http://dx.doi.org/10.5935/0103-5053.20150086 J. Braz. Chem. Soc., Vol. 26, No. 6, 1055-1086, 2015. Printed in Brazil - ©2015 Sociedade Brasileira de Química Review 0103 - 5053 $6.00+0.00 The Multiple Faces of Eugenol. A Versatile Starting Material and Building Block for Organic and Bio-Organic Synthesis and a Convenient Precursor Toward Bio-Based Fine Chemicals Teodoro S. Kaufman* Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK Rosario, Argentina Phenylpropenes are produced by plants as part of their defense strategy against microorganisms and animals, and also as floral attractants of pollinators. Eugenol, the main component of clove’s essential oil, is an inexpensive and easily available phenylpropene that has been known by humankind since antiquity, and used as a medicinal agent, but also for food flavoring and preservation. The review includes the most relevant results obtained during the last 15 years with regard to the synthetic uses of eugenol. Discussed here are the multiple applications of eugenol in organic synthesis, including its use as starting material or building block for the total synthesis of natural products, their analogs and derivatives, as well as other structurally interesting or bioactive compounds. The preparation technologically relevant macrocycles and polymeric derivatives of eugenol, is included, and the impact of biotechnology on the use of eugenol as feedstock for biotransformations, leading to other valuable small molecules is also addressed. Keywords: eugenol, natural products synthesis, polymer science, macrocycles, bioactive compounds 1. Introduction Since the remote antiquity, medicinal plants have been the mainstay of traditional herbal medicine amongst rural All the major groups of angiosperms biosynthesize dwellers worldwide. Natural products have been an integral phenylpropenes. These are stored in their vegetative parts, part of the ancient traditional medicine systems including as a defense against herbivores, parasitic bacteria and fungi, Ayurveda, Chinese and Egyptian. Currently, around 40% or are easily volatilized, being toxic to insects and microbes. of the world population depends directly on plant based In addition, sometimes they are emitted from flowers to medicine for their health care. Hence, the traditional use of attract insect pollinators. plants or parts of plants containing eugenol for medicinal Eugenol (1, Figure 1)1 is one of these key purposes is not an exception. phenylpropenes. The natural product is a major aromatic Eugenol is a natural and generally acting antimicrobial constituent (up to approximately 80% by weight) of and antianimal toxin, with mild analgesic properties. It the essential oil of clove [Eugenia caryophyllata L. is commonly used as a fragrance and flavoring agent in Merr. & Perry (Myrtaceae) = Syzygium aromaticum], a variety of cosmetics, and food products. In addition, which is commonly obtained by hydrodistillation, steam the natural product has shown a number of other distillation, or Soxhlet (ethanol) extraction from leaves, interesting biological activities, including antioxidant, buds, and stems of clove trees (Myrtaceae).2 Eugenol anti-inflammatory, antispasmodic, antidepressant, is also found in Myristica fragrans Houtt. (nutmeg), antigenotoxic, and anticarcinogenic. Proof of the interest Cinnamomum verum J. Presl (true cinnamon), C. loureirii in this subject is the surprisingly high number of articles Nees. (Saigon cinnamon), Ocimum gratissimum Forssk. reviewing these properties, which have been published in (basil), Ocimum basilicum L. (sweet basil), pimento berry recent times.3 and bay oil, among others. On the other hand, methyl eugenol (4-allyl-1,2- dimethoxybenzene, 2) is the methyl ether derivative of eugenol. This is also a natural product,4 which has a relevant *e-mail: [email protected] role in nature, especially in relation to insect behavior 1056 The Multiple Faces of Eugenol J. Braz. Chem. Soc. and pollination.5 This chemical is easily available and has 2.1. Hydroxytyrosol and (E)-4-(4-hydroxy-3-methoxyphenyl) attracted some attention to the point that a green chemistry but-2-enol condition for its access (by alkylation of eugenol with dimethyl carbonate),6 has been published. Compound 2 has Among the wide variety of bioactive components been widely used as a test molecule for the development found in olive oil, several phenolic compounds have been of organic synthetic methodologies,7 it enjoys widespread reported to express beneficial effects on human health.12 use in carbohydrate chemistry, as a reagent to scavenge the The average concentration of phenolics can rise up to PhSOTf formed during sulfoxide glycosylations,8 and has 1 g kg−1 in the