An expedient synthesis of 5-n-alkylresorcinols and novel 5-n-alkylresorcinol haptens

Article abstract of DOI:10.3762/bjoc.5.22

The first synthesis of bioactive long alkyl chain 5-n-alkylresorcinols, present in whole grain products, by a novel modification of the Wittig reaction is described. All the main long chain 5-n-alkylresorcinols present in rye and wheat, including C₂₃ and C₂₅ analogues and haptens, which have not been previously prepared, were synthesised. Microwave-promoted reactions of a semistabilized ylid and alkanals in water gave good yields in both pressurized and open systems. An alternative microwave-promoted synthesis starting from non-stabilized alkyltriphenylphosphonium salts and 3,5-dimethoxybenzaldehyde worked as well. Aqueous media were suitable for the reactions even if the starting materials were not soluble in water. The 5-n-alkylresorcinols are potential biomarkers of whole grain intake, and the new hapten derivatives of 5-n-alkylresorcinols will open the way for the immunochemical detection techniques of alkylresorcinols.

Full text of DOI:10.3762/bjoc.5.22

An expedient synthesis of 5-n-alkylresorcinols and
novel 5-n-alkylresorcinol haptens
Kirsti Parikka1,2 and Kristiina Wähälä*,1
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 22.
1Laboratory of Organic Chemistry, Department of Chemistry, P.O.
Box 55, FIN-00014-University of Helsinki, Finland, tel. +358 9 191
50356, fax +358 9 191 50357 and 2(present address:) Department of
Applied Chemistry and Microbiology, P.O. Box 27,
FIN-00014-University of Helsinki, Finland
doi:10.3762/bjoc.5.22
Received: 15 February 2009
Accepted: 21 April 2009
Published: 19 May 2009
Email:
Associate Editor: D. O’Hagan
Kristiina Wähälä* - kristiina.wahala@helsinki.fi
© 2009 Parikka and Wähälä; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
5-n-alkylresorcinols; haptens; microwave assisted synthesis; Wittig
reaction
Abstract
The first synthesis of bioactive long alkyl chain 5-n-alkylresorcinols, present in whole grain products, by a novel modification of
the Wittig reaction is described. All the main long chain 5-n-alkylresorcinols present in rye and wheat, including C23 and C25
analogues and haptens, which have not been previously prepared, were synthesised. Microwave-promoted reactions of a semi-
stabilized ylid and alkanals in water gave good yields in both pressurized and open systems. An alternative microwave-promoted
synthesis starting from non-stabilized alkyltriphenylphosphonium salts and 3,5-dimethoxybenzaldehyde worked as well. Aqueous
media were suitable for the reactions even if the starting materials were not soluble in water. The 5-n-alkylresorcinols are potential
biomarkers of whole grain intake, and the new hapten derivatives of 5-n-alkylresorcinols will open the way for the immunochem-
ical detection techniques of alkylresorcinols.
Introduction
5-Alk(en)ylresorcinols and related compounds are phenolic
lipids present in several families of plants (e.g. Gramineae,
Anacardiaceae, Proteaceae) and in some families of bacteria [1].
We have recently shown that 5-n-alkylresorcinols (AR, 1, see
Figure 1) act as antioxidants protecting LDL from oxidative
damage in in vitro experiments using synthesized pure
analogues with varying chain lengths [2]. In addition, AR have
Figure 1: 5-n-Alkylresorcinols 1 and new hapten derivatives 2.
various biological effects including antimutagenic activity
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Beilstein Journal of Organic Chemistry 2009, 5, No. 22.
[3-6], antibacterial properties [7], inhibition of enzymes [8-12] Wadsworth-Emmons reactions, using ester enolate type stabil-
and interaction with biological membranes by incorporation to ized phosphonate ylids, have often been conducted in aqueous
the membrane structure [13,14]. Whole grain rye and wheat solutions [29]. The existing cases have mostly been targeted for
products, linked to a healthy diet, are the most important dietary the preparation of stilbenes from benzyltriphenylphosphonium
source of AR [1]. According to animal and human studies, these salts and aryl aldehydes [30,31] and also include reactions of
compounds are absorbed and at least partially metabolised, and stabilized ylids with aryl aldehydes or short alkyl chain alkanals
due to their presence in significant amounts in whole grain [32-36] and the preparation of o- and p-nitrostyrenes from the
products they are currently investigated as highly potential highly reactive formaldehyde [37]. To provide water solubility
biomarkers of whole grain intake [15-21].
