Stereoselective synthesis of naturally occurring unsaturated amide alkaloids by a modified Ramberg-Baecklund reaction

Article abstract of DOI:10.1139/v04-028

A convenient and rapid approach for the synthesis of naturally occurring unsaturated amide alkaloids 1a-1n by the recently developed one-flask Ramberg-Baecklund reaction is described. The starting material was alcohol 3, which was transformed into thiolacetate 4 using the Mitsunobu reaction. In situ cleavage of acetyl moiety of 4, followed by alkylation of the resulting thiol with appropriate chloroacetamide 5, provided the sulfide 6. Oxidation of sulfide 6 gave the corresponding sulfone 2. Treatment of the sulfone 2 with the dibromodifluoromethane in the presence of alumina-supported potassium hydroxide in dichloromethane solution afforded unsaturated amide alkaloids 1a-1n. To the best of our knowledge, the synthesis of 1e and 1i was reported for the first time.

Full text of DOI:10.1139/v04-028

622
Stereoselective synthesis of naturally occurring
unsaturated amide alkaloids by a modified
Ramberg–Bäcklund reaction
Yang Li, Yu Zhang, Zhi Huang, Xiaoping Cao, and Kun Gao
Abstract: A convenient and rapid approach for the synthesis of naturally occurring unsaturated amide alkaloids 1a–1n
by the recently developed one-flask Ramberg–Bäcklund reaction is described. The starting material was alcohol 3,
which was transformed into thiolacetate 4 using the Mitsunobu reaction. In situ cleavage of acetyl moiety of 4, fol-
lowed by alkylation of the resulting thiol with appropriate chloroacetamide 5, provided the sulfide 6. Oxidation of sul-
fide 6 gave the corresponding sulfone 2. Treatment of the sulfone 2 with the dibromodifluoromethane in the presence
of alumina-supported potassium hydroxide in dichloromethane solution afforded unsaturated amide alkaloids 1a–1n. To
the best of our knowledge, the synthesis of 1e and 1i was reported for the first time.
Key words: synthesis, unsaturated amide alkaloids, Ramberg–Bäcklund reaction.
Résumé : Faisant appel à la réaction de Ramberg–Bäcklund monotope développée récemment, on a mis au point une
méthode pratique et rapide de réaliser la synthèse des alcaloïdes naturels 1a–1n comportant une fonction amide non sa-
turée. Le produit de départ est l’alcool 3 qui est transformé en thiolactate 4 à l’aide d’une réaction de Mitsunobu. Le
clivage in situ de la portion acétyle du composé 4, suivi d’une alkylation à l’aide du chloroacétamide 5 approprié du
thiol qui en résulte conduit à la formation du sulfure 6. L’oxydation du sulfure 6 fournit la sulfone 2. Le traitement de
la sulfone 2 à l’aide de dibromodifluorométhane, en présence d’hydroxyde de potassium supporté par de l’alumine dans
le dichlorométhane, conduit à la formation des alcaloïdes recherches 1a–1n. À notre connaissance, il s’agit des premiè-
res synthèses des composés 1e et 1i.
Mots clés : synthèse, alcaloïdes comportant une fonction amide non saturée, réaction de Ramberg–Bäcklund.
[Traduit par la Rédaction] Li et al. 630
Introduction
Artemisia dracunculus, which showed insectical activity
against Sitophilus oryzae and Rhyzopertha dominica (1i).
Pellitorine was also found as having antimalarial properties
(2a), which can be explained by the tendency of the nucleic
acids of the parasites to react with the α,β-unsaturated car-
bonyl moiety of pellitorine in a Michael addition fashion
(2a). Pellitorine and piperine also exhibited antifungal activ-
ity against Cladosporium sphaerospermum (2b). Thus, it
was concluded that the presence of a methylenedioxyphenyl
and an unsaturated alkanoic amide group in the compounds
may be crucial for high biological activity. The fact that un-
saturated amide alkaloids occur naturally in very limited
amounts in some rather inaccessible plant species has
stressed the need for good synthetic methods. A perusal of
numerous reviews on the chemistry of the unsaturated amide
alkaloids reveals that the field is mainly dominated by two
general strategies for the assembly of the unsaturated amide
alkaloids skeleton units. One approach makes use of
amidation with various amines of the stereochemically de-
fined unsaturated acids or esters that are prepared by: (a) the
Various unsaturated amide alkaloids bearing pyrrolidine,
isobutyl, and piperidine moieties are interesting targets of
numerous synthetic investigations, presumably because of
their significant biological activities (1, 2). They are distrib-
uted widely in the plant kingdom. The series of compounds
mostly isolated from the genus Piper, which is used in folk
medicine, are amides of unsaturated alkanoic or arylalkanoic
acids. These compounds display antiinflammatory, antidi-
arrheal, insecticidal, antifungal, antimalarial, as well as 5-
lipoxygenase and cyclooxygenase-1 inhibitory activities (2).
For example, piperine was the first amide to be isolated from
the Piper species. Pharmacological studies reported that pi-
perine had antipyretic, analgesic, and antiinflammatory ac-
tivities (1j), and that it could also inhibit gastric emptying
and gastrointestinal transit in rats and mice (2c). Sarmentine
was isolated from P. sarmentosum, which showed larvicidal
activity against second stage larva of Toxocara canis (1a).
Recently, pellitorine and neopellitorine B were isolated from
Received 29 October 2003. Published on the NRC Research Press Web site at http://canjchem@nrc.ca on 5 May 2004.
Y. Li, Y. Zhang, Z. Huang, X. Cao,1 and K. Gao.2 State Key Laboratory of Applied Organic Chemistry, College of Chemistry
and Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China.
