A pyridinium anionic ring-opening reaction applied to the stereodivergent syntheses of: Piperaceae natural products

Article abstract of DOI:10.1039/d0ob01745k

A stereodivergent strategy has been devised to access the diene motif found in biologically active compounds from the Piperaceae family. Herein the first total syntheses of 2E,4E configured piperchabamide E (2) and its enantiomer (ent-2), as well as 2E,4Z configured scutifoliamide B (3), are narrated. The mainstay in the adopted approach is the gram-scale conversion of quaternized pyridine in a practical three-step sequence to access isomerically pure conjugated bromodiene esters 2E,4E8 and 2E,4Z9 by differential crystallization. Even though the developed oxidation protocol forms the basis of the entailed divergent strategy, the geometrical integrity of the involved bromodiene motive can be controlled by the choice of solvent. Thus, while oxidation of pure bromodienal 2E,4Z7 in methanol yields equal amounts of bromodiene esters 2E,4E8 and 2E,4Z9, only bromodiene ester 2E,4Z10 is formed in isopropanol. Subseqently, capitalizing on a stereoretentive Suzuki cross-coupling and direct amidation of the corresponding esters, the featured natural products can be accessed in five and six steps, respectively. The somewhat surprising (R)-configured amine portion, which has been assigned to piperchabamide E (2), is facilitated by a Curtius rearrangement. Following this, the actual amine portion is shown to be (S)-configured. This journal is

Full text of DOI:10.1039/d0ob01745k

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ARTICLE
A pyridinium anionic ring-opening reaction applied to the
stereodivergent syntheses of Piperaceae natural products †
Karoline G. Primdahl, a Jens M. J. Nolsøe b and Marius Aursnes *a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Abstract
A stereodivergent strategy has been devised to access the diene motif found in biologically active compounds from the
Piperaceae family. Herein the first total syntheses of 2E,4E configured piperchabamide E (2) and its enantiomer (ent-2), as
well as 2E,4Z configured scutifoliamide B (3), are narrated. The mainstay in the adopted approach is the gram-scale
conversion of quaternized pyridine in a practical three-step sequence to access isomerically pure conjugated bromodiene
esters 2E,4E 8 and 2E,4Z 9 by differential crystallization. Even though the developed oxidation protocol forms the basis of
the entailed divergent strategy, the geometrical integrity of the involved bromodiene motive can be controlled by the choice
of solvent. Thus, while oxidation of pure bromodienal 2E,4Z 7 in methanol yields equal amounts of bromodiene esters 2E,4E
8 and 2E,4Z 9, only bromodiene ester 2E,4Z 10 is formed in isopropanol. Subseqently, capitalizing on a stereoretentive Suzuki
cross-coupling and direct amidation of the corresponding esters, the featured natural products can be accessed in five and
six steps, respectively. The somewhat surprising (R)-configured amine portion, which has been assigned to piperchabamide
E (2), is facilitated by a Curtius rearrangement. Following this, the actual amine portion is shown to be (S)-configured.
pharmacological aspects,7 amongst other effects, piperine (1)
has been demonstrated to profoundly inhibit airway
inflammation in a murine asthma model.8
Introduction
Certain members of the Piperaceae family have played an
important role in traditional medicine since time immemorial.
Thus, ancient Ayurvedic texts make references to long pepper
(Piper longum).1 Following the trading routes established in
antiquity, the flow of goods convoyed new ideas between the
East and the West. This not only established various members
of the Piper genus as prized universal gustatory enhancers, but
also shaped the notion of their efficacy as a remedy for various
ailments.2 The foundation of the causative perception has since
been explored in a scientific context, identifying piperine (1) as
a principal component of the dried fruit.3 While the compound
is initially described as tasteless upon ingestion, the bland first
impression is soon taken over by a sharp and distinctly peppery
aftertaste, accompanied by a burning sensation.4 At the basis of
this physiological response is the vanilloid activated
nonselective cation channel TRPV1, which is a neuronal
In general, the alkamide phytochemicals constitute a
significant and characteristic class of secondary metabolites
obtained from the Piper genus.1a Yet, of particular interest to
the present authors are two related structures that exemplify
the rich and varied pharmacopeia of the Piperaceae family,
highlighting the value of a well-conceived synthetic strategy to
furnish the pertinent motifs. Hence, the focal point of the
presented narrative are the alkamides named piperchabamide
E (2) and scutifoliamide B (3) (Figure 1).9,10
receptor and a mediator of heat-induced nociception.5
A
prominent feature of piperine (1) is therefore the sensory effect
associated with TRPV1 agonism.6 However, expounding on the
Fig. 1: Proposed structures of piperchabamide (2) and scutifoliamide (3) in relation to
piperine (1).
Piperchabamide E (2) is an alkamide that closely resembles
piperine (1) to the extent that they have the same non-amine
portion in common. Consequently, the vanillin pharmacophore
takes the shape of a 1,3-benzodioxolane appended to a 2E,4E-
penta-2,4-dienoyl unit in the 5-position. However, instead of a
a. Department of Pharmaceutical Chemistry, University of Oslo, P.O. Box 1068, 0316
Oslo, Norway. E-mail: marius.aursnes@farmasi.uio.no
b. Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of
Life Sciences, P.O. Box 5003, 1432 Ås, Norway.
† Electronic Supplementary Information (ESI) available: Spectra (1H and 13C) of isolated
intermediates and final compounds, as well as chromatograms (HPLC) from purity
analysis performed on final compounds. See DOI: 10.1039/x0xx00000x
piperidine ring, the compound flaunts
a striking (R)-2-
methylbutan-1-amine. This particular topology of the featured
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amine portion was assigned following an acidic hydrolysis of the is of interest, the mixture may be isomerized to the all-E diene
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natural product.9a Isolated from the fruit portion of Piper chaba, system by treatment with a catalytic amount of PTSA in diethyl
DOI: 10.1039/D0OB01745K
which is widespread in Southeast Asia, it has been shown that ether and concomitant slow removal of the solvent. If, however,
piperchabamide E (2) exhibits a strong and dose-dependent both the 2E,4E isomer 6 and the 2E,4Z isomer 7 are of interest,
hepato-protective effect by inhibiting D-GalN/TNF--induced as was the case in the featured endeavour, the mixture may be
cell death in primary cultured mouse hepatocytes.9 In fact, in equilibrated into an equal distribution of the two
this murine model, piperchabamide E (2) outperforms piperine configurational isomers upon standing in hydrated
(1), suggesting that the amine portion is of importance.