first-pressed ‘extra virgin’ type olive oil. found some applications as starting material or building Hydroxytyrosol (4) is a simple catecholic compound and block in organic synthesis. one of the major phenolic compounds present in the olive fruit and olive oil, together with oleuropein (5), from which MeO MeO MeOMe it can be generated by hydrolysis.13 14 HO MeO HO Due to its remarkable antioxidation activity, 123 hydroxytyrosol is suitable as a natural and non-toxic food Figure 1. Chemical structures of eugenol (1), methyleugenol (2) and preservative and a highly promising alternative to synthetic isoeugenol (3). antioxidants. The natural product also contributes to the stability of virgin oil against rancidity caused by oxidation.15 Eugenol is commercially available in large quantities A two-pot four-step synthesis of 4 from eugenol with a market price around US$ 5 per kg; however, despite (Scheme 1) was reported by Deffieux et al.16 The process its easy access, it has been recently used as target for was initiated by ozonolysis of the double bond of 1, synthesis by a metal-free photoallylation of aryl halides followed by an in situ hydride reduction of the ozonide with allyl-tetramethylsilane (TMS) in a MeCN-H2O to afford alcohol 6 in 98% yield. However, subsequent medium.9 The particular structure and ready availability of cleavage of the methyl aryl ether bond with aluminum eugenol has turned the natural product into an interesting iodide17 and a catalytic amount of tetra-n-butylammonium starting material and a useful building block for complex iodide (TBAI) in MeCN,18 afforded only 54% of the synthesis, as well as into a valuable substrate for various expected product. Therefore, a better alternative toward biotransformations. 4 was devised, through the dealkylative oxidation of 10 In 2000, Costa et al. reviewed the chemical reactivity the monomethyl catechol moiety of 6 with NaIO4 to the of eugenol and safrol, and their use in the synthesis of unisolated quinone 6a, followed by a reductive work-up with biologically active natural products and their derivatives. sodium thiosulfate, which furnished hydroxytyrosol (4) in Therefore, in an attempt to complement and extend that an improved 78% yield. work, this review will focus mainly on the advances which On the other hand, (E)-4-(4-hydroxy-3-methoxyphenyl) took place during the last 15 years, in the use of eugenol but-2-enol (7) was originally isolated from the roots of for different synthetic purposes. Zingiber cassumunar, a medicinal plant from Southeast Topics covered range from eugenol being a feedstock Asia possessing antioxidant and antiinflammatory for biotransformations to the applications of the natural a b product as suitable starting material or key building block OH OH toward the synthesis of other natural products and their HO HO HO OMe OMe OH analogs, bioactive compounds, heterocycles, macrocycles 16 4 and polymers.11 However, the numerous applications of the c d OH related isoeugenol (3), a β-methylstyrene natural product, e HO OH O O also available from eugenol, will not be covered. 6a OH O CO2Me 2. Total Synthesis of Natural Products O HO O HO OMe O HO Me OH 7 OH Eugenol was found to be one of the most suitable HO starting materials for the total synthesis of structurally HO 5 different natural products. Since various targets have been reached, the syntheses were grouped and arranged Scheme 1. Reagents and conditions: (a) 1. O3, EtOH; 2. NaBH4, EtOH (98%); (b) AlI , TBAI, MeCN, reflux (54%); (c) NaIO , EtOAc; according to the type of objective, and a subjectively 3 4 (d) Na2S2O4 (work-up, 78% overall); (e) Grubbs II in paraffin, cis-2- determined increasing degree of complexity. butene-1,4-diol, petroleum ether, room temperature (RT), 12 h (98%). Vol. 26, No. 6, 2015 Kaufman 1057 properties.19 Taber et al.20 performed a single-step synthesis nitrate and sodium nitrite, which afforded 11 in 75% yield. of 7 from eugenol, by cross-metathesis with cis-2-butene- In turn, this was subjected to a [3+2] cycloaddition reaction 1,4-diol, and employing Grubbs II catalyst embedded in with 1-heptene in the presence of Et3N and Ac2O, to provide paraffin wax. Similarly, direct self-metathesis, and cross- 40% of the intermediate isoxazoline 12.31 metathesis of eugenol with symmetrical internal olefins The thus prepared heterocycle 12 was hydrogenolyzed and other alkenes,21 and the use of ruthenium-catalyzed in the presence of Raney nickel in moist ethanol to afford olefin cross-metathesis of eugenol with electron deficient β-hydroxy carbonyl intermediate 13, which was further olefins for the synthesis of polyfunctional alkenes have debenzylated to furnish 8, by catalytic hydrogenolysis been reported.22