Highly efficient and concise synthesis of both antipodes of SB204900, clausenamide, neoclausenamide, homoclausenamide and ζ-clausenamide. Implication of biosynthetic pathways of clausena alkaloids

Article abstract of DOI:10.1039/b901965k

The synthesis of both antipodes of N-methyl-N-[(Z)-styryl]-3-phenyloxirane- 2-carboxamide (SB204900), clausenamide, neoclausenamide, homoclausenamide and ζ-clausenamide have been accomplished using (2S,3R)- and (2R,3S)-3-phenyloxirane-2-carboxamides as the starting materials, and SB204900 was found to be a common precursor to other N-heterocyclic clausena alkaloids. Mediated by Bronsted acids under different conditions, for example, SB204900 underwent efficient and diverse alkene-epoxide cyclization, enamide-epoxide cyclization and arene-epoxide cyclization reactions to produce the five-membered N-heterocyclic neoclausenamide, its 6-epimer, the six-membered N-heterocyclic homoclausenamide and the eight-membered N-heterocyclic ζ-clausenamide, respectively, in good to excellent yields. Regiospecific oxidation of neoclausenamide and its 6-epimer afforded neoclausenamidone. Enolization of neoclausenamidone in the presence of LiOH and the subsequent protonation under kinetic conditions at -78 °C led to the epimerization of neoclausenamidone into clausenamidone. Reduction of clausenamidone using NaBH₄ furnished clausenamide in high yield. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b901965k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Highly efficient and concise synthesis of both antipodes of SB204900,
clausenamide, neoclausenamide, homoclausenamide and f-clausenamide.
Implication of biosynthetic pathways of clausena alkaloids†
Luo Yang, De-Xian Wang, Qi-Yu Zheng, Jie Pan, Zhi-Tang Huang and Mei-Xiang Wang*
Received 29th January 2009, Accepted 8th April 2009
First published as an Advance Article on the web 5th May 2009
DOI: 10.1039/b901965k
The synthesis of both antipodes of N-methyl-N-[(Z)-styryl]-3-phenyloxirane-2-carboxamide
(SB204900), clausenamide, neoclausenamide, homoclausenamide and z-clausenamide have been
accomplished using (2S,3R)- and (2R,3S)-3-phenyloxirane-2-carboxamides as the starting materials,
and SB204900 was found to be a common precursor to other N-heterocyclic clausena alkaloids.
Mediated by Brønsted acids under different conditions, for example, SB204900 underwent efficient and
diverse alkene-epoxide cyclization, enamide-epoxide cyclization and arene-epoxide cyclization reactions
to produce the five-membered N-heterocyclic neoclausenamide, its 6-epimer, the six-membered
N-heterocyclic homoclausenamide and the eight-membered N-heterocyclic z-clausenamide,
respectively, in good to excellent yields. Regiospecific oxidation of neoclausenamide and its 6-epimer
afforded neoclausenamidone. Enolization of neoclausenamidone in the presence of LiOH and the
subsequent protonation under kinetic conditions at -78 ◦C led to the epimerization of
neoclausenamidone into clausenamidone. Reduction of clausenamidone using NaBH4 furnished
clausenamide in high yield.
Introduction
Rutaceae Clausena lansium (Lour.) Skeels is a fruit tree widely
distributed in southern China. In folk medicine, its leaves and
fruits are used to treat asthma, influenza, gastrointestinal dis-
orders, viral hepatitis and dermatological diseases.1 Due to the
pioneering work of Huang and her co-workers1 in the mid to late
1980s, a number of clausena alkaloids including clausenamide
1,2,3 neoclausenamide 2 (a diastereoisomer of clausenamide 1),3,4
homoclausenamide 3,5 z-clausenamide 45 and cycloclausenamide
53,4 (Scheme 1) were isolated from the hot-water extract of the
leaves. Interestingly, while the former four alkaloids were isolated
in racemic form, cycloclausenamide was optically active. Clausena
alkaloids have been shown to possess efficacious liver-protecting
and antiamnesia effects.1 Later, lansimide-3 6 (Scheme 1),6
a
hydrated form of homoclausenamide was reported. In 1996,
Milner and co-workers7 isolated the optically active (+)-N-methyl-
N-[(Z)-styryl]-3-phenyloxirane-2-carboxamide, SB-204900 (+)-7
(Scheme 1), from a hexane extract of Clausena lansium leaves.
