 124.2, 126.9, 127.7, 130.9, 132.4, 147.3,
147.8, 148.3, 148.4, 148.5, 148.9 and 164.7; FTIR (neat)
3343, 1689 and 1646 cm21; HRMS calcd for C31H33NO8
(Mþ) m/z 547.2206 found 547.2232.
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4.1.7. Ningalin B hexamethyl ether (32). Into a 100 mL
flask which had been placed under a nitrogen atmosphere
was added 0.0200 g (0.365 mmol) of N-3,4-dimethoxy-
phenethyl-30,4 -bis-(3,4-dimethoxyphenyl)pyrrole-2-car-
boxylic acid (31) and 40 mL of ethyl acetate. LTA (0.94 g,
0.213 mmol) was added in one portion and the reaction
mixture was heated at reflux for 5 h. The solution was
allowed to cool to room temperature, filtered through a
small plug of 50/50 celite/silica gel and washed twice with
20 mL of 20% aqueous citric acid solution. After extraction
with brine and drying over anhydrous sodium sulfate, the
ethyl acetate solution was filtered, and concentrated in
vacuo to give 0.12 g (52% yield) of a yellow solid. An
analytical sample was prepared by subjecting the yellow
solid to flash chromatography16 (ethyl acetate/hexane
mobile phase with gradient elution) to give a pale yellow
(32) solid which exhibited the following physical proper-
ties; mp 183–1878C (lit.2 186–1878C); 1H NMR (CDCl3) d
3.11 (t, J¼7 Hz, 2H), 3.56 (s, 3H), 3.76 (s, 3H), 3.84 (s, 3H),
3.87 (s, 3H), 3.90 (s, 3H), 3.92 (s, 3H), 4.65 (t, J¼7 Hz, 2H),
6.58 (d, J¼1.5 Hz, 1H), 6.70 (dd, J¼8, 2 Hz, 1H), 6.74 (s,
1H), 6.79 (d, J¼8 Hz, 1H), 6.88 (d, J¼1.4 Hz, 1H), 6.92–
6.96 (m, 3H), and 7.09 (s, 1H); 13C NMR (CDCl3) d 37.8,
51.0, 55.8, 55.9, 56.0, 56.1, 100.6, 104.8, 110.4, 111.1,
111.3, 112.1, 113.1, 114.9, 119.1, 120.0, 122.1, 126.7,
127.2, 130.6, 131.9, 145.6, 146.2, 147.8, 148.6, 148.8,
148.9, 149.1 and 155.5; MS (Mþ) m/z 545.
6. Heim, A.; Terpin, A.; Steglich, W. Angew. Chem., Int. Ed.
Engl. 1997, 36, 155.
7. Ishibashi, F.; Miyazaki, Y.; Iwao, M. Tetrahedron 1997, 53,
5951.
8. Liu, J.; Yang, Q.; Mak, T.; Wong, H. J. Org. Chem. 2000, 65,
3587.
9. Quesada, A.; Gravalos, G.; Puentes, F. Br. J. Cancer 1996, 74,
677.
10. (a) Gupton, J.; Krolikowski, D.; Riesinger, S.; Yu, R.;
Sikorski, J. J. Org. Chem. 1990, 55, 4735. (b) Gupton, J.;
Krolikowski, D.; Yu, R.; Sikorski, J.; Vu, P.; Jones, C. J. Org.
Chem. 1992, 57, 5480. (c) Gupton, J.; Petrich, S.; Smith, L.;
Bruce, M.; Vu, P.; Du, K.; Dueno, E.; Jones, C.; Sikorski, J.
Tetrahedron 1996, 52, 6879. (d) Gupton, J.; Petrich, S.; Hicks,
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Tetrahedron 1998, 54, 5075. (f) See also Liebscher, J.;
Hartmann, H. Synthesis 1979, 241 for a review, which details
the applications of chloropropeniminium salts and related
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11. Gupton, J.; Krumpe, K.; Burnham, B.; Webb, T.; Shuford, J.;
Sikorski, J. Tetrahedron 1999, 55, 14515.
12. Dyke, S.; Tiley, E.; White, A.; Gale, D. Tetrahedron 1975, 31,
1219.
13. SanMartin, R.; Marigorta, E.; Dominguez, E. Tetrahedron
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Acknowledgements
15. Elliot, I. US patent 5,034,544, July 23, 1991.
16. We are deeply indebted to Mr Dave Patteson of the Biotage
Corp. for the donation of a Horizon HPFC flash chromato-
graphy system, which was utilized in the final purification of
our synthetic Ningalin B hexamethyl ether. We also thank Dr
Peter Rahn and Mr Jeff Horsman of the Biotage Corp. for their
technical expertise.
We thank the National Institutes of Health (grant no. R15-
CA67236-02), the Jeffress Memorial Trust and the
American Chemical Society’s Petroleum Research Fund
for support of this research. We gratefully acknowledge the
Camille and Henry Dreyfus Foundation for a Scholar/
Fellow Award to John T. Gupton. In addition, we would also
like to thank the Midwest Center for Mass Spectrometry at
the University of Nebraska-Lincoln for providing high-
resolution mass spectral analysis on the compounds reported
in this paper. A recent grant from the MRI program of the
National Science Foundation for the purchase of a 500 MHz
NMR spectrometer is also greatly appreciated.
17. We would like to thank Professor Dale Boger for providing
our research group with NMR, IR and MS spectra of Ningalin
B hexamethyl ether.
18. All purified compounds gave a single spot upon tlc analysis on
silica gel 7GF using an ethyl acetate/hexane mixture as eluent.
All purified compounds gave 13C NMR and 1H NMR spectra
indicative of compounds .95% pure.