Synthesis of phenolic components of Grains of Paradise

Article abstract of DOI:10.1016/j.tetlet.2019.06.050

Two vanilloids, (5E)-8-(4-hydroxy-3-methoxyphenyl)oct-5-en-4-one (1) and 4-[3-hydroxydecyl]-2-methoxyphenol (2), isolated from the dried seeds of Grains of Paradise (Aframomum melegueta), were synthesized; the latter compound was made as the S-enantiomer and the material derived from the seeds was found to be a 1:1.7 mixture of the R and S isomers. The synthetic route used should allow the preparation of analogs having extended alkyl chains and consequently different lipophilicity, and 3, a homolog of 2, was also prepared.

Full text of DOI:10.1016/j.tetlet.2019.06.050

Accepted Manuscript
Synthesis of Phenolic Components of Grains of Paradise
Hiroyuki Hattori, Tohru Mitsunaga, Derrick L.J. Clive
PII:
S0040-4039(19)30611-2
https://doi.org/10.1016/j.tetlet.2019.06.050
TETL 50891
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 April 2019
15 June 2019
24 June 2019
Please cite this article as: Hattori, H., Mitsunaga, T., Clive, D.L.J., Synthesis of Phenolic Components of Grains of
Paradise, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.06.050
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Synthesis of Phenolic Components of Grains of Paradise
a
a
b
By Hiroyuki Hattori, Tohru Mitsunaga, Derrick L. J. Clive*
aThe United Graduate School of Agricultural Science, Gifu University, 1-1 Yanagido, 10 501-
193, Gifu, Japan
1
bChemistry Department, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
ABSTRACT: Two vanilloids, (5E)-8-(4-hydroxy-3-methoxyphenyl)oct-5-en-4-one (1) and 4-
[
3-hydroxydecyl]-2-methoxyphenol (2), isolated from the dried seeds of Grains of Paradise
Aframomum melegueta), were synthesized; the latter compound was made as the S-enantiomer
(
and the material derived from the seeds was found to be a 1:1.7 mixture of the R and S isomers.
The synthetic route used should allow the preparation of analogs having extended alkyl chains
and consequently different lipophilicity, and 3, a homolog of 2, was also prepared.
Keywords:
Grains of Paradise
anti-obesity
malic acid
Wittig reaction
Horner-Wadsworth Emmons olefination
Hydrogenolyis
*
Corresponding author.
E-mail address: derrick.clive@ualberta.ca
Introduction
1
Grains of Paradise is one of the names given to the dried seeds of the tropical plant Aframomum
melegueta, which is widely distributed throughout West Africa. The seeds have long been used
2
3
in folkloric herbal remedies and are known to have, among other properties, antioxidant,
4
1
5
antibacterial and antinociceptive activity. In preliminary studies it was found that intake of a
methanol extract of Grains of Paradise has an anti-obesity effect in mice and lowers hepatic and
serum fats. A reduction in visceral fat has also been observed in humans, using an ethanol
6
7
8
extract. Some of the phenolic compounds present in the seeds were also isolated and found to

2
9
share structural features with vanilloids that were already known to have anti-obesity properties.
Consequently, it was of interest to establish if the vanilloids from Aframomum melegueta were
responsible for the anti-obesity effect. Most of the compounds could be isolated in adequate
1
0
quantities and several were found to possess anti-obesity properties, but the isolated amounts of
8
8,11
the vanilloids 1 and 2 were insufficient for biological evaluation in mice. For this reason we
have synthesized both 1 and 2, as well as the homolog 3, and the synthetic work is described
8
below. Independently of the initial report of 1 the same compound was isolated from a different
plant.12 Compound 2 has been isolated as a racemate by hexane extraction from Aframomum
1
3
melegueta; and by supercritical CO extraction from the rhizomes of ginger (Zingiber officinale
2
Roscoe),14 and has been prepared15 in racemic form by NaBH reduction of [6]-shogaol.
4
Racemic 2 has been found to promote cholesterol efflux from THP-1-derived macrophages.16
Our sample of natural 2,8,11 as isolated, contained a small impurity and had [] –0.46 (c = 0.29
8
D
g/100 mL). After we had prepared the S-enantiomer we established that the natural material was
not racemic but was a 1:1.7 mixture of the R and S enantiomers.17
Results and discussion
Synthesis of compound 1
Compound 1 was synthesized by the method summarized in Scheme 1. Vanillin (1.1) underwent
5
efficient Wittig reaction with ethyl 2-(triphenyl- -phosphanylidene)acetate (1.2) to form a 3:1
mixture of E and Z esters 1.3.18 Hydrogenation afforded the saturated ester 1.4 and DIBAL-H
reduction then gave aldehyde 1.5.18 This underwent Wittig reaction with the readily available

