âOn Waterâ MW-Assisted Synthesis of Hydroxytyrosol Fatty Esters

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On Water MW Assisted Synthesis of Hydroxytyrosol Fatty Esters Manuela Oliverio, Monica Nardi, Luca Cariati, Emanuela Vitale, Sonia Bonacci, and Antonio Procopio ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.5b01201 • Publication Date (Web): 25 Jan 2016 Downloaded from http://pubs.acs.org on January 27, 2016

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ACS Sustainable Chemistry & Engineering

On Water MW Assisted Synthesis of Hydroxytyrosol Fatty Esters M. Oliverio,*aM. Nardi,bL. Cariati,a E. Vitale,a S. Bonaccia and A. Procopioa a

Dipartimento di Scienze della Salute, Università Magna Graecia, Viale Europa, 88100-

Germaneto (CZ), Italy. Email address: [email protected] b

School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N

1AX, UK KEYWORDS . Hydroxytyrosol•Natural Products•Microwave•Water Chemistry•One-pot reaction

ABSTRACT. A new “on water” MW-assisted esterification protocol using fatty chlorides and acetonidehydroxytyrosol as starting materials, giving rise to a one-pot multistep reaction, without any added catalyst is described. The reaction took place at the interface oil/water thus being strictly dependent on the lipophilicity of the fatty acid acyl chloride. The potential scale-up of the method was also reported.

ACS Paragon Plus Environment

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INTRODUCTION: Hydroxytyrosol, or 2-(3,4-dihydroxyphenyl)ethanol, belongs to the family of ortho-diphenolic compounds present as minor components in olive oil.1 It comes from the hydrolysis of the more complex secoiridoid oleuropein and, despite its low partition coefficient (log P= 0.09), it displays an amphiphilic character thanks to its small dimensions.2Hydroxytyrosol acts as natural antioxidant due to its catechol moiety and it displays its protective role especially in bulk oils, as disclaimed by the so called “polar paradox”, establishing that hydrophilic antioxidants work well in lipophilic bulk media.2,3Moreover, hydroxytyrosol has been largely investigated owing to its beneficial effects on human health, in particular against cardiovascular, inflammatory, microbial and cancer diseases.1,3-5 In order to envisage an extensive use of hydroxytyrosol in food, cosmetic and pharmaceuticals, the synthesis of more lipophilic hydroxytyrosyl ether or esters, has been proposed. 3 Lipophilic derivatives were able to display antioxidant activity in oil/water emulsions, especially when the elongation of the chain was comprised between C4 and C8 atoms,6-8 thus opening new possibilities in food preservation. On the other hand, longer chains (C10-C16) allowed new pharmaceutical applications of hydroxytyrosol such as the integration in liposomes 9,10 or the topical administration.11 The biological activity of lipophilic derivatives resulted higher than free hydroxytyrosol, with a variability on the optimal lipophilic chain “cut-off” depending on the specific biological activity under study.12-17 Lipophilic hydroxyl esters are easier metabolized and synthesized compared to ether derivatives.3 In particular, both acid catalyzed 11,18,19 and basic catalyzed methods 3 were reported in the literature for the synthesis of hydroxytyrosol acyl esters, most of them requiring chlorinated or dry solvents, long reaction times or preventive protection steps needed on the catechol moiety. On the other hand, milder reaction conditions and better chemoselectivity have


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been reported for the enzymatic synthesis using lipases from Candida Antartica,8, 20 even if such protocols are still far away from a possible scale-up. A problem that has to take into account for the extensive use of hydroxytyrosol as starting material, concerns its storage and stock. As it exerts a strong antioxidant effect, its catechol moiety can be rapidly converted in a quinone moiety, even when it is stored on the dark and in dry conditions.2 So, some alternative multi-step protocols of esterification/oxidation have been proposed using tyrosol or homovanillic acid as starting materials.21-26 In recent years our group has gained experience in oleuropein derivatives chemical manipulation,4,11, 27 MW- synthesis 28-30 and “on water” reactions in catalyst free conditions.31Thus, in this report, we describe a new “on water” MW-assisted esterification protocol using fatty chlorides and acetonidehydroxytyrosol as starting materials, giving rise to the fatty hydroxytyrosyl esters in a one-pot multistep reaction without any added catalyst. In particular, we demonstrated that the water insolubility of both reagents and products was the driving force of the esterification step and, as the acetonide protecting group can be removed in acid environment, the catechol deprotection occurred in turn due to the HCl formed as byproduct during the first reaction step. EXPERIMENTAL METHODS The MW reactions were performed into the microwave reactor Synthos 3000 by Anton Paar, equipped with a rotor 64MG5 and a IR sensor as temperature external control working in Pcontrolled mode; a conversion factor of 1.214 was applied to calculate the value of internal temperature. Reactions were performed in 0.3-3 ml glass vials closed with a PTFE seal and a screw-cup in PEEK. Reaction was controlled by TLC using silica plates 60-F264 on alumina, commercially available from Merck.