1Corresponding author (e-mail: caoxplzu@163.com).
2Corresponding author (e-mail: miaozm@lzu.edu.cn).
Can. J. Chem. 82: 622–630 (2004)
doi: 10.1139/V04-028
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Li et al.
623
Scheme 1. Strategy of constructed unsaturated amide alkaloids 1.
Wittig type approaches (3a–3d); (b) Pummerer-type reaction
intermediates (3e); (c) Still cross-coupling reactions (3f);
(d) palladium-phase transfer co-catalyzed couplings of
vinylic iodide and acrylate (3g); (e) allyl acetates eliminat-
ing the elements of acetic acid in the presence of O,N-
bis(trimethylsilyl) acetamide and molybdenum hexacarbonyl
(3h); (f) rearrangement of the corresponding 2-ynoic esters
in the presence of Ph3P (3i); and (g) addition of carbon
nucleophiles to aldehyde tosylhydrazones of aromatic and
heteroaromatic compounds (3j). Another method entails the
anchoring of the amide unit to the end of a variable olefinic
double bond that involves: (a) the Wittig methodology (4a);
(b) Knoevenagel condensations (4b–4c); (c) thermal SO2 ex-
trusion from cis-2,5-disubstituted 2,5-dihydrothiofene-1,1-
dioxides (4d); (d) a double elimination of β-acetoxy sulfones
(4e); (e) further functionalization containing the sulfonyl and
the cyano group (4f); (f) isomerization of 2-ynoic amides
catalyzed by ruthenium or iridium complexes (4g);
(g) hydrozirconation of the terminal acetylene using
Schwartz’s reagent (Cp2ZnCl(H)) followed by Pd(0)-cata-
lyzed coupling with the iodo-amide (4h–4i); (h) an easily ac-
cessible bifunctional dienyl compound based upon a double
selective electrophilic substitution followed by coupling
reaction (4j); and (i) the use of δ-tosyl dienamide as δ-
acyldienyl cation equivalents (4k). Although numerous
methods have been reported for the synthesis of unsaturated
amide alkaloids, there still remains the necessity and ur-
gency to discover milder and newer methods for the con-
struction of the series of unsaturated amide alkaloids. We
recently reported a new protocol of the Ramberg–Bäcklund
reaction to effect the transformation of the α- and α′-hydrogen
bearing sulfones directly into alkenes (5). From this investi-
gation emerged the highly stereoselective generation of a
new (E)-double bond with the retention of the configurations
of the preexisting ones. We became interested in establish-
ing a convenient and stereoselective new route to synthesize
unsaturated amide alkaloids (1) (Scheme 1), without resort-
ing to the prior preparation of the α-halosulfone precursors
in a separate step (6). In this paper we extend this methodol-
ogy to the synthesis of unsaturated amide alkaloids (1). The
preparation of 13 natural products and one related analogue,
as well as their full details are reported.
stereocontrolled preparation of alkenyl or alkyl thiolacetates
4 and chloroacetamides 5 (7). The coupling reaction be-
tween stereodefined thiolacetates 4 to pure chloroacetamides
5 assembled the sulfides 6, from which the corresponding
sulfones 2 could be obtained after oxidation. This procedure
invariably demanded a stereoselective preparation of alco-
hols 3, the common intermediate for the requisite
thiolacetates 4 (Scheme 2). Several synthetic methods were
tried. In the end, the alcohols 3 were secured by the Wittig
reaction, and followed by reduction.
The alcohols 3 (R1 = piperonyl, thienyl, or methyl) were
prepared according to the Scheme 3. The commercially
available aldehyde 7, 8, 9, or 10 was used as a starting mate-
rial for the preparation of the alcohols 3. Treatment of 7, 8,
or 10 with Ph3P=CHCO2Et afforded an ester with good (E)-
selectivity, which was followed by regioselective reduction
of the ester moiety with aluminum hydride (AlH3, from
LiAlH4:AlCl3 = 3:1) to furnish the alcohols 3a, 3e, or 3g
(76%, 66%, 51%), respectively. The alcohol 3a was hydro-
genated, oxidized with pyridinium chlorochromate (PCC),
then its carbon chain elongated by a Wittig reaction
(Ph3P=CHCO2Et), and followed by a reduction of the result-
ing ester with aluminum hydride selectively to give the pri-
mary alcohol 3b in 59% yield. On the other hand, treatment
of aldehyde 7 or 9 with Ph3P=CHCH=CHCO2Et followed
by a reduction of the ester moiety with aluminum hydride
gave alcohol 3c or 3f in 60% and 68% yield, respectively.
Hydrogenation of 3c afforded the saturated alcohol 3d in
nearly quantitative yield.
Alcohols 3a–3g were transformed into the corresponding
thiolacetates 4a–4g using the Mitsunobu reaction with
thiolacetic acid in the presence of triphenylphosphine and
diisopropyl azodicarboxylate (DIAD) (8). In situ cleavage of
acetyl moieties of 4a–4g with potassium hydroxide in meth-
anol, followed by alkylation of the resulting thiols with the
appropriate chloroacetamides 5, provided the sulfides 6a–6n
in good yields (Table 1) with no SN2′ substitution products.