Despite the important pharmacological activity and interesting
molecular structures, the synthesis of clausena alkaloids has re-
mained largely unexplored.8 The same is true for the investigation
of biological synthetic pathways9 for the generation of diverse
structures of clausena alkaloids. For years, we have been studying
enantioselective nitrile biotransformations for the synthesis of
Scheme 1 Structures of alkaloids 1–7 from Clausena lansium (Lour.)
Skeels and hypothetic transformations of 7 into five-, six- and eight-mem-
bered lactams.
enantiopure carboxylic acids and their amide derivatives.10 Re-
cently, we established an efficient method for the preparation of
highly enantio-enriched oxirane-carboxamides.11 That study led
us to address the biosynthetic pathways and the organic synthesis
of clausena alkaloids.
We envisioned that the oxirane-containing enamide 7 might
be a common intermediate or precursor to five-, six- and eight-
membered lactam products. As hypothesized in Scheme 1, for
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory
of Molecular Recognition and Function, Institute of Chemistry, Chinese
Academy of Sciences, Beijing, 100190, China. E-mail: mxwang@iccas.ac.cn;
Fax: +8610-62564723; Tel: +8610-62565610
† Electronic supplementary information (ESI) available: Full characteri-
zation of products, 1H and 13C NMR spectra of products, HPLC analysis
of all chiral products. See DOI: 10.1039/b901965k
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Table 1 Reactions of ( )-7 under different conditions
Entry
Conditions
( )-2 + ( )-2¢ (%)a
( )-3 (%)a
( )-4 (%)a
( )-8 (%)a
1
2
3
4
5
6
7
8
9
CH3CN, reflux, 12 h
—
—
—
—
—
—
–
—
—
—
—
—
51
64
44
—
—
—
—
—
—
—
70
86
24
<5
27
37
27
36
—
—
—
—
—
—
—
—
—
42
—
—
—
H2O (2 equiv), CH3CN, reflux, 12 h
CH3CO2H (2 equiv), H2O (2 equiv), CH3CN, reflux, 12 h
HCl (aq.) (2 equiv), CH3CN, rt, 2 h
p-CH3C6H4SO3H (2 equiv), CH3CN, rt, 2 h
p-CH3C6H4SO3H (1 equiv), t-BuOH, rt, 8 h
p-CH3C6H4SO3H (1 equiv), t-BuOH, reflux, 1 h
CF3CO2H (2 equiv), t-BuOH, reflux, 12 h
CF3CO2H (2 equiv), CH3OH, rt, 26 h
H2O, reflux, 5 h
–
–
10
11
12
69b
55b
75b
CH3CO2H (2 equiv), H2O, reflux, 5h
Na2CO3 (2 equiv), H2O, reflux, 5 h
a Isolated yield. b The ratio of neocausenamide 2 over its 6-epimer was 3 : 7.
example, intramolecular enamide-epoxide ring opening reaction
(pathway b) would lead to the formation of six-membered
homoclausenamide while the intramolecular arene-epoxide ring
opening reaction (pathway c) would produce eight-membered
z-clausenamide. The five-membered lactam compound would
result from alkene-epoxide ring opening reaction (pathway a).
Herein we report a systematic study of the transformations of
oxirane-containing enamide 7,12 proposing for the first time the
(bio)synthetic pathways for diverse clausenamide alkaloids. Based
on the (bio)synthetic pathways, we have also accomplished concise
and biomimetic synthesis of both antipodes of five-, six- and eight-
membered lactam alkaloids.