Deviating from the mentioned pharmacophore in terms of
olefin geometry, scutifoliamide B (3) is an alkamide that
contains a relatively rare 2E,4Z-penta-2,4-dienoyl unit. Also, the
amine portion consists of an aminoethanol motif in the form of
1-amino-2-methylpropan-2-yl acetate. Isolated from the leaves
of Piper scutifolium, the compound has demonstrated
antifungal activity in an assay based on inhibition of two fungi
from the genus Cladosporium.10
chloroform.16
Attracted by the fact that both piperchabamide E (2) and
scutifoliamide B (3) are novelties in a synthetic context, the
purpose of the account is to showcase the utility of pyridinium
anionic ring-opening as the means to stringently build up the
entailed motifs.11a Traditional medicine is the origin of modern
pharmacology and the diverse physiological activity
scientifically documented for Pipereceae natural products
called upon our attention.6-10
Scheme
1 Synthesis of isomeric 5-bromo-2,4-dienoates 8 and 9. Reagents and
conditions: (a) KOH (aq), –20 to 25 °C, 7 h, 68%; (b) Br2, Ph3P, CH2Cl2, 0 °C to rt, o.n. 85%;
(c) (i) Oxone®, methanol, rt, 24 h; (ii) recrystallization from hexane at –20 °C, afforded 8
and 9 in 66% combined yield.
Following formation of the consigned isomeric mixture, 6
and 7 were then jointly oxidized to their corresponding methyl
esters 8 and 9, using a mild one-pot reaction consisting of
Oxone in methanol.17 As it was assumed that the two
geometric isomers would differ in their ability to aggregate via
-stacking,18 the mixture was subjected to recrystallization from
hexane. At -20 C, the 2E,4E isomer 8 was only poorly soluble
and consequently crystallized out of the solution, while the
2E,4Z isomer 9 remained in the supernatant. This therefore
allowed separation of the mixture into the individual
bromodiene esters.
As intended, the adjustment of oxidation level conferred an
increased stability on the bromide handle, pre-empting
isomerization and degradation previously observed in the
antecedent aldehydes.15b Thus, both methyl esters 8 and 9
could be stored in a freezer under argon for over a year without
any appreciable alteration. Furthermore, in all regards, i.e.
synthetic preparation, purification and subsequent chemical
manipulations, the dienes functionalized with an ester terminus
rather than a free carboxylic acid, performed better. As a
caveat, though, it must be mentioned that, the oxidative
protocol employed here is not extrinsically conservative in a
geometric sense. Consequently, with regard to scope and
limitations, pure bromodienal 2E,4Z 7 cannot reliably be
oxidized directly to pure 2E,4Z methyl ester 9. Instead, we have
found that an isomerization takes place in methanol to afford a
1:1 mixture of the two geometric esters 8 and 9. However, when
the oxidation was performed in isopropanol, pure bromodienal
2E,4Z 7 was cleanly converted to the corresponding 2E,4Z
isopropyl ester 10. The contrasting outcome is taken to signify
the difference in steric requirements when the alcoholic
medium acts as a nucleophile: While methanol may react with
Results and discussion
The azomethine functionality characteristic of pyridine confers
a latent reactivity on the ring system as the heteroatom
significantly lowers the resonance energy.12 The propensity to
undergo nucleophilic addition is hyphenated once the
orthogonal lone pair is quaternized and the adduct readily
reconfigures to expose the underlying open-chained -system.
Thus, the ring-opening of quaternary pyridinium compounds
leads to a conjugated diene with useful synthetic handles at
each terminus.11a This invites further chemical elaboration and
offers
a potentially attractive alternative to traditional
olefination protocols.11,13
In the case of pyridinium-1-sulfonate 4, treatment with
excess aqueous potassium hydroxide has been reported to
furnish the anhydrous glutaconaldehyde potassium salt 5.14
Modifying the published protocol by desisting from heating the
reaction mixture to 30-40 C, but rather allowing incubation for
a prolonged time at room temperature, it was possible to make
improvement on both quantity and quality of the synthetic
entry point. Accordingly, when performed on a 50 g-scale, the
ring-opened product 5 was obtained in good yield and with high
chemical purity. The outlined transformation of 4 supplied the
backbone of a 3-step procedure devised to divergently deliver
the conjugated motifs found in 2 and 3 (Scheme 1).
With the intent on transition metal catalysed cross-coupling
to forge the union between the aromatic fixture and the
alternate diene portion, the central vinyl bromide functionality
was introduced under Appel conditions.15 In this particular
system the reaction takes place via a 1,6-addition/elimination
pathway to afford the isomeric bromodienals 2E,4E 6 and 2E,4Z
7 in an initial 7:3 ratio, respectively. If solely the 2E,4E isomer 6
the
acyl
bromodiene
moiety
following
a
1,6-
addition/elimination sequence and concomitant geometric
2 | J. Name., 2012, 00, 1-3
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scrambling, isopropanol does clearly not embark on said Reflecting the practical aspects of handling the loVwie-wmAortilcelecOunlalinre-
DOI: 10.1039/D0OB01745K
pathway to any appreciable extent (scheme 2).
weight fragment, we settled on a one-pot interconversion of
enantiopure carboxylic acid 15 to obtain the corresponding Boc-
protected amine 16, capitalizing on Curtius rearrangement and
concomitant carbamate formation.21 Initially, the telescoped
sequence was performed with diphenyl phosphoryl azide in
tert-butanol at 100 C, using triethylamine as a base. Although
the intermediate isocyanate could be trapped with tert-butanol
to afford 16, the reaction was marred by moderate yields and
tedious purification to remove spent reagent together with
various biproducts. Consequently, it was instead opted for a
protocol wherein carboxylic acid 15 was treated with the
constellation of sodium azide and Boc2O, coaxing the desired
conversion with catalytic amounts of zinc triflate and
Scheme 2 Oxidation of bromodienal 2E,4Z 7 and the effect of different alcoholic
media on configurational integrity.
In order to effectuate the stereodivergent strategy we have
outlined for piperchabamide E (2) and scutifoliamide B (3), the
crux was to identify a stereoretentive cross-coupling protocol
that could faithfully reproduce the olefin geometry in both of
the targeted structures. While this was not anticipated to
represent a problem in terms of the 2E,4E configuration, the
retention of the 2E,4Z configuration posed a somewhat more
open question. Thus, π-σ-π equilibration is an immanent
possibility, since, for example, Pd(0) can act as a general
tetrabutylammonium bromide (TBAB) in THF at 40 C.22
A
somewhat prolonged reaction time was needed to ensure
complete consumption of the starting material, but in return,
these conditions cleanly furnished the desired Boc-protected
amine 16 in 80% yield after a straight-forward purification
process. We next focused on devising a procedure for efficient
removal of the Boc-protecting group in order to obtain a
surrogate of the volatile amine 14 in a sufficiently pure and dry
form for the final amidation step. To this end, treating 16 with
3 M HCl in cyclopentyl methyl ether for three hours and then
removing the solvent under vacuum, supplied the well-behaved
amine hydrochloride salt 17.
nucleophile in consort with
a strongly Lewis acidic
organometallic reagent. The result is a π-allyl complex, rather
than a σ-vinyl complex, by a coordinated attack on the 1,6-
conjugated system.19 Consequently, a geometric isomerization
similar to that observed during oxidation of bromodienal 2E,4Z
7 may also accompany Pd-catalysed cross-coupling on 2E,4Z
methyl ester 9. With this in mind, it was opted to take a leaf out
of the Suzuki reaction protocol, using commercially available
boronic acid 11 in the presence of the usual working horse
catalyst, Pd(PPh3)4 (Scheme 3).20 In both cases, cross-coupling
between the mildly Lewis acidic organoboron reagent and the
prenominated substrates proceeded smoothly to establish the
featured structural backbones 12 and 13 of the natural products
in excellent yields. Most importantly, the reactions proceeded
without any observable isomerization of the involved olefin
geometries as verified by evaluation of the observed coupling
constants.
