Synthesis of a tyrosinase inhibitor by consecutive ethenolysis and cross-metathesis of crude cashew nutshell liquid

Article abstract of DOI:10.3762/bjoc.14.252

A convenient and sustainable three-step synthesis of the tyrosinase inhibitor 2-hydroxy-6-tridecylbenzoic acid was developed that starts directly from the anacardic acid component of natural cashew nutshell liquid (CNSL). Natural CNSL contains 60-70% of anacardic acid as a mixture of several double bond isomers. The anacardic acid component was converted into a uniform starting material by ethenolysis of the entire mixture and subsequent selective precipitation of 6-(ω-nonenyl)salicylic acid from cold pentane. The olefinic side chain of this intermediate was elongated by its cross-metathesis with 1-hexene using a first generation Hoveyda-Grubbs catalyst, which was reused as precatalyst in a subsequent hydrogenation step. Overall, the target compound was obtained in an overall yield of 61% based on the unsaturated anacardic acid content and 34% based on the crude CNSL.

Full text of DOI:10.3762/bjoc.14.252

Synthesis of a tyrosinase inhibitor by consecutive
ethenolysis and cross-metathesis of crude
cashew nutshell liquid
Jacqueline Pollini, Valentina Bragoni and Lukas J. Gooßen*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 2737–2744.
Lehrstuhl für Organische Chemie I, Ruhr-Universität Bochum,
ZEMOS, Universitätsstraße 150, 44801 Bochum, Germany
doi:10.3762/bjoc.14.252
Received: 29 August 2018
Accepted: 19 October 2018
Published: 31 October 2018
Email:
Lukas J. Gooßen* - lukas.goossen@ruhr-uni-bochum.de
*
Corresponding author
This article is part of the thematic issue "Progress in metathesis
chemistry III".
Keywords:
cashew nutshell liquid; cross-metathesis; renewable feedstock;
sustainable chemistry; tyrosinase inhibitor
Guest Editor: K. Grela
©
2018 Pollini et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A convenient and sustainable three-step synthesis of the tyrosinase inhibitor 2-hydroxy-6-tridecylbenzoic acid was developed that
starts directly from the anacardic acid component of natural cashew nutshell liquid (CNSL). Natural CNSL contains 60–70% of
anacardic acid as a mixture of several double bond isomers. The anacardic acid component was converted into a uniform starting
material by ethenolysis of the entire mixture and subsequent selective precipitation of 6-(ω-nonenyl)salicylic acid from cold
pentane. The olefinic side chain of this intermediate was elongated by its cross-metathesis with 1-hexene using a first generation
Hoveyda–Grubbs catalyst, which was reused as precatalyst in a subsequent hydrogenation step. Overall, the target compound was
obtained in an overall yield of 61% based on the unsaturated anacardic acid content and 34% based on the crude CNSL.
Introduction
Cashew nutshell liquid (Scheme 1) is an ideal renewable feed- CNSL exhibits a broad range of biological properties and indus-
stock. This non-edible industrial waste product, derived from trial applications, for instance in surfactants, plasticizers, resins,
the cashew nut processing, is abundant available and cheap soft materials and diverse medical applications [7]. Isolated via
[
1-3]. The annual production of cashew nuts with shell reached cold-press or solvent extraction processes, it contains predomi-
.9 million tons in 2016 [4], leading to an estimated CNSL pro- nantly anacardic acid (1). Upon distillation or any other ther-
4
duction of 1.2 million tons per year [5]. CNSL is a mixture of mal treatment, anacardic acid is known to decarboxylate easily
phenolic compounds such as anacardic acid (1), cardol and with formation of technical cashew nutshell liquid (tCNSL),
cardanol, each bearing a C-15 side chain in meta-position to the which consists mainly of cardanol. Due to this industrial pro-
hydroxy group with a varying degree of unsaturation [6].
cessing method, the main focus in research aiming at the chemi-
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Beilstein J. Org. Chem. 2018, 14, 2737–2744.
cal valorization and modification of CNSL is on cardanol- canyl substituted derivative ginkgolic acid (13:0, 3) exhibits the
derived products [8-10]. These include aromatic amines as most promising inhibitory activity.
polymers [11,12], cardanol-based phosphates as modifiers for
epoxy resins [13], cardanol grafted natural rubber as rubber While this modular approach is very appealing for drug-
plasticizers [14], amine-based surfactants [15] and phenol/ discovery, the use of expensive γ-resorcylic acid as the sub-
cardanol-formaldehyde based adhesives [16].
strate basis and the low overall yield over several reaction steps
are certainly drawbacks for larger scale production (Scheme 2)
The chemical valorization of anacardic acid (1) is even more [27].
attractive, because it contains an additional functional group.