of ( )-7, affording z-clausenamide ( )-4 in 70% yield (entry 4,
Table 1). The use of p-toluenesulfonic acid further improved the
conversion of ( )-7 and z-clausenamide ( )-4 was obtained in 86%
yield (entry 5, Table 1). Interestingly, when the p-toluenesulfonic
acid-mediated reaction of ( )-7 was performed in t-butyl alcohol
for 8 h, six-membered homoclausenamide ( )-3 was obtained
in addition to the formation of z-clausenamide ( )-4 (entry 6,
Table 1). Shortening reaction time to 1 h led to the formation of
homoclausenamide ( )-3 in an improved chemical yield (entry 7,
Table 1). It should be noted that trifluoroacetic acid appeared
effective to promote the transformation of ( )-7 into ( )-4 and
( )-3 albeit in low chemical yields (entry 8, Table 1). Methanol as
a solvent was found, however, to have a detrimental effect, as it
attacked the epoxide ring to give simply the epoxide-ring opening
product ( )-8 as the major product (entry 9, Table 1). We finally
tested the transformations of oxirane enamide ( )-7 in water. While
it was quite stable at room temperature in water, oxirane enamide
( )-7 underwent efficient transformations in boiling water. To our
delight, a mixture of five-membered lactam products ( )-2 and ( )-
2¢ was obtained in 69% yield in addition to z-clausenamide ( )-4
in 27% yield (entry 10, Table 1). It is noteworthy that the presence
of acetic acid (2 equiv) was found to favour slightly the formation
of eight-membered lactam ( )-4 (entry 11, Table 1). Basic reaction
conditions using two equivalents of sodium carbonate gave rise
Results and discussion
To test our hypothesis of biosynthetic pathways of clausena
alkaloids, we investigated the transformations of racemic oxirane
enamide ( )-7 under various conditions. We first examined the
reaction of enamide in organic solvents. No reactions were
observed when compound ( )-7 was heated in acetonitrile for 12 h
(entry 1, Table 1). Addition of water (2 equiv) and a weak acid
such as acetic acid (2 equiv) did not effect the transformation
either (entries 2 and 3, Table 1). Hydrochloric acid, a strong
Brønsted acid, was then found to promote efficiently the reaction
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to the exclusive formation of five-membered heterocyclic products
( )-2 and ( )-2¢ in 75% yield (entry 12, Table 1). The ratio of
neoclausenamide ( )-2 over its 6-epimer ( )-2¢, as determined by
measuring the intensity of 6-H signals of ( )-2 and ( )-2¢ in the 1H
NMR spectrum, was roughly 3 : 7 (entries 10–12, Table 1).
The transformations of enamide ( )-7 into five-, six- and
eight-membered lactams under different reaction conditions were
intriguing. It was apparent that the reaction pathways were
strongly influenced by both Brønsted acid and, more remarkably,
solvent used. While the detailed mechanisms await further study,
we proposed in Scheme 2 the plausible chemical conversions of
oxirane-enamide SB204900 ( )-7 into the five-, six- and eight-
membered lactam products ( )-2, ( )-2¢, ( )-3 and ( )-4.
furnish homoclausenamide product ( )-3. The transformation of
( )-7 into the g-lactam products ( )-2 and ( )-2¢ appeared most
surprising. A plausible reaction pathway might involve the attack
of the a-carbon of the enamide moiety of ( )-7 to the benzylic
carbon of the epoxide.13 The resulting zwitterion intermediate 9
reacts with water to yield a mixture of epimers ( )-2 and ( )-2¢.
The function of the a-carbon rather than the b-carbon (enaminic
carbon) of the enamide as the nucleophilic site to attack the
epoxide ring would suggest that the lone pair electrons on the
nitrogen delocalize into the carbonyl rather than the carbon–
carbon double bond. In other words, under the reaction conditions
such as in pure water or under basic conditions, the oxirane-
enamide molecule ( )-7 might adopt the conformation ( )-7¢ in
which the amido plane might be perpendicular to the plane
of the carbon–carbon double bond. This conformation inhibits
delocalization of the lone pair electrons of nitrogen into the
carbon–carbon double bond, alleviating therefore the character
of enamide and the nucleophilicity of the “enaminic b-carbon”
of enamide. The conformation ( )-7¢ also brings the proximity
of the p-orbital of the a-carbon with the benzylic carbon of the
epoxide ring, facilitating the 5-endo-enamide-epoxide cyclization
reaction. In addition, the stabilization gained from the formation
of benzylic cation 9 might also be a factor in the 5-endo-enamide-
epoxide cyclization.
In biological systems, there are microenvironments of varied
acidity and lipophilicity or hydrophility. It is most likely that,
in these different acidic and hydrophilic biological microenviron-
ments, oxirane-epoxide ( )-7 undergoes different intramolecular
reactions to give naturally occurring neoclausenamide ( )-2,
homoclausenamide ( )-3 and z-clausenamide ( )-4. At this point,
however, we cannot exclude an artifact, viz. the possibility of
conversions of ( )-7 into clausena alkaloids ( )-2, ( )-2¢, ( )-3
and ( )-4 during the isolation process.
Although racemic SB204900 ( )-7 was shown convincingly to
be the common precursor to neoclusenamide ( )-2, homocaluse-
namide ( )-3 and z-clausenamide ( )-4, unfortunately, no clause-
namide ( )-1 was obtained from ( )-7 under any of the reaction
conditions tested. We then investigated the reaction of racemic
N-(E-styryl)-3-phenyloxirane-2-carboxamide ( )-13, an isomer of
( )-7, envisaging the configuration of enamide double bond might
play a subtle role in intramolecular cyclization reactions.12b When
refluxed in pure water for 5 h in a large-scale reaction (10 mmol),
( )-13 was efficiently transformed into a mixture of neoclause-
namide ( )-2 and its 6-epimer ( )-2¢ in 91% yield (Scheme 3).