Scheme 4. Total synthesis and subsequent reassignment of piperchabamide E to ent-2.
Reagents and conditions: (a) NaN3, Boc2O, Zn(OTf)2 (cat.), TBAB (cat.), THF, 40 °C, 120 h,
80%; (b) 3 M HCl, CPME, 0 °C to rt, 3 h, 84%; (c) Me3Al, benzene, 0 °C to rt, 1.5 h, then
12, rt to 80 °C, o.n., 85%; (d) Boc2O, Et3N, 0 °C to rt, 3 h, 90%; (e) 3 M HCl, CPME, 0 °C to
rt, 3 h, 79%; (f) Me3Al, benzene, 0 °C to rt, 1.5 h, then 12, rt to 80 °C, o.n., 82%.
Having furnished the individual fragments professed to be
featured in the natural product from Piper chaba, we could then
undertake the last required transformation. Thus, treatment of
amine hydrochloride 17 with one equivalent of
trimethylaluminum generated the corresponding, oxophilic,
methylchloroaluminum amide in situ,23 which subsequently
underwent a smooth reaction with the methyl (2E,4E)-5-
arylpenta-2,4-dienoate 12 (sometimes also referred to as
methyl piperate). This afford the targeted compound 2 in 18%
Scheme 3 Synthesis of isomeric 5-arylpenta-2,4-dienoates 12 and 13.
With the intended stereodivergent aspect established, the
final step in our executive strategy leading to piperchabamide E
(2) involved direct amidation of the methyl (2E,4E)-5-arylpenta-
2,4-dienoate 12 (Scheme 4). This, however, called for a concise
synthesis to furnish the required amine portion, as (R)-2-
methylbutan-1-amine 14 is not commercially available.
This journal is © The Royal Society of Chemistry 20xx
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total yield over 5 steps (longest linear sequence). According to chloroform rapidly compromised the integrity of the analyte, as
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DOI: 10.1039/D0OB01745K
subsequent HPLC analysis, the purity of the material produced noted by visual inspection and subsequent thin-layer
by the outlined sequence was >95%. However, while compound chromatography. The presence of trace impurities (mainly
2 conformed to all of the spectroscopic data provided for phosgene and HCl), and/or added stabilizers (such as EtOH), in
piperchabamide E,9a the recorded optical rotation deviated chloroform, can affect samples adversely.30 We therefore
[훼]20
both in magnitude and in sign. Whereas we registered an
venture that the prepared compound ent-2 represents
D
= ―8.1
(c 0.70, CHCl3) for compound 2, the published value for piperchabamide E - i.e. the material that was isolated from Piper
[훼]20 = +18.0
piperchabamide E was given as
(c 0.72, CHCl3). chaba is piperchabamide E (ent-2).
D
Following this, we concluded that the stereochemical
While applicable to purely aliphatic amines, the presence of
configuration originally assigned to the amine portion found in other proximal heterofunctionalities may pose a problem to the
piperchabamide E must be wrong. However, the finding may utility of trimethylaluminum for direct amidation. Hence, for
not be that surprising, since a credible biogenesis of the introduction of the amine portion present in scutifoliamide B
Piperaceae alkamides points to the enzymatic decarboxylation (3), we varied the synthetic repertoire slightly in order to avoid
of common L-amino acids as the source of the amine portion.27 a superfluous protection scheme in the endgame (Scheme 5).
For the proposed structure of piperchabamide E (2), the Yet, given the hard aspect of methylchloroaluminum amides,
implication is that the appended (R)-2-methylbutan-1-amine 14 we were mindful that a softer rendition of the nitrogen
is derived from a nonproteinogenic precursor, which must nucleophile could result in geometric isomerization of the
either be L-allo-isoleucine or D-isoleucine. Even though L-allo- extended Michael acceptor via addition-elimination. Reacting
isoleucine has been found in dates,28 it is by all accounts an 1-amino-2-methyl-propan-2-ol 18 with the methyl (2E,4Z)-5-
exotic amino acid in plants. Furthermore, the biochemical arylpenta- 2,4-dienoate 13, using sodium carbonate as a base in
pathway that leads to L-allo-isoleucine begins with L- methanol at 80 C furnished the desired amide 19 in good
isoleucine.29
yield.24 Most gratifyingly, we did not observe any undesired
Given the discussion instigated by our contrasting findings, we adducts or the associated configurational scrambling caused by
were obliged to prepare antipodal piperchabamide E (ent-2). the action of a nucleophile (solvent or reagent) on the
However, this also clearly demonstrated the advantages of our conjugated system.
modular approach, since we could now utilize the commercial
(S)-2-methylbutan-1-amine ent-14 as an iterative starting point.
For the purpose of intercomparison with previous values
obtained from optical rotation measurements, (S)-2-
methylbutan-1-amine ent-14 was converted to the Boc-
protected amine ent-16. The two antipodes were found to be in
good agreement on account of similar magnitude and their
opposite signs. Thus, the measurements of optical rotation on
[훼]2D0 = ―4.1
Boc-protected amines 16 and ent-16 gave
+3.8
and
Scheme 5. Total synthesis of scutifoliamide B (3). Reagents and conditions: (a) Amine 17,
Na2CO3, MeOH, 80 °C, o.n.; (b) Ac2O, DIPEA, DMAP (cat.), CH2Cl2, 0 °C to rt, o.n., 66% over
two steps.
(c 1.00, MeOH), respectively.
With Boc-protected amine ent-16 in hand, we then
embarked on the remaining two steps of the previously outlined
sequence. Accordingly, the Boc-group was cleaved off,
whereupon the resulting amine hydrochloride salt ent-17 was
treated in succession with trimethylaluminum and methyl
(2E,4E)-5-arylpenta-2,4-dienoate 12 to afford compound ent-2.