However, the separation and purification of this CNSL compo- Due to the structural similarity of ginkgolic and anacardic acids,
nent without decarboxylation is laborious and relies on wasteful we believed that a particularly desirable synthesis of 2-hydroxy-
and tedious processes such as fractionate precipitation or 6-tridecylbenzoic acid (3) would involve CNSL as the substrate
column chromatography [6,17]. A limited number of derivatiza- basis. However, the functionalization of the anacardic acid com-
tions of anacardic acid are reported by now, including the syn- ponent of CNSL presents several challenges. Since CNSL
thesis of lactones [18-20], sulfonamides [21] or hydrazones consists of a mixture of acids, phenols and resorcins with satu-
[
22], typically bioactive compounds though with low commer- rated and unsaturated side chains, it seemed to be impossible to
cial value. However, several studies suggest that anacardic acid derive a single product with a shorter side chain via a cross-me-
and its derivatives display a broad range of biological activities tathesis with a short olefin, since inevitable, an inseparable mix-
such as antimicrobial [23], antioxidant [24], molluscicidal [25] ture of many compounds would result. It is, thus, necessary to
and antiplaque [26]. Ginkgolic acids, structurally closely related converge as many components as possible into one single com-
analogues of anacardic acid, have been reported to exhibit pound.
tyrosinase inhibitory activity [27]. We herein report a concise
synthesis of the most potent tyrosinase inhibitor among them, Based on concepts that we had previously utilized for the chem-
the ginkgolic acid (13:0), starting from crude CNSL (Scheme 1, ical modification of the cardanol component, we first investigat-
left).
ed strategies based on cross-metathesis of CNSL with ethylene
33-35]. Each unsaturated double bond isomer has the first
[
Tyrosinase is an enzyme [28] which is responsible for browning double bond located at the C-8 position, so that no matter how
of fruits and vegetables as well as skin pigmentation [29]. many other double-bonds are present, the unsaturated side
Furthermore, it is linked to several neurodegenerative diseases chains of all arenes will be shortened to ω-nonenyl groups if
[
30]. Therefore, the study and development of tyrosinase inhibi- ethylene is added in excess. The main difficulty is that thermal
tors from renewable resources is of particular interest for purification of CNSL would inevitably lead to decarboxylation,
research and industry [31,32]. Fu et al. investigated naturally and that unpurified CNSL, as it is obtained in an extraction
occurring ginkgolic acids which they selectively synthesized process, contains a wealth of side components, many of which
from 2,6-dihydroxybenzoic acid (4), and found that the tride- act as catalyst poisons.
Scheme 1: Targeted conversion of CNSL into a tyrosinase inhibitor.
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Beilstein J. Org. Chem. 2018, 14, 2737–2744.
Scheme 2: Previous synthesis of 2-hydroxy-6-tridecylbenzoic acid by Fu et al.
However, if an ethenolysis could be conducted with crude tainable solvents or no solvent at all, the reaction gave almost
CNSL, it would lead to the shortened derivatives of all unsatu- no turnover, regardless of the ruthenium catalyst employed.
rated components. We reasoned that it might be possible to However, as a 1.1 M solution in dichloromethane, the unsatu-
selectively precipitate the 2-hydroxy-6-(non-8-enyl)benzoic rated components of CNSL were converted in high yields at
acid (2) from this product mixture and use this as a substrate for 10 bar of ethylene in the presence of 0.5 mol % of the first gen-
a consecutive cross-metathesis with 1-hexene followed by a eration Hoveyda–Grubbs catalyst Ru-1.
hydrogenation and thus, selectively obtain the target product
2
-hydroxy-6-tridecylbenzoic acid (3).
The resulting mixture was filtered through celite, and the
dichloromethane solvent was removed in vacuo. After addition
of pentane, the mixture was chilled causing selective precipita-
tion of the desired product 2 as a colorless solid in an amount
Results and Discussion
Ethenolysis of crude CNSL
After thorough optimization, we found that natural CNSL, a that is equivalent to 80% of the anacardic acid content or 84%
highly viscous brown oil, obtained by ether extraction of of the unsaturated anacardic acid. Anacardic acid makes up for
cashew nutshells, undergoes smooth ethenolysis only in ca. 70% of the CNSL, so that the yield is 56% based on the
dichloromethane as the solvent (Scheme 3). Using more sus- entire CNSL. We were pleased to find that the saturated
Scheme 3: Ethenolysis of the crude CNSL.