3
Scheme 1. Synthesis of compound 1
1
9
keto ylide 1.6, and the resulting enone 1 could be isolated in good yield as the desired E isomer
8
which was spectroscopically identical with the compound extracted from Grains of Paradise.
Unlike the natural material which was an oil, the synthetic enone was obtained as a crystalline
solid, mp 35–38 °C.
Synthesis of compound 3
We first developed a route to the unnatural homolog 3 before making the natural material 2.
As the absolute configuration and optical purity of compound 2 was unknown at the time,
we made the arbitrary decision to use tartaric acid for our work, along the lines shown in Scheme
2
0
2
. This plan was based on a report that the diketone 2.1 (R = n-C H ) derived from D-(–)-
5 11
tartaric acid could be reduced stereoselectively with K-Selectride to the diol 2.2 (R = n-C H ).
5
11
However, when we attempted to follow an analogous sequence to make 2.4 (R = n-C H ), using
8
17
n-octylmagnesium bromide instead of the reported pentyl reagent, we obtained low yields (ca
Scheme 2. Initial approach based on tartaric acid
4
3%) of the desired diketone 2.1 (R = C H ). This outcome prompted us to change to a route
8 17
based on L-(–)-malic acid. The enantiomer is, of course, available, although it is more
expensive, and there would also be an opportunity to invert the stereochemistry of the hydroxyl-
bearing carbon at a suitable stage.
Initially, we converted malic acid into its O-benzyl dimethyl ester and reduced that
selectively (Scheme 3) to methyl (2S)-4-oxo-3-(phenylmethoxy)butanoate (3.1),21 but in our
hands (working at –78 °C instead of the reported21a temperature of –90 °C) the yield in the
reduction step (DIBAL-H) was low (47%). In addition, attempts to form the olefin 3.3 either by
2
2
Wittig reaction with the phosphonium salt 3.2 or by the Horner-Wadsworth-Emmons process,
2
3
using phosphonate 3.4, were unsatisfactory (Scheme 3). Accordingly, we modified the route to

4
one that involves conversion of malic acid into aldehyde 4.6 (Scheme 4), followed by olefination
with a benzylic phosphonate.
Scheme 3. Initial approach based on malic acid
Scheme 4. Synthesis of aldehyde 4.6
The aldehyde 4.6 was made by regioselective esterification of L-malic acid (4.14.2),
following a literature procedure.24 The remaining carboxyl group was then easily reduced with
BH .SMe and the resulting primary hydroxyl was protected by silylation (4.24.34.4). The
24
3
2
next step, O-benzylation of the secondary hydroxyl in 4.4 was tried by two methods. Use of
2
5
26
freshly-prepared Ag O and BnBr in CH Cl gave the desired product in 30% yield, but the
2
2
2
efficiency of the benzylation was improved (79% yield) by using NaH and BnBr in DMF in the
2
7
presence of Bu NI. Finally, DIBAL-H reduction afforded the aldehyde 4.6 needed as one of
4
the components for the intended olefination.

