Expedient Synthesis of Lupulones and Their Derivatization to 2,8-7H-Dihydrochromen-7-ones

Article abstract of DOI:10.1002/open.202000008

A convenient and improved method for the synthesis of beta acids or lupulones, which are known to possess e. g. anti-cancer, anti-inflammatory, anti-oxidative and antimicrobial activity, has been developed successfully. Further derivatization of these complex structures to the corresponding dihydrochromen-7-ones, including the natural product machuone, was realized to simplify their analysis and to confirm their molecular structure. In addition to practical and safe laboratory procedures, the advantages associated with this new approach involve the use of water as a solvent and the direct crystallization of lupunones from acetonitrile, rendering our strategy more efficient and benign as compared to available methods.

Full text of DOI:10.1002/open.202000008

Communications
doi.org/10.1002/open.202000008
ChemistryOpen
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Expedient Synthesis of Lupulones and Their Derivatization
to 2,8-7H-Dihydrochromen-7-ones
Lena Decuyper,[a] Gurkirat Kaur,[a] Charlotte Versyck,[a] Eline Blondeel,[a] Yves Depetter,[a]
Kristof Van Hecke,[b] and Matthias D’hooghe*[a]
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A convenient and improved method for the synthesis of beta
acids or lupulones, which are known to possess e.g. anti-cancer,
anti-inflammatory, anti-oxidative and antimicrobial activity, has
been developed successfully. Further derivatization of these
complex structures to the corresponding dihydrochromen-7-
ones, including the natural product machuone, was realized to
simplify their analysis and to confirm their molecular structure.
In addition to practical and safe laboratory procedures, the
advantages associated with this new approach involve the use
Figure 1. Hop or bitter acids.
these structures do act as precursors of valuable compounds
important for beer quality. Beta acids and their derivatives are
also relevant from a medicinal point of view, as they have been
shown to display antimicrobial activity toward Gram-positive
bacteria and fungi, and they are known to demonstrate
anticancer, anti-inflammatory and anti-oxidative properties as
well.[3]
Bearing this in mind, hop acids can be considered as eligible
substrates for the development of new biologically active
compounds. Extraction of bitter acids from the hop plant is,
however, not straightforward. This process is time and labour
intensive and requires harsh conditions such as high temper-
atures and pressures, suggesting the need for a chemical
alternative.[4] On the other hand, the available chemical
syntheses suffer from limitations such as lack of selectivity,
practical and safety issues and low yields.
In summary, lupulones (i) received considerably less
attention in the literature as compared to their humulone
counterparts and (ii) constitute interesting substrates for
bioactive compound development, but (iii) they are difficult to
obtain due to cumbersome isolation or inefficient synthesis
procedures. Consequently, the main objective of this work
involved the development of a convenient and practical
alternative method for lupulone synthesis and their structural
investigation.
The premised synthesis of lupulones commenced with
monoacylation of phloroglucinol 3 by means of a traditional
Friedel-Crafts acylation protocol, relying on a classical Fries
rearrangement (Scheme 1).[5] To that end, phloroglucinol 3 was
dissolved in nitrobenzene under inert atmosphere (Ar), after
which acylation took place deploying various acid chlorides at
high temperature mediated by aluminium(III) chloride, giving
rise to acylphloroglucinols 4a–e. After purification via column
chromatography (SiO2) and, if necessary, crystallization from
water/acetonitrile (1:1), pure aryl ketones 4a–e were obtained
and subsequently transformed into the envisioned lupulones
5a–e via a triple prenylation protocol.
of water as a solvent and the direct crystallization of lupunones
from acetonitrile, rendering our strategy more efficient and
benign as compared to available methods.
The hop plant (Humulus lupulus) has been inextricably linked to
beer thanks to the contribution of hop to the typical bitter taste
and the aroma.[1] Moreover, hop also exerts a positive effect on
the stability of the beer foam.[2] These effects are, inter alia,
assigned to the so-called hop acids present in the lupulin
glands of hop cones. Beta acids or lupulones 2 are natural
products originating from the lupulin glands on female
inflorescences of the hop plant.[1] However, alpha acids or
humulones 1 are often considered as the most important
metabolites in hop as they significantly add to the typical bitter
taste and the unique aroma of beer (Figure 1). Consequently,
these compounds received considerable attention from a
scientific point of view, including various studies related to their
chemical synthesis and biological activities. Nonetheless,
although beta acids as such play a minor role in beer brewery,
[a] Dr. L. Decuyper, G. Kaur, C. Versyck, E. Blondeel, Dr. Y. Depetter,
Prof. M. D’hooghe
Department of Green Chemistry and Technology
Faculty of Bioscience Engineering
Ghent University
Coupure Links 653
9000 Ghent (Belgium)
E-mail: Matthias.Dhooghe@UGent.be
[b] Prof. K. Van Hecke
Department of Chemistry
Faculty of Sciences
Ghent University
Krijgslaan 281-S3
9000 Ghent (Belgium)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/open.202000008
© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This
is an open access article under the terms of the Creative Commons Attri-
bution License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited.