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The qualitative identification was performed using a Thermo Scientific Q-ExactiveTM mass spectrometer working in direct injection mode. Ionization was performed by an electrospray ionization source with both negative and positive polarities, at 35.000 resolving power (defined as FWHM at m/z 200), IT 100 ms, and ACG target= 3⋅106, by full scan analysis (mass range 140-600 amu). Source conditions were: spray voltage 2.8 kV, sheath gas: 40, arbitrary units, auxiliary gas= 10, probe heater temperature: 280°C; capillary temperature: 320°C; S-Lens RF Level: 50. The instrument was calibrated by Thermo calibration solutions prior to the beginning of the analysis. All synthetized compounds are known; their 1H-NMR and 13C-NMR spectra were compared with those reported in literature.11 General MW-assisted protocol for Hydroxytyrosol Fatty Esters Synthesis. Hydroxytyrosolacetonide was synthesized from 3,4- dihyodroxyphenilacetic acid using the method reported in the literature. 2 To a water (500 µl) suspension of hydroxytyrosolacetonide (0.26 mmol) into a 3 ml glass vials to acyl chloride (0.31mmol) was added under stirring. The vials was sealed and reacted at 110°C (IR Limit) into a Synthos 3000 microwave oven by Anton Paar, equipped with an 64-MG5 rotor .The disappearance of protected hydroxytyrosol was controlled by TLC and, after, completion, the crude was separated by decantation and purified by flash chromatography. All synthetized compounds are known; their 1H-NMR and 13C-NMR spectra were compared with those reported in literature. 11The recovered water phases were neutralized by adding a saturated solution of NaHCO3 while the acetone was separated by evaporation under vacuum.For the scale-up test the MW oven was equipped with a XF-100 rotor; each 6-30 ml Teflon vials was filled with 5.2 mmol of acetonidehydroxytyrosol and 10 ml of water (overall reactant loading of 41.6 mmol).


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Hydroxytyrosol Stearate (3a): Whyte powder; Rf= 0.82; HRMS: 419.3156 (THEORIC MASS: 419.3167) Hydroxytyrosol Oleate (3b): Colorless Oil; Rf=0.3; HRMS: 417.3012 (THEORIC MASS: 417.3010) Hydroxytyrosol Palmitate (3c): Whyte powder: R=0.61; HRMS: 391.2892 (THEORIC MASS: 391.2854) Hydroxytyrosol Decanoate (3d): Colorless Oil: Rf=0.53; HRMS: 307.1915 (THEORIC MASS: 307.1915) Hydroxytyrosol Exanoate (3e): Colorless Oil: Rf=0.63; HRMS: 251.1288 (THEORIC MASS: 251.1289) RESULT AND DISCUSSION: Organic reactions whose reagents, products and byproducts are characterized by a high difference in lipophilicity, can occur very efficiently in water through the so called “on-water effect”.32 In these cases, water creates an interface with lipophilic reactants where the reaction takes place, the equilibrium being positively affected by the separation of the reaction products from the byproducts in two different phases. According to the Sharpless definition,32 the creation of an interface between water and organic reactants is the condition for an acceleration respect to the same reaction performed in organic solvents; such acceleration is not merely explicable as a consequence of the increased concentration at the interface, being higher than the reaction conducted in solvent free condition and independent from the quantity of water employed. According to the studies by Marcus et al.33 the “on water effect” is due to the


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capability of water to lean forward the organic phase, thus offering to the organic moieties able to form hydrogen bonds, the possibility to interact with the hydroxyl groups “at the interface” in a similar manner than “on a catalytic surface”. Looking at reagents, products and byproducts of hydroxytyrosolacetonide esterification with fatty chlorides, we hypothesized that the “on-water” effect could influence the esterification step and activate in turn the deprotection of hydroxytyrosol. In order to test our hypothesis, a huge stock of acetonidehydroxytyrosol was prepared starting from 3,4- dihyodroxyphenylacetic acid, following the method reported in literature.2 The protected hydroxytyrosol was stored at 4°C in a dark vial and its integrity in time as been proved by HPLC analysis before use. Starting from this material, the 3a-fderivatives of hydroxytyrosol were prepared as shown in Scheme 1.

