Large-ring lactones from plant oils

Lactones are important intermediates in organic synthesis, and they are employed as monomers and used e.g. as fragrances. Smaller cycles, such as ε-caprolactone, are polymerised to polyesters for medical applications taking advantage of their biodegradability. These small cycles are readily accessible on industrial scales by Baeyer–Villiger oxidation of cyclohexanone. Amongst large-ring lactones, pentadecalactone stands out with an annual volume of around 10 metric tons. It is of industrial interest as a fragrance, and used in various cosmetic and non-cosmetic products such as shampoos or household cleaners. Some large-ring lactones occur naturally, e.g. pentadecalactone is a component of Angelica archangelica L. root oil. It is in fact isolated from natural sources, rather than being produced synthetically. An access to even larger ring lactones suffers from a lack of reasonably available starting materials. In the synthesis of macrocyclic lactones, generation of the cycle is the decisive key step. A general approach to large-ring lactones is provided by cyclisation of ω-hydroxy carboxylic acids (e.g. Keck macrolactonisation or photochemical routes, see Scheme S1 in ESI†). However, the high dilution required in these steps is a major limitation. Furthermore, the limited availability of the unsymmetrical α,ω-functionalised starting materials for the ring closure represents a restriction. We now report a general preparative route to macrocyclic compounds, namely lactones and lactams, based on symmetrical α,ω-diesters from the isomerising alkoxycarbonylation of fatty acid esters from high oleic sun flower and rape seed oil, respectively. Sodium-promoted acyloin condensation results in ring closure. That is, the macrolactone ring of the final nonadecalactone (NDL) and tricosalactone (TCL), respectively, originates from the long-chain methylene sequence of the plant oil starting material. The synthesis of the macrocyclic lactones employed the fourstep protocol depicted in Scheme 1. Starting from methyl oleate or ethyl erucate, respectively, [1,2-bis{(di-tert-butylphosphino)methyl}benzene palladium ditriflate] was used as a catalyst precursor for isomerising alkoxycarbonylation to convert the monounsaturated fatty acids into the corresponding saturated longchain aliphatic α,ω-diesters. This reaction offers the advantage of a full linear incorporation of the aliphatic fatty acid chain segment. Due to the incorporation of carbon monoxide into the newly generated terminal ester moiety, odd carbon-number building blocks are generated from the typically even carbonnumber fatty acid chains. The reaction can be conducted conveniently under rather mild conditions (90 °C temperature and 20 bar of CO pressure), allowing for the preparation of diesters using standard laboratory pressure reactors (cf. ESI† for detailed experimental procedures and conditions). Acyloin condensation of the difunctional compounds obtained from isomerising alkoxycarbonylation provided access to macrocycles. To promote the formation of monomeric cycles a low concentration of the diester is required, which was accomplished by slow addition of the starting material. This allowed for working on approximately 20 g scales without the necessity of large volumes of solvents and large reaction vessels. In contrast to cyclisation reactions like the Dieckmann or Thorpe–Ziegler condensation, which exclude one carbon atom from the cycle formed, acyloin condensation incorporates the hydrocarbon chain of the α,ωdiester completely. Although a suitable protocol for purification of the acyloin by recrystallisation had not yet been established, the compound could be isolated by column chromatography. †Electronic supplementary information (ESI) available: Experimental procedures, characterisation of products. See DOI: 10.1039/c3gc40905h Chair of Chemical Materials Science, University of Konstanz, Department of Chemistry, Universitätsstraße 10, 78457 Konstanz, Germany. E-mail: [email protected]; Fax: +49 7531 885152; Tel: +49 7531 882593