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ChemistryOpen
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Scheme 2. Synthesis of deoxyhumulone 8 by George et al.[9]
Table 1. Optimization of the prenylation of 4a.
Entry
Eq. prenyl
bromide
Eq.
KOH
Conc. KOH
[g/L]
Time
[h]
Yield [%] after
crystallization
from CH3CN
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35.7
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Scheme 1. Synthesis of lupulones 5a–e and 2,8-dihydro-7H-chromen-7-one
derivatives 6a–e.
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The desired triprenylation of compounds 4a–e was effected
by three consecutive base-mediated electrophilic substitution
reactions with prenyl bromide. It should be noted, though, that
the occurrence of mono-, di- and tetraprenylated side products
is known to present a significant hurdle in that respect. We first
tested the procedure reported by Drewett and Laws, the most
frequently used and highest yielding method for the synthesis
of analogous lupulones available in the literature.[6] To that end,
commercially available acetophloroglucinol monohydrate 4a
was dissolved in dry diethyl ether and added to dry, liquid
potassium hydroxide and prenyl bromide. The reaction time,
concentration and numbers of equivalents of the reagents were
varied to evaluate the conversion rate and the formation of side
products during the reaction. Apparently, the combination of
five and six equivalents of prenyl bromide and KOH (35.7 g/L),
respectively, proved to be favorable and afforded lupulone 5a
in 40% yield after crystallization from acetonitrile (entry 7). As
comprehensive characterization of lupulone 5a on the basis of
NMR spectral data was complicated due to the presence of
several tautomeric forms, the structure was additionally secured
by means of X-ray crystallography (Figure 2). Next, our new
procedure was validated through the successful synthesis of
°
ammonia at À 78 C. The reaction was then started by the
addition of four equivalents of prenyl bromide (instead of the
reported 7.5 eq). After reaction and work-up as described,[3]
acetolupulone 5a was obtained in 35% yield. However, due to
the hygroscopic character of ammonia, its tendency to react
with CO2, its low boiling point and high explosion risk, the latter
reaction protocol is not devoid of risks.[7]
To search for a more efficient, safe and practical method for
triprenylation of acylphloroglucinols 4a–e, a patented proce-
dure based on the use of the tertiary alcohol 2-methylbut-3-en-
2-ol and zinc(II) chloride as a Lewis acid catalyst was tested
next.[8] However, we were soon urged to look for an alternative
based on irreproducible results and the formation of multiple
side products.
Next, reaction conditions reported by George et al. were
tested and optimized, which had been applied for the synthesis
of m-diprenylacylphloroglucinol 8, a deoxyhumulone, but gave
gem-diprenylated acylphloroglucinol 9 and triprenylated lupu-
lone 10 as side products (Scheme 2).[9]
Our attempts to adapt George’s reaction parameters
(Scheme 2) to increase the selectivity toward formation of
lupulones 5 at the expense of mono-, di- or tetraprenylated
side products are summarized in Table 1. To that end,
compound 4a was dissolved in ice-cooled water along with
Figure 2. Molecular X-ray structure of acetolupulone 5a, thermal displace-
ment ellipsoids are shown at the 50% probability level. An intramolecular
hydrogen bond is indicated.
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other alkyl-substituted analogues, natural product n-lupulone
5b and phenylacetolupulone 5c in an identical way, although
slow, cooled crystallization and recrystallization from
acetonitrile were necessary to obtain pure compounds, result-
ing in slightly lower yields for these derivatives. For aryl
analogues 5d–e, the reaction time was limited to 15 minutes as
conceivable that these natural product-based structures are
more resistant toward oxidative decomposition when compared
to their lupulone precursors, which are typically easily degraded
to bitter hulupones.