Oxidation of the sulfides 6 by oxone (2KHSO5·KHSO4·
K2SO4) (9) in methanol–water (1:1) gave high yields of the
corresponding sulfones 2 except 2j and 2k (Table 1). This is
probably due to the side reaction of the heteroaromatic sul-
fides. As expected, stereochemistry of the double bonds was
retained during these transformations. Subjecting the sul-
fones 2a–2n to the modified Ramberg–Bäcklund reaction
protocol (CBr2F2, KOH–Al2O3, CH2Cl2), previously de-
scribed by us, invariably gave the geometrically defined un-
saturated amide alkaloids 1a–1n with the newly formed
double bond that had the (E)-configuration in good yields
(Table 2). The stereochemistry of the newly formed carbon–
carbon bond in 1a–1n was readily diagnosed by a typical
coupling constant of 14.2–15.0 Hz for trans-olefinic protons.
Examination of the 13C NMR spectra of the products indi-
cated the presence of one isomer in each case. Thus, the
stereoselectivity of the reaction was >95%. All the com-
Results and discussion
Scheme 1 outlines the strategy we pursued in the quest for
stereo-pure unsaturated amide alkaloids 1. We wished to
prepare it from functional sulfones 2. The strategy shown in
Scheme 1 was thought to be feasible because of the success-
ful application of our procedure to the formation of conju-
gated trienes from diallylic sulfones (5b), conjugated
tetraenes from allylic dienylic sulfones (5d), and linear and
cyclic enediynes from dipropargylic sulfones (5e). Our syn-
thetic method was also applied to the synthesis of natural
products containing a triene unit such as galbanolenes. The
procedure reported here started with a functional sulfones 2,
with the amide group and the functional carbon chain al-
ready in place and the new double bond to be realized by
our modified Ramberg–Bäcklund procedure. This disconnec-
tion approach relied on the stereocontrolled synthesis of the
functional sulfones 2, which was in turn prepared by a
1
pounds were characterized by IR, H and 13C NMR, and
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Can. J. Chem. Vol. 82, 2004
Scheme 2. Synthesis of unsaturated amide alkaloids 1. Piperylin (1a), piperlonguminine (1b), piperine (1c), pipercallosidine (1d),
piperine S (1e), chingchengenamide A (1f), piperdardine (1g), piperettine (1h), N-isobutylotanthusic acid amide (1j), N-
piperdineotanthusic acid amide (1k), sarmentine (1l), pellitorine (1m), neopellitorine B (1n).
Scheme 3. Synthesis of alcohols 3a–3g.
high resolution mass spectra. The data of the natural unsatu-
rated amide alkaloids 1a–1h, 1j–1n were in agreement with
those reported in the literature (1). It is noteworthy that 1i is
not a natural alkaloid but one prepared for the first time with
the readily available material in our laboratory. The synthe-
sis of 1i also relied on the functional sulfone 2i, which could
be prepared by the method similar to that used for the other
sulfones (Scheme 4). To the best of our knowledge, 1e and
1i were synthesized for the first time.
action. Investigation of the structure biological activity of
these unsaturated amide alkaloids is in progress.
Experimental
Melting points were measured on a Kofler apparatus and
were uncorrected. IR spectra were recorded on a Nicolet
NEXUS 670 FT-IR spectrophotometer, and reported in wave
1
number (cm–1). H and 13C NMR spectra were recorded on
an Avance-200 or a Mercury Plus-300 spectrometer. The
chemical shifts (δ) are reported in ppm and coupling con-
stants (J) in Hz. Mass spectra (MS) were obtained on a HP-
5988A mass spectrometer. High resolution mass spectra
(HR-MS) were obtained on a Bruker Daltonics APEX II 47e
mass spectrometer. Elemental analyses were performed on a
Germany Varioel elemental instrument. Column chromatog-
raphy was generally performed on silica gel (200–300
mesh), and TLC inspection on silica gel GF254 plates. All
the aldehydes were purchased and used without further puri-
fication.
Chloroacetamides 5 were prepared by acylation of various
amines with chloroacetylchloride in high yields (7).
Conclusion
We have presented a rapid route with our protocol of the
Ramberg–Bäcklund reaction as a key step to stereochemi-
cally defined naturally occurring unsaturated amide alka-
loids. The synthetic transformation utilized readily available
aldehydes as starting materials. The synthesis routes are fac-
ile, the yields are satisfactory, and the reactions can be per-
formed in molar scales. We have also shown that the double
bonds of stereochemically defined sulfone retain their
stereochemistry and that the newly formed double bond has
an (E)-configuration in our modified Ramberg–Bäcklund re-
Alcohols 3
A solution of individual aldehyde 7 (50 mmol), 8
(50 mmol), 9 (50 mmol), or 10 (50 mmol) in benzene
(25 mL) was added dropwise to a well-stirred solution of
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Li et al.
625
Table 1. The important data of sulfides 6 and sulfones 2.
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Can. J. Chem. Vol. 82, 2004
Table 1 (concluded).
aX = S for entry 6 and X = SO2 for entry 2.
b1H and 13C NMR were recorded on an Avance-200 or a Mercury Plus-300 spectrometer; coupling constants (J) in Hz.
Ph3P=CH2CO2Et (60 mmol) in benzene (150 mL) or
Ph3P=CHCH=CHCO2Et (60 mmol) in benzene (200 mL).
The reaction mixture was refluxed for 4 h and then the sol-
vent was evaporated in vacuo. Flash chromatography of the
residue over silica gel (petroleum ether (boiling range 60–
90 °C) : ethyl acetate, 8:1) afforded the (E)-α,β-unsaturated
esters or (E,E)-dienylesters. These esters (40 mmol) in THF
(25 mL) were added dropwise to a well-stirred suspension of
LiAlH4 (120 mmol) and AlCl3 (40 mmol) in THF (150 mL)
at 0 °C, respectively. The reaction mixture was stirred at this
temperature for 1 h and quenched by water (8 mL). The
solid aluminates were removed by filtration. The combined
filtrates were dried (MgSO4) and concentrated in vacuo.