O

OH

O O

1

R

Cl

2a - f H2O, MW, 134°C

O

HO HO

3 a- f

R O

a= CH3(CH2)16; b= CH3(CH2)7CHCH(CH2)7; c=CH3(CH2)14; d=CH3(CH2)8; e=CH3(CH2)4; f=CH3(CH2)2

Scheme 1. Synthesis of Hydroxytyrosol Fatty Esters We decided to start our investigation optimizing the reaction conditions choosing stearoyl chloride as lead compound. The proposed synthetic protocol (Scheme 1) involved the use of hydroxytyrosolacetonide1, (0.26 mmol), and a slight molar excess of 1.1 eq of stearoyl chloride


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2a (0.31mmol). The reaction has been performed in water without any catalyst, in a Synthos 3000 microwave oven (by Anton Paar) equipped with an IR sensor as temperature controller. The acyl chloride was used in molar excess in order to both facilitate the nucleophilic attack and contrast the fatty acid chloride hydrolysis possibly occurring into an acid water medium. A first negative result was obtained when the reaction was performed with an IR limit of 91°C (Tsample= 110°C), even for long reaction time (Table 1, Entry 1, row 1). At the contrary, when the IR limit has been set up at 110°C (Tsample= 134°C), it has had the formation of a white precipitate (Table 1, Entry 1, row 2) after only 15 minutes. Furthermore, the acyl chloride equivalents were increased to 1.2eq in order to contrast the hydrolysis of the reactant and improve the reaction yield (Table 1, Entry 1, row 3); however, higher amounts of reactant did not ameliorate the yield (Table 1, Entry 1, row 4). Finally the attempt to portionwise add 1.2eq of acyl chloride was carried out (Table 1, Entry 1, row 5) thus registering a harder chloride hydrolysis. In order to test if our positive result was due to the “on water effect”,32,33 a comparison with an aprotic organic solvent, such as CH3CN, and a non-polar green solvent, as 2-MeTHF, was performed in the same reaction conditions. As summarized in Table 1, the reaction carried out in CH3CN (entry1, row 6) proceeded slowly towards the same unprotected stearoyl hydroxytyrosol respect to the same reaction performed on water but the heterogeneity of the mixture allows to reach a reasonable yield after 45 minutes. At the contrary, 2-MeTHF completely dissolve both reactants, giving rise to the worst result (entry1, row 7). Moreover, a reaction in solvent free conditions was carried out in order to verify the effect of the concentration on the reaction rate (Table 1, entry 1, row 8). The yield obtained after 30 min is


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comparable whit the “on water” yield after 15 minute. Therefore, even if the concentration is not the only parameter affecting the reaction rate, it has a certain importance in the reaction fate. As the “on water effect” takes place as long as the water quantity is enough to create an interface, the acceleration on the reaction rate is independent on the quantity of water employed.32,33 Thus, a test using a double amount of water was carried out (Table 1, entry 1, row 9), demonstrating that the amount of water is not deleterious for the reaction. Accordingly to the reported results the rate acceleration observed “on water” can be explained as a cooperation between heterogeneity and reactant concentration at the interface, independently from the amount of used water. Finally, in order to explore the contribution of microwaves to the rate acceleration, a reaction under classical heating was performed, giving rise to a comparable yield of the desired product after 8 hours (Table 1, Entry 1, row 10). The recovered water phases were neutralized by adding a saturated solution of NaHCO3 while the acetone was separated by evaporation under vacuum. Indeed, the by-products of the reaction are a water saline solution and acetone, whose environmental impact in terms of environmental or health toxicity and life cycle score are still acceptable according to the GSK solvent list. 34 Once the reaction conditions optimized (Table 1, Entry 1, row 3), we decided to perform the reaction with different fatty acyl chlorides in order to test the protocol versatility.† The reactions were controlled by TLC and the crudes were isolated by decantation and purified by flash chromatography. The products were identified by HRMS while 1H-NMR and 13C-NMR spectra were compared with those reported in literature.11The results are summarized in Table 1.


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Moderate to good yields were obtained for quite all the substrates tested (Entries 2-5,Table 1), with the only exception of butyryl chloride (Entry 6 in Table 1). Longer reaction times did not increase the overall yields and, at the contrary, a degradation reaction was observed (data not showed). In any case, we observed the formation of a white precipitate (compounds 3a and 3c) or a brown oil (compound 3b, 3d and 3e) in a separate phase respect to the reaction solvent, that confirmed the formation of the desired product.

Table 1.Reaction conditions for the synthesis of componds3a-f and dependence of the yields on the LogP of acyl chlorides 2a-f Entry

1

Product

3a

acyl chloride Time (eq.) (min)

Yielda

Chlorid

(%)

CLogPb 9.02

1.1

60

-c

1.1

15

40

1.2

15

67

1.3

15

60

0.5+0.5+0.2

15

26

1.2

45

60d

1.2

45

tracee

1.2

30

65f

1.2

15

67g

1.2

480

70h

1.2

15

65i

2

3b

1.2

30

25

9.12

3

3c

1.2

60

65

8.09

4

3d

1.2

45

60

5.35


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5

3e

1.2

45

60

3.13

6

3f

1.2

15

-

2.07

a

Isolated product; b Theoretical log P values calculated by Actelion Property Explorer. cTsample= 110°C; dReaction performed in CH3CN. e Reaction performed in 2-MeTHF. fReaction performed in solvent free conditions. gReaction performed using a double amount of water. h Reaction performed under conventional heating. iReaction performed on 100 mmol of reactant.