The redefined target, i.e. antipodal piperchabamide E (ent-2),
was obtained in 18% total yield over 5 steps (longest linear
sequence) and in a purity >95%, based on subsequent HPLC
analysis. Compared to compound 2, all the spectroscopic data
obtained from compound ent-2 were identical. In consonance
with the antipodal configuration, the optical rotation recorded
[훼]24 = +7.9
of the amassed analytical data, both with respect to identity and
purity, as well as the sign of the optical rotation, we find that
the structure embodying compound ent-2 is in good alignment
with the material isolated from Piper chaba.9a Despite the
disparity concerning the magnitude of optical rotation, the sign
registered for compound ent-2 is compliant with
piperchabamide E. Furthermore, we observed that the
extended structural motif found in the prepared antipodes is
unstable under certain circumstances: In particular, exposure to
The final step to reach the natural product isolated from
Piper scutifolium involved acetylation of the tertiary alcohol in
19. This was achieved using acetic anhydride in
dichloromethane together with ethyldiisopropylamine and a
catalytic amount of DMAP. Relative to an involved protection
scheme orthogonal to the reaction with trimethylaluminum,
the alternative protocol introduced the pertinent amide motif
in 66% yield for the two steps. Consisting of six linear steps for
the complete sequence, scutifoliamide B (3) was obtained in an
overall yield of 10% and in a purity of 95%, according to
subsequent HPLC analysis.
Of note, through all of these reactions, the spectroscopic
signature of the E,Z-diene configuration established for methyl
(2E,4Z)-5-bromopenta-2,4-dienoate 9 remained unchanged,
with coupling constants of 11.8 and 14.8 Hz for the individual Z-
and E-configured alkene moieties, respectively. Also, in all
respects, the compound 3 prepared by the executed strategy
conformed to the data provided for the natural product.10
for compound ent-2 was
(c 0.70, CHCl3). By virtue
D
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was cooled to room temperature and concentrated in vacuo
until a thick slurry was obtained. The solid was collected in a
Conclusion
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DOI: 10.1039/D0OB01745K
A
versatile pyridinium anionic ring-opening has been
Büchner funnel using vacuum filtration, washed with acetone (5
× 20 mL) and dried overnight under high vacuum to afford a light
brown glutaconaldehyde potassium salt 5. Yield: 29.1 g, 68%; 1H
NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 9.2 Hz, 2H), 7.04 (t, J =
13.1 Hz, 1H), 5.11 (dd, J = 13.1, 9.2 Hz, 2H); 13C{1H} NMR (101
MHz, DMSO-d6) δ 184.4, 159.8, 106.2.
highlighted as the means to establish the central five carbon
motif featured in a class of biologically active Piperaceae
alkamide natural products. The enhanced configurational
stability conferred on conjugated dienes at ester oxidation level
formed the basis of a divergent strategy, delivering the first
total syntheses of the proposed structure of piperchabamide E
(2) and its enantiomer ent-2, as well as scutifoliamide B (3).
Based on the presented work, we suggest the reassignment of
piperchabamide E to ent-2. Capitalizing on a Suzuki cross-
coupling reaction and direct amidation protocols, the targeted
natural products were obtained in a short, flexible and concise
manner (five and six steps, respectively). Thus, the conceived
stratagem was instrumental in the explorative work, leading to
the suggested reassignment of piperchabamide E as ent-2.
Furthermore, the biological activity of compounds adhering to
the TRPV1 pharmacophore, endorsed by piperine (1), makes the
stringent approach a valuable contribution for functional
diversification.
(2E,4E)-5-Bromopenta-2,4-dienal (6) and (2E,4Z)-5-bromo-
penta-2,4-dienal (7).16 Triphenylphosphine (11.2 g, 42.6 mmol,
1.35 equiv.) was dissolved in dichloromethane (150 mL) and
cooled to 0 °C. A solution of bromine (2.10 mL, 41.0 mmol, 3.12
g/mL at 25 °C, 1.3 equiv.) was dissolved in dichloromethane (38
mL) and the solution was added dropwise with efficient stirring.
(If there was a persistent reddish-brown colour after complete
addition of the bromine solution, additional triphenylphosphine
was added in small portions until the colour disappeared).
Potassium (1E,3E)-5-oxopenta-1,3-dien-1-olate (5) (4.3 g, 31.6
mmol, 1 equiv.) was then added in one portion and the reaction
mixture was stirred overnight, allowing it to attain room
temperature. The reaction mixture was then filtered through a
pad of silica gel, the flask was washed with fresh
dichloromethane, with the washings filtered through the silica
gel pad and then the filtrate was concentrated in vacuo. The
material thus obtained was purified by column chromatography
(SiO2, 10% Et2O in hexane) to give a mixture of (2E,4E)-5-
bromopenta-2,4-dienal (6) and (2E,4Z)-5-bromopenta-2,4-
dienal (7). Yield: 4.3 g, 85%. [NB! When only one isomer was
required, separation was also achieved by column
chromatography (SiO2, 10% Et2O in hexane)].
Experimental
General information
Unless stated otherwise, all commercially available reagents
and solvents were used in the form they were supplied without
any further purification. Optical rotations were measured using
a 1 mL cell with a 1.0 dm path length on a Perkin Elmer 341
polarimeter. Mass spectra were recorded at 70 eV on
Micromass Prospec Q or Micromass QTOF 2 W spectrometer
using ESI as the method of ionization. High-resolution mass
spectra were recorded at 70 eV on Micromass Prospec Q or
Micromass QTOF 2W spectrometer using ESI as the method of
ionization. Purity HPLC analyses were performed using a C18
stationary phase (Eclipse XDB-C18, 4.6 × 250 mm, particle size 5
μm, from Agilent Technologies, Santa Clara, CA, USA), applying
the conditions stated.
Potassium (1E,3E)-5-oxopenta-1,3-dien-1-olate (5).14
Pyridinium-1-sulfonate (4) (50 g, 0.314 mol, 1 equiv.) was added
portionwise over 5 minutes to a solution of potassium
hydroxide (71.8 g, 1.28 mol, 4.1 equiv.) in water (175 mL) at −20
C with efficient stirring. Any large lumps that formed were
broken with the aid of a glass rod against a positive pressure of
argon. After complete addition of the pyridine complex, the
yellow reaction mixture was stirred for one hour before the
cooling bath was removed. The flask was stirred for six hours at
room temperature and during this time, the reaction mixture
took on an increasingly dark brown colour. The flask was then
cooled to 0 C, the suspension was filtrated, the crude, solid
product was washed with acetone (4 × 40 mL) and then the
material was dried under vacuum overnight. The crude product
was added to methanol (700 mL) and activated charcoal (5 g)
and refluxed with efficient stirring for 15 minutes before the
contents of the flask was quickly subjected to a hot filtration.