Flash chromatography of the residue over silica gel (petro-
leum ether : ethyl acetate, 4:1) afforded alcohol 3a, 3c, 3e,
3f, or 3g (76%, 60%, 66%, 68%, and 51% yield, respec-
tively). The solution of 3a (15 mmol) in EtOAc–EtOH (2:1,
60 mL) was hydrogenated under a hydrogen atmosphere
(10% Pd–C, 10 mg) for 4 h to give the corresponding satu-
rated alcohol. This saturated alcohol (15 mmol) in CH2Cl2
(10 mL) was added to a suspension of pyridinium
chlorochromate (PCC) (18 mmol) in CH2Cl2 (60 mL). The
reaction mixture was stirred at room temperature for 4 h and
filtered, and the filtrate was concentrated in vacuo. Flash
chromatography of the residue over silica gel (petroleum
ether : ethyl acetate, 8:1) afforded the corresponding satu-
rated aldehyde. After the treatment of this aldehyde with
Ph3P=CH2CO2Et, the resulting ester was reduced with
LiAlH4–AlCl3 as above and alcohol 3b was obtained in 59%
yield. Alcohol 3c was hydrogenated under a hydrogen atmo-
sphere (10% Pd–C, 10 mg) to give saturated alcohol 3d in
nearly quantitative yield. All of these products were easily
confirmed by their 1H NMR and MS spectra. The focal
methylene protons linked within the hydroxyl group of the
unsaturated alcohols 3a–3c and 3e–3g have a chemical shift
value of δ 3.94–4.59 ppm, and the chemical shift of methy-
lene protons linked within the hydroxyl group of the satu-
rated alcohol 3d is 3.66 ppm (10).
Thiol acetates 4
A solution of DIAD (6 mmol) in dry C6H6 (5 mL) was
added to a stirred solution of Ph3P (6 mmol) in C6H6 (5 mL)
at 0 °C. The resulting yellow solution was kept at 0 °C for
15 min and then a precooled mixture of the individual alco-
hols 3a–3g (5 mmol) and CH3COSH (6 mmol) in dry C6H6
(50 mL) was added in one portion. The mixture was stirred
at room temperature for 1 h and the solvent was removed in
vacuo. Flash chromatography of the residue over silica gel
(petroleum ether : ethyl acetate, 10:1) afforded thiol acetate
4a, 4b, 4c, 4d, 4e, 4f, or 4g in 83%, 95%, 93%, 85%, 88%,
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Li et al.
627
Table 2. The important data of unsaturated amide alkaloids 1.
a1H NMR were recorded on an Avance-200 or a Mercury Plus-300 spectrometer; coupling constants (J) in Hz.
Scheme 4. Synthesis of 1-[(2E,4E,6E)-1-oxo-6-methyl-7-phenylheptatrienyl]piperidine (1i).
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Can. J. Chem. Vol. 82, 2004
82%, and 90% yield, respectively. These thiol acetates can
be easily characterized by a comparison with their analogues
(11). The focal methylene protons linked within the S-thio-
acetate group of the unsaturated thiol acetates 4a–4c and 4e–
4g have a chemical shift value of δ 3.43–4.03 ppm, and the
methylene protons of the saturated thiol acetate 4d have a
chemical shift of δ 3.00 ppm, whereas those of the corre-
sponding thiol acetates experience a similar shift value to
that of the alcohols.
gradient to 3:1:1) gave the unsaturated amide alkaloids 1a–
1n. The important data for unsaturated amide alkaloids 1a–
1n are described in Table 2 and their full data follows.
1-[(2E,4E)-1-Oxo-5-(3,4-methylenedioxyl)phenylpenta-
dienyl]pyrrolidin (piperylin, 1a) (1a)
White needles, 85%; mp 147 to 148 °C (lit. (1a) 148 to
149 °C). IR νmax (KBr disc) (cm–1): 2876, 1636, 1420, 1249,
1
1037, 993, and 841. H NMR (300 MHz, CDCl3) δ: 1.86–
2.05 (4H, m, 2 × CH2), 3.45–3.55 (4H, m, 2 × CH2N), 5.98
(2H, s, OCH2O), 6.26 (1H, d, J = 15.0, 2-CH=), 6.74 (1H, d,
J = 15.0, ArCH=), 6.75 (1H, d, J = 8.1, ArH), 6.76–6.99
(3H, m, 2ArH, CH=), and 7.43 (1H, dd, J = 15.0 and 9.0,
CH=). 13C NMR (75 MHz, CDCl3) δ: 24.3, 26.1, 45.9, 46.4,
101.2, 105.6, 108.4, 121.4, 122.5, 125.1, 130.9, 138.6,
141.7, 148.1, 148.1 and 164.9. MS (EI) m/z (%): 271 (M+,
32), 201 (100), 173 (38), 121 (53), and 115 (86).
Chloroacetamides 5
A solution of an appropriate amine (200 mmol) in anhyd
THF (50 mL) was added to chloroacetylchloride (100 mmol)
in anhyd THF (50 mL) under a nitrogen atmosphere. The re-
action mixture was stirred for 10–12 h at room temperature.
The side product ammonium chloride was filtered off and
the solvent evaporated in vacuo to afford the chloroacet-
amides 5 in nearly quantitative yields. They were easily con-
1
(2E,4E)-N-Isobutyl-5-(3,4-methylenedioxyl)phenylpenta-
dienamide (piperlonguminine, 1b) (1b)
firmed by their H NMR and MS spectra (7).