In contrast to the reaction of ( )-7, the E-configured enamide
( )-13 did not undergo intramolecular arene-epoxide cyclization
to produce z-clausenamide ( )-4 at all, because of the unfavourable
molecular geometry. No clausenamide product was formed from
( )-13 either. Interestingly, however, cycloclausenamide ( )-5 was
isolated in 4% yield. Using racemic N-(E-4-methoxyphenylvinyl)-
3-phenyloxirane-2-carboxamide ( )-14 as reactant, the identi-
cal reaction afforded a mixture of neoclausenamide derivatives
( )-15 and ( )-15¢ in 68% and cycloclausenamide derivative ( )-16
in 32% (Scheme 3). These reaction outcomes indicated that the
reaction of ( )-14 in pure water proceeded via the same zwitterion
intermediate 9 as the reaction of ( )-7. Cyclization of 9 led to the
formation of cycloclausenamide ( )-5. In the case of ( )-15, the
introduction of a para-methoxy group at the benzene ring resulted
in the stabilization of the benzyl cation structure of intermediate 9,
Scheme 2 Plausible mechanisms of the transformations of ( )-7.
The formation of z-clausenamide would most probably arise
from an intramolecular Friedel–Crafts reaction.13 As illustrated
in Scheme 2, protonation of epoxide ( )-7 gives rise to oxonium
intermediate 10 which undergoes an electrophilic reaction with the
benzene moiety to afford 5,6-dihydrobenzo[d]azocin-4(3H)-one
structure ( )-4. It should be noted that the facile intramolecular
aryl-epoxide cyclization of ( )-7 in acetonitrile is determined by
its intrinsic favourable electronic effect and folded conformational
structure that was revealed by X-ray single crystal diffraction
analysis.7 Both the delocalization of enamide electrons into the
benzene ring and the perfectly predisposed conformational struc-
ture dictate the 8-endo-epoxy-arene cyclization. When reacted in
t-butyl alcohol, a more polar and protonic solvent, the protonated
intermediate adopts most likely a chair conformation 10. Enam-
inic attack of enamide on the oxonium results in the formation
of iminium intermediate 11, which undergoes deprotonation to
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product ( )-17 (Scheme 4). To account for the formation of
naturally occurring lansamide-3 6, we proposed a rapid trap of
the intermediate 11 by a water molecule.
Since chemical transformation of ( )-7 did not straightfor-
wardly afford clausenamide ( )-1, the naturally occurring clause-
namide ( )-1 would probably be generated from ( )-7 by the action
of an enzyme. Alternatively clausenamide ( )-1 would be formed
from its stereoisomer neoclausenamide ( )-2; viz., a redox process
might be responsible for the conversion of neoclausenamide
( )-2 into clausenamide ( )-1 in the biological system. As depicted
in Scheme 5, selective oxidation of the hydroxyl group at the 6-
position would result in the ketone derivative. The consecutive
epimerization at the 5-position due to the acidity of the 5-position
hydrogen, and the reduction of the carbonyl group would finally
furnish the clausenamide product.
Scheme
3
Reaction of N-(E-styryl)-3-phenyloxirane-2-carboxamide
( )-13.
leading thus to an improved chemical yield of cycloclausenamide
derivative ( )-16.
It is also worth noting that no clausenamide ( )-1 was ob-
tained either from the reaction of ( )-13 under acidic conditions.
Careful scrutiny of a large scale reaction (10 mmol) of oxirane-
containing enamide ( )-13 in the presence of two equivalents of
trifluoroacetic acid, however, allowed us to isolate a trace amount
of a new compound ( )-17 in addition to homoclausenamide ( )-3
(Scheme 3). On the basis of spectroscopic evidence, especially the
NOE data, the compound was assigned as d-lactam ( )-17 with
four substituents on the six-membered N-heterocycle being all
trans-configured to each other. It is a derivative of the stereoisomer
of lansamide-3 6. The formation of ( )-17 is most probably due
to the protonation of homoclausenamide, giving an all trans-
configured iminium intermediate 18 (Scheme 4). Nucleophilic
attack of t-butyl alcohol at iminium intermediate 18 from the
less sterically hindered side of the six-membered ring afforded
Scheme 5 Proposed biosynthetic route from neoclausenamide ( )-2 to
clausenamide ( )-1.