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Beilstein J. Org. Chem. 2018, 14, 2737–2744.
C15-anacardic acid stays in solution along with cardanol and an oil bubbler. This way, the yield was improved to 53%
cardol derivatives. This residue may be utilized for chemical (Table 1, entry 2).
valorization after purification via distillation. This ethenolysis/
purification sequence was successfully performed on multi- The yield was further improved by raising the reaction tempera-
gram scales, yielding up to 16 g product in a single run.
ture to 60 °C (Table 1, entry 3). Now, only 3% starting material
was detected, but unwanted homocoupling of 2 (product 6,
see Supporting Information File 1) became a major side reac-
2
One-pot cross-metathesis/hydrogenation
We next sought for suitable conditions that would allow the tion.
cross-metathesis of 2 with 1-hexene to give 2-hydroxy-6-
(
tridec-8-enyl)benzoic acid (5). When performing the hexenol- We tested several solvents including sustainable solvents like
ysis of 2 with 7 equivalents of 1-hexene using 1 mol % of Ru-1 dimethyl carbonate and p-cymene. Unfortunately, this led to a
in dichloromethane at rt, the desired product was obtained decreased conversion and just 44–47% yield of the desired
only in unsatisfactory yield after 12h (Table 1, entry 1). High product. The use of the halogenated solvent dichloromethane
amounts of starting material were detected in the reaction mix- was still most efficient. Comparative tests with varying amounts
ture which points towards either a low conversion or an unfa- of 1-hexene revealed that an excess of 7 equivalents was
vorable position of the metathesis reaction equilibrium. We optimal. With a smaller amount the yield was decreased
tested several methods to shift the equilibrium by purging the (Table 1, entry 9 and 10), while a higher excess leads to de-
ethylene byproduct from the reaction mixture with inert gas, but creased conversion. This can be explained by the undesired
finally found that the best yields were obtained when allowing homocoupling of 1-hexene as a side reaction, which delivers the
the ethylene to slowly evaporate from the reaction mixture via less active 5-decene (7, see Supporting Information File 1). In
Table 1: Cross-metathesis of 2-hydroxy-6-(non-8-enyl)benzoic acid (2) with 1-hexene.a
entry
catalyst
solvent
1-hexene [equiv]
time
conversion [%]
5 [%]b
1
c
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Ru-1
Ru-2
Ru-3
Ru-4
Ru-5
Ru-6
Ru-7
Ru-1
DCM
DCM
7
7
7
7
7
7
7
7
5
3
7
7
7
7
7
7
7
7
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
12 h
6 h
35
55
97
28
66
64
76
51
94
81
96
98
98
98
93
46
98
97
33
53
2d
3
DCM
73
4
5
6
7
8
9
p-cymene
DMC
3
44
Me-THF
acetone
THF
47
59
42
DCM
69
1
0
1
2
3
4
5
6
7
DCM
65
1
1
1
1
1
1
1
DCM
74
DCM
6 h
72
DCM
6 h
65
DCM
6 h
56
DCM
6 h
55
DCM
6 h
27
DCM
6 h
45
18e
DCM
6 h
76 (72)f
aReaction conditions: 0.5 mmol 2, given equiv 1-hexene, 1 mol % Ru-cat, 60 °C, given time, open system via oil bubbler, bYields determined by GC
using n-tetradecane as internal standard. crt, closed system; drt; e2 mol % Ru-cat; fisolated yield.
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principle, these internal olefins can still undergo metathesis tionate precipitation from cold pentane. The one-pot cross-
albeit with less activity, depending on the catalyst. It was methathesis/hydrogenation was successfully scaled up to multi-
possible to reduce the time of the reaction to 6 h with almost the gram (8 mmol) scale yielding 72% of the hydrogenated product
same yield (Table 1, entry 11).