White needles, 84%; mp 169 to 170 °C. IR νmax (KBr
General procedure for the preparation of sulfides 6
An individual solution of thiol acetates 4a–4g (3 mmol) in
MeOH (25 mL) was added to the solution of KOH (6 mmol)
in MeOH (5 mL). After being stirred at 0 °C for 10 min, a
solution of the appropriate chloroacetamide 5 (2.8 mmol) in
MeOH (5 mL) was added to this well-stirred thiol solution
and the stirring was continued for 1 h at 0 °C. The reaction
mixture was poured into water (10 mL) and extracted with
ethyl acetate (3 × 25 mL). The combined extract was washed
with brine, dried with MgSO4, filtered, and concentrated in
vacuo. Flash chromatography of the residue over silica gel
(petroleum ether : ethyl acetate, 5:1 gradient to 3:1) afforded
the sulfides 6a–6n. The important data for sulfides 6a–6n
are described in Table 1 and their full data are available as
supplementary data.3
disc) (cm–1): 3463, 2985, 1741, 1374, 1245, 1046, 936, and
1
848. H NMR (300 MHz, CDCl3) δ: 0.94 (6H, d, J = 6.6,
2 × CH3), 1.78–1.89 (1H, m, CH(CH3)2), 3.17–3.21 (2H, m,
CH2NH), 5.78 (1H, br s, NH), 5.95 (1H, d, J = 14.4, 2-
CH=), 5.98 (2H, s, OCH2O), 6.67 (1H, dd, J = 15.6 and
10.5, CH=), 6.76 (1H, d, J = 8.1, ArH), 6.77 (1H, d, J =
15.6, ArCH=), 6.88 (1H, d, J = 8.1, ArH), 6.96 (1 H, s,
ArH), and 7.36 (1H, dd, J = 14.4 and 10.5, CH=). 13C NMR
(75 MHz, CDCl3) δ: 20.1, 20.1, 28.6, 47.0, 101.3, 105.6,
108.4, 122.5, 123.2, 124.6, 130.8, 138.7, 140.9, 148.1,
148.1, and 166.2. MS (EI) m/z (%): 273 (M+, 37), 201 (100),
173 (71), and 115 (97).
1-[(2E,4E)-1-Oxo-5-(3,4-methylenedioxyl)phenylpenta-
dienyl]piperidine (piperine, 1c) (1a, 1c)
Yellow needles, 82%; mp 131 to 132 °C (lit. (1a) 132 to
133 °C). IR νmax (KBr disc) (cm–1): 2935, 1636, 1444, 1251,
General procedure for the preparation of sulfones 2
The individual sulfide 6 (2 mmol) was added to a well-
stirred solution of oxone (6 mmol) in MeOH–H2O (1:1,
4 mL). The mixture was then stirred at 0 °C for 2–4 h. The
reaction mixture was diluted with water (10 mL) and ex-
tracted with ethyl acetate (3 × 25 mL). The combined or-
ganic phase was washed with brine, dried with MgSO4,
filtered, and concentrated in vacuo. Flash chromatography of
the residue over silica gel (petroleum ether : ethyl acetate :
CH2Cl2, 4:1: 1 gradient to 2:1:1) afforded the sulfones 2.
The important data for sulfones 2a–2n are described in Ta-
ble 1 and their full data are available as supplementary data.3
1
1036, 929 and 854. H NMR (300 MHz; CDCl3) δ: 1.58–
1.67 (6H, m, 3 × CH2), 3.50–3.62 (4H, m, 2 × CH2N), 5.97
(2H, s, OCH2O), 6.44 (1H, d, J = 14.1, 2-CH=), 6.70 (1H, d,
J = 15.9, ArCH=), 6.71–6.76 (1H, m, CH=), 6.78 (1H, d,
J = 8.1, ArH), 6.90 (1H, d, J = 8.1, ArH), 6.99 (1H, s,
ArH), and 7.41 (1H, dd, J = 14.1 and 10.2, CH=). 13C NMR
(75 MHz, CDCl3) δ: 24.6, 25.6, 26.7, 43.2, 46.9, 101.3,
105.6, 108.5, 120.0, 122.5, 125.3, 130.9, 138.2, 142.5,
148.1, 148.1, and 165.4. MS (EI) m/z (%): 285 (M+, 36), 201
(100), 173 (38), 115 (92), and 84 (42).
(2E)-N-Isobutyl-7-(3,4-methylenedioxyl)phenylhepten-
amide (pipercallosidine, 1d) (1d)
General procedure for the preparation of unsaturated
amide alkaloids 1
White needles, 68%; mp 79–81 °C (lit. (1d) 80–82 <C). IR
A solution of sulfone 2 (1 mmol) in dry CH2Cl2 (6 mL)
was added to a stirred suspension of KOH–Al2O3 (10 mmol
of KOH) in CBr2F2–CH2Cl2 (1:10, 10 mL). This mixture
was then stirred for 1 h at room temperature, the KOH–
Al2O3 was removed by filtering, and the filtrate was concen-
trated in vacuo. Flash chromatography of the residue over
silica gel (petroleum ether : ethyl acetate : CH2Cl2, 5:1:1
ν
max (KBr disc) (cm–1): 3302, 2926, 1629, 1494, 1248, 1039,
1
924, and 808. H NMR (300 MHz, CDCl3) δ: 0.92 (6H, d,
J = 6.3, 2 × CH3), 1.44–1.59 (4H, m, 2 × CH2), 1.75–1.84
(1H, m, CH(CH3)2), 2.16 (2H, dd, J = 7.5 and 6.0,
CH2CH=), 2.53 (2H, t, J = 7.5, ArCH2), 3.15 (2H, t, J = 6.2,
CH2NH), 5.48 (1H, br s, NH), 5.74 (1H, d, J = 15.0, 2-
CH=), 5.92 (2H, s, OCH2O), 6.61 (1H, dd, J = 8.1 and 1.5,
3 Supplementary data may be purchased from the Directory of Unpublished Data, Document Delivery, CISTI, National Research Council
Canada, Ottawa, ON K1A 0S2, Canada (http://www/nrc.ca/cisti/irm/unpub_e.shtml for information on ordering electronically).