Following our hypothetical route, we studied the selective
oxidation of neoclausenamide ( )-2 and its 6-epimer ( )-2¢ [( )-2 :
( )-2¢ = 3 : 7], a mixture obtained directly from ( )-7. Treatment
of the mixture with KMnO4 gave rise to the oxidation of both
hydroxyl groups at 3- and 6-positions, while the use of MnO2 as
an oxidant did not effect any reaction of neoclausenamide or its 6-
epimer. Finally we found that the efficient oxidation reaction using
Jones’ reagent occurred highly selectively at the 6-position of com-
pounds ( )-2 and ( )-2¢, affording the neoclausenamidone product
( )-19 in 93% yield (Scheme 6). Having ketone ( )-19 at hand,
we thought the enolization of neoclausenamidone ( )-19 and the
consecutive reduction of enol in a one-pot reaction fashion might
give rise to the desired clausenamide ( )-1. Hydrogenation of
neoclausenamidone ( )-19 with palladium on carbon (10%) as the
catalyst, however, gave only a mixture of neoclausenamide ( )-2
and its 6-epimer ( )-2¢. Nevertheless, the ratio of neoclausenamide
( )-2 over its 6-epimer ( )-2¢ was increased to 8 : 2 (Scheme 6)
in comparison with that (3 : 7) of the mixture obtained directly
from the intramolecular alkene-epoxide cyclization of ( )-7. When
treated with LiOH in CDCl3–D2O (v/v 10 : 1) solution, the
enolization of ketone ( )-19 was evidenced by the 1H NMR
spectrum in which a new set of proton signals at 4.91 (d, J = 9.7 Hz,
1H), 3.86 (d, J = 9.8 Hz, 1H) and 2.87 (s, 3H) were observed (see
ESI†). The quench of enolate 21 with hydrochloric acid at room
temperature gave mainly the starting neoclausenamidone ( )-19,
with only a small amount of epimer clausenamidone ( )-20 being
generated [( )-19 : ( )-20 = 98 : 2]. This indicated clearly that
Scheme 4 Proposed mechanism for the formation of ( )-17.
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Scheme 6 Conversion of a mixture of ( )-2 and ( )-2¢ into clausenamide
( )-1 and neoclausenamide ( )-2.
neoclausenamidone ( )-19 is thermodynamically more stable than
clausenamidone ( )-20. Under kinetic reaction conditions such as
◦
at a temperature of -78 C, protonation of enolate 21 led to an
improved chemical yield of epimer ( )-20 [( )-19 : ( )-20 = 60 :
18]. Thus, clausenamidone ( )-20 was obtained in 64% yield from
neoclausenamidone ( )-19 after two runs of protonation of enolate
21 at -78 ◦C (Scheme 6). The reduction of clausenamidone ( )-20
by NaBH4 in methanol furnished the desired clausenamide ( )-1
in 92% yield (Scheme 6).
Although clausena alkaloids 1–4 were isolated from nature
in racemic form, pharmacological studies indicate that differ-
ent enantiopure stereoisomers exhibit varied biological activity.1
Having established the reaction pathways for the conversion
of racemic SB204900 ( )-7 into other clausena alkaloids, we
attempted the synthesis of both antipodes of five-, six- and eight-
membered lactam alkaloids (Scheme 7). Starting with (2S,3R)-
3-phenyloxirane-2-carboxamide (+)-22, which was prepared from
Sharpless epoxidation of cinnamyl alcohol followed by oxidation,
esterification and ammonolysis,14 the CuI-catalyzed N-styrylation
of amide (+)-22 with Z-styryl bromide followed by N-methylation
afforded naturally occurring (+)-SB204900 (+)-7 in good yield.
Employing the aforementioned optimized conditions, we readily
converted (+)-7 into eight-membered (-)-z-clausenamide (-)-4
and (-)-homoclausenamide (-)-3 in 86% and 62% yields, respec-
tively. Under basic conditions, enamide (+)-7 underwent 5-endo
cyclization to produce a mixture of neoclausenamide and its 6-
epimer in a total yield of 75%. Oxidation using Jones’ reagent led
to (+)-neoclausenamidone (+)-19 in 91% yield. Hydrogenation of
(+)-19 afforded a quantitative yield of (-)-neoclausenamide (-)-2
and its 6-epimer 2¢ with the ratio being 8 : 2. Epimerization of
(+)-19 under kinetic condition through enolate intermediate gave
(-)-clausenamidone (-)-20. NaBH4 reduction of (-)-clausenami-
done (-)-20 under mild conditions yielded (-)-clausenamide
Scheme 7 Synthesis of enantiopure clausena alkaloids.