3. Combined with the ethenolysis/precipitation step, the entire
sequence afforded 61% overall yield based on unsaturated
We investigated various ruthenium catalysts in search for the anacardic acids present in the CNSL (Scheme 4).
optimal performance (Figure 1). The second generation
Hoveyda–Grubbs catalyst previously used to change the Conclusion
olefinic side chain of cardanol via cross-metathesis [36], only In conclusion, a straightforward sequence of an ethenolysis,
reached a yield of 45% (Table 1, entry 17). Several modified cross-metathesis and hydrogenation was developed for the syn-
second generation catalysts were tested, reaching yields of up to thesis of the tyrosinase inhibitor 3 from the non-edible waste
7
2% of the desired product (Table 1, entry 12). However, the product CNSL. The key step to this process is the ethenolysis of
first generation Hoveyda–Grubbs catalyst Ru-1, which was re- crude CNSL followed by a selective precipitation of 2-hydroxy-
ported in literature to be highly efficient for the ethenolysis of 6-(non-8-enyl)benzoic acid (2), which transforms the complex
several CNSL components [35], showed the best activity. In- substrate mixture into a single, pure compound. The subse-
creasing the catalyst loading to 2% gave only insignificantly quent hexenolysis can be combined with an hydrogenation to an
better yields (Table 1, entry 18).
efficient one-step process to obtain the target molecule
-hydroxy-6-tridecylbenzoic acid (3). Interestingly, it is a first-
2
It is known that ruthenium metathesis catalysts can be trans- generation Hoveyda–Grubbs catalyst Ru-1 that is most effi-
formed in situ into an active hydrogenation catalyst [37,38]. cient for both metathesis steps.
We, thus added charcoal and methanol to the crude reaction
Experimental
mixture of the cross-metathesis and stirred the reaction for addi-
tional 2 h under 5 bar of hydrogen. This way, the products were General methods
fully hydrogenated in quantitative yield. We were pleased to All reactions were performed in oven-dried glassware contain-
find that the desired product 3 could easily be purified by frac- ing a Teflon-coated stirring bar and dry septum under argon at-
Figure 1: State-of-the-art metathesis catalysts.
Scheme 4: Overall process in a preparative scale.
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Beilstein J. Org. Chem. 2018, 14, 2737–2744.
mosphere. All optimization reactions were monitored by GC 10.2, 6.7, 6.7 Hz, 1H), 5.03 (q, J = 1.7 Hz, 1H), 4.89–4.99 (m,
using n-tetradecane as internal standard. Products were sily- 1H), 2.94–3.05 (m, 2H), 2.00–2.10 (m, 2H), 1.56–1.68 (m, 2H),
lated in GC vials with N-methyl-N-(trimethylsilyl)trifluoroacet- 1.29–1.44 (m, 8H) ppm; 13C NMR (75 MHz, CDCl3) δ 176.1,
amide. Response factors of the products with regard to 163.7, 147.8, 139.2, 135.5, 122.8, 115.9, 114.1, 110.3, 36.4,
n-tetradecane were obtained experimentally by analyzing 33.8, 31.9, 29.7, 29.3, 29.1, 28.9 ppm. The analytical data
known quantities of the substances. GC analyses were carried matched those reported in the literature [38].
out using an HP-5 capillary column (phenyl methyl siloxane,
3
0 m × 320 × 0.25, 100/2.3-30-300/3) and a time program Optimization of the reaction conditions for the
beginning with 2 min at 60 °C, heating rate 30 °C/min, 3 min at synthesis of 2-hydroxy-6-(tridec-8-enyl)benzoic
00 °C. NMR spectra were measured at ambient temperature acid (5)
using CDCl3 as solvent, with proton, and carbon resonances at An oven-dried 20 mL vial was charged with Ru-1 (3 mg,
00 MHz/400 MHz and 75 MHz, respectively. All NMR data 5.00 μmol), 2 (131 mg, 0.5 mmol) and closed with a crimp cap.
3
3
are reported in ppm relative to the solvent signal. CHN- The vial was evacuated and backfilled three times with argon.
elemental analyses were performed with a Hanau Elemental 1-Hexene (3.50 mmol, 0.45 mL) and DCM (1 mL) were added
Analyzer vario Micro cube.
simultaneously via syringe under an argon atmosphere. The
continuous elimination of formed ethylene was performed by
Commercial substrates were used as received unless otherwise connecting the reaction vessel via an open system to an oil
stated. All solvents and liquid reactants were degassed with bubbler. The resulting mixture was stirred at 60 °C for 6 h.
Argon for 15 min prior to use. Ethylene was purchased from Air After the reaction was complete, the mixture was filtered
Liquide GmbH (purity 99,95%). All catalysts were donated by through celite and the filter cake was washed with DCM
Umicore.