© 2004 NRC Canada

Li et al.
629
ArH), 6.66 (1H, d, J = 1.5, ArH), 6.72 (1H, d, J = 8.1,
ArH), and 6.82 (1H, dt, J = 15.0 and 7.5, CH=). 13C NMR
(75 MHz, CDCl3) δ: 20.1, 20.1, 27.6, 28.6, 31.0, 31.9, 35.4,
46.8, 100.7, 108.0, 108.8, 121.0, 123.7, 136.2, 144.4, 145.5,
147.5, and 166.0. MS (EI) m/z (%): 303 (M+, 7), 203 (9),
168 (11), and 135 (100).
5.97 (2H, s, OCH2O), 6.38 (1H, d, J = 14.7, 2-CH=), 6.41
(1H, dd, J = 14.7 and 11.4, CH=), 6.57–6.71 (3H, m, 3
CH=), 6.77 (1H, d, J = 8.1, ArH), 6.86 (1H, dd, J = 8.1 and
1.5, ArH), 6.96 (1H, d, J = 1.5, ArH), and 7.35 (1H, dd, J =
14.7 and 11.4, CH=). 13C NMR (75 MHz, CDCl3) δ: 24.6,
25.6 (br), 26.6 (br), 43.2 (br), 46.9 (br), 101.2, 105.5, 108.5,
120.0, 122.0, 126.7, 130.4, 131.5, 135.3, 139.1, 142.4,
147.8, 148.2, and 165.5. MS (EI) m/z (%): 311 (M+, 17), 226
(17), 199 (17), 135 (24), and 112 (100).
1-[(2E)-1-Oxo-7-(3,4-methylenedioxyl)phenylheptenyl]pi-
peridine (piperine S, 1e) (1e)
Yellow needles, 65%; mp 52 to 53 °C (lit. (1e) 52–54 °C).
IR νmax (KBr disc) (cm–1): 2929, 1652, 1444, 1247, 1035,
1-[(2E,4E,6E)-1-Oxo-6-methyl-7-phenylheptatrienyl]pi-
peridine (1i)
1
930, and 809. H NMR (200 MHz, CDCl3) δ: 1.59–1.61
(10H, m, 5 × CH2), 2.21 (2H, dd, J = 7.4 and 6.4,
CH2CH=), 2.54 (2H, t, J = 7.3, ArCH2), 3.49–3.59 (4, m,
2 × CH2N), 5.92 (2H, s, OCH2O), 6.23 (1H, d, J = 15.0, 2-
CH=), 6.64 (1H, d, J = 8.0, ArH), 6.57 (1H, s, ArH) 6.72
(1H, d, J = 8.0, ArH), and 6.82 (1H, dt, J = 15.0 and 7.4,
CH=) 13C NMR (75 MHz, CDCl3) δ: 24.6, 25.6, 26.6, 27.9,
31.3, 32.4, 35.5, 43.1, 46.8, 100.7, 108.0, 108.8, 120.4, 121.0,
136.2, 145.5, 145.6, 147.4, and 165.5. MS (EI) m/z (%): 315
(M+, 13), 202 (16), 180 (30), 166 (74), and 135 (100).
Yellow oil, 83%. IR νmax (film) (cm–1): 3385, 2935, 1733,
1628, 1448, 1251, 1019, and 703. 1H NMR (200 MHz,
CDCl3) δ: 1.59–1.64 (6H, m, 3 × CH2), 2.07 (3H, s, CH3),
3.54–3.60 (4H, m, 2 × CH2N), 6.44 (1H, d, J = 14.1, 2-
CH=), 6.47 (1H, dd, J = 14.1 and 11.0, CH=), 6.67 (1H, s,
ArCH=), 6.73 (1H, d, J = 15.2, CH=), and 7.25–7.41
(6H, m, 5 ArH, CH=). 13C NMR (50 MHz, CDCl3) δ: 13.8,
24.6, 25.6, 26.7, 43.2, 46.9, 120.0, 126.5, 127.0, 128.2,
128.2, 129.3, 129.3, 134.7, 135.4, 137.3, 142.8, 144.2, and
165.5. HR-MS (ESI) calcd. for C19H24NO: 282.1852; found:
282.1854 (M + H+).
(2E,4E)-N-Isobutyl-7-(3,4-methylenedioxyl)phenylhep-
tadienamide (chingchengenamide A, 1f) (1f)
White needles, 78%; mp 130–132 °C (lit. (1f) 126–
128 °C). IR νmax (KBr disc) (cm–1): 3301, 2923, 1623, 1549,
1493, 1246, 1041, 996, and 811. 1H NMR (300 MHz;
CDCl3) δ: 0.92 (6H, d, J = 6.6, 2 × CH3), 1.76–1.84 (1H, m,
CH(CH3)2), 2.42 (2H, dd, J = 7.2 and 6.9, CH2CH=), 2.65
(2H, t, J = 7.2, ArCH2), 3.14–3.18 (2H, m, CH2NH), 5.54
(1H, br s, NH), 5.76 (1H, d, J = 15.0, 2-CH=), 5.92 (2H, s,
OCH2O), 6.06 (1H, dt, J = 15.3 and 6.9, CH=), 6.14 (1H,
dd, J = 15.3 and 10.0, CH=), 6.61 (1H, d, J = 8.1, ArH),
6.66 (1H, s, ArH), 6.72 (1H, d, J = 8.1, ArH), and 7.18 (1H,
dd, J = 15.0 and 10.0, CH=). 13C NMR (75 MHz, CDCl3) δ:
20.1, 20.1, 28.6, 34.9, 34.9, 46.9, 100.7, 108.1, 108.8, 121.1,
122.2, 128.8, 135.0, 141.0, 141.5, 145.7, 147.5, and 166.3.