(-)-1 in 90% yield. In all chemical transformations, no racem-
ization of the compounds was observed. When (2R,3S)-
3-phenyloxirane-2-carboxamide (-)-22, an enantiopure reac-
tant prepared from nitrile biotransformations11a was used,
the same chemical manipulations allowed us to synthesize
(-)-SB20490012a and (+)-homoclausenamide, (+)-z-clausena-
mide,12a (+)-neoclausenamide and (+)-clausenamide (see ESI†).
Conclusion
In summary, we have demonstrated that N-methyl-N-[(Z)-styryl]-
3-phenyloxirane-2-carboxamide, namely, racemic SB204900
( )-7, was a common precursor to other N-heterocyclic alkaloids
in Rutaceae Clausena lansium (Lour.) Skeels. Under different
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conditions, ( )-7 underwent efficient and diverse cyclization reac-
tions to form the five-membered N-heterocyclic neoclausenamide
and its 6-epimer, the six-membered N-heterocyclic homoclause-
namide and the eight-membered N-heterocyclic z-clausenamide,
respectively, in good to excellent yields. We have also shown
that neoclausenamide and its 6-epimer were readily oxidized
regiospecifically to afford neoclausenamidone. Enolization of
neoclausenamidone in the presence of LiOH and the subse-
quent protonation under kinetic conditions at -78 ◦C led to
the epimerization of neoclausenamidone into clausenamidone.
Reduction of neoclausenamidone and clausenamidone furnished
neoclausenamide and clausenamide, respectively, in excellent
yields. The facile interconversions of racemic SB204900 into
other clausena alkaloids and the transformation of neoclause-
namide into clausenamide most probably imply the synthetic
pathways of all clausena alkaloids from SB204900 in biolog-
ical systems. Following the biosynthetic pathways, the con-
cise synthesis of both antipodes of SB204900, clausenamide,
neoclausenamide, homoclausenamide and z-clausenamide have
been accomplished using (2S,3R)- and (2R,3S)-3-phenyloxirane-
2-carboxamides as the starting materials. The easy availability of
a wide variety of N-(2-arylvinyl)-3-aryloxirane-2-carboxamides
should render efficient and diverse reactions powerful for the
construction of natural product-like libraries for biological
studies.
140 mg) and p-TSA (1 mmol, 172 mg) in dry acetonitrile (15 mL)
was stirred at room temperature until the starting material was
completely consumed. Water (100 mL) was added and the mixture
was extracted with ethyl acetate (3 ¥ 50 mL). The organic layer
was dried with anhydrous Na2SO4, filtered and concentrated. The
residue was subjected to a silica gel (200–300 mesh) column eluted
with a mixture of petroleum ether and ethyl acetate (1 : 1) to
afford pure (-)-z-clausenamide (-)-4 (122mg, 86%) as a yellow
oil.
Synthesis of (-)-homoclausenamide (-)-3
Our previous method for the reaction of racemic N-(E-styryl)-
3-phenyloxirane-2-carboxamide ( )-13 was adopted.12b A mixture
of (+)-7 (1 mmol, 279 mg) in dry t-BuOH (30 mL) under argon
protection was heated to reflux. p-TSA (1 mmol, 172 mg) was
then added, and the mixture was refluxed for another 1 h. After
cooling to room temperature, a saturated aqueous solution of
NaHCO3 (30 mL) was added, and the resulting mixture was
extracted with ethyl acetate (3 ¥ 20 mL). The organic layer was
dried with anhydrous Na2SO4, filtered and concentrated under
vacuum. Pure (-)-homoclausenamide (-)-3 (173 mg, 62%) was
obtained after silica gel (200–300 mesh) column chromatography
using a mixture of petroleum ether and ethyl acetate (1 : 1) as an
eluant.
Intramolecular alkene-epoxide cyclization of (+)-7
Experimental section
Refluxing a suspension of (+)-7 (1 mmol, 279 mg) in an aqueous
Na2CO3 solution (2 mmol, 212 mg in 30 mL of pure water) for
5 h under argon protection gave rise to a homogeneous solution.
After addition of brine (30 mL), the mixture was extracted with
ethyl acetate (3 ¥ 20 mL). The organic layer was dried with
anhydrous Na2SO4, filtered and concentrated under vacuum.