Additional boiling in methanol (~100 mL × 2) was used to wash
the remaining solid material in the filtration funnel. The filtrate
(2E,4E)-5-Bromopenta-2,4-dienal (6). Colorless oil; Rf = 0.18
1
(10% Et2O in hexane, KMnO4-stain); H NMR (600 MHz, C6D6);
9.19 (dd, J = 7.7, 2.2 Hz, 1H), 6.24 – 6.12 (m, 1H), 6.07 – 5.95 (m,
1H), 5.94 – 5.81 (m, 1H), 5.72 – 5.57 (m, 1H). 13C{1H} (151 MHz,
C6D6) NMR δ 191.9, 146.6, 135.6, 132.1, 118.7.
(2E,4Z)-5-Bromopenta-2,4-dienal (7). Colorless oil; Rf = 0.24
(10% Et2O in hexane, KMnO4-stain); 1H NMR (600 MHz, C6D6); δ
9.15 (d, J = 7.8 Hz, 1H), 6.87 (dd, J = 15.6, 10.6 Hz, 1H), 5.88 (dd,
J = 10.4, 7.3 Hz, 1H), 5.84-5.76 (m, 2H). 13C{1H} NMR (151 MHz,
C6D6) δ 192.3, 144.1, 134.9, 130.9, 117.4.
Methyl (2E,4E)-5-bromopenta-2,4-dienoate (8) and methyl
(2E,4Z)-5-bromopenta-2,4-dienoate (9). A mixture of E,E- and
E,Z-bromodienal 6 and 7 (3.3 g, 20.5 mmol) was dissolved in dry
methanol (200 mL) and then potassium peroxymonosulfate
(9.45 g, 30.7 mmol, 1.50 equiv.) was added in one portion. The
flask was flushed with argon and stirred 24 hours (Note that TLC
analysis can be deceiving in this case as starting material will
disappear after a few hours and reappear after work-up – likely
due to acetal formation). The flask was then placed on a rotary
evaporator in order to remove most of the methanol until a
slurry was obtained. Next, ethyl acetate (50 mL) was added,
rapid stirring was turned on and an aqueous 1 M solution of HCl
was added carefully until all the salts had dissolved. The
aqueous phase was extracted with ethyl acetate (5 x 50 mL), the
combined organic phase was dried (Na2SO4), filtrated and
concentrated in vacuo. The crude material was purified by
column chromatography (SiO2, 10% Et2O in hexane, KMnO4-
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Journal Name
stain) to give a mixture of geometric isomers. The fractions mixture was heated to 80 °C and stirred oveVrinewigAhrttic.leAOfntliener
containing product were combined and the flask was placed on completion, the reaction mixture wDaOs I: c10o.o10le39d/D0tOoB0r1o7o45mK
a rotary evaporator in order to remove approximately 80% of temperature, quenched by the addition of saturated aqueous
the solvent volume. The flask was then placed in a -20 °C freezer NH4Cl (25 mL) and extracted with Et2O (5 × 20 mL). The
which lead to the crystallization of the E,E-isomer while the E,Z- combined organic extracts were dried, filtered and
isomer remained in solution. The supernatant was carefully concentrated in vacuo. The crude was dissolved in a minimal
transferred into a new flask and the crystals of the E,E-isomer amount of CH2Cl2 (not significantly soluble in the solvent used
were washed with ice-cold hexane (2 × 5 mL). This process gave for column chromatography) and applied to column
pure methyl (2E,4E)-5-bromopenta-2,4-dienoate (8) (1.50 g, chromatography for purification (SiO2, 10% EtOAc in hexane,
7.85 mmol) and methyl (2E,4Z)-5-bromopenta-2,4-dienoate (9) KMnO4 stain) to afford the known methyl (2E,4E)-5-
(1.10 g, 5.76 mmol), the latter contaminated by approximately (benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoate (12). Yield: 238
1
~7% of the former-mentioned E,E-isomer. This process may be mg, 98%; Rf = 0.52 (20% EtOAc in heptane, KMnO4 stain); H
repeated for the E,Z-isomer if necessary. Combined yield: 2.6 g, NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 15.2, 10.8 Hz, 1H), 6.99 (d,
66%; Rf = 0.39 (10% Et2O in hexane, KMnO4-stain). Both isomers J = 1.7 Hz, 1H), 6.91 (dd, J = 8.1, 1.7 Hz, 1H), 6.85 – 6.75 (m, 2H),
co-elute on TLC under these conditions.
6.70 (dd, J = 15.4, 10.8 Hz, 1H), 5.98 (s, 2H), 5.95 (d, J = 15.3 Hz,
Methyl (2E,4E)-5-bromopenta-2,4-dienoate (8). Needle-like, 1H), 3.76 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.7, 148.7,
colorless, crystals; Mp.: 46.5–47.0 °C;1H NMR (400 MHz, CDCl3) 148.4, 145.1, 140.4, 130.7, 124.6, 123.1, 120.1, 108.7, 106.0,
δ 7.16 (dd, J = 15.4, 10.4 Hz, 1H), 6.93–6.67 (m, 2H), 5.92 (d, J = 101.5, 51.7.
15.3 Hz, 1H), 3.74 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.1,
141.4, 135.5, 121.9, 118.1, 51.9.
Methyl
(2E,4Z)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-
dienoate (13).26 A flask was charged with benzo[d][1,3]dioxol-
Methyl (2E,4Z)-5-bromopenta-2,4-dienoate (9). Colorless oil; 1H 5-ylboronic acid (11) benzo[d][1,3]dioxol-5-ylboronic acid (11)
NMR (400 MHz, MeOD) δ 7.58 (ddd, J = 15.5, 10.7, 1.1 Hz, 1H), (208 mg, 1.26 mmol, 1.20 equiv.), methyl (2E,4Z)-5-
6.92 (ddd, J = 10.7, 7.2, 0.8 Hz, 1H), 6.77 (dt, J = 7.3, 0.9 Hz, 1H), bromopenta-2,4-dienoate (9) (200 mg, 1.05 mmol, 1.00 equiv.),
6.18 (d, J = 15.5 Hz, 1H), 3.76 (s, 3H); 13C{1H} NMR (101 MHz, 2.0 M Na2CO3 (3.3 mL) and toluene (5.5 mL). The flask was
MeOD) δ 167.1, 138.9, 130.3, 124.3, 116.5, 50.9.