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at this point, the percentages of trisubstituted lupulones 5d–e Acknowledgements
already reached their maximal level (>86%), while the amounts
of side products were kept at a minimal degree (<4%
diprenylated and <8% tetraprenylated products). Purification
by means of reversed-phase column chromatography eventu-
ally furnished pure target compounds 5d–e.
The authors are indebted to Ghent University for financial support.
KVH thanks the Hercules Foundation (project AUGE/11/029) and
the Special Research Fund (BOF) – UGent (project 01 N03217) for
funding.
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As such, based on the higher yield obtained (for 5a) and its
less time-consuming nature, our new method represents a
suitable alternative to the method of Drewett and Laws.[3] In Conflict of Interest
particular, it is considerably more practical and safe, time
efficient, uses water as a solvent, and allows for direct
crystallization from acetonitrile for alkyl derivatives.
The authors declare no conflict of interest.
As mentioned above, comprehensive characterization of
lupulones 5 on the basis of NMR spectral data was seriously
complicated by the presence of multiple tautomeric forms.
Besides X-ray analysis for compound 5a, further elucidation and
confirmation of the structural identity of the synthesized, in
some cases non-crystalline, products 5 was therefore enabled
through their oxidative intramolecular cyclization into 2,8-
dihydro-7H-chromen-7-one derivatives, in accordance with a
literature protocol (Scheme 1).[9] Thus, lupulones 5 were treated
with 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) and (diacetox-
Keywords: Lupulones · chromenones · hop and beer bitter
acids · triprenylation · medicinal chemistry
[1] M. Verzele, D. De Keukeleire, Chemistry and analysis of hop and beer
bitter acids 1991, 201–377.
[2] K. Asano, N. Hashimoto, J. Am. Soc. Brew. Chem. 1980, 383, 129–137.
[3] a) G. Haseleu, D. Intelmann, T. Hofmann, Food Chem. 2009, 116, 71–81;
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Colston, G. Pirianov, D. Ramanthan, R. Dhillon, A. Sinclair, G. A. Skinner,
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°
yiodo)-benzene in dry THF at À 78 C, initiating a 6π-electro-
cyclic reaction of the O-quinone methide intermediate, formed
through selective hydride withdrawal from precursor 5 by the
in situ generated TEMPO cation.[5] Purification via column
chromatography (SiO2 or C18) and NMR analysis of the
compounds produced in this way eventually confirmed the
structure of cyclic derivatives 6 (as a mixture of two tautomeric
forms for 6a–b) and hence their acyclic counterparts 5. The
polyisoprenylated benzophenone machuone 6d has previously
been isolated from the fruits of Clusia columnaris and Clusia
sandiensis, two plants found in tropic and subtropic areas in
Central and South America,[10] pointing to the relevance of these
chromenone structures from a natural product chemistry point
of view as well.
[4] Z. Zeković, I. Pfaf-Šovljanski, O. Grujić, J. Serb. Chem. Soc. 2007, 72, 81–
87.
[5] K. A. Smith, Structure and synthesis of phloroglucinol derivatives from
Hypericum roeperianum, Thesis (M.Sc.), University of KwaZulu-Natal,
Pietermaritzburg, 2010.
[6] K. Drewett, D. Laws, J. Inst. Brew. 1970, 72, 188–190.
[7] J. J. Lagowski, Synth. React. Inorg. Met.-Org. Nano-Met. Chem. 2007, 37,
115–153.
[8] W. Reininger, A. Hartl, U.S. Patent 4053517A, 1977.
[9] J. H. George, M. D. Hesse, J. E. Baldwin, R. M. Adlington, Org. Lett. 2010,
12, 3532–3535.
In conclusion, a practical and convenient new approach
toward the synthesis of lupulone-like structures has been
accomplished, allowing for the preparation of a variety of beta
acid analogues in the framework of e.g. medicinal chemistry
studies. Furthermore, cyclization of these lupulones expectedly
delivered dihydrochromen-7-one derivatives, allowing for an
easier structural analysis. Moreover, by encapsulation of the
isolated prenyl group in the chromenone fused ring, it is also
[10] a) R. S. Comagnone, A. C. Suarez, S. G. Leitao, F. Delle Monache, Rev.
Bras. Farmacogn. 2008, 18, 6–10; b) F. Delle Monache, G. Delle Monache,
E. Gacs-Baitz, Phytochemistry 1991, 33, 2003–2005.
Manuscript received: January 15, 2020
Revised manuscript received: March 10, 2020
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