MS (EI) m/z (%): 301 (M+, 2), 229 (1), 201 (1), 161 (1), and
135 (100).
(2E,4E,6E)-N-Isobutyl-7-(2-thienyl)heptatrienamide (N-
isobutylotanthusic acid amide, 1j) (1g, 4i)
Yellow solid, 35%; mp 186 to 187 °C (lit. (4i) 186 to
187 °C). IR νmax (KBr disc) (cm–1): 3297, 2924, 1645, 1544,
1
and 995. H NMR (300 MHz, CDCl3) δ: 0.94 (6H, d, J =
6.6, 2 × CH3), 1.79–1.84 (1H, m, CH(CH3)2), 3.18 (2H, t,
J = 6.6, CH2NH), 5.53 (1H, br s, NH), 5.88 (1H, d, J = 14.7,
2-CH=), 6.39 (1H, dd, J = 14.7 and 10.5, CH=), 6.58–6.70
(2H, m, 2 CH=), 6.83 (1H, d, J = 14.7, ArCH=), 6.97–7.02
(2H, m, 2 ArH), 7.21 (1H, d, J = 4.8, ArH), and 7.30 (1H,
dd, J = 14.7 and 10.5, CH=). 13C NMR (75 MHz, CDCl3) δ:
20.1, 20.1, 28.6, 47.0, 123.5, 125.4, 127.0, 127.9, 127.9,
128.4, 130.2, 139.0, 140.7, 142.4, and 166.0. MS (EI) m/z
(%): 261 (M+, 40), 189 (34), 161 (92), 57 (99), and 43 (100).
1-[(2E,4E,6E)-1-Oxo-7-(2-thienyl)heptatrienyl]piperidine
(N-piperidineotanthusic acid amide, 1k) (1g, 4i, 12)
Yellow solid, 32%; mp 113 to 114 °C (lit. (4i) 112.5–
114 °C). IR νmax (KBr disc) (cm–1): 2930, 1632, 1443, 1261,
1-[(2E,4E)-1-Oxo-7-(3,4-methylenedioxyl)phenylhepta-
dienyl]piperidine (piperdardine, 1g) (1c, 12)
Pale yellow oil, 80%. IR νmax (film) (cm–1): 2925, 1713,
1362, 1223, 1093, 1039, and 906. 1H NMR (300 MHz,
CDCl3) δ: 1.56–1.65 (6H, m, 3 CH2), 2.42 (2H, dd, J = 7.5
and 6.9, CH2CH=), 2.66 (2H, t, J = 7.5, ArCH2), 3.49–3.62
(4H, m, 2 CH2N), 5.92 (2H, s, OCH2O), 6.05 (1H, dt, J =
15.0 and 6.9, CH=), 6.19 (1H, dd, J = 15.0 and 10.2, CH=),
6.26 (1H, d, J = 15.0, 2-CH=), 6.60 (1H, dd, J = 7.8 and
1.8, ArH), 6.66 (1H, d, J = 1.8, ArH), 6.72 (1H, d, J = 7.8,
ArH), and 7.22 (1H, dd, J = 15.0 and 10.2, CH=). 13C NMR
(75 MHz, CDCl3) δ: 24.6, 25.6 (br), 26.6 (br), 35.0, 35.0,
43.1 (br), 46.9 (br), 100.8, 108.1, 108.8, 119.1, 121.1, 129.5,
135.1, 140.8, 142.4, 145.7, 147.5, and 165.5. MS (EI) m/z
(%): 313 (M+, 2), 201 (1), 178 (2), 164 (2), and 135 (100).
1
1004, and 852. H NMR (300 MHz, CDCl3) δ: 1.55–1.66
(6H, m, 3 × CH2), 3.56–3.60 (4H, m, 2 × CH2N), 6.38 (1H,
d, J = 14.4, 2-CH=), 6.41 (1H, dd, J = 14.4 and 10.5, CH=),
6.60 (1H, dd, J = 14.4 and 10.5, CH=), 6.65 (1H, dd, J =
14.4 and 10.5, CH=), 6.82 (1H, d, J = 14.4, ArCH=), 6.98
(1H, dd, J = 5.4 and 3.6, ArH), 7.02 (1H, d, J = 3.6), 7.21
(1H, d, J = 5.4, ArH), and 7.34 (1H, dd, J = 14.4 and 10.5,
CH=). 13C NMR (75 MHz, CDCl3) δ: 24.6, 25.6 (br), 26.7
(br), 43.3 (br), 46.9 (br), 120.3, 125.3, 126.9, 127.8, 128.0,
128.2, 130.9, 138.5, 142.2, 142.4, and 165.4. MS (EI) m/z
(%): 273 (M+, 61), 188 (38), 161 (88), 112 (98), and 84
(100).