Isopropyl (2E,4Z)-5-bromopenta-2,4-dienoate
evacuated and vented with argon and then Pd(PPh3)4 (12.2 mg,
(10). 12.6 µmol, 1.0 mol%) was added. The flask was again evacuated
(2E,4Z)-5-Bromopenta-2,4-dienal (7) (561 mg, 3.38 mmol, 1 and vented with argon (3×) and then the reaction mixture was
equiv.), which had been freshly purified from an equilibrated heated to 80 °C and stirred overnight. After completion, the
mixture of geometric isomers16 by flash column reaction mixture was cooled to room temperature, quenched
chromatography, was dissolved in dry isopropanol (35 mL). by the addition of saturated aqueous NH4Cl (25 mL) and
Potassium peroxymonosulfate (1.61 g, 5.23 mmol, 1.5 equiv.) extracted with Et2O (5 × 20 mL). The combined organic extracts
was added in one portion and the reaction mixture was stirred were dried, filtered and concentrated in vacuo. The crude was
for 24 hours. The flask was then placed on a rotary evaporator dissolved in a minimal amount of CH2Cl2 (not significantly
in order to remove most of the isopropanol and a slurry was soluble in the solvent used for column chromatography) and
obtained. Next, ethyl acetate (10 mL) was added, rapid stirring applied to column chromatography for purification (SiO2,
was turned on and an aqueous 1 M solution of HCl was added 5→15% EtOAc in hexane, KMnO4 stain) to give known methyl
carefully until all of the salts had dissolved. The aqueous phase (2E,4Z)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoate
(13).
was extracted with ethyl acetate (5 × 10 mL), the combined Yield: 219 mg, 90%; Rf = 0.54 (20% EtOAc in heptane, KMnO4
organic phase was dried (Na2SO4), filtrated and concentrated in stain); 1H NMR (600 MHz, CDCl3) δ 7.76 (ddd, J = 15.3, 11.8, 1.2
vacuo. The crude material was purified by column Hz, 1H), 6.84–6.83 (m, 1H), 6.83–6.80 (m, 2H), 6.70 (d, J = 11.3
chromatography (SiO2, 6% Et2O in hexane, KMnO4-stain) to give Hz, 1H), 6.32–6.18 (m, 1H), 6.01 (dt, J = 15.3, 0.8 Hz, 1H), 5.99
isopropyl ester 10 as a colorless oil. Yield: 589 mg, 77%; Rf = 0.37 (s, 2H), 3.75 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 167.7,
(6% Et2O in hexane, KMnO4-stain); 1H NMR (400 MHz, MeOD) δ 148.0, 147.8, 140.7, 137.7, 130.6, 126.4, 123.8, 122.9, 109.4,
7.55 (ddd, J = 15.5, 10.7, 1.1 Hz, 1H), 6.91 (ddd, J = 10.7, 7.2, 0.8 108.6, 101.4, 51.7.
Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.14 (dt, J = 15.5, 0.8 Hz, 1H),
tert-Butyl (R)-(2-methylbutyl)carbamate (16). (R)-3-
5.06 (hept, J = 6.2 Hz, 1H), 1.28 (d, J = 6.3 Hz, 6H); 13C{1H} NMR Methylpentanoic acid 15 (630 mg, 5.42 mmol, 1.00 equiv.),
(101 MHz, MeOD) δ 167.5, 139.9, 131.8, 126.5, 117.6, 69.4, NaN3 (704 mg, 10.8 mmol, 2.00 equiv.), TBAB (157 mg, 0.488
22.1; Exact mass calculated for C8H11BrNaO2 [M+Na]+ m/z mmol, 9 mol%) and Zn(OTf)2 (39.4 mg, 0.108 mmol, 2 mol%)
240.9834, found 240.9835.
were added in succession to a flame-dried flask under argon.
Methyl (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4- The flask was evacuated and vented with argon (3×) and THF (27
dienoate (12).25 A flask was charged with benzo[d][1,3]dioxol- mL) was added. The reaction mixture was heated to 40 C, and
5-ylboronic acid (11) (208 mg, 1.26 mmol, 1.20 equiv.), methyl then di-tert-butyl dicarbonate (1.40 mL, 6.09 mmol, 0.95 g/mL
(2E,4E)-5-bromopenta-2,4-dienoate (8) (200 mg, 1.05 mmol, at 25 C, 1.10 equiv.) was added dropwise via cannula. The
1.00 equiv.), 2.0 M Na2CO3 (3.3 mL) and toluene (5.5 mL). The reaction mixture was stirred for 120 hours at 40 C, cooled to
flask was evacuated and vented with argon and then Pd(PPh3)4 room temperature, quenched by the addition of a 10% aqueous
(12.2 mg, 12.6 µmol, 1.0 mol%) was added. The flask was again solution of NaNO2 (~10 mL) and then the reaction mixture was
evacuated and vented with argon (3×) and then the reaction stirred for 30 minutes. NaCl (~5 grams) was added to the flask,
6 | J. Name., 2012, 00, 1-3
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the organic phase was separated, and the aqueous phase was removed under a stream of nitrogen and then further
View Article Online
extracted with diethyl ether (4 × 30 mL). The combined organic concentrated in vacuo. The solid materDiaOl I:th10u.1s03o9b/tDa0iOneBd017w45aKs
phase was dried (Na2SO4), filtrated and concentrated in vacuo. purified by trituration with hexane (3 × 25 mL) and then dried
The crude material thus obtained was purified by column under
chromatography (SiO2, 10 to 15% EtOAc in hexane, KMnO4- hydrochloride (ent-17) as a white salt. Yield 521 mg, 79%;
vacuum
to
yield
(S)-2-methylbutan-1-amine
[훼]20
D
= ―0.55
stain) to give tert-butyl (R)-(2-methylbutyl)carbamate (16) as a
(c 1.00, MeOH). The recorded spectra match those
clear oil. Yield: 813 mg, 80%; Rf = 0.39 (15% EtOAc in hexane. cited for (R)-2-methylbutan-1-amine hydrochloride (17).
[훼]20 = ―4.1 (푐 1.00, MeOH)
KMnO4-stain);
;
1H NMR (400
(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N-((R)-2-
D
MHz, CDCl3) δ 4.53 (br s, 1H), 3.06 (dd, J = 13.6, 5.8 Hz, 1H), 2.91 methylbutyl)penta-2,4-dienamide (2).9a To a suspension of (R)-
(dd, J = 13.7, 7.1 Hz, 1H), 1.60–1.30 (m, 2H), 1.44 (s, 9H), 1.19– 2-methylbutan-1-amine hydrochloride 17 (16.7 mg, 0.135
1.07 (m, 1H), 0.93 – 0.83 (m, 6H); 13C{1H} NMR (101 MHz, CDCl3) mmol, 2.00 equiv.) in benzene (0.14 mL) was carefully added
δ 156.3, 79.1, 46.4, 35.4, 28.6, 27.0, 17.2, 11.4; Exact mass trimethylaluminum (67.5 L, 0.135 mmol, 2 M in toluene) at 0
calculated for C10H21NNaO2 [M+Na]+ m/z 210.1463, found °C. After complete addition, the reaction mixture was allowed
210.1464.