more generally, aryl modified phosphonium salts, carrying a
–COOH group [38] or PEG attachments [39], have been
However, AR are not generally nor readily available. Thus an developed but require extensive synthetic work. Previously,
efficient preparation method is needed for various analytical, non-stabilized alkylphosphonium salts have appeared much less
metabolic or bioactivity investigations. The critical step in the amenable than the benzyl analogues. A single paper describes
synthesis of long alkyl chain (≥C15) AR is the formation of C–C the synthesis of two 1-phenylalkenes in 20–30% yield using
bond between the aromatic ring and the alkyl chain. The previ- benzaldehyde and a CH2Cl2/H2O solvent [31].
ously reported multistep syntheses utilize techniques that are
time-consuming, require an inert atmosphere and give highly We report here a fast and efficient synthesis of the long chain
variable overall yields. Undoubtedly, the most common 5-n-alkylresorcinols 1 and the new potential hapten derivatives
approach has been Grignard or alkyllithium techniques starting of 5-n-alkylresorcinols 2, ready for the development of anti-
from 3,5-dimethoxybenzaldehyde (18–48% yields whenever bodies. We also report that the use of microwave (MW) irradi-
reported) [22-26]. Additional synthetic methods have been ation brings major benefits as regards reaction times and yields
developed for shorter chain AR (<C15), such as the aromatiza- in aqueous Wittig reactions. Both semi-stabilized and non-
tion of cyclohexane derivatives in 61–66% yield [27]. A recent stabilized ylids provide an expedient entry to 5-(1-
Wittig approach utilises the ozonolysis product of a pentadecyl- alkenyl)resorcinols, readily converted to AR and AR haptens.
resorcinol (C15) and odd carbon chain ylids, but its use is
limited because of the poor availability of odd carbon chain Results and Discussion
alkyl bromides [28]. The synthesis of hapten derivatives of We approached the Wittig synthesis of the precursors of AR
alkylresorcinols 2, potential compounds in the development of and AR haptens from two aspects choosing semi-stabilized and
immunochemical analysis techniques, has not been reported non-stabilized benzylphosphonium or alkylphosphonium ylids
previously.
(from salts 3 and 4,) as starting materials with 5 or 6, respect-
ively. Water or a mixture of water and an organic solvent were
Only few papers have reported Wittig reactions in water used as a reaction medium with K2CO3. MW irradiation was
without an organic solvent, although the related Horner- used to speed up reaction rates after the preliminary experi-
Scheme 1: Synthesis of AR derivatives and haptens. a) sealed vessel: MW, 0.1M K2CO3, 100–150°C, 100–150 W, 4–9 bar, 66–81%; b) open vessel:
MW, 0.1M K2CO3, 80 °C, 50–150W, 89%; c) 9-BBN, K3PO4, Pd(PPh3)4, I−(CH2)10COOMe, 26%; d) H2, Pd/C, CH2Cl2, 90–91%; e) HBr, reflux,
77–79%.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 22.
Table 1: Wittig reactions performed in 0.1M K2CO3 or DMSO/H2O.
Phosphonium
salt
Aldehyde
Product
Time (min)
Yield % (Open
vessel)
Yield %
(Pressure
vessel)
Solvent
3
5a
5b
5c
5d
6
7a
7b
7c
7d
8a
8a
8b
8c
8d
8e
8f
3
3
89
–
81a
78
77
66b
–
0.1 M K2CO3
0.1 M K2CO3
0.1 M K2CO3
0.1 M K2CO3
DMSO/H2O
sat. K2CO3
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
DMSO/H2O
3
3
3
–
3
10
5
–
4a
4a
4b
4c
4d
4e
4f
4g
4h
81
–
6
5
48
–
6
5
78
75
76
70
68
68
65
6
5
–
6
5
–
6
5
–
6
5
–
6
8g
8h
5
–
6
5
–
a4 bar pressure, otherwise 9 bar.
b3 equiv of the phosphonium salt was used in the reaction.
ments under conventional heating were found to require very saturated). Of those, the saturated solution gave less than 50%
long reaction times.
at best. A DMSO/H2O solution was found to be optimal for
these reactions giving the products 8 in 65–81% yield. In both
For the reactions of 3 and 5, 0.1 M K2CO3 was an optimal approaches, MW heating shortened the reaction time to minutes
solvent. The reactions were performed in 3 or 10 min yielding and increased the yield (e.g. products 7a and 8e) in comparison
66–89% of 7a–d (Scheme 1, Table 1). The methyl group at C-2 with the reactions performed under conventional conditions
of 5d hindered the reaction and required the use of an increased (refluxing several hours in e.g. dioxane/H2O/K2CO3).
amount of 3 to give a yield of 66%.