It is critical to note that neither the reagents nor the products are soluble in water, thus creating an oil/water interface where the reaction could take place. We supposed that water played a pivotal role in accelerating the reaction. In particular hydroxytyrosolacetonide and the fatty acyl chloride should react at the interface between water and acyl donor itself. During the reaction, the produced lipophilic hydroxytyrosol ester will stay in a separate phase respect to the byproducts, namely acetone and hydrochloric acid, besides the deprotected hydroxytyrosol possibly present, thus driving reaction to completion. A proof of the hypothesis that the reaction driving force is the interface formation of the products, was represented by the failure of the reaction with butyryl chloride, that is soluble in water (Entry 6, Table 1). The hydroxyl group effects a nucleophilic attack on the carbonyl group thus releasing HCl. The acidified water solution resulting from this first step is able to carry out in turn the cleavage of the acetonide giving rise to the desired product and acetone as by-product. This hypothesis was confirmed by the HRMS analysis of the reaction mixture stopped at an intermediate reaction time showing the presence of the intermediate protected stearoyl ester (See supporting information). Finally the assay to scale up the protocol was performed on the lead compound, exploiting the bigger capacity of the XF-100 rotor in the Synthos 3000 MW-oven; eight Teflon vials positions,


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each containing 10 ml of water, where reacted at the same time on the same reaction conditions, thus resulting in a final loading of 41.6 mmol of reactant and giving rise to an overall yield of 65% of pure stearoylhydroxytyrosol ester (Table 1, Entry 1, row 11). Overall 8 g of reactant can be processed and 11 g of desired product can be obtained, each 15 minutes. This result, besides the simplicity in the reaction work-up and the absence of any kind of added catalysts, can suggest that the method could be easily scaled for bigger reactors. Microwave irradiation clearly permitted to increase the rate of the reaction compared to rates obtained by different procedures reported in the literature.18-26 Noteworthy, in the present method, no catalyst was used and any toxic organic solvent was avoided. The cooperation between the MW-assistance and the “on water effect” allows to perform “two steps in one-pot” in a very eco-friendly and economic way, thus achieving yields for the overall transformation comparable to those obtained in the literature solely for the esterification step. The method allows to answer to a big issues of the lipophilic hydroxytyrosol synthesis concerning the use of a protected hydroxytyrosol, namely suitable for huge stocks of this natural antioxidant, directly as starting material. The possibility to avoid the catalyst, to substitute a dry organic solvent with water, to reduce and simplify the work-up procedures and to potentially scale-up the protocol, are the advantages of the present method respect to other reported in the literature. CONCLUSIONS: In conclusion we have developed a new economic and eco-friendly protocol to synthesize hydroxytyrosol fatty esters without using any catalyst and toxic organic solvent. This compounds were synthetized by MW-assisted one-pot reaction in water, directly using hydroxytyrosolacetonide as starting material, thus allowing an overall work-up procedure simplification. The reaction took place at the interface oil/water thus being strictly dependent on the lipophilicity of the fatty acid acyl chloride. Such protocol open the possibility to promptly


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dispose of active fatty hydroxytyrosol derivatives directly starting from its protected form, thus answering at the same time to both the industrial challenges of the starting material long term storage and the simplified environmental friendly synthetic protocol. ASSOCIATED CONTENT Supporting Information. High resolution mass spectra were used to identify the products and to perform the reaction mechanism test. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *Dr. Manuela Oliverio, Tel: +39.0961.3694121, Fax: +39.0961.3694237, email address: [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. ACKNOWLEDGMENT Financial

supporting

by

the

grants:

PON

a3_00359

CUP

F61D11000120007

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On Water MW Assisted Synthesis of Hydroxytyrosol Fatty Esters. M. Oliverio,*a M. Nardi,cL.Cariati,a E. Vitale,a S. Bonaccia and A. Procopioa

A new “on water” MW-assisted protocol for the one-pot multistep for the synthesis of hydroxytyrosol fatty esters starting from acetonidehydroxytyrosol without any added catalyst is described. The reaction took place at the interface oil/water. The potential scale-up of the method was proven.


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âOn Waterâ MW-Assisted Synthesis of Hydroxytyrosol Fatty Esters

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âOn Waterâ MW-Assisted Synthesis of Hydroxytyrosol Fatty Esters