5
a
b
Ar = (4-benzyloxy-3-methoxy)phenyl. A single isomer was obtained when starting from E-5.3.
Scheme 5. Olefination of aldehyde 4.6 [Ar = (4-benzyloxy-3-methoxy)phenyl]
Deprotonation of phosphonate 3.4 with (Me Si) NLi in a 4:1 (v/v) mixture of THF and
3
2
2
8
HMPA, followed by addition of aldehyde 4.6 gave the olefins 5.1. In the first experiment the E
and Z isomers were isolated in yields of 70% and 6%, respectively, but in subsequent work the
isomer mixture was used. Use of HMPA in the olefination was essential; without it very low
yields were obtained. Desilylation proceeded without incident, but oxidation of the resulting
alcohols (5.2) with PCC gave a very low yield. Fortunately, the Dess-Martin periodinane was
extremely effective in generating the desired aldehyde 5.3 (95% yield), and a Wittig reaction
then took the route as far as 5.4, which was obtained as a mixture of isomers. We had originally
intended to subject 5.4 to hydrogenation of the double bonds over Pd/C and then in situ
hydrogenolysis of the benzyloxy groups but, in the event, significant hydrogenolysis of the
allylic C—O bond occurred. Therefore 5.4 was first reduced over 5% Rh-Al O to saturate the
2
3
1
double bonds (monitored by H NMR and tlc), and then the benzyl groups were removed by
hydrogenolysis (Pd/C) so as to obtain the target alcohol (5.45.53).
In order to establish the optical purity of 3 we needed a racemic sample. Several attempts
2
9
to selectively oxidize the aliphatic hydroxyl of 3 were unsuccessful, but the phenolic hydroxyl
was easily benzylated (BnBr, K CO , 96%) and the remaining secondary hydroxyl could be
2
3
oxidized with the Dess-Martin reagent. Then reduction (NaBH ) and hydrogenolysis provided a
4
reference sample of racemic 3. Chiral HPLC analysis served to establish that the ee of (S)-3
{
[] 8.35 (c = 1.233, CHCl )} was 90%.
D
3
Synthesis of compound 2

6
With a practical route to (S)-3 we next diverted the advanced intermediate 5.3 to the natural
product 2. To this end, 5.3 was subjected to Wittig reaction with the ylide generated from
pentyltriphenylphosphonium bromide (Scheme 6). The resulting dienes were first hydrogenated
over Rh-Al O and then subjected to hydrogenolysis over Pd/C to afford (S)-2 as a crystalline
2
3
solid (6.16.22). To make a racemic sample, the phenolic hydroxyl of (S)-2 was benzylated,
following our earlier procedure, and the secondary alcohol was oxidized to a ketone, which was
then reduced (NaBH ) and subjected to hydrogenolysis to liberate the phenol. With racemic and
4
optically active samples in hand, chiral HPLC showed that synthetic (S)-2 {[] 6.31 (c = 1.049,
D
CHCl )} had an ee of 68% and, surprisingly, that the natural sample was a 1:1.7 mixture of R and
3
S isomers. We did not establish why the optical purity of (S)-2 is lower than that of the homolog
(S)-3, but suspect that the reason is due to the fact that in making (S)-2 the epimerizable aldehyde
4
.6 was not used immediately after its preparation. The negative value of the specific rotation of
natural phenolic alcohol 2 must be due to a minor impurity, as the predominance of the S-isomer
should result in a positive value.
Scheme 6. Conversion of 5.3 to 6.3
Conclusions
The two naturally occurring vanilloids 1 and 2, isolated from the seeds of Aframomum
melegueta, were synthesized by routes that provide adequate quantities for biological testing and
that should allow variation in alkyl chain length with consequent alteration in the lipophilicity of
the final vanilloid. Unlike other reports on the isolation of 2, the natural material was not
racemic but was a 1:1.7 mixture of R and S isomers, and the present synthetic route should allow
biological evaluation of the individual enantiomers since both enantiomers of malic acid are
available.
Acknowledgements

7
We thank NSERC and Gifu University (Head Office for Glocalization) for financial support and
E. Fu (Chemistry Department, University of Alberta) for the chiral HPLC measurements.
Appendix A. Supplementary data
Supplementary data (copies of spectra and experimental procedures) related to this article
can be found at https://doi.org/
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Highlights



Synthesis of vanilloids from Grains of Paradise
Establishment that a naturally-occurring vanilloid is a 1:1.7 R/S mixture
Synthesis of a vanilloid homolog

9