The reactions were performed in either open vessels or sealed
The reactions of 4 and 6 required the presence of an organic pressure vessels. The yields of the reactions of the alkylphos-
solvent (Scheme 2, Table 1), as the yield was not satisfactory in phonium salts 4 in sealed vessels were not good due to degrada-
the different K2CO3 solutions tested (0.1 M/1 M/5 M/ tion of the ylids under high pressure (ca. 9 bar). In contrast,
Scheme 2: Synthesis of 5-n-AR and haptens. a) PPh3, toluene, reflux, 79–87%; b) open vessel: MW, DMSO/H2O 10:1, K2CO3, 130–150 °C, 150 W,
65–81%; c) H2, Pd/C, CH2Cl2, 90–97%; d) BBr3, 80–84%.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 22.
reaction of the semi-stabilized benzylic ylid from 3 gave good Conclusion
yield under pressurized conditions, as well as in the open vessel We have shown that the MW catalyzed reactions of semi-stabil-
(product 5, Table 1). A one-pot procedure was investigated ized ylids and alkanals give good yield in pressurized or open
using alkyl bromide, PPh3 and 6 in various organic solvents but systems and without organic solvent, even if they are not
remained unsuccessful.
soluble in water, being thus practical starting materials for
alkylresorcinols and related compounds. An alternative MW
Mixtures of cis and trans isomers 7a–d and 8 had Z/E ratios catalyzed synthesis route where 3,5-dimethoxy benzaldehyde
varying from ca. 40:60 (8) to ca. 80:20 (7a, both in open and and unstabilized alkyltriphenyl phosphonium ylids react in
sealed vessel) according to 1H NMR and GC-MS. As the ulti- DMSO/H2O works as well and alkylresorcinol precursors that
mate targets were the C=C reduced AR, the lack of stereochem- do not have a commercially available alkanal starting material
ical control was of no consequence. Following the Wittig reac- can be synthesized rapidly and efficiently by way of this
tion, catalytic hydrogenation and demethylation gave AR and approach. The procedure is suitable for all the long chain 5-n-
AR haptens in ca. 40% overall yield. The Wittig product 7b was alkylresorcinols, including the C23:0 and C25:0 analogues, for
a practical starting material for the C23 hapten (2d), for which which synthesis has not been reported previously. Functional
commercial alkanal or alkyl bromide precursors are not avail- groups enhancing the solubility in water are not necessary in the
able (Scheme 1). 5a was readily synthesised by Swern-type MW promoted Wittig reactions of the long alkyl chain react-
oxidation (see Supporting Information File 1).
ants. Thus an efficient preparation method of 5-n-alkylresor-
cinols and their hapten derivatives was developed. There was no
The Wittig reagents were poorly soluble in water. Nevertheless, need for dry solvents or inert atmosphere.
functional groups enhancing their solubility, such as previously
reported –COOH or PEG attachments [38,39], were not neces-
Supporting Information
sary. Both the yields of the preliminary experiments without
MW irradiation and the yields of the MW promoted reactions
Supporting Information File 1
were superior to those reported previously (20–30%) for Wittig
reactions of non-stabilized ylids [31].
Experimental and data
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-22-S1.doc]
The monitoring of AR from biological samples, including
human plasma [15], human and animal ileostomy fluids [16,17]
and e.g. perirenal adipose tissue [18], has mainly been
performed by gas chromatography-mass spectrometry (GC-MS)
requiring time-consuming sample preparation such as extrac-
tion, derivatisation, chromatography, and special equipment.
Compared with this, immunochemical techniques would be
relatively straightforward being rapid and suitable for screening
purposes in large populations. In the development of immun-
oanalytical methods, haptens are needed for the preparation of
immunogens, which produce specific antisera. Due to the lack
of the required haptens, immunoassay has not yet been used in
the analysis of AR.
Acknowledgments
Jenny and Antti Wihuri Foundation, the Academy of Finland
and the Graduate School of Bio-organic and Medicinal Chem-
istry are gratefully acknowledged for participating in the finan-
cial support. We thank Dr. Jorma Matikainen and Dr. Petri
Heinonen for running the HRMS spectra.
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