1-[(2E,4E,6E)-1-Oxo-7-(3,4-methylenedioxyl)phenyl-
heptatrienyl]piperidine (piperettine 1h) (1a, 1c, 12)
White needles, 83%; mp 146 to 147 °C (lit. (1a) 147–
153 °C). IR νmax (KBr disc) (cm–1): 3390, 2932, 1635, 1446,
1-[(2E,4E)-1-Oxo-decadienyl]pyrrolidin (Sarmentine, 1l)
(1h)
Yellow oil, 89%. IR νmax (film) (cm–1): 3360, 2930, 1718,
1
1618, and 1447. H NMR (300 MHz, CDCl3) δ: 0.89 (3H, t,
1
1252, 1036, 930, and 811. H NMR (300 MHz, CDCl3):
J = 6.3, CH3), 1.26–1.47 (6H, m, 3 CH2), 1.86–1.98 (4H, m,
2 CH2), 2.15–2.17 (2H, m, CH2CH=), 3.50–3.54 (4H, m,
1.58–1.75 (6H, m, 3 × CH2), 3.50–3.60 (4H, m, 2 CH2N),
© 2004 NRC Canada

630
Can. J. Chem. Vol. 82, 2004
Prasad, J. Wengel, C.E. Olsen, and P.M. Boll. Phytochemistry,
46, 597 (1997).
2 CH2N), 6.06 (1H, dt, J = 15.0 and 7.5, CH=), 6.08 (1H, d,
J = 15.0, 2-CH=), 6.19 (1H, dd, J = 15.0 and 9.9, CH=), and
7.27 (1H, dd, J = 15.0 and 9.9, CH=). 13C NMR (75 MHz,
CDCl3) δ: 14.0, 22.4, 24.3, 26.0, 28.4, 31.3, 32.9, 45.8, 46.4,
119.8, 128.6, 142.1, 143.1, and 165.2. MS (EI) m/z (%): 221
(M+, 22), 178 (12), 164 (15), 150 (100), and 81 (80)
2. (a) H. Weenen, M.H.H. Nkunya, D.H. Bray, L.B.
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Med. 67, 176 (2001); (d) S. Tsukamoto, B.C. Cha, and T.
Ohta. Tetrahedron, 58, 1667 (2002).
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Indian Chem. Soc. 67, 995 (1990); (b) G.L. Kad, A.K. Arora,
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and C. Ramaro. Tetrahedron Lett. 41, 2667 (2000).
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(b) E.V. Dehmlow and A.R. Shamout. J. Chem. Res. Synop.
106 (1981); (c) J.E. Semple. Org. Prep. Proced. Int. 27, 582
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42, 4975 (1986); (e) T. Mandai, T. Moriyama, K. Tsujimoto,
M. Kawada, and J. Otera. Tetrahedron Lett. 27, 603 (1986);
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(2E,4E)-N-Isobutyl-2,4-decadienamide (pellitorine, 1m)
(1h)
White solid, 77%; mp 64 to 65 °C (lit. (1h) 66–68 °C). IR
ν
max (KBr disc) (cm–1): 3301, 2928, 1668, 1549, 1464, 1269,
1
and 1161. H NMR (300 MHz, CDCl3) δ: 0.89 (3H, t, J =
7.2, CH3), 0.93 (6H, d, J = 6.3, 2 CHCH3), 1.26–1.47
(6H, m, 3 × CH2), 1.76–1.87 (1H, m, CH(CH3)2), 2.14 (2H,
dt, J = 7.2 and 6.6, CH2CH=), 3.17 (2H, t, J = 6.0,
CH2NH), 5.52 (1H, br s, NH), 5.76 (1H, d, J = 15.0, 2-
CH=), 6.04 (1H, dt, J = 15.0 and 7.2, CH=), 6.14 (1H, dd,
J = 15.0 and 9.3, CH=), and 7.20 (1H, dd, J = 15.0 and 9.3,
CH=). 13C NMR (75 MHz, CDCl3) δ: 14.0, 20.1, 20.1, 22.4,
28.4, 28.6, 31.3, 32.9, 46.9, 121.7, 128.1, 141.3, 143.2, and
166.4. MS (EI) m/z (%): 223 (M+, 24), 151 (100), 96 (62),
and 81 (69).
1-[(2E,4E)-1-Oxo-decadienyl]piperidine (neopellitorine B,
1n) (1i, 12)
Yellow oil, 75%. IR νmax (film) (cm–1): 3374, 2930, 1620,
1
1446, 1258, and 1019. H NMR (300 MHz, CDCl3) δ: 0.89
(3H, t, J = 6.6, CH3), 1.26–1.47 (6H, m, 3 × CH2), 1.53–
1.68 (6H, m, 3 × CH2), 2.14 (2H, dt, J = 7.2 and 7.2,
CH2CH=), 3.55–3.60 (4H, m, 2 × CH2N), 6.06 (1H, dt, J =
15.0 and 7.2, CH=), 6.18 (1H, dd, J = 15.0 and 10.5, CH=),
6.26 (1H, d, J = 15.0, 2-CH=), and 7.24 (1H, dd, J = 15.0
and 10.5, CH=). 13C NMR (75 MHz, CDCl3) δ: 14.0, 22.4,
24.6, 26.3 (br), 28.5, 31.3, 32.9, 43.3 (br), 46.6 (br), 118.5,
128.8, 142.6, 142.8, and 165.7. MS (EI) m/z (%): 235 (M+,
3), 164 (8), 138 (100), 112 (8), and 84 (53).
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dron Lett. 37, 1049 (1996); (d) X.P. Cao. Tetrahedron, 58,
1301 (2002); (e) X.P. Cao, Y.Y. Yang, and X.L. Wang. J.
Chem. Soc. Perkin Trans. 1, 2485 (2002).
Acknowledgements
We are grateful to the National Natural Science Founda-
tion of China (NSFC, QT program, No. 20021001) and the
Natural Science Foundation of Gansu province (ZS011-A25-
003-Z).
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© 2004 NRC Canada