(2 × 5 mL). The solvent was removed in vacuo and the residue
was dissolved in pentane (5 mL) and stored in the freezer until
precipitation of the solid. Product 5 was isolated as colorless
Preparation of CNSL
Cashew nutshell liquid was extracted following the procedure solid (120 mg, 72%). CHN-elemental analysis calcd for
described in the reference [34]: Cashew nutshells (500 g), C20H30O3: C, 75.43; H, 9.50; found: C, 75.43; H, 9.36;
collected from Naliendele in Mtwara, Tanzania, were commin- 1H NMR (400 MHz, CDCl3) δ 11.00 (s, 1H), 7.38 (t,
uted into ≈1 mm small particles which were than treated by J = 7.9 Hz, 1H), 6.86–6.91 (m, 1H), 6.76–6.82 (m, 1H),
Soxhlet extraction with Et2O (500 mL) at 50 °C for 6 h. 5.33–5.44 (m, 2H), 2.95–3.03 (m, 2H), 1.92–2.08 (m, 4H),
Removal of the solvent in vacuo resulted in a highly viscous 1.56–1.66 (m, 2H), 1.25–1.43 (m, 12H), 0.86–0.92 (m, 3H)
brown oil (160 g, 32 wt %). The CNSL was used without ppm; 13C NMR (75 MHz, CDCl3) δ 175.9, 163.7, 147.8, 135.5,
further purification.
130.4, 130.3, 129.9, 129.8, 122.8, 115.9, 110.3, 36.5, 32.6, 32.3,
2, 31.8, 29.8, 29.6, 29.3, 29.1, 26.9, 22.3, 22.2, 14 ppm. The
analytical data matched those reported in the literature [39].
3
Synthesis of 2-hydroxy-6-(non-8-enyl)benzoic acid
(2) via ethenolysis of CNSL
A 1 L Parr autoclave was charged with the metathesis catalyst One-pot synthesis of 2-hydroxy-6-tridecylbenzoic
Ru-1 (330 mg, 0.55 mmol), CNSL (37.7 g, 110 mmol) and acid (3)
DCM (100 mL) under ethylene atmosphere. The system was An oven-dried 20 mL vial was charged with Ru-1 (3 mg,
evacuated and backfilled with ethylene (5 bar) three times and 5.00 μmol), 2 (131 mg, 0.50 mmol) and closed with a crimp
finally pressurized to 10 bar. The mixture was stirred at cap. The vial was evacuated and backfilled three times with
5
00 rpm at room temperature for 12 h. After the reaction time, argon. 1-Hexene (3.50 mmol, 0.45 mL) and DCM (1 mL) were
the reaction mixture was filtered through celite and the filter added simultaneously via syringe under an argon atmosphere.
cake was washed with DCM (2 × 10 mL). The solvent was re- The continuous elimination of formed ethylene was performed
moved in vacuo and the residue was dissolved in pentane by connecting the reaction vessel via an open system to an oil
(
50 mL) and stored in the freezer until precipitation of the solid. bubbler. The resulting mixture was stirred at 60 °C for 6 h.
The precipitate was filtered and washed with cold pentane After the reaction was complete, methanol (0.5 mL) and acti-
2 × 20 mL) yielding the product 2-hydroxy-6-(non-8- vated charcoal (20.0 mg) were added. The vial was closed with
(
enyl)benzoic acid (2) as colorless solid (16,2 g, 84%). CHN- a septum cap, penetrated with a cannula for pressure equilibra-
elemental analysis calcd for C16H22O3: C, 73.25; H, 8.45; tion and placed into an autoclave. The system was purged twice
found: C, 73.55; H, 8.53; 1H NMR (300 MHz, CDCl3) δ 10.98 with H2 (5 bar) and finally pressurized to 5 bar. The resulting
(
br. s., 1H), 7.38 (dd, J = 8.4, 7.5 Hz, 1H), 6.89 (dd, J = 8.3, mixture was stirred for 3 h at 50 °C. After cooling down to
.3 Hz, 1H), 6.79 (dd, J = 7.5, 1.3 Hz, 1H), 5.82 (ddt, J = 17.0, room temperature, the pressure was slowly released under con-
1
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Beilstein J. Org. Chem. 2018, 14, 2737–2744.
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9
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Supporting Information File 1
4
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‘
3MET’ and Cluster of Excellence RESOLV, EXC 1069) for
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2
2.Swamy, B. N.; Suma, T. K.; Rao, G. V.; Reddy, G. C.
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ORCID® iDs
Lukas J. Gooßen - https://orcid.org/0000-0002-2547-3037
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