to warm to room temperature and stirred for 1.5 hour. A
tert-Butyl (S)-(2-methylbutyl)carbamate (ent-16). (S)-(-)-2- solution of methyl (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-
methylbutylamine ent-14 (1.00 g, 1.36 mL, 11.5 mmol, 0.738 2,4-dienoate (12) (15 mg, 64.6 mol, 1.00 equiv.) in benzene
g/mL, 1.00 equiv.) was dissolved in dichloromethane (16 mL) (0.75 mL) was then added the resulting mixture was stirred for
was cooled to 0 °C. Triethylamine (2.32 g, 3.20 mL, 22.9 mmol, 80 °C overnight. The reaction mixture was cooled to room
0.726 g/mL, 2.00 equiv.) was added followed by the dropwise temperature and slowly quenched with the addition of aqueous
addition of di-tert-butyl dicarbonate (2.75 g, 2.9 mL, 12.6 mmol, 5% HCl. The organic layer was separated, and the aqueous layer
0.95 g/mL, 1.10 equiv.). After complete addition, the reaction extracted with ethyl acetate (4 × 1 mL). The combined organic
mixture was allowed to warm to room temperature and stirred phase was dried (Na2SO4), concentrated in vacuo and purified
until deemed complete by TLC analysis (3 hours). The reaction by column chromatography (SiO2, 20 to 40% EtOAc in hexane,
was quenched by the addition of saturated aqueous NH4Cl (10 KMnO4-stain) to yield (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-
mL) and extracted with dichloromethane (3 × 10 mL). The ((R)-2-methylbutyl)-penta-2,4-dienamide (2) as a white solid.
combined organic phase was dried (Na2SO4), filtrated and Yield: 16 mg, 85%; Rf = 0.27 (40% EtOAc in hexane, KMnO4-
[훼]24 = ― 8.1
1
concentrated in vacuo to give the tert-butyl (S)-(2- stain);
(c 0.70, CHCl3); H NMR (600 MHz, C6D6) δ
D
methylbutyl)carbamate (ent-16) as a clear oil. Yield: 1.67 g, 90%; 7.67 (dd, J = 14.8, 11.0 Hz, 1H), 6.85 (d, J = 1.4 Hz, 1H), 6.59–
[훼]20
Rf
=
0.39 (15% EtOAc in hexane. KMnO4-stain);
6.53 (m, 3H), 6.43 (d, J = 15.5 Hz, 1H), 5.61 (dd, J = 14.9, 0.8 Hz,
D
= +3.8 (푐 1.00, MeOH)
; The recorded spectra match those 1H), 5.26 (s, 2H), 3.23 (dd, J = 13.3, 6.2 Hz, 1H), 3.10 (dd, J = 13.3,
cited for (R)-(2-methylbutyl)carbamate (16). 7.2 Hz, 1H), 1.43 (dq, J = 13.3, 6.7 Hz, 1H), 1.33–1.24 (m, 1H),
(R)-2-Methylbutan-1-amine hydrochloride (17). A flask was 1.07–0.96 (m, 1H), 0.82 (t, J = 7.4 Hz, 3H), 0.78 (d, J = 6.7 Hz, 3H);
charged with Boc-protected amine 16 (200 mg, 1.07 mmol, 1.00 13C{1H} NMR (151 MHz, C6D6) δ 165.4, 148.7, 148.6, 140.9,
equiv.) and cooled to 0 C. A solution of 3M HCl in CPME (5.4 138.6, 131.5, 125.3, 124.4, 122.9, 108.7, 106.1, 101.2, 45.3,
mL, 16.0 mmol, 15.0 equiv.) was added in a dropwise manner. 35.6, 27.3, 17.3, 11.5; Exact mass calculated for C17H21NNaO3
The cooling bath was removed after 10 minutes, the reaction [M+Na]+ m/z 310.1413, found 310.1414. The purity was
mixture was allowed to warm to room temperature and then determined by HPLC analysis (Eclipse XDB-C18, MeOH/H2O
stirred until no starting material was observed based on TLC 60:40, 1.0 mL/min, 254 nm) tR = 23.99, >95%.
analysis (~3 hours). The bulk of solvent was removed under a
stream of nitrogen and then further concentrated in vacuo. The methylbutyl)penta-2,4-dienamide (ent-2) - Piperchabamide E
solid material thus obtained was purified by trituration with (ent-2).9a To
suspension of (S)-2-methylbutan-1-amine
(2E,4E)-5-(Benzo[d][1,3]dioxol-5-yl)-N-((S)-2-
a
hexane (3 × 5 mL) and then dried under vacuum to yield (R)-2- hydrochloride ent-17 (16.7 mg, 0.135 mmol, 2.00 equiv.) in
methylbutan-1-amine hydrochloride (17) as a white salt. Yield benzene (0.14 mL) was carefully added trimethylaluminum
[훼]2D0 = +0.43 (푐 1.00,MeOH)
;
1H NMR (400 (67.5 L, 0.135 mmol, 2 M in toluene) at 0 °C. After complete
111 mg, 84%;
MHz, DMSO-d6) δ 8.03 (br s, 3H), 2.71 (dd, J = 12.6, 6.1 Hz, 1H), addition, the reaction mixture was allowed to warm to room
2.55 (dd, J = 12.6, 7.7 Hz, 1H), 1.72–1.59 (m, 1H), 1.47–1.34 (m, temperature and stirred for 1.5 hour. A solution of methyl
1H), 1.20–1.06 (m, 1H), 0.90 (d, J = 6.8 Hz, 1H), 0.85 (t, J = 7.4 (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-dienoate (12) (15
Hz, 1H); 13C{1H} NMR (101 MHz, DMSO-d6) δ 44.0, 32.5, 26.1, mg, 64.6 mol, 1.00 equiv.) in benzene (0.75 mL) was then
16.6, 10.8; C5H14N [M+H]+ m/z 88.1121, found 88.1121.
added the resulting mixture was stirred for 80 °C overnight. The
(S)-2-Methylbutan-1-amine hydrochloride (ent-17). A flask reaction mixture was cooled to room temperature and slowly
was charged with Boc-protected amine ent-16 (1.00 g, 5.35 quenched with the addition of aqueous 5% HCl. The organic
mmol, 1.00 equiv.) and cooled to 0 C. A solution of 3M HCl in layer was separated, and the aqueous layer extracted with ethyl
CPME (26.5 mL, 80.0 mmol, 15.0 equiv.) was added in a acetate (4 × 1 mL). The combined organic phase was dried
dropwise manner. The cooling bath was removed after 10 (Na2SO4), concentrated in vacuo and purified by column
minutes, the reaction mixture was allowed to warm to room chromatography (SiO2, 20 to 40% EtOAc in hexane, KMnO4-
temperature and then stirred until no starting material was stain) to yield (2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-N-((S)-2-
observed based on TLC analysis (~3 hours). The bulk of solvent methylbutyl)-penta-2,4-dienamide (ent-2) - piperchabamide E
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
(ent-2) as a white solid. Yield: 15.2 mg, 85%; Rf = 0.27 (40%
[훼]24 = + 7.9
Acknowledgements
View Article Online
MA gratefully acknowledges the ResearDchOI:C1o0u.1n03c9il/Do0fONBo01r7w4a5Ky
(RCN) for a grant (FRINATEK, 262901). A research scholarship to
JMJN (FRIPRO, 287416) from the Research Council of Norway
(RCN) is also gratefully acknowledged. This work was partly
supported by the Research Council of Norway through the
Norwegian NMR Package in 1994 and partly supported by the
Research Council of Norway through the Norwegian NMR
Platform, NNP (226244/F50). Additional support by the
Department of Chemistry and the Faculty of Mathematics and
Natural Sciences at University of Oslo is also acknowledged.