Chromatography on a silica gel (200–300 mesh) column eluting
with a mixture of ethyl acetate and methanol (95 : 5) gave a mixture
of enantiopure products 2 and 2¢ (224 mg, 75%). The ratio of 2 over
2¢, which was determined roughly by 1H NMR integration, was 3 :
7. The same mixture of racemic products was obtained from the
reaction of racemic N-(E-styryl)-3-phenyloxirane-2-carboxamide
( )-13 in boiling water.12b
Synthesis of (+)-SB204900 (+)-7
The synthesis of (+)-SB204900 (+)-7 was based on our previous
method for its enantiomer (-)-7.12a Under argon protection, a
mixture of enantiopure (2S,3R)-3-phenyloxirane-2-carboxamide14
(1 mmol, 163 mg), CuI (0.4 mmol, 76 mg), N,N-dimethylglycine
hydrochloride (0.8 mmol, 112 mg), Cs2CO3 (2 mmol, 650 mg) and
Z-styryl bromide (3 mmol, 549 mg) in dry 1,4-dioxane (34 mL)
was refluxed for 3 h. After cooling to room temperature, ethyl
acetate (100 mL) was added and the resulting mixture was filtered
through a short silica gel (100–200 mesh) pad. The filtrate was
concentrated and the residue was subjected to a silica gel (200–
300 mesh) column eluted with a mixture of petroleum ether and
ethyl acetate (10 : 1) to give (+)-23 (201 mg, 76%) as the pure
product.
Preparation of (+)-neoclausenamidone (+)-19
To an ice-bath cooled solution of (+)-23 (0.5 mmol, 133 mg)
in dry DMF (3 mL) under argon protection was added NaH
(2 mmol, 48 mg). After stirring for 0.5 h, methyl iodide (6 mmol,
0.375 mL) was added and the resulting mixture was kept stirring
for another 2 h. Water (50 mL) was then added and the mixture
was extracted with ethyl acetate (3 ¥ 15 mL). The organic layer
was washed with brine and dried with anhydrous Na2SO4, filtered
and concentrated. Pure (+)-SB204900 (+)-7 was obtained as a pale
yellow oil (124 mg, 94%) from silica gel (200–300 mesh) column
chromatography using a mixture of petroleum ether and ethyl
acetate (3 : 1) as the mobile phase.
A mixture of enantiopure 2 and 2¢ (2 : 2¢ = 3 : 7) (0.5 mmol, 149 mg)
was dissolved in acetone (20 mL). Jones’ reagent (0.5 mmol,
2.672 M, 0.187 mL) was then added while stirring. After 5 min,
water (100 mL) was added and the mixture was extracted with
ethyl acetate (3 ¥ 50 mL). The combined organic layer was
dried with anhydrous Na2SO4, filtered and concentrated. The
residue was subjected to a silica gel (200–300 mesh) column eluted
with a mixture of CH2Cl2 and ethyl acetate (1 : 1) to afford
pure (+)-neoclausenamidone (+)-19 (134 mg, 91%) as a white
solid.
Synthesis of (-)-neoclausenamide (-)-2
Synthesis of (-)-f-clausenamide (-)-4
(+)-Neoclausenamidone (+)-19 (0.5 mmol, 148 mg) and
LiOH·H2O (1 mmol, 42 mg) were dissolved in a mixture of THF
and H2O (v/v = 1 : 1, 15 mL). After stirring at room temperature
The synthesis of z-clausenamide (-)-4 was based on our previous
method for its enantiomer (+)-4.12a A solution of (+)-7 (0.5 mmol,
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for 30 min, Pd/C (15 mg, 10%) was added and the resulting
mixture was stirred at room temperature overnight under hydrogen
atmosphere using a hydrogen balloon. Water (50 mL) was added
and the mixture was extracted with ethyl acetate (3 ¥ 50 mL). The
combined organic layer was dried with anhydrous Na2SO4, filtered
and concentrated under vacuum. The residue was subjected to a
silica gel (200–300 mesh) column eluted with a mixture of CH2Cl2
and ethyl acetate (1 : 2) to afford a mixture of (-)-neoclausenamide
(-)-2 and its 6-epimer 2¢ (149 mg, 100%) as a white solid. The
Acknowledgements
We thank the Ministry of Science and Technology
(2009CB724704, 2006CB806106), the National Natural Science
Foundation of China (20772132, 20820102034) and Chinese
Academy of Sciences for financial support.
Notes and references
1 L. Huang, M.-Z. Wang, J.-T. Zhang, and C.-J. Zhu, in The Chemistry
and Biology of Chiral Drugs, ed. L. Huang, L.-X. Dai, C.-P. Du and L.
Wu, Chemical Industry Press, Beijing, 2002, pp. 6–67.
2 M.-H. Yang, Y.-H. Cao, W.-X. Li, Y.-Q. Yang, Y.-Y. Chen and L.
Huang, Acta Pharm. Sin., 1987, 22, 33.
1
ratio of 2 over 2¢, which was determined by H NMR, was 8 :
2. Recrystallization of the mixture in petroleum ether and ethyl
acetate afforded pure (-)-neoclausenamide (-)-2.
3 M.-H. Yang, Y.-Y. Chen and L. Huang, Phytochemistry, 1988, 27, 445.
4 M.-H. Yang, Y.-Y. Chen and L. Huang, Acta Chim. Sin., 1987, 45,
1170.
5 M.-H. Yang, Y.-Y. Chen and L. Huang, Chin. Chem. Lett., 1991, 2,
291.
Conversion of (+)-neoclausenamidone (+)-19 into
(-)-clausenamidone (-)-20
(+)-Neoclausenamidone (+)-19 (0.5 mmol, 148 mg) and
LiOH·H2O (2 mmol, 84 mg) were mixed in THF and H2O (v/v =
1 : 1, 10 mL). After stirrin◦g at room temperatur◦e for 12 h, the
mixture was cooled to -78 C and stirred at -78 C for another
12 h. Then, a solution of HCl in THF (2 M, 1 mL) was added
using a syringe at -78 ◦C. The temperature of the reaction mixture
was then raised gradually to room temperature within about 2 h.
Water (50 mL) was added and the mixture was extracted with
ethyl acetate (3 ¥ 50 mL). The combined organic layer was dried
with anhydrous Na2SO4, filtered and concentrated under vacuum.
The residue was subjected to a silica gel (200–300 mesh) column
eluted with a mixture of CH2Cl2 and ethyl acetate (1 : 1) to afford
pure (-)-clausenamidone (46 mg) as a white solid. The recovered
(+)-neoclausenamidone (102 mg) was subjected to epimerization
again to give another 44 mg of pure (-)-clausenamidone (-)-20.
The combined yield was 61%.
6 X. Ji, D. Van der Helm, V. Lakshmi, A. K. Agarwal and R. S. Kapil,
Acta Crystallogr., Sect. C, 1992, 48, 1082.
7 P. H. Milner, N. J. Coates, M. L. Gilpin and S. R. Spear, J. Nat. Prod.,
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Wang and W.-S. Tian, J. Chem. Soc., Perkin Trans. 1, 1996, 209; (c) N.
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(g) M. W. Cappi, W.-P. Chen, R. W. Flood, Y.-W. Liao, S. M. Roberts,
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nitriles, see: M.-X. Wang, Top. Catal., 2005, 35, 117–130; (b) For recent
examples, see: D.-Y. Ma, D.-X. Wang, J. Pan, Z.-T. Huang and M.-X.
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Synthesis of (-)-clausenamide (-)-1
The reduction of (-)-clausenamidone (-)-20 followed a literature
method.8g To a solution of (-)-clausenamidone (-)-20 (0.5 mmol,
148 mg) in methanol (10 mL) was added NaBH4 (0.5 mmol,
20 mg) while stirring at room temperature. Monitored by TLC, the
reactant was completely consumed in 2 h. Water (10 mL) and 2 mL
of hydrochloric acid (2 M) were added consecutively to decompose
reducing agent NaBH4. The mixture was neutralized by aqueous
NaOH solution (1 M) and extracted with ethyl acetate (3 ¥ 50 mL).
The combined organic layer was dried with anhydrous Na2SO4,
filtered and concentrated. The residue was subjected to a silica
gel (200–300 mesh) column eluted with a mixture of methanol
and ethyl acetate (5 : 95) to afford pure (-)-clausenamide (-)-1
(133 mg, 90%) as a white solid.
11 (a) M.-X. Wang, S.-J. Lin, C.-S. Liu, Q.-Y. Zheng and J.-S. Li, J. Org.
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Int., 1992, 24, 245.
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Chem. Soc., 1980, 102, 5974–5978; (b) Y. Gao, R. M. Hanson, J. M.
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see: D.-F. Huang and L. Huang, Tetrahedron, 1990, 46, 3135.
2634 | Org. Biomol. Chem., 2009, 7, 2628–2634
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The Royal Society of Chemistry 2009
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