EtOAc in hexane, KMnO4-stain);
(c 0.70, CHCl3).
D
The recorded spectra match those cited for (2E,4E)-5-
(benzo[d][1,3]dioxol-5-yl)-N-((R)-2-methylbutyl)penta-2,4-
dienamide (2); The purity was determined by HPLC analysis
(Eclipse XDB-C18, MeOH/H2O 60:40, 1.0 mL/min, 254 nm) tR
(major) = 24.03 and tR (minor) = 25.53, >95%.
1-((2E,4Z)-5-(benzo[d][1,3]dioxol-5-yl)penta-2,4-
dienamido)-2- methylpropan-2-yl acetate (3) – Scutifoliamide
B (3).10 Methyl ester 12 (30 mg, 0.129 mmol, 1.00 equiv.) was
dissolved in methanol (0.13 mL) and 1-amino-2- methylpropan-
2-ol 18 (62.6 μL, 0.646 mmol, 0.92 g/mL at 25 C, 5.00 equiv.)
and then Na2CO3 (13.7 mg, 0.129 mmol, 1.00 equiv.) was added.
The reaction flask was flushed with argon, capped and then
heated to 80 C overnight. The flask was cooled, and the
volatiles were removed under a stream of argon. The crude
((2E,4Z)-5-(benzo[d][1,3]dioxol-5-yl)-N-(2-hydroxy-2-
methylpropyl)penta-2,4-dienamide 19 was taken up in a
minimal amount of ethyl acetate and loaded directly onto a
short plug of silica gel – eluting with 70% EtOAc/1% MeOH in
hexane (Rf = 0.53; KMnO4-stain). The fractions containing the
product were combined and concentrated in vacuo. The
material thus obtained (29 mg) was dissolved in
Notes and references
1
(a) G. M. Strunz, Unsaturated Amides from Piper Species
(Piperaceae). In Studies in Natural Product Chemistry:
Bioactive Natural Products; Atta-ur-Rahman, Ed.; Elsevier
Science: 2000, 24, pp 683–738; (b) P. N. Ravindran and J. A.
Kallupurackal, Black pepper. In Handbook of Herbs and
Spices; Peter, K.V., Ed.; Woodhead Publishing: 2012, p 104.
M. Toussaint-Samat, Spice at Any Price. In History of Food,
2nd ed.; A. Bell, Translator; Wiley-Blackwell, UK: 2009, pp
441–446.
(a) H. C. Ørsted, Über das Piperin, ein neues
Pflanzenalkaloid. Schweiggers Journal für Chemie und
Physik, 1820, 29, 80–82; (b) K. Srinivasan, Black Pepper and
its Pungent Principle – Piperine: A Review of Diverse
Physiological Effects. Crit. Rev. Food Sci. Nutr., 2007, 47,
735–748.
2
3
dichloromethane (0.3 mL) and cooled to
0
C.
Ethyldiisopropylamine (25.7 μL, 0.150 mmol, 0.757 g/mL at 25
C, 1.50 equiv.), DMAP (1.22 mg, 10.0 mol, 10 mol%) and
acetic anhydride (12.3 μL, 0.130 mmol, 1.08 g/mL at 25 C, 1.30
equiv.) were added in succession and the reaction mixture was
allowed to warm up to room temperature and then stirred
overnight. The reaction was cooled to 0 C and quenched by the
addition of saturated aqueous NaH2PO4 (0.3 mL) and ethyl
acetate (0.3 mL). The organic phase was separated, and the
aqueous phase extracted with ethyl acetate (4 × 0.3 mL). The
combined organic phase was dried (Na2SO4), filtrated and
concentrated in vacuo. The crude material thus obtained was
purified by column chromatography (SiO2, 40% EtOAc in
hexane) to give scutifoliamide B (3) as a slightly yellow oil. Yield:
28 mg, 66% over two steps; Rf = 0.12 (40% EtOAc in hexane,
4
5
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1
KMnO4-stain); H NMR (400 MHz, CDCl3) δ 7.74 (ddd, J = 14.8,
11.8, 1.1 Hz, 1H), 6.87–6.74 (m, 3H), 6.64 (d, J = 11.3 Hz, 1H),
6.25 (t, J = 11.8 Hz, 1H), 6.03 (d, J = 14.8 Hz, 1H), 5.97 (s, 2H),
3.59 (d, J = 6.0 Hz, 2H), 2.02 (s, 3H), 1.45 (s, 6H); 13C{1H} NMR
(101 MHz, CDCl3) δ 170.9, 166.1, 147.8, 147.5, 137.1, 136.3,
130.6, 126.3, 125.7, 123.5, 109.3, 108.4, 101.2, 82.4, 48.1, 24.1,
22.4; Exact mass calculated for C18H21NNaO5 [M+Na]+ m/z
354.1311, found 354.1312; The purity was determined by HPLC
analysis (Eclipse XDB-C18, MeOH/H2O 60:40, 1.0 mL/min, 254
nm) tR (minor) = 13.37 and tR (major) = 14.16, 95%.
6
7
Author contributions
The authors contributed equally.
8
Conflicts of interest
There are no conflicts to declare.
8 | J. Name., 2012, 00, 1-3
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Journal Name
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Organic & Biomolecular Chemistry
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The central motif found in biologically active compounds from the Piperaceae family has been obtained by a stereDoOdiIv: e10rg.1e0n3t9/sDtr0aOteBg0y1.745K
To this end, the utility of a pyridinium anionic ring-opening reaction was used as the means to stringently tackle the entailed isomeric
dienes 2E,4E 6 and 2E,4Z 7. Herein we report the first total syntheses of piperchabamide E (2) and its enantiomer (ent-2), as well as
2E,4Z configured scutifoliamide B (3). Following our analysis, the flexible strategy allowed the reassignment of piperchabamide E (2)
to its enantiomer (ent-2).
O
H
6 steps
5 steps
N
O
O
O
O
N
H
OAc
O
N
SO3
2 Piperchabamide E in lieu
3 Scutifoliamide B
4
CO2Me
Br
5 steps
Br
CO2Me
6
7
O
O
O
N
H
ent-2 Piperchabamide E revised